Formulation and immunological evaluation of a trivalent vaccine comprising emulsified submicron particles and inactivated virions of H5N1/EV71/JEV

PubMed Central

Lin, Chih-Wei; Chang, Ching-Yun; Chen, Wei-Lin; Lin, Shih-Chang; Liao, Chien-Chun; Chang, Jui-Yuan; Liu, Chia-Chyi; Hu, Alan Yung-Chih; Lu, Tsung-Chun; Chou, Ai-Hsiang; Wu, Suh-Chin; Chong, Pele; Huang, Ming-Hsi

2013-01-01

Combination vaccines can reduce the number of injections and simplify the immunization schedule required to prevent different diseases. Here we assessed the immunogenicity in a mouse model of a vaccine composition comprising inactivated influenza viruses (H5N1/H1N1), enterovirus 71 (EV71), and/or Japanese encephalitis virus (JEV) and investigated whether the vaccine formulations can overcome the immunologic interference between the individual vaccine components. We demonstrated that the antigenic competition happens between H5N1/H1N1 or H5N1/EV71 inactivated virions when the vaccine combinations either formulated with Alum suspensions or without adjuvant. In the presence of PELC emulsified particles, EV71-specific immune responses before and after incorporating H5N1 virus into EV71 vaccine were detected of no significant difference; in addition, H5N1- and EV71-specific immune responses were found at the same level when H5N1/EV71/JEV consolidating into combination vaccine. Emulsified vaccine formulation was represented as a potential tool that is found to reduce the number of injections required to prevent multiple infectious strains causing the same disease (H5N1/H1N1) and/or that protect against different diseases (H5N1/EV71). Combination vaccines can also include a third component to protect against H5N1/EV71/JEV at the same time. PMID:23838466

Efficacy of a Trivalent Hand, Foot, and Mouth Disease Vaccine against Enterovirus 71 and Coxsackieviruses A16 and A6 in Mice.

PubMed

Caine, Elizabeth A; Fuchs, Jeremy; Das, Subash C; Partidos, Charalambos D; Osorio, Jorge E

2015-11-17

Hand, foot, and mouth disease (HFMD) has recently emerged as a major public health concern across the Asian-Pacific region. Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) are the primary causative agents of HFMD, but other members of the Enterovirus A species, including Coxsackievirus A6 (CVA6), can cause disease. The lack of small animal models for these viruses have hampered the development of a licensed HFMD vaccine or antivirals. We have previously reported on the development of a mouse model for EV71 and demonstrated the protective efficacy of an inactivated EV71 vaccine candidate. Here, mouse-adapted strains of CVA16 and CVA6 were produced by sequential passage of the viruses through mice deficient in interferon (IFN) α/β (A129) and α/β and γ (AG129) receptors. Adapted viruses were capable of infecting 3 week-old A129 (CVA6) and 12 week-old AG129 (CVA16) mice. Accordingly, these models were used in active and passive immunization studies to test the efficacy of a trivalent vaccine candidate containing inactivated EV71, CVA16, and CVA6. Full protection from lethal challenge against EV71 and CVA16 was observed in trivalent vaccinated groups. In contrast, monovalent vaccinated groups with non-homologous challenges failed to cross protect. Protection from CVA6 challenge was accomplished through a passive transfer study involving serum raised against the trivalent vaccine. These animal models will be useful for future studies on HFMD related pathogenesis and the efficacy of vaccine candidates.

Cost-effectiveness of a national enterovirus 71 vaccination program in China.

PubMed

Wang, Wenjun; Song, Jianwen; Wang, Jingjing; Li, Yaping; Deng, Huiling; Li, Mei; Gao, Ning; Zhai, Song; Dang, Shuangsuo; Zhang, Xin; Jia, Xiaoli

2017-09-01

Enterovirus 71 (EV71) has caused great morbidity, mortality, and use of health service in children younger than five years in China. Vaccines against EV71 have been proved effective and safe by recent phase 3 trials and are now available in China. The purpose of this study was to evaluate the health impact and cost-effectiveness of a national EV71 vaccination program in China. Using Microsoft Excel, a decision model was built to calculate the net clinical and economic outcomes of EV71 vaccination compared with no EV71 vaccination in a birth cohort of 1,000,000 Chinese children followed for five years. Model parameters came from published epidemiology, clinical and cost data. In the base-case, vaccination would annually avert 37,872 cases of hand, foot and mouth disease (HFMD), 2,629 herpangina cases, 72,900 outpatient visits, 6,363 admissions to hospital, 29 deaths, and 945 disability adjusted life years. The break-even price of the vaccine was $5.2/dose. When the price was less than $8.3 or $14.6/dose, the vaccination program would be highly cost-effective or cost-effective, respectively (incremental cost-effectiveness ratio less than or between one to three times China GDP per capita, respectively). In one-way sensitivity analyses, the HFMD incidence was the only influential parameter at the price of $5/dose. Within the price range of current routine vaccines paid by the government, a national EV71 vaccination program would be cost-saving or highly cost-effective to prevent EV71 related morbidity, mortality, and use of health service among children younger than five years in China. Policy makers should consider including EV71 vaccination as part of China's routine childhood immunization schedule.

Five-year immunity persistence following immunization with inactivated enterovirus 71 type (EV71) vaccine in healthy children: A further observation.

PubMed

Hu, Yuemei; Zeng, Gang; Chu, Kai; Zhang, Jing; Han, Weixiao; Zhang, Ying; Li, Jing; Zhu, Fengcai

2018-02-26

The longevity of antibodies induced by inactivated enterovirus 71 type (EV71) vaccine is not well studied. To estimate the immunity persistence following two-dose vaccination of EV71 vaccine, a five-year follow-up study was conducted as an extension of a Phase III clinical trial. In this study, a sub-cohort of volunteers who was eligible for enrollment and randomly administrated either 2 dose EV71 vaccine or placebo in the phase III clinical trial was selected, and then further observed 64 months post the 1st vaccination. 211 Subjects (106 vaccine subjects and 105 placebo subjects) who provided a full series of blood samples (at all the sampling points) were included in the final analyzed population. Seropositive rate (SR) and geometric mean titer (GMT) of the neutralizing antibodies (NAb) was calculated to detect the dynamic profiles of EV71 vaccine-induced immunogenicity. SR at the 5th year remained 94.34% in the vaccine subjects, with a GMT of 141.42. The SR was 71.43% in the placebo subjects, with a GMT of 71.83. Despite natural infection consistently promoted the NAb increase in the placebo subjects, the SR and GMT in vaccine subjects remained significantly higher than that in the placebo subjects at all the sampling points. The inactivated EV71 vaccine-induced immunity had a good persistence, within 5 years following the primary vaccination.

Structures of Coxsackievirus A16 Capsids with Native Antigenicity: Implications for Particle Expansion, Receptor Binding, and Immunogenicity.

PubMed

Ren, Jingshan; Wang, Xiangxi; Zhu, Ling; Hu, Zhongyu; Gao, Qiang; Yang, Pan; Li, Xuemei; Wang, Junzhi; Shen, Xinliang; Fry, Elizabeth E; Rao, Zihe; Stuart, David I

2015-10-01

Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the primary causes of the epidemics of hand-foot-and-mouth disease (HFMD) that affect more than a million children in China each year and lead to hundreds of deaths. Although there has been progress with vaccines for EV71, the development of a CVA16 vaccine has proved more challenging, and the EV71 vaccine does not give useful cross-protection, despite the capsid proteins of the two viruses sharing about 80% sequence identity. The structural details of the expanded forms of the capsids, which possess nonnative antigenicity, are now well understood, but high resolution information for the native antigenic form of CVA16 has been missing. Here, we remedy this with high resolution X-ray structures of both mature and natural empty CVA16 particles and also of empty recombinant viruslike particles of CVA16 produced in insect cells, a potential vaccine antigen. All three structures are unexpanded native particles and antigenically identical. The recombinant particles have recruited a lipid moiety to stabilize the native antigenic state that is different from the one used in a natural virus infection. As expected, the mature CVA16 virus is similar to EV71; however, structural and immunogenic comparisons highlight differences that may have implications for vaccine production. Hand-foot-and-mouth disease is a serious public health threat to children in Asian-Pacific countries, resulting in millions of cases. EV71 and CVA16 are the two dominant causative agents of the disease that, while usually mild, can cause severe neurological complications, leading to hundreds of deaths. EV71 vaccines do not provide protection against CVA16. A CVA16 vaccine or bivalent EV71/CVA16 vaccine is therefore urgently needed. We report atomic structures for the mature CVA16 virus, a natural empty particle, and a recombinant CVA16 virus-like particle that does not contain the viral genome. All three particles have similar structures and identical antigenicity. The recombinant particles, produced in insect cells (a system suitable for making vaccine antigen), are stabilized by recruiting from the insect cells a small molecule that is different from that used by the virus in a normal infection. We present structural and immunogenic comparisons with EV71 to facilitate structure-based drug design and vaccine development. Copyright © 2015, Ren et al.

Routine Pediatric Enterovirus 71 Vaccination in China: a Cost-Effectiveness Analysis.

PubMed

Wu, Joseph T; Jit, Mark; Zheng, Yaming; Leung, Kathy; Xing, Weijia; Yang, Juan; Liao, Qiaohong; Cowling, Benjamin J; Yang, Bingyi; Lau, Eric H Y; Takahashi, Saki; Farrar, Jeremy J; Grenfell, Bryan T; Leung, Gabriel M; Yu, Hongjie

2016-03-01

China accounted for 87% (9.8 million/11.3 million) of all hand, foot, and mouth disease (HFMD) cases reported to WHO during 2010-2014. Enterovirus 71 (EV71) is responsible for most of the severe HFMD cases. Three EV71 vaccines recently demonstrated good efficacy in children aged 6-71 mo. Here we assessed the cost-effectiveness of routine pediatric EV71 vaccination in China. We characterized the economic and health burden of EV71-associated HFMD (EV71-HFMD) in China using (i) the national surveillance database, (ii) virological surveillance records from all provinces, and (iii) a caregiver survey on the household costs and health utility loss for 1,787 laboratory-confirmed pediatric cases. Using a static model parameterized with these data, we estimated the effective vaccine cost (EVC, defined as cost/efficacy or simply the cost of a 100% efficacious vaccine) below which routine pediatric vaccination would be considered cost-effective. We performed the base-case analysis from the societal perspective with a willingness-to-pay threshold of one times the gross domestic product per capita (GDPpc) and an annual discount rate of 3%. We performed uncertainty analysis by (i) accounting for the uncertainty in the risk of EV71-HFMD due to missing laboratory data in the national database, (ii) excluding productivity loss of parents and caregivers, (iii) increasing the willingness-to-pay threshold to three times GDPpc, (iv) increasing the discount rate to 6%, and (v) accounting for the proportion of EV71-HFMD cases not registered by national surveillance. In each of these scenarios, we performed probabilistic sensitivity analysis to account for parametric uncertainty in our estimates of the risk of EV71-HFMD and the expected costs and health utility loss due to EV71-HFMD. Routine pediatric EV71 vaccination would be cost-saving if the all-inclusive EVC is below US$10.6 (95% CI US$9.7-US$11.5) and would remain cost-effective if EVC is below US$17.9 (95% CI US$16.9-US$18.8) in the base case, but these ceilings could be up to 66% higher if all the test-negative cases with missing laboratory data are EV71-HFMD. The EVC ceiling is (i) 10%-14% lower if productivity loss of parents/caregivers is excluded, (ii) 58%-84% higher if the willingness-to-pay threshold is increased to three times GDPpc, (iii) 14%-19% lower if the discount rate is increased to 6%, and (iv) 36% (95% CI 23%-50%) higher if the proportion of EV71-HFMD registered by national surveillance is the same as that observed in the three EV71 vaccine phase III trials. The validity of our results relies on the following assumptions: (i) self-reported hospital charges are a good proxy for the opportunity cost of care, (ii) the cost and health utility loss estimates based on laboratory-confirmed EV71-HFMD cases are representative of all EV71-HFMD cases, and (iii) the long-term average risk of EV71-HFMD in the future is similar to that registered by national surveillance during 2010-2013. Compared to no vaccination, routine pediatric EV71 vaccination would be very cost-effective in China if the cost of immunization (including all logistical, procurement, and administration costs needed to confer 5 y of vaccine protection) is below US$12.0-US$18.3, depending on the choice of vaccine among the three candidates. Given that the annual number of births in China has been around 16 million in recent years, the annual costs for routine pediatric EV71 vaccination at this cost range should not exceed US$192-US$293 million. Our results can be used to determine the optimal vaccine when the prices of the three vaccines are known.

Routine Pediatric Enterovirus 71 Vaccination in China: a Cost-Effectiveness Analysis

PubMed Central

Leung, Kathy; Xing, Weijia; Yang, Juan; Liao, Qiaohong; Cowling, Benjamin J.; Yang, Bingyi; Lau, Eric H. Y.; Takahashi, Saki; Farrar, Jeremy J.; Grenfell, Bryan T.; Leung, Gabriel M.; Yu, Hongjie

2016-01-01

Background China accounted for 87% (9.8 million/11.3 million) of all hand, foot, and mouth disease (HFMD) cases reported to WHO during 2010–2014. Enterovirus 71 (EV71) is responsible for most of the severe HFMD cases. Three EV71 vaccines recently demonstrated good efficacy in children aged 6–71 mo. Here we assessed the cost-effectiveness of routine pediatric EV71 vaccination in China. Methods and Findings We characterized the economic and health burden of EV71-associated HFMD (EV71-HFMD) in China using (i) the national surveillance database, (ii) virological surveillance records from all provinces, and (iii) a caregiver survey on the household costs and health utility loss for 1,787 laboratory-confirmed pediatric cases. Using a static model parameterized with these data, we estimated the effective vaccine cost (EVC, defined as cost/efficacy or simply the cost of a 100% efficacious vaccine) below which routine pediatric vaccination would be considered cost-effective. We performed the base-case analysis from the societal perspective with a willingness-to-pay threshold of one times the gross domestic product per capita (GDPpc) and an annual discount rate of 3%. We performed uncertainty analysis by (i) accounting for the uncertainty in the risk of EV71-HFMD due to missing laboratory data in the national database, (ii) excluding productivity loss of parents and caregivers, (iii) increasing the willingness-to-pay threshold to three times GDPpc, (iv) increasing the discount rate to 6%, and (v) accounting for the proportion of EV71-HFMD cases not registered by national surveillance. In each of these scenarios, we performed probabilistic sensitivity analysis to account for parametric uncertainty in our estimates of the risk of EV71-HFMD and the expected costs and health utility loss due to EV71-HFMD. Routine pediatric EV71 vaccination would be cost-saving if the all-inclusive EVC is below US$10.6 (95% CI US$9.7–US$11.5) and would remain cost-effective if EVC is below US$17.9 (95% CI US$16.9–US$18.8) in the base case, but these ceilings could be up to 66% higher if all the test-negative cases with missing laboratory data are EV71-HFMD. The EVC ceiling is (i) 10%–14% lower if productivity loss of parents/caregivers is excluded, (ii) 58%–84% higher if the willingness-to-pay threshold is increased to three times GDPpc, (iii) 14%–19% lower if the discount rate is increased to 6%, and (iv) 36% (95% CI 23%–50%) higher if the proportion of EV71-HFMD registered by national surveillance is the same as that observed in the three EV71 vaccine phase III trials. The validity of our results relies on the following assumptions: (i) self-reported hospital charges are a good proxy for the opportunity cost of care, (ii) the cost and health utility loss estimates based on laboratory-confirmed EV71-HFMD cases are representative of all EV71-HFMD cases, and (iii) the long-term average risk of EV71-HFMD in the future is similar to that registered by national surveillance during 2010–2013. Conclusions Compared to no vaccination, routine pediatric EV71 vaccination would be very cost-effective in China if the cost of immunization (including all logistical, procurement, and administration costs needed to confer 5 y of vaccine protection) is below US$12.0–US$18.3, depending on the choice of vaccine among the three candidates. Given that the annual number of births in China has been around 16 million in recent years, the annual costs for routine pediatric EV71 vaccination at this cost range should not exceed US$192–US$293 million. Our results can be used to determine the optimal vaccine when the prices of the three vaccines are known. PMID:26978565

Hand, Foot, and Mouth Disease in China: Modeling Epidemic Dynamics of Enterovirus Serotypes and Implications for Vaccination

PubMed Central

Takahashi, Saki; Liao, Qiaohong; Van Boeckel, Thomas P.; Xing, Weijia; Sun, Junling; Hsiao, Victor Y.; Metcalf, C. Jessica E.; Chang, Zhaorui; Liu, Fengfeng; Zhang, Jing; Wu, Joseph T.; Cowling, Benjamin J.; Leung, Gabriel M.; Farrar, Jeremy J.; van Doorn, H. Rogier; Grenfell, Bryan T.; Yu, Hongjie

2016-01-01

Background Hand, foot, and mouth disease (HFMD) is a common childhood illness caused by serotypes of the Enterovirus A species in the genus Enterovirus of the Picornaviridae family. The disease has had a substantial burden throughout East and Southeast Asia over the past 15 y. China reported 9 million cases of HFMD between 2008 and 2013, with the two serotypes Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16) being responsible for the majority of these cases. Three recent phase 3 clinical trials showed that inactivated monovalent EV-A71 vaccines manufactured in China were highly efficacious against HFMD associated with EV-A71, but offered no protection against HFMD caused by CV-A16. To better inform vaccination policy, we used mathematical models to evaluate the effect of prospective vaccination against EV-A71-associated HFMD and the potential risk of serotype replacement by CV-A16. We also extended the model to address the co-circulation, and implications for vaccination, of additional non-EV-A71, non-CV-A16 serotypes of enterovirus. Methods and Findings Weekly reports of HFMD incidence from 31 provinces in Mainland China from 1 January 2009 to 31 December 2013 were used to fit multi-serotype time series susceptible–infected–recovered (TSIR) epidemic models. We obtained good model fit for the two-serotype TSIR with cross-protection, capturing the seasonality and geographic heterogeneity of province-level transmission, with strong correlation between the observed and simulated epidemic series. The national estimate of the basic reproduction number, R 0, weighted by provincial population size, was 26.63 for EV-A71 (interquartile range [IQR]: 23.14, 30.40) and 27.13 for CV-A16 (IQR: 23.15, 31.34), with considerable variation between provinces (however, predictions about the overall impact of vaccination were robust to this variation). EV-A71 incidence was projected to decrease monotonically with higher coverage rates of EV-A71 vaccination. Across provinces, CV-A16 incidence in the post-EV-A71-vaccination period remained either comparable to or only slightly increased from levels prior to vaccination. The duration and strength of cross-protection following infection with EV-A71 or CV-A16 was estimated to be 9.95 wk (95% confidence interval [CI]: 3.31, 23.40) in 68% of the population (95% CI: 37%, 96%). Our predictions are limited by the necessarily short and under-sampled time series and the possible circulation of unidentified serotypes, but, nonetheless, sensitivity analyses indicate that our results are robust in predicting that the vaccine should drastically reduce incidence of EV-A71 without a substantial competitive release of CV-A16. Conclusions The ability of our models to capture the observed epidemic cycles suggests that herd immunity is driving the epidemic dynamics caused by the multiple serotypes of enterovirus. Our results predict that the EV-A71 and CV-A16 serotypes provide a temporary immunizing effect against each other. Achieving high coverage rates of EV-A71 vaccination would be necessary to eliminate the ongoing transmission of EV-A71, but serotype replacement by CV-A16 following EV-A71 vaccination is likely to be transient and minor compared to the corresponding reduction in the burden of EV-A71-associated HFMD. Therefore, a mass EV-A71 vaccination program of infants and young children should provide significant benefits in terms of a reduction in overall HFMD burden. PMID:26882540

Hand, Foot, and Mouth Disease in China: Modeling Epidemic Dynamics of Enterovirus Serotypes and Implications for Vaccination.

PubMed

Takahashi, Saki; Liao, Qiaohong; Van Boeckel, Thomas P; Xing, Weijia; Sun, Junling; Hsiao, Victor Y; Metcalf, C Jessica E; Chang, Zhaorui; Liu, Fengfeng; Zhang, Jing; Wu, Joseph T; Cowling, Benjamin J; Leung, Gabriel M; Farrar, Jeremy J; van Doorn, H Rogier; Grenfell, Bryan T; Yu, Hongjie

2016-02-01

Hand, foot, and mouth disease (HFMD) is a common childhood illness caused by serotypes of the Enterovirus A species in the genus Enterovirus of the Picornaviridae family. The disease has had a substantial burden throughout East and Southeast Asia over the past 15 y. China reported 9 million cases of HFMD between 2008 and 2013, with the two serotypes Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16) being responsible for the majority of these cases. Three recent phase 3 clinical trials showed that inactivated monovalent EV-A71 vaccines manufactured in China were highly efficacious against HFMD associated with EV-A71, but offered no protection against HFMD caused by CV-A16. To better inform vaccination policy, we used mathematical models to evaluate the effect of prospective vaccination against EV-A71-associated HFMD and the potential risk of serotype replacement by CV-A16. We also extended the model to address the co-circulation, and implications for vaccination, of additional non-EV-A71, non-CV-A16 serotypes of enterovirus. Weekly reports of HFMD incidence from 31 provinces in Mainland China from 1 January 2009 to 31 December 2013 were used to fit multi-serotype time series susceptible-infected-recovered (TSIR) epidemic models. We obtained good model fit for the two-serotype TSIR with cross-protection, capturing the seasonality and geographic heterogeneity of province-level transmission, with strong correlation between the observed and simulated epidemic series. The national estimate of the basic reproduction number, R0, weighted by provincial population size, was 26.63 for EV-A71 (interquartile range [IQR]: 23.14, 30.40) and 27.13 for CV-A16 (IQR: 23.15, 31.34), with considerable variation between provinces (however, predictions about the overall impact of vaccination were robust to this variation). EV-A71 incidence was projected to decrease monotonically with higher coverage rates of EV-A71 vaccination. Across provinces, CV-A16 incidence in the post-EV-A71-vaccination period remained either comparable to or only slightly increased from levels prior to vaccination. The duration and strength of cross-protection following infection with EV-A71 or CV-A16 was estimated to be 9.95 wk (95% confidence interval [CI]: 3.31, 23.40) in 68% of the population (95% CI: 37%, 96%). Our predictions are limited by the necessarily short and under-sampled time series and the possible circulation of unidentified serotypes, but, nonetheless, sensitivity analyses indicate that our results are robust in predicting that the vaccine should drastically reduce incidence of EV-A71 without a substantial competitive release of CV-A16. The ability of our models to capture the observed epidemic cycles suggests that herd immunity is driving the epidemic dynamics caused by the multiple serotypes of enterovirus. Our results predict that the EV-A71 and CV-A16 serotypes provide a temporary immunizing effect against each other. Achieving high coverage rates of EV-A71 vaccination would be necessary to eliminate the ongoing transmission of EV-A71, but serotype replacement by CV-A16 following EV-A71 vaccination is likely to be transient and minor compared to the corresponding reduction in the burden of EV-A71-associated HFMD. Therefore, a mass EV-A71 vaccination program of infants and young children should provide significant benefits in terms of a reduction in overall HFMD burden.

Oral immunization with recombinant enterovirus 71 VP1 formulated with chitosan protects mice against lethal challenge

PubMed Central

2014-01-01

Background Enterovirus 71 (EV71) is the etiologic agent of hand-foot-and-mouth disease (HFMD) in the Asia-Pacific region, Many strategies have been applied to develop EV71 vaccines but no vaccines are currently available. Mucosal immunization of the VP1, a major immunogenic capsid protein of EV71, may be an alternative way to prevent EV71 infection. Results In this study, mucosal immunogenicity and protect function of recombinant VP1 protein (rVP1) in formulation with chitosan were tested and assessed in female ICR mouse model. The results showed that the oral immunization with rVP1 induced VP1-specific IgA antibodies in intestine, feces, vagina, and the respiratory tract and serum-specific IgG and neutralization antibodies in vaccinated mice. Splenocytes from rVP1-immunized mice induced high levels of Th1 (cytokine IFN-γ), Th2 (cytokine IL-4) and Th3 (cytokine TGF-β) type immune responses after stimulation. Moreover, rVP1-immunized mother mice conferred protection (survival rate up to 30%) on neonatal mice against a lethal challenge of 103 plaque-forming units (PFU) EV71. Conclusions These data indicated that oral immunization with rVP1 in formulation with chitosan was effective in inducing broad-spectrum immune responses and might be a promising subunit vaccine candidate for preventing EV71 infection. PMID:24885121

Mapping Enterovirus A71 Antigenic Determinants from Viral Evolution.

PubMed

Huang, Sheng-Wen; Tai, Ching-Hui; Fonville, Judith M; Lin, Chin-Hui; Wang, Shih-Min; Liu, Ching-Chung; Su, Ih-Jen; Smith, Derek J; Wang, Jen-Ren

2015-11-01

Human enterovirus A71 (EV-A71) belongs to the Enterovirus A species in the Picornaviridae family. Several vaccines against EV-A71, a disease causing severe neurological complications or even death, are currently under development and being tested in clinical trials, and preventative vaccination programs are expected to start soon. To characterize the potential for antigenic change of EV-A71, we compared the sequences of two antigenically diverse genotype B4 and B5 strains of EV-A71 and identified substitutions at residues 98, 145, and 164 in the VP1 capsid protein as antigenic determinants. To examine the effects of these three substitutions on antigenicity, we constructed a series of recombinant viruses containing different mutation combinations at these three residues with a reverse genetics system and then investigated the molecular basis of antigenic changes with antigenic cartography. We found that a novel EV-A71 mutant, containing lysine, glutamine, and glutamic acid at the respective residues 98, 145, and 164 in the VP1 capsid protein, exhibited neutralization reduction against patients' antisera and substantially increased virus binding ability to human cells. These observations indicated that this low-neutralization-reactive EV-A71 VP1-98K/145Q/164E mutant potentially increases viral binding ability and that surveillance studies should look out for these mutants, which could compromise vaccine efficacy. Emerging and reemerging EV-A71 viruses can cause severe neurological etiology, primarily affecting children, especially around Asia-Pacific countries. We identified a set of mutations in EV-A71 that both reduced neutralization activity against humoral immunity in antisera of patients and healthy adults and greatly increased the viral binding ability to cells. These findings provide important insights for EV-A71 antigenic determinants and emphasize the importance of continuous surveillance, especially after EV-A71 vaccination programs begin. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Mapping Enterovirus A71 Antigenic Determinants from Viral Evolution

PubMed Central

Huang, Sheng-Wen; Tai, Ching-Hui; Fonville, Judith M.; Lin, Chin-Hui; Wang, Shih-Min; Liu, Ching-Chung; Su, Ih-Jen

2015-01-01

ABSTRACT Human enterovirus A71 (EV-A71) belongs to the Enterovirus A species in the Picornaviridae family. Several vaccines against EV-A71, a disease causing severe neurological complications or even death, are currently under development and being tested in clinical trials, and preventative vaccination programs are expected to start soon. To characterize the potential for antigenic change of EV-A71, we compared the sequences of two antigenically diverse genotype B4 and B5 strains of EV-A71 and identified substitutions at residues 98, 145, and 164 in the VP1 capsid protein as antigenic determinants. To examine the effects of these three substitutions on antigenicity, we constructed a series of recombinant viruses containing different mutation combinations at these three residues with a reverse genetics system and then investigated the molecular basis of antigenic changes with antigenic cartography. We found that a novel EV-A71 mutant, containing lysine, glutamine, and glutamic acid at the respective residues 98, 145, and 164 in the VP1 capsid protein, exhibited neutralization reduction against patients' antisera and substantially increased virus binding ability to human cells. These observations indicated that this low-neutralization-reactive EV-A71 VP1-98K/145Q/164E mutant potentially increases viral binding ability and that surveillance studies should look out for these mutants, which could compromise vaccine efficacy. IMPORTANCE Emerging and reemerging EV-A71 viruses can cause severe neurological etiology, primarily affecting children, especially around Asia-Pacific countries. We identified a set of mutations in EV-A71 that both reduced neutralization activity against humoral immunity in antisera of patients and healthy adults and greatly increased the viral binding ability to cells. These findings provide important insights for EV-A71 antigenic determinants and emphasize the importance of continuous surveillance, especially after EV-A71 vaccination programs begin. PMID:26339057

A booster dose of an inactivated enterovirus 71 vaccine in chinese young children: a randomized, double-blind, placebo-controlled clinical trial.

PubMed

Shenyu, Wang; Jingxin, Li; Zhenglun, Liang; Xiuling, Li; Qunying, Mao; Fanyue, Meng; Hua, Wang; Yuntao, Zhang; Fan, Gao; Qinghua, Chen; Yuemei, Hu; Xin, Yao; Huijie, Guo; Fengcai, Zhu

2014-10-01

A significant waning of enterovirus 71 (EV71) antibody titer after priming immunization with an inactivated EV71 vaccine implied the potential need for a booster dose. In this randomized, double-blind, placebo-controlled clinical trial, we recruited participants who had received at least 1 dose of priming EV71 vaccine in an early phase 2 clinical trial that was conducted in healthy infants and children aged 6-35 months. All participants were grouped according to the priming EV71 vaccine formulations (160 U, 320 U, and 640 U with adjuvant and 640 U without adjuvant) and then randomly assigned (ratio, 2:1) to receive a booster dose of vaccine or placebo within each formulation group. The primary end point was the geometric mean titer 28 days after the booster dose. A total of 773 participants were enrolled. Significantly greater immunological responses were induced by the booster shot of all 4 formulations of EV71 vaccine, compared with that induced by placebo (P < .0001). The frequencies of adverse reactions were similar between vaccine and placebo groups within each formulation group. A booster dose of EV71 vaccine 1 year after the priming EV71 immunization shows excellent immunogenicity and good safety profile. Clinical Trials Registration: NCT01734408. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Willingness and influential factors of parents to vaccinate their children with novel inactivated enterovirus 71 vaccines in Guangzhou, China.

PubMed

Li, Tiegang; Wang, Hui; Lu, Yin; Li, Qin; Chen, Chun; Wang, Dahu; Li, Meixia; Li, Yilan; Lu, Jianyun; Chen, Zongqiu; Ma, Yu; Liu, Wenhui; Ma, Mengmeng; Wu, Di; Lu, Jiachun; Yang, Zhicong

2018-05-15

Hand, foot and mouth disease (HFMD) primarily affects children younger than 5 years of age. Recently, HFMD has ranked as the top notifiable infectious disease in China. In December 2015, China approved two novel inactivated enterovirus 71 vaccines (EV71 vaccines) for HFMD. Parents' acceptance is often essential for vaccination program success. The goal of this study was to identify willingness and influential factors to vaccinate among parents of kindergarteners in Guangzhou, China. A cross-sectional survey of face-to-face interviews was conducted from March to July 2016. Fifty-five kindergartens were randomly selected from 11 districts of Guangzhou. An anonymous self-designed questionnaire was used to investigate awareness, knowledge and attitude towards HFMD and EV71 vaccines. A total of 868 parents participated in the survey. Mean(±standard deviation) knowledge score of HFMD was 6.32(±1.70). Approximately 32.03% of parents had heard of the EV71 vaccines with 22.58% receiving information before this study. Nearly 44.24% of parents showed willingness to vaccinate their children. Previously receiving EV71 vaccine-related information [adjusted odds ratio (aOR) = 1.48, 95% confidence interval (CI): 1.04-2.11], no fear of adverse effects (aOR = 4.25, 95%CI: 2.77-6.53), perceived susceptibility of children to HFMD (aOR = 2.15, 95%CI: 1.42-3.25) and children not previously diagnosed with HFMD (aOR = 1.56, 95%CI: 1.07-2.27) were positively associated with EV71 vaccination acceptability. However, parental education background (aOR = 0.54, 95%CI: 0.37-0.80) was negatively correlated with vaccination acceptability. Our study provides baseline information for future vaccination campaigns to help improve the EV71 vaccine uptake rate. Special efforts are urgently needed to improve the awareness and knowledge of EV71 vaccines in China. Copyright © 2018 Elsevier Ltd. All rights reserved.

Enhancing enterovirus A71 vaccine production yield by microcarrier profusion bioreactor culture.

PubMed

Liu, Chia-Chyi; Wu, Suh-Chin; Wu, Shang-Rung; Lin, Hsiao-Yu; Guo, Meng-Shin; Yung-Chih Hu, Alan; Chow, Yen-Hung; Chiang, Jen-Ron; Shieh, Dar-Bin; Chong, Pele

2018-05-24

Hand, foot and mouth diseases (HFMD) are mainly caused by Enterovirus A71 (EV-A71) infections. Clinical trials in Asia conducted with formalin-inactivated EV-A71 vaccine candidates produced from serum-free Vero cell culture using either roller bottle or cell factory technology, are found to be safe and highly efficacious. To increase vaccine yields and reduce the production costs, the bioprocess improvement for EV-A71 vaccine manufacturing is currently being investigated. The parameters that could affect and enhance the production yields of EV-A71 virus growth in the microcarrier bioreactor were investigated. The medium replacement culture strategy included a multi-harvested semi-batch process and perfusion technology and was found to increase the production yields more than 7-14 folds. Based on the western blot and cryo-EM analyses of the EV-A71 virus particles produced from either the multi-harvested semi-batch (MHSBC) or perfusion cultures were found to be similar to those virus particles obtained from the single batch culture. Mouse immunogenicity studies indicate that the EV-A71 vaccine candidates produced from the perfusion culture have similar potency to those obtained from single batch bioprocess. The physical structures of the EV-A71 particles revealed by the cryo-EM analysis were found to be spherical capsid particles. These results provide feasible technical bioprocesses for increasing virus yields and the scale up of EV-A71 vaccine manufacturing using the bioreactor cell culture methods. Copyright © 2017 Elsevier Ltd. All rights reserved.

2-Year Efficacy, Immunogenicity, and Safety of Vigoo Enterovirus 71 Vaccine in Healthy Chinese Children: A Randomized Open-Label Study.

PubMed

Wei, Mingwei; Meng, Fanyue; Wang, Shiyuan; Li, Jingxin; Zhang, Yuntao; Mao, Qunying; Hu, Yuemei; Liu, Pei; Shi, Nianmin; Tao, Hong; Chu, Kai; Wang, Yuxiao; Liang, Zhenglun; Li, Xiuling; Zhu, Fengcai

2017-01-01

 This study evaluated the 2-year efficacy, immunogenicity, and safety of the Vigoo enterovirus 71 (EV71) vaccine.  In an initial phase 3 study, we randomly assigned healthy infants and children aged 6-35 months (ratio, 1:1) to receive 2 doses of either EV71 vaccine (5120 participants) or placebo (5125 participants) at days 0 and 28, and followed them for 12 months after vaccination. In this extended follow-up study, we continued to evaluate the efficacy, immunogenicity, and safety of the EV71 vaccine for up to 2 years.  Overall efficacy was 94.84% (95% confidence interval [CI], 83.53%-98.38%) during the 2-year follow-up period (P < .0001), and the vaccine efficacy during the second year was 100.00% (95% CI, 84.15%-100.00%) against EV71-associated hand-foot-and-mouth disease (HFMD; P < .0001). Geometric mean titers of neutralizing antibody in participants remained high during the 2-year follow-up period, and no vaccine-related serious adverse events were recorded.  Two doses of Vigoo EV71 vaccine could provide sustained protection against EV71-associated HFMD in healthy Chinese children.  NCT01508247. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Structure, Immunogenicity, and Protective Mechanism of an Engineered Enterovirus 71-Like Particle Vaccine Mimicking 80S Empty Capsid.

PubMed

Wang, Xiaoli; Ku, Zhiqiang; Zhang, Xiang; Ye, Xiaohua; Chen, Jinhuan; Liu, Qingwei; Zhang, Wei; Zhang, Chao; Fu, Zhenglin; Jin, Xia; Cong, Yao; Huang, Zhong

2018-01-01

Enterovirus 71 (EV71) is the major causative agent of severe hand, foot, and mouth disease, which affects millions of young children in the Asia-Pacific region annually. In this study, we engineered a novel EV71 virus-like particle (VLP) that lacks VP4 (therefore designated VLP ΔVP4 ) and investigated its structure, antigenicity, and vaccine potential. The cryo-electron microscopy (cryo-EM) structure of VLP ΔVP4 was reconstructed to 3.71-Å resolution. Results from structural and biochemical analyses revealed that VLP ΔVP4 resembles the end product of the viral uncoating process, the 80S empty capsid. VLP ΔVP4 is able to elicit high-titer neutralizing antibodies and to fully protect mice against lethal viral challenge. Mechanistic studies showed that, at the cellular level, the anti-VLP ΔVP4 sera exert neutralization effects at both pre- and postattachment stages by inhibiting both virus attachment and internalization, and at the molecular level, the antisera can block multiple interactions between EV71 and its key receptors. Our study gives a better understanding of EV71 capsid assembly and provides important information for the design and development of new-generation vaccines for EV71, and perhaps for other enteroviruses, as well. IMPORTANCE Enterovirus 71 (EV71) infection may lead to severe hand, foot, and mouth disease, with significant morbidity and mortality. Knowledge regarding EV71 particle assembly remains limited. Here, we report the generation and characterization of a novel EV71 virus-like particle that lacks the VP4 capsid subunit protein. This particle, termed VLP ΔVP4 , structurally mimics the 80S empty capsid, which is the end stage of EV71 uncoating. We further show that VLP ΔVP4 exhibits desirable immunogenicity and protective efficacy in proof-of-concept studies. In addition, the inhibitory mechanisms of the VLP ΔVP4 -induced antibodies are unraveled at both the cellular and molecular levels. Our work provides the first evidence of picornaviral particle assembly in the complete absence of VP4 and identifies VLP ΔVP4 as an improved EV71 vaccine candidate with desirable traits. These findings not only enhance our understanding of particle assembly and uncoating of picornaviruses, but also provide important information for structure-guided vaccine design for EV71 and other enteroviruses. Copyright © 2017 American Society for Microbiology.

Hexon-modified recombinant E1-deleted adenoviral vectors as bivalent vaccine carriers for Coxsackievirus A16 and Enterovirus 71.

PubMed

Zhang, Chao; Yang, Yong; Chi, Yudan; Yin, Jieyun; Yan, Lijun; Ku, Zhiqiang; Liu, Qingwei; Huang, Zhong; Zhou, Dongming

2015-09-22

Hand, foot and mouth disease (HFMD) is a major public health concern in Asia; more efficient vaccines against HFMD are urgently required. Adenoviral (Ad) capsids have been used widely for the presentation of foreign antigens to induce specific immune responses in the host. Here, we describe a novel bivalent vaccine for HFMD based on the hexon-modified, E1-deleted chimpanzee adenovirus serotype 68 (AdC68). The novel vaccine candidate was generated by incorporating the neutralising epitope of Coxsackievirus A16 (CA16), PEP71, into hypervariable region 1 (HVR1), and a shortened neutralising epitope of Enterovirus 71 (EV71), sSP70, into HVR2 of the AdC68 hexon. In order to enhance the immunogenicity of EV71, VP1 of EV71 was cloned into the E1-region of the AdC68 vectors. The results demonstrated that these two epitopes were well presented on the virion surface and had high affinity towards specific antibodies, and VP1 of EV71 was also significantly expressed. In pre-clinical mouse models, the hexon-modified AdC68 elicited neutralising antibodies against both CA16 and EV71, which conferred protection to suckling mice against a lethal challenge of CA16 and EV71. In summary, this study demonstrates that the hexon-modified AdC68 may represent a promising bivalent vaccine carrier against EV71 and CA16 and an epitope-display platform for other pathogens. Copyright © 2015 Elsevier Ltd. All rights reserved.

Oral immunization of mice using transgenic tomato fruit expressing VP1 protein from enterovirus 71.

PubMed

Chen, Hsuan-Fu; Chang, Meng-Huei; Chiang, Bor-Luen; Jeng, Shih-Tong

2006-04-05

Enterovirus 71 (EV71) causes seasonal epidemics of hand-foot-and-mouth disease associated with fatal neurological complications in young children, and several major outbreaks have occurred recently. This study developed an effective antiviral agent by transforming the gene for VP1 protein, a previously defined epitope and also a coat protein of EV71, into tomato plant. VP1 protein was first fused with sorting signals to enable it to be retained in the endoplasmic reticulum of tomato plant, and its expression level increased to 27 microg/g of fresh tomato fruit. Transgenic tomato fruit expressing VP1 protein was then used as an oral vaccine, and the development of VP1-specific fecal IgA and serum IgG were observed in BALB/c mice. Additionally, serum from mice fed transgenic tomato could neutralize the infection of EV71 to rhabdomyosarcoma cells, indicating that tomato fruit expressing VP1 was successful in orally immunizing mice. Moreover, the proliferation of spleen cells from orally immunized mice was stimulated by VP1 protein, and provided further evidence of both humoral and cellular immunity. Results of this study not only demonstrate the feasibility of using transgenic tomato as an oral vaccine to generate protective immunity in mice against EV71, but also suggest the probability of enterovirus vaccine development.

The Enterovirus 71 Procapsid Binds Neutralizing Antibodies and Rescues Virus Infection In Vitro

PubMed Central

Shingler, Kristin L.; Cifuente, Javier O.; Ashley, Robert E.; Makhov, Alexander M.; Conway, James F.

2014-01-01

ABSTRACT Enterovirus 71 (EV71) is responsible for seasonal outbreaks of hand, foot, and mouth disease in the Asia-Pacific region. The virus has the capability to cause severe disease and death, especially in young children. Although several vaccines are currently in clinical trials, no vaccines or therapeutics have been approved for use. Previous structural studies have revealed that two antigenically distinct capsid forms are produced in EV71-infected cells: an expanded empty capsid, sometimes called a procapsid, and the infectious virus. Specifically, an immunodominant epitope of EV71 that maps to the virus canyon is structurally different in the procapsid and virus. This structure-function study shows that the procapsid can sequester antibodies, thus enhancing EV71 infection in vitro. The results presented here suggest that, due to conformational differences between the EV71 procapsid and virus, the presence of the procapsid in natural virus infections should be considered in the future design of vaccines or therapeutics. IMPORTANCE In a picornavirus infection, both an infectious and a noninfectious empty capsid, sometimes referred to as a procapsid, are produced. It was novel to discover that the procapsid form of EV71 was expanded and antigenically distinct from the infectious virus. Previously, it had been supposed that this empty capsid was an off-pathway dead end or at best served for storage of pentameric subunits, which was later shown to be unlikely. It remains unexplained why picornaviruses evolutionarily conserve the wasteful production of so much noninfectious capsid. Here, we demonstrate that the EV71 procapsid has different antigenic properties than the infectious virus. Thus, the procapsid has the capacity to sequester neutralizing antibody and protect the virus, promoting or restoring a successful infection in vitro. This important observation should be considered in the future design and development of vaccines and therapeutics. PMID:25428877

Inactivated Enterovirus 71 Vaccine Produced by 200-L Scale Serum-Free Microcarrier Bioreactor System Provides Cross-Protective Efficacy in Human SCARB2 Transgenic Mouse.

PubMed

Wu, Chia-Ying; Lin, Yi-Wen; Kuo, Chia-Ho; Liu, Wan-Hsin; Tai, Hsiu-Fen; Pan, Chien-Hung; Chen, Yung-Tsung; Hsiao, Pei-Wen; Chan, Chi-Hsien; Chang, Ching-Chuan; Liu, Chung-Cheng; Chow, Yen-Hung; Chen, Juine-Ruey

2015-01-01

Epidemics and outbreaks caused by infections of several subgenotypes of EV71 and other serotypes of coxsackie A viruses have raised serious public health concerns in the Asia-Pacific region. These concerns highlight the urgent need to develop a scalable manufacturing platform for producing an effective and sufficient quantity of vaccines against deadly enteroviruses. In this report, we present a platform for the large-scale production of a vaccine based on the inactivated EV71(E59-B4) virus. The viruses were produced in Vero cells in a 200 L bioreactor with serum-free medium, and the viral titer reached 10(7) TCID50/mL 10 days after infection when using an MOI of 10(-4). The EV71 virus particles were harvested and purified by sucrose density gradient centrifugation. Fractions containing viral particles were pooled based on ELISA and SDS-PAGE. TEM was used to characterize the morphologies of the viral particles. To evaluate the cross-protective efficacy of the EV71 vaccine, the pooled antigens were combined with squalene-based adjuvant (AddaVAX) or aluminum phosphate (AlPO4) and tested in human SCARB2 transgenic (Tg) mice. The Tg mice immunized with either the AddaVAX- or AlPO4-adjuvanted EV71 vaccine were fully protected from challenges by the subgenotype C2 and C4 viruses, and surviving animals did not show any degree of neurological paralysis symptoms or muscle damage. Vaccine treatments significantly reduced virus antigen presented in the central nervous system of Tg mice and alleviated the virus-associated inflammatory response. These results strongly suggest that this preparation results in an efficacious vaccine and that the microcarrier/bioreactor platform offers a superior alternative to the previously described roller-bottle system.

Characterizing Enterovirus 71 and Coxsackievirus A16 virus-like particles production in insect cells.

PubMed

Somasundaram, Balaji; Chang, Cindy; Fan, Yuan Y; Lim, Pei-Yin; Cardosa, Jane; Lua, Linda

2016-02-15

Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) are two viruses commonly responsible for hand, foot and mouth disease (HFMD) in children. The lack of prophylactic or therapeutic measures against HFMD is a major public health concern. Insect cell-based EV71 and CVA16 virus-like particles (VLPs) are promising vaccine candidates against HFMD and are currently under development. In this paper, the influence of insect cell line, incubation temperature, and serial passaging effect and stability of budded virus (BV) stocks on EV71 and CVA16 VLP production was investigated. Enhanced EV71 and CVA16 VLP production was observed in Sf9 cells compared to High Five™ cells. Lowering the incubation temperature from the standard 27°C to 21°C increased the production of both VLPs in Sf9 cells. Serial passaging of CVA16 BV stocks in cell culture had a detrimental effect on the productivity of the structural proteins and the effect was observed with only 5 passages of BV stocks. A 2.7× higher production yield was achieved with EV71 compared to CVA16. High-resolution asymmetric flow field-flow fractionation couple with multi-angle light scattering (AF4-MALS) was used for the first time to characterize EV71 and CVA16 VLPs, displaying an average root mean square radius of 15±1nm and 15.3±5.8 nm respectively. This study highlights the need for different approaches in the design of production process to develop a bivalent EV71 and CVA16 vaccine. Copyright © 2015 Elsevier Inc. All rights reserved.

A generic assay for whole-genome amplification and deep sequencing of enterovirus A71

PubMed Central

Tan, Le Van; Tuyen, Nguyen Thi Kim; Thanh, Tran Tan; Ngan, Tran Thuy; Van, Hoang Minh Tu; Sabanathan, Saraswathy; Van, Tran Thi My; Thanh, Le Thi My; Nguyet, Lam Anh; Geoghegan, Jemma L.; Ong, Kien Chai; Perera, David; Hang, Vu Thi Ty; Ny, Nguyen Thi Han; Anh, Nguyen To; Ha, Do Quang; Qui, Phan Tu; Viet, Do Chau; Tuan, Ha Manh; Wong, Kum Thong; Holmes, Edward C.; Chau, Nguyen Van Vinh; Thwaites, Guy; van Doorn, H. Rogier

2015-01-01

Enterovirus A71 (EV-A71) has emerged as the most important cause of large outbreaks of severe and sometimes fatal hand, foot and mouth disease (HFMD) across the Asia-Pacific region. EV-A71 outbreaks have been associated with (sub)genogroup switches, sometimes accompanied by recombination events. Understanding EV-A71 population dynamics is therefore essential for understanding this emerging infection, and may provide pivotal information for vaccine development. Despite the public health burden of EV-A71, relatively few EV-A71 complete-genome sequences are available for analysis and from limited geographical localities. The availability of an efficient procedure for whole-genome sequencing would stimulate effort to generate more viral sequence data. Herein, we report for the first time the development of a next-generation sequencing based protocol for whole-genome sequencing of EV-A71 directly from clinical specimens. We were able to sequence viruses of subgenogroup C4 and B5, while RNA from culture materials of diverse EV-A71 subgenogroups belonging to both genogroup B and C was successfully amplified. The nature of intra-host genetic diversity was explored in 22 clinical samples, revealing 107 positions carrying minor variants (ranging from 0 to 15 variants per sample). Our analysis of EV-A71 strains sampled in 2013 showed that they all belonged to subgenogroup B5, representing the first report of this subgenogroup in Vietnam. In conclusion, we have successfully developed a high-throughput next-generation sequencing-based assay for whole-genome sequencing of EV-A71 from clinical samples. PMID:25704598

Tolerability and immunogenicity of an inactivated enterovirus 71 vaccine in Chinese healthy adults and children: an open label, phase 1 clinical trial.

PubMed

Meng, Fan-Yue; Li, Jing-Xin; Li, Xiu-Ling; Chu, Kai; Zhang, Yun-Tao; Ji, Hong; Li, Liang; Liang, Zheng-Lun; Zhu, Feng-Cai

2012-05-01

In this open labeled phase 1 clinical trial with enterovirus 71 (EV71) vaccine (ClinicalTrials.gov number: NCT01267903) performed in Donghai County, Jiangsu Province, China, in January 2011. A total of 100 healthy participants, stratified by age (40 adults aged 16-22 y and 60 children aged 6-15 y), were enrolled from volunteers and sequentially received EV71 vaccines of 160U (only for children), 320U, or 640U on day 0 and 28, in a manner of dose escalation. All the participants were followed for 28 d after each shot. During the study period, 37 participants reported at least one injection-site or systemic adverse reaction. No case of grade 3 adverse reaction or serious adverse event (SAE) was observed. Also no dose-related increase in reaction rate was noticed. Pain at injection-site and fever were the most frequently reported local and systematic reaction, respectively. The studied EV71 vaccines demonstrated acceptable tolerability and no anti-nuclear antibody (ANA) seropositive was detected pre or post vaccinations in participants. Also, no clinically significant abnormal change for the liver or kidney function indexes was found. In the according-to-protocol cohort for immunogenicity, it was observed one dose of EV71 vaccine elicited good immune response in the participants, especially for the ones with sero-positive baseline. No obvious dose-response relationship for immunogenicity was found.

Japanese encephalitis virus replicon-based vaccine expressing enterovirus-71 epitope confers dual protection from lethal challenges.

PubMed

Huang, Yi-Ting; Liao, Jia-Teh; Yen, Li-Chen; Chang, Yung-Kun; Lin, Yi-Ling; Liao, Ching-Len

2015-09-11

To construct safer recombinant flavivirus vaccine, we exploited Japanese encephalitis virus (JEV) replicon-based platform to generate single-round infectious particles (SRIPs) that expressed heterologous neutralizing epitope SP70 derived from enterovirus-71 (EV71). Such pseudo-infectious virus particles, named SRIP-SP70, although are not genuine viable viruses, closely mimic live virus infection to elicit immune responses within one round of viral life cycle. We found that, besides gaining of full protection to thwart JEV lethal challenge, female outbred ICR mice, when were immunized with SRIP-SP70 by prime-boost protocol, could not only induce SP70-specific and IgG2a predominant antibodies but also provide their newborns certain degree of protection against EV71 lethal challenge. Our results therefore exemplify that this vaccination strategy could indeed confer an immunized host a dual protective immunity against subsequent lethal challenge from JEV or EV71.

Pros and cons of VP1-specific maternal IgG for the protection of Enterovirus 71 infection.

PubMed

Kim, Young-In; Song, Jae-Hyoung; Kwon, Bo-Eun; Kim, Ha-Neul; Seo, Min-Duk; Park, KwiSung; Lee, SangWon; Yeo, Sang-Gu; Kweon, Mi-Na; Ko, Hyun-Jeong; Chang, Sun-Young

2015-11-27

Enterovirus 71 (EV71) causes hand, foot, and mouth diseases and can result in severe neurological disorders when it infects the central nervous system. Thus, there is a need for the development of effective vaccines against EV71 infection. Here we report that viral capsid protein 1 (VP1), one of the main capsid proteins of EV71, efficiently elicited VP1-specific immunoglobulin G (IgG) in the serum of mice immunized with recombinant VP1. The VP1-specific IgG produced in female mice was efficiently transferred to their offspring, conferring protection against EV71 infection immediately after birth. VP1-specific antibody can neutralize EV71 infection and protect host cells. VP1-specific maternal IgG in offspring was maintained for over 6 months. However, the pre-existence of VP1-specific maternal IgG interfered with the production of VP1-specific IgG antibody secreting cells by active immunization in offspring. Therefore, although our results showed the potential for VP1-specific maternal IgG protection against EV71 in neonatal mice, other strategies must be developed to overcome the hindrance of maternal IgG in active immunization. In this study, we developed an effective and feasible animal model to evaluate the protective efficacy of humoral immunity against EV71 infection using a maternal immunity concept. Copyright © 2015 Elsevier Ltd. All rights reserved.

Hand, foot and mouth disease (HFMD): emerging epidemiology and the need for a vaccine strategy.

PubMed

Aswathyraj, S; Arunkumar, G; Alidjinou, E K; Hober, D

2016-10-01

Hand, foot, and mouth disease (HFMD) is a contagious viral disease and mainly affects infants and young children. The main manifestations are fever, vesicular rashes on hand, feet and buttocks and ulcers in the oral mucosa. Usually, HFMD is self-limiting, but a small proportion of children may experience severe complications such as meningitis, encephalitis, acute flaccid paralysis and neurorespiratory syndrome. Historically, outbreaks of HFMD were mainly caused by two enteroviruses: the coxsackievirus A16 (CV-A16) and the enterovirus 71 (EV-A71). In the recent years, coxsackievirus A6 and coxsackievirus A10 have been widely associated with both sporadic cases and outbreaks of HFMD worldwide, particularly in India, South East Asia and Europe with an increased frequency of neurological complications as well as mortality. Currently, there is no pharmacological intervention or vaccine available for HFMD. A formalin-inactivated EV-A71 vaccine has completed clinical trial in several Asian countries. However, this vaccine cannot protect against other major emerging etiologies of HFMD such as CV-A16, CV-A6 and CV-A10. Therefore, the development of a globally representative multivalent HFMD vaccine could be the best strategy.

Immunodominant IgM and IgG Epitopes Recognized by Antibodies Induced in Enterovirus A71-Associated Hand, Foot and Mouth Disease Patients

PubMed Central

Aw-Yong, Kam Leng; Sam, I-Ching; Koh, Mia Tuang

2016-01-01

Enterovirus A71 (EV-A71) is one of the main causative agents of hand, foot and mouth disease (HFMD). Unlike other enteroviruses that cause HFMD, EV-A71 is more frequently associated with severe neurological complications and fatality. To date, no effective licensed antivirals are available to combat EV-A71 infection. Little is known about the immunogenicity of viral non-structural proteins in humans. Previous studies have mainly focused on characterization of epitopes of EV-A71 structural proteins by using immunized animal antisera. In this study, we have characterized human antibody responses against the structural and non-structural proteins of EV-A71. Each viral protein was cloned and expressed in either bacterial or mammalian systems, and tested with antisera by western blot. Results revealed that all structural proteins (VP1-4), and non-structural proteins 2A, 3C and 3D were targets of EV-A71 IgM, whereas EV-A71 IgG recognized all the structural and non-structural proteins. Sixty three synthetic peptides predicted to be immunogenic in silico were synthesized and used for the characterization of EV-A71 linear B-cell epitopes. In total, we identified 22 IgM and four IgG dominant epitopes. Synthetic peptide PEP27, corresponding to residues 142–156 of VP1, was identified as the EV-A71 IgM-specific immunodominant epitope. PEP23, mapped to VP1 41–55, was recognized as the EV-A71 IgG cross-reactive immunodominant epitope. The structural protein VP1 is the major immunodominant site targeted by anti-EV-A71 IgM and IgG antibodies, but epitopes against non-structural proteins were also detected. These data provide new understanding of the immune response to EV-A71 infection, which benefits the development of diagnostic tools, potential therapeutics and subunit vaccine candidates. PMID:27806091

Inhibition of enterovirus 71 (EV-71) infections by a novel antiviral peptide derived from EV-71 capsid protein VP1.

PubMed

Tan, Chee Wah; Chan, Yoke Fun; Sim, Kooi Mow; Tan, Eng Lee; Poh, Chit Laa

2012-01-01

Enterovirus 71 (EV-71) is the main causative agent of hand, foot and mouth disease (HFMD). In recent years, EV-71 infections were reported to cause high fatalities and severe neurological complications in Asia. Currently, no effective antiviral or vaccine is available to treat or prevent EV-71 infection. In this study, we have discovered a synthetic peptide which could be developed as a potential antiviral for inhibition of EV-71. Ninety five synthetic peptides (15-mers) overlapping the entire EV-71 capsid protein, VP1, were chemically synthesized and tested for antiviral properties against EV-71 in human Rhabdomyosarcoma (RD) cells. One peptide, SP40, was found to significantly reduce cytopathic effects of all representative EV-71 strains from genotypes A, B and C tested, with IC(50) values ranging from 6-9.3 µM in RD cells. The in vitro inhibitory effect of SP40 exhibited a dose dependent concentration corresponding to a decrease in infectious viral particles, total viral RNA and the levels of VP1 protein. The antiviral activity of SP40 peptide was not restricted to a specific cell line as inhibition of EV-71 was observed in RD, HeLa, HT-29 and Vero cells. Besides inhibition of EV-71, it also had antiviral activities against CV-A16 and poliovirus type 1 in cell culture. Mechanism of action studies suggested that the SP40 peptide was not virucidal but was able to block viral attachment to the RD cells. Substitutions of arginine and lysine residues with alanine in the SP40 peptide at positions R3A, R4A, K5A and R13A were found to significantly decrease antiviral activities, implying the importance of positively charged amino acids for the antiviral activities. The data demonstrated the potential and feasibility of SP40 as a broad spectrum antiviral agent against EV-71.

A Modular Vaccine Development Platform Based on Sortase-Mediated Site-Specific Tagging of Antigens onto Virus-Like Particles

PubMed Central

Tang, Shubing; Xuan, Baoqin; Ye, Xiaohua; Huang, Zhong; Qian, Zhikang

2016-01-01

Virus-like particles (VLPs) can be used as powerful nanoscale weapons to fight against virus infection. In addition to direct use as vaccines, VLPs have been extensively exploited as platforms on which to display foreign antigens for prophylactic vaccination and immunotherapeutic treatment. Unfortunately, fabrication of new chimeric VLP vaccines in a versatile, site-specific and highly efficient manner is beyond the capability of traditional VLP vaccine design approaches, genetic insertion and chemical conjugation. In this study, we described a greatly improved VLP display strategy by chemoenzymatic site-specific tailoring antigens on VLPs surface with high efficiency. Through the transpeptidation mediated by sortase A, one protein and two epitopes containing N-terminal oligoglycine were conjugated to the LPET motif on the surface of hepatitis B virus core protein (HBc) VLPs with high density. All of the new chimeric VLPs induced strong specific IgG responses. Furthermore, the chimeric VLPs with sortase A tagged enterovirus 71 (EV71) SP70 epitope could elicit effective antibodies against EV71 lethal challenging as well as the genetic insertion chimeric VLPs. The sortase A mediated chemoenzymatic site-specific tailoring of the HBc VLP approach shows great potential in new VLP vaccine design for its simplicity, site specificity, high efficiency, and versatility. PMID:27170066

Single dose of an adenovirus vectored mouse interferon-α protects mice from lethal EV71 challenge.

PubMed

Sun, Jialei; Ennis, Jane; Turner, Jeffrey D; Chu, Justin Jang Hann

2016-10-01

Enterovirus 71 (EV71) causes hand-foot-and-mouth diseases as well as neurological complications in young children. Interferon (IFN) can inhibit the replication of many viruses with low cytotoxic effects. Previously, an adenovirus vectored mouse interferon-α (DEF201), subtype 5, was generated by Wu et al, 2007. In this study, the antiviral effects of DEF201 against EV71 were evaluated in a murine model. 6-day-old BALB/c mice were administered a single dose of DEF201 before or after infection with lethal dose of EV71. The survival rate, clinical symptoms, tissue viral loads and histology pathogenesis were evaluated. IFN gene expression following a single dose of DEF201 maintained high concentrations of 100-9000 pg/mL for more than 7 days in mice serum. Pre-infection administration of a single dose of 10 6  PFU of DEF201 offered full protection of the mice against EV71 infection compared with the empty Ad5 vector control. In addition, virus load in DEF201-treated mice muscle tissue was significantly decreased as compared with empty vector control. Histopathology analysis revealed that DEF201 significantly prevented the development of severe tissue damage with reduction of viral antigen in the murine muscle tissue. Post-infection treatment at 6 h offered full protection and partial protection at 12 h, indicating that DEF201 could be used as an anti-EV71 therapeutic agent in early stage of EV71 infection. In addition, our study showed that DEF201 enhanced the neutralization ability of serum in EV71-vaccinated mice, implying that DEF201 could promote the production of specific anti-EV71 antibodies. In conclusion, single dose of DEF201 is highly efficacious as a prophylactic agent against EV71 infection in vivo. Copyright © 2016 Elsevier B.V. All rights reserved.

A comparative study of multiple clinical enterovirus 71 isolates and evaluation of cross protection of inactivated vaccine strain FY-23 K-B in vitro.

PubMed

Yang, Ting; Li, Hua; Yue, Lei; Song, Xia; Xie, Tianhong; Ma, Shaohui; Meng, Huaqing; Zhang, Ye; He, Xin; Long, Runxiang; Yang, Rong; Luo, Fangyu; Xie, Zhongping; Li, Qihan

2017-10-26

Enterovirus 71 (EV71) is one of the causative agents of hand, foot and mouth disease, which mostly affects infants and children and leads to severe neurological diseases. Vaccination offers the best option for disease control. We have screened the virus strain FY-23 K-B, which is used as an inactivated vaccine strain. An important issue in the development of vaccines is whether they provide cross protection against all other strains. We collected and identified 19 clinical EV71 isolates from mainland China, which all belong to the C4 genotype. We established growth curves of the strains in Vero cells, performed genetic analysis, and evaluated the cross protection efficacy through neutralizing assays using antisera from a rabbit, monkey and adult human immunized with the FY-23 K-B vaccine strain. The antisera showed broad cross protection among the C4 subgroup strains and homotype strain. Neutralizing indexes (NIs) among the isolates and homotype strain of antisera varied between 56.2-1995.3 for rabbit, 17.8-42,169.7 for monkey and 31.6-17,782.8 for human, whereas NIs against Coxsackievirus A16 or other enteroviruses were below 10. These results suggested that FY-23 K-B used as an antigen could elicit broad spectrum neutralizing antibodies with cross protective efficacy among C4 genotype strains.

Risk Factors for Enterovirus A71 Seropositivity in Rural Indigenous Populations in West Malaysia.

PubMed

NikNadia, Nmn; Sam, I-Ching; Khaidir, Nasibah; Ngui, Romano; Lim, Yvonne A L; Goh, Xiang Ting; Choy, Seow Huey; Chan, Yoke Fun

2016-01-01

Enterovirus A71 (EV-A71), which is transmitted by the fecal-oral route, causes hand, foot and mouth disease and, rarely, severe neurological complications. In Malaysia, the indigenous rural community (Orang Asli) has a high prevalence of parasitic diseases due to poor sanitation, water supply and hygiene practices. This cross-sectional study compared the seroepidemiology of EV-A71 among rural Orang Asli and urban Kuala Lumpur populations in West Malaysia, and determined the risk factors associated with EV-A71 seropositivity in rural Orang Asli. Seropositive rates were determined by neutralization assay. EV-A71 seropositivity was strongly associated with increasing age in both populations. Rural Orang Asli children ≤12 years had significantly higher EV-A71 seropositivity rates than urban Kuala Lumpur children (95.5% vs 57.6%, P < 0.001), and also higher rates in the age groups of 1-3, 4-6 and 7-12 years. Multivariate analysis confirmed that age ≤12 years (adjusted OR 8.1, 95% CI 3.2-20.7, P < 0.001) and using untreated water (adjusted OR 6.2, 95% CI 2.3-16.6, P < 0.001) were independently associated with EV-A71 seropositivity in the Orang Asli population. Supply of clean drinking water may reduce the risk of EV-A71 infection. With significantly higher EV-A71 seropositive rates, younger rural children should be a priority target for future vaccination programs in Malaysia.

Risk Factors for Enterovirus A71 Seropositivity in Rural Indigenous Populations in West Malaysia

PubMed Central

NikNadia, NMN; Sam, I-Ching; Khaidir, Nasibah; Ngui, Romano; Lim, Yvonne A. L.; Goh, Xiang Ting; Choy, Seow Huey; Chan, Yoke Fun

2016-01-01

Enterovirus A71 (EV-A71), which is transmitted by the fecal-oral route, causes hand, foot and mouth disease and, rarely, severe neurological complications. In Malaysia, the indigenous rural community (Orang Asli) has a high prevalence of parasitic diseases due to poor sanitation, water supply and hygiene practices. This cross-sectional study compared the seroepidemiology of EV-A71 among rural Orang Asli and urban Kuala Lumpur populations in West Malaysia, and determined the risk factors associated with EV-A71 seropositivity in rural Orang Asli. Seropositive rates were determined by neutralization assay. EV-A71 seropositivity was strongly associated with increasing age in both populations. Rural Orang Asli children ≤12 years had significantly higher EV-A71 seropositivity rates than urban Kuala Lumpur children (95.5% vs 57.6%, P < 0.001), and also higher rates in the age groups of 1–3, 4–6 and 7–12 years. Multivariate analysis confirmed that age ≤12 years (adjusted OR 8.1, 95% CI 3.2–20.7, P < 0.001) and using untreated water (adjusted OR 6.2, 95% CI 2.3–16.6, P < 0.001) were independently associated with EV-A71 seropositivity in the Orang Asli population. Supply of clean drinking water may reduce the risk of EV-A71 infection. With significantly higher EV-A71 seropositive rates, younger rural children should be a priority target for future vaccination programs in Malaysia. PMID:26866912

Cooperative effect of the attenuation determinants derived from poliovirus sabin 1 strain is essential for attenuation of enterovirus 71 in the NOD/SCID mouse infection model.

PubMed

Arita, Minetaro; Ami, Yasushi; Wakita, Takaji; Shimizu, Hiroyuki

2008-02-01

Enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease and is also associated with serious neurological disorders. An attenuated EV71 strain [EV71(S1-3')] has been established in the cynomolgus monkey infection model; this strain contains the attenuation determinants derived from the type 1 poliovirus vaccine strain, Sabin 1 [PV1(Sabin)], in the 5' nontranslated region (NTR), 3D polymerase, and 3' NTR. In this study, we analyzed the effect of the attenuation determinants of PV1(Sabin) on EV71 infection in a NOD/SCID mouse infection model. We isolated a mouse-adapted EV71 strain [EV71(NOD/SCID)] that causes paralysis of the hind limbs in 3- to 4-week-old NOD/SCID mice by adaptation of the virulent EV71(Nagoya) strain in the brains of NOD/SCID mice. A single mutation at nucleotide 2876 that caused an amino acid change in capsid protein VP1 (change of the glycine at position 145 to glutamic acid) was essential for the mouse-adapted phenotype in NOD/SCID mice. Next, we introduced attenuation determinants derived from PV1(Sabin) along with the mouse adaptation mutation into the EV71(Nagoya) genome. In 4-week-old mice, the determinants in the 3D polymerase and 3' NTR, which are the major temperature-sensitive determinants, had a strong effect on attenuation. In contrast, the effect of individual determinants was weak in 3-week-old NOD/SCID mice, and all the determinants were required for substantial attenuation. These results suggest that a cooperative effect of the attenuation determinants of PV1(Sabin) is essential for attenuated neurovirulence of EV71.

Spectrum of Enterovirus Serotypes Causing Uncomplicated Hand, Foot, and Mouth Disease and Enteroviral diagnostic yield of different clinical samples.

PubMed

Gao, Lidong; Zou, Gang; Liao, Qiaohong; Zhou, Yonghong; Liu, Fengfeng; Dai, Bingbing; Liu, Jia; Chen, Zhiyong; Xing, Weijia; Yang, Le; Liang, Hong; Zhang, Yi; Chen, Zhenhua; Luo, Li; Li, Qing; Luo, Kaiwei; Wu, Peng; Mo, Xiaowei; Wang, Lili; Lan, Ke; Horby, Peter W; Cowling, Benjamin J; Simmonds, Peter; Altmeyer, Ralf; van Doorn, H Rogier; Yu, Hongjie

2018-04-24

Hand, foot, and mouth disease (HFMD) represents a substantial disease burden in the Western Pacific region. We investigated the spectrum of causative enteroviruses of HFMD, and evaluated different clinical samples' diagnostic yield for enteroviruses. We enrolled pediatric patients hospitalized for HFMD among six hospitals in Anhua County, Hunan Province, China between October 2013 and September 2016. Throat swabs and stool samples (or rectal swabs) were collected to detect the enterovirus serotypes by real time RT-PCR or nested PCR. Among the 2,836 patients only one developed severe illness. Seventeen serotypes were identified in 2,401 patients (85%), with the most frequently detected being CV-A16 (29%, 814), CV-A6 (28%, 784), EV-A71 (17%, 491), CV-A10 (4%, 114), and CV-A4 (2%, 53). Children were younger in CV-A6, CV-A10, and CV-A4 infections (median 12 months, IQR 12-24 months) than EV-A71 and CV-A16 infections (median 24 months, IQR 12-36 months, p<0.05). Annual peaks of HFMD hospitalization occurred during April-June. The predominant enterovirus serotype shifted between CV-A16 and CV-A6 during the three years. Stool had a higher diagnostic yield (89%) than rectal (79%) and throat swabs (74%). Detection rates reached 93% when testing stools followed by throat swabs if stools were negative, and 89% when testing rectal swabs followed by throat swabs if rectal swabs were negative. Our results provide a virological benchmark for future surveillance and diagnostics. Continuous comprehensive virological surveillance is essential, especially after implementation of the EV-A71 vaccine in China, to monitor serotype replacement and the impact of EV-A71 vaccine.

Cyclical Patterns of Hand, Foot and Mouth Disease Caused by Enterovirus A71 in Malaysia

PubMed Central

NikNadia, NMN; Sam, I-Ching; Rampal, Sanjay; WanNorAmalina, WMZ; NurAtifah, Ghazali; Verasahib, Khebir; Ong, Chia Ching; MohdAdib, MohdAidinniza; Chan, Yoke Fun

2016-01-01

Enterovirus A71 (EV-A71) is an important emerging pathogen causing large epidemics of hand, foot and mouth disease (HFMD) in children. In Malaysia, since the first EV-A71 epidemic in 1997, recurrent cyclical epidemics have occurred every 2–3 years for reasons that remain unclear. We hypothesize that this cyclical pattern is due to changes in population immunity in children (measured as seroprevalence). Neutralizing antibody titers against EV-A71 were measured in 2,141 residual serum samples collected from children ≤12 years old between 1995 and 2012 to determine the seroprevalence of EV-A71. Reported national HFMD incidence was highest in children <2 years, and decreased with age; in support of this, EV-A71 seroprevalence was significantly associated with age, indicating greater susceptibility in younger children. EV-A71 epidemics are also characterized by peaks of increased genetic diversity, often with genotype changes. Cross-sectional time series analysis was used to model the association between EV-A71 epidemic periods and EV-A71 seroprevalence adjusting for age and climatic variables (temperature, rainfall, rain days and ultraviolet radiance). A 10% increase in absolute monthly EV-A71 seroprevalence was associated with a 45% higher odds of an epidemic (adjusted odds ratio, aOR1.45; 95% CI 1.24–1.69; P<0.001). Every 10% decrease in seroprevalence between preceding and current months was associated with a 16% higher odds of an epidemic (aOR = 1.16; CI 1.01–1.34 P<0.034). In summary, the 2–3 year cyclical pattern of EV-A71 epidemics in Malaysia is mainly due to the fall of population immunity accompanying the accumulation of susceptible children between epidemics. This study will impact the future planning, timing and target populations for vaccine programs. PMID:27010319

Genetic characterization of Enterovirus 71 strains circulating in Vietnam in 2012.

PubMed

Donato, Celeste; Hoi, Le Thi; Hoa, Nguyen Thi; Hoa, Tran Mai; Van Duyet, Le; Dieu Ngan, Ta Thi; Van Kinh, Nguyen; Vu Trung, Nguyen; Vijaykrishna, Dhanasekaran

2016-08-01

Enterovirus 71 subgenogroup C4 caused the largest outbreak of Hand, Foot and Mouth Disease (HFMD) in Vietnam during 2011-2012, resulting in over 200,000 hospitalisations and 207 fatalities. A total of 1917 samples with adequate volume for RT-PCR analysis were collected from patients hospitalised with HFMD throughout Vietnam and 637 were positive for EV71. VP1 gene (n=87) and complete genome (n=9) sequencing was performed. Maximum-likelihood phylogenetic analysis was performed to characterise the B5, C4 and C5 strains detected. Sequence analyses revealed that the dominant subgenogroup associated with the 2012 outbreak was C4, with B5 and C5 strains representing a small proportion of these cases. Numerous countries in the region including Malaysia, Taiwan and China have a large influence on strain diversity in Vietnam and understanding the transmission of EV71 throughout Southeast Asia is vital to inform preventative public health measures and vaccine development efforts. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Phylodynamics of Enterovirus A71-Associated Hand, Foot, and Mouth Disease in Viet Nam.

PubMed

Geoghegan, Jemma L; Tan, Le Van; Kühnert, Denise; Halpin, Rebecca A; Lin, Xudong; Simenauer, Ari; Akopov, Asmik; Das, Suman R; Stockwell, Timothy B; Shrivastava, Susmita; Ngoc, Nghiem My; Uyen, Le Thi Tam; Tuyen, Nguyen Thi Kim; Thanh, Tran Tan; Hang, Vu Thi Ty; Qui, Phan Tu; Hung, Nguyen Thanh; Khanh, Truong Huu; Thinh, Le Quoc; Nhan, Le Nguyen Thanh; Van, Hoang Minh Tu; Viet, Do Chau; Tuan, Ha Manh; Viet, Ho Lu; Hien, Tran Tinh; Chau, Nguyen Van Vinh; Thwaites, Guy; Grenfell, Bryan T; Stadler, Tanja; Wentworth, David E; Holmes, Edward C; Van Doorn, H Rogier

2015-09-01

Enterovirus A71 (EV-A71) is a major cause of hand, foot, and mouth disease (HFMD) and is particularly prevalent in parts of Southeast Asia, affecting thousands of children and infants each year. Revealing the evolutionary and epidemiological dynamics of EV-A71 through time and space is central to understanding its outbreak potential. We generated the full genome sequences of 200 EV-A71 strains sampled from various locations in Viet Nam between 2011 and 2013 and used these sequence data to determine the evolutionary history and phylodynamics of EV-A71 in Viet Nam, providing estimates of the effective reproduction number (Re) of the infection through time. In addition, we described the phylogeography of EV-A71 throughout Southeast Asia, documenting patterns of viral gene flow. Accordingly, our analysis reveals that a rapid genogroup switch from C4 to B5 likely took place during 2012 in Viet Nam. We show that the Re of subgenogroup C4 decreased during the time frame of sampling, whereas that of B5 increased and remained >1 at the end of 2013, corresponding to a rise in B5 prevalence. Our study reveals that the subgenogroup B5 virus that emerged into Viet Nam is closely related to variants that were responsible for large epidemics in Malaysia and Taiwan and therefore extends our knowledge regarding its associated area of endemicity. Subgenogroup B5 evidently has the potential to cause more widespread outbreaks across Southeast Asia. EV-A71 is one of many viruses that cause HFMD, a common syndrome that largely affects infants and children. HFMD usually causes only mild illness with no long-term consequences. Occasionally, however, severe infection may arise, especially in very young children, causing neurological complications and even death. EV-A71 is highly contagious and is associated with the most severe HFMD cases, with large and frequent epidemics of the virus recorded worldwide. Although major advances have been made in the development of a potential EV-A71 vaccine, there is no current prevention and little is known about the patterns and dynamics of EV-A71 spread. In this study, we utilize full-length genome sequence data obtained from HFMD patients in Viet Nam, a geographical region where the disease has been endemic since 2003, to characterize the phylodynamics of this important emerging virus. Copyright © 2015 Geoghegan et al.

Phylodynamics of Enterovirus A71-Associated Hand, Foot, and Mouth Disease in Viet Nam

PubMed Central

Kühnert, Denise; Halpin, Rebecca A.; Lin, Xudong; Simenauer, Ari; Akopov, Asmik; Das, Suman R.; Stockwell, Timothy B.; Shrivastava, Susmita; Ngoc, Nghiem My; Uyen, Le Thi Tam; Tuyen, Nguyen Thi Kim; Thanh, Tran Tan; Hang, Vu Thi Ty; Qui, Phan Tu; Hung, Nguyen Thanh; Khanh, Truong Huu; Thinh, Le Quoc; Nhan, Le Nguyen Thanh; Van, Hoang Minh Tu; Viet, Do Chau; Tuan, Ha Manh; Viet, Ho Lu; Hien, Tran Tinh; Chau, Nguyen Van Vinh; Thwaites, Guy; Grenfell, Bryan T.; Stadler, Tanja; Wentworth, David E.; Holmes, Edward C.; Van Doorn, H. Rogier

2015-01-01

ABSTRACT Enterovirus A71 (EV-A71) is a major cause of hand, foot, and mouth disease (HFMD) and is particularly prevalent in parts of Southeast Asia, affecting thousands of children and infants each year. Revealing the evolutionary and epidemiological dynamics of EV-A71 through time and space is central to understanding its outbreak potential. We generated the full genome sequences of 200 EV-A71 strains sampled from various locations in Viet Nam between 2011 and 2013 and used these sequence data to determine the evolutionary history and phylodynamics of EV-A71 in Viet Nam, providing estimates of the effective reproduction number (Re) of the infection through time. In addition, we described the phylogeography of EV-A71 throughout Southeast Asia, documenting patterns of viral gene flow. Accordingly, our analysis reveals that a rapid genogroup switch from C4 to B5 likely took place during 2012 in Viet Nam. We show that the Re of subgenogroup C4 decreased during the time frame of sampling, whereas that of B5 increased and remained >1 at the end of 2013, corresponding to a rise in B5 prevalence. Our study reveals that the subgenogroup B5 virus that emerged into Viet Nam is closely related to variants that were responsible for large epidemics in Malaysia and Taiwan and therefore extends our knowledge regarding its associated area of endemicity. Subgenogroup B5 evidently has the potential to cause more widespread outbreaks across Southeast Asia. IMPORTANCE EV-A71 is one of many viruses that cause HFMD, a common syndrome that largely affects infants and children. HFMD usually causes only mild illness with no long-term consequences. Occasionally, however, severe infection may arise, especially in very young children, causing neurological complications and even death. EV-A71 is highly contagious and is associated with the most severe HFMD cases, with large and frequent epidemics of the virus recorded worldwide. Although major advances have been made in the development of a potential EV-A71 vaccine, there is no current prevention and little is known about the patterns and dynamics of EV-A71 spread. In this study, we utilize full-length genome sequence data obtained from HFMD patients in Viet Nam, a geographical region where the disease has been endemic since 2003, to characterize the phylodynamics of this important emerging virus. PMID:26085170

The Epidemiology of Hand, Foot and Mouth Disease in Asia: A Systematic Review and Analysis.

PubMed

Koh, Wee Ming; Bogich, Tiffany; Siegel, Karen; Jin, Jing; Chong, Elizabeth Y; Tan, Chong Yew; Chen, Mark Ic; Horby, Peter; Cook, Alex R

2016-10-01

Hand, foot and mouth disease (HFMD) is a widespread pediatric disease caused primarily by human enterovirus 71 (EV-A71) and Coxsackievirus A16 (CV-A16). This study reports a systematic review of the epidemiology of HFMD in Asia. PubMed, Web of Science and Google Scholar were searched up to December 2014. Two reviewers independently assessed studies for epidemiologic and serologic information about prevalence and incidence of HFMD against predetermined inclusion/exclusion criteria. Two reviewers extracted answers for 8 specific research questions on HFMD epidemiology. The results are checked by 3 others. HFMD is found to be seasonal in temperate Asia with a summer peak and in subtropical Asia with spring and fall peaks, but not in tropical Asia; evidence of a climatic role was identified for temperate Japan. Risk factors for HFMD include hygiene, age, gender and social contacts, but most studies were underpowered to adjust rigorously for confounding variables. Both community-level and school-level transmission have been implicated, but their relative importance for HFMD is inconclusive. Epidemiologic indices are poorly understood: No supporting quantitative evidence was found for the incubation period of EV-A71; the symptomatic rate of EV-A71/Coxsackievirus A16 infection was from 10% to 71% in 4 studies; while the basic reproduction number was between 1.1 and 5.5 in 3 studies. The uncertainty in these estimates inhibits their use for further analysis. Diversity of study designs complicates attempts to identify features of HFMD epidemiology. Knowledge on HFMD remains insufficient to guide interventions such as the incorporation of an EV-A71 vaccine in pediatric vaccination schedules. Research is urgently needed to fill these gaps.

The Epidemiology of Hand, Foot and Mouth Disease in Asia

PubMed Central

Koh, Wee Ming; Bogich, Tiffany; Siegel, Karen; Jin, Jing; Chong, Elizabeth Y.; Tan, Chong Yew; Chen, Mark IC; Horby, Peter

2016-01-01

Context: Hand, foot and mouth disease (HFMD) is a widespread pediatric disease caused primarily by human enterovirus 71 (EV-A71) and Coxsackievirus A16 (CV-A16). Objective: This study reports a systematic review of the epidemiology of HFMD in Asia. Data Sources: PubMed, Web of Science and Google Scholar were searched up to December 2014. Study Selection: Two reviewers independently assessed studies for epidemiologic and serologic information about prevalence and incidence of HFMD against predetermined inclusion/exclusion criteria. Data Extraction: Two reviewers extracted answers for 8 specific research questions on HFMD epidemiology. The results are checked by 3 others. Results: HFMD is found to be seasonal in temperate Asia with a summer peak and in subtropical Asia with spring and fall peaks, but not in tropical Asia; evidence of a climatic role was identified for temperate Japan. Risk factors for HFMD include hygiene, age, gender and social contacts, but most studies were underpowered to adjust rigorously for confounding variables. Both community-level and school-level transmission have been implicated, but their relative importance for HFMD is inconclusive. Epidemiologic indices are poorly understood: No supporting quantitative evidence was found for the incubation period of EV-A71; the symptomatic rate of EV-A71/Coxsackievirus A16 infection was from 10% to 71% in 4 studies; while the basic reproduction number was between 1.1 and 5.5 in 3 studies. The uncertainty in these estimates inhibits their use for further analysis. Limitations: Diversity of study designs complicates attempts to identify features of HFMD epidemiology. Conclusions: Knowledge on HFMD remains insufficient to guide interventions such as the incorporation of an EV-A71 vaccine in pediatric vaccination schedules. Research is urgently needed to fill these gaps. PMID:27273688

Inhibition of EV71 by curcumin in intestinal epithelial cells.

PubMed

Huang, Hsing-I; Chio, Chi-Chong; Lin, Jhao-Yin

2018-01-01

EV71 is a positive-sense single-stranded RNA virus that belongs to the Picornaviridae family. EV71 infection may cause various symptoms ranging from hand-foot-and-mouth disease to neurological pathological conditions such as aseptic meningitis, ataxia, and acute transverse myelitis. There is currently no effective treatment or vaccine available. Various compounds have been examined for their ability to restrict EV71 replication. However, most experiments have been performed in rhabdomyosarcoma or Vero cells. Since the gastrointestinal tract is the entry site for this pathogen, we anticipated that orally ingested agents may exert beneficial effects by decreasing virus replication in intestinal epithelial cells. In this study, curcumin (diferuloylmethane, C21H20O6), an active ingredient of turmeric (Curcuma longa Linn) with anti-cancer properties, was investigated for its anti-enterovirus activity. We demonstrate that curcumin treatment inhibits viral translation and increases host cell viability. Curcumin does not exert its anti-EV71 effects by modulating virus attachment or virus internal ribosome entry site (IRES) activity. Furthermore, curcumin-mediated regulation of mitogen-activated protein kinase (MAPK) signaling pathways is not involved. We found that protein kinase C delta (PKCδ) plays a role in virus translation in EV71-infected intestinal epithelial cells and that curcumin treatment decreases the phosphorylation of this enzyme. In addition, we show evidence that curcumin also limits viral translation in differentiated human intestinal epithelial cells. In summary, our data demonstrate the anti-EV71 properties of curcumin, suggesting that ingestion of this phytochemical may protect against enteroviral infections.

Inhibition of EV71 by curcumin in intestinal epithelial cells

PubMed Central

Chio, Chi-Chong; Lin, Jhao-Yin

2018-01-01

EV71 is a positive-sense single-stranded RNA virus that belongs to the Picornaviridae family. EV71 infection may cause various symptoms ranging from hand-foot-and-mouth disease to neurological pathological conditions such as aseptic meningitis, ataxia, and acute transverse myelitis. There is currently no effective treatment or vaccine available. Various compounds have been examined for their ability to restrict EV71 replication. However, most experiments have been performed in rhabdomyosarcoma or Vero cells. Since the gastrointestinal tract is the entry site for this pathogen, we anticipated that orally ingested agents may exert beneficial effects by decreasing virus replication in intestinal epithelial cells. In this study, curcumin (diferuloylmethane, C21H20O6), an active ingredient of turmeric (Curcuma longa Linn) with anti-cancer properties, was investigated for its anti-enterovirus activity. We demonstrate that curcumin treatment inhibits viral translation and increases host cell viability. Curcumin does not exert its anti-EV71 effects by modulating virus attachment or virus internal ribosome entry site (IRES) activity. Furthermore, curcumin-mediated regulation of mitogen-activated protein kinase (MAPK) signaling pathways is not involved. We found that protein kinase C delta (PKCδ) plays a role in virus translation in EV71-infected intestinal epithelial cells and that curcumin treatment decreases the phosphorylation of this enzyme. In addition, we show evidence that curcumin also limits viral translation in differentiated human intestinal epithelial cells. In summary, our data demonstrate the anti-EV71 properties of curcumin, suggesting that ingestion of this phytochemical may protect against enteroviral infections. PMID:29370243

Enterovirus 71 viral capsid protein linear epitopes: Identification and characterization

PubMed Central

2012-01-01

Background To characterize the human humoral immune response against enterovirus 71 (EV71) infection and map human epitopes on the viral capsid proteins. Methods A series of 256 peptides spanning the capsid proteins (VP1, VP2, VP3) of BJ08 strain (genomic C4) were synthesized. An indirect enzyme-linked immunosorbent assay (ELISA) was carried out to detect anti-EV71 IgM and IgG in sera of infected children in acute or recovery phase. The partially overlapped peptides contained 12 amino acids and were coated in the plate as antigen (0.1 μg/μl). Sera from rabbits immunized with inactivated BJ08 virus were also used to screen the peptide panel. Results A total of 10 human anti-EV71 IgM epitopes (vp1-14 in VP1; vp2-6, 21, 40 and 50 in VP2 and vp3-10, 12, 15, 24 and 75 in VP3) were identified in acute phase sera. In contrast, only one anti-EV71 IgG epitope in VP1 (vp1-15) was identified in sera of recovery stage. Four rabbit anti-EV71 IgG epitopes (vp1-14, 31, 54 and 71) were identified and mapped to VP1. Conclusion These data suggested that human IgM epitopes were mainly mapped to VP2 and VP3 with multi-epitope responses occurred at acute infection, while the only IgG epitope located on protein VP1 was activated in recovery phase sera. The dynamic changes of humoral immune response at different stages of infection may have public health significance in evaluation of EV71 vaccine immunogenicity and the clinical application of diagnostic reagents. PMID:22264266

Disease burden of enterovirus 71 in rural central China: A community-based survey.

PubMed

Gan, Zheng-kai; Jin, Hui; Li, Jing-xin; Yao, Xue-jun; Zhou, Yang; Zhang, Xue-feng; Zhu, Feng-cai

2015-01-01

In recent years, the epidemics of hand, foot, and mouth disease (HFMD) centered in the Asian-Pacific region have been characterized by high morbidity and mortality. Enterovirus 71 (EV71) infections were responsible for the majority of the infections leading to severe cases of HFMD and death. This is a community-based survey aimed to estimate the disease burden of EV71 in rural central China, especially for HFMD. From 2011 to 2013, demographic and socio-economic data were gathered from 343 ill children and their parents using a structured questionnaire. We quantified the health burden of disease resulting from EV71 infection in disability-adjusted life years (DALYs). Among 343 cases, 303 had confirmed HFMD, 6 presented with herpangina, 25 presented with respiratory symptoms, and 9 presented with non-specific symptoms. The number of severe cases was 47 (including 1 death) and all of these presented with HFMD. The total cost per patient for severe HFMD, mild HFMD, herpangina, respiratory disease, and non-specific disease was $2149.47, $513.22, $53.28, $31.95, and $39.25, respectively. The overall cost of EV71-related diseases as a proportion of local farmers' per capita net income ranged from 0.18% for those with non-specific disease to 187.12% for those with severe HFMD. The loss of DALYs for the 5 forms of disease were 3.47, 1.76, 1.07, 1.44, 1.22 person-years per 1000 persons, respectively. This study provides data on cost of treatment and health burden for diseases caused by EV71, which can be used in the evaluation of EV71 vaccine cost-effectiveness.

Coxsackievirus A6: a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide.

PubMed

Bian, Lianlian; Wang, Yiping; Yao, Xin; Mao, Qunying; Xu, Miao; Liang, Zhenglun

2015-01-01

Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the predominant pathogens causing outbreaks of hand, foot and mouth disease (HFMD) worldwide. Other human enterovirus A (HEV-A) serotypes tend to cause only sporadic HFMD cases. However, since a HFMD caused by coxsackievirus A6 broke out in Finland in 2008, CA6 has been identified as the responsible pathogen for a series of HFMD outbreaks in Europe, North America and Asia. Because of the severity of the clinical manifestations and the underestimated public health burden, the epidemic of CA6-associated HFMD presents a new challenge to the control of HFMD. This article reviewed the epidemic characteristics, molecular epidemiology, clinical features and laboratory diagnosis of CA6 infection. The genetic evolution of CA6 strains associated with HFMD was also analyzed. It indicated that the development of a multivalent vaccine combining EV71, CA16 and CA6 is an urgent necessity to control HFMD.

Modelling person-to-person transmission in an Enterovirus A71 orally infected hamster model of hand-foot-and-mouth disease and encephalomyelitis.

PubMed

Phyu, Win Kyaw; Ong, Kien Chai; Wong, Kum Thong

2017-07-12

Enterovirus A71 (EV-A71) causes hand-foot-and-mouth disease (HFMD), which may be complicated by fatal encephalomyelitis. Although fecal-oral or oral-oral routes are important in person-to-person transmission, how viral shedding and exposure may predispose individuals to infection remains unknown. We investigated person-to-person transmission by using a model of HFMD and encephalomyelitis based on EV-A71 oral infection of 2-week-old hamsters. Animals (index animals) infected with 10 4 50% cell culture infective doses of virus uniformly developed severe disease four days post-infection (dpi), whereas littermate contacts developed severe disease after six to seven days of exposure to index animals. Virus was detected in oral washes and feces at 3-4 dpi in index animals and at three to eight days after exposure to index animals in littermate contact animals. In a second experiment, non-littermate contact animals exposed for 8 or 12 h to index animals developed the disease six and four days post-exposure, respectively. Tissues from killed index and contact animals, studied by light microscopy, immunohistochemistry and in situ hybridization, exhibited mild inflammatory lesions and/or viral antigens/RNA in the squamous epithelia of the oral cavity, tongue, paws, skin, esophagus, gastric epithelium, salivary glands, lacrimal glands, central nervous system neurons, muscles (skeletal, cardiac and smooth muscles) and liver. Orally shed viruses were probably derived from infected oral mucosa and salivary glands, whereas fecal viruses may have derived from these sites as well as from esophageal and gastric epithelia. Asymptomatic seroconversion in exposed mother hamsters was demonstrated. Our hamster model should be useful in studying person-to-person EV-A71 transmission and how drugs and vaccines may interrupt transmission.

Modelling person-to-person transmission in an Enterovirus A71 orally infected hamster model of hand-foot-and-mouth disease and encephalomyelitis

PubMed Central

Phyu, Win Kyaw; Ong, Kien Chai; Wong, Kum Thong

2017-01-01

Enterovirus A71 (EV-A71) causes hand-foot-and-mouth disease (HFMD), which may be complicated by fatal encephalomyelitis. Although fecal–oral or oral–oral routes are important in person-to-person transmission, how viral shedding and exposure may predispose individuals to infection remains unknown. We investigated person-to-person transmission by using a model of HFMD and encephalomyelitis based on EV-A71 oral infection of 2-week-old hamsters. Animals (index animals) infected with 104 50% cell culture infective doses of virus uniformly developed severe disease four days post-infection (dpi), whereas littermate contacts developed severe disease after six to seven days of exposure to index animals. Virus was detected in oral washes and feces at 3–4 dpi in index animals and at three to eight days after exposure to index animals in littermate contact animals. In a second experiment, non-littermate contact animals exposed for 8 or 12 h to index animals developed the disease six and four days post-exposure, respectively. Tissues from killed index and contact animals, studied by light microscopy, immunohistochemistry and in situ hybridization, exhibited mild inflammatory lesions and/or viral antigens/RNA in the squamous epithelia of the oral cavity, tongue, paws, skin, esophagus, gastric epithelium, salivary glands, lacrimal glands, central nervous system neurons, muscles (skeletal, cardiac and smooth muscles) and liver. Orally shed viruses were probably derived from infected oral mucosa and salivary glands, whereas fecal viruses may have derived from these sites as well as from esophageal and gastric epithelia. Asymptomatic seroconversion in exposed mother hamsters was demonstrated. Our hamster model should be useful in studying person-to-person EV-A71 transmission and how drugs and vaccines may interrupt transmission. PMID:28698666

Development of duplex real-time RT-PCR based on Taqman technology for detecting simultaneously the genome of pan-enterovirus and enterovirus 71.

PubMed

Hwang, Seoyeon; Kang, Byunghak; Hong, Jiyoung; Kim, Ahyoun; Kim, Hyejin; Kim, Kisang; Cheon, Doo-Sung

2013-07-01

Human enterovirus (EV) 71 is the main etiological agent of hand, foot, and mouth disease (HFMD). It is associated with neurological complications, and caused fatalities during recent outbreaks in the Asia-Pacific region. Infections caused by EV71 could lead to many complications, ranging from brainstem encephalitis to pulmonary oedema, resulting in high mortality. In this study, a duplex real-time RT-PCR assay was developed in order to simultaneously detect pan-EV and EV71. EV71-specific primers and probes were designed based on the highly conserved VP1 region of EV71. Five EV71 strains were detected as positive, and no positive fluorescence signal was observed in the duplex real-time RT-PCR for other viral RNA, which showed 100% specificity for the selected panel, and no cross-reactions were observed in this duplex real-time RT-PCR. The EV71-specific duplex real-time RT-PCR was more sensitive than conventional RT-PCR, and detected viral titers that were 10-fold lower than those measured by the latter. Of the 381 HFMD clinical specimens, 196 (51.4%) cases were pan-EV-positive, of which 170 (86.7%) were EV71-positive when tested by pan-EV and EV71-specific duplex real-time RT-PCR. EV71-specific duplex real-time RT-PCR offers a rapid and sensitive method to detect EV71 from clinical specimens, and will allow quarantine measures to be taken more effectively during outbreaks. Copyright © 2013 Wiley Periodicals, Inc.

Rapid and highly sensitive detection of Enterovirus 71 by using nanogold-enhanced electrochemical impedance spectroscopy

NASA Astrophysics Data System (ADS)

Li, Hsing-Yuan; Tseng, Shing-Hua; Cheng, Tsai-Mu; Chu, Hsueh-Liang; Lu, Yu-Ning; Wang, Fang-Yu; Tsai, Li-Yun; Shieh, Juo-Yu; Yang, Jyh-Yuan; Juan, Chien-Chang; Tu, Lung-Chen; Chang, Chia-Ching

2013-07-01

Enterovirus 71 (EV71) infection is an emerging infectious disease causing neurological complications and/or death within two to three days after the development of fever and rash. A low viral titre in clinical specimens makes the detection of EV71 difficult. Conventional approaches for detecting EV71 are time consuming, poorly sensitive, or complicated, and cannot be used effectively for clinical diagnosis. Furthermore, EV71 and Coxsackie virus A16 (CA16) may cross react in conventional assays. Therefore, a rapid, highly sensitive, specific, and user-friendly test is needed. We developed an EV71-specific nanogold-modified working electrode for electrochemical impedance spectroscopy in the detection of EV71. Our results show that EV71 can be distinguished from CA16, Herpes simplex virus, and lysozyme, with the modified nanogold electrode being able to detect EV71 in concentrations as low as 1 copy number/50 μl reaction volume, and the duration between sample preparation and detection being 11 min. This detection platform may have the potential for use in point-of-care diagnostics.

Vaccines, our shared responsibility.

PubMed

Pagliusi, Sonia; Jain, Rishabh; Suri, Rajinder Kumar

2015-05-05

The Developing Countries Vaccine Manufacturers' Network (DCVMN) held its fifteenth annual meeting from October 27-29, 2014, New Delhi, India. The DCVMN, together with the co-organizing institution Panacea Biotec, welcomed over 240 delegates representing high-profile governmental and nongovernmental global health organizations from 36 countries. Over the three-day meeting, attendees exchanged information about their efforts to achieve their shared goal of preventing death and disability from known and emerging infectious diseases. Special praise was extended to all stakeholders involved in the success of polio eradication in South East Asia and highlighted challenges in vaccine supply for measles-rubella immunization over the coming decades. Innovative vaccines and vaccine delivery technologies indicated creative solutions for achieving global immunization goals. Discussions were focused on three major themes including regulatory challenges for developing countries that may be overcome with better communication; global collaborations and partnerships for leveraging investments and enable uninterrupted supply of affordable and suitable vaccines; and leading innovation in vaccines difficult to develop, such as dengue, Chikungunya, typhoid-conjugated and EV71, and needle-free technologies that may speed up vaccine delivery. Moving further into the Decade of Vaccines, participants renewed their commitment to shared responsibility toward a world free of vaccine-preventable diseases. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Development of a sensitive and specific epitope-blocking ELISA for universal detection of antibodies to human enterovirus 71 strains.

PubMed

He, Fang; Kiener, Tanja K; Lim, Xiao Fang; Tan, Yunrui; Raj, Kattur Venkatachalam Ashok; Tang, Manli; Chow, Vincent T K; Chen, Qingfeng; Kwang, Jimmy

2013-01-01

Human Enterovirus 71 (EV71) is a common cause of hand, foot and mouth disease (HFMD) in young children. It is often associated with severe neurological diseases and mortalities in recent outbreaks across the Asia Pacific region. Currently, there is no efficient universal antibody test available to detect EV71 infections. In the present study, an epitope-blocking ELISA was developed to detect specific antibodies to human EV71 viruses in human or animal sera. The assay relies on a novel monoclonal antibody (Mab 1C6) that specifically binds to capsid proteins in whole EV71 viruses without any cross reaction to any EV71 capsid protein expressed alone. The sensitivity and specificity of the epitope-blocking ELISA for EV71 was evaluated and compared to microneutralization using immunized animal sera to multiple virus genotypes of EV71 and coxsackieviruses. Further, 200 serum sample from human individuals who were potentially infected with EV71 viruses were tested in both the blocking ELISA and microneutralization. Results indicated that antibodies to EV71 were readily detected in immunized animals or human sera by the epitope blocking ELISA whereas specimens with antibodies to other enteroviruses yielded negative results. This assay is not only simpler to perform but also shows higher sensitivity and specificity as compared to microneutralization. The epitope-blocking ELISA based on a unique Mab 1C6 provided highly sensitive and 100% specific detection of antibodies to human EV71 viruses in human sera.

A Consistent Orally-Infected Hamster Model for Enterovirus A71 Encephalomyelitis Demonstrates Squamous Lesions in the Paws, Skin and Oral Cavity Reminiscent of Hand-Foot-and-Mouth Disease.

PubMed

Phyu, Win Kyaw; Ong, Kien Chai; Wong, Kum Thong

2016-01-01

Enterovirus A71 (EV-A71) causes self-limiting, hand-foot-and-mouth disease (HFMD) that may rarely be complicated by encephalomyelitis. Person-to-person transmission is usually by fecal-oral or oral-oral routes. To study viral replication sites in the oral cavity and other tissues, and to gain further insights into virus shedding and neuropathogenesis, we developed a consistent, orally-infected, 2-week-old hamster model of HFMD and EV-A71 encephalomyelitis. Tissues from orally-infected, 2-week-old hamsters were studied by light microscopy, immunohistochemistry and in situ hybridization to detect viral antigens and RNA, respectively, and by virus titration. Hamsters developed the disease and died after 4-8 days post infection; LD50 was 25 CCID50. Macroscopic cutaneous lesions around the oral cavity and paws were observed. Squamous epithelium in the lip, oral cavity, paw, skin, and esophagus, showed multiple small inflammatory foci around squamous cells that demonstrated viral antigens/RNA. Neurons (brainstem, spinal cord, sensory ganglia), acinar cells (salivary gland, lacrimal gland), lymphoid cells (lymph node, spleen), and muscle fibres (skeletal, cardiac and smooth muscles), liver and gastric epithelium also showed varying amounts of viral antigens/RNA. Intestinal epithelium, Peyer's patches, thymus, pancreas, lung and kidney were negative. Virus was isolated from oral washes, feces, brain, spinal cord, skeletal muscle, serum, and other tissues. Our animal model should be useful to study squamous epitheliotropism, neuropathogenesis, oral/fecal shedding in EV-A71 infection, person-to-person transmission, and to test anti-viral drugs and vaccines.

A Consistent Orally-Infected Hamster Model for Enterovirus A71 Encephalomyelitis Demonstrates Squamous Lesions in the Paws, Skin and Oral Cavity Reminiscent of Hand-Foot-and-Mouth Disease

PubMed Central

Phyu, Win Kyaw; Ong, Kien Chai; Wong, Kum Thong

2016-01-01

Enterovirus A71 (EV-A71) causes self-limiting, hand-foot-and-mouth disease (HFMD) that may rarely be complicated by encephalomyelitis. Person-to-person transmission is usually by fecal-oral or oral-oral routes. To study viral replication sites in the oral cavity and other tissues, and to gain further insights into virus shedding and neuropathogenesis, we developed a consistent, orally-infected, 2-week-old hamster model of HFMD and EV-A71 encephalomyelitis. Tissues from orally-infected, 2-week-old hamsters were studied by light microscopy, immunohistochemistry and in situ hybridization to detect viral antigens and RNA, respectively, and by virus titration. Hamsters developed the disease and died after 4–8 days post infection; LD50 was 25 CCID50. Macroscopic cutaneous lesions around the oral cavity and paws were observed. Squamous epithelium in the lip, oral cavity, paw, skin, and esophagus, showed multiple small inflammatory foci around squamous cells that demonstrated viral antigens/RNA. Neurons (brainstem, spinal cord, sensory ganglia), acinar cells (salivary gland, lacrimal gland), lymphoid cells (lymph node, spleen), and muscle fibres (skeletal, cardiac and smooth muscles), liver and gastric epithelium also showed varying amounts of viral antigens/RNA. Intestinal epithelium, Peyer’s patches, thymus, pancreas, lung and kidney were negative. Virus was isolated from oral washes, feces, brain, spinal cord, skeletal muscle, serum, and other tissues. Our animal model should be useful to study squamous epitheliotropism, neuropathogenesis, oral/fecal shedding in EV-A71 infection, person-to-person transmission, and to test anti-viral drugs and vaccines. PMID:26815859

Biochemical characterization of recombinant Enterovirus 71 3C protease with fluorogenic model peptide substrates and development of a biochemical assay.

PubMed

Shang, Luqing; Zhang, Shumei; Yang, Xi; Sun, Jixue; Li, Linfeng; Cui, Zhengjie; He, Qiuhong; Guo, Yu; Sun, Yuna; Yin, Zheng

2015-04-01

Enterovirus 71 (EV71), a primary pathogen of hand, foot, and mouth disease (HFMD), affects primarily infants and children. Currently, there are no effective drugs against HFMD. EV71 3C protease performs multiple tasks in the viral replication, which makes it an ideal antiviral target. We synthesized a small set of fluorogenic model peptides derived from cleavage sites of EV71 polyprotein and examined their efficiencies of cleavage by EV71 3C protease. The novel peptide P08 [(2-(N-methylamino)benzoyl) (NMA)-IEALFQGPPK(DNP)FR] was determined to be the most efficiently cleaved by EV71 3C protease, with a kinetic constant kcat/Km of 11.8 ± 0.82 mM(-1) min(-1). Compared with literature reports, P08 gave significant improvement in the signal/background ratio, which makes it an attractive substrate for assay development. A Molecular dynamics simulation study elaborated the interactions between substrate P08 and EV71 3C protease. Arg39, which is located at the bottom of the S2 pocket of EV71 3C protease, may participate in the proteolysis process of substrates. With an aim to evaluate EV71 3C protease inhibitors, a reliable and robust biochemical assay with a Z' factor of 0.87 ± 0.05 was developed. A novel compound (compound 3) (50% inhibitory concentration [IC50] = 1.89 ± 0.25 μM) was discovered using this assay, which effectively suppressed the proliferation of EV 71 (strain Fuyang) in rhabdomyosarcoma (RD) cells with a highly selective index (50% effective concentration [EC50] = 4.54 ± 0.51 μM; 50% cytotoxic concentration [CC50] > 100 μM). This fast and efficient assay for lead discovery and optimization provides an ideal platform for anti-EV71 drug development targeting 3C protease. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Identification of specific antigenic epitope at N-terminal segment of enterovirus 71 (EV-71) VP1 protein and characterization of its use in recombinant form for early diagnosis of EV-71 infection.

PubMed

Zhang, Jianhua; Jiang, Bingfu; Xu, Mingjie; Dai, Xing; Purdy, Michael A; Meng, Jihong

2014-08-30

Human enterovirus 71 (EV-71) is the main etiologic agent of hand, foot and mouth disease (HFMD). We sought to identify EV-71 specific antigens and develop serologic assays for acute-phase EV-71 infection. A series of truncated proteins within the N-terminal 100 amino acids (aa) of EV-71 VP1 was expressed in Escherichia coli. Western blot (WB) analysis showed that positions around 11-21 aa contain EV-71-specific antigenic sites, whereas positions 1-5 and 51-100 contain epitopes shared with human coxsackievirus A16 (CV-A16) and human echovirus 6 (E-6). The N-terminal truncated protein of VP1, VP₁₆₋₄₃, exhibited good stability and was recognized by anti-EV-71 specific rabbit sera. Alignment analysis showed that VP₁₆₋₄₃ is highly conserved among EV-71 strains from different genotypes but was heterologous among other enteroviruses. When the GST-VP₁₆₋₄₃ fusion protein was incorporated as antibody-capture agent in a WB assay and an ELISA for detecting anti-EV-71 IgM in human sera, sensitivities of 91.7% and 77.8% were achieved, respectively, with 100% specificity for both. The characterized EV-71 VP1 protein truncated to positions 6-43 aa has potential as an antigen for detection of anti-EV-71 IgM for early diagnosis of EV-71 infection in a WB format. Copyright © 2014 Elsevier B.V. All rights reserved.

High sensitivity and label-free detection of Enterovirus 71 by nanogold modified electrochemical impedance spectroscopy

NASA Astrophysics Data System (ADS)

Wang, Fang-Yu; Li, Hsing-Yuan; Tseng, Shing-Hua; Cheng, Tsai-Mu; Chu, Hsueh-Liang; Yang, Jyh-Yuan; Chang, Chia-Ching

2013-03-01

Enterovirus 71 (EV71), which is the most fulminant and invasive species of enterovirus, can cause children neurologic complications and death within 2-3 days after fever and rash developed. Besides, EV71 has high sequence similarity with Coxsackie A 16 (CA16) that makes differential diagnosis difficult in clinic and laboratory. Since conventional viral diagnostic method cannot diagnose EV71 quickly and EV71 can transmit at low viral titer, the patients might delay in treatment. A quick, high sensitive, and high specific test for EV71 detection is pivotal. Electrochemical impedance spectroscopy (EIS) has been applied for detecting bio-molecules as biosensors recently. In this study, we try to build a detection platform for EV71 detection by nanogold modified EIS probe. The result shows that our probe can detect 3.6 VP1/50 μl (one EV71 particle has 60 VP1) in 3 minutes. The test can also distinguish EV71 from CA16 and lysozyme. Diagnosis of enterovirus 71 by electrochemical impedance spectroscopy has the potential to apply in clinic.

Cyclophilin A Associates with Enterovirus-71 Virus Capsid and Plays an Essential Role in Viral Infection as an Uncoating Regulator

PubMed Central

Huang, Jiaoyan; Yan, Wenzhong; Wang, Jinglan; Su, Dan; Ni, Cheng; Li, Jian; Rao, Zihe; Liu, Lei; Lou, Zhiyong

2014-01-01

Viruses utilize host factors for their efficient proliferation. By evaluating the inhibitory effects of compounds in our library, we identified inhibitors of cyclophilin A (CypA), a known immunosuppressor with peptidyl-prolyl cis-trans isomerase activity, can significantly attenuate EV71 proliferation. We demonstrated that CypA played an essential role in EV71 entry and that the RNA interference-mediated reduction of endogenous CypA expression led to decreased EV71 multiplication. We further revealed that CypA directly interacted with and modified the conformation of H-I loop of the VP1 protein in EV71 capsid, and thus regulated the uncoating process of EV71 entry step in a pH-dependent manner. Our results aid in the understanding of how host factors influence EV71 life cycle and provide new potential targets for developing antiviral agents against EV71 infection. PMID:25275585

Comparison of mouse, guinea pig and rabbit models for evaluation of plague subunit vaccine F1+rV270.

PubMed

Qi, Zhizhen; Zhou, Lei; Zhang, Qingwen; Ren, Lingling; Dai, Ruixia; Wu, Benchuan; Wang, Tang; Zhu, Ziwen; Yang, Yonghai; Cui, Baizhong; Wang, Zuyun; Wang, Hu; Qiu, Yefeng; Guo, Zhaobiao; Yang, Ruifu; Wang, Xiaoyi

2010-02-10

In this study, a new subunit vaccine that comprised native F1 and recombinant rV270 was evaluated for protective efficacy using mouse, guinea pig and rabbit models in comparison with the live attenuated vaccine EV76. Complete protection against challenging with 10(6) colony-forming units (CFU) of virulent Yersinia pestis strain 141 was observed for mice immunized with the subunit vaccines and EV76 vaccine. In contrast, the subunit vaccine recipes VII (F1-20 microg+rV270-10 microg) and IX (F1-40 microg+rV270-20 microg) and EV76 vaccine provided 86%, 79% and 93% protection against the same level of challenge in guinea pigs and 100%, 83% and 100% protection in rabbits, respectively. The immunized mice with the vaccines had significantly higher IgG titres than the guinea pigs and rabbits, and the immunized guinea pigs developed significantly higher IgG titres than the rabbits, but the anti-F1 response in guinea pigs was more variable than in the mice and rabbits, indicating that guinea pig is not an ideal model for evaluating protective efficacy of plague subunit vaccine, instead the rabbits could be used as an alternative model. All the immunized animals with EV76 developed a negligible IgG titre to rV270 antigen. Furthermore, analysis of IgG subclasses in the immunized animals showed a strong response for IgG1, whereas those receiving EV76 immunization demonstrated predominant production of IgG1 and IgG2a isotypes. The subunit vaccine and EV76 vaccine are able to provide protection for animals against Y. pestis challenge, but the subunit vaccines have obvious advantages over EV76 in terms of safety of use. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Enterovirus A71 DNA-Launched Infectious Clone as a Robust Reverse Genetic Tool

PubMed Central

Tan, Chee Wah; Tee, Han Kang; Lee, Michelle Hui Pheng; Sam, I-Ching; Chan, Yoke Fun

2016-01-01

Enterovirus A71 (EV-A71) causes major outbreaks of hand, foot and mouth disease, and is occasionally associated with neurological complications and death in children. Reverse genetics is widely used in the field of virology for functional study of viral genes. For EV-A71, such tools are limited to clones that are transcriptionally controlled by T7/SP6 bacteriophage promoter. This is often time-consuming and expensive. Here, we describe the development of infectious plasmid DNA-based EV-A71 clones, for which EV-A71 genome expression is under transcriptional control by the CMV-intermediate early promoter and SV40 transcriptional-termination signal. Transfection of this EV-A71 infectious DNA produces good virus yield similar to in vitro-transcribed EV-A71 infectious RNA, 6.4 and 5.8 log10PFU/ml, respectively. Infectious plasmid with enhanced green fluorescence protein and Nano luciferase reporter genes also produced good virus titers, with 4.3 and 5.0 log10 PFU/ml, respectively. Another infectious plasmid with both CMV and T7 promoters was also developed for easy manipulation of in vitro transcription or direct plasmid transfection. Transfection with either dual-promoter infectious plasmid DNA or infectious RNA derived from this dual-promoter clone produced infectious viral particles. Incorporation of hepatitis delta virus ribozyme, which yields precise 3’ ends of the DNA-launched EV-A71 genomic transcripts, increased infectious viral production. In contrast, the incorporation of hammerhead ribozyme in the DNA-launched EV-A71 resulted in lower virus yield, but improved the virus titers for T7 promoter-derived infectious RNA. This study describes rapid and robust reverse genetic tools for EV-A71. PMID:27617744

Formulation and In Vitro Release Kinetics of Mucoadhesive Blend Gels Containing Matrine for Buccal Administration.

PubMed

Chen, Xiaojin; Yan, Jun; Yu, Shuying; Wang, Pingping

2018-01-01

Enterovirus 71 (EV71) is a pathogenic factor of severe hand, foot, and mouth disease (HFMD). No vaccine or specific treatment is currently available for EV71 infection. Hence, we developed a buccal mucoadhesive gel containing matrine to protect against HFMD. Mucoadhesive gels were prepared by Carbopol 974P and were combined with Carbopol 971P, sodium carboxymethyl cellulose (CMC-Na), or hydroxypropylmethy cellulose (HPMC K100M). The formulations were characterized in terms of tensile testing and continuous flow techniques for mucoadhesion. The rheological studies and in vitro drug release characteristics were also investigated. The results showed that combinations of two polymers significantly improved mucoadhesion, especially Carbopol 974P blended with HPMC. Carbopol 974P to HPMC blend ratios of 1:1 and 2:1 induced better mucoadhesion in the tensile test and continuous flow method, respectively. The most sustained release was obtained at a Carbopol 974P to HPMC ratio of 2.5:1. A predominantly non-Fickian diffusion release mechanism was obtained. The gel containing 2.5% Carbopol 974P combined with 1% HPMC showed good mucoadhesion properties and sustained drug release.

Enterovirus 71 pathogenicity in monkeys and cotton rats.

PubMed

Koroleva, Galina A; Karmysheva, Valentina Ya; Lukashev, Alexander N

2014-05-01

Enterovirus 71 (EV71) is a neurovirulent non-polio enterovirus that can cause severe central nervous system (CNS) infection in infants. Vervet monkeys infected intracerebrally or intramuscularly with EV71 isolates from the Bulgarian outbreak of 1975 developed clinical manifestations and pathological signs of encephalomyelitis and spinal poliomyelitis that were similar to EV71 neuroinfection in children. In addition, vervet monkeys with encephalomyelitis had severe alterations in the choroid plexus. EV71 neuroinfection could also be reproduced in young (3- to 4-week old) cotton rats with clinical and pathological signs comparable with those observed in vervet monkeys.

[Epidemiological characteristics of enterovirus type 71 diseases].

PubMed

Gan, Zhengkai; Li, Jingxin; Meng, Fanyue; Hu, Yuemei; Yao, Xuejun; Zhang, Xuefeng; Zhu, Fengcai

2015-01-01

The objective of this study was to investigate the epidemiological characteristics of disease caused by enterovirus type 71. A total of 10 158 children aged between 6 and 35 months, were recruited from 7 sites where EV71 inactivated vaccine phase 3 clinical trial was carried out. All the subjects were followed up to one year to investigate the epidemiological characteristics of the disease caused by EV71. The accumulate incidence density of disease caused by EV71 was 15.17/1 000 person-year. Of all the cases, hand, foot and mouth disease (HFMD), herpangina, respiratory system diseases, digestive system diseases and other diseases accounted for 82.00%, 2.67%, 13.33%, 1.33% and 0.67%, respectively. The difference of the incidence density between boys and girls showed no statistical significance. Majority of the patients were between 12 and 23 months of age, which accounted for 58.67% of the total patients. The differences of incidence density between different months of age were statistically significant (χ(2) = 7.789, P = 0.020). The peak incidence density of disease caused by EV71 occurred from April to June. Nine cases showed severe symptoms or signs that accounted for 6.00% of all the cases. All severe cases were identified as HFMD, of which 7 were boys and 2 were girls. The number of severe cases in different months of age appeared to be 1, 7, and 1, all occurred between April and June. The median courses of HFMD cases and non-HFMD cases were 9 and 6 days, with difference statistically significant (Z = -4.000, P < 0.001). Median of excretion cycle for HFMD and non-HFMD cases were 9 and 11 days respectively. But with no statistically significant difference between the two. Majority of the disease that caused by EV71 appeared as HFMD. Most of them were younger children and with seasonal variation.

Enterovirus and parechovirus infection in children: a brief overview.

PubMed

de Crom, S C M; Rossen, J W A; van Furth, A M; Obihara, C C

2016-08-01

Enterovirus and parechovirus are a frequent cause of infection in children. This review is an overview of what is known from enterovirus and parechovirus infection in children and contains information about the epidemiology, pathogenesis, clinical presentation, diagnosis, treatment, and prognosis of enterovirus and parechovirus infection in children. EV and HPeV infections are a frequent cause of infection in childhood. The clinical presentation is diverse. RT-qPCR is the best way to detect an EV or HPeV. Cerebrospinal fluid, blood and feces have the highest sensitivity for detecting an EV or HPeV. There is no treatment for EV and HPeV infections. Two vaccines against EV 71 are just licensed in China and will be available on the private market. Little is known about the prognosis of EV and HPeV infections. •EV and HPeV are a frequent cause of infection in children. What is new: •This review gives a brief overview over EV and HPeV infection in children.

Anti-enterovirus 71 activity screening of chinese herbs with anti-infection and inflammation activities.

PubMed

Lin, Tzou-Yien; Liu, Yi-Chun; Jheng, Jia-Rong; Tsai, Hui-Ping; Jan, Jia-Tsrong; Wong, Wen-Rou; Horng, Jim-Tong

2009-01-01

Antipyretic and toxin-eliminating traditional Chinese herbs are believed to possess antiviral activity. In this study, we screened extracts of 22 herbs for activity against enterovirus 71 (EV71). We found that only extracts of Houttuynia cordata Thunb. could neutralize EV71-induced cytopathic effects in Vero cells. The 50% inhibitory concentration of H. cordata extract for EV71 was 125.92 +/- 27.84 mug/ml. Antiviral screening of herb extracts was also conducted on 3 genotypes of EV71, coxsackievirus A16 and echovirus 9. H. cordata extract had the highest activity against genotype A of EV71. A plaque reduction assay showed that H. cordata extract significantly reduced plaque formation. Viral protein expression, viral RNA synthesis and virus-induced caspase 3 activation were inhibited in the presence of H. cordata extract, suggesting that it affected apoptotic processes in EV71-infected Vero cells by inhibiting viral replication. The antiviral activity of H. cordata extract was greater in cells pretreated with extract than those treated after infection. We conclude that H. cordata extract has antiviral activity, and it offers a potential to develop a new anti-EV71 agent.

Extracellular vesicles from parasitic helminths and their potential utility as vaccines.

PubMed

Mekonnen, Gebeyaw Getnet; Pearson, Mark; Loukas, Alex; Sotillo, Javier

2018-03-01

Helminths are multicellular parasites affecting nearly three billion people worldwide. To orchestrate a parasitic existence, helminths secrete different molecules, either in soluble form or contained within extracellular vesicles (EVs). EVs are secreted by most cell types and organisms, and have varied roles in intercellular communication, including immune modulation and pathogenesis. Areas covered: In this review, we describe the nucleic acid and proteomic composition of EVs from helminths, with a focus on the protein vaccine candidates present on the EV surface membrane, and discuss the potential utility of helminth EVs and their constituent proteins in the fight against helminth infections. Expert commentary: A significant number of proteins present in helminth-secreted EVs are known vaccine candidates. The characterization of helminth EV proteomes will shed light on host-pathogen interactions, facilitate the discovery of new diagnostic biomarkers, and provide a novel approach for the development of new control measures against helminth infections.

Development of single-step multiplex real-time RT-PCR assays for rapid diagnosis of enterovirus 71, coxsackievirus A6, and A16 in patients with hand, foot, and mouth disease.

PubMed

Puenpa, Jiratchaya; Suwannakarn, Kamol; Chansaenroj, Jira; Vongpunsawad, Sompong; Poovorawan, Yong

2017-10-01

Real-time reverse-transcription polymerase chain reaction (rRT-PCR) to detect enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16) has facilitated the rapid and accurate identification of the two most common etiological agents underlying hand, foot, and mouth disease (HFMD). However, the worldwide emergence of CV-A6 infection in HFMD necessitates development of an improved multiplex rRT-PCR method. To rapidly determine the etiology of HFMD, two rRT-PCR assays using TaqMan probes were developed to differentiate among three selected common enteroviruses (EV-A71, CV-A16 and CV-A6) and to enable broad detection of enteroviruses (pan-enterovirus assay). No cross-reactions were observed with other RNA viruses examined. The detection limits of both assays were 10 copies per microliter for EV-A71, CV-A6 and CV-A16, and pan-enterovirus. The methods showed high accuracy (EV-A71, 90.6%; CV-A6, 92.0%; CV-A16, 100%), sensitivity (EV-A71, 96.5%; CV-A6, 95.8%; CV-A16, 99.0%), and specificity (EV-A71, 100%; CV-A6, 99.9%; CV-A16, 99.9%) in testing clinical specimens (n=1049) during 2014-2016, superior to those of conventional RT-PCR. Overall, the multiplex rRT-PCR assays enabled highly sensitive detection and rapid simultaneous typing of EV-A71, CV-A6 and CV-A16, and enteroviruses, rendering them feasible and attractive methods for large-scale surveillance of enteroviruses associated with HFMD outbreaks. Copyright © 2017 Elsevier B.V. All rights reserved.

A clinically authentic mouse model of enterovirus 71 (EV-A71)-induced neurogenic pulmonary oedema.

PubMed

Victorio, Carla Bianca Luena; Xu, Yishi; Ng, Qimei; Chua, Beng Hooi; Alonso, Sylvie; Chow, Vincent T K; Chua, Kaw Bing

2016-06-30

Enterovirus 71 (EV-A71) is a neurotropic virus that sporadically causes fatal neurologic illness among infected children. Animal models of EV-A71 infection exist, but they do not recapitulate in animals the spectrum of disease and pathology observed in fatal human cases. Specifically, neurogenic pulmonary oedema (NPE)-the main cause of EV-A71 infection-related mortality-is not observed in any of these models. This limits their utility in understanding viral pathogenesis of neurologic infections. We report the development of a mouse model of EV-A71 infection displaying NPE in severely affected animals. We inoculated one-week-old BALB/c mice with an adapted EV-A71 strain and identified clinical signs consistent with observations in human cases and other animal models. We also observed respiratory distress in some mice. At necropsy, we found their lungs to be heavier and incompletely collapsed compared to other mice. Serum levels of catecholamines and histopathology of lung and brain tissues of these mice strongly indicated onset of NPE. The localization of virally-induced brain lesions also suggested a potential pathogenic mechanism for EV-A71-induced NPE. This novel mouse model of virally-induced NPE represents a valuable resource for studying viral mechanisms of neuro-pathogenesis and pre-clinical testing of potential therapeutics and prophylactics against EV-A71-related neurologic complications.

Nuclear Protein Sam68 Interacts with the Enterovirus 71 Internal Ribosome Entry Site and Positively Regulates Viral Protein Translation.

PubMed

Zhang, Hua; Song, Lei; Cong, Haolong; Tien, Po

2015-10-01

Enterovirus 71 (EV71) recruits various cellular factors to assist in the replication and translation of its genome. Identification of the host factors involved in the EV71 life cycle not only will enable a better understanding of the infection mechanism but also has the potential to be of use in the development of antiviral therapeutics. In this study, we demonstrated that the cellular factor 68-kDa Src-associated protein in mitosis (Sam68) acts as an internal ribosome entry site (IRES) trans-acting factor (ITAF) that binds specifically to the EV71 5' untranslated region (5'UTR). Interaction sites in both the viral IRES (stem-loops IV and V) and the heterogeneous nuclear ribonucleoprotein K homology (KH) domain of Sam68 protein were further mapped using an electrophoretic mobility shift assay (EMSA) and biotin RNA pulldown assay. More importantly, dual-luciferase (firefly) reporter analysis suggested that overexpression of Sam68 positively regulated IRES-dependent translation of virus proteins. In contrast, both IRES activity and viral protein translation significantly decreased in Sam68 knockdown cells compared with the negative-control cells treated with short hairpin RNA (shRNA). However, downregulation of Sam68 did not have a significant inhibitory effect on the accumulation of the EV71 genome. Moreover, Sam68 was redistributed from the nucleus to the cytoplasm and interacts with cellular factors, such as poly(rC)-binding protein 2 (PCBP2) and poly(A)-binding protein (PABP), during EV71 infection. The cytoplasmic relocalization of Sam68 in EV71-infected cells may be involved in the enhancement of EV71 IRES-mediated translation. Since Sam68 is known to be a RNA-binding protein, these results provide direct evidence that Sam68 is a novel ITAF that interacts with EV71 IRES and positively regulates viral protein translation. The nuclear protein Sam68 is found as an additional new host factor that interacts with the EV71 IRES during infection and could potentially enhance the translation of virus protein. To our knowledge, this is the first report that describes Sam68 actively participating in the life cycle of EV71 at a molecular level. These studies will not only improve our understanding of the replication of EV71 but also have the potential for aiding in developing a therapeutic strategy against EV71 infection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Formononetin inhibits enterovirus 71 replication by regulating COX- 2/PGE₂ expression.

PubMed

Wang, Huiqiang; Zhang, Dajun; Ge, Miao; Li, Zhuorong; Jiang, Jiandong; Li, Yuhuan

2015-03-01

The activation of ERK, p38 and JNK signal cascade in host cells has been demonstrated to up-regulate of enterovirus 71 (EV71)-induced cyclooxygenase-2 (COX-2)/ prostaglandins E2 (PGE₂) expression which is essential for viral replication. So, we want to know whether a compound can inhibit EV71 infection by suppressing COX-2/PGE₂ expression. The antiviral effect of formononetin was determined by cytopathic effect (CPE) assay and the time course assays. The influence of formononetin for EV71 replication was determined by immunofluorescence assay, western blotting assay and qRT-PCR assay. The mechanism of the antiviral activity of formononetin was determined by western blotting assay and ELISA assay. Formononetin could reduce EV71 RNA and protein synthesis in a dose-dependent manner. The time course assays showed that formononetin displayed significant antiviral activity both before (24 or 12 h) and after (0-6 h) EV71 inoculation in SK-N-SH cells. Formononetin was also able to prevent EV71-induced cytopathic effect (CPE) and suppress the activation of ERK, p38 and JNK signal pathways. Furthermore, formononetin could suppress the EV71-induced COX-2/PGE₂ expression. Also, formononetin exhibited similar antiviral activities against other members of Picornaviridae including coxsackievirus B2 (CVB2), coxsackievirus B3 (CVB3) and coxsackievirus B6 (CVB6). Formononetin could inhibit EV71-induced COX-2 expression and PGE₂ production via MAPKs pathway including ERK, p38 and JNK. Formononetin exhibited antiviral activities against some members of Picornaviridae. These findings suggest that formononetin could be a potential lead or supplement for the development of new anti-EV71 agents in the future.

Impact of enterovirus and other enteric pathogens on oral polio and rotavirus vaccine performance in Bangladeshi infants.

PubMed

Taniuchi, Mami; Platts-Mills, James A; Begum, Sharmin; Uddin, Md Jashim; Sobuz, Shihab U; Liu, Jie; Kirkpatrick, Beth D; Colgate, E Ross; Carmolli, Marya P; Dickson, Dorothy M; Nayak, Uma; Haque, Rashidul; Petri, William A; Houpt, Eric R

2016-06-08

Oral polio vaccine (OPV) and rotavirus vaccine (RV) exhibit poorer performance in low-income settings compared to high-income settings. Prior studies have suggested an inhibitory effect of concurrent non-polio enterovirus (NPEV) infection, but the impact of other enteric infections has not been comprehensively evaluated. In urban Bangladesh, we tested stools for a broad range of enteric viruses, bacteria, parasites, and fungi by quantitative PCR from infants at weeks 6 and 10 of life, coincident with the first OPV and RV administration respectively, and examined the association between enteropathogen quantity and subsequent OPV serum neutralizing titers, serum rotavirus IgA, and rotavirus diarrhea. Campylobacter and enterovirus (EV) quantity at the time of administration of the first dose of OPV was associated with lower OPV1-2 serum neutralizing titers, while enterovirus quantity was also associated with diminished rotavirus IgA (-0.08 change in log titer per tenfold increase in quantity; P=0.037), failure to seroconvert (OR 0.78, 95% CI: 0.64-0.96; P=0.022), and breakthrough rotavirus diarrhea (OR 1.34, 95% CI: 1.05-1.71; P=0.020) after adjusting for potential confounders. These associations were not observed for Sabin strain poliovirus quantity. In this broad survey of enteropathogens and oral vaccine performance we find a particular association between EV carriage, particularly NPEV, and OPV immunogenicity and RV protection. Strategies to reduce EV infections may improve oral vaccine responses. ClinicalTrials.gov Identifier: NCT01375647. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Cytokine Immunopathogenesis of Enterovirus 71 Brain Stem Encephalitis

PubMed Central

Wang, Shih-Min; Lei, Huan-Yao; Liu, Ching-Chuan

2012-01-01

Enterovirus 71 (EV71) is one of the most important causes of herpangina and hand, foot, and mouth disease. It can also cause severe complications of the central nervous system (CNS). Brain stem encephalitis with pulmonary edema is the severe complication that can lead to death. EV71 replicates in leukocytes, endothelial cells, and dendritic cells resulting in the production of immune and inflammatory mediators that shape innate and acquired immune responses and the complications of disease. Cytokines, as a part of innate immunity, favor the development of antiviral and Th1 immune responses. Cytokines and chemokines play an important role in the pathogenesis EV71 brain stem encephalitis. Both the CNS and the systemic inflammatory responses to infection play important, but distinctly different, roles in the pathogenesis of EV71 pulmonary edema. Administration of intravenous immunoglobulin and milrinone, a phosphodiesterase inhibitor, has been shown to modulate inflammation, to reduce sympathetic overactivity, and to improve survival in patients with EV71 autonomic nervous system dysregulation and pulmonary edema. PMID:22956971

SYBR Green Real-Time PCR for the Detection of All Enterovirus-A71 Genogroups

PubMed Central

Dubot-Pérès, Audrey; Tan, Charlene Y. Q.; de Chesse, Reine; Sibounheuang, Bountoy; Vongsouvath, Manivanh; Phommasone, Koukeo; Bessaud, Maël; Gazin, Céline; Thirion, Laurence; Phetsouvanh, Rattanaphone; Newton, Paul N.; de Lamballerie, Xavier

2014-01-01

Enterovirus A71 (EV-A71) has recently become an important public health threat, especially in South-East Asia, where it has caused massive outbreaks of Hand, Foot and Mouth disease every year, resulting in significant mortality. Rapid detection of EV-A71 early in outbreaks would facilitate implementation of prevention and control measures to limit spread. Real-time RT-PCR is the technique of choice for the rapid diagnosis of EV-A71 infection and several systems have been developed to detect circulating strains. Although eight genogroups have been described globally, none of these PCR techniques detect all eight. We describe, for the first time, a SYBR Green real-time RT-PCR system validated to detect all 8 EV-A71 genogroups. This tool could permit the early detection and shift in genogroup circulation and the standardization of HFMD virological diagnosis, facilitating networking of laboratories working on EV-A71 in different regions. PMID:24651608

Development of a highly sensitive real-time nested RT-PCR assay in a single closed tube for detection of enterovirus 71 in hand, foot, and mouth disease.

PubMed

Niu, Peihua; Qi, Shunxiang; Yu, Benzhang; Zhang, Chen; Wang, Ji; Li, Qi; Ma, Xuejun

2016-11-01

Enterovirus 71 (EV71) is one of the major causative agents of outbreaks of hand, foot, and mouth disease (HFMD). A commercial TaqMan probe-based real-time PCR assay has been widely used for the differential detection of EV71 despite its relatively high cost and failure to detect samples with a low viral load (Ct value > 35). In this study, a highly sensitive real-time nested RT-PCR (RTN RT-PCR) assay in a single closed tube for detection of EV71 in HFMD was developed. The sensitivity and specificity of this assay were evaluated using a reference EV71 stock and a panel of controls consisting of coxsackievirus A16 (CVA16) and common respiratory viruses, respectively. The clinical performance of this assay was evaluated and compared with those of a commercial TaqMan probe-based real-time PCR (qRT-PCR) assay and a traditional two-step nested RT-PCR assay. The limit of detection for the RTN RT-PCR assay was 0.01 TCID50/ml, with a Ct value of 38.3, which was the same as that of the traditional two-step nested RT-PCR assay and approximately tenfold lower than that of the qRT-PCR assay. When testing the reference strain EV71, this assay showed favorable detection reproducibility and no obvious cross-reactivity. The testing results of 100 clinical throat swabs from HFMD-suspected patients revealed that 41 samples were positive for EV71 by both RTN RT-PCR and traditional two-step nested RT-PCR assays, whereas only 29 were EV71 positive by qRT-PCR assay.

The Role of VP1 Amino Acid Residue 145 of Enterovirus 71 in Viral Fitness and Pathogenesis in a Cynomolgus Monkey Model

PubMed Central

Kataoka, Chikako; Suzuki, Tadaki; Kotani, Osamu; Iwata-Yoshikawa, Naoko; Nagata, Noriyo; Ami, Yasushi; Wakita, Takaji; Nishimura, Yorihiro; Shimizu, Hiroyuki

2015-01-01

Enterovirus 71 (EV71), a major causative agent of hand, foot, and mouth disease, occasionally causes severe neurological symptoms. We identified P-selectin glycoprotein ligand-1 (PSGL-1) as an EV71 receptor and found that an amino acid residue 145 in the capsid protein VP1 (VP1-145) defined PSGL-1-binding (PB) and PSGL-1-nonbinding (non-PB) phenotypes of EV71. However, the role of PSGL-1-dependent EV71 replication in neuropathogenesis remains poorly understood. In this study, we investigated viral replication, genetic stability, and the pathogenicity of PB and non-PB strains of EV71 in a cynomolgus monkey model. Monkeys were intravenously inoculated with cDNA-derived PB and non-PB strains of EV71, EV71-02363-EG and EV71-02363-KE strains, respectively, with two amino acid differences at VP1-98 and VP1-145. Mild neurological symptoms, transient lymphocytopenia, and inflammatory cytokine responses, were found predominantly in the 02363-KE-inoculated monkeys. During the early stage of infection, viruses were frequently detected in clinical samples from 02363-KE-inoculated monkeys but rarely in samples from 02363-EG-inoculated monkeys. Histopathological analysis of central nervous system (CNS) tissues at 10 days postinfection revealed that 02363-KE induced neuropathogenesis more efficiently than that induced by 02363-EG. After inoculation with 02363-EG, almost all EV71 variants detected in clinical samples, CNS, and non-CNS tissues, possessed a G to E amino acid substitution at VP1-145, suggesting a strong in vivo selection of VP1-145E variants and CNS spread presumably in a PSGL-1-independent manner. EV71 variants with VP1-145G were identified only in peripheral blood mononuclear cells in two out of four 02363-EG-inoculated monkeys. Thus, VP1-145E variants are mainly responsible for the development of viremia and neuropathogenesis in a non-human primate model, further suggesting the in vivo involvement of amino acid polymorphism at VP1-145 in cell-specific viral replication, in vivo fitness, and pathogenesis in EV71-infected individuals. PMID:26181772

Enterovirus serotypes in patients with central nervous system and respiratory infections in Viet Nam 1997-2010.

PubMed

B'Krong, Nguyen Thi Thuy Chinh; Minh, Ngo Ngoc Quang; Qui, Phan Tu; Chau, Tran Thi Hong; Nghia, Ho Dang Trung; Do, Lien Anh Ha; Nhung, Nguyen Ngoc; Van Vinh Chau, Nguyen; Thwaites, Guy; Van Tan, Le; van Doorn, H Rogier; Thanh, Tran Tan

2018-04-12

Enteroviruses are the most common causative agents of human illness. Enteroviruses have been associated with regional and global epidemics, recently, including with severe disease (Enterovirus A71 and D68), and are of interest as emerging viruses. Here, we typed Enterovirus A-D (EV) from central nervous system (CNS) and respiratory infections in Viet Nam. Data and specimens from prospective observational clinical studies conducted between 1997 and 2010 were used. Species and serotypes were determined using type-specific RT-PCR and viral protein 1 or 4 (VP1, VP4) sequencing. Samples from patients with CNS infection (51 children - 10 CSF and 41 respiratory/rectal swabs) and 28 adults (28 CSF) and respiratory infection (124 children - 124 respiratory swabs) were analysed. Twenty-six different serotypes of the four Enterovirus species (A-D) were identified, including EV-A71 and EV-D68. Enterovirus B was associated with viral meningitis in children and adults. Hand, foot and mouth disease associated Enteroviruses A (EV-A71 and Coxsackievirus [CV] A10) were detected in children with encephalitis. Diverse serotypes of all four Enterovirus species were found in respiratory samples, including 2 polio-vaccine viruses, but also 8 CV-A24 and 8 EV-D68. With the exception of EV-D68, the relevance of these viruses in respiratory infection remains unknown. We describe the diverse spectrum of enteroviruses from patients with CNS and respiratory infections in Viet Nam between 1997 and 2010. These data confirm the global circulation of Enterovirus genera and their associations and are important for clinical diagnostics, patient management, and outbreak response.

Peptidyl aldehyde NK-1.8k suppresses enterovirus 71 and enterovirus 68 infection by targeting protease 3C.

PubMed

Wang, Yaxin; Yang, Ben; Zhai, Yangyang; Yin, Zheng; Sun, Yuna; Rao, Zihe

2015-05-01

Enterovirus (EV) is one of the major causative agents of hand, foot, and mouth disease in the Pacific-Asia region. In particular, EV71 causes severe central nervous system infections, and the fatality rates from EV71 infection are high. Moreover, an outbreak of respiratory illnesses caused by an emerging EV, EV68, recently occurred among over 1,000 young children in the United States and was also associated with neurological infections. Although enterovirus has emerged as a considerable global public health threat, no antiviral drug for clinical use is available. In the present work, we screened our compound library for agents targeting viral protease and identified a peptidyl aldehyde, NK-1.8k, that inhibits the proliferation of different EV71 strains and one EV68 strain and that had a 50% effective concentration of 90 nM. Low cytotoxicity (50% cytotoxic concentration, >200 μM) indicated a high selective index of over 2,000. We further characterized a single amino acid substitution inside protease 3C (3C(pro)), N69S, which conferred EV71 resistance to NK-1.8k, possibly by increasing the flexibility of the substrate binding pocket of 3C(pro). The combination of NK-1.8k and an EV71 RNA-dependent RNA polymerase inhibitor or entry inhibitor exhibited a strong synergistic anti-EV71 effect. Our findings suggest that NK-1.8k could potentially be developed for anti-EV therapy. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Characterization of three small molecule inhibitors of enterovirus 71 identified from screening of a library of natural products.

PubMed

Li, Guiming; Gao, Qianqian; Yuan, Shilin; Wang, Lili; Altmeyer, Ralf; Lan, Ke; Yin, Feifei; Zou, Gang

2017-07-01

Enterovirus 71 (EV-A71) is a major cause of hand, foot, and mouth disease (HFMD). Infection with EV-A71 is more often associated with neurological complications in children and is responsible for the majority of fatalities, but currently there is no approved antiviral therapy for treatment. Here, we identified auraptene, formononetin, and yangonin as effective inhibitors of EV-A71 infection in the low-micromolar range from screening of a natural product library. Among them, formononetin and yangonin selectively inhibited EV-A71 while auraptene could inhibit viruses within the enterovirus species A. Time of addition studies showed that all the three inhibitors inhibit both attachment and postattachment step of entry. We found mutations conferring the resistance to these inhibitors in the VP1 and VP4 capsid proteins and confirmed the target residues using a reverse genetic approach. Interestingly, auraptene- and formononetin-resistant viruses exhibit cross-resistance to other inhibitors while yangonin-resistant virus still remains susceptible to auraptene and formononetin. Moreover, auraptene and formononetin, but not yangonin protected EV-A71 against thermal inactivation, indicating a direct stabilizing effect of both compounds on virion capsid conformation. Finally, neither biochanin A (an analog of formononetin) nor DL-Kavain (an analog of yangonin) exhibited anti-EV-A71 activity, suggesting the structural elements required for anti-EV-A71 activity. Taken together, these compounds could become potential lead compounds for anti-EV-A71 drug development and also serve as tool compounds for studying virus entry. Copyright © 2017 Elsevier B.V. All rights reserved.

[Effect of immune modulation on immunogenic and protective activity of a live plague vaccine].

PubMed

Karal'nik, B V; Ponomareva, T S; Deriabin, P N; Denisova, T G; Mel'nikova, N N; Tugambaev, T I; Atshabar, B B; Zakarian, S B

2014-01-01

Comparative evaluation of the effect of polyoxidonium and betaleukin on immunogenic and protective activity of a live plague vaccine in model animal experiments. Plague vaccine EV, polyoxidonium, betaleukin, erythrocytic antigenic diagnosticum for determination of F1 antibodies and immune reagents for detection of lymphocytes with F1 receptors (LFR) in adhesive test developed by the authors were used. The experiments were carried out in 12 rabbits and 169 guinea pigs. Immune modulation accelerated the appearance and disappearance of LFR (early phase) and ensured a more rapid and intensive antibody formation (effector phase). Activation by betaleukin is more pronounced than by polyoxidonium. The more rapid and intensive was the development of early phase, the more effective was antibody response to the vaccine. Immune modulation in the experiment with guinea pigs significantly increased protective activity of the vaccine. The use of immune modulators increased immunogenic (in both early and effector phases of antigen-specific response) and protective activity of the EV vaccine. A connection between the acceleration of the first phase of antigen-specific response and general intensity of effector phase of immune response to the EV vaccine was detected. ,

Seroprevalence of enterovirus 71 and no evidence of crossprotection of enterovirus 71 antibody against the other enteroviruses in kindergarten children in Taipei city.

PubMed

Huang, Wen-Chan; Huang, Li-Min; Kao, Chuan-Liang; Lu, Chun-Yi; Shao, Pei-Lan; Cheng, Ai-Ling; Fan, Tsui-Yien; Chi, Hsin; Chang, Luan-Yin

2012-04-01

Enterovirus 71 (EV71) infection may cause severe neurological and cardiopulmonary complications, especially in preschool children. This study is to investigate the seroprevalence and seroconversion of EV71, and the crossprotection of EV71 antibody against other enteroviruses among kindergarteners. Overall 228 children in a public kindergarten were enrolled during two academic years, 2006 and 2007, in Taipei, Taiwan and we measured their EV71 neutralizing antibody. When the participants had herpangina; hand, foot and mouth disease (HFMD); febrile illness or respiratory symptoms, throat swabs were sampled and processed for viral culture and enterovirus real-time reverse transcriptase polymerase chain reaction (RT-PCR). Questionnaires, completed by the participants' guardians, surveyed the history of allergy and annual incidence of symptoms related to enterovirus infection. Seropositive rates of EV71 were 20% (32/163) in 2006 and 6% (4/65) in 2007. The rate of EV71 seropositivity increased with age (p < 0.01) in 2006 but it did not differ between genders (p = 0.14). No seroconversion was observed from 2006 to 2007. Herpangina occurred in 64% of children with EV71 seropositivity and 48% of those without EV71 antibodies (p = 0.12). Non-71 enterovirus infection, confirmed by viral study, occurred in 53% (19/36) of the EV71-seropositive children and in 53% (102/192) of EV71-seronegative children (p = 0.89). No participants had EV71 infection during the study period. EV71 did not frequently circulate in Taipei City from September 2006 to June 2008. Presence of EV71 neutralizing antibody was not associated with lower incidence of enterovirus infection caused by non-71 serotypes. Copyright © 2011. Published by Elsevier B.V.

Enterovirus 71 infection in children with hand, foot, and mouth disease in Shanghai, China: epidemiology, clinical feature and diagnosis.

PubMed

Wang, Ying; Zou, Gang; Xia, Aimei; Wang, Xiangshi; Cai, Jiehao; Gao, Qianqian; Yuan, Shilin; He, Guimei; Zhang, Shuyi; Zeng, Mei; Altmeyer, Ralf

2015-06-03

In 2012 a large outbreak of hand, foot, and mouth disease (HFMD) widely spread over China, causing more than 2 million cases and 567 deaths. Our purpose was to characterize the major pathogens responsible for the 2012 HFMD outbreak and analyze the genetic characterization of the enterovirus 71 (EV71) strains in Shanghai; also, to analyze the dynamic patterns of neutralizing antibody (NAb) against EV71 and evaluate the diagnostic value of several methods for clinical detection of EV71. Clinical samples including stool, serum and CSF were collected from 396 enrolled HFMD inpatients during the peak seasons in 2012. We analyzed the molecular epidemiology, clinical feature, and diagnostic tests of EV71 infection. EV71 was responsible for 60.35 % of HFMD inpatients and 88.46 % of severe cases. The circulating EV71 strains belonged to subgenogroup C4a. The nucleotide sequences of VP1 between severe cases and uncomplicated cases shared 99.2 ~ 100 % of homology. Among 218 cases with EV71 infection, 211 (96.79 %) serum samples showed NAb positive against EV71 and NAb titer reached higher level 3 days after disease onset. Of 92 cases with EV71-associated meningitis or encephalitis, 5 (5.43 %) of 92 had EV71 RNA detected in CSF samples. The blood anti-EV71 IgM assay showed a sensitivity of 93.30 % and a specificity of 50 %. EV71 C4a remained the predominant subgenotype circulating in Shanghai. The severity of the EV71 infection is not associated with the virulence determinants in VP1. RT-PCR together with IgM detection can enhance the early diagnosis of severe EV71-associated HFMD.

Apigenin Inhibits Enterovirus-71 Infection by Disrupting Viral RNA Association with trans-Acting Factors

PubMed Central

Zhang, Wei; Qiao, Haishi; Lv, Yuanzi; Wang, Jingjing; Chen, Xiaoqing; Hou, Yayi; Tan, Renxiang; Li, Erguang

2014-01-01

Flavonoids are widely distributed natural products with broad biological activities. Apigenin is a dietary flavonoid that has recently been demonstrated to interact with heterogeneous nuclear ribonucleoproteins (hnRNPs) and interferes with their RNA editing activity. We investigated whether apigenin possessed antiviral activity against enterovirus-71 (EV71) infection since EV71 infection requires of hnRNP proteins. We found that apigenin selectively blocks EV71 infection by disrupting viral RNA association with hnRNP A1 and A2 proteins. The estimated EC50 value for apigenin to block EV71 infection was determined at 10.3 µM, while the CC50 was estimated at 79.0 µM. The anti-EV71 activity was selective since no activity was detected against several DNA and RNA viruses. Although flavonoids in general share similar structural features, apigenin and kaempferol were among tested compounds with significant activity against EV71 infection. hnRNP proteins function as trans-acting factors regulating EV71 translation. We found that apigenin treatment did not affect EV71-induced nucleocytoplasmic redistribution of hnRNP A1 and A2 proteins. Instead, it prevented EV71 RNA association with hnRNP A1 and A2 proteins. Accordingly, suppression of hnRNP A1 and A2 expression markedly reduced EV71 infection. As a positive sense, single strand RNA virus, EV71 has a type I internal ribosome entry site (IRES) that cooperates with host factors and regulates EV71 translation. The effect of apigenin on EV71 infection was further demonstrated using a bicistronic vector that has the expression of a GFP protein under the control of EV71 5′-UTR. We found that apigenin treatment selectively suppressed the expression of GFP, but not a control gene. In addition to identification of apigenin as an antiviral agent against EV71 infection, this study also exemplifies the significance in antiviral agent discovery by targeting host factors essential for viral replication. PMID:25330384

Antiviral effects of two Ganoderma lucidum triterpenoids against enterovirus 71 infection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Wenjing; Tao, Junyan; Yang, Xiaoping

Highlights: • Triterpenoids GLTA and GLTB display anti-EV71 activities without cytotoxicity. • The compounds prevent EV71 infection by blocking adsorption of the virus to the cells. • GLTA and GLTB bind to EV71 capsid at the hydrophobic pocket to block EV71 uncoating. • The two compounds significantly inhibit the replication of EV71 viral RNA. • GLTA and GLTB may be used as potential therapeutic agents to treat EV71 infection. - Abstract: Enterovirus 71 (EV71) is a major causative agent for hand, foot and mouth disease (HFMD), and fatal neurological and systemic complications in children. However, there is currently no clinicalmore » approved antiviral drug available for the prevention and treatment of the viral infection. Here, we evaluated the antiviral activities of two Ganoderma lucidum triterpenoids (GLTs), Lanosta-7,9(11),24-trien-3-one,15;26-dihydroxy (GLTA) and Ganoderic acid Y (GLTB), against EV71 infection. The results showed that the two natural compounds display significant anti-EV71 activities without cytotoxicity in human rhabdomyosarcoma (RD) cells as evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation assay. The mechanisms by which the two compounds affect EV71 infection were further elucidated by three action modes using Ribavirin, a common antiviral drug, as a positive control. The results suggested that GLTA and GLTB prevent EV71 infection through interacting with the viral particle to block the adsorption of virus to the cells. In addition, the interactions between EV71 virion and the compounds were predicated by computer molecular docking, which illustrated that GLTA and GLTB may bind to the viral capsid protein at a hydrophobic pocket (F site), and thus may block uncoating of EV71. Moreover, we demonstrated that GLTA and GLTB significantly inhibit the replication of the viral RNA (vRNA) of EV71 replication through blocking EV71 uncoating. Thus, GLTA and GLTB may represent two potential therapeutic agents to control and treat EV71 infection.« less

Enterovirus 71 Uses Cell Surface Heparan Sulfate Glycosaminoglycan as an Attachment Receptor

PubMed Central

Tan, Chee Wah; Poh, Chit Laa; Sam, I-Ching

2013-01-01

Enterovirus 71 (EV-71) infections are usually associated with mild hand, foot, and mouth disease in young children but have been reported to cause severe neurological complications with high mortality rates. To date, four EV-71 receptors have been identified, but inhibition of these receptors by antagonists did not completely abolish EV-71 infection, implying that there is an as yet undiscovered receptor(s). Since EV-71 has a wide range of tissue tropisms, we hypothesize that EV-71 infections may be facilitated by using receptors that are widely expressed in all cell types, such as heparan sulfate. In this study, heparin, polysulfated dextran sulfate, and suramin were found to significantly prevent EV-71 infection. Heparin inhibited infection by all the EV-71 strains tested, including those with a single-passage history. Neutralization of the cell surface anionic charge by polycationic poly-d-lysine and blockage of heparan sulfate by an anti-heparan sulfate peptide also inhibited EV-71 infection. Interference with heparan sulfate biosynthesis either by sodium chlorate treatment or through transient knockdown of N-deacetylase/N-sulfotransferase-1 and exostosin-1 expression reduced EV-71 infection in RD cells. Enzymatic removal of cell surface heparan sulfate by heparinase I/II/III inhibited EV-71 infection. Furthermore, the level of EV-71 attachment to CHO cell lines that are variably deficient in cell surface glycosaminoglycans was significantly lower than that to wild-type CHO cells. Direct binding of EV-71 particles to heparin-Sepharose columns under physiological salt conditions was demonstrated. We conclude that EV-71 infection requires initial binding to heparan sulfate as an attachment receptor. PMID:23097443

Characterization of severe hand, foot, and mouth disease in Shenzhen, China, 2009-2013.

PubMed

Huang, Yun; Zhou, Yuanping; Lu, Hong; Yang, Hong; Feng, Qianjin; Dai, Yingchun; Chen, Long; Yu, Shouyi; Yao, Xiangjie; Zhang, Hailong; Jiang, Ming; Wang, Yujie; Han, Ning; Hu, Guifang; He, Yaqing

2015-09-01

Hand, foot, and mouth disease (HFMD) is caused by human enteroviruses, especially by enterovirus 71 (EV71) and coxsackievirus A16 (CA16). Patients infected with different enteroviruses show varied clinical symptoms. The aim of this study was to determine whether the etiological spectrum of mild and severe HFMD changed, and the association between pathogens and clinical features. From 2009 to 2013, a total of 2,299 stool or rectal specimens were collected with corresponding patient data. A dynamic view of the etiological spectrum of mild and severe HFMD in Shenzhen city of China was provided. EV71 accounted for the majority proportion of severe HFMD cases and fatalities during 2009-2013. CA16 and EV71 were gradually replaced by coxsackievirus A6 (CA6) as the most common serotype for mild HFMD since 2010. Myoclonic jerk and vomiting were the most frequent severe symptoms. Nervous system complications, including aseptic encephalitis and aseptic meningitis were observed mainly in patients infected by EV71. Among EV71, CA16, CA6, and CA10 infection, fever and pharyngalgia were more likely to develop, vesicles on the hand, foot, elbow, knee and buttock were less likely to develop in patients infected with CA10. Vesicles on the mouth more frequently occurred in the patients with CA6, but less in the patient with EV71. Associations between diverse enterovirus serotypes and various clinical features were discovered in the present study, which may offer further insight into early detection, diagnosis and treatment of HFMD. © 2015 Wiley Periodicals, Inc.

SIRT1 inhibits EV71 genome replication and RNA translation by interfering with the viral polymerase and 5′UTR RNA

PubMed Central

Han, Yang; Wang, Lvyin; Cui, Jin; Song, Yu; Luo, Zhen; Chen, Junbo; Xiong, Ying; Zhang, Qi; Liu, Fang; Ho, Wenzhe; Liu, Yingle; Wu, Jianguo

2016-01-01

ABSTRACT Enterovirus 71 (EV71) possesses a single-stranded positive RNA genome that contains a single open reading frame (ORF) flanked by a 5′ untranslated region (5′UTR) and a polyadenylated 3′UTR. Here, we demonstrated that EV71 activates the production of silent mating type information regulation 2 homolog 1 (SIRT1), a histone deacetylase (HDAC). EV71 further stimulates SIRT1 sumoylation and deacetylase activity, and enhances SIRT1 translocation from the nucleus to the cytoplasm. More interestingly, activated SIRT1 subsequently binds with the EV71 3Dpol protein (a viral RNA-dependent RNA polymerase, RdRp) to repress the acetylation and RdRp activity of 3Dpol, resulting in the attenuation of viral genome replication. Moreover, SIRT1 interacts with the cloverleaf structure of the EV71 RNA 5′UTR to inhibit viral RNA transcription, and binds to the internal ribosome entry site (IRES) of the EV71 5′UTR to attenuate viral RNA translation. Thus, EV71 stimulates SIRT1 production and activity, which in turn represses EV71 genome replication by inhibiting viral polymerase, and attenuates EV71 RNA transcription and translation by interfering with viral RNA. These results uncover a new function of SIRT1 and reveal a new mechanism underlying the regulation of EV71 replication. PMID:27875274

Prohibitin plays a critical role in Enterovirus 71 neuropathogenesis

PubMed Central

Too, Issac Horng Khit; Bonne, Isabelle; Tan, Eng Lee; Chu, Justin Jang Hann; Alonso, Sylvie

2018-01-01

A close relative of poliovirus, enterovirus 71 (EV71) is regarded as an important neurotropic virus of serious public health concern. EV71 causes Hand, Foot and Mouth Disease and has been associated with neurological complications in young children. Our limited understanding of the mechanisms involved in its neuropathogenesis has hampered the development of effective therapeutic options. Here, using a two-dimensional proteomics approach combined with mass spectrometry, we have identified a unique panel of host proteins that were differentially and dynamically modulated during EV71 infection of motor-neuron NSC-34 cells, which are found at the neuromuscular junctions where EV71 is believed to enter the central nervous system. Meta-analysis with previously published proteomics studies in neuroblastoma or muscle cell lines revealed minimal overlapping which suggests unique host-pathogen interactions in NSC-34 cells. Among the candidate proteins, we focused our attention on prohibitin (PHB), a protein that is involved in multiple cellular functions and the target of anti-cancer drug Rocaglamide (Roc-A). We demonstrated that cell surface-expressed PHB is involved in EV71 entry into neuronal cells specifically, while membrane-bound mitochondrial PHB associates with the virus replication complex and facilitates viral replication. Furthermore, Roc-A treatment of EV71-infected neuronal cells reduced significantly virus yields. However, the inhibitory effect of Roc-A on PHB in NSC-34 cells was not through blocking the CRAF/MEK/ERK pathway as previously reported. Instead, Roc-A treated NSC-34 cells had lower mitochondria-associated PHB and lower ATP levels that correlated with impaired mitochondria integrity. In vivo, EV71-infected mice treated with Roc-A survived longer than the vehicle-treated animals and had significantly lower virus loads in their spinal cord and brain, whereas virus titers in their limb muscles were comparable to controls. Together, this study uncovers PHB as the first host factor that is specifically involved in EV71 neuropathogenesis and a potential drug target to limit neurological complications. PMID:29324904

[The genetical evolution of the full length genes of 5 EV 71 strains from 5 Shenzhen patients with hand-food-mouth disease associated with EV71 infection].

PubMed

Liu, Wei-long; Yang, Gui-lin; Wei, Qing; Zhang, Ming-xia; Chen, Xin-chun; Liu, Ying-xia; Gao, Yang; Zhou, Bo-ping

2011-02-01

To investigate the characteristics of molecular epidemiology and molecular evolution of 5 EV 71 (enterovirus 71, EV71) strains from 5 Shenzhen patients with hand-food-mouth disease associated with EV 71 infection. 5 EV 71 strains were isolated, and sequenced to analyzed the full length gene sequences in order to compare nucleotide and amino acid homology with other EV71 strains from other regions and countries as well as previous strains across the world through bioinformatics software. 5 strains of EV 71 belonged to sub-genotype C4 by analysis of nucleotide sequences of VP1 and VP4 of EV 71. The differences of nucleotide and amino acid sequences were much small with nucleotide homology of 93% and amino acid homology of 98% among these 5 strains. A phylogenetic tree analysis indicated that 2008 Shenzhen epidemic strains were the most close to 2004 Shenzhen circulating strains, and also much close to 1998 Shenzhen epidemic strains and 2008 Fuyang Anhui strains. The dead strain was very close to 2008 Fuyang Anhui epidemic strains. It can be speculated that this epidemic strains of EV 71 probably originate from the same ancient strain in the history, may from 1998 Shenzhen strain.

A reverse genetics system for enterovirus D68 using human RNA polymerase I.

PubMed

Pan, Minglei; Gao, Shuai; Zhou, Zhenwei; Zhang, Keke; Liu, Sihua; Wang, Zhiyun; Wang, Tao

2018-05-17

Human enterovirus D68 (EV-D68) is a highly contagious virus, which causes respiratory tract infections. However, no effective vaccines are currently available for controlling EV-D68 infection. Here, we developed a reverse genetics system to recover EV-D68 minireplicons and infectious EV-D68 from transfected plasmids using the RNA polymerase I (Pol I) promoter. The EV-D68 minireplicons contained the luciferase reporter gene, which flanked by the non-coding regions of the EV-D68 RNA. The luciferase signals could be detected in cells after transfection and Pol I promoter-mediated luciferase signal was significantly stronger than that mediated by the T7 promoter. Furthermore, recombinant viruses were generated by transfecting plasmids that contained the genomic RNA segments of EV-D68, under the control of Pol I promoter into 293T cells or RD cells. On plaque morphology and growth kinetics, the rescued virus and parental virus were indistinguishable. In addition, we showed that the G394C mutation disrupts the viral 5'-UTR structure and suppresses the viral cap-independent translation. This reverse genetics system for EV-D68 recovery can greatly facilitate research into EV-D68 biology. Moreover, this system could accelerate the development of EV-D68 vaccines and anti-EV-D68 drugs.

Cross-reactivity of anti-EV71 IgM and neutralizing antibody in series sera of patients infected with Enterovirus 71 and Coxsackievirus A 16.

PubMed

Lin, Yulong; Wen, Kun; Pan, Yuxian; Wang, Yadi; Che, Xiaoyan; Wang, Bin

2011-01-01

To evaluate the cross-reactivity of anti-EV71 IgM and neutralizing antibody in series sera of patients infected with EV71 and CA16. Real-time RT-PCR, virus isolation, ELISA and neutralization test were used to detect enteroviruses from clinical specimens and series sera of 79 HFMD patients. 27 EV71, 37 CA16, and 11 other enterovirus-infected patients were identified by RT-PCR. Among EV71 infected patients, anti-EV71 IgM positive ratios were 87.5% during 1-3 days after onset and 100% over 4 days after onset. In CA16 infected patients, the positive ratios were 7.4%, 26.4%, and 62.5% during 1-3 days, 4-6 days, and over 6 days after onset, respectively. Meanwhile, the results of neutralization test showed 18.9% of CA16 infected patients and 11.1% of EV71 infected patients present high cross-neutralization antibody against each other. Cross-reactivity of anti-EV71 IgM in patients infected with EV71 and CA16 becomes stronger with the progress of disease. Moreover, high cross-neutralization antibody existing in part of patients suggests that the immune reactivity to EV71 infection can be recalled by CA16, and the immune reactivity to CA16 infection can be recalled by EV71. Therefore, identifying enteroviruses by neutralization test may not be an ideal selection.

The Antiviral Effect of Baicalin on Enterovirus 71 In Vitro

PubMed Central

Li, Xiang; Liu, Yuanyuan; Wu, Tingting; Jin, Yue; Cheng, Jianpin; Wan, Changbiao; Qian, Weihe; Xing, Fei; Shi, Weifeng

2015-01-01

Baicalin is a flavonoid compound extracted from Scutellaria roots that has been reported to possess antibacterial, anti-inflammatory, and antiviral activities. However, the antiviral effect of baicalin on enterovirus 71 (EV71) is still unknown. In this study, we found that baicalin showed inhibitory activity on EV71 infection and was independent of direct virucidal or prophylactic effect and inhibitory viral absorption. The expressions of EV71/3D mRNA and polymerase were significantly blocked by baicalin treatment at early stages of EV71 infection. In addition, baicalin could decrease the expressions of FasL and caspase-3, as well as inhibit the apoptosis of EV71-infected human embryonal rhabdomyosarcoma (RD) cells. Altogether, these results indicate that baicalin exhibits potent antiviral effect on EV71 infection, probably through inhibiting EV71/3D polymerase expression and Fas/FasL signaling pathways. PMID:26295407

Novel Multiplex Oligonucleotide-Conjugated Bead Suspension Array for Rapid Identification of Enterovirus 71 Subgenogroups▿ §

PubMed Central

Wu, Y.; Tan, E. L.; Yeo, A.; Chan, K. P.; Nishimura, H.; Cardosa, M. J.; Poh, C. L.; Quak, S. H.; Chow, Vincent T.

2011-01-01

A high-throughput multiplex bead suspension array was developed for the rapid subgenogrouping of EV71 strains, based on single nucleotide polymorphisms observed within the VP1 region with a high sensitivity as low as 1 PFU. Of 33 viral isolates and 55 clinical samples, all EV71 strains were successfully detected and correctly subgenogrouped. PMID:21084510

The combination effects of licl and the active leflunomide metabolite, A771726, on viral-induced interleukin 6 production and EV-A71 replication.

PubMed

Hung, Hui-Chen; Shih, Shin-Ru; Chang, Teng-Yuan; Fang, Ming-Yu; Hsu, John T-A

2014-01-01

Enterovirus 71 (EV-A71) is a neurotropic virus that can cause severe complications involving the central nervous system. No effective antiviral therapeutics are available for treating EV-A71 infection and drug discovery efforts are rarely focused to target this disease. Thus, the main goal of this study was to discover existing drugs with novel indications that may effectively inhibit EV-A71 replication and the inflammatory cytokines elevation. In this study, we showed that LiCl, a GSK3β inhibitor, effectively suppressed EV-A71 replication, apoptosis and inflammatory cytokines production (Interleukin 6, Interleukin-1β) in infected cells. Furthermore, LiCl and an immunomodular agent were shown to strongly synergize with each other in suppressing EV-A71 replication. The results highlighted potential new treatment regimens in suppressing sequelae caused by EV-A71 replication.

Enterovirus spectrum from the active surveillance of hand foot and mouth disease patients under the clinical trial of inactivated Enterovirus A71 vaccine in Jiangsu, China, 2012-2013.

PubMed

Yao, Xin; Bian, Lian-Lian; Lu, Wei-Wei; Li, Jing-Xin; Mao, Qun-Ying; Wang, Yi-Ping; Gao, Fan; Wu, Xing; Ye, Qiang; Xu, Miao; Li, Xiu-Ling; Zhu, Feng-Cai; Liang, Zheng-Lun

2015-12-01

Epidemiological data from active surveillance on human enterovirus, which could cause hand, foot, and mouth disease, were limited. An active surveillance system was used to investigate the enterovirus spectrum and the incidence of different enteroviruses in infants aged 6-35 months in Jiangsu Province from 2012 to 2013. Fifty-nine infants were randomly selected from 522 non-EV-A71/CV-A16 HFMD patients. We collected 173 throat swabs and 174 rectal swabs from these infants. RT-PCR was used to amplify 5'-UTR and VP1 regions of enteroviruses and the serotypes were determined by the sequence comparison using BLAST. Twenty-one non-EV-A71/CA16 enterovirus serotypes were detected in those infants. E16, E18 were firstly reported in HFMD patients. The four top common non-EV-A71/CV-A enteroviruses among infants were CV-B3, CV-A10, CV-A6, and E9 with the HFMD incidence rates at 1.4%, 0.84%, 0.56%, and 0.47%, respectively. Over 20.8% patients were co-infected with multiple enteroviruses. Neither the course of sickness nor clinical symptoms of the co-infected patients was more severe than those infected with single enterovirus. Two patients were infected different enterovirus successively within 2 months. Several new enterovirus serotypes and multiple models of infection associated with HFMD were discovered through the active surveillance system. These data provide a better understanding of the viral etiology of HFMD. © 2015 Wiley Periodicals, Inc.

Structural Basis for Recognition of Human Enterovirus 71 by a Bivalent Broadly Neutralizing Monoclonal Antibody

PubMed Central

Ku, Zhiqiang; Zuo, Teng; Kong, Liangliang; Zhang, Chao; Shi, Jinping; Liu, Qingwei; Chen, Tan; Zhang, Yingyi; Jiang, Wen; Zhang, Linqi; Huang, Zhong; Cong, Yao

2016-01-01

Enterovirus 71 (EV71) is the main pathogen responsible for hand, foot and mouth disease with severe neurological complications and even death in young children. We have recently identified a highly potent anti-EV71 neutralizing monoclonal antibody, termed D5. Here we investigated the structural basis for recognition of EV71 by the antibody D5. Four three-dimensional structures of EV71 particles in complex with IgG or Fab of D5 were reconstructed by cryo-electron microscopy (cryo-EM) single particle analysis all at subnanometer resolutions. The most critical EV71 mature virion-Fab structure was resolved to a resolution of 4.8 Å, which is rare in cryo-EM studies of virus-antibody complex so far. The structures reveal a bivalent binding pattern of D5 antibody across the icosahedral 2-fold axis on mature virion, suggesting that D5 binding may rigidify virions to prevent their conformational changes required for subsequent RNA release. Moreover, we also identified that the complementary determining region 3 (CDR3) of D5 heavy chain directly interacts with the extremely conserved VP1 GH-loop of EV71, which was validated by biochemical and virological assays. We further showed that D5 is indeed able to neutralize a variety of EV71 genotypes and strains. Moreover, D5 could potently confer protection in a mouse model of EV71 infection. Since the conserved VP1 GH-loop is involved in EV71 binding with its uncoating receptor, the scavenger receptor class B, member 2 (SCARB2), the broadly neutralizing ability of D5 might attribute to its inhibition of EV71 from binding SCARB2. Altogether, our results elucidate the structural basis for the binding and neutralization of EV71 by the broadly neutralizing antibody D5, thereby enhancing our understanding of antibody-based protection against EV71 infection. PMID:26938634

[Step Fisher discriminant analysis on severe clinical features of hand foot and mouth disease between enterovirus (EV) 71 and other EV].

PubMed

Ruan, Feng; Tan, Ai-jun; Zhang, Xue-bao; Chen, Xue-qin; Xiao, Song-jian; Ye, Zhong-wen; Wang, Song

2011-07-01

To compare the clinical features of severe hand foot and mouth disease between enterovirus (EV) 71 and other EV to find specific diagnosis index of EV71 severe hand foot and mouth disease. Case definition were adopted from national guideline of hand foot and mouth disease diagnose (Version 2010). Clinical data of severe hand foot and mouth disease came from case history and contents of questionnaire would include the ones between the time of onset and diagnoses being made. EV and EV71, Cox A16 nucleic acid tested were by RT-PCR in stool samples. Clinical features of severe hand foot and mouth disease between EV71 and other EV were compare. There appeared statistical differences between neurologic symptoms such as tremor, myoclonic jerk, listlessness, convulsion and white blood cell counts in CSF (P < 0.05). Results from the step Fisher discriminant analysis showed only tremor and white blood cell had an increase in CSF, with statistically significant differences. The discriminant equation of EV71 was Y = 3.059X(1) + 3.83X(5) - 2.742 and the equation of other EV was Y = 1.634X(1) + 1.623X(5) - 1.693. The specificity of EV71 was 91% and the specificity of other EV was 40%. The increase of clinical features of tremor and white blood cell in CSF could be used as diagnosis index of severe EV71.

The Seroprevalence and Seroincidence of Enterovirus71 Infection in Infants and Children in Ho Chi Minh City, Viet Nam

PubMed Central

Tran, Chau Bich Nguyen; Nguyen, Hieu Trong; Phan, Ha Thanh Thi; Tran, Ngoc Van; Wills, Bridget; Farrar, Jeremy; Santangelo, Joseph D.; Simmons, Cameron P.

2011-01-01

Enterovirus 71 (EV71)-associated hand, foot and mouth disease has emerged as a serious public health problem in South East Asia over the last decade. To better understand the prevalence of EV71 infection, we determined EV71 seroprevalence and seroincidence amongst healthy infants and children in Ho Chi Minh City, Viet Nam. In a cohort of 200 newborns, 55% of cord blood samples contained EV71 neutralizing antibodies and these decayed to undetectable levels by 6 months of age in 98% of infants. The EV71 neutralizing antibody seroconversion rate was 5.6% in the first year and 14% in the second year of life. In children 5–15 yrs of age, seroprevalence of EV71 neutralizing antibodies was 84% and in cord blood it was 55%. Taken together, these data suggest EV71 force of infection is high and highlights the need for more research into its epidemiology and pathogenesis in high disease burden countries. PMID:21765891

2BC Non-Structural Protein of Enterovirus A71 Interacts with SNARE Proteins to Trigger Autolysosome Formation.

PubMed

Lai, Jeffrey K F; Sam, I-Ching; Verlhac, Pauline; Baguet, Joël; Eskelinen, Eeva-Liisa; Faure, Mathias; Chan, Yoke Fun

2017-07-04

Viruses have evolved unique strategies to evade or subvert autophagy machinery. Enterovirus A71 (EV-A71) induces autophagy during infection in vitro and in vivo. In this study, we report that EV-A71 triggers autolysosome formation during infection in human rhabdomyosarcoma (RD) cells to facilitate its replication. Blocking autophagosome-lysosome fusion with chloroquine inhibited virus RNA replication, resulting in lower viral titres, viral RNA copies and viral proteins. Overexpression of the non-structural protein 2BC of EV-A71 induced autolysosome formation. Yeast 2-hybrid and co-affinity purification assays showed that 2BC physically and specifically interacted with a N -ethylmaleimide-sensitive factor attachment receptor (SNARE) protein, syntaxin-17 (STX17). Co-immunoprecipitation assay further showed that 2BC binds to SNARE proteins, STX17 and synaptosome associated protein 29 (SNAP29). Transient knockdown of STX17, SNAP29, and microtubule-associated protein 1 light chain 3B (LC3B), crucial proteins in the fusion between autophagosomes and lysosomes) as well as the lysosomal-associated membrane protein 1 (LAMP1) impaired production of infectious EV-A71 in RD cells. Collectively, these results demonstrate that the generation of autolysosomes triggered by the 2BC non-structural protein is important for EV-A71 replication, revealing a potential molecular pathway targeted by the virus to exploit autophagy. This study opens the possibility for the development of novel antivirals that specifically target 2BC to inhibit formation of autolysosomes during EV-A71 infection.

2BC Non-Structural Protein of Enterovirus A71 Interacts with SNARE Proteins to Trigger Autolysosome Formation

PubMed Central

Lai, Jeffrey K. F.; Sam, I-Ching; Verlhac, Pauline; Baguet, Joël; Faure, Mathias

2017-01-01

Viruses have evolved unique strategies to evade or subvert autophagy machinery. Enterovirus A71 (EV-A71) induces autophagy during infection in vitro and in vivo. In this study, we report that EV-A71 triggers autolysosome formation during infection in human rhabdomyosarcoma (RD) cells to facilitate its replication. Blocking autophagosome-lysosome fusion with chloroquine inhibited virus RNA replication, resulting in lower viral titres, viral RNA copies and viral proteins. Overexpression of the non-structural protein 2BC of EV-A71 induced autolysosome formation. Yeast 2-hybrid and co-affinity purification assays showed that 2BC physically and specifically interacted with a N-ethylmaleimide-sensitive factor attachment receptor (SNARE) protein, syntaxin-17 (STX17). Co-immunoprecipitation assay further showed that 2BC binds to SNARE proteins, STX17 and synaptosome associated protein 29 (SNAP29). Transient knockdown of STX17, SNAP29, and microtubule-associated protein 1 light chain 3B (LC3B), crucial proteins in the fusion between autophagosomes and lysosomes) as well as the lysosomal-associated membrane protein 1 (LAMP1) impaired production of infectious EV-A71 in RD cells. Collectively, these results demonstrate that the generation of autolysosomes triggered by the 2BC non-structural protein is important for EV-A71 replication, revealing a potential molecular pathway targeted by the virus to exploit autophagy. This study opens the possibility for the development of novel antivirals that specifically target 2BC to inhibit formation of autolysosomes during EV-A71 infection. PMID:28677644

A protein-based smallpox vaccine protects mice from vaccinia and ectromelia virus challenges when given as a prime and single boost

PubMed Central

Xiao, Yuhong; Aldaz-Carroll, Lydia; Ortiz, Alexandra M.; Whitbeck, J. Charles; Alexander, Edward; Lou, Huan; Davis, J. Heather L.; Braciale, Thomas J.; Eisenberg, Roselyn J.; Cohen, Gary H.; Isaacs, Stuart N.

2007-01-01

The heightened concern about the intentional release of variola virus has led to the need to develop safer smallpox vaccines. While subunit vaccine strategies are safer than live virus vaccines, subunit vaccines have been hampered by the need for multiple boosts to confer optimal protection. Here we developed a protein-based subunit vaccine strategy that provides rapid protection in mouse models of orthopoxvirus infections after a prime and single boost. Mice vaccinated with vaccinia virus envelope proteins from the mature virus (MV) and extracellular virus (EV) adjuvanted with CpG-ODN and alum were protected from lethal intranasal challenge with vaccinia virus and the mouse-specific ectromelia virus. Organs from mice vaccinated with three proteins (A33, B5 and L1) and then sacrificed after challenge contained significantly lower titers of virus when compared to control groups of mice that were not vaccinated or that received sub-optimal formulations of the vaccine. Sera from groups of mice obtained prior to challenge had neutralizing activity against the MV and also inhibited comet formation indicating anti-EV activity. Long-term partial protection was also seen in mice challenged with vaccinia virus 6 months after initial vaccinations. Thus, this work represents a step toward the development of a practical subunit smallpox vaccine. PMID:17098336

[Expression of EV71-VP1, PSGL-1 and SCARB2 in Tissues of Infants with Brain Stem Encephalitis].

PubMed

Li, Ming; Kong, Xiao-ping; Liu, Hong; Cheng, Ling-xi; Huang, Jing-lu; Quan, Li; Wu, Fang-yu; Hao, Bo; Liu, Chao; Luo, Bin

2015-04-01

To understand the correlation of enterovirus 71 (EV71), P-selectin glycoprotein ligand-1 (PSGL-1), and scavenger receptor B2 (SCARB2) and to explore the possible pathway and mechanism of EV71 infection by observing the expression of EV71, PSGL-1 and SCARB2 in tissues of infants with brain stem encephalitis. The organs and tissues of infants with EV71-VP1 positivity in their brain stems were chosen. Expression and distribution of EV71-VP1, PSGL-1, and SCARB2 were detected and compared by immunohistochemistry. Strong staining of EV71 -VP1 was observed in the neuron, glial cells, the inflammatory cells of perivascular cuffing, parietal cells of the gastric fundus gland while alveolar macrophages, intestinal gland epithelium cells, mucosa lymphoid nodule and lymphocyte of palatine tonsil showed moderate staining and weak staining were displayed in mesenteric lymph nodes and lymphocyte of spleen. PSGL-1 expression was detected in parietal cells of the gastric fundus gland, tonsillar crypt squamous epithelium, alveolar macrophages and leukocytes in each tissue. SCARB2 expression was observed in all the above tissues except the intestines and spleen. The distribution of EV71 correlates with SCARB2 expression. SCARB2 plays an important role in virus infection and replication. Stomach may be an important site for EV71 replication.

Molecular Comparison and Evolutionary Analyses of VP1 Nucleotide Sequences of New African Human Enterovirus 71 Isolates Reveal a Wide Genetic Diversity

PubMed Central

Nougairède, Antoine; Joffret, Marie-Line; Deshpande, Jagadish M.; Dubot-Pérès, Audrey; Héraud, Jean-Michel

2014-01-01

Most circulating strains of Human enterovirus 71 (EV-A71) have been classified primarily into three genogroups (A to C) on the basis of genetic divergence between the 1D gene, which encodes the VP1 capsid protein. The aim of the present study was to provide further insights into the diversity of the EV-A71 genogroups following the recent description of highly divergent isolates, in particular those from African countries, including Madagascar. We classified recent EV-A71 isolates by a large comparison of 3,346 VP1 nucleotidic sequences collected from GenBank. Analysis of genetic distances and phylogenetic investigations indicated that some recently-reported isolates did not fall into the genogroups A-C and clustered into three additional genogroups, including one Indian genogroup (genogroup D) and 2 African ones (E and F). Our Bayesian phylogenetic analysis provided consistent data showing that the genogroup D isolates share a recent common ancestor with the members of genogroup E, while the isolates of genogroup F evolved from a recent common ancestor shared with the members of the genogroup B. Our results reveal the wide diversity that exists among EV-A71 isolates and suggest that the number of circulating genogroups is probably underestimated, particularly in developing countries where EV-A71 epidemiology has been poorly studied. PMID:24598878

Co-Circulation and Genomic Recombination of Coxsackievirus A16 and Enterovirus 71 during a Large Outbreak of Hand, Foot, and Mouth Disease in Central China

PubMed Central

Liu, Weiyong; Wu, Shimin; Xiong, Ying; Li, Tongya; Wen, Zhou; Yan, Mingzhe; Qin, Kai; Liu, Yingle; Wu, Jianguo

2014-01-01

A total of 1844 patients with hand, foot, and mouth disease (HFMD), most of them were children of age 1–3-year-old, in Central China were hospitalized from 2011 to 2012. Among them, 422 were infected with coxsackievirus A16 (CVA16), 334 were infected with enterovirus 71 (EV71), 38 were co-infected with EV71 and CVA16, and 35 were infected with other enteroviruses. Molecular epidemiology analysis revealed that EV71 and CVA16 were detected year-round, but EV71 circulated mainly in July and CVA16 circulated predominantly in November, and incidence of HFMD was reduced in January and February and increased in March. Clinical data showed that hyperglycemia and neurologic complications were significantly higher in EV71-infected patients, while upper respiratory tract infection and C-reactive protein were significantly higher in CVA16-associated patients. 124 EV71 and 80 CVA16 strains were isolated, among them 56 and 68 EV71 strains were C4a and C4b, while 25 and 55 CVA16 strains were B1a and B1b, respectively. Similarity plots and bootscan analyses based on entire genomic sequences revealed that the three C4a sub-genotype EV71 strains were recombinant with C4b sub-genotype EV71 in 2B–2C region, and the three CVA16 strains were recombinant with EV71 in 2A–2B region. Thus, CVA16 and EV71 were the major causative agents in a large HFMD outbreak in Central China. HFMD incidence was high for children among household contact and was detected year-round, but outbreak was seasonal dependent. CVA16 B1b and EV71 C4b reemerged and caused a large epidemic in China after a quiet period of many years. Moreover, EV71 and CVA16 were co-circulated during the outbreak, which may have contributed to the genomic recombination between the pathogens. It should gain more attention as there may be an upward trend in co-circulation of the two pathogens globally and the new role recombination plays in the emergence of new enterovirus variants. PMID:24776922

Enterovirus-71 genotype C isolated in Peru between 2006 and 2009.

PubMed

Huaman, Jose L; Carrion, Gladys; Ampuero, Julia S; Ocaña, Victor; Laguna-Torres, V Alberto; Hontz, Robert D

2016-12-01

Enterovirus-71 (EV71) was first isolated in California, United States in 1969, belongs to the genus Enterovirus, family Picornaviridae. Although infection normally causes mild, often undiagnosed illness, it can cause central nervous system infections that could turn fatal. Based on VP1 gene analysis, EV71 has been classified into six separate genotypes. Although the molecular epidemiology of EV71 has been well described via studies originating from Asia and Europe, it is mostly unknown in South America. From our study, four EV71 isolates from Peru were characterized using phylogenetic methods to determine their relationship with known reference strains. These four Peruvian EV71 isolates from between 2006 and 2009 were analyzed by RT-PCR using primers capable of amplifying the entire VP1 gene. Reference strains representing all six known genotypes were used to determine any recognizable phylogenetic relationships. In fact, all of our isolates clustered together within the genotype C1 lineage- separate from Asian, European, North American, and Australian strains. We present evidence that EV71 genotype C1 exists in Peru, and this is the first such report documenting EV71 genotype C1 circulating in South America. Gathering additional isolates will help elucidate a more complete global epidemiological picture of EV71 infections. Published by Elsevier B.V.

[The early diagnosis value of EV 71 IgM class antibodies in the hand, foot and mouth disease].

PubMed

Zhao, Jing; Xu, Jun; Chen, Wei-wei; Li, Yong-li; Tang, Yan; Li, Jia; Wang, Hai-bin; Guo, Tong-sheng; Zhao, Min; Li, Bo-an; Mao, Yuan-li

2011-04-01

Assessment of detection of IgM antibodies for human enterovirus 71 (EV 71) in early diagnosis for the hand, foot and mouth disease (HFMD). The sera and throat swabs from 38 patients which were clinical diagnosis as HFMD, were continuous daily collected in our hospital in 2010. These specimens were detected by EV 71 IgM antibodies assay, real time RT-PCR methods for EV 71 and Enterovirus. Among 38 HFMD patients, the cumulative positive rates of EV 71 IgM antibodies were: 60.5% on day 1, 71.1% on day 2, 81.5% in the first 3-4 days, 92.1% on day 5, 92.1% on day 6, and the positive rate of nucleic acid detected by the real time RT-PCR for EV 71 and Enterovirus were 60.5%, 73.6%. The positive rate of EV 71 IgM antibodies in the hand, foot and mouth disease just can occur on day 1, and reach to peak on day 5, which can be used as one of indicators of early diagnosis of hand, foot and mouth disease.

SUMO Modification Stabilizes Enterovirus 71 Polymerase 3D To Facilitate Viral Replication

PubMed Central

Liu, Yan; Shu, Bo; Meng, Jin; Zhang, Yuan; Zheng, Caishang; Ke, Xianliang; Gong, Peng; Hu, Qinxue; Wang, Hanzhong

2016-01-01

ABSTRACT Accumulating evidence suggests that viruses hijack cellular proteins to circumvent the host immune system. Ubiquitination and SUMOylation are extensively studied posttranslational modifications (PTMs) that play critical roles in diverse biological processes. Cross talk between ubiquitination and SUMOylation of both host and viral proteins has been reported to result in distinct functional consequences. Enterovirus 71 (EV71), an RNA virus belonging to the family Picornaviridae, is a common cause of hand, foot, and mouth disease. Little is known concerning how host PTM systems interact with enteroviruses. Here, we demonstrate that the 3D protein, an RNA-dependent RNA polymerase (RdRp) of EV71, is modified by small ubiquitin-like modifier 1 (SUMO-1) both during infection and in vitro. Residues K159 and L150/D151/L152 were responsible for 3D SUMOylation as determined by bioinformatics prediction combined with site-directed mutagenesis. Also, primer-dependent polymerase assays indicated that mutation of SUMOylation sites impaired 3D polymerase activity and virus replication. Moreover, 3D is ubiquitinated in a SUMO-dependent manner, and SUMOylation is crucial for 3D stability, which may be due to the interplay between the two PTMs. Importantly, increasing the level of SUMO-1 in EV71-infected cells augmented the SUMOylation and ubiquitination levels of 3D, leading to enhanced replication of EV71. These results together suggested that SUMO and ubiquitin cooperatively regulated EV71 infection, either by SUMO-ubiquitin hybrid chains or by ubiquitin conjugating to the exposed lysine residue through SUMOylation. Our study provides new insight into how a virus utilizes cellular pathways to facilitate its replication. IMPORTANCE Infection with enterovirus 71 (EV71) often causes neurological diseases in children, and EV71 is responsible for the majority of fatalities. Based on a better understanding of interplay between virus and host cell, antiviral drugs against enteroviruses may be developed. As a dynamic cellular process of posttranslational modification, SUMOylation regulates global cellular protein localization, interaction, stability, and enzymatic activity. However, little is known concerning how SUMOylation directly influences virus replication by targeting viral polymerase. Here, we found that EV71 polymerase 3D was SUMOylated during EV71 infection and in vitro. Moreover, the SUMOylation sites were determined, and in vitro polymerase assays indicated that mutations at SUMOylation sites could impair polymerase synthesis. Importantly, 3D is ubiquitinated in a SUMOylation-dependent manner that enhances the stability of the viral polymerase. Our findings indicate that the two modifications likely cooperatively enhance virus replication. Our study may offer a new therapeutic strategy against virus replication. PMID:27630238

Molecular Determinants of Enterovirus 71 Viral Entry

PubMed Central

Chen, Pan; Song, Zilin; Qi, Yonghe; Feng, Xiaofeng; Xu, Naiqing; Sun, Yinyan; Wu, Xing; Yao, Xin; Mao, Qunyin; Li, Xiuling; Dong, Wenjuan; Wan, Xiaobo; Huang, Niu; Shen, Xinliang; Liang, Zhenglun; Li, Wenhui

2012-01-01

Enterovirus 71 (EV71) is one of the major pathogens that cause hand, foot, and mouth disease outbreaks in young children in the Asia-Pacific region in recent years. Human scavenger receptor class B 2 (SCARB2) is the main cellular receptor for EV71 on target cells. The requirements of the EV71-SCARB2 interaction have not been fully characterized, and it has not been determined whether SCARB2 serves as an uncoating receptor for EV71. Here we compared the efficiency of the receptor from different species including human, horseshoe bat, mouse, and hamster and demonstrated that the residues between 144 and 151 are critical for SCARB2 binding to viral capsid protein VP1 of EV71 and seven residues from the human receptor could convert murine SCARB2, an otherwise inefficient receptor, to an efficient receptor for EV71 viral infection. We also identified that EV71 binds to SCARB2 via a canyon of VP1 around residue Gln-172. Soluble SCARB2 could convert the EV71 virions from 160 S to 135 S particles, indicating that SCARB2 is an uncoating receptor of the virus. The uncoating efficiency of SCARB2 significantly increased in an acidic environment (pH 5.6). These studies elucidated the viral capsid and receptor determinants of enterovirus 71 infection and revealed a possible target for antiviral interventions. PMID:22219187

Enterovirus 71 Outbreak, Brunei

PubMed Central

Sam, I-Ching; Yusof, Jaliha; Lim, Meng Keang; Misbah, Suzana; Hooi, Poh-Sim

2009-01-01

Enterovirus 71 (EV71) outbreaks occur periodically in the Asia-Pacific region. In 2006, Brunei reported its first major outbreak of EV71 infections, associated with fatalities from neurologic complications. Isolated EV71 strains formed a distinct lineage with low diversity within subgenogroup B5, suggesting recent introduction and rapid spread within Brunei. PMID:19116058

Co-circulation of multiple subtypes of enterovirus A71 (EV- A71) genotype C, including novel recombinants characterised by use of whole genome sequencing (WGS), Denmark 2016.

PubMed

Midgley, Sofie E; Nielsen, Astrid G; Trebbien, Ramona; Poulsen, Mille W; Andersen, Peter H; Fischer, Thea K

2017-06-29

In Europe, enterovirus A71 (EV-A71) has primarily been associated with sporadic cases of neurological disease. The recent emergence of new genotypes and larger outbreaks with severely ill patients demonstrates a potential for the spread of new, highly pathogenic EV-A71 strains. Detection and characterisation of these new emerging EV variants is challenging as standard EV assays may not be adequate, necessitating the use of whole genome analysis. This article is copyright of The Authors, 2017.

Severe paediatric conditions linked with EV-A71 and EV-D68, France, May to October 2016

PubMed Central

Antona, Denise; Kossorotoff, Manoëlle; Schuffenecker, Isabelle; Mirand, Audrey; Leruez-Ville, Marianne; Bassi, Clément; Aubart, Mélodie; Moulin, Florence; Lévy-Bruhl, Daniel; Henquell, Cécile; Lina, Bruno; Desguerre, Isabelle

2016-01-01

We report 59 cases of severe paediatric conditions linked with enterovirus (EV)-A71 and EV-D68 in France between May and October 2016. Fifty-two children had severe neurological symptoms. EV sequence-based typing for 42 cases revealed EV-A71 in 21 (18 subgenotype C1, detected for the first time in France) and EV-D68 in eight. Clinicians should be encouraged to obtain stool and respiratory specimens from patients presenting with severe neurological disorders for EV detection and characterisation. PMID:27918268

Pluripotent Human embryonic stem cell derived neural lineages for in vitro modelling of enterovirus 71 infection and therapy.

PubMed

Yap, May Shin; Tang, Yin Quan; Yeo, Yin; Lim, Wei Ling; Lim, Lee Wei; Tan, Kuan Onn; Richards, Mark; Othman, Iekhsan; Poh, Chit Laa; Heng, Boon Chin

2016-01-06

The incidence of neurological complications and fatalities associated with Hand, Foot & Mouth disease has increased over recent years, due to emergence of newly-evolved strains of Enterovirus 71 (EV71). In the search for new antiviral therapeutics against EV71, accurate and sensitive in vitro cellular models for preliminary studies of EV71 pathogenesis is an essential prerequisite, before progressing to expensive and time-consuming live animal studies and clinical trials. This study thus investigated whether neural lineages derived from pluripotent human embryonic stem cells (hESC) can fulfil this purpose. EV71 infection of hESC-derived neural stem cells (NSC) and mature neurons (MN) was carried out in vitro, in comparison with RD and SH-SY5Y cell lines. Upon assessment of post-infection survivability and EV71 production by the various types, it was observed that NSC were significantly more susceptible to EV71 infection compared to MN, RD (rhabdomyosarcoma) and SH-SY5Y cells, which was consistent with previous studies on mice. The SP81 peptide had significantly greater inhibitory effect on EV71 production by NSC and MN compared to the cancer-derived RD and SH-SY5Y cell lines. Hence, this study demonstrates that hESC-derived neural lineages can be utilized as in vitro models for studying EV71 pathogenesis and for screening of antiviral therapeutics.

Analysis of the synonymous codon usage bias in recently emerged enterovirus D68 strains.

PubMed

Karniychuk, Uladzimir U

2016-09-02

Understanding the codon usage pattern of a pathogen and relationship between pathogen and host's codon usage patterns has fundamental and applied interests. Enterovirus D68 (EV-D68) is an emerging pathogen with a potentially high public health significance. In the present study, the synonymous codon usage bias of 27 recently emerged, and historical EV-D68 strains was analyzed. In contrast to previously studied enteroviruses (enterovirus 71 and poliovirus), EV-D68 and human host have a high discrepancy between favored codons. Analysis of viral synonymous codon usage bias metrics, viral nucleotide/dinucleotide compositional parameters, and viral protein properties showed that mutational pressure is more involved in shaping the synonymous codon usage bias of EV-D68 than translation selection. Computation of codon adaptation indices allowed to estimate expression potential of the EV-D68 genome in several commonly used laboratory animals. This approach requires experimental validation and may provide an auxiliary tool for the rational selection of laboratory animals to model emerging viral diseases. Enterovirus D68 genome compositional and codon usage data can be useful for further pathogenesis, animal model, and vaccine design studies. Copyright © 2016 Elsevier B.V. All rights reserved.

Berberine inhibits enterovirus 71 replication by downregulating the MEK/ERK signaling pathway and autophagy.

PubMed

Wang, Huiqiang; Li, Ke; Ma, Linlin; Wu, Shuo; Hu, Jin; Yan, Haiyan; Jiang, Jiandong; Li, Yuhuan

2017-01-11

The MEK-ERK signaling pathway and autophagy play an important role for enterovirus71(EV71) replication. Inhibition of MEK-ERK signaling pathway and autophagy is shown to impair EV71 replication. Berberine (BBR), an isoquinoline alkaloid isolated from Berberis vulgaris L., has been reported to have ability to regulate this signaling pathway and autophagy. Herein, we want to determine whether berberine can inhibit EV71 infection by downregulating the MEK/ERK signaling pathway and autophagy. The antiviral effect of berberine was determined by cytopathic effect (CPE) assay, western blotting assay and qRT-PCR assay. The mechanism of BBR anti-virus was determined by western blotting assay and immunofluorescence assay. We showed that berberine does-dependently reduced EV71 RNA and protein synthesis, which was, at least in part, the result of inhibition of activation of MEK/ERK signaling pathway. Furthermore, we found that berberine suppressed the EV71-induced autophagy by activating AKT protein and inhibiting the phosphorylation of JNK and PI3KIII. BBR inhibited EV71 replication by downregulating autophagy and MEK/ERK signaling pathway. These findings suggest that BBR may be a potential agent or supplement against EV71 infection.

Rheum emodin inhibits enterovirus 71 viral replication and affects the host cell cycle environment

PubMed Central

Zhong, Ting; Zhang, Li-ying; Wang, Zeng-yan; Wang, Yue; Song, Feng-mei; Zhang, Ya-hong; Yu, Jing-hua

2017-01-01

Human enterovirus 71 (EV71) is the primary causative agent of recent large-scale outbreaks of hand, foot, and mouth disease (HFMD) in Asia. Currently, there are no drugs available for the prevention and treatment of HFMD. In this study, we compared the anti-EV71 activities of three natural compounds, rheum emodin, artemisinin and astragaloside extracted from Chinese herbs Chinese rhubarb, Artemisia carvifolia and Astragalus, respectively, which have been traditionally used for the treatment and prevention of epidemic diseases. Human lung fibroblast cell line MRC5 was mock-infected or infected with EV71, and treated with drugs. The cytotoxicity of the drugs was detected with MTT assay. The cytopathic effects such as cell death and condensed nuclei were morphologically observed. The VP1-coding sequence required for EV71 genome replication was assayed with qRT-PCR. Viral protein expression was analyzed with Western blotting. Viral TCID50 was determined to evaluate EV71 virulence. Flow cytometry analysis of propidium iodide staining was performed to analyze the cell cycle distribution of MRC5 cells. Rheum emodin (29.6 μmol/L) effectively protected MRC5 cells from EV71-induced cytopathic effects, which resulted from the inhibiting viral replication: rheum emodin treatment decreased viral genomic levels by 5.34-fold, viral protein expression by less than 30-fold and EV71 virulence by 0.33107-fold. The fact that inhibition of rheum emodin on viral virulence was much stronger than its effects on genomic levels and viral protein expression suggested that rheum emodin inhibited viral maturation. Furthermore, rheum emodin treatment markedly diminished cell cycle arrest at S phase in MRC5 cells, which was induced by EV71 infection and favored the viral replication. In contrast, neither astragaloside (50 μmol/L) nor artemisinin (50 μmol/L) showed similar anti-EV71 activities. Among the three natural compounds tested, rheum emodin effectively suppressed EV71 viral replication, thus is a candidate anti-HFMD drug. PMID:27840410

Rheum emodin inhibits enterovirus 71 viral replication and affects the host cell cycle environment.

PubMed

Zhong, Ting; Zhang, Li-Ying; Wang, Zeng-Yan; Wang, Yue; Song, Feng-Mei; Zhang, Ya-Hong; Yu, Jing-Hua

2017-03-01

Human enterovirus 71 (EV71) is the primary causative agent of recent large-scale outbreaks of hand, foot, and mouth disease (HFMD) in Asia. Currently, there are no drugs available for the prevention and treatment of HFMD. In this study, we compared the anti-EV71 activities of three natural compounds, rheum emodin, artemisinin and astragaloside extracted from Chinese herbs Chinese rhubarb, Artemisia carvifolia and Astragalus, respectively, which have been traditionally used for the treatment and prevention of epidemic diseases. Human lung fibroblast cell line MRC5 was mock-infected or infected with EV71, and treated with drugs. The cytotoxicity of the drugs was detected with MTT assay. The cytopathic effects such as cell death and condensed nuclei were morphologically observed. The VP1-coding sequence required for EV71 genome replication was assayed with qRT-PCR. Viral protein expression was analyzed with Western blotting. Viral TCID50 was determined to evaluate EV71 virulence. Flow cytometry analysis of propidium iodide staining was performed to analyze the cell cycle distribution of MRC5 cells. Rheum emodin (29.6 μmol/L) effectively protected MRC5 cells from EV71-induced cytopathic effects, which resulted from the inhibiting viral replication: rheum emodin treatment decreased viral genomic levels by 5.34-fold, viral protein expression by less than 30-fold and EV71 virulence by 0.33107-fold. The fact that inhibition of rheum emodin on viral virulence was much stronger than its effects on genomic levels and viral protein expression suggested that rheum emodin inhibited viral maturation. Furthermore, rheum emodin treatment markedly diminished cell cycle arrest at S phase in MRC5 cells, which was induced by EV71 infection and favored the viral replication. In contrast, neither astragaloside (50 μmol/L) nor artemisinin (50 μmol/L) showed similar anti-EV71 activities. Among the three natural compounds tested, rheum emodin effectively suppressed EV71 viral replication, thus is a candidate anti-HFMD drug.

Molecular epidemiology of enterovirus 71 infection in the central region of Taiwan from 2002 to 2012.

PubMed

Wu, Wen-Hao; Kuo, Ta-Cheng; Lin, Yu-Ting; Huang, Szu-Wei; Liu, Hsin-Fu; Wang, John; Chen, Yi-Ming Arthur

2013-01-01

Enterovirus 71 (EV71), a causative agent of hand, foot, and mouth disease can be classified into three genotypes and many subtypes. The objectives of this study were to conduct a molecular epidemiological study of EV71 in the central region of Taiwan from 2002-2012 and to test the hypothesis that whether the alternative appearance of different EV71 subtypes in Taiwan is due to transmission from neighboring countries or from re-emergence of pre-existing local strains. We selected 174 EV71 isolates and used reverse transcription-polymerase chain reaction to amplify their VP1 region for DNA sequencing. Phylogenetic analyses were conducted using Neighbor-Joining, Maximum Likelihood and Bayesian methods. We found that the major subtypes of EV71 in Taiwan were B4 for 2002 epidemic, C4 for 2004-2005 epidemic, B5 for 2008-2009 epidemic, C4 for 2010 epidemic and B5 for 2011-2012 epidemic. Phylogenetic analysis demonstrated that the 2002 and 2008 epidemics were associated with EV71 from Malaysia and Singapore; while both 2010 and 2011-2012 epidemics originated from different regions of mainland China including Shanghai, Henan, Xiamen and Gong-Dong. Furthermore, minor strains have been identified in each epidemic and some of them were correlated with the subsequent outbreaks. Therefore, the EV71 infection in Taiwan may originate from pre-existing minor strains or from other regions in Asia including mainland China. In addition, 101 EV71 isolates were selected for the detection of new recombinant strains using the nucleotide sequences spanning the VP1-2A-2B region. No new recombinant strain was found. Analysis of clinical manifestations showed that patients infected with C4 had significantly higher rates of pharyngeal vesicles or ulcers than patients infected with B5. This is the first study demonstrating that different EV 71 genotypes may have different clinical manifestations and the association of EV71 infections between Taiwan and mainland China.

Severe paediatric conditions linked with EV-A71 and EV-D68, France, May to October 2016.

PubMed

Antona, Denise; Kossorotoff, Manoëlle; Schuffenecker, Isabelle; Mirand, Audrey; Leruez-Ville, Marianne; Bassi, Clément; Aubart, Mélodie; Moulin, Florence; Lévy-Bruhl, Daniel; Henquell, Cécile; Lina, Bruno; Desguerre, Isabelle

2016-11-17

We report 59 cases of severe paediatric conditions linked with enterovirus (EV)-A71 and EV-D68 in France between May and October 2016. Fifty-two children had severe neurological symptoms. EV sequence-based typing for 42 cases revealed EV-A71 in 21 (18 subgenotype C1, detected for the first time in France) and EV-D68 in eight. Clinicians should be encouraged to obtain stool and respiratory specimens from patients presenting with severe neurological disorders for EV detection and characterisation. This article is copyright of The Authors, 2016.

Effect of Meteorological Conditions and Geographical Factors in the Onset of Enterovirus 71

NASA Astrophysics Data System (ADS)

Chen, Yu-An; Yu, Hwa-Lung

2015-04-01

Since it was first recognized in California in 1969, enterovirus 71 (EV71) infection has been a significant cause of neurological disorder and death in children worldwide. In 1998 a historic epidemic of EV71 infection caused hand-foot-and-mouth disease and herpangina in thousands of people in Taiwan. The impact of EV71 infection is greatest during the summer months in Asia, and epidemics recur with a seasonal pattern. It was reported that seasonal patterns of EV71 differed by geographical localities. Previous studies have also showed significant relationships between meteorological variables, in particular, temperature and relative humidity, and the seasonal epidemic patterns of EV71. However, important issues that remain unclear include the spatiotemporal pattern of the EV71 outbreaks in Taiwan, and what role of favorable meteorological conditions in the transmission of the disease in the space-time domain. Thus, this study used a semiparametric generalized additive model (GAM) to understand the association between EV71 and meteorological factors across space and time. This study utilized a population-based database containing space-time data for clinic and hospital visits (i.e., hospital location and appointment times) of EV71 occurring in children less than 18 years old in Taipei from 1998 to 2008. Meteorological data (i.e., temperature, rainfall, and relative humidity) for the study period were provided by the Taiwan Central Weather Bureau. This study expect to find out an important meteorological factor and threshold.

The life cycle of non-polio enteroviruses and how to target it.

PubMed

Baggen, Jim; Thibaut, Hendrik Jan; Strating, Jeroen R P M; van Kuppeveld, Frank J M

2018-06-01

The genus Enterovirus (EV) of the family Picornaviridae includes poliovirus, coxsackieviruses, echoviruses, numbered enteroviruses and rhinoviruses. These diverse viruses cause a variety of diseases, including non-specific febrile illness, hand-foot-and-mouth disease, neonatal sepsis-like disease, encephalitis, paralysis and respiratory diseases. In recent years, several non-polio enteroviruses (NPEVs) have emerged as serious public health concerns. These include EV-A71, which has caused epidemics of hand-foot-and-mouth disease in Southeast Asia, and EV-D68, which recently caused a large outbreak of severe lower respiratory tract disease in North America. Infections with these viruses are associated with severe neurological complications. For decades, most research has focused on poliovirus, but in recent years, our knowledge of NPEVs has increased considerably. In this Review, we summarize recent insights from enterovirus research with a special emphasis on NPEVs. We discuss virion structures, host-receptor interactions, viral uncoating and the recent discovery of a universal enterovirus host factor that is involved in viral genome release. Moreover, we briefly explain the mechanisms of viral genome replication, virion assembly and virion release, and describe potential targets for antiviral therapy. We reflect on how these recent discoveries may help the development of antiviral therapies and vaccines.

Enterovirus 71 induces anti-viral stress granule-like structures in RD cells.

PubMed

Zhu, Yuanmei; Wang, Bei; Huang, He; Zhao, Zhendong

2016-08-05

Stress granules (SGs) are dynamic cytoplasmic granules formed in response to a variety of stresses, including viral infection. Several viruses can modulate the formation of SG with different effects, but the relationship between SG formation and EV71 infection is poorly understood. In this study, we report that EV71 inhibits canonical SGs formation in infected cells and induces the formation of novel RNA granules that were distinguished from canonical SGs in composition and morphology, which we termed 'SG like structures'. Our results also demonstrated that EV71 triggered formation of SG-like structures is dependent on PKR and eIF2α phosphorylation and requires ongoing cellular mRNA synthesis. Finally, we found that SG-like structures are antiviral RNA granules that promote cellular apoptosis and suppress EV71 propagation. Taken together, our findings explain the formation mechanism of SG-like structures induced by EV71 and shed light on virus-host interaction and molecular mechanism underlying EV71 pathogenesis. Copyright © 2016. Published by Elsevier Inc.

Immunopathogenesis and Virus–Host Interactions of Enterovirus 71 in Patients with Hand, Foot and Mouth Disease

PubMed Central

Cox, Jonathan A.; Hiscox, Julian A.; Solomon, Tom; Ooi, Mong-How; Ng, Lisa F. P.

2017-01-01

Enterovirus 71 (EV71) is a global infectious disease that affects millions of people. The virus is the main etiological agent for hand, foot, and mouth disease with outbreaks and epidemics being reported globally. Infection can cause severe neurological, cardiac, and respiratory problems in children under the age of 5. Despite on-going efforts, little is known about the pathogenesis of EV71, how the host immune system responds to the virus and the molecular mechanisms behind these responses. Moreover, current animal models remain limited, because they do not recapitulate similar disease patterns and symptoms observed in humans. In this review the role of the host–viral interactions of EV71 are discussed together with the various models available to examine: how EV71 utilizes its proteins to cleave host factors and proteins, aiding virus replication; how EV71 uses its own viral proteins to disrupt host immune responses and aid in its immune evasion. These discoveries along with others, such as the EV71 crystal structure, have provided possible targets for treatment and drug interventions. PMID:29238324

New Introductions of Enterovirus 71 Subgenogroup C4 Strains, France, 2012

PubMed Central

Henquell, Cécile; Mirand, Audrey; Coste-Burel, Marianne; Marque-Juillet, Stéphanie; Desbois, Delphine; Lagathu, Gisèle; Bornebusch, Laure; Bailly, Jean-Luc; Lina, Bruno

2014-01-01

In France during 2012, human enterovirus 71 (EV-A71) subgenogroup C4 strains were detected in 4 children hospitalized for neonatal fever or meningitis. Phylogenetic analysis showed novel and independent EV-A71 introductions, presumably from China, and suggested circulation of C4 strains throughout France. This observation emphasizes the need for monitoring EV-A71 infections in Europe. PMID:25061698

Epidemiology and seroepidemiology of human enterovirus 71 among Thai populations

PubMed Central

2014-01-01

Background Human enterovirus 71 (EV71) is an important pathogen caused large outbreaks in Asian-Pacific region with severe neurological complications and may lead to death in young children. Understanding of the etiological spectrum and epidemic changes of enterovirus and population’s immunity against EV71 are crucial for the implementation of future therapeutic and prophylactic intervention. Results A total of 1,182 patients who presented with the symptoms of hand foot and mouth disease (67.3%) or herpangina (HA) (16.7%) and admitted to the hospitals during 2008-2013 were tested for enterovirus using pan-enterovirus PCR targeting 5′-untranslated region and specific PCR for viral capsid protein 1 gene. Overall, 59.7% were pan-enterovirus positive comprising 9.1% EV71 and 31.2% coxsackievirus species A (CV-A) including 70.5% CV-A6, 27.6% CV-A16, 1.1% CV-A10, and 0.8% CV-A5. HFMD and HA occurred endemically during 2008-2011. The number of cases increased dramatically in June 2012 with the percentage of the recently emerged CV-A6 significantly rose to 28.4%. Co-circulation between different EV71 genotypes was observed during the outbreak. Total of 161 sera obtained from healthy individuals were tested for neutralizing antibodies (NAb) against EV71 subgenotype B5 (EV71-B5) using microneutralization assay. The seropositive rate of EV71-B5 was 65.8%. The age-adjusted seroprevalence for individuals was found to be lowest in children aged >6 months to 2 years (42.5%). The seropositive rate remained relatively low in preschool children aged > 2 years to 6 years (48.3%) and thereafter increased sharply to more than 80% in individuals aged > 6 years. Conclusions This study describes longitudinal data reflecting changing patterns of enterovirus prevalence over 6 years and demonstrates high seroprevalences of EV71-B5 NAb among Thai individuals. The rate of EV71 seropositive increased with age but without gender-specific significant difference. We identified that relative lower EV71 seropositive rate in early 2012 may demonstrate widely presented of EV71-B5 in the population before account for a large outbreak scale epidemic occurred in 2012 with due to a relatively high susceptibility of the younger population. PMID:24548776

Genetic evolution of Human Enterovirus A71 subgenotype C4 in Shenzhen, China, 1998-2013.

PubMed

He, Yaqing; Zou, Linjie; Chong, Marc Ka Chun; Men, Ruoting; Xu, Wenbo; Yang, Hong; Yao, Xiangjie; Chen, Long; Xian, Huixia; Zhang, Hailong; Luo, Min; Cheng, Jinquan; Ma, Hanwu; Feng, Qianjin; Huang, Yun; Wang, Yujie; Yeoh, Eng-Kiong; Zee, Benny Chung-Ying; Zhou, Yuanping; He, Ming-Liang; Wang, Maggie Haitian

2016-06-01

Human Enterovirus A71 (EV-A71) is one of the severest enteroviruses that causes hand, foot, and mouth disease (HFMD) among children. This study identified the mutations of EV-A71 VP1 amino acid residues over a number of years and explored the possible association of identified mutations and HFMD epidemic outbreaks in Shenzhen, China. A total of 3760 stool specimens were collected from HFMD patients by Shenzhen Centers for Disease Control and Prevention (CDC) between 1998 and 2013. In total 289 VP1 strains were sequenced in this study, and amino acids mutation frequency was calculated. There were 2040 China nationwide sequences downloaded from Genebank as replication data. In our samples, 1036 subjects (27.6%) were EV-A71 infected. Three amino acid positions on VP1 protein were found to have high mutation prevalence. These are Q22H, S283T, and A289H. Site 22 showed a fast mutation fixation in the year 2008, at the time of the large scale epidemic outbreak in Shenzhen. Analysis of the nationwide data replicated the same trend of mutation prevalence of the three sites. The switching from Q to H on site 22 of the EV-A71 VP1 strain might be associated with the HFMD outbreak in Shenzhen in 2008. The identified amino acid sites 22, 283 and 289 provided information for developing anti-viral drugs against EV-A71 in the future. Copyright © 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Genetic Characterization of Enterovirus A71 Circulating in Africa.

PubMed

Fernandez-Garcia, Maria Dolores; Volle, Romain; Joffret, Marie-Line; Sadeuh-Mba, Serge Alain; Gouandjika-Vasilache, Ionela; Kebe, Ousmane; Wiley, Michael R; Majumdar, Manasi; Simon-Loriere, Etienne; Sakuntabhai, Anavaj; Palacios, Gustavo; Martin, Javier; Delpeyroux, Francis; Ndiaye, Kader; Bessaud, Maël

2018-04-01

We analyzed whole-genome sequences of 8 enterovirus A71 isolates (EV-A71). We confirm the circulation of genogroup C and the new genogroup E in West Africa. Our analysis demonstrates wide geographic circulation and describes genetic exchanges between EV-A71 and autochthonous EV-A that might contribute to the emergence of pathogenic lineages.

Genetic Characterization of Enterovirus A71 Circulating in Africa

PubMed Central

Volle, Romain; Joffret, Marie-Line; Sadeuh-Mba, Serge Alain; Gouandjika-Vasilache, Ionela; Kebe, Ousmane; Wiley, Michael R.; Majumdar, Manasi; Simon-Loriere, Etienne; Sakuntabhai, Anavaj; Palacios, Gustavo; Martin, Javier; Delpeyroux, Francis; Ndiaye, Kader; Bessaud, Maël

2018-01-01

We analyzed whole-genome sequences of 8 enterovirus A71 isolates (EV-A71). We confirm the circulation of genogroup C and the new genogroup E in West Africa. Our analysis demonstrates wide geographic circulation and describes genetic exchanges between EV-A71 and autochthonous EV-A that might contribute to the emergence of pathogenic lineages. PMID:29553325

[Distribution of human enterovirus 71 in brainstem of infants with brain stem encephalitis and infection mechanism].

PubMed

Hao, Bo; Gao, Di; Tang, Da-Wei; Wang, Xiao-Guang; Liu, Shui-Ping; Kong, Xiao-Ping; Liu, Chao; Huang, Jing-Lu; Bi, Qi-Ming; Quan, Li; Luo, Bin

2012-04-01

To explore the mechanism that how human enterovirus 71 (EV71) invades the brainstem and how intercellular adhesion molecules-1 (ICAM-1) participates by analyzing the expression and distribution of human EV71, and ICAM-1 in brainstem of infants with brain stem encephalitis. Twenty-two brainstem of infants with brain stem encephalitis were collected as the experimental group and 10 brainstems of fatal congenital heart disease were selected as the control group. The sections with perivascular cuffings were selected to observe EV71-VP1 expression by immunohistochemistry method and ICAM-1 expression was detected for the sections with EV71-VP1 positive expression. The staining image analysis and statistics analysis were performed. The experiment and control groups were compared. (1) EV71-VP1 positive cells in the experimental group were mainly astrocytes in brainstem with nigger-brown particles, and the control group was negative. (2) ICAM-1 positive cells showed nigger-brown. The expression in inflammatory cells (around blood vessels of brain stem and in glial nodules) and gliocytes increased. The results showed statistical difference comparing with control group (P < 0.05). The brainstem encephalitis can be used to diagnose fatal EV71 infection in infants. EV71 can invade the brainstem via hematogenous route. ICAM-1 may play an important role in the pathogenic process.

Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

PubMed Central

Lei, Xiaobo; Zhang, Zhenzhen; Xiao, Xia; Qi, Jianli

2017-01-01

ABSTRACT Enterovirus 71 (EV71) can cause hand-foot-and-mouth disease (HFMD) in young children. Severe infection with EV71 can lead to neurological complications and even death. However, the molecular basis of viral pathogenesis remains poorly understood. Here, we report that EV71 induces degradation of gasdermin D (GSDMD), an essential component of pyroptosis. Remarkably, the viral protease 3C directly targets GSDMD and induces its cleavage, which is dependent on the protease activity. Further analyses show that the Q193-G194 pair within GSDMD is the cleavage site of 3C. This cleavage produces a shorter N-terminal fragment spanning amino acids 1 to 193 (GSDMD1–193). However, unlike the N-terminal fragment produced by caspase-1 cleavage, this fragment fails to trigger cell death or inhibit EV71 replication. Importantly, a T239D or F240D substitution abrogates the activity of GSDMD consisting of amino acids 1 to 275 (GSDMD1–275). This is correlated with the lack of pyroptosis or inhibition of viral replication. These results reveal a previously unrecognized strategy for EV71 to evade the antiviral response. IMPORTANCE Recently, it has been reported that GSDMD plays a critical role in regulating lipopolysaccharide and NLRP3-mediated interleukin-1β (IL-1β) secretion. In this process, the N-terminal domain of p30 released from GSDMD acts as an effector in cell pyroptosis. We show that EV71 infection downregulates GSDMD. EV71 3C cleaves GSDMD at the Q193-G194 pair, resulting in a truncated N-terminal fragment disrupted for inducing cell pyroptosis. Notably, GSDMD1–275 (p30) inhibits EV71 replication whereas GSDMD1–193 does not. These results reveal a new strategy for EV71 to evade the antiviral response. PMID:28679757

Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D.

PubMed

Lei, Xiaobo; Zhang, Zhenzhen; Xiao, Xia; Qi, Jianli; He, Bin; Wang, Jianwei

2017-09-15

Enterovirus 71 (EV71) can cause hand-foot-and-mouth disease (HFMD) in young children. Severe infection with EV71 can lead to neurological complications and even death. However, the molecular basis of viral pathogenesis remains poorly understood. Here, we report that EV71 induces degradation of gasdermin D (GSDMD), an essential component of pyroptosis. Remarkably, the viral protease 3C directly targets GSDMD and induces its cleavage, which is dependent on the protease activity. Further analyses show that the Q193-G194 pair within GSDMD is the cleavage site of 3C. This cleavage produces a shorter N-terminal fragment spanning amino acids 1 to 193 (GSDMD 1-193 ). However, unlike the N-terminal fragment produced by caspase-1 cleavage, this fragment fails to trigger cell death or inhibit EV71 replication. Importantly, a T239D or F240D substitution abrogates the activity of GSDMD consisting of amino acids 1 to 275 (GSDMD 1-275 ). This is correlated with the lack of pyroptosis or inhibition of viral replication. These results reveal a previously unrecognized strategy for EV71 to evade the antiviral response. IMPORTANCE Recently, it has been reported that GSDMD plays a critical role in regulating lipopolysaccharide and NLRP3-mediated interleukin-1β (IL-1β) secretion. In this process, the N-terminal domain of p30 released from GSDMD acts as an effector in cell pyroptosis. We show that EV71 infection downregulates GSDMD. EV71 3C cleaves GSDMD at the Q193-G194 pair, resulting in a truncated N-terminal fragment disrupted for inducing cell pyroptosis. Notably, GSDMD 1-275 (p30) inhibits EV71 replication whereas GSDMD 1-193 does not. These results reveal a new strategy for EV71 to evade the antiviral response. Copyright © 2017 American Society for Microbiology.

Current status of anti-picornavirus therapies.

PubMed

Barnard, Dale L

2006-01-01

Picornaviruses are important human pathogens causing severe morbidity and some mortality with the potential to cause worldwide crippling disease. Currently, there are few treatments for many of the viruses in the Picornaviridae, For rhinoviruses, there are no approved treatments, although ruprintrivir looks promising in clinical trials and pyridazinyl oxime ethers may prove useful. Poliovirus treatments are needed to supplement the World Health Organization's polio eradication plan in order to treat infections caused by reversion of the attenuated vaccine virus and to supplement vaccine coverage control in polio endemic areas. However, no promising compounds for treatment of poliovirus have been developed due to the efficacy of the vaccines in use. Broad-spectrum inhibitors developed for other picornavirus may be useful for poliovirus infections. Coxsackievirus infections in children and in infants are being treated with pleconaril with some efficacy in reducing mortality and improving recovery, albeit the treatment is often on a compassionate use basis. There are no therapies for echovirus infections. Very little drug discovery research is being done to develop inhibitors for echovirus infections, probably due to the broad-spectrum inhibition exhibited by capsid binding agents and protease inhibitors discovered for treatment of other picornaviruses. For example, pyridazinyl oxime ethers are inhibitory to most echoviruses. Treatments for enterovirus infections are also limited, although in a small clinical trial, milrinone seemed to reduce mortality and improve recovery from EV71-induced pulmonary edema. Thus, these results strongly emphasize the need for the development of potent and nontoxic compounds for the treatment of picornavirus infections.

Enterovirus 71 infection of human airway organoids reveals VP1-145 as a viral infectivity determinant.

PubMed

van der Sanden, Sabine M G; Sachs, Norman; Koekkoek, Sylvie M; Koen, Gerrit; Pajkrt, Dasja; Clevers, Hans; Wolthers, Katja C

2018-05-09

Human enteroviruses frequently cause severe diseases in children. Human enteroviruses are transmitted via the fecal-oral route and respiratory droplets, and primary replication occurs in the gastro-intestinal and respiratory tracts; however, how enteroviruses infect these sites is largely unknown. Human intestinal organoids have recently proven to be valuable tools for studying enterovirus-host interactions in the intestinal tract. In this study, we demonstrated the susceptibility of a newly developed human airway organoid model for enterovirus 71 (EV71) infection. We showed for the first time in a human physiological model that EV71 replication kinetics are strain-dependent. A glutamine at position 145 of the VP1 capsid protein was identified as a key determinant of infectivity, and residues VP1-98K and VP1-104D were identified as potential infectivity markers. The results from this study provide new insights into EV71 infectivity in the human airway epithelia and demonstrate the value of organoid technology for virus research.

Reemergence of enterovirus 71 epidemic in northern Taiwan, 2012.

PubMed

Luo, Shu-Ting; Chiang, Pai-Shan; Chung, Wan-Yu; Chia, Min-Yuan; Tsao, Kuo-Chien; Wang, Ying-Hsiang; Lin, Tzou-Yien; Lee, Min-Shi

2015-01-01

Enterovirus 71 (EV71) belongs to picornavirus family and could be classified phylogenetically into three major genogroups (A, B and C) including 11 genotypes (A, B1-B5 and C1-C5). Since 1997, EV71 has caused large-scale of epidemics with neurological complications in Asian children. In Taiwan, nationwide EV71 epidemics with different predominant genotypes have occurred cyclically since 1998. A nationwide EV71 epidemic occurred again in 2012. We conducted genetic and antigenic characterizations of the 2012 epidemic. Chang Gung Memorial Hospital (CGMH) is a medical center in northern Taiwan. In CGMH, specimens were collected from pediatric inpatients with suspected enterovirus infections for virus isolation. Enterovirus isolates were serotyped and genotyped and sera from EV71 inpatients were collected for measuring neutralizing antibody titers. There were 10, 16 and 99 EV71 inpatients identified in 2010, 2011 and 2012, respectively. There were 82 EV71 isolates genotyped, which identified 17 genotype C4a viruses and 65 genotype B5 viruses. The genotype B5 viruses were not detected until November 2011 and caused epidemics in 2012. Interestingly, the B5-2011 viruses were genetically distinguishable from the B5 viruses causing the 2008 epidemic and are likely introduced from China or Southeastern Asia. Based on antigenic analysis, minor antigenic variations were detected among the B5-2008, B5-2011, C4a-2008 and C4a-2012 viruses but these viruses antigenically differed from genotype A. Genotype B5 and C4a viruses antigenically differ from genotype A viruses which have disappeared globally for 30 years but have been detected in China since 2008. Enterovirus surveillance should monitor genetic and antigenic variations of EV71.

Changes in the EV-A71 Genome through Recombination and Spontaneous Mutations: Impact on Virulence.

PubMed

Mandary, Madiiha Bibi; Poh, Chit Laa

2018-06-12

Enterovirus 71 (EV-A71) is a major etiological agent of hand, foot and mouth disease (HFMD) that mainly affects young children less than five years old. The onset of severe HFMD is due to neurological complications bringing about acute flaccid paralysis and pulmonary oedema. In this review, we address how genetic events such as recombination and spontaneous mutations could change the genomic organization of EV-A71, leading to an impact on viral virulence. An understanding of the recombination mechanism of the poliovirus and non-polio enteroviruses will provide further evidence of the emergence of novel strains responsible for fatal HFMD outbreaks. We aim to see if the virulence of EV-A71 is contributed solely by the presence of fatal strains or is due to the co-operation of quasispecies within a viral population. The phenomenon of quasispecies within the poliovirus is discussed to reflect viral fitness, virulence and its implications for EV-A71. Ultimately, this review gives an insight into the evolution patterns of EV-A71 by looking into its recombination history and how spontaneous mutations would affect its virulence.

COPI Is Required for Enterovirus 71 Replication

PubMed Central

Wang, Jianmin; Wu, Zhiqiang; Jin, Qi

2012-01-01

Enterovirus 71 (EV71), a member of the Picornaviridae family, is found in Asian countries where it causes a wide range of human diseases. No effective therapy is available for the treatment of these infections. Picornaviruses undergo RNA replication in association with membranes of infected cells. COPI and COPII have been shown to be involved in the formation of picornavirus-induced vesicles. Replication of several picornaviruses, including poliovirus and Echovirus 11 (EV11), is dependent on COPI or COPII. Here, we report that COPI, but not COPII, is required for EV71 replication. Replication of EV71 was inhibited by brefeldin A and golgicide A, inhibitors of COPI activity. Furthermore, we found EV71 2C protein interacted with COPI subunits by co-immunoprecipitation and GST pull-down assay, indicating that COPI coatomer might be directed to the viral replication complex through viral 2C protein. Additionally, because the pathway is conserved among different species of enteroviruses, it may represent a novel target for antiviral therapies. PMID:22662263

External quality assessment for enterovirus 71 and coxsackievirus A16 detection by reverse transcription-PCR using armored RNA as a virus surrogate.

PubMed

Song, Liqiong; Sun, Shipeng; Li, Bo; Pan, Yang; Li, Wenli; Zhang, Kuo; Li, Jinming

2011-10-01

Three armored RNAs (virus-like particles [VLPs]) containing target sequences from enterovirus 71 (EV71) and coxsackievirus A16 (CA16) and a pan-enterovirus (pan-EV) sequence were constructed and used in an external quality assessment (EQA) to determine the performance of laboratories in the detection of EV71 and CA16. The EQA panel, which consisted of 20 samples, including 14 positive samples with different concentrations of EV and either EV71 or CA16 armored RNAs, 2 samples with all 3 armored RNAs, and 4 negative-control samples (NaN(3)-preserved minimal essential medium [MEM] without VLPs), was distributed to 54 laboratories that perform molecular diagnosis of hand, foot, and mouth disease (HFMD) virus infections. A total of 41 data sets from 41 participants were returned; 5 (12.2%) were generated using conventional in-house reverse transcription-PCR (RT-PCR) assays, and 36 (87.8%) were generated using commercial real-time RT-PCR assays. Performance assessments of laboratories differed; 12 (29.3%) showed a need for improvement. Surprisingly, 4 laboratories were unable to detect EV71 RNA in any samples, even those containing the highest concentration of 10(7) IU/ml. Furthermore, the detection sensitivity for EV71 among all laboratories (82.1%) was substantially lower than that for EV (97.4%) or CA16 (95.1%). Overall, the results of the present study indicate that EQA should be performed periodically to help laboratories monitor their ability to detect HFMD viruses and to improve the comparability of results from different laboratories.

External Quality Assessment for Enterovirus 71 and Coxsackievirus A16 Detection by Reverse Transcription-PCR Using Armored RNA as a Virus Surrogate▿†

PubMed Central

Song, Liqiong; Sun, Shipeng; Li, Bo; Pan, Yang; Li, Wenli; Zhang, Kuo; Li, Jinming

2011-01-01

Three armored RNAs (virus-like particles [VLPs]) containing target sequences from enterovirus 71 (EV71) and coxsackievirus A16 (CA16) and a pan-enterovirus (pan-EV) sequence were constructed and used in an external quality assessment (EQA) to determine the performance of laboratories in the detection of EV71 and CA16. The EQA panel, which consisted of 20 samples, including 14 positive samples with different concentrations of EV and either EV71 or CA16 armored RNAs, 2 samples with all 3 armored RNAs, and 4 negative-control samples (NaN3-preserved minimal essential medium [MEM] without VLPs), was distributed to 54 laboratories that perform molecular diagnosis of hand, foot, and mouth disease (HFMD) virus infections. A total of 41 data sets from 41 participants were returned; 5 (12.2%) were generated using conventional in-house reverse transcription-PCR (RT-PCR) assays, and 36 (87.8%) were generated using commercial real-time RT-PCR assays. Performance assessments of laboratories differed; 12 (29.3%) showed a need for improvement. Surprisingly, 4 laboratories were unable to detect EV71 RNA in any samples, even those containing the highest concentration of 107 IU/ml. Furthermore, the detection sensitivity for EV71 among all laboratories (82.1%) was substantially lower than that for EV (97.4%) or CA16 (95.1%). Overall, the results of the present study indicate that EQA should be performed periodically to help laboratories monitor their ability to detect HFMD viruses and to improve the comparability of results from different laboratories. PMID:21865426

MicroRNA-302 Cluster Downregulates Enterovirus 71-Induced Innate Immune Response by Targeting KPNA2.

PubMed

Peng, Nanfang; Yang, Xuecheng; Zhu, Chengliang; Zhou, Li; Yu, Haisheng; Li, Mengqi; Lin, Yong; Wang, Xueyu; Li, Qian; She, Yinglong; Wang, Jun; Zhao, Qian; Lu, Mengji; Zhu, Ying; Liu, Shi

2018-05-18

Enterovirus 71 (EV71) induces significantly elevated levels of cytokines and chemokines, leading to local or systemic inflammation and severe complications. As shown in our previous study, microRNA (miR) 302c regulates influenza A virus-induced IFN expression by targeting NF-κB-inducing kinase. However, little is known about the role of the miR-302 cluster in EV71-mediated proinflammatory responses. In this study, we found that the miR-302 cluster controls EV71-induced cytokine expression. Further studies demonstrated that karyopherin α2 (KPNA2) is a direct target of the miR-302 cluster. Interestingly, we also found that EV71 infection upregulates KPNA2 expression by downregulating miR-302 cluster expression. Upon investigating the mechanisms behind this event, we found that KPNA2 intracellularly associates with JNK1/JNK2 and p38, leading to translocation of those transcription factors from the cytosol into the nucleus. In EV71-infected patients, miR-302 cluster expression was downregulated and KPNA2 expression was upregulated compared with controls, and their expression levels were closely correlated. Taken together, our work establishes a link between the miR-302/ KPNA2 axis and EV71-induced cytokine expression and represents a promising target for future antiviral therapy. Copyright © 2018 by The American Association of Immunologists, Inc.

Serological detection and analysis of anti-VP1 responses against various enteroviruses (EV) (EV-A, EV-B and EV-C) in Chinese individuals.

PubMed

Gao, Caixia; Ding, Yingying; Zhou, Peng; Feng, Jiaojiao; Qian, Baohua; Lin, Ziyu; Wang, Lili; Wang, Jinhong; Zhao, Chunyan; Li, Xiangyu; Cao, Mingmei; Peng, Heng; Rui, Bing; Pan, Wei

2016-02-26

The overall serological prevalence of EV infections based on ELISA remains unknown. In the present study, the antibody responses against VP1 of the EV-A species (enterovirus 71 (EV71), Coxsackievirus A16 (CA16), Coxsackievirus A5 (CA5) and Coxsackievirus A6 (CA6)), of the EV-B species (Coxsackievirus B3 (CB3)), and of the EV-C species (Poliovirus 1 (PV1)) were detected and analyzed by a NEIBM (novel evolved immunoglobulin-binding molecule)-based ELISA in Shanghai blood donors. The serological prevalence of anti-CB3 VP1 antibodies was demonstrated to show the highest level, with anti-PV1 VP1 antibodies at the second highest level, and anti-CA5, CA6, CA16 and EV71 VP1 antibodies at a comparatively low level. All reactions were significantly correlated at different levels, which were approximately proportional to their sequence similarities. Antibody responses against EV71 VP1 showed obvious differences with responses against other EV-A viruses. Obvious differences in antibody responses between August 2013 and May 2014 were revealed. These findings are the first to describe the detailed information of the serological prevalence of human antibody responses against the VP1 of EV-A, B and C viruses, and could be helpful for understanding of the ubiquity of EV infections and for identifying an effective approach for seroepidemiological surveillance based on ELISA.

Human rhinoviruses and enteroviruses in influenza-like illness in Latin America

PubMed Central

2013-01-01

Background Human rhinoviruses (HRVs) belong to the Picornaviridae family with high similarity to human enteroviruses (HEVs). Limited data is available from Latin America regarding the clinical presentation and strains of these viruses in respiratory disease. Methods We collected nasopharyngeal swabs at clinics located in eight Latin American countries from 3,375 subjects aged 25 years or younger who presented with influenza-like illness. Results Our subjects had a median age of 3 years and a 1.2:1.0 male:female ratio. HRV was identified in 16% and HEV was identified in 3%. HRVs accounted for a higher frequency of isolates in those of younger age, in particular children < 1 years old. HRV-C accounted for 38% of all HRVs detected. Phylogenetic analysis revealed a high proportion of recombinant strains between HRV-A/HRV-C and between HEV-A/HEV-B. In addition, both EV-D68 and EV-A71 were identified. Conclusions In Latin America as in other regions, HRVs and HEVs account for a substantial proportion of respiratory viruses identified in young people with ILI, a finding that provides additional support for the development of pharmaceuticals and vaccines targeting these pathogens. PMID:24119298

[Polymorphisms of TLR7 rs3853839 and rs179010 are associated with susceptibility to and severity of hand, foot and mouth disease caused by enterovirus 71 in male children].

PubMed

Li, Yaping; Zhai, Song; Li, Mei; Wang, Yuan; Lu, Tong; Deng, Huiling; Zhang, Xin; Dang, Shuangsuo

2017-07-01

Objective To investigate whether the polymorphisms of TLR7/MyD88 signaling pathway is associated with the susceptibility to and severity of hand, foot and mouth disease (HFMD) caused by enterovirus 71 (EV71) in children. Methods We collected 180 EV71 HFMD cases and 201 healthy controls from both the Second Affiliated Hospital of Xi'an Jiaotong University and Xi'an Children's Hospital. The genotypes including rs3853839, rs179010 of TLR7, and rs7744 of MyD88 were detected in the 381 samples by SNPscan kit. Results The susceptibility risk (OR=2.343, 95%CI:1.516-3.621) and severity risk (OR=1.939, 95%CI: 1.064-3.521) of TLR7 rs3853839 allele C significantly increased in the male children with EV71 HFMD. Also, the susceptibility risk (OR=1.701, 95%CI: 1.142-2.535) and severity risk (OR=1.852, 95%CI: 1.038-3.305) of TLR7 rs179010 allele T significantly increased in the male children with EV71 HFMD. But there was no significant difference in the distribution of TLR7 rs179010 and rs3853839 genes between female children with EV71 HFMD and female controls. There was no correlation between the genetic polymorphisms of MyD88 rs7744 and the susceptibility to and severity of EV71 HFMD in the children. Conclusion Polymorphisms of TLR7 rs3853839 and rs179010 are correlated to the susceptibility to and severity of EV71 HFMD in male children.

The multi-targeted kinase inhibitor sorafenib inhibits enterovirus 71 replication by regulating IRES-dependent translation of viral proteins.

PubMed

Gao, Meng; Duan, Hao; Liu, Jing; Zhang, Hao; Wang, Xin; Zhu, Meng; Guo, Jitao; Zhao, Zhenlong; Meng, Lirong; Peng, Yihong

2014-06-01

The activation of ERK and p38 signal cascade in host cells has been demonstrated to be essential for picornavirus enterovirus 71 (EV71) replication and up-regulation of virus-induced cyclooxygenase-2 (COX-2)/prostaglandins E2 (PGE2) expression. The aim of this study was to examine the effects of sorafenib, a clinically approved anti-cancer multi-targeted kinase inhibitor, on the propagation and pathogenesis of EV71, with a view to its possible mechanism and potential use in the design of therapy regimes for Hand foot and mouth disease (HFMD) patients with life threatening neurological complications. In this study, non-toxic concentrations of sorafenib were shown to inhibit the yield of infectious progeny EV71 (clinical BC08 strain) by about 90% in three different cell types. A similar inhibitory effect of sorafenib was observed on the synthesis of both viral genomic RNA and the VP1 protein. Interestingly, sorafenib exerted obvious inhibition of the EV71 internal ribosomal entry site (IRES)-mediated translation, the first step in picornavirus replication, by linking it to a firefly luciferase reporter gene. Sorafenib was also able to prevent both EV71-induced CPE and the activation of ERK and p38, which contributes to up-regulation COX-2/PGE2 expression induced by the virus. Overall, this study shows that sorafenib strongly inhibits EV71 replication at least in part by regulating viral IRES-dependent translation of viral proteins, indicating a novel potential strategy for the treatment of HFMD patients with severe neurological complications. To our knowledge, this is the first report that investigates the mechanism by which sorafenib inhibits EV71 replication. Copyright © 2014 Elsevier B.V. All rights reserved.

Antiviral activities of peptide-based covalent inhibitors of the Enterovirus 71 3C protease

PubMed Central

Tan, Yong Wah; Ang, Melgious Jin Yan; Lau, Qiu Ying; Poulsen, Anders; Ng, Fui Mee; Then, Siew Wen; Peng, Jianhe; Hill, Jeffrey; Hong, Wan Jin; Chia, Cheng San Brian; Chu, Justin Jang Hann

2016-01-01

Hand, Foot and Mouth Disease is a highly contagious disease caused by a range of human enteroviruses. Outbreaks occur regularly, especially in the Asia-Pacific region, putting a burden on public healthcare systems. Currently, there is no antiviral for treating this infectious disease and the only vaccines are limited to circulation in China, presenting an unmet medical need that needs to be filled urgently. The human enterovirus 3 C protease has been deemed a plausible drug target due to its essential roles in viral replication. In this study, we designed and synthesized 10 analogues of the Rhinovirus 3 C protease inhibitor, Rupintrivir, and tested their 3 C protease inhibitory activities followed by a cellular assay using human enterovirus 71 (EV71)-infected human RD cells. Our results revealed that a peptide-based compound containing a trifluoromethyl moiety to be the most potent analogue, with an EC50 of 65 nM, suggesting its potential as a lead for antiviral drug discovery. PMID:27645381

Transcutaneous immunization via rapidly dissolvable microneedles protects against hand-foot-and-mouth disease caused by enterovirus 71.

PubMed

Zhu, Zhuangzhi; Ye, Xiaohua; Ku, Zhiqiang; Liu, Qingwei; Shen, Chaoyun; Luo, Huafei; Luan, Hansen; Zhang, Chenghao; Tian, Shaoqiong; Lim, CheeYen; Huang, Zhong; Wang, Hao

2016-12-10

Recent large outbreaks of hand-foot-and-mouth disease (HFMD) have seriously affected the health of young children. Enterovirus 71 (EV71) is the main causative agent of HFMD. Herein, for the first time, rapidly dissolvable microneedles (MNs) loaded with EV71 virus-like particles (VLPs) were evaluated whether they could induce robust immune responses that confer protection against EV71 infection. The characteristics of prepared MNs including hygroscopy, mechanical strength, insertion capacity, dissolution profile, skin irritation and storage stability were comprehensively assessed. EV71 VLPs remained morphologically stable during fabrication. The MNs made of sodium hyaluronate maintained their insertion ability for at least 3h even at a high relative humidity of 75%. With the aid of spring-operated applicator, EV71 MNs (approximately 500μm length) could be readily penetrated into the mouse skin in vivo, and then rapidly dissolved to release encapsulated antigen within 2min. Additionally, MNs induced slight erythema that disappeared within a few hours. More importantly, mouse immunization and virus challenge studies demonstrated that MNs immunization induced high level of antibody responses conferring full protection against lethal EV71 virus challenge that were comparable to conventional intramuscular injection, but with only 1/10th of the delivered antigen (dose sparing). Consequently, our rapidly dissolving MNs may present as an effective and promising transcutaneous immunization device for HFMD prophylaxis among children. Copyright © 2016 Elsevier B.V. All rights reserved.

Heat shock protein-90-beta facilitates enterovirus 71 viral particles assembly

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Robert Y.L., E-mail: yuwang@mail.cgu.edu.tw; Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 333 Taiwan; Kuo, Rei-Lin

2013-09-01

Molecular chaperones are reported to be crucial for virus propagation, but are not yet addressed in Human Enterovirus 71 (EV71). Here we describe the specific association of heat shock protein-90-beta (Hsp90β), but not alpha form (Hsp90α), with EV71 viral particles by the co-purification with virions using sucrose density gradient ultracentrifugation, and by the colocalization with viral particles, as assessed by immunogold electron microscopy. The reduction of the Hsp90β protein using RNA interference decreased the correct assembly of viral particles, without affecting EV71 replication levels. Tracking ectopically expressed Hsp90β protein associated with EV71 virions revealed that Hsp90β protein was transmitted tomore » new host cells through its direct association with infectious viral particles. Our findings suggest a new antiviral strategy in which extracellular Hsp90β protein is targeted to decrease the infectivity of EV71 and other enteroviruses, without affecting the broader functions of this constitutively expressed molecular chaperone. - Highlights: • Hsp90β is associated with EV71 virion and is secreted with the release virus. • Hsp90β effects on the correct assembly of viral particles. • Viral titer of cultured medium was reduced in the presence of geldanamycin. • Viral titer was also reduced when Hsp90β was suppressed by siRNA treatment. • The extracellular Hsp90β was also observed in other RNA viruses-infected cells.« less

Effect of the Deletion of Genes Encoding Proteins of the Extracellular Virion Form of Vaccinia Virus on Vaccine Immunogenicity and Protective Effectiveness in the Mouse Model

PubMed Central

Meseda, Clement A.; Campbell, Joseph; Kumar, Arunima; Garcia, Alonzo D.; Merchlinsky, Michael; Weir, Jerry P.

2013-01-01

Antibodies to both infectious forms of vaccinia virus, the mature virion (MV) and the enveloped virion (EV), as well as cell-mediated immune response appear to be important for protection against smallpox. EV virus particles, although more labile and less numerous than MV, are important for dissemination and spread of virus in infected hosts and thus important in virus pathogenesis. The importance of the EV A33 and B5 proteins for vaccine induced immunity and protection in a murine intranasal challenge model was evaluated by deletion of both the A33R and B5R genes in a vaccine-derived strain of vaccinia virus. Deletion of either A33R or B5R resulted in viruses with a small plaque phenotype and reduced virus yields, as reported previously, whereas deletion of both EV protein-encoding genes resulted in a virus that formed small infection foci that were detectable and quantifiable only by immunostaining and an even more dramatic decrease in total virus yield in cell culture. Deletion of B5R, either as a single gene knockout or in the double EV gene knockout virus, resulted in a loss of EV neutralizing activity, but all EV gene knockout viruses still induced a robust neutralizing activity against the vaccinia MV form of the virus. The effect of elimination of A33 and/or B5 on the protection afforded by vaccination was evaluated by intranasal challenge with a lethal dose of either vaccinia virus WR or IHD-J, a strain of vaccinia virus that produces relatively higher amounts of EV virus. The results from multiple experiments, using a range of vaccination doses and virus challenge doses, and using mortality, morbidity, and virus dissemination as endpoints, indicate that the absence of A33 and B5 have little effect on the ability of a vaccinia vaccine virus to provide protection against a lethal intranasal challenge in a mouse model. PMID:23785523

A mathematical framework for the selection of an optimal set of peptides for epitope-based vaccines.

PubMed

Toussaint, Nora C; Dönnes, Pierre; Kohlbacher, Oliver

2008-12-01

Epitope-based vaccines (EVs) have a wide range of applications: from therapeutic to prophylactic approaches, from infectious diseases to cancer. The development of an EV is based on the knowledge of target-specific antigens from which immunogenic peptides, so-called epitopes, are derived. Such epitopes form the key components of the EV. Due to regulatory, economic, and practical concerns the number of epitopes that can be included in an EV is limited. Furthermore, as the major histocompatibility complex (MHC) binding these epitopes is highly polymorphic, every patient possesses a set of MHC class I and class II molecules of differing specificities. A peptide combination effective for one person can thus be completely ineffective for another. This renders the optimal selection of these epitopes an important and interesting optimization problem. In this work we present a mathematical framework based on integer linear programming (ILP) that allows the formulation of various flavors of the vaccine design problem and the efficient identification of optimal sets of epitopes. Out of a user-defined set of predicted or experimentally determined epitopes, the framework selects the set with the maximum likelihood of eliciting a broad and potent immune response. Our ILP approach allows an elegant and flexible formulation of numerous variants of the EV design problem. In order to demonstrate this, we show how common immunological requirements for a good EV (e.g., coverage of epitopes from each antigen, coverage of all MHC alleles in a set, or avoidance of epitopes with high mutation rates) can be translated into constraints or modifications of the objective function within the ILP framework. An implementation of the algorithm outperforms a simple greedy strategy as well as a previously suggested evolutionary algorithm and has runtimes on the order of seconds for typical problem sizes.

[Role of Toll-like receptor 7 in the production of inflammatory cytokines in EV-A71-infected human Jurkat T cells].

PubMed

Chi, Jing; He, Yaqing; Yu, Guangqing; Lei, Lei

2016-03-01

To investigate the expression of Toll-like receptor (TLR) mRNA in enterovirus 71(EV-A71) infected human Jurkat T cells and clarify the role of TLRs in the pathogenesis of EV-A71 infection-induced inflammation. EV-A71 strains were isolated from feces of children patients with hand, foot and mouth disease in 2014 by Shenzhen Center for Disease Control and Prevention. Human Jurkat T cells were infected with 200 μl EV-A71 at 10(3) cell culture infective dose 50%(CCID50)/ml. The expression of TLR1-TLR10 mRNA in human Jurkat T cells was assessed at different exposure time by RT-PCR. Levels of TLR7 mRNA expression were detected by real-time PCR, and levels of myeloid differentiation factor 88 (MyD88) by western blot. The cytokine secretion of interleukin (IL)-6, IL-8 and Tumor Necrosis Factor α (TNF-α) was analyzed by ELISA assay. The relative expression level of TLR7 mRNA in human Jurkat T cells were 1.26 ± 0.15, 1.75 ± 0.20, 2.26 ± 0.23 and 3.74 ± 0.62 in 6, 12, 24 and 48 h after EV-A71 infection, which the differences were significant with mock-infected group(t values were -2.96, -6.38, -9.57, -7.71; P<0.05). Western blot showed that the protein expression levels of MyD88 had increased 1.34 times and 2.17 times in 24 h and 48 h after EV-A71 infection compared with mock-infected group. After infected for 24 h and 48 h, the levels of IL-6 were (302.86 ± 38.11), (179.70 ± 14.50) pg/ml, which were significantly higher than mock-infected group (176.42 ± 9.60), (179.70 ± 14.50) pg/ml (t values were -5.57, -18.54, P<0.05). The levels of TNF-α in EV-A71 infected group (100.81 ± 9.81) pg/ml was higher than that in mock-infected group (56.19 ± 6.94) pg/ml, and the difference was significant (t=-6.43, P=0.003). TLR7 is the main pattern recognition receptor responsible for EV-A71 recognition in immune cells, which then leads to the activation of TLR7 downstream signaling and the production of proinflammatory cytokines.

Exosome-mediated miR-146a transfer suppresses type I interferon response and facilitates EV71 infection

PubMed Central

Fu, Yuxuan; Zhang, Li; Zhang, Fang; Tang, Ting; Zhou, Qi; Feng, Chunhong; Jin, Yu

2017-01-01

Exosomes can transfer genetic materials between cells. Their roles in viral infections are beginning to be appreciated. Researches have shown that exosomes released from virus-infected cells contain a variety of viral and host cellular factors that are able to modulate recipient’s cellular response and result in productive infection of the recipient host. Here, we showed that EV71 infection resulted in upregulated exosome secretion and differential packaging of the viral genomic RNA and miR-146a into exosomes. We provided evidence showing that miR-146a was preferentially enriched in exosomes while the viral RNA was not in infected cells. Moreover, the exosomes contained replication-competent EV71 RNA in complex with miR-146a, Ago2, and GW182 and could mediate EV71 transmission independent of virus-specific receptor. The exosomal viral RNA could be transferred to and replicate in a new target cell while the exosomal miR-146a suppressed type I interferon response in the target cell, thus facilitating the viral replication. Additionally, we found that the IFN-stimulated gene factors (ISGs), BST-2/tetherin, were involved in regulating EV71-induced upregulation of exosome secretion. Importantly, in vivo study showed that exosomal viral RNA exhibited differential tissue accumulation as compared to the free virus particles. Together, our findings provide evidence that exosomes secreted by EV71-infected cells selectively packaged high level miR-146a that can be functionally transferred to and facilitate exosomal EV71 RNA to replicate in the recipient cells by suppressing type I interferon response. PMID:28910400

The Association of Recombination Events in the Founding and Emergence of Subgenogroup Evolutionary Lineages of Human Enterovirus 71

PubMed Central

McWilliam Leitch, E. C.; Cabrerizo, M.; Cardosa, J.; Harvala, H.; Ivanova, O. E.; Koike, S.; Kroes, A. C. M.; Lukashev, A.; Perera, D.; Roivainen, M.; Susi, P.; Trallero, G.; Evans, D. J.

2012-01-01

Enterovirus 71 (EV71) is responsible for frequent large-scale outbreaks of hand, foot, and mouth disease worldwide and represent a major etiological agent of severe, sometimes fatal neurological disease. EV71 variants have been classified into three genogroups (GgA, GgB, and GgC), and the latter two are further subdivided into subgenogroups B1 to B5 and C1 to C5. To investigate the dual roles of recombination and evolution in the epidemiology and transmission of EV71 worldwide, we performed a large-scale genetic analysis of isolates (n = 308) collected from 19 countries worldwide over a 40-year period. A series of recombination events occurred over this period, which have been identified through incongruities in sequence grouping between the VP1 and 3Dpol regions. Eleven 3Dpol clades were identified, each specific to EV71 and associated with specific subgenogroups but interspersed phylogenetically with clades of coxsackievirus A16 and other EV species A serotypes. The likelihood of recombination increased with VP1 sequence divergence; mean half-lives for EV71 recombinant forms (RFs) of 6 and 9 years for GgB and GgC overlapped with those observed for the EV-B serotypes, echovirus 9 (E9), E30, and E11, respectively (1.3 to 9.8 years). Furthermore, within genogroups, sporadic recombination events occurred, such as the linkage of two B4 variants to RF-W instead of RF-A and of two C4 variants to RF-H. Intriguingly, recombination events occurred as a founding event of most subgenogroups immediately preceding their lineage expansion and global emergence. The possibility that recombination contributed to their subsequent spread through improved fitness requires further biological and immunological characterization. PMID:22205739

Antiviral activity of Lactobacillus reuteri Protectis against Coxsackievirus A and Enterovirus 71 infection in human skeletal muscle and colon cell lines.

PubMed

Ang, Lei Yin Emily; Too, Horng Khit Issac; Tan, Eng Lee; Chow, Tak-Kwong Vincent; Shek, Lynette Pei-Chi; Tham, Elizabeth Huiwen; Alonso, Sylvie

2016-06-24

Recurrence of hand, foot and mouth disease (HFMD) pandemics continues to threaten public health. Despite increasing awareness and efforts, effective vaccine and drug treatment have yet to be available. Probiotics have gained recognition in the field of healthcare worldwide, and have been extensively prescribed to babies and young children to relieve gastrointestinal (GI) disturbances and diseases, associated or not with microbial infections. Since the faecal-oral axis represents the major route of HFMD transmission, transient persistence of probiotic bacteria in the GI tract may confer some protection against HFMD and limit transmission among children. In this work, the antiviral activity of two commercially available probiotics, namely Lactobacillus reuteri Protectis (L. reuteri Protectis) and Lactobacillus casei Shirota (L. casei Shirota), was assayed against Coxsackieviruses and Enterovirus 71 (EV71), the main agents responsible for HFMD. In vitro infection set-ups using human skeletal muscle and colon cell lines were designed to assess the antiviral effect of the probiotic bacteria during entry and post-entry steps of the infection cycle. Our findings indicate that L. reuteri Protectis displays a significant dose-dependent antiviral activity against Coxsackievirus type A (CA) strain 6 (CA6), CA16 and EV71, but not against Coxsackievirus type B strain 2. Our data support that the antiviral effect is likely achieved through direct physical interaction between bacteria and virus particles, which impairs virus entry into its mammalian host cell. In contrast, no significant antiviral effect was observed with L. casei Shirota. Should the antiviral activity of L. reuteri Protectis observed in vitro be translated in vivo, such probiotics-based therapeutic approach may have the potential to address the urgent need for a safe and effective means to protect against HFMD and limit its transmission among children.

[Analysis on the change of genotype of enteroviruses associated hand, foot and mouth disease in Beijing during 2013 to 2014].

PubMed

Song, Qinwei; Huang, Hui; Deng, Jie; Zhao, Linqing; Deng, Li; Sun, Yu; Wang, Fang; Oian, Yuan; Zhu, Runan

2015-08-01

To analyze the genotype, epidemic pattern and the characteristics of the disease of enteroviruses during the epidemic season of hand, foot and mouth disease (HMFD) in children from 2013 to 2014 in Beijing to provide the scientific evidence for prevention and treatment of HFMD. During April to September in 2013 and March to October in 2014, a total of 977 throat swabs were collected from children who visited the Children's Hospital Affiliated to Capital Institute of Pediatrics, including 147 from patients with HFMD in 2013, 343 with HFMD, 201 with atypical HFMD, 83 with herpangina, 25 with fever with convulsions, 64 fever with rash and 114 with rash in 2014. Enteroviruses universal type (EV), Enteroviruses type 71 (EV71) and Coxsackievirus group A 16 (CA16) were detected by real-time RT-PCR respectively. The nucleic acid of specimens which were identified with non-EV71, non-CA16 was tested by nested PCR and analyzed by VP1 sequencing. The detection rate and epidemic pattern of different genotypes of enterovirus were analyzed among different age groups and between 2013 and 2014. Of 977 throat swabs, 80. 1% samples were detected positive for enteroviruses. The positive rates of CA16, EV71, CA6, CA10, CA4 and other EVs were 25. 6% (250/977), 18. 9% (185/977), 20. 0% (195/977), 5. 0% (49/977), 1.5% (15/977) and 9.1% (89/977), respectively. Twenty six of the 89 other EVs included CA2, CA5, CA8, CA9, CA12, CA14, CB2, CB5, E6, E9 and E25, each genotype of which was no more than 3. The nucleotide homologies shared among CA6, CA10 and CA4 strains between 2013 and 2014 were 94. 3% - 100%, 93. 8% - 99. 1% and 92.7% - 99. 8%, respectively. The positive rates of ≤1 year group were 71. 1% (106/149), which was lower than that of other age groups (all P <0. 05), but similar to that of >5 year group (χ2 =1. 181,P = 0. 277). In 2013, the positive rate of EV was 85. 7% (126/147) and the predominant genotype was CA6 54. 8% (69/126), followed by CA16 20. 6% (26/126) and EV71 11. 9% (15/126). In 2014, the positive rate of EV was 85. 4% (293/343) in the 343 children with HFMD, the predominant genotypes were CA16 with the positive rate of 42. 7% (125/293), EV71 with 38. 2% (112/293) and CA6 with only 11. 3% (33/293). In 2014, the positive rates of EV in 201 atypical HFMD, 83 herpangina, 25 fever with convulsions, 64 fever with rash and 114 rash were 83. 6% (168/201), 80. 7% (67/83), 76. 0% (19/25), 64. 1% (41/64) and 60. 5% (69/114), respectively. All genotypes of enteroviruses peaked mainly during May to August every year, but there were no obvious epidemiological pattern about each genotype. CA6 became the main causative agent of HFMD in 2013, however, CA16 and EV71 predominated again in 2014 in Beijing. The clinical manifestations caused by CA6, CA10, CA4 and other genotype of enteroviruses differed from EV71 and CA16. Besides EV71 and CA16, more attention should be paid to CA6, CA10, CA4 and other type of enteroviruses.

Detection and characterization of viruses causing hand, foot and mouth disease from children in Seri Kembangan, Malaysia.

PubMed

Ling, Beh Poay; Jalilian, Farid Azizi; Harmal, Nabil Saad; Yubbu, Putri; Sekawi, Zamberi

2014-12-01

Hand, foot and mouth disease (HFMD) is a common viral infection among infants and children. The major causative agents of HFMD are enterovirus 71 (EV71) and coxsackievirus A16 (CVA16). Recently, coxsackievirus A6 (CVA6) infections were reported in neighboring countries. Infected infants and children may present with fever, mouth/throat ulcers, rashes and vesicles on hands and feet. Moreover, EV71 infections might cause fatal neurological complications. Since 1997, EV71 caused fatalities in Sarawak and Peninsula Malaysia. The purpose of this study was to identify and classify the viruses which detected from the patients who presenting clinical signs and symptoms of HFMD in Seri Kembangan, Malaysia. From December 2012 until July 2013, a total of 28 specimens were collected from patients with clinical case definitions of HFMD. The HFMD viruses were detected by using semi-nested reverse transcription polymerase chain reaction (snRT-PCR). The positive snRT-PCR products were sequenced and phylogenetic analyses of the viruses were performed. 12 of 28 specimens (42.9%) were positive in snRT-PCR, seven are CVA6 (58.3%), two CVA16 (16.7%) and three EV71 (25%). Based on phylogenetic analysis studies, EV71 strains were identified as sub-genotype B5; CVA16 strains classified into sub-genotype B2b and B2c; CVA6 strains closely related to strains in Taiwan and Japan. In this study, HFMD in Seri Kembangan were caused by different types of Enterovirus, which were EV71, CVA6 and CVA16.

Identification and characterization of avian retroviruses in chicken embryo-derived yellow fever vaccines: investigation of transmission to vaccine recipients.

PubMed

Hussain, Althaf I; Johnson, Jeffrey A; Da Silva Freire, Marcos; Heneine, Walid

2003-01-01

All currently licensed yellow fever (YF) vaccines are propagated in chicken embryos. Recent studies of chick cell-derived measles and mumps vaccines show evidence of two types of retrovirus particles, the endogenous avian retrovirus (EAV) and the endogenous avian leukosis virus (ALV-E), which originate from the chicken embryonic fibroblast substrates. In this study, we investigated substrate-derived avian retrovirus contamination in YF vaccines currently produced by three manufacturers (YF-vax [Connaught Laboratories], Stamaril [Aventis], and YF-FIOCRUZ [FIOCRUZ-Bio-Manguinhos]). Testing for reverse transcriptase (RT) activity was not possible because of assay inhibition. However, Western blot analysis of virus pellets with anti-ALV RT antiserum detected three distinct RT proteins in all vaccines, indicating that more than one source is responsible for the RTs present in the vaccines. PCR analysis of both chicken substrate DNA and particle-associated RNA from the YF vaccines showed no evidence of the long terminal repeat sequences of exogenous ALV subgroups A to D in any of the vaccines. In contrast, both ALV-E and EAV particle-associated RNA were detected at equivalent titers in each vaccine by RT-PCR. Quantitative real-time RT-PCR revealed 61,600, 348,000, and 1,665,000 ALV-E RNA copies per dose of Stamaril, YF-FIOCRUZ, and YF-vax vaccines, respectively. ev locus-specific PCR testing of the vaccine-associated chicken substrate DNA was positive both for the nondefective ev-12 locus in two vaccines and for the defective ev-1 locus in all three vaccines. Both intact and ev-1 pol sequences were also identified in the particle-associated RNA. To investigate the risks of transmission, serum samples from 43 YF vaccine recipients were studied. None of the samples were seropositive by an ALV-E-based Western blot assay or had detectable EAV or ALV-E RNA sequences by RT-PCR. YF vaccines produced by the three manufacturers all have particles containing EAV genomes and various levels of defective or nondefective ALV-E sequences. The absence of evidence of infection with ALV-E or EAV in 43 YF vaccine recipients suggests low risks for transmission of these viruses, further supporting the safety of these vaccines.

Highly Sensitive Naked-Eye Assay for Enterovirus 71 Detection Based on Catalytic Nanoparticle Aggregation and Immunomagnetic Amplification.

PubMed

Xiong, Ling-Hong; He, Xuewen; Xia, Junjie; Ma, Hanwu; Yang, Fan; Zhang, Qian; Huang, Dana; Chen, Long; Wu, Chunli; Zhang, Xiaomin; Zhao, Zheng; Wan, Chengsong; Zhang, Renli; Cheng, Jinquan

2017-05-03

Development of sensitive, convenient, and cost-effective virus detection product is of great significance to meet the growing demand of clinical diagnosis at the early stage of virus infection. Herein, a naked-eye readout of immunoassay by means of virion bridged catalase-mediated in situ reduction of gold ions and growth of nanoparticles, has been successfully proposed for rapid visual detection of Enterovirus 71 (EV71). Through tailoring the morphologies of the produced gold nanoparticles (GNPs) varying between dispersion and aggregation, a distinguishing color changing was ready for observation. This colorimetric detection assay, by further orchestrating the efficient magnetic enrichment and the high catalytic activity of enzyme, is managed to realize highly sensitive detection of EV71 virions with the limit of detection (LOD) down to 0.65 ng/mL. Our proposed method showed a much lower LOD value than the commercial ELISA for EV71 virion detection. Comparing to the current clinical gold standard polymerase chain reaction (PCR) method, our strategy provided the same diagnostic outcomes after testing real clinical samples. Besides, this strategy has no need of complicated sample pretreatment or expensive instruments. Our presented naked-eye immunoassay method holds a promising prospect for the early detection of virus-infectious disease especially in resource-constrained settings.

Pulmonary and central nervous system pathology in fatal cases of hand foot and mouth disease caused by enterovirus A71 infection.

PubMed

Wang, Zijun; Nicholls, John M; Liu, Fengfeng; Wang, Joshua; Feng, Zijian; Liu, Dongge; Sun, Yanni; Zhou, Cheng; Li, Yunqian; Li, Hai; Qi, Shunxiang; Huang, Xueyong; Sui, Jilin; Liao, Qiaohong; Peiris, Malik; Yu, Hongjie; Wang, Yu

2016-04-01

In the past 17 years, neurological disease associated with enterovirus A71 (EV-A71) has increased dramatically in the Asia-Pacific region with a high fatality rate in young infants, often due to pulmonary oedema, however the mechanism of this oedema remains obscure. We analysed the brainstem, heart and lungs of 15 fatal cases of confirmed EV-A71 infection in order to understand the pathophysiological mechanism of death and pulmonary oedema. In keeping with other case studies, the main cause of death was neurogenic pulmonary oedema. In the brainstem, 11 cases showed inflammation and all cases showed parenchymal inflammation with seven cases showing moderate or severe clasmatodendrosis. No viral antigen was detected in sections of the brainstem in any of the cases. All fatal cases showed evidence of pulmonary oedema; however, there was absence of direct pulmonary viral damage or myocarditis-induced damage and EV-A71 viral antigen staining was negative. Though there was no increase in staining for Na/K-ATPase, 11 of the 15 cases showed a marked reduction in aquaporin-4 staining in the lung, and this reduction may contribute to the development of fatal pulmonary oedema. Copyright © 2016. Published by Elsevier B.V.

Enterovirus 71 2C Protein Inhibits NF-κB Activation by Binding to RelA(p65)

PubMed Central

Du, Haiwei; Yin, Peiqi; Yang, Xiaojie; Zhang, Leiliang; Jin, Qi; Zhu, Guofeng

2015-01-01

Viruses evolve multiple ways to interfere with NF-κB signaling, a key regulator of innate and adaptive immunity. Enterovirus 71 (EV71) is one of primary pathogens that cause hand-foot-mouth disease. Here, we identify RelA(p65) as a novel binding partner for EV71 2C protein from yeast two-hybrid screen. By interaction with IPT domain of p65, 2C reduces the formation of heterodimer p65/p50, the predominant form of NF-κB. We also show that picornavirus 2C family proteins inhibit NF-κB activation and associate with p65 and IKKβ. Our findings provide a novel mechanism how EV71 antagonizes innate immunity. PMID:26394554

Prediction of Protection against Asian Enterovirus 71 Outbreak Strains by Cross-neutralizing Capacity of Serum from Dutch Donors, The Netherlands

PubMed Central

Koen, Gerrit; van Eijk, Hetty; Koekkoek, Sylvie M.; de Jong, Menno D.; Wolthers, Katja C.

2016-01-01

Outbreaks of human enterovirus 71 (EV-71) in Asia are related to high illness and death rates among children. To gain insight into the potential threat for the population of Europe, we determined the neutralizing activity in intravenous immunoglobulin (IVIg) batches and individual serum samples from donors in the Netherlands against EV-71 strains isolated in Europe and in Asia. All IVIg batches and 41%, 79%, and 65% of serum samples from children ≤5 years of age, women of childbearing age, and HIV-positive men, respectively, showed high neutralizing activity against a Dutch C1 strain, confirming widespread circulation of EV-71 in the Netherlands. Asian B3–4 and C4 strains were efficiently cross-neutralized, predicting possible protection against extensive circulation and associated outbreaks of those types in Europe. However, C2 and C5 strains that had few mutations in the capsid region consistently escaped neutralization, emphasizing the importance of monitoring antigenic diversity among circulating EV-71 strains. PMID:27533024

The effectiveness of vaccine day and educational interventions on influenza vaccine coverage among health care workers at long-term care facilities.

PubMed

Kimura, Akiko C; Nguyen, Christine N; Higa, Jeffrey I; Hurwitz, Eric L; Vugia, Duc J

2007-04-01

We examined barriers to influenza vaccination among long-term care facility (LTCF) health care workers in Southern California and developed simple, effective interventions to improve influenza vaccine coverage of these workers. In 2002, health care workers at LTCFs were surveyed regarding their knowledge and attitudes about influenza and the influenza vaccine. Results were used to develop 2 interventions, an educational campaign and Vaccine Day (a well-publicized day for free influenza vaccination of all employees at the worksite). Seventy facilities were recruited to participate in an intervention trial and randomly assigned to 4 study groups. The combination of Vaccine Day and an educational campaign was most effective in increasing vaccine coverage (53% coverage; prevalence ratio [PR]=1.45; 95% confidence interval [CI]=1.24, 1.71, compared with 27% coverage in the control group). Vaccine Day alone was also effective (46% coverage; PR= 1.41; 95% CI=1.17, 1.71). The educational campaign alone was not effective in improving coverage levels (34% coverage; PR=1.18; 95% CI=0.93, 1.50). Influenza vaccine coverage of LTCF health care workers can be improved by providing free vaccinations at the worksite with a well-publicized Vaccine Day.

Genetic Diversity of Enterovirus A71, India

PubMed Central

Saxena, Vinay K.; Sane, Sudhir; Nadkarni, Sushma S.; Sharma, Deepa K.

2015-01-01

We have identified circulation of 3 genogroups of enterovirus (EV) A71 in India. A new genogroup (proposed designation G) was discovered during this study. We isolated genogroups D and G in wide geographic areas but detected subgenogroup C1 only in 1 focus in western India. A systematic nationwide search for EV-A71 is warranted. PMID:25531549

Therapeutic and prevention strategies against human enterovirus 71 infection

PubMed Central

Kok, Chee Choy

2015-01-01

Human enterovirus 71 (HEV71) is the cause of hand, foot and mouth disease and associated neurological complications in children under five years of age. There has been an increase in HEV71 epidemic activity throughout the Asia-Pacific region in the past decade, and it is predicted to replace poliovirus as the extant neurotropic enterovirus of highest global public health significance. To date there is no effective antiviral treatment and no vaccine is available to prevent HEV71 infection. The increase in prevalence, virulence and geographic spread of HEV71 infection over the past decade provides increasing incentive for the development of new therapeutic and prevention strategies against this emerging viral infection. The current review focuses on the potential, advantages and disadvantages of these strategies. Since the explosion of outbreaks leading to large epidemics in China, research in natural therapeutic products has identified several groups of compounds with anti-HEV71 activities. Concurrently, the search for effective synthetic antivirals has produced promising results. Other therapeutic strategies including immunotherapy and the use of oligonucleotides have also been explored. A sound prevention strategy is crucial in order to control the spread of HEV71. To this end the ultimate goal is the rapid development, regulatory approval and widespread implementation of a safe and effective vaccine. The various forms of HEV71 vaccine designs are highlighted in this review. Given the rapid progress of research in this area, eradication of the virus is likely to be achieved. PMID:25964873

Differential permissivity of human cerebrovascular endothelial cells to enterovirus infection and specificities of serotype EV-A71 in crossing an in vitro model of the human blood-brain barrier.

PubMed

Volle, Romain; Archimbaud, Christine; Couraud, Pierre-Olivier; Romero, Ignacio A; Weksler, Babette; Mirand, Audrey; Pereira, Bruno; Henquell, Cécile; Peigue-Lafeuille, Hélène; Bailly, Jean-Luc

2015-07-01

Human cerebral microvascular endothelial cells (hCMEC/D3 cell line) form a steady polarized barrier when cultured in vitro on a permeable membrane. Their susceptibility to enterovirus (EV) strains was analysed to investigate how these viruses may cross the blood-brain barrier. A sample of 88 virus strains was selected on phylogenetic features amongst 43 epidemiologically relevant types of the four EV species A-D. The EV-A71 genome was replicated at substantial rates, whilst the infectious virus was released at extremely low but sustained rates at both barrier sides for at least 4 days. EV-A71 antigens were detected in a limited number of cells. The properties of the endothelial barrier (structure and permeability) remained intact throughout infection. The chronic EV-A71 infection was in sharp contrast to the productive infection of cytolytic EVs (e.g. echoviruses E-6 and E-30). The hCMEC/D3 barriers infected with the latter EVs exhibited elevated proportions of apoptotic and necrotic cells, which resulted in major injuries to the endothelial barriers with a dramatic increase of paracellular permeability and virus crossing to the abluminal side. The following intracellular rearrangements were also seen: early destruction of the actin cytoskeleton, remodelling of intracellular membranes and reorganization of the mitochondrion network in a small cluster near the perinuclear space.

Comparative Analysis of Serum Proteins from Patients with Severe and Mild EV-A71-induced HFMD using iTRAQ-Coupled LC-MS/MS Screening.

PubMed

Fan, Peihu; Chen, Wei; Yu, Pin; Bao, Linlin; Xu, Lili; Qin, Chuan

2017-12-01

This study was designed to provide a rationale for monitoring the development of severe hand, foot, and mouth disease (HFMD) and predicting the onset of this disease via global comparative analysis between patients with severe and mild HFMD. The authors collected serum from five groups: mild (E-M) and severe (E-S) EV-A71-induced HFMD; mild (NE-M) and severe (NE-S) non-EV-A71-induced HFMD; and healthy control subjects (CON). The authors then performed comparative analysis and identified specific differentially expressed proteins (DEPs) of E-S using isobaric mass tag (isobaric tags for relative and absolute quantitation, iTRAQ) labeling coupled with multidimensional liquid chromatography-mass spectrometry (LC-MS/MS). Moreover, The authors validated specific DEPs by multiple reaction monitoring (MRM). The authors identified 10 specific proteins that were significantly altered in E-S patients. Bioinformatics analysis revealed that most of these DEPs are primarily involved in the acute response to infection, which was common to all groups. More importantly, up-regulated proteins associated with neural injury were specifically identified in the E-S group. These findings conclude that severe HFMD symptoms may be caused by EV-A71 infection-mediated injury of the neural system and provide a reference for future research on the course and prognosis of severe HFMD. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Development of Eczema Vaccinatum in Atopic Mouse Models and Efficacy of MVA Vaccination against Lethal Poxviral Infection

PubMed Central

Knitlova, Jarmila; Hajkova, Vera; Voska, Ludek; Elsterova, Jana; Obrova, Barbora; Melkova, Zora

2014-01-01

Smallpox vaccine based on live, replicating vaccinia virus (VACV) is associated with several potentially serious and deadly complications. Consequently, a new generation of vaccine based on non-replicating Modified vaccinia virus Ankara (MVA) has been under clinical development. MVA seems to induce good immune responses in blood tests, but it is impossible to test its efficacy in vivo in human. One of the serious complications of the replicating vaccine is eczema vaccinatum (EV) occurring in individuals with atopic dermatitis (AD), thus excluding them from all preventive vaccination schemes. In this study, we first characterized and compared development of eczema vaccinatum in different mouse strains. Nc/Nga, Balb/c and C57Bl/6J mice were epicutaneously sensitized with ovalbumin (OVA) or saline control to induce signs of atopic dermatitis and subsequently trans-dermally (t.d.) immunized with VACV strain Western Reserve (WR). Large primary lesions occurred in both mock- and OVA-sensitized Nc/Nga mice, while they remained small in Balb/c and C57Bl/6J mice. Satellite lesions developed in both mock- and OVA-sensitized Nc/Nga and in OVA-sensitized Balb/c mice with the rate 40–50%. Presence of mastocytes and eosinophils was the highest in Nc/Nga mice. Consequently, we have chosen Nc/Nga mice as a model of AD/EV and tested efficacy of MVA and Dryvax vaccinations against a lethal intra-nasal (i.n.) challenge with WR, the surrogate of smallpox. Inoculation of MVA intra-muscularly (i.m.) or t.d. resulted in no lesions, while inoculation of Dryvax t.d. yielded large primary and many satellite lesions similar to WR. Eighty three and 92% of mice vaccinated with a single dose of MVA i.m. or t.d., respectively, survived a lethal i.n. challenge with WR without any serious illness, while all Dryvax-vaccinated animals survived. This is the first formal prove of protective immunity against a lethal poxvirus challenge induced by vaccination with MVA in an atopic organism. PMID:25486419

Detection of human enterovirus 71 and coxsackievirus A16 in children with hand, foot and mouth disease in China.

PubMed

Chen, Ling; Mou, Xiaozhou; Zhang, Qiong; Li, Yifei; Lin, Jian; Liu, Fanlong; Yuan, Li; Tang, Yiming; Xiang, Charlie

2012-04-01

The aims of the present study were to investigate the genetic characteristics of enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) strains in China and to evaluate the relationship between the genotypes of CVA16 and EV71 and their geographical distribution. A total of 399 stool specimens were collected from children with symptoms of hand, foot and mouth disease (HFMD) in Zhejiang Province. The presence of enteroviruses was determined using reverse transcription-semi-nested PCR targeted to the VP1 gene of all human enteroviruses and DNA sequencing. EV71 and CVA16, the major etiological agents of HFMD, were detected in 38.4% (38/99) and 35.4% (35/99) of HEV-A species-positive cases, respectively. Based on the phylogenetic analysis of the VP1 gene, EV71 strains identified in this study belong to subgenotype C4, and CVA16 strains herein were classified into clusters B2a and B2b within the genotype B2. Taking into consideration other published data, we conclude that the genetic characteristics of enteroviruses in China reflect the pattern of the endemic circulation of the subgenotype C4 to EV71 and clusters B2a and B2b within genotype B2 to CVA16, which have been continuously circulating in China since 1997. This observation indicates that the genetic characteristics of enteroviruses in China seem to depend on their special geographical and climatical features allowing them to be sustained with little external effect.

Detection of human enterovirus 71 and coxsackievirus A16 in children with hand, foot and mouth disease in China

PubMed Central

CHEN, LING; MOU, XIAOZHOU; ZHANG, QIONG; LI, YIFEI; LIN, JIAN; LIU, FANLONG; YUAN, LI; TANG, YIMING; XIANG, CHARLIE

2012-01-01

The aims of the present study were to investigate the genetic characteristics of enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) strains in China and to evaluate the relationship between the genotypes of CVA16 and EV71 and their geographical distribution. A total of 399 stool specimens were collected from children with symptoms of hand, foot and mouth disease (HFMD) in Zhejiang Province. The presence of enteroviruses was determined using reverse transcription-semi-nested PCR targeted to the VP1 gene of all human enteroviruses and DNA sequencing. EV71 and CVA16, the major etiological agents of HFMD, were detected in 38.4% (38/99) and 35.4% (35/99) of HEV-A species-positive cases, respectively. Based on the phylogenetic analysis of the VP1 gene, EV71 strains identified in this study belong to subgenotype C4, and CVA16 strains herein were classified into clusters B2a and B2b within the genotype B2. Taking into consideration other published data, we conclude that the genetic characteristics of enteroviruses in China reflect the pattern of the endemic circulation of the subgenotype C4 to EV71 and clusters B2a and B2b within genotype B2 to CVA16, which have been continuously circulating in China since 1997. This observation indicates that the genetic characteristics of enteroviruses in China seem to depend on their special geographical and climatical features allowing them to be sustained with little external effect. PMID:22218731

Unusual Features of Vaccinia Virus Extracellular Virion Form Neutralization Resistance Revealed in Human Antibody Responses to the Smallpox Vaccine

PubMed Central

Benhnia, Mohammed Rafii-El-Idrissi; Maybeno, Matthew; Blum, David; Aguilar-Sino, Rowena; Matho, Michael; Meng, Xiangzhi; Head, Steven; Felgner, Philip L.; Zajonc, Dirk M.; Koriazova, Lilia; Kato, Shinichiro; Burton, Dennis R.; Xiang, Yan; Crowe, James E.; Peters, Bjoern

2013-01-01

The extracellular virion form (EV) of vaccinia virus (VACV) is essential for viral pathogenesis and is difficult to neutralize with antibodies. Why this is the case and how the smallpox vaccine overcomes this challenge remain incompletely understood. We previously showed that high concentrations of anti-B5 antibodies are insufficient to directly neutralize EV (M. R. Benhnia, et al., J. Virol. 83:1201–1215, 2009). This allowed for at least two possible interpretations: covering the EV surface is insufficient for neutralization, or there are insufficient copies of B5 to allow anti-B5 IgG to cover the whole surface of EV and another viral receptor protein remains active. We endeavored to test these possibilities, focusing on the antibody responses elicited by immunization against smallpox. We tested whether human monoclonal antibodies (MAbs) against the three major EV antigens, B5, A33, and A56, could individually or together neutralize EV. While anti-B5 or anti-A33 (but not anti-A56) MAbs of appropriate isotypes were capable of neutralizing EV in the presence of complement, a mixture of anti-B5, anti-A33, and anti-A56 MAbs was incapable of directly neutralizing EV, even at high concentrations. This remained true when neutralizing the IHD-J strain, which lacks a functional version of the fourth and final known EV surface protein, A34. These immunological data are consistent with the possibility that viral proteins may not be the active component of the EV surface for target cell binding and infectivity. We conclude that the protection afforded by the smallpox vaccine anti-EV response is predominantly mediated not by direct neutralization but by isotype-dependent effector functions, such as complement recruitment for antibodies targeting B5 and A33. PMID:23152530

Picornavirus 2A protease regulates stress granule formation to facilitate viral translation

PubMed Central

Yang, Xiaodan; Hu, Zhulong; Fan, Shanshan; Zhang, Qiang; Zhong, Yi; Guo, Dong; Qin, Yali

2018-01-01

Stress granules (SGs) contain stalled messenger ribonucleoprotein complexes and are related to the regulation of mRNA translation. Picornavirus infection can interfere with the formation of SGs. However, the detailed molecular mechanisms and functions of picornavirus-mediated regulation of SG formation are not clear. Here, we found that the 2A protease of a picornavirus, EV71, induced atypical stress granule (aSG), but not typical stress granule (tSG), formation via cleavage of eIF4GI. Furthermore, 2A was required and sufficient to inhibit tSGs induced by EV71 infection, sodium arsenite, or heat shock. Infection of 2A protease activity-inactivated recombinant EV71 (EV71-2AC110S) failed to induce aSG formation and only induced tSG formation, which is PKR and eIF2α phosphorylation-dependent. By using a Renilla luciferase mRNA reporter system and RNA fluorescence in situ hybridization assay, we found that EV71-induced aSGs were beneficial to viral translation through sequestering only cellular mRNAs, but not viral mRNAs. In addition, we found that the 2A protease of other picornaviruses such as poliovirus and coxsackievirus also induced aSG formation and blocked tSG formation. Taken together, our results demonstrate that, on one hand, EV71 infection induces tSG formation via the PKR-eIF2α pathway, and on the other hand, 2A, but not 3C, blocks tSG formation. Instead, 2A induces aSG formation by cleaving eIF4GI to sequester cellular mRNA but release viral mRNA, thereby facilitating viral translation. PMID:29415027

Developing live vaccines against Yersinia pestis

PubMed Central

Sun, Wei; Roland, Kenneth L.; Curtiss, Roy

2014-01-01

Three great plague pandemics caused by the gram-negative bacterium Yersinia pestis have killed nearly 200 million people and it has been linked to biowarfare in the past. Plague is endemic in many parts of the world. In addition, the risk of plague as a bioweapon has prompted increased research to develop plague vaccines against this disease. Injectable subunit vaccines are being developed in the United States and United Kingdom. However, the live attenuated Y. pestis-EV NIIEG strain has been used as a vaccine for more than 70 years in the former Soviet Union and in some parts of Asia and provides a high degree of efficacy against plague. This vaccine has not gained general acceptance because of safety concerns. In recent years, modern molecular biological techniques have been applied to Y. pestis to construct strains with specific defined mutations designed to create safe, immunogenic vaccines with potential for use in humans and as bait vaccines to reduce the load of Y. pestis in the environment. In addition, a number of live, vectored vaccines have been reported using attenuated viral vectors or attenuated Salmonella strains to deliver plague antigens. Here we summarize the progress of live attenuated vaccines against plague. PMID:21918302

Structure-activity relationship studies on a Trp dendrimer with dual activities against HIV and enterovirus A71. Modifications on the amino acid.

PubMed

Martínez-Gualda, Belén; Sun, Liang; Rivero-Buceta, Eva; Flores, Aida; Quesada, Ernesto; Balzarini, Jan; Noppen, Sam; Liekens, Sandra; Schols, Dominique; Neyts, Johan; Leyssen, Pieter; Mirabelli, Carmen; Camarasa, María-José; San-Félix, Ana

2017-03-01

We have recently described a new class of dendrimers with tryptophan (Trp) on the surface that show dual antiviral activities against HIV and EV71 enterovirus. The prototype compound of this family is a pentaerythritol derivative with 12 Trps on the periphery. Here we complete the structure-activity relationship studies of this family to identify key features that might be significant for the antiviral activity. With this aim, novel dendrimers containing different amino acids (aromatic and non-aromatic), tryptamine (a "decarboxylated" analogue of Trp) and N-methyl Trp on the periphery have been prepared. Dendrimer with N-Methyl Trp was the most active against HIV-1 and HIV-2 while dendrimer with tyrosine was endowed with the most potent antiviral activity against EV71. This tyrosine dendrimer proved to inhibit a large panel of EV71 clinical isolates (belonging to different clusters) in the low nanomolar/high picomolar range. In addition, a new synthetic procedure (convergent approach) has been developed for the synthesis of the prototype and some other dendrimers. This convergent approach proved more efficient (higher yields, easier purification) than the divergent approach previously reported. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Enterovirus 3A Facilitates Viral Replication by Promoting Phosphatidylinositol 4-Kinase IIIβ–ACBD3 Interaction

PubMed Central

Xiao, Xia; Lei, Xiaobo; Zhang, Zhenzhen; Ma, Yijie; Qi, Jianli; Wu, Chao; Xiao, Yan; Li, Li

2017-01-01

ABSTRACT Like other enteroviruses, enterovirus 71 (EV71) relies on phosphatidylinositol 4-kinase IIIβ (PI4KB) for genome RNA replication. However, how PI4KB is recruited to the genome replication sites of EV71 remains elusive. Recently, we reported that a host factor, ACBD3, is needed for EV71 replication by interacting with viral 3A protein. Here, we show that ACBD3 is required for the recruitment of PI4KB to RNA replication sites. Overexpression of viral 3A or EV71 infection stimulates the interaction of PI4KB and ACBD3. Consistently, EV71 infection induces the production of phosphatidylinositol-4-phosphate (PI4P). Furthermore, PI4KB, ACBD3, and 3A are all localized to the viral-RNA replication sites. Accordingly, PI4KB or ACBD3 depletion by small interfering RNA (siRNA) leads to a reduction in PI4P production after EV71 infection. I44A or H54Y substitution in 3A interrupts the stimulation of PI4KB and ACBD3. Further analysis suggests that stimulation of ACBD3-PI4KB interaction is also important for the replication of enterovirus 68 but disadvantageous to human rhinovirus 16. These results reveal a mechanism of enterovirus replication that involves a selective strategy for recruitment of PI4KB to the RNA replication sites. IMPORTANCE Enterovirus 71, like other human enteroviruses, replicates its genome within host cells, where viral proteins efficiently utilize cellular machineries. While multiple factors are involved, it is largely unclear how viral replication is controlled. We show that the 3A protein of enterovirus 71 recruits an enzyme, phosphatidylinositol 4-kinase IIIβ, by interacting with ACBD3, which alters cellular membranes through the production of a lipid, PI4P. Consequently, the viral and host proteins form a large complex that is necessary for RNA synthesis at replication sites. Notably, PI4KB-ACBD3 interaction also differentially mediates the replication of enterovirus 68 and rhinovirus 16. These results provide new insight into the molecular network of enterovirus replication. PMID:28701404

9 CFR 113.71 - Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Chlamydia Psittaci Vaccine (Feline... VECTORS STANDARD REQUIREMENTS Live Bacterial Vaccines § 113.71 Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia. Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia, shall be...

9 CFR 113.71 - Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Chlamydia Psittaci Vaccine (Feline... VECTORS STANDARD REQUIREMENTS Live Bacterial Vaccines § 113.71 Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia. Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia, shall be...

9 CFR 113.71 - Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Chlamydia Psittaci Vaccine (Feline... VECTORS STANDARD REQUIREMENTS Live Bacterial Vaccines § 113.71 Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia. Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia, shall be...

9 CFR 113.71 - Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Chlamydia Psittaci Vaccine (Feline... VECTORS STANDARD REQUIREMENTS Live Bacterial Vaccines § 113.71 Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia. Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia, shall be...

9 CFR 113.71 - Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Chlamydia Psittaci Vaccine (Feline... VECTORS STANDARD REQUIREMENTS Live Bacterial Vaccines § 113.71 Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia. Chlamydia Psittaci Vaccine (Feline Pneumonitis), Live Chlamydia, shall be...

TIA-1 and TIAR interact with 5'-UTR of enterovirus 71 genome and facilitate viral replication.

PubMed

Wang, Xiaohui; Wang, Huanru; Li, Yixuan; Jin, Yu; Chu, Ying; Su, Airong; Wu, Zhiwei

2015-10-16

Enterovirus 71 is one of the major causative pathogens of HFMD in children. Upon infection, the viral RNA is translated in an IRES-dependent manner and requires several host factors for effective replication. Here, we found that T-cell-restricted intracellular antigen 1 (TIA-1), and TIA-1 related protein (TIAR) were translocated from nucleus to cytoplasm after EV71 infection and localized to the sites of viral replication. We found that TIA-1 and TIAR can facilitate EV71 replication by enhancing the viral genome synthesis in host cells. We demonstrated that both proteins bound to the stem-loop I of 5'-UTR of viral genome and improved the stability of viral genomic RNA. Our results suggest that TIA-1 and TIAR are two new host factors that interact with 5-UTR of EV71 genome and positively regulate viral replication. Copyright © 2015 Elsevier Inc. All rights reserved.

Phylogenetic Analysis of Enterovirus 71 Strains Isolated during Linked Epidemics in Malaysia, Singapore, and Western Australia

PubMed Central

McMinn, Peter; Lindsay, Katie; Perera, David; Chan, Hung Ming; Chan, Kwai Peng; Cardosa, Mary Jane

2001-01-01

Enterovirus 71 (EV71) is a frequent cause of hand, foot, and mouth disease (HFMD) epidemics associated with severe neurological sequelae in a small proportion of cases. There has been a significant increase in EV71 epidemic activity throughout the Asia-Pacific region since 1997. Recent HFMD epidemics in this region have been associated with a severe form of brainstem encephalitis associated with pulmonary edema and high case fatality rates. In this study, we show that four genetic lineages of EV71 have been prevalent in the Asia-Pacific region since 1997, including two previously undescribed genogroups (B3 and B4). Furthermore, we show that viruses belonging to genogroups B3 and B4 have circulated endemically in Southeast Asia during this period and have been the primary cause of several large HFMD or encephalitis epidemics in Malaysia, Singapore, and Western Australia. PMID:11462047

Comparative Evaluation of Vaccine Efficacy of Recombinant Marek's Disease Virus Vaccine Lacking Meq Oncogene in Commercial Chickens

USDA-ARS?s Scientific Manuscript database

Marek's disease virus oncogene meq has been identified as the gene involved in tumorigenesis in chickens. We have recently developed a Meq-null virus, rMd5delMeq, in which the oncogene Meq was deleted. Vaccine efficacy experiments conducted in ADOL 15I5 x 71 chickens vaccinated with rMd5delMeq virus...

Evolution and Emergence of Enteroviruses through Intra- and Inter-species Recombination: Plasticity and Phenotypic Impact of Modular Genetic Exchanges in the 5' Untranslated Region.

PubMed

Muslin, Claire; Joffret, Marie-Line; Pelletier, Isabelle; Blondel, Bruno; Delpeyroux, Francis

2015-01-01

Genetic recombination shapes the diversity of RNA viruses, including enteroviruses (EVs), which frequently have mosaic genomes. Pathogenic circulating vaccine-derived poliovirus (cVDPV) genomes consist of mutated vaccine poliovirus (PV) sequences encoding capsid proteins, and sequences encoding nonstructural proteins derived from other species' C EVs, including certain coxsackieviruses A (CV-A) in particular. Many cVDPV genomes also have an exogenous 5' untranslated region (5' UTR). This region is involved in virulence and includes the cloverleaf (CL) and the internal ribosomal entry site, which play major roles in replication and the initiation of translation, respectively. We investigated the plasticity of the PV genome in terms of recombination in the 5' UTR, by developing an experimental model involving the rescue of a bipartite PV/CV-A cVDPV genome rendered defective by mutations in the CL, following the co-transfection of cells with 5' UTR RNAs from each of the four human EV species (EV-A to -D). The defective cVDPV was rescued by recombination with 5' UTR sequences from the four EV species. Homologous and nonhomologous recombinants with large deletions or insertions in three hotspots were isolated, revealing a striking plasticity of the 5' UTR. By contrast to the recombination of the cVDPV with the 5' UTR of group II (EV-A and -B), which can decrease viral replication and virulence, recombination with the 5' UTRs of group I (EV-C and -D) appeared to be evolutionarily neutral or associated with a gain in fitness. This study illustrates how the genomes of positive-strand RNA viruses can evolve into mosaic recombinant genomes through intra- or inter-species modular genetic exchanges, favoring the emergence of new recombinant lineages.

Enterovirus 71 can directly infect the brainstem via cranial nerves and infection can be ameliorated by passive immunization.

PubMed

Tan, Soon Hao; Ong, Kien Chai; Wong, Kum Thong

2014-11-01

Enterovirus 71 (EV71)-associated hand, foot, and mouth disease may be complicated by encephalomyelitis. We investigated EV71 brainstem infection and whether this infection could be ameliorated by passive immunization in a mouse model. Enterovirus 71 was injected into unilateral jaw/facial muscles of 2-week-old mice, and hyperimmune sera were given before or after infection. Harvested tissues were studied by light microscopy, immunohistochemistry, in situ hybridization, and viral titration. In unimmunized mice, viral antigen and RNA were detected within 24 hours after infection only in ipsilateral cranial nerves, motor trigeminal nucleus, reticular formation, and facial nucleus; viral titers were significantly higher in the brainstem than in the spinal cord samples. Mice given preinfection hyperimmune serum showed a marked reduction of ipsilateral viral antigen/RNA and viral titers in the brainstem in a dose-dependent manner. With optimum hyperimmune serum given after infection, brainstem infection was significantly reduced in a time-dependent manner. A delay in disease onset and a reduction of disease severity and mortality were also observed. Thus, EV71 can directly infect the brainstem, including the medulla, via cranial nerves, most likely by retrograde axonal transport. This may explain the sudden cardiorespiratory collapse in human patients with fatal encephalomyelitis. Moreover, our results suggest that passive immunization may still benefit EV71-infected patients who have neurologic complications.

Time series analysis of reported cases of hand, foot, and mouth disease from 2010 to 2013 in Wuhan, China.

PubMed

Chen, Banghua; Sumi, Ayako; Toyoda, Shin'ichi; Hu, Quan; Zhou, Dunjin; Mise, Keiji; Zhao, Junchan; Kobayashi, Nobumichi

2015-11-03

Hand, foot, and mouth disease (HFMD) is an infectious disease caused by a group of enteroviruses, including Coxsackievirus A16 (CVA16) and Enterovirus A71 (EV-A71). In recent decades, Asian countries have experienced frequent and widespread HFMD outbreaks, with deaths predominantly among children. In several Asian countries, epidemics usually peak in the late spring/early summer, with a second small peak in late autumn/early winter. We investigated the possible underlying association between the seasonality of HFMD epidemics and meteorological variables, which could improve our ability to predict HFMD epidemics. We used a time series analysis composed of a spectral analysis based on the maximum entropy method (MEM) in the frequency domain and the nonlinear least squares method in the time domain. The time series analysis was applied to three kinds of monthly time series data collected in Wuhan, China, where high-quality surveillance data for HFMD have been collected: (i) reported cases of HFMD, (ii) reported cases of EV-A71 and CVA16 detected in HFMD patients, and (iii) meteorological variables. In the power spectral densities for HFMD and EV-A71, the dominant spectral lines were observed at frequency positions corresponding to 1-year and 6-month cycles. The optimum least squares fitting (LSF) curves calculated for the 1-year and 6-month cycles reproduced the bimodal cycles that were clearly observed in the HFMD and EV-A71 data. The peak months on the LSF curves for the HFMD data were consistent with those for the EV-A71 data. The risk of infection was relatively high at 10 °C ≤ t < 15 °C (t, temperature [°C]) and 15 °C ≤ t < 20 °C, and peaked at 20 °C ≤ t < 25 °C. In this study, the HFMD infections occurring in Wuhan showed two seasonal peaks, in summer (June) and winter (November or December). The results obtained with a time series analysis suggest that the bimodal seasonal peaks in HFMD epidemics are attributable to EV-A71 epidemics. Our results suggest that controlling the spread of EV-A71 infections when the temperature is approximately 20-25 °C should be considered to prevent HFMD infections in Wuhan, China.

[Genetic evidence for recombination and mutation in the emergence of human enterovirus 71].

PubMed

Liu, Ai-Ping; Tan, Hui; Xie, Qun; Chen, Bai-Tang; Liu, Xiao-Feng; Zhang, Yong

2014-09-01

We wished to understand the genetic recombination and phylogenetic characteristics of human en- terovirus A71 (EV-A71) and to explore its potential virulence-related sites. Full-length genomes of three EV-A71 strains isolated from patients in Chenzhou City (China) were sequenced and analyzed. Possible re- combination events and crossover sites were analyzed with Recombination Detection Program v4. 1. 6 by comparison with the complete genome sequences of 231 strains of EV-A71. Similarly, plot and bootscanning analyses were undertaken with SimPlot v3. 5. 1. Phylogenetic trees based on the sequences of VP1 regions were constructed with MEGA v5. 2 using the Kimura two-parameter model and neighbor-joining method. Results suggested that recombination events were detected among the three EV-A71 isolates from Chenzhou City. The common main parent sequence was from JF799986 isolated from samples in Guang- zhou City (China) in 2009, and the minor parent sequence was TW/70516/08. Intertypic recombination e- vents were found in the C4b strain (strain SHZH98 isolated in 1998) and C4a strain (Fuyang strain isola- ted in 2008) with the prototype strains of CVA4 and CVA14 in the 3D region. The chi-square test was used to screen-out potential virulence-related sites with nucleotide substitutions of different types of hand, foot, and mouth disease (HFMD) cases using SPSS v19.0. Results suggested that there were no significant nucleotide substitutions between death cases and severe-HFMD cases. Eighteen significant nucleotide substitutions were found between death/severe-HFMD cases and mild-HFMD cases, and all these 18 substitutions were distributed only in P2 and P3 regions. Intertypic recombination among the predominant circulating EV-A71 strains in the Chinese mainland and other EV-A strains probably dates before 1998, and intratypic recombination might have occurred frequently in the HFMD outbreak from 2008 to 2012. Substitutions in the non-capsid region may be correlated with the changes in virulence of EV-A71. These data suggest that researchers should pay more attention to the relationships between substitutions in the noncapsid region and the virulence of the virus.

Structures of the Procapsid and Mature Virion of Enterovirus 71 Strain 1095

PubMed Central

Cifuente, Javier O.; Lee, Hyunwook; Yoder, Joshua D.; Shingler, Kristin L.; Carnegie, Michael S.; Yoder, Jennifer L.; Ashley, Robert E.; Makhov, Alexander M.; Conway, James F.

2013-01-01

Enterovirus 71 (EV71) is an important emerging human pathogen with a global distribution and presents a disease pattern resembling poliomyelitis with seasonal epidemics that include cases of severe neurological complications, such as acute flaccid paralysis. EV71 is a member of the Picornaviridae family, which consists of icosahedral, nonenveloped, single-stranded RNA viruses. Here we report structures derived from X-ray crystallography and cryoelectron microscopy (cryo-EM) for the 1095 strain of EV71, including a putative precursor in virus assembly, the procapsid, and the mature virus capsid. The cryo-EM map of the procapsid provides new structural information on portions of the capsid proteins VP0 and VP1 that are disordered in the higher-resolution crystal structures. Our structures solved from virus particles in solution are largely in agreement with those from prior X-ray crystallographic studies; however, we observe small but significant structural differences for the 1095 procapsid compared to a structure solved in a previous study (X. Wang, W. Peng, J. Ren, Z. Hu, J. Xu, Z. Lou, X. Li, W. Yin, X. Shen, C. Porta, T. S. Walter, G. Evans, D. Axford, R. Owen, D. J. Rowlands, J. Wang, D. I. Stuart, E. E. Fry, and Z. Rao, Nat. Struct. Mol. Biol. 19:424–429, 2012) for a different strain of EV71. For both EV71 strains, the procapsid is significantly larger in diameter than the mature capsid, unlike in any other picornavirus. Nonetheless, our results demonstrate that picornavirus capsid expansion is possible without RNA encapsidation and that picornavirus assembly may involve an inward radial collapse of the procapsid to yield the native virion. PMID:23637404

Yersinia pestis biovar Microtus strain 201, an avirulent strain to humans, provides protection against bubonic plague in rhesus macaques.

PubMed

Zhang, Qingwen; Wang, Qiong; Tian, Guang; Qi, Zhizhen; Zhang, Xuecan; Wu, Xiaohong; Qiu, Yefeng; Bi, Yujing; Yang, Xiaoyan; Xin, Youquan; He, Jian; Zhou, Jiyuan; Zeng, Lin; Yang, Ruifu; Wang, Xiaoyi

2014-01-01

Yersinia pestis biovar Microtus is considered to be a virulent to larger mammals, including guinea pigs, rabbits and humans. It may be used as live attenuated plague vaccine candidates in terms of its low virulence. However, the Microtus strain's protection against plague has yet to be demonstrated in larger mammals. In this study, we evaluated the protective efficacy of the Microtus strain 201 as a live attenuated plague vaccine candidate. Our results show that this strain is highly attenuated by subcutaneous route, elicits an F1-specific antibody titer similar to the EV and provides a protective efficacy similar to the EV against bubonic plague in Chinese-origin rhesus macaques. The Microtus strain 201 could induce elevated secretion of both Th1-associated cytokines (IFN-γ, IL-2 and TNF-α) and Th2-associated cytokines (IL-4, IL-5, and IL-6), as well as chemokines MCP-1 and IL-8. However, the protected animals developed skin ulcer at challenge site with different severity in most of the immunized and some of the EV-immunized monkeys. Generally, the Microtus strain 201 represented a good plague vaccine candidate based on its ability to generate strong humoral and cell-mediated immune responses as well as its good protection against high dose of subcutaneous virulent Y. pestis challenge.

Yersinia pestis biovar Microtus strain 201, an avirulent strain to humans, provides protection against bubonic plague in rhesus macaques

PubMed Central

Zhang, Qingwen; Wang, Qiong; Tian, Guang; Qi, Zhizhen; Zhang, Xuecan; Wu, Xiaohong; Qiu, Yefeng; Bi, Yujing; Yang, Xiaoyan; Xin, Youquan; He, Jian; Zhou, Jiyuan; Zeng, Lin; Yang, Ruifu; Wang, Xiaoyi

2014-01-01

Yersinia pestis biovar Microtus is considered to be a virulent to larger mammals, including guinea pigs, rabbits and humans. It may be used as live attenuated plague vaccine candidates in terms of its low virulence. However, the Microtus strain’s protection against plague has yet to be demonstrated in larger mammals. In this study, we evaluated the protective efficacy of the Microtus strain 201 as a live attenuated plague vaccine candidate. Our results show that this strain is highly attenuated by subcutaneous route, elicits an F1-specific antibody titer similar to the EV and provides a protective efficacy similar to the EV against bubonic plague in Chinese-origin rhesus macaques. The Microtus strain 201 could induce elevated secretion of both Th1-associated cytokines (IFN-γ, IL-2 and TNF-α) and Th2-associated cytokines (IL-4, IL-5, and IL-6), as well as chemokines MCP-1 and IL-8. However, the protected animals developed skin ulcer at challenge site with different severity in most of the immunized and some of the EV-immunized monkeys. Generally, the Microtus strain 201 represented a good plague vaccine candidate based on its ability to generate strong humoral and cell-mediated immune responses as well as its good protection against high dose of subcutaneous virulent Y. pestis challenge. PMID:24225642

Fragment-wise design of inhibitors to 3C proteinase from enterovirus 71.

PubMed

Wu, Caiming; Zhang, Lanjun; Li, Peng; Cai, Qixu; Peng, Xuanjia; Yin, Ke; Chen, Xinsheng; Ren, Haixia; Zhong, Shilin; Weng, Yuwei; Guan, Yi; Chen, Shuhui; Wu, Jinzhun; Li, Jian; Lin, Tianwei

2016-06-01

Enterovirus 71 (EV71) is a causative agent of hand, foot and mouth disease (HFMD), which can spread its infection to central nervous and other systems with severe consequence. A key factor in the replication of EV71 is its 3C proteinase (3C(pro)), a significant drug target. Peptidomimetics were employed as inhibitors of this enzyme for developing antivirals. However, the peptide bonds in these peptidomimetics are a source of low bioavailability due to their susceptibility to protease digestion. To produce non-peptidomimetic inhibitors by replacing these peptide bonds, it would be important to gain better understanding on the contribution of each component to the interaction and potency. A series of compounds of different lengths targeting 3C(pro) and having an α,β-unsaturated ester as the warhead were synthesized and their interactions with the enzyme were evaluated by complex structure analyses and potency assays for a better understanding on the relationship between potency and evolution of interaction. The P2 moiety of the compound would need to be oriented to interact in the S2 site in the substrate binding cleft and the P3-P4 moieties were required to generate sufficient potency. A hydrophobic terminal group will benefit the cellular uptake and improve the activity in vivo. The data presented here provide a basis for designing a new generation of non-peptidomimetics to target EV71 3C(pro). Copyright © 2016 Elsevier B.V. All rights reserved.

Characterization of systemic and pneumonic murine models of plague infection using a conditionally virulent strain.

PubMed

Mellado-Sanchez, Gabriela; Ramirez, Karina; Drachenberg, Cinthia B; Diaz-McNair, Jovita; Rodriguez, Ana L; Galen, James E; Nataro, James P; Pasetti, Marcela F

2013-03-01

Yersinia pestis causes bubonic and pneumonic plague in humans. The pneumonic infection is the most severe and invariably fatal if untreated. Because of its high virulence, ease of delivery and precedent of use in warfare, Y. pestis is considered as a potential bioterror agent. No licensed plague vaccine is currently available in the US. Laboratory research with virulent strains requires appropriate biocontainment (i.e., Biosafety Level 3 (BSL-3) for procedures that generate aerosol/droplets) and secure facilities that comply with federal select agent regulations. To assist in the identification of promising vaccine candidates during the early phases of development, we characterized mouse models of systemic and pneumonic plague infection using the Y. pestis strain EV76, an attenuated human vaccine strain that can be rendered virulent in mice under in vivo iron supplementation. Mice inoculated intranasally or intravenously with Y. pestis EV76 in the presence of iron developed a systemic and pneumonic plague infection that resulted in disease and lethality. Bacteria replicated and severely compromised the spleen, liver and lungs. Susceptibility was age dependent, with younger mice being more vulnerable to pneumonic infection. We used these models of infection to assess the protective capacity of newly developed Salmonella-based plague vaccines. The protective outcome varied depending on the route and dose of infection. Protection was associated with the induction of specific immunological effectors in systemic/mucosal compartments. The models of infection described could serve as safe and practical tools for identifying promising vaccine candidates that warrant further potency evaluation using fully virulent strains in BSL-3 settings. Copyright © 2012 Elsevier Ltd. All rights reserved.

Extracellular Vesicles: Role in Inflammatory Responses and Potential Uses in Vaccination in Cancer and Infectious Diseases.

PubMed

Campos, João Henrique; Soares, Rodrigo Pedro; Ribeiro, Kleber; Andrade, André Cronemberger; Batista, Wagner Luiz; Torrecilhas, Ana Claudia

2015-01-01

Almost all cells and organisms release membrane structures containing proteins, lipids, and nucleic acids called extracellular vesicles (EVs), which have a wide range of functions concerning intercellular communication and signaling events. Recently, the characterization and understanding of their biological role have become a main research area due to their potential role in vaccination, as biomarkers antigens, early diagnostic tools, and therapeutic applications. Here, we will overview the recent advances and studies of Evs shed by tumor cells, bacteria, parasites, and fungi, focusing on their inflammatory role and their potential use in vaccination and diagnostic of cancer and infectious diseases.

Extracellular Vesicles: Role in Inflammatory Responses and Potential Uses in Vaccination in Cancer and Infectious Diseases

PubMed Central

Campos, João Henrique; Soares, Rodrigo Pedro; Ribeiro, Kleber; Cronemberger Andrade, André; Batista, Wagner Luiz; Torrecilhas, Ana Claudia

2015-01-01

Almost all cells and organisms release membrane structures containing proteins, lipids, and nucleic acids called extracellular vesicles (EVs), which have a wide range of functions concerning intercellular communication and signaling events. Recently, the characterization and understanding of their biological role have become a main research area due to their potential role in vaccination, as biomarkers antigens, early diagnostic tools, and therapeutic applications. Here, we will overview the recent advances and studies of Evs shed by tumor cells, bacteria, parasites, and fungi, focusing on their inflammatory role and their potential use in vaccination and diagnostic of cancer and infectious diseases. PMID:26380326

BA71ΔCD2: a New Recombinant Live Attenuated African Swine Fever Virus with Cross-Protective Capabilities.

PubMed

Monteagudo, Paula L; Lacasta, Anna; López, Elisabeth; Bosch, Laia; Collado, Javier; Pina-Pedrero, Sonia; Correa-Fiz, Florencia; Accensi, Francesc; Navas, María Jesús; Vidal, Enric; Bustos, María J; Rodríguez, Javier M; Gallei, Andreas; Nikolin, Veljko; Salas, María L; Rodríguez, Fernando

2017-11-01

African swine fever is a highly contagious viral disease of mandatory declaration to the World Organization for Animal Health (OIE). The lack of available vaccines makes its control difficult; thus, African swine fever virus (ASFV) represents a major threat to the swine industry. Inactivated vaccines do not confer solid protection against ASFV. Conversely, live attenuated viruses (LAV), either naturally isolated or obtained by genetic manipulation, have demonstrated reliable protection against homologous ASFV strains, although little or no protection has been demonstrated against heterologous viruses. Safety concerns are a major issue for the use of ASFV attenuated vaccine candidates and have hampered their implementation in the field so far. While trying to develop safer and efficient ASFV vaccines, we found that the deletion of the viral CD2v (EP402R) gene highly attenuated the virulent BA71 strain in vivo Inoculation of pigs with the deletion mutant virus BA71ΔCD2 conferred protection not only against lethal challenge with the parental BA71 but also against the heterologous E75 (both genotype I strains). The protection induced was dose dependent, and the cross-protection observed in vivo correlated with the ability of BA71ΔCD2 to induce specific CD8 + T cells capable of recognizing both BA71 and E75 viruses in vitro Interestingly, 100% of the pigs immunized with BA71ΔCD2 also survived lethal challenge with Georgia 2007/1, the genotype II strain of ASFV currently circulating in continental Europe. These results open new avenues to design ASFV cross-protective vaccines, essential to fight ASFV in areas where the virus is endemic and where multiple viruses are circulating. IMPORTANCE African swine fever virus (ASFV) remains enzootic in most countries of Sub-Saharan Africa, today representing a major threat for the development of their swine industry. The uncontrolled presence of ASFV has favored its periodic exportation to other countries, the last event being in Georgia in 2007. Since then, ASFV has spread toward neighboring countries, reaching the European Union's east border in 2014. The lack of available vaccines against ASFV makes its control difficult; so far, only live attenuated viruses have demonstrated solid protection against homologous experimental challenges, but they have failed at inducing solid cross-protective immunity against heterologous viruses. Here we describe a new LAV candidate with unique cross-protective abilities: BA71ΔCD2. Inoculation of BA71ΔCD2 protected pigs not only against experimental challenge with BA71, the virulent parental strain, but also against heterologous viruses, including Georgia 2007/1, the genotype II strain of ASFV currently circulating in Eastern Europe. Copyright © 2017 Monteagudo et al.

BA71ΔCD2: a New Recombinant Live Attenuated African Swine Fever Virus with Cross-Protective Capabilities

PubMed Central

Monteagudo, Paula L.; Lacasta, Anna; López, Elisabeth; Bosch, Laia; Collado, Javier; Pina-Pedrero, Sonia; Correa-Fiz, Florencia; Accensi, Francesc; Navas, María Jesús; Vidal, Enric; Bustos, María J.; Rodríguez, Javier M.; Gallei, Andreas; Nikolin, Veljko; Salas, María L.

2017-01-01

ABSTRACT African swine fever is a highly contagious viral disease of mandatory declaration to the World Organization for Animal Health (OIE). The lack of available vaccines makes its control difficult; thus, African swine fever virus (ASFV) represents a major threat to the swine industry. Inactivated vaccines do not confer solid protection against ASFV. Conversely, live attenuated viruses (LAV), either naturally isolated or obtained by genetic manipulation, have demonstrated reliable protection against homologous ASFV strains, although little or no protection has been demonstrated against heterologous viruses. Safety concerns are a major issue for the use of ASFV attenuated vaccine candidates and have hampered their implementation in the field so far. While trying to develop safer and efficient ASFV vaccines, we found that the deletion of the viral CD2v (EP402R) gene highly attenuated the virulent BA71 strain in vivo. Inoculation of pigs with the deletion mutant virus BA71ΔCD2 conferred protection not only against lethal challenge with the parental BA71 but also against the heterologous E75 (both genotype I strains). The protection induced was dose dependent, and the cross-protection observed in vivo correlated with the ability of BA71ΔCD2 to induce specific CD8+ T cells capable of recognizing both BA71 and E75 viruses in vitro. Interestingly, 100% of the pigs immunized with BA71ΔCD2 also survived lethal challenge with Georgia 2007/1, the genotype II strain of ASFV currently circulating in continental Europe. These results open new avenues to design ASFV cross-protective vaccines, essential to fight ASFV in areas where the virus is endemic and where multiple viruses are circulating. IMPORTANCE African swine fever virus (ASFV) remains enzootic in most countries of Sub-Saharan Africa, today representing a major threat for the development of their swine industry. The uncontrolled presence of ASFV has favored its periodic exportation to other countries, the last event being in Georgia in 2007. Since then, ASFV has spread toward neighboring countries, reaching the European Union's east border in 2014. The lack of available vaccines against ASFV makes its control difficult; so far, only live attenuated viruses have demonstrated solid protection against homologous experimental challenges, but they have failed at inducing solid cross-protective immunity against heterologous viruses. Here we describe a new LAV candidate with unique cross-protective abilities: BA71ΔCD2. Inoculation of BA71ΔCD2 protected pigs not only against experimental challenge with BA71, the virulent parental strain, but also against heterologous viruses, including Georgia 2007/1, the genotype II strain of ASFV currently circulating in Eastern Europe. PMID:28814514

Polio and Measles Down the Drain: Environmental Enterovirus Surveillance in the Netherlands, 2005 to 2015.

PubMed

Benschop, Kimberley S M; van der Avoort, Harrie G; Jusic, Edin; Vennema, Harry; van Binnendijk, Rob; Duizer, Erwin

2017-07-01

Polioviruses (PVs) are members of the genus Enterovirus In the Netherlands, the exclusion of PV circulation is based on clinical enterovirus (EV) surveillance (CEVS) of EV-positive cases and routine environmental EV surveillance (EEVS) conducted on sewage samples collected in the region of the Netherlands where vaccination coverage is low due to religious reasons. We compared the EEVS data to those of the CEVS to gain insight into the relevance of EEVS for poliovirus and nonpolio enterovirus surveillance. Following the polio outbreak in Syria, EEVS was performed at the primary refugee center in Ter Apel in the Netherlands, and data were compared to those of CEVS and EEVS. Furthermore, we assessed the feasibility of poliovirus detection by EEVS using measles virus detection in sewage during a measles outbreak as a proxy. Two Sabin-like PVs were found in routine EEVS, 11 Sabin-like PVs were detected in the CEVS, and one Sabin-like PV was found in the Ter Apel sewage. We observed significant differences between the three programs regarding which EVs were found. In 6 sewage samples collected during the measles outbreak in 2013, measles virus RNA was detected in regions where measles cases were identified. In conclusion, we detected PVs, nonpolio EVs, and measles virus in sewage and showed that environmental surveillance is useful for poliovirus detection in the Netherlands, where live oral poliovirus vaccine is not used and communities with lower vaccination coverage exist. EEVS led to the detection of EV types not seen in the CEVS, showing that EEVS is complementary to CEVS. IMPORTANCE We show that environmental enterovirus surveillance complements clinical enterovirus surveillance for poliovirus detection, or exclusion, and for nonpolio enterovirus surveillance. Even in the presence of adequate surveillance, only a very limited number of Sabin-like poliovirus strains were detected in a 10-year period, and no signs of transmission of oral polio vaccine (OPV) strains were found in a country using exclusively inactivated polio vaccine (IPV). Measles viruses can be detected during an outbreak in sewage samples collected and concentrated following procedures used for environmental enterovirus surveillance. Copyright © 2017 American Society for Microbiology.

Polio and Measles Down the Drain: Environmental Enterovirus Surveillance in the Netherlands, 2005 to 2015

PubMed Central

Benschop, Kimberley S. M.; van der Avoort, Harrie G.; Jusic, Edin; Vennema, Harry; van Binnendijk, Rob

2017-01-01

ABSTRACT Polioviruses (PVs) are members of the genus Enterovirus. In the Netherlands, the exclusion of PV circulation is based on clinical enterovirus (EV) surveillance (CEVS) of EV-positive cases and routine environmental EV surveillance (EEVS) conducted on sewage samples collected in the region of the Netherlands where vaccination coverage is low due to religious reasons. We compared the EEVS data to those of the CEVS to gain insight into the relevance of EEVS for poliovirus and nonpolio enterovirus surveillance. Following the polio outbreak in Syria, EEVS was performed at the primary refugee center in Ter Apel in the Netherlands, and data were compared to those of CEVS and EEVS. Furthermore, we assessed the feasibility of poliovirus detection by EEVS using measles virus detection in sewage during a measles outbreak as a proxy. Two Sabin-like PVs were found in routine EEVS, 11 Sabin-like PVs were detected in the CEVS, and one Sabin-like PV was found in the Ter Apel sewage. We observed significant differences between the three programs regarding which EVs were found. In 6 sewage samples collected during the measles outbreak in 2013, measles virus RNA was detected in regions where measles cases were identified. In conclusion, we detected PVs, nonpolio EVs, and measles virus in sewage and showed that environmental surveillance is useful for poliovirus detection in the Netherlands, where live oral poliovirus vaccine is not used and communities with lower vaccination coverage exist. EEVS led to the detection of EV types not seen in the CEVS, showing that EEVS is complementary to CEVS. IMPORTANCE We show that environmental enterovirus surveillance complements clinical enterovirus surveillance for poliovirus detection, or exclusion, and for nonpolio enterovirus surveillance. Even in the presence of adequate surveillance, only a very limited number of Sabin-like poliovirus strains were detected in a 10-year period, and no signs of transmission of oral polio vaccine (OPV) strains were found in a country using exclusively inactivated polio vaccine (IPV). Measles viruses can be detected during an outbreak in sewage samples collected and concentrated following procedures used for environmental enterovirus surveillance. PMID:28432101

Transmission of vaccinia virus, possibly through sexual contact, to a woman at high risk for adverse complications.

PubMed

Said, Maria A; Haile, Charles; Palabindala, Venkataraman; Barker, Naomi; Myers, Robert; Thompson, Ruth; Wilson, Lucy; Allan-Martinez, Frances; Montgomery, Jay; Monroe, Benjamin; Tack, Danielle; Reynolds, Mary; Damon, Inger; Blythe, David

2013-12-01

Severe adverse events, including eczema vaccinatum (EV), can result after smallpox vaccination. Persons at risk for EV include those with underlying dermatologic conditions, such as atopic dermatitis. We investigated a case of vaccinia infection, possibly acquired during sexual contact with a recently vaccinated military service member, in a female Maryland resident with atopic dermatitis. The U.S. Department of Defense's Vaccine Healthcare Centers Network (VHCN) and the Centers for Disease Control and Prevention (CDC) worked in conjunction with the patient's physician and the Maryland Department of Health and Mental Hygiene (DHMH) to confirm the diagnosis, ensure treatment, and prevent further transmission. Specimens collected from the patient were tested at the DHMH laboratories and were positive by real-time polymerase chain reaction for nonvariola orthopoxvirus. Testing at the CDC verified the presence of vaccinia-specific DNA signatures. Continuing spread of the patient's lesions led to the administration of vaccinia immune globulin and strict infection control measures to prevent tertiary transmission to vulnerable family members, also with atopic dermatitis. VHCN contacted the service member to reinforce vaccination site care and hygiene. This case underscores the importance of prevaccination education for those receiving the smallpox vaccine to protect contacts at risk for developing severe adverse reactions. Reprint & Copyright © 2013 Association of Military Surgeons of the U.S.

Genetic characterization of enterovirus strains identified in Hand, Foot and Mouth Disease (HFMD): Emergence of B1c, C1 subgenotypes, E2 sublineage of CVA16, EV71 and CVA6 strains in India.

PubMed

Ganorkar, Nital N; Patil, Pooja R; Tikute, Sanjay S; Gopalkrishna, Varanasi

2017-10-01

Hand, Foot and Mouth disease (HFMD) is a common childhood disease and caused due to Enterovirus-A (EV-A), EV-B and EV-C species worldwide. Cases of HFMD were reported from, Ahmedabad (Gujarat, 2012) and Pune (Maharashtra, 2013-2014) in India. The present study highlights the identification of EV strains (CVA16, CVA6, CVA4 and Echo12), characterization of subgenotypes of CVA16, CVA6 strains during 2012-14 and CVA16, CVA6, EV71 strains reported from the earlier study (2009-10) in HFMD cases from India. A total 158 clinical specimens collected from 64 HFMD cases (2012-2014) were included in the study. EV detection was carried out by 5'NCR based RT-PCR, molecular typing and subgenotyping was by VP1/2A junction or VP1, full VP1 gene amplification respectively followed by phylogenetic analysis. The present study reports 63.92% (101/158) EV positivity by RT-PCR. Ninety four of the 101 (93.06%) EV positive strains were amplified by VP1/2A junction or VP1 regions. Sequence analysis revealed the presence of CVA16 (61.7%), CVA6 (34.04%), CVA4 and Echo12 (4.3%). A total of 114 EV positive strains were genotyped using full and partial VP1 region. All CVA16 Indian strains (n=70) clustered with rarely reported B1c subgenotype, CVA6 (n=43) and EV71 (n=1) strains clustered with sub-lineage E2 and C1 subgenotypes respectively. In summary, the study reports genetic characterization of CVA16, CVA6, CVA4 and Echo12 strains in HFMD cases from India. Circulation of B1c subgenotype of CVA16, E2 sub-lineage of CVA6 and C1 subgenotype of EV 71 strains in HFMD cases were reported for the first time from India. This study helps to understand the genotype distribution, genetic diversity of EV strains associated with HFMD from Eastern, Western and Southern regions in India. Copyright © 2017 Elsevier B.V. All rights reserved.

Enterovirus 71 encephalomyelitis and Japanese encephalitis can be distinguished by topographic distribution of inflammation and specific intraneuronal detection of viral antigen and RNA.

PubMed

Wong, K T; Ng, K Y; Ong, K C; Ng, W F; Shankar, S K; Mahadevan, A; Radotra, B; Su, I J; Lau, G; Ling, A E; Chan, K P; Macorelles, P; Vallet, S; Cardosa, M J; Desai, A; Ravi, V; Nagata, N; Shimizu, H; Takasaki, T

2012-08-01

To investigate if two important epidemic viral encephalitis in children, Enterovirus 71 (EV71) encephalomyelitis and Japanese encephalitis (JE) whose clinical and pathological features may be nonspecific and overlapping, could be distinguished. Tissue sections from the central nervous system of infected cases were examined by light microscopy, immunohistochemistry and in situ hybridization. All 13 cases of EV71 encephalomyelitis collected from Asia and France invariably showed stereotyped distribution of inflammation in the spinal cord, brainstem, hypothalamus, cerebellar dentate nucleus and, to a lesser extent, cerebral cortex and meninges. Anterior pons, corpus striatum, thalamus, temporal lobe, hippocampus and cerebellar cortex were always uninflamed. In contrast, the eight JE cases studied showed inflammation involving most neuronal areas of the central nervous system, including the areas that were uninflamed in EV71 encephalomyelitis. Lesions in both infections were nonspecific, consisting of perivascular and parenchymal infiltration by inflammatory cells, oedematous/necrolytic areas, microglial nodules and neuronophagia. Viral inclusions were absent. Immunohistochemistry and in situ hybridization assays were useful to identify the causative virus, localizing viral antigens and RNA, respectively, almost exclusively to neurones. The stereotyped distribution of inflammatory lesions in EV71 encephalomyelitis appears to be very useful to help distinguish it from JE. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.

Exploration of the anti-enterovirus activity of a series of pleconaril/pirodavir-like compounds.

PubMed

Bernard, Angela; Lacroix, Céline; Cabiddu, Maria G; Neyts, Johan; Leyssen, Pieter; Pompei, Raffaello

2015-04-01

The Enterovirus genus of the Picornaviridae is represented by several viral pathogens that are associated with human disease, namely Poliovirus 1, Enterovirus 71 and Rhinoviruses. Enterovirus 71 has been associated with encephalitis, while Rhinoviruses are a major cause of asthma exacerbations and chronic obstructive pulmonary disease. Based on the structure of both pleconaril and pirodavir, we previously synthesized some original compounds as potential inhibitors of Rhinovirus replication. These compounds were explored for in vitro antiviral potential on other human pathogenic Enteroviruses, namely Enterovirus 71 on rhabdo-myosarcoma cells, Coxsackievirus B3 on Vero cells, Poliovirus 1 and Echovirus 11 on BGM cells. Activity was confirmed for compound against Rhinovirus 14. Furthermore, few compounds showed a cell-protective effect on Enterovirus 71, presented a marked improvement as compared to the reference drug pleconaril for inhibitory activity on both Enterovirus 71 and Poliovirus 1. The most striking observation was the clear cell protective effect for the set of analogues in a virus-cell-based assay for Echovirus 11 with an effective concentration (EC50) as low as 0.3 µM (Selectivity index or SI = 483), and selectivity indexes greater than 857 (EC50 = 0.6 µM) and 1524 (EC50 = 0.33 µM). Some of the evaluated compounds showed potent and selective antiviral activity against several enterovirus species, such as Enterovirus 71 (EV-A), Echovirus 11 (EV-B), and Poliovirus 1 (EV-C). This could be used as a starting point for the development of other pleconaril/pirodavir-like enterovirus inhibitors with broad-spectrum activity and improved effects as compared to the reference drugs. © The Author(s) 2015.

Enterovirus genotypes causing hand foot and mouth disease in Shanghai, China: a molecular epidemiological analysis.

PubMed

Xu, Menghua; Su, Liyun; Cao, Lingfeng; Zhong, Huaqing; Dong, Niuniu; Xu, Jin

2013-10-22

A rapid expansion of hand, foot, and mouth disease (HFMD) outbreaks has occurred and caused deaths in China in recent years, but little is known about the other etiologic agents except enterovirus 71 (EV71) and coxsackievirus A 16 (CA16). The objective of this study is to determine the genotype compositions of enterovirus causing HFMD in Shanghai and identify any associations between enterovirus types and clinical manifestations. Stool specimens were collected from patients hospitalized for treatment of HFMD, from May 2010 to April 2011. Enterovirus was detected by reverse transcription PCR and directly genotyped by sequencing the PCR products. Phylogenetic analysis was based on the VP1 partial gene. Of 290 specimens, 277 (95.5%) tested positive for enterovirus. The major genotypes were EV71 (63.8%), CA10 (9.0%), CA6 (8.3%), CA16 (6.9%), CA12 (2.4%), and CA4 (1.4%). The EV71 strains belonged to the C4a subtype and CA16 belonged to the B subtype. CA6 was closely related to strains detected in Japan, Taiwan and China, and CA10, CA12 and CA4 were phylogenetically similar to other strains circulating in China. Mean hospital stays and the prevalence of complications in patients with EV71 infection were higher than those in patients in CA6, CA10 or CA16 infection (P < 0.05 for all comparisons). Children with CA12 infection were the youngest, and most likely have the highest risk of complications when compared to the other non-EV71 infection groups. This study demonstrated a diversified pathogen compositions attributing to HFMD and clinical symptoms differing in enterovirus genotypes. It deserves our attention as early identification of enterovirus genotypes is important for diagnosis and treatment of HFMD patients.

EV71 3D Protein Binds with NLRP3 and Enhances the Assembly of Inflammasome Complex

PubMed Central

Wan, Pin; Pan, Pan; Zhang, Yecheng; Wu, Kailang; Liu, Yingle; Wu, Jianguo

2017-01-01

Activation of NLRP3 inflammasome is important for effective host defense against invading pathogen. Together with apoptosis-associated speck-like protein containing CARD domain (ASC), NLRP3 induces the cleavage of caspase-1 to facilitate the maturation of interleukin-1beta (IL-1β), an important pro-inflammatory cytokine. IL-1β subsequently plays critical roles in inflammatory responses by activating immune cells and inducing many secondary pro-inflammatory cytokines. Although the role of NLRP3 inflammasome in immune response is well defined, the mechanism underlying its assembly modulated by pathogen infection remains largely unknown. Here, we identified a novel mechanism by which enterovirus 71 (EV71) facilitates the assembly of NLRP3 inflammasome. Our results show that EV71 induces production and secretion of IL-1β in macrophages and peripheral blood mononuclear cells (PBMCs) through activation of NLRP3 inflammasome. EV71 replication and protein synthesis are required for NLRP3-mediated activation of IL-1β. Interestingly, EV71 3D protein, a RNA-dependent RNA polymerase (RdRp) was found to stimulate the activation of NLRP3 inflammasome, the cleavage of pro-caspase-1, and the release of IL-1β through direct binding to NLRP3. More importantly, 3D interacts with NLRP3 to facilitate the assembly of inflammasome complex by forming a 3D-NLRP3-ASC ring-like structure, resulting in the activation of IL-1β. These findings demonstrate a new role of 3D as an important player in the activation of inflammatory response, and identify a novel mechanism underlying the modulation of inflammasome assembly and function induced by pathogen invasion. PMID:28060938

Epidemiologic and clinical features of non-polio enteroviral infections in northern Taiwan in 2008.

PubMed

Hsu, Chien-Hui; Lu, Chun-Yi; Shao, Pei-Lan; Lee, Ping-Ing; Kao, Chuan-Liang; Chung, Ming-Yi; Chang, Luan-Yin; Huang, Li-Min

2011-08-01

Non-polio enteroviruses may cause different diseases, including herpangina, hand-foot-mouth disease (HFMD), meningitis, and nonspecific febrile illness; and cause epidemic outbreak annually. This study delineates the diversity of clinical presentations based on different serotypes and different groups [human enterovirus (HEV)-A and HEV-B] of enteroviruses (EVs) during the 2008 epidemic in National Taiwan University Hospital (NTUH). We retrospectively identified patients younger than 18 years who had positive isolates of non-polio EV in throat swabs, rectal swabs, or cerebrospinal fluid, in NTUH from January 1 to December 31, 2008. For serotyping, immunofluorescence assay and polymerase chain reaction followed by viral structure protein-1 sequencing were applied. We analyzed and compared their clinical features among different serotypes and different groups of EVs. Among 172 patients who were enrolled, 16 serotypes were identified. The major serotype in NTUH was EV71 (25.6%) followed by coxsackievirus A (CA)16 and coxsackievirus B (CB)4. EV71 manifested mostly as HFMD (89%) and was complicated with encephalomyelitis in three patients. Serotypes of HFMD included EV71 (70%), CA16 (27%), CA4, and CA6. Serotypes of herpangina were heterogeneous, and the major serotype was CA2 (35.7%) followed by CB4 (23.8%). Aseptic meningitis was entirely caused by HEV-B and mostly infected by echovirus 30 (50%). Among children with EV-related respiratory tract infection, CB4 (32%) was dominant in upper respiratory tract infection, whereas echovirus 4 (71%) was the major cause of lower respiratory tract infection. Cases of HEV-A were significantly younger than the cases of HEV-B (p = 0.04). Multivariate analysis revealed that the most significant factor associated with hospitalization is HEV-B (odds ratio, 2.2; 95% confidence interval, 1.1-4.2; p = 0.02). At least 16 serotypes circulated in northern Taiwan in 2008. EV71 is the predominant strain in this outbreak. All patients with HFMD were infected by HEV-A, but HEV-B was associated with a higher rate of hospitalization and aseptic meningitis, which should be a cause of alert regarding public health. Copyright © 2011. Published by Elsevier B.V.

Accuracy of Diagnostic Methods and Surveillance Sensitivity for Human Enterovirus, South Korea, 1999–2011

PubMed Central

Hyeon, Ji-Yeon; Hwang, Seoyeon; Kim, Hyejin; Song, Jaehyoung; Ahn, Jeongbae; Kang, Byunghak; Kim, Kisoon; Choi, Wooyoung; Chung, Jae Keun; Kim, Cheon-Hyun; Cho, Kyungsoon; Jee, Youngmee; Kim, Jonghyun; Kim, Kisang; Kim, Sun-Hee; Kim, Min-Ji

2013-01-01

The epidemiology of enteroviral infection in South Korea during 1999–2011 chronicles nationwide outbreaks and changing detection and subtyping methods used over the 13-year period. Of 14,657 patients whose samples were tested, 4,762 (32.5%) samples were positive for human enterovirus (human EV); as diagnostic methods improved, the rate of positive results increased. A seasonal trend of outbreaks was documented. Genotypes enterovirus 71, echovirus 30, coxsackievirus B5, enterovirus 6, and coxsackievirus B2 were the most common genotypes identified. Accurate test results correlated clinical syndromes to enterovirus genotypes: aseptic meningitis to echovirus 30, enterovirus 6, and coxsackievirus B5; hand, foot and mouth disease to coxsackievirus A16; and hand, foot and mouth disease with neurologic complications to enterovirus 71. There are currently no treatments specific to human EV infections; surveillance of enterovirus infections such as this study provides may assist with evaluating the need to research and develop treatments for infections caused by virulent human EV genotypes. PMID:23876671

Coxsackievirus A6 and enterovirus 71 causing hand, foot and mouth disease in Cuba, 2011-2013.

PubMed

Fonseca, Magilé C; Sarmiento, Luis; Resik, Sonia; Martínez, Yenisleidys; Hung, Lai Heng; Morier, Luis; Piñón, Alexander; Valdéz, Odalys; Kourí, Vivian; González, Guelsys

2014-09-01

Hand, foot and mouth disease (HFMD) is usually caused by coxsackievirus A16 or enterovirus 71 (EV71). Between 2011 and 2013, HFMD cases were reported from different Cuban provinces. A total of 42 clinical specimens were obtained from 23 patients. Detection, identification and phylogenetic analysis of enterovirus-associated HFMD were carried out by virus isolation, specific enterovirus PCR and partial VP1 sequences. HEV was detected in 11 HFMD cases. Emerging genetic variants of coxsackievirus A6 and EV71 were identified as the causative agents of the Cuban HFMD cases.

In enterovirus 71 encephalitis with cardio-respiratory compromise, elevated interleukin 1β, interleukin 1 receptor antagonist, and granulocyte colony-stimulating factor levels are markers of poor prognosis.

PubMed

Griffiths, Michael J; Ooi, Mong H; Wong, See C; Mohan, Anand; Podin, Yuwana; Perera, David; Chieng, Chae H; Tio, Phaik H; Cardosa, Mary J; Solomon, Tom

2012-09-15

Enterovirus 71 (EV71) causes large outbreaks of hand, foot, and mouth disease (HFMD), with severe neurological complications and cardio-respiratory compromise, but the pathogenesis is poorly understood. We measured levels of 30 chemokines and cytokines in serum and cerebrospinal fluid (CSF) samples from Malaysian children hospitalized with EV71 infection (n = 88), comprising uncomplicated HFMD (n = 47), meningitis (n = 8), acute flaccid paralysis (n = 1), encephalitis (n = 21), and encephalitis with cardiorespiratory compromise (n = 11). Four of the latter patients died. Both pro-inflammatory and anti-inflammatory mediator levels were elevated, with different patterns of mediator abundance in the CSF and vascular compartments. Serum concentrations of interleukin 1β (IL-1β), interleukin 1 receptor antagonist (IL-1Ra), and granulocyte colony-stimulating factor (G-CSF) were raised significantly in patients who developed cardio-respiratory compromise (P = .013, P = .004, and P < .001, respectively). Serum IL-1Ra and G-CSF levels were also significantly elevated in patients who died, with a serum G-CSF to interleukin 5 ratio of >100 at admission being the most accurate prognostic marker for death (P < .001; accuracy, 85.5%; sensitivity, 100%; specificity, 84.7%). Given that IL-1β has a negative inotropic action on the heart, and that both its natural antagonist, IL-1Ra, and G-CSF are being assessed as treatments for acute cardiac impairment, the findings suggest we have identified functional markers of EV71-related cardiac dysfunction and potential treatment options.

Enterovirus infections in hospitals of Ile de France region over 2013.

PubMed

Molet, Lucie; Saloum, Kenda; Marque-Juillet, Stéphanie; Garbarg-Chenon, Antoine; Henquell, Cécile; Schuffenecker, Isabelle; Peigue-Lafeuille, Hélène; Rozenberg, Flore; Mirand, Audrey

2016-01-01

The monitoring and genotyping of Enterovirus (EV) infections can help to associate particular or severe clinical manifestations with specific EV types and to identify the aetiology of infectious outbreaks. To describe the epidemiological features of EV infections diagnosed during the year 2013 in the Greater Paris area (Ile de France). During 2013, 2497 samples taken from 470 patients in 33 hospitals of Ile-de France were tested for EV genome by RT-PCR. EV genotyping was performed by the National Reference Centre (NRC) laboratories. EV infections were retrospectively reviewed by retrieving clinical and genotyping data from the NRC database. Of the 2497 samples, 490 (19.6%) was positive for EV genome detection. These EV infections represented 88.7% and 24.1%, respectively, of all reported regional and national infections. Twenty-seven different genotypes were identified. Echovirus 30 (E-30) accounted for 54.1% of all characterized strains and caused a large outbreak. Four severe neonatal infections were reported, of which two were caused by EV-A71. Respiratory infections involving EV-D68 were observed in two adults. One fatal case of Coxsackievirus A2-associated myocarditis was reported. Monitoring EV infections in combination with EV genotyping via the French EV network characterized the epidemiology of EV infections in the Ile de France region in 2013 and documented severe EV infections associated with EV-A71 or CV-A2. Copyright © 2015 Elsevier B.V. All rights reserved.

Downregulation of MicroRNA miR-526a by Enterovirus Inhibits RIG-I-Dependent Innate Immune Response

PubMed Central

Xu, Changzhi; He, Xiang; Zheng, Zirui; Zhang, Zhe; Wei, Congwen; Guan, Kai; Hou, Lihua; Zhang, Buchang; Zhu, Lin; Cao, Yuan; Zhang, Yanhong; Cao, Ye; Ma, Shengli; Wang, Penghao; Zhang, Pingping; Xu, Quanbin; Ling, Youguo

2014-01-01

ABSTRACT Retinoic acid-inducible gene I (RIG-I) is an intracellular RNA virus sensor that induces type I interferon-mediated host-protective innate immunity against viral infection. Although cylindromatosis (CYLD) has been shown to negatively regulate innate antiviral response by removing K-63-linked polyubiquitin from RIG-I, the regulation of its expression and the underlying regulatory mechanisms are still incompletely understood. Here we show that RIG-I activity is regulated by inhibition of CYLD expression mediated by the microRNA miR-526a. We found that viral infection specifically upregulates miR-526a expression in macrophages via interferon regulatory factor (IRF)-dependent mechanisms. In turn, miR-526a positively regulates virus-triggered type I interferon (IFN-I) production, thus suppressing viral replication, the underlying mechanism of which is the enhancement of RIG-I K63-linked ubiquitination by miR-526a via suppression of the expression of CYLD. Remarkably, virus-induced miR-526a upregulation and CYLD downregulation are blocked by enterovirus 71 (EV71) 3C protein, while ectopic miR-526a expression inhibits the replication of EV71 virus. The collective results of this study suggest a novel mechanism of the regulation of RIG-I activity during RNA virus infection by miR-526a and suggest a novel mechanism for the evasion of the innate immune response controlled by EV71. IMPORTANCE RNA virus infection upregulates the expression of miR-526a in macrophages through IRF-dependent pathways. In turn, miR-526a positively regulates virus-triggered type I IFN production and inhibits viral replication, the underlying mechanism of which is the enhancement of RIG-I K-63 ubiquitination by miR-526a via suppression of the expression of CYLD. Remarkably, virus-induced miR-526a upregulation and CYLD downregulation are blocked by enterovirus 71 (EV71) 3C protein; cells with overexpressed miR-526a were highly resistant to EV71 infection. The collective results of this study suggest a novel mechanism of the regulation of RIG-I activity during RNA virus infection by miR-526a and propose a novel mechanism for the evasion of the innate immune response controlled by EV71. PMID:25056901

Clinical Characteristics and Functional Motor Outcomes of Enterovirus 71 Neurological Disease in Children.

PubMed

Teoh, Hooi-Ling; Mohammad, Shekeeb S; Britton, Philip N; Kandula, Tejaswi; Lorentzos, Michelle S; Booy, Robert; Jones, Cheryl A; Rawlinson, William; Ramachandran, Vidiya; Rodriguez, Michael L; Andrews, P Ian; Dale, Russell C; Farrar, Michelle A; Sampaio, Hugo

2016-03-01

Enterovirus 71 (EV71) causes a spectrum of neurological complications with significant morbidity and mortality. Further understanding of the characteristics of EV71-related neurological disease, factors related to outcome, and potential responsiveness to treatments is important in developing therapeutic guidelines. To further characterize EV71-related neurological disease and neurological outcome in children. Prospective 2-hospital (The Sydney Children's Hospitals Network) inpatient study of 61 children with enterovirus-related neurological disease during a 2013 outbreak of EV71 in Sydney, Australia. The dates of our analysis were January 1, to June 30, 2013. Clinical, neuroimaging, laboratory, and pathological characteristics, together with treatment administered and functional motor outcomes, were assessed. Among 61 patients, there were 4 precipitous deaths (7%), despite resuscitation at presentation. Among 57 surviving patients, the age range was 0.3 to 5.2 years (median age, 1.5 years), and 36 (63%) were male. Fever (100% [57 of 57]), myoclonic jerks (86% [49 of 57]), ataxia (54% [29 of 54]), and vomiting (54% [29 of 54]) were common initial clinical manifestations. In 57 surviving patients, EV71 neurological disease included encephalomyelitis in 23 (40%), brainstem encephalitis in 20 (35%), encephalitis in 6 (11%), acute flaccid paralysis in 4 (7%), and autonomic dysregulation with pulmonary edema in 4 (7%). Enterovirus RNA was more commonly identified in feces (42 of 44 [95%]), rectal swabs (35 of 37 [95%]), and throat swabs (33 of 39 [85%]) rather than in cerebrospinal fluid (10 of 41 [24%]). Magnetic resonance imaging revealed characteristic increased T2-weighted signal in the dorsal pons and spinal cord. All 4 patients with pulmonary edema (severe disease) demonstrated dorsal brainstem restricted diffusion (odds ratio, 2; 95% CI, 1-4; P = .001). Brainstem or motor dysfunction had resolved in 44 of 57 (77%) at 2 months and in 51 of 57 (90%) at 12 months. Focal paresis was evident in 23 of 57 (40%) at presentation and was the most common persisting clinical and functional problem at 12 months (observed in 5 of 6 patients), with 1 patient also requiring invasive ventilation. Patients initially seen with acute flaccid paralysis or pulmonary edema had significantly greater frequencies of motor dysfunction at follow-up compared with patients initially seen with other syndromes (odds ratio, 15; 95% CI, 3-79; P < .001). Enterovirus 71 may cause serious neurological disease in young patients. The distinct clinicoradiological syndromes, predominantly within the spinal cord and brainstem, enable rapid recognition within evolving outbreaks. Long-term functional neurological morbidity is associated with paresis linked to involvement of gray matter in the brainstem or spinal cord.

Epidemiological and genetic analysis concerning the non-enterovirus 71 and non-coxsackievirus A16 causative agents related to hand, foot and mouth disease in Anyang city, Henan Province, China, from 2011 to 2015.

PubMed

Li, Yang; Bao, Honghong; Zhang, Xiangping; Zhai, Mingqiang; Bao, Xiaobing; Wang, Demin; Zhang, Shuanhu

2017-10-01

Enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16) are major pathogens of hand, foot, and mouth disease (HFMD) and have been associated with consecutive outbreaks of HFMD in China over the past years. Although several other human enteroviruses (HEVs) have also acted as causative agents of HFMD, published information on their roles in the prevalence of HFMD is limited. This study was conducted to reveal the characteristics of the pathogenic spectrum and molecular epidemiology of the non-EV-71 and -CV-A16 HEVs in Anyang City, which is located in north-central China and has a population of five million. From 2011 to 2015, 2270 samples were collected from HFMD patients (3.89 ± 1.06 years of age), and 1863 HEV-positive samples, including 524 samples with 23 non-EV-71 and non-CV-A16 serotypes, were identified. Based on the nucleotide sequence of the VP1 gene, 6 common non-EV-71 and non-CV-A16 HEVs, including coxsackievirus A2, A6, A10, A14, B2, and B5, were studied to determine their phylogenies and selective pressures. Phylogenetic analyses revealed a high level of genetic divergence and a pattern of lineage replacement over time in Mainland China. Selective pressure analyses showed that purifying selection was predominant in the evolution of the VP1 gene, whereas positive selection acted on individual codons. Overall, non-EV-71 and non-CV-A16 HEVs were important constituents of the pathogenic spectrum of HFMD in Anyang City during 2011-2015. Some of these HEVs with complex and active phylogenies represent a potential threat to public health, suggesting that long-term monitoring of these pathogens should be implemented to prevent HFMD outbreaks. © 2017 Wiley Periodicals, Inc.

Identification of Site-Specific Adaptations Conferring Increased Neural Cell Tropism during Human Enterovirus 71 Infection

PubMed Central

Schibler, Manuel; Martinez, Yannick; Gerlach, Daniel; van Belle, Sandra; Turin, Lara; Zdobnov, Evgeny; Kaiser, Laurent; Tapparel, Caroline

2012-01-01

Enterovirus 71 (EV71) is one of the most virulent enteroviruses, but the specific molecular features that enhance its ability to disseminate in humans remain unknown. We analyzed the genomic features of EV71 in an immunocompromised host with disseminated disease according to the different sites of infection. Comparison of five full-length genomes sequenced directly from respiratory, gastrointestinal, nervous system, and blood specimens revealed three nucleotide changes that occurred within a five-day period: a non-conservative amino acid change in VP1 located within the BC loop (L97R), a region considered as an immunogenic site and possibly important in poliovirus host adaptation; a conservative amino acid substitution in protein 2B (A38V); and a silent mutation in protein 3D (L175). Infectious clones were constructed using both BrCr (lineage A) and the clinical strain (lineage C) backgrounds containing either one or both non-synonymous mutations. In vitro cell tropism and competition assays revealed that the VP197 Leu to Arg substitution within the BC loop conferred a replicative advantage in SH-SY5Y cells of neuroblastoma origin. Interestingly, this mutation was frequently associated in vitro with a second non-conservative mutation (E167G or E167A) in the VP1 EF loop in neuroblastoma cells. Comparative models of these EV71 VP1 variants were built to determine how the substitutions might affect VP1 structure and/or interactions with host cells and suggest that, while no significant structural changes were observed, the substitutions may alter interactions with host cell receptors. Taken together, our results show that the VP1 BC loop region of EV71 plays a critical role in cell tropism independent of EV71 lineage and, thus, may have contributed to dissemination and neurotropism in the immunocompromised patient. PMID:22910880

Evolution and Spatiotemporal Dynamics of Enterovirus A71 Subgenogroups in Vietnam.

PubMed

Thao, Nguyen Thi Thanh; Donato, Celeste; Trang, Vu Thi Huyen; Kien, Nguyen Trung; Trang, Ph M Mai Thuy; Khanh, Tran Quoc; Nguyet, Dang Thi; Sessions, October M; Cuong, Hoang Quoc; Lan, Phan Trong; Huong, Vu Thi Que; van Doorn, H Rogier; Vijaykrishna, Dhanasekaran

2017-12-12

Enterovirus A71 (EV-A71) is the major cause of severe hand, foot, and mouth disease and viral encephalitis in children across the Asia-Pacific region, including in Vietnam, which has experienced a high burden of disease in recent years. Multiple subgenogroups (C1, C4, C5, and B5) concurrently circulate in the region with a large variation in epidemic severity. The relative differences in their evolution and epidemiology were examined within Vietnam and globally. A total of 752 VP1 gene sequences were analyzed (413 generated in this study combined with 339 obtained from GenBank), collected from patients in 36 provinces in Vietnam during 2003-2013, along with epidemiological metadata. Globally representative VP1 gene datasets of subgenogroups were used to coestimate time-resolved phylogenies and relative genetic diversity to infer virus origins and regional transmission network. Despite frequent virus migration between countries, the highest genetic diversity of individual subgenogroups was maintained independently for several years in specific Asian countries representing genogroup-specific sources of EV-A71 diversity. This study highlights a persistent transmission network of EV-A71, with specific Asian countries seeding other countries in the region and beyond, emphasizing the need for improved EV-A71 surveillance and detailed genetic and antigenic characterization. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Changes in enterovirus serotype constituent ratios altered the clinical features of infected children in Guangdong Province, China, from 2010 to 2013.

PubMed

Zhou, Hong-Tao; Guo, Yong-Hui; Chen, Man-Jun; Pan, Yu-Xian; Xue, Lin; Wang, Bin; Tao, Shao-Hua; Yu, Nan

2016-08-09

Enterovirus (EV)-related hand, foot, and mouth disease/herpangina (HFMD/HA) has been prevalent in Guangdong Province, China, since 2010. Clinical data for EV-related HFMD/HA inpatients admitted to the Department of Paediatrics of Zhujiang Hospital from 2010 to 2013 were retrospectively reviewed. The corresponding EV serotypes were also determined by reverse transcription-polymerase chain reaction or BLAST analysis of the sequenced partial lengths of the viral protein1/5'-untranslated region. A total of 867 eligible inpatients admitted during 2010-2013 were included in the study. Of these, the serotype of the responsible EV was successfully identified in 824 cases. The incidence of enterovirus 71 (EV71) infection amongst pediatric HFMD/HA inpatients decreased dramatically from 55.5 % in 2010 to 8.1 % in 2013, with a similar decrease recorded for coxsackievirus A16 (CVA16). However, the incidence of non-EV71/CVA16 infection increased from 30.0 % in 2010 to 83.8 % in 2013. We noted that the types of infection caused by different EV serotypes varied: EV71 was responsible for 100 % of the paralysis cases (26/26), 84.6 % of the deaths (11/13), and 84.1 % of cases with severe central nervous system involvement (SCNSI) (74/88); echovirus contributed to 16.4 % of the deaths (2/13) and 4.4 % of the SCNSI cases; and coxsackievirus accounted for only 2.2 % of the SCNSI cases (2/90). The clinical features of HFMD/HA cases varied greatly during the time period examined, with drastic changes in the hospitalization rates (45.1, 63.7, 36.4, and 19.1 % for 2010, 2011, 2012, and 21013, respectively), mortality rates (2.3, 0.9, 2.5, and 0.0 %, respectively), paralysis (5.1, 1.2, 5.4, and 0.0 %, respectively), SCNSI (16.8, 7.1, 12.7, and 2.2 %, respectively), and acute respiratory infection (21.1, 22.0, 45.9, and 59.0 %, respectively). The incidences of infection caused by different EV serotypes, along with the clinical features of HFMD/HA cases, changed drastically in Guangdong Province, China, from 2010 to 2013, with the biggest changes observed in 2013. The changed constituent ratios of the different EV serotypes might therefore be responsible for the differences in the observed clinical features of HFMD/HA during this period.

Evolution and Emergence of Enteroviruses through Intra- and Inter-species Recombination: Plasticity and Phenotypic Impact of Modular Genetic Exchanges in the 5’ Untranslated Region

PubMed Central

Muslin, Claire; Joffret, Marie-Line; Pelletier, Isabelle; Blondel, Bruno; Delpeyroux, Francis

2015-01-01

Genetic recombination shapes the diversity of RNA viruses, including enteroviruses (EVs), which frequently have mosaic genomes. Pathogenic circulating vaccine-derived poliovirus (cVDPV) genomes consist of mutated vaccine poliovirus (PV) sequences encoding capsid proteins, and sequences encoding nonstructural proteins derived from other species’ C EVs, including certain coxsackieviruses A (CV-A) in particular. Many cVDPV genomes also have an exogenous 5’ untranslated region (5’ UTR). This region is involved in virulence and includes the cloverleaf (CL) and the internal ribosomal entry site, which play major roles in replication and the initiation of translation, respectively. We investigated the plasticity of the PV genome in terms of recombination in the 5’ UTR, by developing an experimental model involving the rescue of a bipartite PV/CV-A cVDPV genome rendered defective by mutations in the CL, following the co-transfection of cells with 5’ UTR RNAs from each of the four human EV species (EV-A to -D). The defective cVDPV was rescued by recombination with 5’ UTR sequences from the four EV species. Homologous and nonhomologous recombinants with large deletions or insertions in three hotspots were isolated, revealing a striking plasticity of the 5’ UTR. By contrast to the recombination of the cVDPV with the 5’ UTR of group II (EV-A and -B), which can decrease viral replication and virulence, recombination with the 5’ UTRs of group I (EV-C and -D) appeared to be evolutionarily neutral or associated with a gain in fitness. This study illustrates how the genomes of positive-strand RNA viruses can evolve into mosaic recombinant genomes through intra- or inter-species modular genetic exchanges, favoring the emergence of new recombinant lineages. PMID:26562151

Pyroptosis induced by enterovirus A71 infection in cultured human neuroblastoma cells.

PubMed

Zhu, Xiaojuan; Wu, Tao; Chi, Ying; Ge, Yiyue; Wu, Bin; Zhou, Minghao; Zhu, Fengcai; Ji, Minjun; Cui, Lunbiao

2018-06-07

Enterovirus A71 (EV-A71) infection can cause hand, foot and mouth disease (HFMD), and even fatal meningoencephalitis. Unfortunately, there is currently no effective treatment for EV-A71 infection due to the lack of understanding of the mechanism of neurological diseases. In this study, we employed SH-SY5Y human neuroblastoma cells to explore the roles of caspase-1 in neuropathogenesis. The expression and activity of caspase-1 were analyzed. The potential immuneconsequences mediated by caspase-1 including cell death, lysis, DNA degradation, and secretion of pro-inflammatory were also examined. We found the gene expression levels of caspase-1, IL-1β, IL-18 and active caspase-1 were markedly increased in the SH-SY5Y cells at 48 h post EV-A71 infection. The cell death, lysis, and DNA degradation were also increased during infection, which could be significantly alleviated by caspase-1 inhibition. These observations provided additional experimental evidence supporting caspase-1-mediated pyroptosis as a novel pathway of inflammatory programmed cell death. Copyright © 2018 Elsevier Inc. All rights reserved.

Development of the PANVAC-VF vaccine for pancreatic cancer.

PubMed

Petrulio, Christian A; Kaufman, Howard L

2006-02-01

PANVAC-VF is a vaccine regimen composed of a priming dose of recombinant vaccinia virus and booster doses of recombinant fowlpox virus expressing carcinoembryonic antigen, mucin-1 and a triad of costimulatory molecules (TRICOM), which include B7.1, intercellular adhesion molecule-1 and leukocyte function-associated antigen-3. Vaccination is administered by subcutaneous injection followed by 4 days of local recombinant adjuvant granulocyte-macrophage colony-stimulating factor at the vaccination site. The vaccine has been developed for patients with advanced pancreatic cancer and has now entered a randomized Phase III clinical trial. This review will describe the background of recombinant poxvirus technology for tumor vaccine development, detail the key preclinical studies supporting the regimen, review the clinical trials supporting the current Phase III study, and highlight the key challenges and future obstacles to successful implementation of PANVAC-VF for pancreatic cancer.

[The etiological and clinical characteristics of hospitalized children with hand, foot and mouth disease in Beijing in 2013].

PubMed

Gu, Hongyan; Liu, Zhida; Zhang, Ling; Chen, Yong; Yang, Siyuan; Zhang, Weiyan; Li, Xingwang

2015-06-01

To investigate the etiology of hand, foot and mouth disease (HFMD) in Beijing during 2013, and study the clinical characteristics of HFMD caused by the main serotypes of enterovirus in the study. Clinical data and 128 stool samples were collected from 128 hospitalized children with HFMD in Beijing Ditan Hospital during 2013. One step RT-PCR method was used for enterovirus genotyping to investigate the etiology of HFMD. Clinical characteristics of HFMD caused by the main serotypes of enterovirus were analyzed. And VP1 segments of the main virus were amplified to construct phylogenetic tree for the phylogenetic analysis. A total of 128 hospitalized children with HFMD were included. HFMD was more likely developed in children under 2 years of age (81.6%, 102/125); 11 different enteroviruses were genotyped, with a total enterovirus positive rate of 76.6% (98/128); the positive rate of coxsackievirus A6 (CA6), 43.0% ( 55/128), was the highest, followed by enterovirus 71 (EV71), accounting for 14.8% (19/128). HFMD caused by CA6 was atypical, the rashes of which involved the perioral, trunk, limbs, face and neck (47%, 26/55), besides the common parts. Of the 55 cases caused by CA6, 6 children had clinical manifestations of nervous system involvement, one of whom even displayed type 2 respiratory failure. Mental status change more likely to occur in EV71-infected children than in CA6-infected ones (42% (8/19) vs. 11% (6/55) (χ(2)=7.041, P=0.008)); 13 children displayed onychomadesis, including 12 CA6 cases (23%, 12/53) and 1 CA10 cases (17%, 1/6), in the convalescence of hand, foot and mouth disease, and the correlation between onychomadesis and CA6 infection was significant (χ(2)=9.297, P=0.002). Phylogenetic analysis of 33 CA6 VP1 showed that the CA6 isolates of this study were highly similar to that of Taiwan and the nucleotide similarity was 95.91%-98.89%. CA6 was the major pathogen of hospitalized children with hand, foot and mouth disease in Beijing during 2013, followed by EV71. The rashes caused by CA6 involved a wide range of skin sites and patients with CA6 infection displayed manifestations of neurological involvement or pulmonary edema similar to EV71 infection. Mental status change more likely occurred in EV71-infected children when neurological system was involved..

42 CFR 71.3 - Designation of yellow fever vaccination centers; Validation stamps.

Code of Federal Regulations, 2012 CFR

2012-10-01

...; Validation stamps. 71.3 Section 71.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN... Designation of yellow fever vaccination centers; Validation stamps. (a) Designation of yellow fever... health department, may revoke designation. (b) Validation stamps. International Certificates of...

42 CFR 71.3 - Designation of yellow fever vaccination centers; Validation stamps.

Code of Federal Regulations, 2014 CFR

2014-10-01

...; Validation stamps. 71.3 Section 71.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN... Designation of yellow fever vaccination centers; Validation stamps. (a) Designation of yellow fever... health department, may revoke designation. (b) Validation stamps. International Certificates of...

42 CFR 71.3 - Designation of yellow fever vaccination centers; Validation stamps.

Code of Federal Regulations, 2011 CFR

2011-10-01

...; Validation stamps. 71.3 Section 71.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN... Designation of yellow fever vaccination centers; Validation stamps. (a) Designation of yellow fever... health department, may revoke designation. (b) Validation stamps. International Certificates of...

42 CFR 71.3 - Designation of yellow fever vaccination centers; Validation stamps.

Code of Federal Regulations, 2013 CFR

2013-10-01

...; Validation stamps. 71.3 Section 71.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN... Designation of yellow fever vaccination centers; Validation stamps. (a) Designation of yellow fever... health department, may revoke designation. (b) Validation stamps. International Certificates of...

Clinical Analysis of 134 Children with Nervous System Damage Caused by Enterovirus 71 Infection.

PubMed

Hu, Yue; Jiang, Li; Peng, Hai-lun

2015-07-01

The purpose of this study was to evaluate the clinical characteristics of nervous system damage caused by enterovirus 71 (EV71) infection in pediatric patients. Clinical data and outcomes were retrospectively analyzed for 134 cases of laboratory confirmed pediatric EV71 infection admitted to the Children's Hospital of Chongqing Medical University from January to December 2013. EV71 infection was significantly more common in patients 1-4 years of age, in males and during the months of April-July. Fifty-six cases complicated by hand, foot and mouth disease were diagnosed. Fever was the most common symptom (128 of 134 patients) and lasted on average 5.3 ± 2.1 days. The most common neurologic complication was aseptic meningitis (n = 74), followed by brain stem encephalitis (n = 24), acute flaccid paralysis (AFP; n = 20), acute parencephalitis (n = 12) and encephalomyelitis (n = 4). Each was characterized by a unique profile of clinical symptoms. Damage to the pons and medulla oblongata was apparent in 28 brain magnetic resonance images. Lesions associated with AFP were concentrated in the cervical spinal cord and thoracic 8. The anterior root of the spinal anterior horn was a specific lesion. Fourteen of the AFP patients had unilateral or bilateral femoral nerve involvement. None of the patients died, and in 132 of 134 patients, follow-up visits showed that their physical and neuropsychologic abilities had returned to normal. Most children infected with EV71 have a good prognosis if they are diagnosed early and receive proper supportive treatment.

The Clinical Correlation of Regulatory T Cells and Cyclic Adenosine Monophosphate in Enterovirus 71 Infection

PubMed Central

Wang, Shih-Min; Chen, I-Chun; Liao, Yu-Ting; Liu, Ching-Chuan

2014-01-01

Background Brainstem encephalitis (BE) and pulmonary edema (PE) are notable complications of enterovirus 71 (EV71) infection. Objective This study investigated the immunoregulatory characterizations of EV71 neurological complications by disease severity and milrinone treatment. Study Design Patients <18 years with virologically confirmed EV71 infections were enrolled and divided into 2 groups: the hand, foot, and mouth disease (HFMD) or BE group, and the autonomic nervous system (ANS) dysregulation or PE group. Cytokine and cyclic adenosine monophosphate (cAMP) levels, and the regulatory T cell (Tregs) profiles of the patients were determined. Results Patients with ANS dysregulation or PE exhibited significantly low frequency of CD4+CD25+Foxp3+ and CD4+Foxp3+ T cells compared with patients with HFMD or BE. The expression frequency of CD4−CD8− was also significantly decreased in patients with ANS dysregulation or PE. Among patients with ANS dysregulation or PE, the expression frequency of CD4+Foxp3+ increased markedly after milrinone treatment, and was associated with reduction of plasma levels IL-6, IL-8 and IL-10. Plasma concentrations of cAMP were significantly decreased in patients with ANS dysregulation or PE compared with patients with HFMD or BE; however, cAMP levels increased after milrinone treatment. Conclusions These findings suggested decreased different regulatory T populations and cAMP expression correlate with increased EV71 disease severity. Improved outcome after milrinone treatment may associate with increased regulatory T populations, cAMP expression and modulation of cytokines levels. PMID:25010330

Viral chimeras decrypt the role of enterovirus capsid proteins in viral tropism, acid sensitivity and optimal growth temperature

PubMed Central

Royston, Léna; Essaidi-Laziosi, Manel; Piuz, Isabelle; Geiser, Johan; Huang, Song; Kaiser, Laurent; Garcin, Dominique

2018-01-01

Despite their genetic similarities, enteric and respiratory enteroviruses (EVs) have highly heterogeneous biophysical properties and cause a vast diversity of human pathologies. In vitro differences include acid sensitivity, optimal growth temperature and tissue tropism, which reflect a preferential in vivo replication in the respiratory or gastrointestinal tract and are thus key determinants of EV virulence. To investigate the underlying cause of these differences, we generated chimeras at the capsid-level between EV-D68 (a respiratory EV) and EV-D94 (an enteric EV). Although some chimeras were nonfunctional, EV-D94 with both the capsid and 2A protease or the capsid only of EV-D68 were both viable. Using this latter construct, we performed several functional assays, which indicated that capsid proteins determine acid sensitivity and tropism in cell lines and in respiratory, intestinal and neural tissues. Additionally, capsid genes were shown to also participate in determining the optimal growth temperature, since EV-D94 temperature adaptation relied on single mutations in VP1, while constructs with EV-D68 capsid could not adapt to higher temperatures. Finally, we demonstrate that EV-D68 maintains residual binding-capacity after acid-treatment despite a loss of infectivity. In contrast, non-structural rather than capsid proteins modulate the innate immune response in tissues. These unique biophysical insights expose another layer in the phenotypic diversity of one of world’s most prevalent pathogens and could aid target selection for vaccine or antiviral development. PMID:29630666

Enterovirus genotypes causing hand foot and mouth disease in Shanghai, China: a molecular epidemiological analysis

PubMed Central

2013-01-01

Background A rapid expansion of hand, foot, and mouth disease (HFMD) outbreaks has occurred and caused deaths in China in recent years, but little is known about the other etiologic agents except enterovirus 71 (EV71) and coxsackievirus A 16 (CA16). The objective of this study is to determine the genotype compositions of enterovirus causing HFMD in Shanghai and identify any associations between enterovirus types and clinical manifestations. Methods Stool specimens were collected from patients hospitalized for treatment of HFMD, from May 2010 to April 2011. Enterovirus was detected by reverse transcription PCR and directly genotyped by sequencing the PCR products. Phylogenetic analysis was based on the VP1 partial gene. Results Of 290 specimens, 277 (95.5%) tested positive for enterovirus. The major genotypes were EV71 (63.8%), CA10 (9.0%), CA6 (8.3%), CA16 (6.9%), CA12 (2.4%), and CA4 (1.4%). The EV71 strains belonged to the C4a subtype and CA16 belonged to the B subtype. CA6 was closely related to strains detected in Japan, Taiwan and China, and CA10, CA12 and CA4 were phylogenetically similar to other strains circulating in China. Mean hospital stays and the prevalence of complications in patients with EV71 infection were higher than those in patients in CA6, CA10 or CA16 infection (P < 0.05 for all comparisons). Children with CA12 infection were the youngest, and most likely have the highest risk of complications when compared to the other non-EV71 infection groups. Conclusions This study demonstrated a diversified pathogen compositions attributing to HFMD and clinical symptoms differing in enterovirus genotypes. It deserves our attention as early identification of enterovirus genotypes is important for diagnosis and treatment of HFMD patients. PMID:24148902

A Laboratory Evaluation of Medicinal Herbs Used in China for the Treatment of Hand, Foot, and Mouth Disease

PubMed Central

Chen, Xiaoqing; Wang, Chunyang; Xu, Lanfang; Chen, Xiaoshuang; Wang, Wei; Yang, Guang; Tan, Ren Xiang; Li, Erguang; Jin, Yu

2013-01-01

Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the causative agents of hand, foot, and mouth disease (HFMD). During recent epidemics of HFMD in China, medicinal herbals and preparations containing herbal extracts have demonstrated therapeutic efficacy with relative safety profiles. There have been no microbiological studies to validate their usefulness for HFMD. We selected 12 commonly used herbs for HFMD from government recommended guidelines as well as published reports and tested for their antiviral activity and anti-inflammatory activity. A water extract of Houttuynia cordata Thunb. (HCT) inhibited EV71 infection significantly and was marginally active against CVA16 infection. The IC50 (concentration to have 50% inhibitory effect) values of HCT against a Fuyang strain and a BrCr strain of EV71 were determined at 8.9 μg/mL and 20.6 μg/mL, respectively. Mentha haplocalyx Briq. (MHB) water extract was active against CVA16, with an IC50 value of 70.3 μg/mL. The extract did not exhibit activity against EV71 infection. Although the majority of the extracts showed no activity against viral infection, several extracts demonstrated activity in blocking proinflammatory response by viral infection. This study therefore validates the effectiveness of Chinese herbs for HFMD since some formulations containing the correct combination of the herbs can block viral replication as well as proinflammatory response of HFMD. PMID:23554831

Engineering Enhanced Vaccine Cell Lines To Eradicate Vaccine-Preventable Diseases: the Polio End Game

PubMed Central

van der Sanden, Sabine M. G.; Wu, Weilin; Dybdahl-Sissoko, Naomi; Weldon, William C.; Brooks, Paula; O'Donnell, Jason; Jones, Les P.; Brown, Cedric; Tompkins, S. Mark; Karpilow, Jon; Tripp, Ralph A.

2015-01-01

ABSTRACT Vaccine manufacturing costs prevent a significant portion of the world's population from accessing protection from vaccine-preventable diseases. To enhance vaccine production at reduced costs, a genome-wide RNA interference (RNAi) screen was performed to identify gene knockdown events that enhanced poliovirus replication. Primary screen hits were validated in a Vero vaccine manufacturing cell line using attenuated and wild-type poliovirus strains. Multiple single and dual gene silencing events increased poliovirus titers >20-fold and >50-fold, respectively. Host gene knockdown events did not affect virus antigenicity, and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9-mediated knockout of the top candidates dramatically improved viral vaccine strain production. Interestingly, silencing of several genes that enhanced poliovirus replication also enhanced replication of enterovirus 71, a clinically relevant virus to which vaccines are being targeted. The discovery that host gene modulation can markedly increase virus vaccine production dramatically alters mammalian cell-based vaccine manufacturing possibilities and should facilitate polio eradication using the inactivated poliovirus vaccine. IMPORTANCE Using a genome-wide RNAi screen, a collection of host virus resistance genes was identified that, upon silencing, increased poliovirus and enterovirus 71 production by from 10-fold to >50-fold in a Vero vaccine manufacturing cell line. This report provides novel insights into enterovirus-host interactions and describes an approach to developing the next generation of vaccine manufacturing through engineered vaccine cell lines. The results show that specific gene silencing and knockout events can enhance viral titers of both attenuated (Sabin strain) and wild-type polioviruses, a finding that should greatly facilitate global implementation of inactivated polio vaccine as well as further reduce costs for live-attenuated oral polio vaccines. This work describes a platform-enabling technology applicable to most vaccine-preventable diseases. PMID:26581994

[Human enterovirus infection status and clinical characteristics of 274 patients with viral encephalitis in Henan Province, 2011-2012].

PubMed

Ma, H X; Pan, J J; Li, Y; Kang, K; Huang, X Y; You, A G; Xu, B L

2017-02-06

Objective: To investigate human enterovirus (HEV) infection and clinical characteristics of viral encephalitis patients in Pingdingshan, Henan Province. Methods: Cerebrospinal fluid specimens and epidemiological information were collected from 274 viral encephalitis patients in the departments of pediatrics and neurology in hospitals in Pingdingshan, Henan Province, from April 2011 to August 2012. Patients with bacterial infections were excluded from the study. Demographic information was collected by questionnaires and clinical information was mainly obtained from hospital examinations. Viral RNA was extracted using magnetic bead extraction. Real-time RT-PCR was then performed for HEV, CV-A16, and EV-A71 testing. SPSS statistical software was statistical analyses. Significant differences were determined using the chi-squared test ( P< 0.05). Results: Among 274 cases of viral encephalitis, 180 cases (65.7%) were male and 94 cases were female (34.3%). The median age was 2.17 years. Approximately 61.3% (168) of patients were younger than 3 years of age. A total of 107 (39.1%), 2 (0.7%), and 42 (15.3%) cases were positive for HEV, CV-A16, and EV-A71, respectively. Eleven patients were younger than 6 months of age and one patient was co-infected with HEV and EV-A71. In the<3, 3-5, 6-15, and>15 years old age groups, HEV infections comprised 31.5% (53/168), 52.9% (18/34), 53.0% (35/66), and 16.7% (1/6) (χ(2)=13.10, P= 0.003), respectively. The EV-A71 infection rates were 17.9% (30/168), 23.5% (8/34), 6.1% (4/66), and 0 (χ(2)=8.04, P= 0.045), respectively. The other enterovirus (OEV) infection rates were 12.5% (21/168), 29.4% (10/34), 48.5% (32/66), and 16.7% (1/6) (χ(2)=35.19, P< 0.001), respectively. The rate of vomiting in OEV and EV-A71 infected patients was 73% (44/60) and 26% (11/42), respectively, while the frequency of skin rash in OEV and EV-A71 infected patients was 32% (19/60) and 79% (33/42), respectively. Approximately 95% (99/104) of patients infected with HEV had a fever, and the breathing rhythm change rate was 19% (20/104), which was lower than that of patients without HEV infection (36.8% (60/163)) (χ(2)=9.35, P= 0.002). Conclusion: In Pingdingshan, HEV was a major causative agent of viral encephalitis and the rate of OEV infection was high, especially in children aged 3-15 years old. Fever was a common clinical symptom of patients infected with HEV. Patients infected with OEV primarily exhibited vomiting symptoms and EV-A71 infected patients showed skin rash.

Antiviral activities of extracts and selected pure constituents of Ocimum basilicum.

PubMed

Chiang, Lien-Chai; Ng, Lean-Teik; Cheng, Pei-Win; Chiang, Win; Lin, Chun-Ching

2005-10-01

1. Ocimum basilicum (OB), also known as sweet basil, is a well known medicinal herb in traditional Chinese medicine preparations. In the present study, extracts and purified components of OB were used to identify possible antiviral activities against DNA viruses (herpes viruses (HSV), adenoviruses (ADV) and hepatitis B virus) and RNA viruses (coxsackievirus B1 (CVB1) and enterovirus 71 (EV71)). 2. The results show that crude aqueous and ethanolic extracts of OB and selected purified components, namely apigenin, linalool and ursolic acid, exhibit a broad spectrum of antiviral activity. Of these compounds, ursolic acid showed the strongest activity against HSV-1 (EC50 = 6.6 mg/L; selectivity index (SI) = 15.2), ADV-8 (EC50 = 4.2 mg/L; SI = 23.8), CVB1 (EC50 = 0.4 mg/L; SI = 251.3) and EV71 (EC50 = 0.5 mg/L; SI = 201), whereas apigenin showed the highest activity against HSV-2 (EC50 = 9.7 mg/L; SI = 6.2), ADV-3 (EC50 = 11.1 mg/L; SI = 5.4), hepatitis B surface antigen (EC50 = 7.1 mg/L; SI = 2.3) and hepatitis B e antigen (EC50 = 12.8 mg/L; SI = 1.3) and linalool showed strongest activity against AVD-II (EC50 = 16.9 mg/L; SI = 10.5). 3. No activity was noted for carvone, cineole, beta-caryophyllene, farnesol, fenchone, geraniol, beta-myrcene and alpha-thujone. 4. The action of ursolic acid against CVB1 and EV71 was found to occur during the infection process and the replication phase. 5. With SI values greater than 200, the potential use of ursolic acid for treating infection with CVB1 and EV71 merits further investigation.

Evaluation of Montanide™ ISA 71 VG Adjuvant during Profilin Vaccination against Experimental Coccidiosis

PubMed Central

Lillehoj, Hyun S.; Lee, Sung Hyen; Lee, Kyung Woo; Bertrand, François; Dupuis, Laurent; Deville, Sébastien; Ben Arous, Juliette; Lillehoj, Erik P.

2013-01-01

Chickens were immunized subcutaneously with an Eimeria recombinant profilin protein plus Montanide™ ISA 70 VG (ISA 70) or Montanide™ ISA 71 VG (ISA 71) water-in-oil adjuvants, or with profilin alone, and comparative RNA microarray hybridizations were performed to ascertain global transcriptome changes induced by profilin/ISA 70 vs. profilin alone and by profilin/ISA 71 vs. profilin alone. While immunization with profilin/ISA 70 vs. profilin alone altered the levels of more total transcripts compared with profilin/ISA 71 vs. profilin alone (509 vs. 296), the latter was associated with a greater number of unique biological functions, and a larger number of genes within these functions, compared with the former. Further, canonical pathway analysis identified 10 pathways that were associated with genes encoding the altered transcripts in animals immunized with profilin/ISA 71 vs. profilin alone, compared with only 2 pathways in profilin/ISA 70 vs. profilin alone. Therefore, ISA 71 was selected as a candidate adjuvant in conjunction with profilin vaccination for in vivo disease protection studies. Vaccination with profilin/ISA 71 was associated with greater body weight gain following E. acervulina infection, and decreased parasite fecal shedding after E. maxima infection, compared with profilin alone. Anti-profilin antibody levels were higher in sera of E. maxima- and E. tenella-infected chickens vaccinated with profilin/ISA 71 compared with profilin alone. Finally, the levels of transcripts encoding interferon-γ, interleukin (IL)-2, IL-10, and IL-17A were increased in intestinal lymphocytes from E. acervulina-, E. maxima-, and/or E. tenella-infected chickens vaccinated with profilin/ISA 71 compared with profilin alone. None of these effects were seen in chickens injected with ISA 71 alone indicating that the adjuvant was not conferring non-specific immune stimulation. These results suggest that profilin plus ISA 71 augments protective immunity against selective Eimeria species in chickens. PMID:23593150

Vaccination with Clostridium perfringens recombinant proteins in combination with Montanide™ ISA 71 VG adjuvant increases protection against experimental necrotic enteritis in commercial broiler chickens

USDA-ARS?s Scientific Manuscript database

This study was performed to compare four Clostridium perfringens recombinant proteins as vaccine candidates using the Montanide™ ISA 71 VG adjuvant in an experimental model of necrotic enteritis. Broiler chickens were immunized with clostridial recombinant proteins with ISA 71 VG, and intestinal le...

Montanide ISA 71 VG adjuvant enhances antibody and cell-ediated immune responses to profilin subunit antigen vaccination and promotes protection against Eimeria acervulina and Eimeria tenella

USDA-ARS?s Scientific Manuscript database

The present study was conducted to investigate the immunoenhancing effects of ISA 71 VG adjuvant on profilin subunit antigen vaccination. Broiler chickens were immunized subcutaneously with a purified Eimeria acervulina recombinant profilin protein, either alone or mixed with ISA 71 VG, and host imm...

Montanide™ ISA 71 VG adjuvant enhances antibody and cell-mediated immune responses to profilin subunit antigen vaccination and promotes protection against Eimeria acervulina and Eimeria tenella. Experimental Parasitology

USDA-ARS?s Scientific Manuscript database

The present study was conducted to investigate the immunoenhancing effects of MontanideTM ISA 71 VG adjuvant on profilin subunit antigen vaccination. Broiler chickens were immunized subcutaneously with a purified Eimeria acervulina recombinant profilin protein, either alone or mixed with ISA 71 VG, ...

Human Enterovirus 68 Interferes with the Host Cell Cycle to Facilitate Viral Production

PubMed Central

Wang, Zeng-yan; Zhong, Ting; Wang, Yue; Song, Feng-mei; Yu, Xiao-feng; Xing, Li-ping; Zhang, Wen-yan; Yu, Jing-hua; Hua, Shu-cheng; Yu, Xiao-fang

2017-01-01

Enterovirus D68 (EV-D68) is an emerging pathogen that recently caused a large outbreak of severe respiratory disease in the United States and other countries. Little is known about the relationship between EV-D68 virus and host cells. In this study, we assessed the effect of the host cell cycle on EV-D68 viral production, as well as the ability of EV-D68 to manipulate host cell cycle progression. The results suggest that synchronization in G0/G1 phase, but not S phase, promotes viral production, while synchronization in G2/M inhibits viral production. Both an early EV-D68 isolate and currently circulating strains of EV-D68 can manipulate the host cell cycle to arrest cells in the G0/G1 phase, thus providing favorable conditions for virus production. Cell cycle regulation by EV-D68 was associated with corresponding effects on the expression of cyclins and CDKs, which were observed at the level of the protein and/or mRNA. Furthermore, the viral non-structural protein 3D of EV-D68 prevents progression from G0/G1 to S. Interestingly, another member of the Picornaviridae family, EV-A71, differs from EV-D68 in that G0/G1 synchronization inhibits, rather than promotes, EV-A71 viral replication. However, these viruses are similar in that G2/M synchronization inhibits the production and activity of both viruses, which is suggestive of a common therapeutic target for both types of enterovirus. These results further clarify the pathogenic mechanisms of enteroviruses and provide a potential strategy for the treatment and prevention of EV-D68-related disease. PMID:28229049

Cultural and morphological properties of the vaccine strain Yersinia pestis EV NIIEG bacteria after photodynamic inactivation

NASA Astrophysics Data System (ADS)

Ulianova, Onega V.; Lyapina, Anna M.; Khizhnyakova, Mariya A.; Laskavy, Vladislav N.; Feodorova, Valentina A.; Ulyanov, Sergey S.

2015-03-01

New method of photoinactivation of plague microbes (bacteria Yersinia pestis) has been suggested. Rate of growth of colonies of Y. pestis EV NIIEG at specific regimes of photo processing have been analyzed. Dependence of growth on exposure time and concentrations of photosensitizer (methylene blue) has been studied. Number of colony forming units of Y. pestis EV NIIEG bacteria as a function of intensity of light and concentration of methylene blue has been scrutinized.

A Yersinia pestis lpxM-mutant live vaccine induces enhanced immunity against bubonic plague in mice and guinea pigs.

PubMed

Feodorova, V A; Pan'kina, L N; Savostina, E P; Sayapina, L V; Motin, V L; Dentovskaya, S V; Shaikhutdinova, R Z; Ivanov, S A; Lindner, B; Kondakova, A N; Bystrova, O V; Kocharova, N A; Senchenkova, S N; Holst, O; Pier, G B; Knirel, Y A; Anisimov, A P

2007-11-01

The lpxM mutant of the live vaccine Yersinia pestis EV NIIEG strain synthesising a less toxic penta-acylated lipopolysaccharide was found to be avirulent in mice and guinea pigs, notably showing no measurable virulence in Balb/c mice which do retain some susceptibility to the parental strain itself. Twenty-one days after a single injection of the lpxM-mutant, 85-100% protection was achieved in outbred mice and guinea pigs, whereas a 43% protection rate was achieved in Balb/c mice given single low doses (10(3) to 2.5 x 10(4) CFU) of this vaccine. A subcutaneous challenge with 2000 median lethal doses (equal to 20,000 CFU) of fully virulent Y. pestis 231 strain, is a 6-10-fold higher dose than that which the EV NIIEG itself can protect against.

Nasal Infection of Enterovirus D68 Leading to Lower Respiratory Tract Pathogenesis in Ferrets (Mustela putorius furo)

PubMed Central

Zheng, Hui-Wen; Sun, Ming; Guo, Lei; Wang, Jing-Jing; Song, Jie; Li, Jia-Qi; Li, Hong-Zhe; Ning, Ruo-Tong; Yang, Ze-Ning; Fan, Hai-Tao; He, Zhan-Long; Liu, Long-Ding

2017-01-01

Data from EV-D68-infected patients demonstrate that pathological changes in the lower respiratory tract are principally characterized by severe respiratory illness in children and acute flaccid myelitis. However, lack of a suitable animal model for EV-D68 infection has limited the study on the pathogenesis of this critical pathogen, and the development of a vaccine. Ferrets have been widely used to evaluate respiratory virus infections. In the current study, we used EV-D68-infected ferrets as a potential animal to identify impersonal indices, involving clinical features and histopathological changes in the upper and lower respiratory tract (URT and LRT). The research results demonstrate that the EV-D68 virus leads to minimal clinical symptoms in ferrets. According to the viral load detection in the feces, nasal, and respiratory tracts, the infection and shedding of EV-D68 in the ferret model was confirmed, and these results were supported by the EV-D68 VP1 immunofluorescence confocal imaging with α2,6-linked sialic acid (SA) in lung tissues. Furthermore, we detected the inflammatory cytokine/chemokine expression level, which implied high expression levels of interleukin (IL)-1a, IL-8, IL-5, IL-12, IL-13, and IL-17a in the lungs. These data indicate that systemic observation of responses following infection with EV-D68 in ferrets could be used as a model for EV-D68 infection and pathogenesis. PMID:28489053

Nasal Infection of Enterovirus D68 Leading to Lower Respiratory Tract Pathogenesis in Ferrets (Mustela putorius furo).

PubMed

Zheng, Hui-Wen; Sun, Ming; Guo, Lei; Wang, Jing-Jing; Song, Jie; Li, Jia-Qi; Li, Hong-Zhe; Ning, Ruo-Tong; Yang, Ze-Ning; Fan, Hai-Tao; He, Zhan-Long; Liu, Long-Ding

2017-05-10

Data from EV-D68-infected patients demonstrate that pathological changes in the lower respiratory tract are principally characterized by severe respiratory illness in children and acute flaccid myelitis. However, lack of a suitable animal model for EV-D68 infection has limited the study on the pathogenesis of this critical pathogen, and the development of a vaccine. Ferrets have been widely used to evaluate respiratory virus infections. In the current study, we used EV-D68-infected ferrets as a potential animal to identify impersonal indices, involving clinical features and histopathological changes in the upper and lower respiratory tract (URT and LRT). The research results demonstrate that the EV-D68 virus leads to minimal clinical symptoms in ferrets. According to the viral load detection in the feces, nasal, and respiratory tracts, the infection and shedding of EV-D68 in the ferret model was confirmed, and these results were supported by the EV-D68 VP1 immunofluorescence confocal imaging with α2,6-linked sialic acid (SA) in lung tissues. Furthermore, we detected the inflammatory cytokine/chemokine expression level, which implied high expression levels of interleukin (IL)-1a, IL-8, IL-5, IL-12, IL-13, and IL-17a in the lungs. These data indicate that systemic observation of responses following infection with EV-D68 in ferrets could be used as a model for EV-D68 infection and pathogenesis.

Phylogenetic analysis of the major causative agents of hand, foot and mouth disease in Suzhou city, Jiangsu province, China, in 2012–2013

PubMed Central

Zhang, Chao; Zhu, Rui; Yang, Yong; Chi, Yudan; Yin, Jieyun; Tang, Xinying; Yu, Luogang; Zhang, Chiyu; Huang, Zhong; Zhou, Dongming

2015-01-01

Hand, foot and mouth disease (HFMD) is a serious public health problem that has emerged over the past several decades. Pathogen detection by the Chinese national HFMD surveillance system has focused mainly on enterovirus 71 (EV71) and coxsackievirus A16 (CA16). Therefore, epidemiological information regarding the other causative enteroviruses is limited. To identify the pandemic enterovirus in Suzhou, Jiangsu province, China, clinical samples from patients with HFMD were collected from 2012 to 2013 and analyzed. The results revealed that CA16 was the most dominant HFMD pathogen in 2012, whereas CA6 and CA10 were the dominant pathogens in 2013. Phylogenetic analysis revealed that the C4a sub-genogroup of EV71 and the B1a and B1b sub-genogroups of CA16 continued to evolve and circulate in Suzhou. The CA6 strains were assigned to six genotypes (A–F) and the CA10 strains were assigned to seven genotypes (A–G), with clear geographical and temporal distributions. All of the CA6 strains in Suzhou belonged to genogroup F, and there were several lineages circulating in Suzhou. All of the CA10 strains in Suzhou belonged to genogroup G, and they had the same genetic origin. Co-infections of EV71/CA16 and CA6/CA10 were found in the samples, and bootscan analysis of 5′-untranslated regions (UTRs) revealed that some CA16 strains in Suzhou had genetic recombination with EV71. This property might allow CA16 to alter its evolvability and circulating ability. This study underscores the need for surveillance of CA6 and CA10 in the Yangtze River Delta and East China. PMID:26038764

Engineering Enhanced Vaccine Cell Lines To Eradicate Vaccine-Preventable Diseases: the Polio End Game.

PubMed

van der Sanden, Sabine M G; Wu, Weilin; Dybdahl-Sissoko, Naomi; Weldon, William C; Brooks, Paula; O'Donnell, Jason; Jones, Les P; Brown, Cedric; Tompkins, S Mark; Oberste, M Steven; Karpilow, Jon; Tripp, Ralph A

2016-02-15

Vaccine manufacturing costs prevent a significant portion of the world's population from accessing protection from vaccine-preventable diseases. To enhance vaccine production at reduced costs, a genome-wide RNA interference (RNAi) screen was performed to identify gene knockdown events that enhanced poliovirus replication. Primary screen hits were validated in a Vero vaccine manufacturing cell line using attenuated and wild-type poliovirus strains. Multiple single and dual gene silencing events increased poliovirus titers >20-fold and >50-fold, respectively. Host gene knockdown events did not affect virus antigenicity, and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9-mediated knockout of the top candidates dramatically improved viral vaccine strain production. Interestingly, silencing of several genes that enhanced poliovirus replication also enhanced replication of enterovirus 71, a clinically relevant virus to which vaccines are being targeted. The discovery that host gene modulation can markedly increase virus vaccine production dramatically alters mammalian cell-based vaccine manufacturing possibilities and should facilitate polio eradication using the inactivated poliovirus vaccine. Using a genome-wide RNAi screen, a collection of host virus resistance genes was identified that, upon silencing, increased poliovirus and enterovirus 71 production by from 10-fold to >50-fold in a Vero vaccine manufacturing cell line. This report provides novel insights into enterovirus-host interactions and describes an approach to developing the next generation of vaccine manufacturing through engineered vaccine cell lines. The results show that specific gene silencing and knockout events can enhance viral titers of both attenuated (Sabin strain) and wild-type polioviruses, a finding that should greatly facilitate global implementation of inactivated polio vaccine as well as further reduce costs for live-attenuated oral polio vaccines. This work describes a platform-enabling technology applicable to most vaccine-preventable diseases. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

A randomized, double-blind, dose-finding Phase II study to evaluate immunogenicity and safety of the third generation smallpox vaccine candidate IMVAMUNE®

PubMed Central

von Krempelhuber, Alfred; Vollmar, Jens; Pokorny, Rolf; Rapp, Petra; Wulff, Niels; Petzold, Barbara; Handley, Amanda; Mateo, Lyn; Siersbol, Henriette; Kollaritsch, Herwig; Chaplin, Paul

2009-01-01

IMVAMUNE® is a Modified Vaccinia Ankara-based virus that is being developed as a safer 3rd generation smallpox vaccine. In order to determine the optimal dose for further development, a double-blind, randomized Phase II trial was performed testing three different doses of IMVAMUNE® in 164 healthy volunteers. All three IMVAMUNE® doses displayed a favourable safety profile, with local reactions as the most frequent observation. The 1×108 TCID50 IMVAMUNE® dose induced a total antibody response in 94% of the subjects following the first vaccination and the highest peak seroconversion rates by ELISA (100%) and PRNT (71%). This IMVAMUNE® dose was considered to be optimal for the further clinical development of this highly attenuated poxvirus as a safer smallpox vaccine. PMID:19944151

Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper

PubMed Central

Lener, Thomas; Gimona, Mario; Aigner, Ludwig; Börger, Verena; Buzas, Edit; Camussi, Giovanni; Chaput, Nathalie; Chatterjee, Devasis; Court, Felipe A.; del Portillo, Hernando A.; O'Driscoll, Lorraine; Fais, Stefano; Falcon-Perez, Juan M.; Felderhoff-Mueser, Ursula; Fraile, Lorenzo; Gho, Yong Song; Görgens, André; Gupta, Ramesh C.; Hendrix, An; Hermann, Dirk M.; Hill, Andrew F.; Hochberg, Fred; Horn, Peter A.; de Kleijn, Dominique; Kordelas, Lambros; Kramer, Boris W.; Krämer-Albers, Eva-Maria; Laner-Plamberger, Sandra; Laitinen, Saara; Leonardi, Tommaso; Lorenowicz, Magdalena J.; Lim, Sai Kiang; Lötvall, Jan; Maguire, Casey A.; Marcilla, Antonio; Nazarenko, Irina; Ochiya, Takahiro; Patel, Tushar; Pedersen, Shona; Pocsfalvi, Gabriella; Pluchino, Stefano; Quesenberry, Peter; Reischl, Ilona G.; Rivera, Francisco J.; Sanzenbacher, Ralf; Schallmoser, Katharina; Slaper-Cortenbach, Ineke; Strunk, Dirk; Tonn, Torsten; Vader, Pieter; van Balkom, Bas W. M.; Wauben, Marca; Andaloussi, Samir El; Théry, Clotilde; Rohde, Eva; Giebel, Bernd

2015-01-01

Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed. PMID:26725829

Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper.

PubMed

Lener, Thomas; Gimona, Mario; Aigner, Ludwig; Börger, Verena; Buzas, Edit; Camussi, Giovanni; Chaput, Nathalie; Chatterjee, Devasis; Court, Felipe A; Del Portillo, Hernando A; O'Driscoll, Lorraine; Fais, Stefano; Falcon-Perez, Juan M; Felderhoff-Mueser, Ursula; Fraile, Lorenzo; Gho, Yong Song; Görgens, André; Gupta, Ramesh C; Hendrix, An; Hermann, Dirk M; Hill, Andrew F; Hochberg, Fred; Horn, Peter A; de Kleijn, Dominique; Kordelas, Lambros; Kramer, Boris W; Krämer-Albers, Eva-Maria; Laner-Plamberger, Sandra; Laitinen, Saara; Leonardi, Tommaso; Lorenowicz, Magdalena J; Lim, Sai Kiang; Lötvall, Jan; Maguire, Casey A; Marcilla, Antonio; Nazarenko, Irina; Ochiya, Takahiro; Patel, Tushar; Pedersen, Shona; Pocsfalvi, Gabriella; Pluchino, Stefano; Quesenberry, Peter; Reischl, Ilona G; Rivera, Francisco J; Sanzenbacher, Ralf; Schallmoser, Katharina; Slaper-Cortenbach, Ineke; Strunk, Dirk; Tonn, Torsten; Vader, Pieter; van Balkom, Bas W M; Wauben, Marca; Andaloussi, Samir El; Théry, Clotilde; Rohde, Eva; Giebel, Bernd

2015-01-01

Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.

Visualizing nanoscale phase morphology for understanding photovoltaic performance of PTB7: PC71BM solar cell

NASA Astrophysics Data System (ADS)

Supasai, Thidarat; Amornkitbamrung, Vittaya; Thanachayanont, Chanchana; Tang, I.-Ming; Sutthibutpong, Thana; Rujisamphan, Nopporn

2017-11-01

Visualizing and controlling the phase separation of the donor and acceptor domains in organic bulk-hetero-junction (BHJ) solar devices made with poly([4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b']dithiophene-2,6-diyl][3-fluoro-2-[(2-ethyl-hexyl)carbon-yl]thieno[3,4-bthiophenediyl]) (PTB7) and [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) are needed to achieve high power conversion efficiency (PCE). Traditional bright-field (BF) imaging, especially of polymeric materials, produces images of poor contrast when done at the nanoscale level. Clear nanoscale morphologies of the PTB7:PC71BM blends prepared with different 1,8-diiodooctane (DIO) concentrations were seen when using the energy-filtered transmission electron microscopy (EFTEM). The electron energy loss (EELS) spectra of the pure PTB7 and PC71BM samples are centered at 22.7 eV and 24.5 eV, respectively. Using the electrons whose energy losses are in the range of 16-30 eV, detail information of the phase morphology at the nanoscale was obtained. Correlations between the improvement in the photovoltaic performances and the increased electron mobility were seen. These correlations are discussed in terms of the changes (at the nanoscale level) in blending phase morphology when different DIO concentrations are added.

Detection of non-polio enteroviruses in Hungary 2000-2008 and molecular epidemiology of enterovirus 71, coxsackievirus A16, and echovirus 30.

PubMed

Kapusinszky, Beatrix; Szomor, Katalin N; Farkas, Agnes; Takács, Mária; Berencsi, György

2010-04-01

Human enteroviruses are associated with various clinical syndromes from minor febrile illness to severe, potentially fatal conditions like aseptic meningitis, paralysis, myocarditis, and neonatal enteroviral sepsis. Between June 2000 and August 2008 echovirus (E) type 2, 4, 6, 7, 9, 11, 13, 25, 30, coxsackievirus (CV) -A16, -A19, -B5, and enterovirus 71 (EV71) were reported in Hungary. In this study, 29 previously enterovirus positive samples from 28 patients diagnosed with hand, foot and mouth disease, meningitis and encephalitis, were molecularly typed. The genetic relationships of identified serotypes CV-A16, EV71, and E30 were assessed by direct sequencing of genomic region encoding the capsid protein VP1. The sequences were compared to each other and sequences from other geographical regions possessed in Genbank. The phylogenetic analysis of CV-A16 revealed that the viruses were mostly of Far-Eastern or Asia-Pacific origin. Typing of EV71 showed that one virus from 2000 belonged to genotype C1 and five viruses observed in 2004 and 2005 were identified as genotype C4. The 11 echovirus 30 strains showed homology with those of neighbor European countries. The molecular examination of E30 revealed that three separate lineages circulated in 2000, 2001, and 2004-2006 in Hungary.

Assessing the Potential Cost-Effectiveness of Microneedle Patches in Childhood Measles Vaccination Programs: The Case for Further Research and Development.

PubMed

Adhikari, Bishwa B; Goodson, James L; Chu, Susan Y; Rota, Paul A; Meltzer, Martin I

2016-12-01

Currently available measles vaccines are administered by subcutaneous injections and require reconstitution with a diluent and a cold chain, which is resource intensive and challenging to maintain. To overcome these challenges and potentially increase vaccination coverage, microneedle patches are being developed to deliver the measles vaccine. This study compares the cost-effectiveness of using microneedle patches with traditional vaccine delivery by syringe-and-needle (subcutaneous vaccination) in children's measles vaccination programs. We built a simple spreadsheet model to compute the vaccination costs for using microneedle patch and syringe-and-needle technologies. We assumed that microneedle vaccines will be, compared with current vaccines, more heat stable and require less expensive cool chains when used in the field. We used historical data on the incidence of measles among communities with low measles vaccination rates. The cost of microneedle vaccination was estimated at US$0.95 (range US$0.71-US$1.18) for the first dose, compared with US$1.65 (range US$1.24-US$2.06) for the first dose delivered by subcutaneous vaccination. At 95 % vaccination coverage, microneedle patch vaccination was estimated to cost US$1.66 per measles case averted (range US$1.24-US$2.07) compared with an estimated cost of US$2.64 per case averted (range US$1.98-US$3.30) using subcutaneous vaccination. Use of microneedle patches may reduce costs; however, the cost-effectiveness of patches would depend on the vaccine recipients' acceptability and vaccine effectiveness of the patches relative to the existing conventional vaccine-delivery method. This study emphasizes the need to continue research and development of this vaccine-delivery method that could boost measles elimination efforts through improved access to vaccines and increased vaccination coverage.

The Effects of Weather Factors on Hand, Foot and Mouth Disease in Beijing.

PubMed

Dong, Weihua; Li, Xian'en; Yang, Peng; Liao, Hua; Wang, Xiaoli; Wang, Quanyi

2016-01-12

The morbidity and mortality of hand, foot and mouth disease (HFMD) are increasing in Beijing, China. Previous studies have indicated an association between incidents of HFMD and weather factors. However, the seasonal influence of these factors on the disease is not yet understood, and their relationship with the enterovirus 71 (EV71) and Coxsackie virus A16 (CV-A16) viruses are not well documented. We analysed 84,502 HFMD cases from 2008 to 2011 in Beijing to explore the seasonal influence of weather factors (average temperature [AT], average relative humidity [ARH], total precipitation [TP] and average wind speed [AWS]) on incidents of HFMD by using a geographically weighted regression (GWR) model. The results indicated that weather factors differ significantly in their influence on HFMD depending on the season. AT had the greatest effect among the four weather factors, and while the influence of AT and AWS was greater in the summer than in the winter, the influence of TP was positive in the summer and negative in the winter. ARH was negatively correlated with HFMD. Also, we observed more EV71-associated cases than CV-A16 but there is no convincing evidence to show significant differences between the influences of the weather factors on EV71 and CV-A16.

The Effects of Weather Factors on Hand, Foot and Mouth Disease in Beijing

NASA Astrophysics Data System (ADS)

Dong, Weihua; Li, Xian'En; Yang, Peng; Liao, Hua; Wang, Xiaoli; Wang, Quanyi

2016-01-01

The morbidity and mortality of hand, foot and mouth disease (HFMD) are increasing in Beijing, China. Previous studies have indicated an association between incidents of HFMD and weather factors. However, the seasonal influence of these factors on the disease is not yet understood, and their relationship with the enterovirus 71 (EV71) and Coxsackie virus A16 (CV-A16) viruses are not well documented. We analysed 84,502 HFMD cases from 2008 to 2011 in Beijing to explore the seasonal influence of weather factors (average temperature [AT], average relative humidity [ARH], total precipitation [TP] and average wind speed [AWS]) on incidents of HFMD by using a geographically weighted regression (GWR) model. The results indicated that weather factors differ significantly in their influence on HFMD depending on the season. AT had the greatest effect among the four weather factors, and while the influence of AT and AWS was greater in the summer than in the winter, the influence of TP was positive in the summer and negative in the winter. ARH was negatively correlated with HFMD. Also, we observed more EV71-associated cases than CV-A16 but there is no convincing evidence to show significant differences between the influences of the weather factors on EV71 and CV-A16.

The Effects of Weather Factors on Hand, Foot and Mouth Disease in Beijing

PubMed Central

Dong, Weihua; Li, Xian’en; Yang, Peng; Liao, Hua; Wang, Xiaoli; Wang, Quanyi

2016-01-01

The morbidity and mortality of hand, foot and mouth disease (HFMD) are increasing in Beijing, China. Previous studies have indicated an association between incidents of HFMD and weather factors. However, the seasonal influence of these factors on the disease is not yet understood, and their relationship with the enterovirus 71 (EV71) and Coxsackie virus A16 (CV-A16) viruses are not well documented. We analysed 84,502 HFMD cases from 2008 to 2011 in Beijing to explore the seasonal influence of weather factors (average temperature [AT], average relative humidity [ARH], total precipitation [TP] and average wind speed [AWS]) on incidents of HFMD by using a geographically weighted regression (GWR) model. The results indicated that weather factors differ significantly in their influence on HFMD depending on the season. AT had the greatest effect among the four weather factors, and while the influence of AT and AWS was greater in the summer than in the winter, the influence of TP was positive in the summer and negative in the winter. ARH was negatively correlated with HFMD. Also, we observed more EV71-associated cases than CV-A16 but there is no convincing evidence to show significant differences between the influences of the weather factors on EV71 and CV-A16. PMID:26755102

Therapeutic Applications of Extracellular Vesicles: Clinical Promise and Open Questions

PubMed Central

Breakefield, Xandra O.; Leonard, Joshua N.

2015-01-01

This review provides an updated perspective on rapidly proliferating efforts to harness extracellular vesicles (EVs) for therapeutic applications. We summarize current knowledge, emerging strategies, and open questions pertaining to clinical potential and translation. Potentially useful EVs comprise diverse products of various cell types and species. EV components may also be combined with liposomes and nanoparticles to facilitate manufacturing as well as product safety and evaluation. Potential therapeutic cargoes include RNA, proteins, and drugs. Strategic issues considered herein include choice of therapeutic agent, means of loading cargoes into EVs, promotion of EV stability, tissue targeting, and functional delivery of cargo to recipient cells. Some applications may harness natural EV properties, such as immune modulation, regeneration promotion, and pathogen suppression. These properties can be enhanced or customized to enable a wide range of therapeutic applications, including vaccination, improvement of pregnancy outcome, and treatment of autoimmune disease, cancer, and tissue injury. PMID:25292428

42 CFR 71.3 - Designation of yellow fever vaccination centers; Validation stamps.

Code of Federal Regulations, 2010 CFR

2010-10-01

... safe, potent, and pure yellow fever vaccine. Medical facilities of Federal agencies are authorized to obtain yellow fever vaccine without being designated as a yellow fever vaccination center by the Director..., storage, and administration of yellow fever vaccine. If a designated center fails to comply with such...

Immune responses to baculovirus-displayed enterovirus 71 VP1 antigen.

PubMed

Kiener, Tanja K; Premanand, Balraj; Kwang, Jimmy

2013-04-01

The increased distribution and neurovirulence of enterovirus 71 is an important health threat for young children in Asia Pacific. Vaccine design has concentrated on inactivated virus with the most advanced undergoing Phase III clinical trials. By using a subunit vaccine approach, production costs could be reduced by lowering the need for biocontainment. In addition, novel mutations could be rapidly incorporated to reflect the emergence of new enterovirus 71 subgenogroups. To circumvent the problems associated with conventional subunit vaccines, the antigen can be displayed on a viral vector that conveys stability and facilitates purification. Additional advantages of viral-vectored subunit vaccines are their ability to stimulate the innate immune system by transducing cells and the possibility of oral or nasal delivery, which dispenses with the need for syringes and medical personnel. Baculovirus-displayed VP1 combines all these benefits with protection that is as efficient as inactivated virus.

ADVERSE EVENTS POST-DTAP AND DTwP VACCINATION IN THAI CHILDREN.

PubMed

Fortuna, Librada; Sirivichayakul, Chukiat; Watanaveeradej, Veerachai; Soonthornworasiri, Ngamphol; Sitcharungsi, Raweerat

2015-07-01

We conducted a prospective study to compare the development of fever (axillary T ≥ 37.9 °C) within 4 hours of vaccination, determine the proportion of children who develop high fever (T ≥ 39°C) and evaluate parental days missed from work due to their children's vaccination with either the diphtheria-tetanus-whole cell pertussis (DTwP) or diphtheria-tetanus-acellular pertussis (DTaP) vaccine. The results of this study can help physicians and parents decide whether to have their child vaccinated with the DTwP or more expensive DTaP vaccine. We studied 140 healthy Thai children aged 2 months to 6 years from December 2011 to March 2012 who presented for vaccination. Parents recorded their child's temperature, local and systemic adverse reactions and missed days from work due to these adverse events on a diary card. Of the 140 participants, 72 received the DTwP vaccine and 68 received the DTaP vaccine. The median (IQR) age was 4 (2-6) months and the median weight was 7.1 (5.6-8.7) kg. Twenty children developed fever (axillary T ≥ 37.9°C) within 4 hours following vaccination, 17 (23.6%) had received the DTwP vaccine and 3 (4.4%) had received the DTaP vaccine (p = 0.040). One child (1.4%) who had received the DTwP vaccine and none who received the DTaP vaccine developed high fever (T ≥ 39°C) within 4 hours of vaccination (p = 0.329). Parents of two children who received the DTwP vaccine and one child who received the DTaP vaccine missed work following vaccination (p = 0.059). In conclusion, children who received the DTwP vaccines were more likely to have early post-vaccination fever and higher fever but there was no significant difference between the two groups in parental days lost from work.

Involvement of the renin-angiotensin system in the progression of severe hand-foot-and-mouth disease.

PubMed

Zhang, Chao; Chen, Shuaiyin; Zhou, Guangyuan; Jin, Yuefei; Zhang, Rongguang; Yang, Haiyan; Xi, Yuanlin; Ren, Jingchao; Duan, Guangcai

2018-01-01

Hand-foot-and-mouth disease (HFMD) is generally considered as a mild exanthematous disease to infants and young children worldwide. HFMD cases are usually mild and self-limiting but for few cases leads to complicated severe clinical outcomes, and even death. Previous studies have indicated that serum Ang II levels in patients with H7N9 infection were related to the severity of infection. However, the mechanisms underlying the pathogenesis of severe HFMD remain unclear. This study was undertaken to clarify the role of the renin-angiotensin system (RAS) in the progression of severe HFMD. In the present study, 162 children including HFMD patients and healthy controls were recruited. The data was analyzed by time-series fashion. Concentrations of angiotensin II (Ang II) and noradrenaline (NA) in serum of patients were measured with ELISA. We established a mouse model for enterovirus 71 (EV71) infection and determined concentrations of Ang II, NA in tissue lysates at 3, 5 and 7 days post infection (dpi). The concentrations of Ang II and NA in serum of the HFMD patients with mild or severe symptoms were significantly higher than that in healthy controls. Additionally, the concentrations of Ang II and NA in serum of severe cases were significantly higher than those mild cases and the increased concentrations of Ang II and NA showed the same time trend during the progression of HFMD in the severe cases. Furthermore, the concentrations of Ang II and NA in target organs of EV71-infected mice including brains, skeletal muscle, and lungs were increased with the progression of EV71 infection in mice. Histopathological alterations were observed in the brains, skeletal muscle and lungs of EV71-infected mice. Our study suggested that activation of the RAS is implicated in the pathogenesis of severe HFMD.

Development of a Genetically-Engineered Venezuelan Equine Encephalitis virus Vaccine

DTIC Science & Technology

1989-11-13

necrosis. We have evaluated the efficacy of a recombinant vaccinia/VEE virus vaccine (TC-5A) to protect horses against challenge with equine virulent...of horse vaccinees with equine virulent VEE virus 71-180 and vaccinia viruses ........ 27 7. ELISA cross-reactivity of sera from immunized equines ...antibodies in equines after immuniza- tion with TC-83, TC-5A and wild-type vaccinia viruses . .40 5. Body temperature of horses immunized with TC-5A (A

Coverage of pilot parenteral vaccination campaign against canine rabies in N'Djaména, Chad.

PubMed Central

Kayali, U.; Mindekem, R.; Yémadji, N.; Vounatsou, P.; Kaninga, Y.; Ndoutamia, A. G.; Zinsstag, J.

2003-01-01

Canine rabies, and thus human exposure to rabies, can be controlled through mass vaccination of the animal reservoir if dog owners are willing to cooperate. Inaccessible, ownerless dogs, however, reduce the vaccination coverage achieved in parenteral campaigns. This study aimed to estimate the vaccination coverage in dogs in three study zones of N'Djaména, Chad, after a pilot free parenteral mass vaccination campaign against rabies. We used a capture-mark-recapture approach for population estimates, with a Bayesian, Markov chain, Monte Carlo method to estimate the total number of owned dogs, and the ratio of ownerless to owned dogs to calculate vaccination coverage. When we took into account ownerless dogs, the vaccination coverage in the dog populations was 87% (95% confidence interval (CI), 84-89%) in study zone I, 71% (95% CI, 64-76%) in zone II, and 64% (95% CI, 58-71%) in zone III. The proportions of ownerless dogs to owned dogs were 1.1% (95% CI, 0-3.1%), 7.6% (95% CI, 0.7-16.5%), and 10.6% (95% CI, 1.6-19.1%) in the three study zones, respectively. Vaccination coverage in the three populations of owned dogs was 88% (95% CI, 84-92%) in zone I, 76% (95% CI, 71-81%) in zone II, and 70% (95% CI, 66-76%) in zone III. Participation of dog owners in the free campaign was high, and the number of inaccessible ownerless dogs was low. High levels of vaccination coverage could be achieved with parenteral mass vaccination. Regular parenteral vaccination campaigns to cover all of N'Djaména should be considered as an ethical way of preventing human rabies when post-exposure treatment is of limited availability and high in cost. PMID:14758434

Systematic review of incremental non-vaccine cost estimates used in cost-effectiveness analysis on the introduction of rotavirus and pneumococcal vaccines.

PubMed

De la Hoz-Restrepo, Fernando; Castañeda-Orjuela, Carlos; Paternina, Angel; Alvis-Guzman, Nelson

2013-07-02

To review the approaches used in the cost-effectiveness analysis (CEAs) literature to estimate the cost of expanded program on immunization (EPI) activities, other than vaccine purchase, for rotavirus and pneumococcal vaccines. A systematic review in PubMed and NHS EED databases of rotavirus and pneumococcal vaccines CEAs was done. Selected articles were read and information on how EPI costs were calculated was extracted. EPI costing approaches were classified according to the method or assumption used for estimation. Seventy-nine studies that evaluated cost effectiveness of rotavirus (n=43) or pneumococcal (n=36) vaccines were identified. In general, there are few details on how EPI costs other than vaccine procurement were estimated. While 30 studies used some measurement of that cost, only one study on pneumococcal vaccine used a primary cost evaluation (bottom-up costing analysis) and one study used a costing tool. Twenty-seven studies (17 on rotavirus and 10 on pneumococcal vaccine) assumed the non-vaccine costs. Five studies made no reference to additional costs. Fourteen studies (9 rotavirus and 5 pneumococcal) did not consider any additional EPI cost beyond vaccine procurement. For rotavirus studies, the median for non-vaccine cost per dose was US$0.74 in developing countries and US$6.39 in developed countries. For pneumococcal vaccines, the median for non-vaccine cost per dose was US$1.27 in developing countries and US$8.71 in developed countries. Many pneumococcal (52.8%) and rotavirus (60.4%) cost-effectiveness analyses did not consider additional EPI costs or used poorly supported assumptions. Ignoring EPI costs in addition to those for vaccine procurement in CEA analysis of new vaccines may lead to significant errors in the estimations of ICERs since several factors like personnel, cold chain, or social mobilization can be substantially affected by the introduction of new vaccines. Copyright © 2013 Elsevier Ltd. All rights reserved.

Wide bandgap OPV polymers based on pyridinonedithiophene unit with efficiency >5%

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schneider, Alexander M.; Lu, Luyao; Manley, Eric F.

2015-06-04

We report the properties of a new series of wide band gap photovoltaic polymers based on the N-alkyl 2-pyridone dithiophene (PDT) unit. These polymers are effective bulk heterojunction solar cell materials when blended with phenyl-C 71-butyric acid methyl ester (PC 71BM). They achieve power conversion efficiencies (up to 5.33%) high for polymers having such large bandgaps, ca. 2.0 eV (optical) and 2.5 eV (electrochemical). As a result, grazing incidence wide-angle X-ray scattering (GIWAXS) reveals strong correlations between π–π stacking distance and regularity, polymer backbone planarity, optical absorption maximum energy, and photovoltaic efficiency.

Circulation of multiple serotypes of highly divergent enterovirus C in the Xinjiang Uighur Autonomous Region of China

PubMed Central

Zhang, Yong; Sun, Qiang; Cui, Hui; Yan, Dongmei; Fan, Qin; Song, Yang; Zhu, Shuangli; Li, Xiaolei; Huang, Guohong; Ji, Tianjiao; Hu, Lan; Wang, Dongyan; Yang, Qian; Xu, Wenbo

2016-01-01

Poliomyelitis associated with circulating vaccine-derived polioviruses (cVDPVs) is a serious public health issue in the post-eradication era, and the occurrence of recombinant cVDPVs emphasizes the need to elucidate enterovirus C (EV-C) epidemiology. Stool samples were collected from 826 healthy children in Southern Xinjiang in 2011 to investigate EV-C circulation and epidemiology. Thirty-six EV-Cs were isolated and assigned to eight EV-C serotypes by molecular serotyping, suggesting the circulation of diverse EV-Cs in Xinjiang. Phylogenetic analysis showed that the Xinjiang EV-C strains had larger variation compared to the prototype and other modern strains. Additionally, the results showed unique characteristics of Xinjiang EV-Cs, such as the cytopathicity of CV-A1 strains to RD cells; the high divergence in CV-A11, CV-A13, CV-A17, and CV-A20 strains; the divergence of Xinjiang CV-A24 from AHC-related CV-A24 variant stains distributed worldwide; and the circulation of two novel EV-C serotypes (EV-C96 and EV-C99). Evaluations of this dense and diverse EV-C ecosystem will help elucidate the processes shaping enteroviral biodiversity. This study will improve our understanding of the evolution of enteroviruses and the recombination potential between polioviruses and other EV-Cs. PMID:27642136

PREVALENCE OF HUMAN ENTEROVIRUS AMONG PATIENTS WITH HAND, FOOT, AND MOUTH DISEASE AND HERPANGINA IN THAILAND, 2013.

PubMed

Mauleekoonphairoj, John; Puenpa, Jiratchaya; Korkong, Sumeth; Vongpunsawad, Sompong; Poovorawan, Yong

2015-11-01

Human enterovirus (EV) infection causes hand, foot, and mouth disease (HFMD) and herpangina (HA). We studied the prevalence of enterovirus (EV) among patients with HFMD and HA in Thailand during 2013. We conducted a study in archived specimens of patients sent for screening for enterovirus. A total of 203 clinical specimens from 184 individuals with painful blister in the oropharynx and on the palms, soles, knees, elbows or buttock were examined by semi-nested polymerase chain reaction (PCR) for the 5'UTR and VP1 genes of EV. Eighty-six samples were positive: EV71 was detected in 14 (30%), CV-A8 in 12 (26%) and CV-A16 in 10 (21%). Classification of EV species detected revealed that 46 specimens were EV-A, 14 specimens were EV-B, 1 specimen was EV-D, and 16 specimens were positive for unclassified enterovirus. The majority of individuals with EV infection were aged 2-6 years. Multiple EV-A serotypes were detected among HFMD and HA patients in our study.

42 CFR 102.71 - Insufficient documentation for eligibility and benefits determinations.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Insufficient documentation for eligibility and benefits determinations. 102.71 Section 102.71 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES VACCINES SMALLPOX COMPENSATION PROGRAM Secretarial Determinations § 102.71...

42 CFR 102.71 - Insufficient documentation for eligibility and benefits determinations.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false Insufficient documentation for eligibility and benefits determinations. 102.71 Section 102.71 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES VACCINES SMALLPOX COMPENSATION PROGRAM Secretarial Determinations § 102.71...

42 CFR 102.71 - Insufficient documentation for eligibility and benefits determinations.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Insufficient documentation for eligibility and benefits determinations. 102.71 Section 102.71 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES VACCINES SMALLPOX COMPENSATION PROGRAM Secretarial Determinations § 102.71...

42 CFR 102.71 - Insufficient documentation for eligibility and benefits determinations.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false Insufficient documentation for eligibility and benefits determinations. 102.71 Section 102.71 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES VACCINES SMALLPOX COMPENSATION PROGRAM Secretarial Determinations § 102.71...

42 CFR 102.71 - Insufficient documentation for eligibility and benefits determinations.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false Insufficient documentation for eligibility and benefits determinations. 102.71 Section 102.71 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES VACCINES SMALLPOX COMPENSATION PROGRAM Secretarial Determinations § 102.71...

Indian parents prefer vaccinating their daughters against HPV at older ages.

PubMed

Madhivanan, Purnima; Srinivas, Vijaya; Marlow, Laura; Mukherjee, Soumyadeep; Narayanappa, Doddaiah; Mysore, Shekar; Arun, Anjali; Krupp, Karl

2014-01-01

Increasing uptake of human papillomavirus (HPV) vaccine should be a priority in developing countries since they suffer 88% of the world's cervical cancer burden. In many countries studies show that age at vaccination is an important determinate of parental acceptability. This study explores parental preferences on age-to-vaccinate for adolescent school-going girls. The sample was selected using a two-stage probability proportional to size cluster sampling methodology. Questionnaires were sent home with a random sample of 800 adolescent girls attending 12 schools in Mysore to be completed by parents. Descriptive statistics including frequencies, percentages and proportions were generated for independent variables and bivariate analyses (Chi square test) were used to assess the relationship between independent and appropriate age-to-vaccinate. HPV vaccination acceptability was high at 71%. While 5.3% of parents felt girls should be vaccinated by 10 years or younger; 38.3% said 11-15 years; 14.8% said 16-18 years; 5.8% suggested over 19 years; and 33% didn't know. Only 2.8% of parents would not vaccinate their daughters. Delaying HPV vaccination until later ages may significantly increase uptake of the HPV vaccine in India.

Production of negative ions by dissociative electron attachment to SO2

NASA Technical Reports Server (NTRS)

Orient, O. J.; Srivastava, S. K.

1983-01-01

Dissociative electron attachment cross section measurements for the production of O(-), S(-), and SO(-) have been performed utilizing a crossed target SO2 molecule beam-electron beam geometry. The relative flow technique is employed to determine the absolute values of cross sections. The attachment energies corresponding to various cross section maxima are: 4.30 and 7.1 eV for O(-)/SO2; 4.0, 7.5, and 8.9 eV for S(-)/SO2, and 4.7 and 7.5 eV for SO(-)/SO2.

Rapid and Accurate Sequencing of Enterovirus Genomes Using MinION Nanopore Sequencer.

PubMed

Wang, Ji; Ke, Yue Hua; Zhang, Yong; Huang, Ke Qiang; Wang, Lei; Shen, Xin Xin; Dong, Xiao Ping; Xu, Wen Bo; Ma, Xue Jun

2017-10-01

Knowledge of an enterovirus genome sequence is very important in epidemiological investigation to identify transmission patterns and ascertain the extent of an outbreak. The MinION sequencer is increasingly used to sequence various viral pathogens in many clinical situations because of its long reads, portability, real-time accessibility of sequenced data, and very low initial costs. However, information is lacking on MinION sequencing of enterovirus genomes. In this proof-of-concept study using Enterovirus 71 (EV71) and Coxsackievirus A16 (CA16) strains as examples, we established an amplicon-based whole genome sequencing method using MinION. We explored the accuracy, minimum sequencing time, discrimination and high-throughput sequencing ability of MinION, and compared its performance with Sanger sequencing. Within the first minute (min) of sequencing, the accuracy of MinION was 98.5% for the single EV71 strain and 94.12%-97.33% for 10 genetically-related CA16 strains. In as little as 14 min, 99% identity was reached for the single EV71 strain, and in 17 min (on average), 99% identity was achieved for 10 CA16 strains in a single run. MinION is suitable for whole genome sequencing of enteroviruses with sufficient accuracy and fine discrimination and has the potential as a fast, reliable and convenient method for routine use. Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

Basic reproduction number of coxsackievirus type A6 and A16 and enterovirus 71: estimates from outbreaks of hand, foot and mouth disease in Singapore, a tropical city-state.

PubMed

Lim, C T K; Jiang, L; Ma, S; James, L; Ang, L W

2016-04-01

Coxsackievirus A6 (CV-A6), coxsackievirus A16 (CV-A16) and enterovirus 71 (EV-A71) were the major enteroviruses causing nationwide hand, foot and mouth disease (HFMD) epidemics in Singapore in the last decade. We estimated the basic reproduction number (R 0) of these enteroviruses to obtain a better understanding of their transmission dynamics. We merged records of cases from HFMD outbreaks reported between 2007 and 2012 with laboratory results from virological surveillance. R 0 was estimated based on the cumulative number of reported cases in the initial growth phase of each outbreak associated with the particular enterovirus type. A total of 33 HFMD outbreaks were selected based on the inclusion criteria specified for our study, of which five were associated with CV-A6, 13 with CV-A16, and 15 with EV-A71. The median R 0 was estimated to be 5·04 [interquartile range (IQR) 3·57-5·16] for CV-A6, 2·42 (IQR 1·85-3·36) for CV-A16, and 3·50 (IQR 2·36-4·53) for EV-A71. R 0 was not significantly associated with number of infected children (P = 0·86), number of exposed children (P = 0·94), and duration of the outbreak (P = 0·05). These enterovirus-specific R 0 estimates will be helpful in providing insights into the potential growth of future HFMD epidemics and outbreaks for timely implementation of disease control measures, together with disease dynamics such as severity of the cases.

Shift of Enterovirus species among children in Cameroon--identification of a new enterovirus, EV-A119.

PubMed

Ayukekbong, James; Kabayiza, Jean-Claude; Lindh, Magnus; Nkuo-Akenji, Theresia; Tah, Ferdinand; Bergström, Tomas; Norder, Helene

2013-09-01

Infections caused by human enteroviruses (EVs) are often asymptomatic or mild, although they may cause more severe illnesses as meningitis and acute flaccid paralysis. EVs have globally posed a threat to children, and outbreaks of aseptic meningitis and hand, foot and mouth disease are frequently reported. To identify EV strains circulating among healthy children in a small community in Limbe, Cameroon two years apart. Species and EV types were obtained by partial 5'UTR-VP4 and VP1 sequencing of RNA from stool samples collected in October 2009 and September 2011 from 150 children in Cameroon. In all, 74 children (49%) were infected with 28 different types of EV. There were 29 (54%) infected children in 2009, and 45 (47%) in 2011. There was a significant difference between detected species of EV, with 15 (47%) children infected with EV-A in 2009, and 22 (71%) with EV-B in 2011 (p=0.0001). In 2009, one child was infected by a divergent EV, which was most similar to EV-A90. Based on the complete VP1 sequence, it was shown to be a new EV designated EV-A119. The current study shows a high heterogeneity of circulating EV types among children in Limbe, Cameroon, and a previously not described shift in predominating EV species. Copyright © 2013 Elsevier B.V. All rights reserved.

Dogs that develop rabies post-vaccination usually manifest the paralytic subtype.

PubMed

Tepsumethanon, Veera; Likitsuntonwong, Wanlop; Thorner, Paul Scott; Shuangshoti, Shanop

2016-09-01

Rabies infection can manifest as either encephalitic (furious) or paralytic (dumb) types, with a ratio of approximately 2:1 in dogs. The clinical type of rabies that develops post-vaccination has only been reported in studies from one country, all with similar findings. We report a study of 36 rabid dogs with obtainable vaccination history, presenting to The Queen Saovabha Memorial Institute, Bangkok, Thailand during 2002-2008. Dogs were classified into encephalitic or paralytic types. Of 22 non-vaccinated dogs, 16 (73%) had the encephalitic type. In contrast, of the 14 vaccinated dogs, 10 (71%) had the paralytic type, a difference that was significant (p=0.016). Recent studies on canine brains have shown that lymphocyte response is more pronounced in paralytic rabies at the brainstem level, whereas viral burden is greater in the encephalitic form. We postulate partial immune response in the vaccinated dogs might influence rabies to manifest as the paralytic type. These results can serve as a natural experiment that can help explain the basis for the differences between the paralytic and encephalitic forms of canine rabies. Copyright © 2016 Elsevier B.V. All rights reserved.

Structure-activity relationship study of peptidomimetic aldehydes as enterovirus 71 3C protease inhibitors.

PubMed

Zhai, Yangyang; Ma, Yuying; Ma, Fei; Nie, Quandeng; Ren, Xuejiao; Wang, Yaxin; Shang, Luqing; Yin, Zheng

2016-11-29

A series of peptidomimetic aldehydes were designed, synthesized, and evaluated for their biochemical activity against 3C protease (3C pro ) and anti-enterovirus 71 (EV71) activity in vitro. Molecular docking revealed that 5s (IC 50  = 0.22 ± 0.07 μM, EC 50  = 0.18 ± 0.05 μM) could bind well to the active site of EV71 3C pro , which was consistent with the biological data compared to reference 5a (IC 50  = 0.54 ± 0.02 μM, EC 50  = 0.26 ± 0.07 μM). Structure and relationship study led to the discovery of aldehyde 5x (IC 50  = 0.10 ± 0.02 μM, EC 50  = 0.11 ± 0.07 μM), which exhibited the most potent 3C pro inhibitory and antiviral activity. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Valine/isoleucine variants drive selective pressure in the VP1 sequence of EV-A71 enteroviruses.

PubMed

Duy, Nghia Ngu; Huong, Le Thi Thanh; Ravel, Patrice; Huong, Le Thi Song; Dwivedi, Ankit; Sessions, October Michael; Hou, Yan'An; Chua, Robert; Kister, Guilhem; Afelt, Aneta; Moulia, Catherine; Gubler, Duane J; Thiem, Vu Dinh; Thanh, Nguyen Thi Hien; Devaux, Christian; Duong, Tran Nhu; Hien, Nguyen Tran; Cornillot, Emmanuel; Gavotte, Laurent; Frutos, Roger

2017-05-08

In 2011-2012, Northern Vietnam experienced its first large scale hand foot and mouth disease (HFMD) epidemic. In 2011, a major HFMD epidemic was also reported in South Vietnam with fatal cases. This 2011-2012 outbreak was the first one to occur in North Vietnam providing grounds to study the etiology, origin and dynamic of the disease. We report here the analysis of the VP1 gene of strains isolated throughout North Vietnam during the 2011-2012 outbreak and before. The VP1 gene of 106 EV-A71 isolates from North Vietnam and 2 from Central Vietnam were sequenced. Sequence alignments were analyzed at the nucleic acid and protein level. Gene polymorphism was also analyzed. A Factorial Correspondence Analysis was performed to correlate amino acid mutations with clinical parameters. The sequences were distributed into four phylogenetic clusters. Three clusters corresponded to the subgenogroup C4 and the last one corresponded to the subgenogroup C5. Each cluster displayed different polymorphism characteristics. Proteins were highly conserved but three sites bearing only Isoleucine (I) or Valine (V) were characterized. The isoleucine/valine variability matched the clusters. Spatiotemporal analysis of the I/V variants showed that all variants which emerged in 2011 and then in 2012 were not the same but were all present in the region prior to the 2011-2012 outbreak. Some correlation was found between certain I/V variants and ethnicity and severity. The 2011-2012 outbreak was not caused by an exogenous strain coming from South Vietnam or elsewhere but by strains already present and circulating at low level in North Vietnam. However, what triggered the outbreak remains unclear. A selective pressure is applied on I/V variants which matches the genetic clusters. I/V variants were shown on other viruses to correlate with pathogenicity. This should be investigated in EV-A71. I/V variants are an easy and efficient way to survey and identify circulating EV-A71 strains.

Mass Measles Vaccination Campaign in Aila Cyclone-Affected Areas of West Bengal, India: An In-depth Analysis and Experiences.

PubMed

Mallik, Sarmila; Mandal, Pankaj Kumar; Ghosh, Pramit; Manna, Nirmalya; Chatterjee, Chitra; Chakrabarty, Debadatta; Bagchi, Saumendra Nath; Dasgupta, Samir

2011-12-01

Disaster-affected populations are highly vulnerable to outbreaks of measles. Therefore, a mass vaccination against measles was conducted in Aila cyclone-affected blocks of West Bengal, India in July 2009. The objectives of the present report were to conduct an in depth analysis of the campaign, and to discuss the major challenges. A block level micro-plan, which included mapping of the villages, health facilities, temporary settlements of disaster-affected population, communications available, formation of vaccination team, information education communication, vaccine storage, waste disposal, surveillance for adverse events following immunization, supervision and monitoring was developed. The rate of six months to five years old children, who were vaccinated by measles vaccine, was 70.7% and that of those who received one dose of vitamin A was 71.3%. Wastage factor for vaccine doses and auto-disable syringes were 1.09 and 1.07, respectively. Only 13 cases of adverse events following immunization were reported. An average of 0.91 puncture-proof containers per vaccination session was used. Despite the major challenges faced due to difficult to reach areas, inadequate infrastructure, manpower and communication, problems of vaccine storage and transport, the campaign achieved a remarkable success regarding measles vaccine coverage, improvements of cold chain infrastructure, formulating an efficient surveillance and reporting system for adverse events following immunization, building self-confidence of the stakeholders, and developing a biomedical waste disposal system.

Mass Measles Vaccination Campaign in Aila Cyclone-Affected Areas of West Bengal, India: An In-depth Analysis and Experiences

PubMed Central

Mallik, Sarmila; Mandal, Pankaj Kumar; Ghosh, Pramit; Manna, Nirmalya; Chatterjee, Chitra; Chakrabarty, Debadatta; Bagchi, Saumendra Nath; Dasgupta, Samir

2011-01-01

Disaster-affected populations are highly vulnerable to outbreaks of measles. Therefore, a mass vaccination against measles was conducted in Aila cyclone-affected blocks of West Bengal, India in July 2009. The objectives of the present report were to conduct an in depth analysis of the campaign, and to discuss the major challenges. A block level micro-plan, which included mapping of the villages, health facilities, temporary settlements of disaster-affected population, communications available, formation of vaccination team, information education communication, vaccine storage, waste disposal, surveillance for adverse events following immunization, supervision and monitoring was developed. The rate of six months to five years old children, who were vaccinated by measles vaccine, was 70.7% and that of those who received one dose of vitamin A was 71.3%. Wastage factor for vaccine doses and auto-disable syringes were 1.09 and 1.07, respectively. Only 13 cases of adverse events following immunization were reported. An average of 0.91 puncture-proof containers per vaccination session was used. Despite the major challenges faced due to difficult to reach areas, inadequate infrastructure, manpower and communication, problems of vaccine storage and transport, the campaign achieved a remarkable success regarding measles vaccine coverage, improvements of cold chain infrastructure, formulating an efficient surveillance and reporting system for adverse events following immunization, building self-confidence of the stakeholders, and developing a biomedical waste disposal system. PMID:23115416

Opto-electronic characterizations of oriented nano-structure CdSe film/Si (0 0 1) heterostructure

NASA Astrophysics Data System (ADS)

Al-Kotb, M. S.; Al-Waheidi, Jumana Z.; Kotkata, M. F.

2014-05-01

Nano-crystalline CdSe thin films were fabricated by evaporating CdSe nano-powders on glass and p-Si (0 0 1) substrates. X-ray diffraction analysis indicated the hexagonal structure for the growing film along the (0 0 2) plane. The results revealed that the thermally evaporated thin film has a comparatively smoother surface with grain size ˜21 nm. Analysis of the absorption coefficient dependence on the photon energy predicts two direct band-gap values of 2.11 ± 0.02 and 1.71 ± 0.03 eV. On the basis of the Wemple-diDomenico single oscillator model, the values of single oscillator energy (Eu) and oscillator dispersion energy (Ed) found to be 2.71 ± 0.09 and 12.94 ± 0.35 eV, respectively. The photoluminescence measurements show levels at the following values: 1.824, 1.786, 1.682, and 1.617 eV confirming the native defects existence in the gap of CdSe films because of stoichiometric deviation. The forward I-V characteristics of Ni/CdSe/p-Si (0 0 1) structure have been primarily analyzed within the framework of a standard thermionic emission theory over the temperature range of 160-360 K. The characteristic parameters of the Ni/CdSe/p-Si(0 0 1) structure such as barrier height (φb), ideality factor (n), and series resistance (Rs) have been calculated using a method developed by Cheung-Cheung.

Evaluation of a Real-Time Reverse Transcription-PCR Assay for Detection of Enterovirus D68 in Clinical Samples from an Outbreak in New York State in 2014.

PubMed

Zhuge, Jian; Vail, Eric; Bush, Jeffrey L; Singelakis, Lauren; Huang, Weihua; Nolan, Sheila M; Haas, Janet P; Engel, Helen; Della Posta, Millicent; Yoon, Esther C; Fallon, John T; Wang, Guiqing

2015-06-01

An outbreak of severe respiratory illness associated with enterovirus D68 (EV-D68) infection was reported in mid-August 2014 in the United States. In this study, we evaluated the diagnostic utility of an EV-D68-specific real-time reverse transcription-PCR (rRT-PCR) that was recently developed by the Centers for Disease Control and Prevention in clinical samples. Nasopharyngeal (NP) swab specimens from patients in a recent outbreak of respiratory illness in the lower Hudson Valley, New York State, were collected and examined for the presence of human rhinovirus or enterovirus using the FilmArray Respiratory Panel (RP) assay. Samples positive by RP were assessed using EV-D68 rRT-PCR, and the data were compared to results from sequencing analysis of partial VP1 and 5' untranslated region (5'-UTR) sequences of the EV genome. A total of 285 RP-positive NP specimens (260 from the 2014 outbreak and 25 from 2013) were analyzed by rRT-PCR; EV-D68 was detected in 74 of 285 (26.0%) specimens examined. Data for comparisons between rRT-PCR and sequencing analysis were obtained from 194 NP specimens. EV-D68 detection was confirmed by sequencing analysis in 71 of 74 positive and in 1 of 120 randomly selected negative specimens by rRT-PCR. The EV-D68 rRT-PCR showed diagnostic sensitivity and specificity of 98.6% and 97.5%, respectively. Our data suggest that the EV-D68 rRT-PCR is a reliable assay for detection of EV-D68 in clinical samples and has a potential to be used as a tool for rapid diagnosis and outbreak investigation of EV-D68-associated infections in clinical and public health laboratories. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Evaluation of a Real-Time Reverse Transcription-PCR Assay for Detection of Enterovirus D68 in Clinical Samples from an Outbreak in New York State in 2014

PubMed Central

Zhuge, Jian; Vail, Eric; Bush, Jeffrey L.; Singelakis, Lauren; Huang, Weihua; Nolan, Sheila M.; Haas, Janet P.; Engel, Helen; Della Posta, Millicent; Yoon, Esther C.; Fallon, John T.

2015-01-01

An outbreak of severe respiratory illness associated with enterovirus D68 (EV-D68) infection was reported in mid-August 2014 in the United States. In this study, we evaluated the diagnostic utility of an EV-D68-specific real-time reverse transcription-PCR (rRT-PCR) that was recently developed by the Centers for Disease Control and Prevention in clinical samples. Nasopharyngeal (NP) swab specimens from patients in a recent outbreak of respiratory illness in the lower Hudson Valley, New York State, were collected and examined for the presence of human rhinovirus or enterovirus using the FilmArray Respiratory Panel (RP) assay. Samples positive by RP were assessed using EV-D68 rRT-PCR, and the data were compared to results from sequencing analysis of partial VP1 and 5′ untranslated region (5′-UTR) sequences of the EV genome. A total of 285 RP-positive NP specimens (260 from the 2014 outbreak and 25 from 2013) were analyzed by rRT-PCR; EV-D68 was detected in 74 of 285 (26.0%) specimens examined. Data for comparisons between rRT-PCR and sequencing analysis were obtained from 194 NP specimens. EV-D68 detection was confirmed by sequencing analysis in 71 of 74 positive and in 1 of 120 randomly selected negative specimens by rRT-PCR. The EV-D68 rRT-PCR showed diagnostic sensitivity and specificity of 98.6% and 97.5%, respectively. Our data suggest that the EV-D68 rRT-PCR is a reliable assay for detection of EV-D68 in clinical samples and has a potential to be used as a tool for rapid diagnosis and outbreak investigation of EV-D68-associated infections in clinical and public health laboratories. PMID:25854481

Construction and comparison of different source neuraminidase candidate vaccine strains for human infection with Eurasian avian-like influenza H1N1 virus.

PubMed

Liu, Liqi; Lu, Jian; Zhou, Jianfang; Li, Zi; Zhang, Heng; Wang, Dayan; Shu, Yuelong

2017-12-01

Human infections with Eurasian avian-like swine influenza H1N1 viruses have been reported in China in past years. One case resulted in death and others were mild case. In 2016, the World Health Organization recommended the use of A/Hunan/42443/2015(H1N1) virus to construct the first candidate vaccine strain for Eurasian avian-like swine influenza H1N1 viruses. Previous reports showed that the neuraminidase of A/Puerto Rico/8/34(H1N1) might improve the viral yield of reassortant viruses. Therefore, we constructed two reassortant candidate vaccine viruses of A/Hunan/42443/2015(H1N1) by reverse genetic technology, with (6+2) and (7+1) gene constitution, respectively. The (6+2) virus had hemagglutinin and neuraminidase from A/Hunan/42443/2015, and the (7+1) one had hemagglutinin from A/Hunan/42443/2015, while all the other genes were from A/Puerto Rico/8/34. Our data revealed that although the neuraminidase of the (7+1) virus was from high yield A/Puerto Rico/8/34, the hemagglutination titer and the hemagglutinin protein content of the (7+1) virus was not higher than that of the (6+2) virus. Both of the (7+1) and (6+2) viruses reached a similar level to that of A/Puerto Rico/8/34 at the usual harvest time in vitro. Therefore, both reassortant viruses are potential candidate vaccine viruses, which could contribute to pandemic preparedness. Copyright © 2017. Published by Elsevier Masson SAS.

42 CFR 110.71 - Insufficient documentation for eligibility and benefits determinations.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false Insufficient documentation for eligibility and benefits determinations. 110.71 Section 110.71 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES VACCINES COUNTERMEASURES INJURY COMPENSATION PROGRAM Secretarial Determinations...

42 CFR 110.71 - Insufficient documentation for eligibility and benefits determinations.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false Insufficient documentation for eligibility and benefits determinations. 110.71 Section 110.71 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES VACCINES COUNTERMEASURES INJURY COMPENSATION PROGRAM Secretarial Determinations...

42 CFR 110.71 - Insufficient documentation for eligibility and benefits determinations.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Insufficient documentation for eligibility and benefits determinations. 110.71 Section 110.71 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES VACCINES COUNTERMEASURES INJURY COMPENSATION PROGRAM Secretarial Determinations...

42 CFR 110.71 - Insufficient documentation for eligibility and benefits determinations.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false Insufficient documentation for eligibility and benefits determinations. 110.71 Section 110.71 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES VACCINES COUNTERMEASURES INJURY COMPENSATION PROGRAM Secretarial Determinations...

Surveillance and laboratory detection for non-polio enteroviruses in the European Union/European Economic Area, 2016

PubMed Central

Harvala, Heli; Jasir, Aftab; Penttinen, Pasi; Pastore Celentano, Lucia; Greco, Donato; Broberg, Eeva

2017-01-01

Enteroviruses (EVs) cause severe outbreaks of respiratory and neurological disease as illustrated by EV-D68 and EV-A71 outbreaks, respectively. We have mapped European laboratory capacity for identification and characterisation of non-polio EVs to improve preparedness to respond to (re)-emerging EVs linked to severe disease. An online questionnaire on non-polio EV surveillance and laboratory detection was submitted to all 30 European Union (EU)/European Economic Area (EEA) countries. Twenty-nine countries responded; 26 conducted laboratory-based non-polio EV surveillance, and 24 included neurological infections in their surveillance. Eleven countries have established specific surveillance for EV-D68 via sentinel influenza surveillance (n = 7), typing EV-positive respiratory samples (n = 10) and/or acute flaccid paralysis surveillance (n = 5). Of 26 countries performing non-polio EV characterisation/typing, 10 further characterised culture-positive EV isolates, whereas the remainder typed PCR-positive but culture-negative samples. Although 19 countries have introduced sequence-based EV typing, seven still rely entirely on virus isolation. Based on 2015 data, six countries typed over 300 specimens mostly by sequencing, whereas 11 countries characterised under 50 EV-positive samples. EV surveillance activity varied between EU/EEA countries, and did not always specifically target patients with neurological and/or respiratory infections. Introduction of sequence-based typing methods is needed throughout the EU/EEA to enhance laboratory capacity for the detection of EVs. PMID:29162204

Surveillance and laboratory detection for non-polio enteroviruses in the European Union/European Economic Area, 2016.

PubMed

Harvala, Heli; Jasir, Aftab; Penttinen, Pasi; Pastore Celentano, Lucia; Greco, Donato; Broberg, Eeva

2017-11-01

Enteroviruses (EVs) cause severe outbreaks of respiratory and neurological disease as illustrated by EV-D68 and EV-A71 outbreaks, respectively. We have mapped European laboratory capacity for identification and characterisation of non-polio EVs to improve preparedness to respond to (re)-emerging EVs linked to severe disease. An online questionnaire on non-polio EV surveillance and laboratory detection was submitted to all 30 European Union (EU)/European Economic Area (EEA) countries. Twenty-nine countries responded; 26 conducted laboratory-based non-polio EV surveillance, and 24 included neurological infections in their surveillance. Eleven countries have established specific surveillance for EV-D68 via sentinel influenza surveillance (n = 7), typing EV-positive respiratory samples (n = 10) and/or acute flaccid paralysis surveillance (n = 5). Of 26 countries performing non-polio EV characterisation/typing, 10 further characterised culture-positive EV isolates, whereas the remainder typed PCR-positive but culture-negative samples. Although 19 countries have introduced sequence-based EV typing, seven still rely entirely on virus isolation. Based on 2015 data, six countries typed over 300 specimens mostly by sequencing, whereas 11 countries characterised under 50 EV-positive samples. EV surveillance activity varied between EU/EEA countries, and did not always specifically target patients with neurological and/or respiratory infections. Introduction of sequence-based typing methods is needed throughout the EU/EEA to enhance laboratory capacity for the detection of EVs.

Vaccine Hesitancy Among Caregivers and Association with Childhood Vaccination Timeliness in Addis Ababa, Ethiopia.

PubMed

Masters, Nina B; Tefera, Yemesrach A; Wagner, Abram L; Boulton, Matthew L

2018-05-24

Vaccines are vital to reducing childhood mortality, and prevent an estimated 2 to 3 million deaths annually which disproportionately occur in the developing world. Overall vaccine coverage is typically used as a metric to evaluate the adequacy of vaccine program performance, though it does not account for untimely administration, which may unnecessarily prolong children's susceptibility to disease. This study explored a hypothesized positive association between increasing vaccine hesitancy and untimeliness of immunizations administered under the Expanded Program on Immunization (EPI) in Addis Ababa, Ethiopia. This cross-sectional survey employed a multistage sampling design, randomly selecting one health center within five sub-cities of Addis Ababa. Caregivers of 3 to 12-month-old infants completed a questionnaire on vaccine hesitancy, and their infants' vaccination cards were examined to assess timeliness of received vaccinations. The sample comprised 350 caregivers. Overall, 82.3% of the surveyed children received all recommended vaccines, although only 55.9% of these vaccinations were timely. Few caregivers (3.4%) reported ever hesitating and 3.7% reported ever refusing a vaccine for their child. Vaccine hesitancy significantly increased the odds of untimely vaccination (AOR 1.94, 95% CI: 1.02, 3.71) in the adjusted analysis. This study found high vaccine coverage among a sample of 350 young children in Addis Ababa, though only half received all recommended vaccines on time. High vaccine hesitancy was strongly associated with infants' untimely vaccination, indicating that increased efforts to educate community members and providers about vaccines may have a beneficial impact on vaccine timeliness in Addis Ababa.

Mining SNPs in extracellular vesicular transcriptome of Trypanosoma cruzi: a step closer to early diagnosis of neglected Chagas disease.

PubMed

Gaur, Pallavi; Chaturvedi, Anoop

2016-01-01

One of the newest and strongest members of intercellular communicators, the Extracellular vesicles (EVs) and their enclosed RNAs; Extracellular RNAs (exRNAs) have been acknowledged as putative biomarkers and therapeutic targets for various diseases. Although a very deep insight has not been possible into the physiology of these vesicles, they are believed to be involved in cell-to-cell communication and host-pathogen interactions. EVs might be significantly helpful in discovering biomarkers for possible target identification as well as prognostics, diagnostics and developing vaccines. In recent studies, highly bioactive EVs have drawn attention of parasitologists for being able to communicate between different cells and having likeliness of reflecting both source and target environments. Next-generation sequencing (NGS) has eased the way to have a deeper insight into these vesicles and their roles in various diseases. This article arises from bioinformatics-based analysis and predictive data mining of transcriptomic (RNA-Seq) data of EVs, derived from different life stages of Trypanosoma cruzi ; a causing agent of neglected Chagas disease. Variants (Single Nucleotide Polymorphisms (SNPs)) were mined from Extracellular vesicular transcriptomic data and functionally analyzed using different bioinformatics based approaches. Functional analysis showed the association of these variants with various important factors like Trans-Sialidase (TS), Alpha Tubulin, P-Type H+-ATPase, etc. which, in turn, are associated with disease in different ways. Some of the 'candidate SNPs' were found to be stage-specific, which strengthens the probability of finding stage-specific biomarkers. These results may lead to a better understanding of Chagas disease, and improved knowledge may provide further development of the biomarkers for prognosis, diagnosis and drug development for treating Chagas disease.

Acceptance of a vaccine against novel influenza A (H1N1) virus among health care workers in two major cities in Mexico.

PubMed

Esteves-Jaramillo, Alejandra; Omer, Saad B; Gonzalez-Diaz, Esteban; Salmon, Daniel A; Hixson, Brooke; Navarro, Francisco; Kawa-Karasik, Simon; Frew, Paula; Morfin-Otero, Rayo; Rodriguez-Noriega, Eduardo; Ramirez, Ylean; Rosas, Araceli; Acosta, Edgar; Varela-Badillo, Vianey; Del Rio, Carlos

2009-11-01

Further cases of novel influenza A (H1N1) outbreak are expected in the coming months. Vaccination has been proven to be essential to control a pandemic of influenza; therefore, considerable efforts and resources have been devoted to develop a vaccine against the influenza A (H1N1) virus. With the current availability of the vaccine, it will be important to immunize as many people as possible. However, previous data with seasonal influenza vaccines have shown that there are multiple barriers related to perceptions and attitudes of the population that influence vaccine use. The aim of the study was to evaluate the acceptance of a newly developed vaccine against pandemic (H1N1) 2009 influenza A among healthcare workers (HCW) in Mexico. We conducted a cross-sectional study among HCW in three hospitals in the two largest cities in Mexico-Mexico City and Guadalajara-between June and September 2009. A total of 1097 HCW participated in the survey. Overall, 80% (n = 880) intended to accept the H1N1 pandemic vaccine and 71.6% (n = 786) reported they would recommend the vaccine to their patients. Doctors were more likely to accept and recommend the vaccine than nurses. HCWs who intend to be immunized will be more likely to do so if they know that the vaccine is safe and effective. Knowledge of the willingness to accept the vaccine can be used to plan strategies that will effectively respond to the needs of the population studied, reducing the health and economic impact of novel influenza A (H1N1) virus.

Evaluation of Montanide ISA 71 VG adjuvant during profilin vaccination against experimental coccidiosis

USDA-ARS?s Scientific Manuscript database

Chickens were immunized subcutaneously with an Eimeria recombinant profilin protein plus ISA 70 VG (ISA 70) or ISA 71 VG (ISA 71) water-in-oil adjuvants, or with profilin alone, and comparative RNA microarray hybridizations were performed to ascertain global transcriptome changes induced by profilin...

Maternal antibody, vaccination and reproductive failure in dogs with parvovirus infection.

PubMed

Gooding, G E; Robinson, W F

1982-12-01

The maternal antibody (MAb) titre to canine parvovirus (CPV) was determined on consecutive serums from 39 puppies in 7 litters. Vaccination with inactivated CPV was performed at a variety of ages and the response of the puppies determined. Transfer of MAb was demonstrated in 71% (5/7) of the litters and persisted for up to 10 weeks in some litters. MAb titres of greater than 20 precluded a vaccination response by puppies. Sixty- one per cent (8/13) of puppies responded to vaccination when the MAb titre was less than 20. However, no anamestic response occurred and in some cases a decrease in antibody titre was observed following a second vaccination. During an outbreak of canine parvovirus enteritis (CPE) in the kennel, 33 puppies developed clinical signs of enteritis. Of these puppies 85% (28) had MAb titres of less than 80 at the onset of clinical signs. Fifty per cent (4/8) of the puppies which responded to vaccination developed CPE, whereas 100% (5/5) of those that did not respond to vaccination developed CPE. The results indicate that MAb may persist for up to 10 weeks and puppies with MAb in the titre range greater than 20 to less than 80 do not respond to vaccination but are still susceptible to infection. It is also apparent that a significant minority of puppies with MAb less than 20 do not respond to vaccination. An examination of the breeding records of the kennel for the 7 year period 1973-1981 demonstrated a sudden decrease in reproductive efficiency during and subsequent to 1978. This coincided with the recognition of cases of CPV infection in the kennel. It is suggested that further investigation is required into the possible role of CPV in reproductive failure.

Identification of a nucleotide in 5′ untranslated region contributing to virus replication and virulence of Coxsackievirus A16

PubMed Central

Li, Zhaolong; Liu, Xin; Wang, Shaohua; Li, Jingliang; Hou, Min; Liu, Guanchen; Zhang, Wenyan; Yu, Xiao-Fang

2016-01-01

Coxsackievirus A16 (CA16) and enterovirus 71 (EV71) are two main causative pathogens of hand, foot and mouth disease (HFMD). Unlike EV71, virulence determinants of CA16, particularly within 5′ untranslated region (5′UTR), have not been investigated until now. Here, a series of nucleotides present in 5′UTR of lethal but not in non-lethal CA16 strains were screened by aligning nucleotide sequences of lethal circulating Changchun CA16 and the prototype G10 as well as non-lethal SHZH05 strains. A representative infectious clone based on a lethal Changchun024 sequence and infectious mutants with various nucleotide alterations in 5′UTR were constructed and further investigated by assessing virus replication in vitro and virulence in neonatal mice. Compared to the lethal infectious clone, the M2 mutant with a change from cytosine to uracil at nucleotide 104 showed weaker virulence and lower replication capacity. The predicted secondary structure of the 5′UTR of CA16 RNA showed that M2 mutant located between the cloverleaf and stem-loop II, affected interactions between the 5′UTR and the heterogeneous nuclear ribonucleoprotein K (hnRNP K) and A1 (hnRNP A1) that are important for translational activity. Thus, our research determined a virulence-associated site in the 5′UTR of CA16, providing a crucial molecular target for antiviral drug development. PMID:26861413

Preparation of quaternary amine monolithic column for strong anion-exchange chromatography and its application to the separation of Enterovirus 71.

PubMed

Gu, Huimin; Yin, Dezhong; Ren, Jie; Zhang, Baoliang; Zhang, Qiuyu

2016-10-15

Large size virion is unable to diffuse into pores of conventional porous chromatography particles. Therefore, separation of virion by conventional column-packing materials is not quite efficient. To solve this problem, a monolithic column with large convective pores and quaternary amine groups was prepared and was applied to separate Enterovirus 71 (EV71, ≈5700-6000kDa). Cross-section, pore structure, hydrodynamic performance, adsorption property and dynamic binding capacity of prepared monolithic column were determined. Double-pore structures, macropore at 2472nm and mesopore at 5-60nm, were formed. The porosity was up to 63.3%, which enable higher permeability and lower back pressure of the monolithic column than commercial UNO™ Q1 column. Based on the breakthrough curves, the loading capacity of bovine serum albumin was calculated to be 42.0mg per column. In addition, prepared quaternary amine monolithic column was proved to be suitable for the separation of protein mixture by strong anion-exchange chromatography. As a practical application, prepared monolith column presents excellent performance to the separation of EV71 from virus-proteins mixture. Copyright © 2016 Elsevier B.V. All rights reserved.

Freeze-dried live attenuated smallpox vaccine prepared in cell culture "LC16-KAKETSUKEN": Post-marketing surveillance study on safety and efficacy compliant with Good Clinical Practice.

PubMed

Nishiyama, Yasumasa; Fujii, Tatsuya; Kanatani, Yasuhiro; Shinmura, Yasuhiko; Yokote, Hiroyuki; Hashizume, So

2015-11-09

In Japan, production of smallpox vaccine LC16m8 (named LC16-KAKETSUKEN) was restarted and was determined to be maintained as a national stockpile in March 2002. To conduct a post-marketing surveillance study of the vaccination of freeze-dried live attenuated smallpox vaccine prepared in cell culture LC16-KAKETSUKEN using attenuated vaccinia strain LC16m8. The study complied with Good Clinical Practice, focusing on a comparison between primary vaccinees and re-vaccinees. 268 personnel (261 males and 7 females) of the Japan Ground Self-Defense Force were inoculated with LC16-KAKETSUKEN and thereafter adverse events and efficacy were evaluated. Among 268 vaccinee participants, the following vaccinees showed adverse events, none serious: 53 of 196 primary vaccinees (without previous smallpox vaccination), 4 of 71 re-vaccinees (with previous smallpox vaccination) and 1 vaccinee with unknown previous vaccination history. A breakdown of adverse events observed in this study (total 268 vaccinees) showed the following minor or mild adverse events: 52 (19.4%) swelling of axillary lymph node, 4 (1.5%) fever, 2 (0.7%) fatigue, 1 (0.4%) of rash, 14 (5.2%) erythema at the inoculation site, 1 (0.4%) swelling at the inoculation site and 1 (0.4%) autoinoculation. The incidence of adverse events for primary vaccinees (53/196; 27.0%) was significantly higher than for re-vaccinees (4/71; 5.6%). However, the proportion of vaccine take was significantly higher for primary vaccinees (185/196; 94.4%) than for re-vaccinees (58/71; 81.7%). Although the proportion of vaccine take of re-vaccinees was significantly lower than for primary vaccinees due to preexisting immunity by previous vaccination, no significant difference was found in neutralizing antibody titers between primary vaccinees and re-vaccinees at 1, 4 and 7 months after LC16-KAKETSUKEN vaccination. The present post-marketing surveillance study compliant with Good Clinical Practice demonstrated the efficacy and safety of the smallpox vaccine LC16-KAKETSUKEN in an adult population. LC16-KAKETSUKEN is the sole currently available licensed smallpox vaccine for both adult and pediatric populations. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Molecular characterization of enteroviruses including a new type EV-C99 isolated from Xinjiang students in Shandong, China in 2011.

PubMed

Tao, Zexin; Yuan, Qun; Lin, Xiaojuan; Wang, Suting; Liu, Yao; Ji, Feng; Xiong, Ping; Cui, Ning; Song, Lizhi; Wang, Mei; Xu, Aiqiang

2014-10-09

The last case of infection with wild-type poliovirus indigenous to China was reported in 1994. In 2011, a poliomyelitis outbreak caused by imported wide-type poliovirus occurred in Xinjiang Uighur Autonomous Region. Here, we report the results of enterovirus (EV) isolation from Xinjiang students that returned to school in Shandong after summer vacation during this outbreak. Stool specimens from 376 students were collected and 10 EV strains were isolated including 4 polioviruses (All Sabin strains), 1 coxsackievirus (CV) A13, 3 CVA17 and 2 EV-C99. VP1 sequence analysis revealed these CVA13, CVA17 and EV-C99 strains had 71.3-81.8%, 76.5-84.6% and 74.2-82.9% nucleotide similarity with strains from other countries within a serotype, respectively. EV-C99 strains had 82.7-92.8% VP1 similarity with two previously reported Xinjiang strains. Complete genome analysis on EV-C99 strains revealed intra-serotypic genetic recombination events. These findings reflect great genetic divergence between Chinese strains and strains from other countries of the three types, and provide valuable information on monitoring EV transmission over long distance.

Effectiveness of Early Measles, Mumps, and Rubella Vaccination Among 6-14-Month-Old Infants During an Epidemic in the Netherlands: An Observational Cohort Study.

PubMed

Woudenberg, Tom; van der Maas, Nicoline A T; Knol, Mirjam J; de Melker, Hester; van Binnendijk, Rob S; Hahné, Susan J M

2017-04-15

Routinely, the first measles, mumps, and rubella (MMR) vaccine dose is given at 14 months of age in the Netherlands. However, during a measles epidemic in 2013-2014, MMR vaccination was also offered to 6-14-month-olds in municipalities with <90% MMR vaccination coverage. We studied the effectiveness of the early MMR vaccination schedule. Parents of all infants targeted for early MMR vaccination were asked to participate. When parent(s) suspected measles, their infant's saliva was tested for measles-specific antibodies. The vaccine effectiveness (VE) against laboratory-confirmed and self-reported measles was estimated using Cox regression, with VE calculated as 1 minus the hazard ratio. Three vaccinated and 10 unvaccinated laboratory-confirmed cases occurred over observation times of 106631 and 23769 days, respectively. The unadjusted VE against laboratory-confirmed measles was 94% (95% confidence interval [CI], 79%-98%). After adjustment for religion and sibling's vaccination status, the VE decreased to 71% (-72%-95%). For self-reported measles, the unadjusted and adjusted VE was 67% (40%-82%) and 43% (-12%-71%), respectively. Infants vaccinated between 6 and 14 months of age had a lower risk of measles than unvaccinated infants. However, part of the effect was caused by herd immunity, since vaccinated infants were more likely to be surrounded by other vaccinated individuals. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Going Social: Success in Online Recruitment of Men Who Have Sex with Men for Prevention HIV Vaccine Research

PubMed Central

BUCKINGHAM, Lindsey; BECHER, Julie; VOYTEK, Chelsea D; FIORE, Danielle; Dunbar, Debora; DAVIS-VOGEL, Annet; METZGER, David S; FRANK, Ian

2017-01-01

Objective To compare the use of four different social media sites to recruit men who have sex with men (MSM) and transgender women to a phase 2b HIV prevention vaccine trial, HVTN 505. Design Retrospective, observational study. Methods The University of Pennsylvania HIV Vaccine Trials Unit (Penn HVTU) employed street outreach and online recruitment methods to recruit participants for HVTN 505 using a combination of national recruitment images/messages with Philadelphia-specific language and imagery. We compared the efficiency (number of enrolled participants per number of completed phone screens) and effectiveness (number of enrolled participants per time interval employed) of each strategy, as well as the demographics and risk behaviors of the populations. Results Online recruitment strategies populated 37% (71/191) of trial participants at our site. Among the four social media strategies employed, 45.1% (32/71) were enrolled through Facebook, 16.9% (12/71) through Craigslist, 15.5% (11/71) through a web-based marketing company (WBMC), and 22.5% (16/71) via GRINDR. The number of participants enrolled per month of strategy and the months the strategy was employed were Facebook - 32(33 months), Craigslist - 12(33 months), WBMC -11(6 months), and GRINDR – 16(0.56 months). In-person and online recruitment strategies yielded participants of similar demographics and levels of risk behavior. Conclusion Use of several social media recruitment modalities produced large numbers of MSM engaging in high risk behavior and willing to participate in an HIV prevention vaccine trial. In comparison to other social media and online strategies, recruitment via GRINDR was the most effective. PMID:28526330

Going social: Success in online recruitment of men who have sex with men for prevention HIV vaccine research.

PubMed

Buckingham, Lindsey; Becher, Julie; Voytek, Chelsea D; Fiore, Danielle; Dunbar, Debora; Davis-Vogel, Annet; Metzger, David S; Frank, Ian

2017-06-14

To compare the use of four different social media sites to recruit men who have sex with men (MSM) and transgender women to a phase 2b HIV prevention vaccine trial, HVTN 505. Retrospective, observational study. The University of Pennsylvania HIV Vaccine Trials Unit (Penn HVTU) employed street outreach and online recruitment methods to recruit participants for HVTN 505 using a combination of national recruitment images/messages with Philadelphia-specific language and imagery. We compared the efficiency (number of enrolled participants per number of completed phone screens) and effectiveness (number of enrolled participants per time interval employed) of each strategy, as well as the demographics and risk behaviors of the populations. Online recruitment strategies populated 37% (71/191) of trial participants at our site. Among the four social media strategies employed, 45.1% (32/71) were enrolled through Facebook, 16.9% (12/71) through Craigslist, 15.5% (11/71) through a web-based marketing company (WBMC), and 22.5% (16/71) via GRINDR. The number of participants enrolled per month of strategy and the months the strategy was employed were Facebook - 32(33months), Craigslist - 12(33months), WBMC - 11(6months), and GRINDR - 16(0.56months). In-person and online recruitment strategies yielded participants of similar demographics and levels of risk behavior. Use of several social media recruitment modalities produced large numbers of MSM engaging in high risk behavior and willing to participate in an HIV prevention vaccine trial. In comparison to other social media and online strategies, recruitment via GRINDR was the most effective. Copyright © 2017. Published by Elsevier Ltd.

[Relationship between G6PD deficiency and hand-foot-mouth disease induced by enterovirus 71].

PubMed

Ou, Jun-Bin; Zhang, Cui-Mei; Fu, Si-Mao; Huang, Xiang; Huang, Lian-Hong

2013-09-01

To study the influence of glucose-6-phosphate dehydrogenase (G6PD) deficiency on hand-foot-mouth disease (HFMD) induced by enterovirus 71 (EV71) , and possible mechanisms. A total of 220 boys with HFMD induced by EV71 were classified into two groups based on disease severity: mild/moderate (n=145) and severe HFMD groups (n=75), and 132 healthy boys were selected as the control group. The activity of G6PD and levels of reduced glutathione (GSH) and malonaldehyde (MDA) in blood were measured using the automatic biochemical analyzer. The percentage of G6PD deficiency cases in the severe HFMD group was significantly higher than in the control group (P<0.0125). In the severe HFMD group, the durations of fever, mental abnormality, limb trembling and hospital stay were significantly longer in children with G6PD deficiency than in those with normal G6PD activity (P<0.05). In the acute and recovery stages, patients in the mild/moderate and severe HFMD groups had significantly lower GSH levels and G6PD activity and significantly higher MDA levels compared with those in the control group (P<0.05). In the acute stage, children in the mild/moderate and severe HFMD groups with G6PD deficiency had significantly lower GSH levels and significantly higher MDA levels compared with those with normal G6PD activity (P<0.01). In the acute and recovery stages, GSH level in children with HFMD was positively correlated with G6PD activity (r=0.61, P<0.01; r=0.58, P<0.01), and in the acute stage, MDA level was negatively correlated with G6PD activity (r=-0.29, P<0.01). G6PD deficiency is probably a predisposing factor for HFMD induced by EV71 and may aggravate the patient's condition. Its mechanism might be related to oxidative stress.

Prevention of HPV-related cancers in Norway: cost-effectiveness of expanding the HPV vaccination program to include pre-adolescent boys.

PubMed

Burger, Emily A; Sy, Stephen; Nygård, Mari; Kristiansen, Ivar S; Kim, Jane J

2014-01-01

Increasingly, countries have introduced female vaccination against human papillomavirus (HPV), causally linked to several cancers and genital warts, but few have recommended vaccination of boys. Declining vaccine prices and strong evidence of vaccine impact on reducing HPV-related conditions in both women and men prompt countries to reevaluate whether HPV vaccination of boys is warranted. A previously-published dynamic model of HPV transmission was empirically calibrated to Norway. Reductions in the incidence of HPV, including both direct and indirect benefits, were applied to a natural history model of cervical cancer, and to incidence-based models for other non-cervical HPV-related diseases. We calculated the health outcomes and costs of the different HPV-related conditions under a gender-neutral vaccination program compared to a female-only program. Vaccine price had a decisive impact on results. For example, assuming 71% coverage, high vaccine efficacy and a reasonable vaccine tender price of $75 per dose, we found vaccinating both girls and boys fell below a commonly cited cost-effectiveness threshold in Norway ($83,000/quality-adjusted life year (QALY) gained) when including vaccine benefit for all HPV-related diseases. However, at the current market price, including boys would not be considered 'good value for money.' For settings with a lower cost-effectiveness threshold ($30,000/QALY), it would not be considered cost-effective to expand the current program to include boys, unless the vaccine price was less than $36/dose. Increasing vaccination coverage to 90% among girls was more effective and less costly than the benefits achieved by vaccinating both genders with 71% coverage. At the anticipated tender price, expanding the HPV vaccination program to boys may be cost-effective and may warrant a change in the current female-only vaccination policy in Norway. However, increasing coverage in girls is uniformly more effective and cost-effective than expanding vaccination coverage to boys and should be considered a priority.

Phase 2 Assessment of the Safety and Immunogenicity of Two Inactivated Pandemic Monovalent H1N1 Vaccines in Adults as a Component of the U.S. Pandemic Preparedness Plan in 2009

PubMed Central

Chen, Wilbur H.; Winokur, Patricia L.; Edwards, Kathryn M.; Jackson, Lisa A.; Wald, Anna; Walter, Emmanuel B.; Noah, Diana L.; Wolff, Mark; Kotloff, Karen L.

2012-01-01

Background The influenza A/H1N1 pandemic in 2009 created an urgent need to develop vaccines for mass immunization. To guide decisions regarding the optimal immunization dosage and schedule for adults, we evaluated two monovalent, inactivated, unadjuvanted H1N1 influenza vaccines in independent, but simultaneously conducted, multi-center Phase 2 trials of identical design. Methods Healthy adults, stratified by age (18 to 64 years and ≥65 years), were randomized (1:1 allocation), in a double-blind, parallel-group design, to receive two intramuscular doses (21 days apart) of vaccine containing approximately 15 μg or 30 μg of hemagglutinin (HA). Primary endpoints were safety (reactogenicity for 8 days after each vaccination and vaccine-associated serious adverse events during the 7 month study) and immunogenicity (proportion of subjects, stratified by age, achieving a serum hemagglutination inhibition [HI] antibody titer ≥1:40 or a ≥4-fold rise in titer after a single injection of either dosage). Results Both vaccines were well-tolerated. A single 15 μg dose induced HI titers ≥1:40 in 90% of younger adults (95% confidence interval [CI] 82%-95%) and 81% of elderly (95% CI 71%–88%) who received Sanofi-Pasteur vaccine (subsequently found to contain 24 μg HA in the standard potency assay), and in 80% of younger adults (95% CI 71%–88%) and 60% of elderly (95% CI 50%–70%) who received CSL vaccine. Both vaccines were significantly more immunogenic in younger compared with elderly adults by at least one endpoint measure. Increasing the dose to 30 μg raised the frequency of HI titers ≥1:40 in the elderly by approximately 10%. Higher dosage did not significantly enhance immunogenicity in younger adults and a second dose provided little additional benefit to either age group. Conclusion These trials provided evidence for policymakers that a single 15 μg dose of 2009 A/H1N1 vaccine would likely protect most U.S. adults and suggest a potential benefit of a 30 μg dose for the elderly. PMID:22537984

Phase 2 assessment of the safety and immunogenicity of two inactivated pandemic monovalent H1N1 vaccines in adults as a component of the U.S. pandemic preparedness plan in 2009.

PubMed

Chen, Wilbur H; Winokur, Patricia L; Edwards, Kathryn M; Jackson, Lisa A; Wald, Anna; Walter, Emmanuel B; Noah, Diana L; Wolff, Mark; Kotloff, Karen L

2012-06-13

The influenza A/H1N1 pandemic in 2009 created an urgent need to develop vaccines for mass immunization. To guide decisions regarding the optimal immunization dosage and schedule for adults, we evaluated two monovalent, inactivated, unadjuvanted H1N1 influenza vaccines in independent, but simultaneously conducted, multi-center Phase 2 trials of identical design. Healthy adults, stratified by age (18-64 years and ≥65 years), were randomized (1:1 allocation), in a double-blind, parallel-group design, to receive two intramuscular doses (21 days apart) of vaccine containing approximately 15 μg or 30 μg of hemagglutinin (HA). Primary endpoints were safety (reactogenicity for 8 days after each vaccination and vaccine-associated serious adverse events during the 7 month study) and immunogenicity (proportion of subjects, stratified by age, achieving a serum hemagglutination inhibition [HI] antibody titer ≥1:40 or a ≥4-fold rise in titer after a single injection of either dosage). Both vaccines were well-tolerated. A single 15 μg dose induced HI titers ≥1:40 in 90% of younger adults (95% confidence interval [CI] 82-95%) and 81% of elderly (95% CI 71-88%) who received Sanofi-Pasteur vaccine (subsequently found to contain 24 μg HA in the standard potency assay), and in 80% of younger adults (95% CI 71-88%) and 60% of elderly (95% CI 50-70%) who received CSL vaccine. Both vaccines were significantly more immunogenic in younger compared with elderly adults by at least one endpoint measure. Increasing the dose to 30 μg raised the frequency of HI titers ≥1:40 in the elderly by approximately 10%. Higher dosage did not significantly enhance immunogenicity in younger adults and a second dose provided little additional benefit to either age group. These trials provided evidence for policymakers that a single 15 μg dose of 2009 A/H1N1 vaccine would likely protect most U.S. adults and suggest a potential benefit of a 30 μg dose for the elderly. Copyright © 2012 Elsevier Ltd. All rights reserved.

Impact of quadrivalent human papillomavirus vaccine on genital warts in an opportunistic vaccination structure.

PubMed

Lurie, Samuel; Mizrachi, Yossi; Chodick, Gabi; Katz, Rachel; Schejter, Eduardo

2017-08-01

Genital warts are the most common sexually transmitted disease and have a detrimental impact on quality of life. Genital warts could be prevented by prophylactic HPV vaccination. The objective was to study real-life benefit of opportunistic HPV vaccination on age and gender specific incidence of genital warts. We performed a register-based population cohort study from publicly funded health-care provider in Israel. The incidence of genital warts was assessed during three time frame intervals: 2006-2008 (pre-vaccination effect period) 2009-2012 (early post-vaccination effect period) and 2013-2015 (late post-vaccination effect period), with an average annual number of members of 1,765,481, 1,906,774 and 2,042,678 in the years 2006-2008, 2009-2012 and 2013-2015, respectively. Among females, annual incidence of genital warts per 100,000 women decreased from 210.43 to 161.71 (OR 0.76, 95%CI 0.71-0.82, p<0.001) and to 146.8 (OR 0.69, 95%CI 0.66-0.72, p<0.001) between pre-vaccination period and early and late post-vaccination periods, respectively. Among males, annual incidence of genital warts per 100,000 men decreased from 262.85 to 232.40 (OR 0.88, 95%CI 0.83-0.93, p<0.001) and to 234.01 (OR 0.88, 95%CI 0.86-0.91, p<0.001) between pre-vaccination period and early and late post-vaccination periods, respectively. There is a potential benefit in reducing incidence of genital warts even in opportunistic HPV vaccination structure. This information may be relevant for health-care providers in countries where national immunization programs do not include HPV vaccines. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluation of Montanide TM ISA 71 VG adjuvant during profilin vaccination against experimental coccidiosis

USDA-ARS?s Scientific Manuscript database

Chickens were immunized subcutaneously with an Eimeria recombinant profilin protein plus MontanideTM ISA 70 VG (ISA 70) or MontanideTM ISA 71 VG (ISA 71) water-in-oil adjuvants, or with profilin alone, and comparative RNA microarray analyses were performed to ascertain global transcriptomic changes ...

Intranasal vaccine trial for canine infectious tracheobronchitis (kennel cough).

PubMed

Glickman, L T; Appel, M J

1981-08-01

Two field trials were conducted during periods of endemic (summer) and epizootic (winter) canine infectious tracheobronchitis activity to evaluate the efficacy of three intranasal vaccines in a closed commercial beagle breeding kennel. A trivalent vaccine containing Bordetella bronchiseptica, canine parainfluenza, and canine adenovirus-2 was administered at 3 weeks of age. The vaccine was 71.2% and 81.8% effective in decreasing the incidence of coughing during the winter and summer trials, respectively. The number of deaths was lower in each of the vaccine groups than in the placebo groups. No adverse reactions were observed with any of the intranasal vaccines.

[Influenza vaccination of hospital healthcare staff from the perspective of the employer: a positive balance].

PubMed

Hak, Eelko; Knol, Lisanne M; Wilschut, Jan C; Postma, Maarten J

2010-01-01

To assess the annual productivity loss among hospital healthcare workers attributable to influenza and to estimate the costs and economic benefits of a vaccination programme from the perspective of the the employer. Cost-benefit analysis. The percentage of work loss due to influenza was determined using monthly age and gender specific figures for productivity loss among healthcare workers of the University Medical Center Groningen (UMCG), the Netherlands over the period January 2006-June 2008. Influenza periods were determined on the basis of national surveillance data. The average increase in productivity loss in these periods was estimated by comparison with the periods outside influenza seasons. The direct costs of productivity loss from the perspective of the employer were estimated using the friction cost method. In the sensitivity analyses various modelling parameters were varied, such as the vaccination coverage. In the UMCG, with approximately 9,400 employees, the estimated annual costs associated with productivity loss due to influenza before the introduction of the yearly influenza vaccination program were € 675,242 or on average, € 72 per employee. The economic benefits of the current vaccination program with a vaccination coverage of 24% with a vaccine effectiveness of 71% were estimated at € 89,858 or € 10 per employee. The nett economic benefits of a vaccination program with a target vaccination coverage of 70% with a vaccine effectiveness of 71% were estimated at € 244,325 or € 26 per employee. This modelling study performed from the perspective of the employer showed that an annual influenza vaccination programme for hospital personnel can save costs.

Substantial Decline in Vaccine-Type Human Papillomavirus (HPV) Among Vaccinated Young Women During the First 8 Years After HPV Vaccine Introduction in a Community

PubMed Central

Kahn, Jessica A.; Widdice, Lea E.; Ding, Lili; Huang, Bin; Brown, Darron R.; Franco, Eduardo L.; Bernstein, David I.

2016-01-01

Background. Human papillomavirus (HPV) vaccine effectiveness and herd protection are not well established in community settings. Our objective was to determine trends in vaccine-type HPV in young women during the 8 years after vaccine introduction, to assess changes in HPV prevalence and characterize herd protection in a community. Methods. We recruited 3 samples of sexually experienced, 13–26-year-old adolescent girls and young women (hereafter women; N = 1180) from 2006–2014: before widespread vaccine introduction (wave 1) and 3 (wave 2) and 7 (wave 3) years after vaccine introduction. We determined the prevalence of vaccine-type HPV (HPV-6, -11, -16, and -18) among all, vaccinated, and unvaccinated women at waves 1, 2, and 3, adjusted for differences in participant characteristics, then examined whether changes in HPV prevalence were significant using inverse propensity score–weighted logistic regression. Results. Vaccination rates increased from 0% to 71.3% across the 3 waves. Adjusted vaccine-type HPV prevalence changed from 34.8% to 8.7% (75.0% decline) in all women, from 34.9% to 3.2% (90.8% decline) in vaccinated women, and from 32.5% to 22.0% (32.3% decline) in unvaccinated women. Among vaccinated participants, vaccine-type HPV prevalence decreased significantly from wave 1 to wave 2 (adjusted odds ratio, 0.21; 95% confidence interval, .13–.34) and from wave 1 to wave 3 (0.06; .03–.13). The same decreases were also significant among unvaccinated participants (adjusted odds ratios, 0.44; [95% confidence interval, .27–.71] and 0.59; [.35–.98], respectively). Conclusions. The prevalence of vaccine-type HPV decreased >90% in vaccinated women, demonstrating high effectiveness in a community setting, and >30% in unvaccinated women, providing evidence of herd protection. PMID:27655996

Expression of membrane anchored cytokines and B7-1 alters tumor microenvironment and induces protective antitumor immunity in a murine breast cancer model.

PubMed

Bozeman, Erica N; Cimino-Mathews, Ashley; Machiah, Deepa K; Patel, Jaina M; Krishnamoorthy, Arun; Tien, Linda; Shashidharamurthy, Rangaiah; Selvaraj, Periasamy

2013-05-07

Many studies have shown that the systemic administration of cytokines or vaccination with cytokine-secreting tumors augments an antitumor immune response that can result in eradication of tumors. However, these approaches are hampered by the risk of systemic toxicity induced by soluble cytokines. In this study, we have evaluated the efficacy of 4TO7, a highly tumorigenic murine mammary tumor cell line, expressing glycosyl phosphatidylinositol (GPI)-anchored form of cytokine molecules alone or in combination with the costimulatory molecule B7-1 as a model for potential cell or membrane-based breast cancer vaccines. We observed that the GPI-anchored cytokines expressed on the surface of tumor cells greatly reduced the overall tumorigenicity of the 4TO7 tumor cells following direct live cell challenge as evidenced by transient tumor growth and complete regression within 30 days post challenge. Tumors co-expressing B7-1 and GPI-IL-12 grew the least and for the shortest duration, suggesting that this combination of immunostimulatory molecules is most potent. Protective immune responses were also observed following secondary tumor challenge. Further, the 4TO7-B7-1/GPI-IL-2 and 4TO7-B7-1/GPI-IL-12 transfectants were capable of inducing regression of a wild-type tumor growing at a distant site in a concomitant tumor challenge model, suggesting the tumor immunity elicited by the transfectants can act systemically and inhibit the tumor growth at a distant site. Additionally, when used as irradiated whole cell vaccines, 4TO7-B7-1/GPI-IL-12 led to a significant inhibition in tumor growth of day 7 established tumors. Lastly, we observed a significant decrease in the prevalence of myeloid-derived suppressor cells and regulatory T-cells in the tumor microenvironment on day 7 post challenge with 4TO7-B7-1/GPI-IL-12 cells, which provides mechanistic insight into antitumor efficacy of the tumor-cell membrane expressed IL-12. These studies have implications in designing membrane-based therapeutic vaccines with GPI-anchored cytokines for breast cancer. Copyright © 2013 Elsevier Ltd. All rights reserved.

Obstetricians and the 2009-2010 H1N1 vaccination effort: implications for future pandemics.

PubMed

Clark, Sarah J; Cowan, Anne E; Wortley, Pascale M

2013-09-01

Our objective was to describe the experiences of obstetricians during the 2009-2010 H1N1 vaccination campaign in order to identify possible improvements for future pandemic situations. We conducted a cross-sectional mail survey of a national random sample of 4,000 obstetricians, fielded in Summer 2010. Survey items included availability, recommendation, and patient acceptance of H1N1 vaccine; prioritization of H1N1 vaccine when supply was limited; problems with H1N1 vaccination; and likelihood of providing vaccine during a future influenza pandemic. Response rate was 66 %. Obstetricians strongly recommended H1N1 vaccine during the second (85 %) and third (86 %) trimesters, and less often during the first trimester (71 %) or the immediate postpartum period (76 %); patient preferences followed a similar pattern. H1N1 vaccine was typically available in outpatient obstetrics clinics (80 %). Overall vaccine supply was a major problem for 30 % of obstetricians, but few rated lack of thimerosal-free vaccine as a major problem (12 %). Over half of obstetricians had no major problems with the H1N1 vaccine campaign. Based on this experience, 74 % would be "very likely" and 12 % "likely" to provide vaccine in the event of a future influenza pandemic. Most obstetricians strongly recommended H1N1 vaccine, had few logistical problems beyond limited vaccine supply, and are willing to vaccinate in a future pandemic. Addressing concerns about first-trimester vaccination, developing guidance for prioritization of vaccine in the event of severe supply constraints, and continued facilitation of the logistical aspects of vaccination should be emphasized in future influenza pandemics.

Management of the 2014 Enterovirus 68 Outbreak at a Pediatric Tertiary Care Center.

PubMed

Schuster, Jennifer E; Newland, Jason G

2015-11-01

Enterovirus 68 (EV-D68) is an uncommonly recognized cause of acute respiratory tract infections. During the late summer of 2014, an international EV-D68 outbreak occurred. We review the steps of outbreak recognition and management in the context of 1 hospital's experience with the EV-D68 outbreak. We reviewed the role of Children's Mercy Hospital as one of the first hospitals to recognize the 2014 EV-D68 outbreak in the United States. The steps of outbreak management were applied to real-life examples as the outbreak unfolded at our hospital. Management of the 2014 EV-D68 outbreak was a multifaceted effort requiring close coordination with hospitals, local and state health departments, and the Centers for Disease Control and Prevention. The importance of clear and frequent communication is highlighted both intra- and interinstitutionally. Increased respiratory disease-related pediatric admissions at hospitals nationally were attributed to EV-D68. Outcomes for these children, including the association of EV-D68 with acute flaccid myelitis, remain under investigation. Following the steps of outbreak management is critical to providing optimal patient care and ensuring the health of the public. During the 2014 EV-D68 outbreak, close adherence to outbreak principles led to swift recognition of illness, rapid diagnostic measures, institution of appropriate therapies, and dissemination of information to health care providers and the public. Equally important was the subsequent identification of an increase in acute flaccid myelitis cases against the backdrop of an increase in EV-D68 detections nationally. Future prospective studies are needed to determine the true burden of EV-D68 disease, potential vaccines and therapeutics, and outcomes of children with EV-D68 infection. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Mycoplasma hyopneumoniae bacterins and porcine circovirus type 2 (PCV2) infection: Induction of postweaning multisystemic wasting syndrome (PMWS) in the gnotobiotic swine model of PCV2-associated disease

PubMed Central

Krakowka, Steven; Ellis, John; McNeilly, Francis; Waldner, Cheryl; Rings, D. Michael; Allan, Gordon

2007-01-01

Groups (5 to 15 per group) of gnotobiotic swine were infected oronasally with porcine circovirus type 2 (PCV2) at 3 days of age and then given 1 of 6 different commercial Mycoplasma hyopneumoniae (M. hyopneumoniae) bacterins as either a single dose (7 d of age, 1 application products) or 2 doses (7 and 21 d of age, 2 application product). Control groups received PCV2 alone (n = 9) or were infected with PCV2 and immunized twice with keyhole limpet hemocyanin (KLH) emulsified in incomplete Freund’s adjuvant (ICFA) (n = 7). Five of 7 (71%) PCV2-infected piglets immunized with KLH/ICFA developed mild or overt PMWS, whereas none of 9 piglets infected with PCV2 alone developed PMWS. Five of 12 (42%) piglets vaccinated with a commercial bacterin containing mineral oil adjuvant developed PMWS following vaccination. None of the PCV2-infected piglets in the other bacterin-vaccinated groups developed PMWS in this model of PCV2-associated disease. This difference in prevalence of PMWS in piglets given the mineral oil-adjuvanted M. hyopneumoniae bacterin and the other M. hyopneumoniae bacterin vaccination groups was statistically significant (P < 0.05). PMID:17824156

Enterovirus D68 detection in respiratory specimens: Association with severe disease.

PubMed

Engelmann, Ilka; Fatoux, Marie; Lazrek, Mouna; Alidjinou, Enagnon K; Mirand, Audrey; Henquell, Cécile; Dewilde, Anny; Hober, Didier

2017-07-01

Molecular techniques increased the number of documented respiratory infections. In a substantial number of cases the causative agent remains undetected. Since August 2014, an increase in Enterovirus(EV)-D68 infections was reported. We aimed to investigate epidemiology and clinical relevance of EV-D68. From June to December 2014 and from September to December 2015, 803 and 847 respiratory specimens, respectively, were tested for respiratory viruses with a multiplex RT-PCR. This multiplex RT-PCR does not detect EV-D68. Therefore, 457 (2014) and 343 (2015) specimens with negative results were submitted to an EV-specific-RT-PCR. EV-positive specimens were tested with an EV-D68-specific-RT-PCR and genotyped. Eleven specimens of 2014 tested positive in the EV-specific-RT-PCR and of these seven were positive in the EV-D68-specific-RT-PCR. Typing confirmed these as EV-D68. Median age of EV-D68-positive patients was 3 years (1 month-91 years). Common symptoms included fever (n = 6, 86%), respiratory distress (n = 5, 71%), and cough (n = 4, 57%). All EV-D68-positive patients were admitted to hospital, 4 (57%) were admitted to intensive care units and 6 (86%) received oxygen. One patient suffered from acute flaccid paralysis. Seven specimens of 2015 were positive in the EV-specific-RT-PCR but negative in the EV-D68-specific-RT-PCR. In conclusion, use of an EV-specific-RT-PCR allowed us to detect EV-D68 circulation in autumn 2014 that was not detected by the multiplex RT-PCR and was associated with severe disease. © 2017 Wiley Periodicals, Inc.

Clinical Characterization of Children Presenting to the Hospital with Enterovirus D68 Infection During the 2014 Outbreak in St. Louis

PubMed Central

Orvedahl, Anthony; Padhye, Amruta; Barton, Kevin; O’Bryan, Kevin; Baty, Jack; Gruchala, Nancy; Niesen, Angela; Margoni, Angeliki; Srinivasan, Mythili

2016-01-01

Background The largest known outbreak of enterovirus D68 (EV-D68) infections occurred during 2014. The goal of our study is to characterize the illness severity and clinical presentation of children infected with enterovirus-D68 (EV-D68) in comparison to non-EV-D68-Human Rhino/Enteroviruses (HR/EV). Method Our study is a retrospective analysis of severity level, charges and length of stay of children who presented to St. Louis Children’s Hospital from 8/31/2014–10/31/2014 and tested positive for EV-D68 in comparison to non-EV-D68-HR/EV infected patients. Chart review was performed for all EV-D68 infected patients and age and severity matched non-EV-D68-HR/EV infected patients. Result There was a striking increase in hospital census in August of 2014 in our hospital with simultaneous increase in the number of patients with EV-D68 infection. There was no significant difference in severity of illness, length of stay or total charges between EV-D68 and non-EV-D68-HR/EV infected children. EV-D68 infection was characterized by presenting complaints of difficulty breathing (80%) and wheezing (67%), and by findings of tachypnea (65%), wheezing (71%) and retractions (65%) on examination. The most common interventions were albuterol (79%) and corticosteroid (68%) treatments and the most common discharge diagnosis was asthma exacerbation (55%). Conclusion EV-D68 caused a significant outbreak in 2014 with increased hospital admissions and associated increased charges. There was no significant difference in severity of illness caused by EV-D68 and non-EV-D68-HR/EV infections suggesting that the impact from EV-D68 was due to increased number of infected children presenting to the hospital and not necessarily due to increased severity of illness. PMID:26771663

Burden of Norovirus and Rotavirus in Children after Rotavirus Vaccine Introduction, Cochabamba, Bolivia

PubMed Central

McAtee, Casey L.; Webman, Rachel; Gilman, Robert H.; Mejia, Carolina; Bern, Caryn; Apaza, Sonia; Espetia, Susan; Pajuelo, Mónica; Saito, Mayuko; Challappa, Roxanna; Soria, Richard; Ribera, Jose P.; Lozano, Daniel; Torrico, Faustino

2016-01-01

The effectiveness of rotavirus vaccine in the field may set the stage for a changing landscape of diarrheal illness affecting children worldwide. Norovirus and rotavirus are the two major viral enteropathogens of childhood. This study describes the prevalence of norovirus and rotavirus 2 years after widespread rotavirus vaccination in Cochabamba, Bolivia. Stool samples from hospitalized children with acute gastroenteritis (AGE) and outpatients aged 5–24 months without AGE were recruited from an urban hospital serving Bolivia's third largest city. Both viruses were genotyped, and norovirus GII.4 was further sequenced. Norovirus was found much more frequently than rotavirus. Norovirus was detected in 69/201 (34.3%) of specimens from children with AGE and 13/71 (18.3%) of those without diarrhea. Rotavirus was detected in 38/201 (18.9%) of diarrheal specimens and 3/71 (4.2%) of non-diarrheal specimens. Norovirus GII was identified in 97.8% of norovirus-positive samples; GII.4 was the most common genotype (71.4% of typed specimens). Rotavirus G3P[8] was the most prevalent rotavirus genotype (44.0% of typed specimens) and G2P[4] was second most prevalent (16.0% of typed specimens). This community is likely part of a trend toward norovirus predominance over rotavirus in children after widespread vaccination against rotavirus. PMID:26598569

Therapeutic efficacy of PD-L1 blockade in a breast cancer model is enhanced by cellular vaccines expressing B7-1 and glycolipid-anchored IL-12.

PubMed

Bozeman, Erica N; He, Sara; Shafizadeh, Yalda; Selvaraj, Periasamy

2016-01-01

Immunotherapeutic approaches have emerged as promising strategies to treat various cancers, including breast cancer. A single approach, however, is unlikely to effectively combat the complex, immune evasive strategies found within the tumor microenvironment, thus novel, effective combination treatments must be explored. In this study, we investigated the efficacy of a combination therapy consisting of PD-L1 immune checkpoint blockade and whole cell vaccination in a HER-2 positive mouse model of breast cancer. We demonstrate that tumorigenicity is completely abrogated when adjuvanted with immune stimulatory molecules (ISMs) B7-1 and a cell-surface anchored (GPI) form of IL-12 or GM-CSF. Irradiated cellular vaccines expressing the combination of adjuvants B7-1 and GPI-IL-12 completely inhibited tumor formation which was correlative with robust HER-2 specific CTL activity. However, in a therapeutic setting, both cellular vaccination and PD-L1 blockade induced only 10-20% tumor regression when administered alone but resulted in 50% tumor regression as a combination therapy. This protection was significantly hindered following CD4 or CD8 depletion indicating the essential role played by cellular immunity. Collectively, these pre-clinical studies provide a strong rationale for further investigation into the efficacy of combination therapy with tumor cell vaccines adjuvanted with membrane-anchored ISMs along with PD-L1 blockade for the treatment of breast cancer.

Therapeutic efficacy of PD-L1 blockade in a breast cancer model is enhanced by cellular vaccines expressing B7-1 and glycolipid-anchored IL-12

PubMed Central

Bozeman, Erica N; He, Sara; Shafizadeh, Yalda; Selvaraj, Periasamy

2016-01-01

Immunotherapeutic approaches have emerged as promising strategies to treat various cancers, including breast cancer. A single approach, however, is unlikely to effectively combat the complex, immune evasive strategies found within the tumor microenvironment, thus novel, effective combination treatments must be explored. In this study, we investigated the efficacy of a combination therapy consisting of PD-L1 immune checkpoint blockade and whole cell vaccination in a HER-2 positive mouse model of breast cancer. We demonstrate that tumorigenicity is completely abrogated when adjuvanted with immune stimulatory molecules (ISMs) B7-1 and a cell-surface anchored (GPI) form of IL-12 or GM-CSF. Irradiated cellular vaccines expressing the combination of adjuvants B7-1 and GPI-IL-12 completely inhibited tumor formation which was correlative with robust HER-2 specific CTL activity. However, in a therapeutic setting, both cellular vaccination and PD-L1 blockade induced only 10–20% tumor regression when administered alone but resulted in 50% tumor regression as a combination therapy. This protection was significantly hindered following CD4 or CD8 depletion indicating the essential role played by cellular immunity. Collectively, these pre-clinical studies provide a strong rationale for further investigation into the efficacy of combination therapy with tumor cell vaccines adjuvanted with membrane-anchored ISMs along with PD-L1 blockade for the treatment of breast cancer. PMID:26308597

Effectiveness of pertussis vaccination and duration of immunity

PubMed Central

Schwartz, Kevin L.; Kwong, Jeffrey C.; Deeks, Shelley L.; Campitelli, Michael A.; Jamieson, Frances B.; Marchand-Austin, Alex; Stukel, Therese A.; Rosella, Laura; Daneman, Nick; Bolotin, Shelly; Drews, Steven J.; Rilkoff, Heather; Crowcroft, Natasha S.

2016-01-01

Background: A resurgence of pertussis cases among both vaccinated and unvaccinated people raises questions about vaccine effectiveness over time. Our objective was to study the effectiveness of the pertussis vaccine and characterize the effect of waning immunity and whole-cell vaccine priming. Methods: We used the test-negative design, a nested case–control study with test-negative individuals as controls. We constructed multivariable logistic regression models to estimate odds ratios (ORs). Vaccine effectiveness was calculated as (1 – OR) × 100. We assessed waning immunity by calculating the odds of developing pertussis per year since last vaccination and evaluated the relative effectiveness of priming with acellular versus whole-cell vaccine. Results: Between Dec. 7, 2009, and Mar. 31, 2013, data on 5867 individuals (486 test-positive cases and 5381 test-negative controls) were available for analysis. Adjusted vaccine effectiveness was 80% (95% confidence interval [CI] 71% to 86%) at 15–364 days, 84% (95% CI 77% to 89%) at 1–3 years, 62% (95% CI 42% to 75%) at 4–7 years and 41% (95% CI 0% to 66%) at 8 or more years since last vaccination. We observed waning immunity with the acellular vaccine, with an adjusted OR for pertussis infection of 1.27 (95% CI 1.20 to 1.34) per year since last vaccination. Acellular, versus whole-cell, vaccine priming was associated with an increased odds of pertussis (adjusted OR 2.15, 95% CI 1.30 to 3.57). Interpretation: We observed high early effectiveness of the pertussis vaccine that rapidly declined as time since last vaccination surpassed 4 years, particularly with acellular vaccine priming. Considering whole-cell vaccine priming and/or boosters in pregnancy to optimize pertussis control may be prudent. PMID:27672225

Electrical properties and interface state energy distributions of Cr/n-Si Schottky barrier diode

NASA Astrophysics Data System (ADS)

Karataş, Şükrü; Yildirim, Nezir; Türüt, Abdülmecit

2013-12-01

In this study, the electrical characteristics of the Cr/n-type Si (MS) Schottky barrier diode have been investigated by the current-voltage (I-V) and capacitance-voltage (C-V) measurements at 300 K temperature. Using the thermionic emission theory, the values of ideality factor and the barrier height have been obtained to be 1.22, 0.71 and 1.01, 0.83 eV, from the results of the I-V and C-V measurements, respectively. The barrier height (Φb) and the series resistance (RS) obtained from Norde’s function have been compared with those obtained from Cheung functions, and a good agreement between the results of both methods was seen. The interface state density (NSS) calculated without the RS is obtained to be increasing exponentially with bias from 2.40 × 1012 cm-2 eV-1 in (EC-0.623) eV to 1.94 × 1014 cm-2 eV-1 in (EC-0.495) eV, also, the NSS obtained taking into account the RS has increased exponentially with bias from 2.07 × 1012 cm-2 eV-1 to 1.47 × 1014 cm-2 eV-1 in the same interval.

Vaccinols J-S, ten new salicyloid derivatives from the marine mangrove-derived endophytic fungus Pestalotiopsis vaccinii.

PubMed

Wang, Jun-Feng; Liang, Rui; Liao, Sheng-Rong; Yang, Bin; Tu, Zheng-Chao; Lin, Xiu-Ping; Wang, Bin-Gui; Liu, Yonghong

2017-07-01

Ten new salicyloid derivatives, namely vaccinols J-S (1-10), along with five known compounds (11-15) were isolated from Pestalotiopsis vaccinii (cgmcc3.9199) endogenous with the mangrove plant Kandelia candel (L.) Druce (Rhizophoraceae). Their structures including absolute configurations were established on the basis of spectroscopic analysis, optical rotation, CD spectra, quantum ECD calculations. To the best of our knowledge, vaccinol J (1) is the first example of salicyloid derivatives containing 2-methylfuran moiety. All of the new compounds were tested for their anti-enterovirus 7l (EV71) and cytotoxic activities. Among them, vaccinol J (1) exhibited in vitro anti-EV71 with IC 50 value of 30.7μM (IC 50 177.0μM for the positive control ribavirin). Copyright © 2017. Published by Elsevier B.V.

Effect of maternal HIV status on vaccination coverage among sub-Saharan African children: A socio-ecological analysis.

PubMed

Adetokunboh, Olatunji O; Uthman, Olalekan A; Wiysonge, Charles S

2018-05-02

We investigated the relationship between maternal HIV status and uptake of the full series of three doses of diphtheria-tetanus-pertussis containing vaccines (DTP3) in sub-Saharan African children. We used data obtained from demographic and health surveys conducted in sub-Saharan Africa. We conducted meta-analysis and calculated pooled odds ratios (OR) for the association between maternal HIV status and DTP3 vaccination status for each country. A total of 4,187 out of 5,537 children of women living with HIV received DTP3 (75.6%), compared to 71,290 of 113,513 (62.8%) children of HIV negative women. National DTP3 coverage among children of HIV-positive women varied between 24% and 96% while among children of HIV negative women it was between 26% and 92%. Overall pooled result showed no significant difference in DTP3 coverage between the two groups (OR = 1.05; 95% confidence interval 0.91 - 1.22), with statistically significant heterogeneity (Chi 2 = 91.63, P = 0.000, I 2 = 71.6%). There was no significant association between DTP3 coverage and maternal HIV status in sub-Saharan Africa. However, DTP3 coverage for both HIV-exposed and non-exposed children were below the required target. Meta-regression revealed no significant association between DTP3 coverage and country characteristics (e.g. HIV prevalence among women, antiretroviral therapy coverage, gross domestic product per capita, human development index, adult literacy rate and sub-region). Improved prevention of mother-to-child transmission services might have contributed to some extent to the higher DTP3 vaccination coverage among the HIV-exposed children. There is also need to address barriers impeding uptake of vaccination among HIV-exposed and non-exposed children.

Complete coding regions of the prototypes enterovirus B93 and C95: phylogenetic analyses of the P1 and P3 regions of EV-B and EV-C strains.

PubMed

Junttila, N; Lévêque, N; Magnius, L O; Kabue, J P; Muyembe-Tamfum, J J; Maslin, J; Lina, B; Norder, H

2015-03-01

Complete coding regions were sequenced for two new enterovirus genomes: EV-B93 previously identified by VP1 sequencing, derived from a child with acute flaccid paralysis in the Democratic Republic of Congo; and EV-C95 from a French soldier with acute gastroenteritis in Djibouti. The EV-B93 P1 had more than 30% nucleotide divergence from other EV-B types, with highest similarity to E-15 and EV-B80. The P1 nucleotide sequence of EV-C95 was most similar, 71%, to CV-A21. Complete coding regions for the new enteroviruses were compared with those of 135 EV-B and 176 EV-C strains representing all types available in GenBank. When strains from the same outbreak or strains isolated during the same year in the same geographical region were excluded, 27 of the 58 EV-B, and 16 of the 23 EV-C types were represented by more than one sequence. However, for EV-B the P3 sequences formed three clades mainly according to origin or time of isolation, irrespective of type, while for EV-C the P3 sequences segregated mainly according to disease manifestation, with most strains causing paralysis, including polioviruses, forming one clade, and strains causing respiratory illness forming another. There was no intermixing of types between these two clades, apart from two EV-C96 strains. The EV-B P3 sequences had lower inter-clade and higher intra-clade variability as compared to the EV-C sequences, which may explain why inter-clade recombinations are more frequent in EV-B. Further analysis of more isolates may shed light on the role of recombinations in the evolution of EV-B in geographical context. © 2014 Wiley Periodicals, Inc.

[Efficacy of commercially available vaccines against HPV infection in women: a systematic review and meta-analysis].

PubMed

Araujo, Silvia Cristina Fonseca de; Caetano, Rosângela; Braga, Jose Ueleres; Costa e Silva, Frances Valéria

2013-11-01

Persistent HPV infection is a necessary condition for the occurrence of cervical cancer. Prophylactic HPV vaccines have been developed to reduce the incidence of cervical cancer. Two vaccines are commercially available: bivalent (types 16, 18) and quadrivalent (6, 11, 16 and 18). This study aimed to perform a systematic review and metaanalysis of the HPV vaccines' efficacy in women, focusing its performance stratified by clinical outcomes. Randomized controlled trials (RCT) published between 2000 and 2009 were identified from searches of MEDLINE, LILACS and Cochrane Library, and evaluated by two independent reviewers. Six RCT were selected. The vaccines reduced the risk of precursor lesions of cervical cancer, presenting efficacy of 97% (95%CI: 90-99) for CIN 2 and 96% (95%CI: 89-99) for CIN 3, in the per protocol analysis. The efficacies in the analysis by intention to treat were smaller: 63% (95%CI: 52-71) and 42% (95%CI: 26-55), respectively. In order to evaluate its effectiveness on the incidence and mortality rates for cervical cancer, longer-term studies will be needed.

Cost-effectiveness of introducing a rotavirus vaccine in developing countries: The case of Mexico

PubMed Central

Valencia-Mendoza, Atanacio; Bertozzi, Stefano M; Gutierrez, Juan-Pablo; Itzler, Robbin

2008-01-01

Background In developing countries rotavirus is the leading cause of severe diarrhoea and diarrhoeal deaths in children under 5. Vaccination could greatly alleviate that burden, but in Mexico as in most low- and middle-income countries the decision to add rotavirus vaccine to the national immunisation program will depend heavily on its cost-effectiveness and affordability. The objective of this study was to assess the cost-effectiveness of including the pentavalent rotavirus vaccine in Mexico's national immunisation program. Methods A cost-effectiveness model was developed from the perspective of the health system, modelling the vaccination of a hypothetical birth cohort of 2 million children monitored from birth through 60 months of age. It compares the cost and disease burden of rotavirus in an unvaccinated cohort of children with one vaccinated as recommended at 2, 4, and 6 months. Results Including the pentavalent vaccine in the national immunisation program could prevent 71,464 medical visits (59%), 5,040 hospital admissions (66%), and 612 deaths from rotavirus gastroenteritis (70%). At US$10 per dose and a cost of administration of US$13.70 per 3-dose regimen, vaccination would cost US$122,058 per death prevented, US$4,383 per discounted life-year saved, at a total net cost of US$74.7 million dollars to the health care system. Key variables influencing the results were, in order of importance, case fatality, vaccine price, vaccine efficacy, serotype prevalence, and annual loss of efficacy. The results are also very sensitive to the discount rate assumed when calculated per life-year saved. Conclusion At prices below US $15 per dose, the cost per life-year saved is estimated to be lower than one GNP per capita and hence highly cost effective by the WHO Commission on Macroeconomics and Health criteria. The cost-effectiveness estimates are highly dependent upon the mortality in the absence of the vaccine, which suggests that the vaccine is likely to be significantly more cost-effective among poorer populations and among those with less access to prompt medical care – such that poverty reduction programs would be expected to reduce the future cost-effectiveness of the vaccine. PMID:18664280

Cost-effectiveness of introducing a rotavirus vaccine in developing countries: the case of Mexico.

PubMed

Valencia-Mendoza, Atanacio; Bertozzi, Stefano M; Gutierrez, Juan-Pablo; Itzler, Robbin

2008-07-29

In developing countries rotavirus is the leading cause of severe diarrhoea and diarrhoeal deaths in children under 5. Vaccination could greatly alleviate that burden, but in Mexico as in most low- and middle-income countries the decision to add rotavirus vaccine to the national immunisation program will depend heavily on its cost-effectiveness and affordability. The objective of this study was to assess the cost-effectiveness of including the pentavalent rotavirus vaccine in Mexico's national immunisation program. A cost-effectiveness model was developed from the perspective of the health system, modelling the vaccination of a hypothetical birth cohort of 2 million children monitored from birth through 60 months of age. It compares the cost and disease burden of rotavirus in an unvaccinated cohort of children with one vaccinated as recommended at 2, 4, and 6 months. Including the pentavalent vaccine in the national immunisation program could prevent 71,464 medical visits (59%), 5,040 hospital admissions (66%), and 612 deaths from rotavirus gastroenteritis (70%). At US$10 per dose and a cost of administration of US$13.70 per 3-dose regimen, vaccination would cost US$122,058 per death prevented, US$4,383 per discounted life-year saved, at a total net cost of US$74.7 million dollars to the health care system. Key variables influencing the results were, in order of importance, case fatality, vaccine price, vaccine efficacy, serotype prevalence, and annual loss of efficacy. The results are also very sensitive to the discount rate assumed when calculated per life-year saved. At prices below US $15 per dose, the cost per life-year saved is estimated to be lower than one GNP per capita and hence highly cost effective by the WHO Commission on Macroeconomics and Health criteria. The cost-effectiveness estimates are highly dependent upon the mortality in the absence of the vaccine, which suggests that the vaccine is likely to be significantly more cost-effective among poorer populations and among those with less access to prompt medical care - such that poverty reduction programs would be expected to reduce the future cost-effectiveness of the vaccine.

Introducing vaccination against serogroup B meningococcal disease: An economic and mathematical modelling study of potential impact

PubMed Central

Christensen, Hannah; Hickman, Matthew; Edmunds, W. John; Trotter, Caroline L.

2013-01-01

Background Meningococcal disease remains an important cause of morbidity and mortality worldwide. The first broadly effective vaccine against group B disease (which causes considerable meningococcal disease in Europe, the Americas and Australasia) was licensed in the EU in January 2013; our objective was to estimate the potential impact of introducing such a vaccine in England. Methods We developed two models to estimate the impact of introducing a new ‘MenB’ vaccine. The cohort model assumes the vaccine protects against disease only; the transmission dynamic model also allows the vaccine to protect against carriage (accounting for herd effects). We used these, and economic models, to estimate the case reduction and cost-effectiveness of a number of different vaccine strategies. Results We estimate 27% of meningococcal disease cases could be prevented over the lifetime of an English birth cohort by vaccinating infants at 2,3,4 and 12 months of age with a vaccine that prevents disease only; this strategy could be cost-effective at £9 per vaccine dose. Substantial reductions in disease (71%) can be produced after 10 years by routinely vaccinating infants in combination with a large-scale catch-up campaign, using a vaccine which protects against carriage as well as disease; this could be cost-effective at £17 per vaccine dose. Conclusions New ‘MenB’ vaccines could substantially reduce disease in England and be cost-effective if competitively priced, particularly if the vaccines can prevent carriage as well as disease. These results are relevant to other countries, with a similar epidemiology to England, considering the introduction of a new ‘MenB’ vaccine. PMID:23566946

Estimating medical practice expenses from administering adult influenza vaccinations.

PubMed

Coleman, Margaret S; Fontanesi, John; Meltzer, Martin I; Shefer, Abigail; Fishbein, Daniel B; Bennett, Nancy M; Stryker, David

2005-01-04

Potential business losses incurred vaccinating adults against influenza have not been defined because of a lack of estimates for medical practice costs incurred delivering vaccines. We collected data on vaccination labor time and other associated expenses. We modeled estimates of per-vaccination medical practice business costs associated with delivering adult influenza vaccine in different sized practices. Per-shot costs ranged from USD 13.87 to USD 46.27 (2001 dollars). When compared with average Medicare payments of USD 11.71, per-shot losses ranged from US$ 2.16 to USD 34.56. More research is needed to determine less expensive delivery settings and/or whether third-party payers need to make higher payments for adult vaccinations.

Evidence-Based Clinical Use of Nanoscale Extracellular Vesicles in Nanomedicine.

PubMed

Fais, Stefano; O'Driscoll, Lorraine; Borras, Francesc E; Buzas, Edit; Camussi, Giovanni; Cappello, Francesco; Carvalho, Joana; Cordeiro da Silva, Anabela; Del Portillo, Hernando; El Andaloussi, Samir; Ficko Trček, Tanja; Furlan, Roberto; Hendrix, An; Gursel, Ihsan; Kralj-Iglic, Veronika; Kaeffer, Bertrand; Kosanovic, Maja; Lekka, Marilena E; Lipps, Georg; Logozzi, Mariantonia; Marcilla, Antonio; Sammar, Marei; Llorente, Alicia; Nazarenko, Irina; Oliveira, Carla; Pocsfalvi, Gabriella; Rajendran, Lawrence; Raposo, Graça; Rohde, Eva; Siljander, Pia; van Niel, Guillaume; Vasconcelos, M Helena; Yáñez-Mó, María; Yliperttula, Marjo L; Zarovni, Natasa; Zavec, Apolonija Bedina; Giebel, Bernd

2016-04-26

Recent research has demonstrated that all body fluids assessed contain substantial amounts of vesicles that range in size from 30 to 1000 nm and that are surrounded by phospholipid membranes containing different membrane microdomains such as lipid rafts and caveolae. The most prominent representatives of these so-called extracellular vesicles (EVs) are nanosized exosomes (70-150 nm), which are derivatives of the endosomal system, and microvesicles (100-1000 nm), which are produced by outward budding of the plasma membrane. Nanosized EVs are released by almost all cell types and mediate targeted intercellular communication under physiological and pathophysiological conditions. Containing cell-type-specific signatures, EVs have been proposed as biomarkers in a variety of diseases. Furthermore, according to their physical functions, EVs of selected cell types have been used as therapeutic agents in immune therapy, vaccination trials, regenerative medicine, and drug delivery. Undoubtedly, the rapidly emerging field of basic and applied EV research will significantly influence the biomedicinal landscape in the future. In this Perspective, we, a network of European scientists from clinical, academic, and industry settings collaborating through the H2020 European Cooperation in Science and Technology (COST) program European Network on Microvesicles and Exosomes in Health and Disease (ME-HAD), demonstrate the high potential of nanosized EVs for both diagnostic and therapeutic (i.e., theranostic) areas of nanomedicine.

A fused-ring acceptor unit in d-a copolymers benefits photovoltaic performance.

PubMed

Zuo, Chuantian; Cao, Jiamin; Ding, Liming

2014-08-01

Pentacyclic lactam acceptor unit TPTI invented by our group is proved to be a good building block for efficient D-A copolymers used in organic solar cells. Here, two D-A copolymers PBTTPTI and PTTTPTI are developed by copolymerizing TPTI with 2,2'-bithiophene (BT) or thieno[3,2-b]thiophene (TT). PBTTPTI and PTTTPTI exhibit good solubility and strong interchain π-π interaction even in dilute solution. They possess deep HOMO levels (ca. -5.3 eV), partial crystallinity, and good hole mobilities. Blending with PC71 BM, PBTTPTI and PTTTPTI give decent power conversion efficiencies (PCE) up to 6.83% and 5.86%, with outstanding fill factors (FF) of 74.3% and 71.3%, respectively. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and photovoltaic properties of 2,6-bis(2-thienyl) benzobisazole and 4,8-bis(thienyl)-benzo[1,2- B :4,5- B' ]dithiophene copolymers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhuwalka, Achala; Ewan, Monique D.; Elshobaki, Moneim

2015-08-22

In an effort to design efficient low-cost polymers for use in organic photovoltaic cells the easily prepared donor–acceptor–donor triad of a either cis-benzobisoxazole, trans-benzobisoxazole or trans-benzobisthiazole flanked by two thiophene rings was combined with the electron-rich 4,8-bis(5-(2-ethylhexyl)-thien-2-yl)-benzo[1,2-b:4,5-b']dithiophene. The electrochemical, optical, morphological, charge transport, and photovoltaic properties of the resulting terpolymers were investigated. Although the polymers differed in the arrangement and/or nature of the chalcogens, they all had similar highest occupied molecular orbital energy levels (-5.2 to -5.3 eV) and optical band gaps (2.1–2.2 eV). However, the lowest unoccupied molecular orbital energy levels ranged from -3.1 to -3.5 eV. When themore » polymers were used as electron donors in bulk heterojunction photovoltaic devices with PC71BM ([6,6]-phenyl C71-butyric acid methyl ester) as the acceptor, the trans-benzobisoxazole polymer had the best performance with a power conversion efficiency of 2.8%.« less

Preparation of mucosal nanoparticles and polymer-based inactivated vaccine for Newcastle disease and H9N2 AI viruses

PubMed Central

Naggar, Heba M. El; Madkour, Mohamed Sayed; Hussein, Hussein Ali

2017-01-01

Aim: To develop a mucosal inactivated vaccines for Newcastle disease (ND) and H9N2 viruses to protect against these viruses at sites of infections through mucosal immunity. Materials and Methods: In this study, we prepared two new formulations for mucosal bivalent inactivated vaccine formulations for Newcastle and Avian Influenza (H9N2) based on the use of nanoparticles and polymer adjuvants. The prepared vaccines were delivered via intranasal and spray routes of administration in specific pathogen-free chickens. Cell-mediated and humoral immune response was measured as well as challenge trial was carried out. In addition, ISA71 water in oil was also evaluated. Results: Our results showed that the use of spray route as vaccination delivery method of polymer and nanoparticles Montanide™ adjuvants revealed that it enhanced the cell mediated immune response as indicated by phagocytic activity, gamma interferon and interleukin 6 responses and induced protection against challenge with Newcastle and Avian Influenza (H9N2) viruses. Conclusion: The results of this study demonstrate the potentiality of polymer compared to nanoparticles adjuvantes when used via spray route. Mass application of such vaccines will add value to improve the vaccination strategies against ND virus and Avian influenza viruses. PMID:28344402

BCG vaccination of full-term infants with chronic intrauterine malnutrition: influence of immunization age on development of post-vaccination, delayed tuberculin hypersensitivity.

PubMed Central

Mussi-Pinhata, M. M.; Goncalves, A. L.; Foss, N. T.

1993-01-01

To determine the effect of intrauterine growth retardation (IUGR) on the response to BCG vaccination, we evaluated the specific delayed tuberculin hypersensitivity of 57 full-term infants with symmetric IUGR (SGA or small for gestational age) and 52 full-term infants with normal intrauterine growth (AGA or appropriate for gestational age). The infants were evaluated using post-vaccination skin tests to tuberculin purified protein derivative (PPD) and tuberculin lymphocyte transformation tests. Using a positive response to the skin test as an indicator of delayed hypersensitivity, we found that the rate of response to BCG in the SGA and AGA groups was similar. A total of 65% of infants with IUGR responded to BCG vaccination. The response rate among SGA infants who were vaccinated at 5 days of age, about 26 days of age (weight > or = 2500 g), 3 months of age, and 6 months of age was 68%, 47%, 69%, and 88%, respectively. The overall response rate for infants with no IUGR was 71%; the rate response to BCG vaccination among this group was 52% (those vaccinated at 5 days of age), 90% (3 months of age), and 80% (6 months of age). Our data suggest that the immunogenicity of BCG vaccine is similar in term infants who have normal or abnormal intrauterine growth and the presence of IUGR should not be a reason for delaying BCG vaccination. PMID:8440036

Hepatitis C performance measure on hepatitis A and B vaccination: missed opportunities?

PubMed

Hernandez, Bridget; Hasson, Noelle K; Cheung, Ramsey

2009-08-01

Prevention of hepatitis A virus (HAV) and hepatitis B virus (HBV) infection in patients with chronic hepatitis C (CHC) through vaccination is endorsed by all major professional societies. This study was conducted to determine adherence to the recently adopted physician performance measure on HAV and HBV vaccination. This was a retrospective study. Hepatitis A and B serology data and immunization records between 2000 and 2007 from CHC patients with detectable hepatitis C virus (HCV) RNA were analyzed. A total of 2,968 CHC patients were included in the study. Of these, 2,143 patients (72%) were tested for susceptibility to HAV, of which 53% had immunity. Of the non-immune patients, 746 (74%) were vaccinated as well as an additional 218 without prior testing. For HBV, 2,303 patients (78%) were tested for immunity and 782 (34%) were immune. Of the susceptible patients, 1,086 (71%) were vaccinated as well as an additional 197 patients without prior testing. The overall vaccination performance measure adherence rate was 71% for HAV, 70% for HBV, and 62% for both HAV and HBV. Random review of 176 charts found the major reasons for non-adherence were missed opportunity (41%), change of health care system (31%), and documented vaccination outside our health care system (22%). Our study found a high and improved adherence to the recommendations, but missed opportunity was still the main reason of non-adherence. This study also supported the strategy of selective vaccination in the veteran population.

Prevention of HPV-Related Cancers in Norway: Cost-Effectiveness of Expanding the HPV Vaccination Program to Include Pre-Adolescent Boys

PubMed Central

Burger, Emily A.; Sy, Stephen; Nygård, Mari; Kristiansen, Ivar S.; Kim, Jane J.

2014-01-01

Background Increasingly, countries have introduced female vaccination against human papillomavirus (HPV), causally linked to several cancers and genital warts, but few have recommended vaccination of boys. Declining vaccine prices and strong evidence of vaccine impact on reducing HPV-related conditions in both women and men prompt countries to reevaluate whether HPV vaccination of boys is warranted. Methods A previously-published dynamic model of HPV transmission was empirically calibrated to Norway. Reductions in the incidence of HPV, including both direct and indirect benefits, were applied to a natural history model of cervical cancer, and to incidence-based models for other non-cervical HPV-related diseases. We calculated the health outcomes and costs of the different HPV-related conditions under a gender-neutral vaccination program compared to a female-only program. Results Vaccine price had a decisive impact on results. For example, assuming 71% coverage, high vaccine efficacy and a reasonable vaccine tender price of $75 per dose, we found vaccinating both girls and boys fell below a commonly cited cost-effectiveness threshold in Norway ($83,000/quality-adjusted life year (QALY) gained) when including vaccine benefit for all HPV-related diseases. However, at the current market price, including boys would not be considered ‘good value for money.’ For settings with a lower cost-effectiveness threshold ($30,000/QALY), it would not be considered cost-effective to expand the current program to include boys, unless the vaccine price was less than $36/dose. Increasing vaccination coverage to 90% among girls was more effective and less costly than the benefits achieved by vaccinating both genders with 71% coverage. Conclusions At the anticipated tender price, expanding the HPV vaccination program to boys may be cost-effective and may warrant a change in the current female-only vaccination policy in Norway. However, increasing coverage in girls is uniformly more effective and cost-effective than expanding vaccination coverage to boys and should be considered a priority. PMID:24651645

A Randomized Phase II Study of Concurrent Docetaxel Plus Vaccine Versus Vaccine Alone in Metastatic Androgen Independent Prostate Cancer

PubMed Central

Arlen, Philip M.; Gulley, James L.; Parker, Catherine; Skarupa, Lisa; Pazdur, Mary; Panicali, Dennis; Beetham, Patricia; Tsang, Kwong Y.; Grosenbach, Douglas W.; Feldman, Jarett; Steinberg, Seth M.; Jones, Elizabeth; Chen, Clara; Marte, Jennifer; Schlom, Jeffrey; Dahut, William

2006-01-01

Purpose: Docetaxel has activity against androgen insensitive prostate cancer (AIPC) and preclinical studies have demonstrated that taxane-based chemotherapy can enhance antitumor response of vaccines. The primary objective of this study was to determine if concurrent docetaxel (with dexamethasone) had any effect on generating an immune response to the vaccine. Secondary endpoints were whether vaccine could be given safely with docetaxel and the clinical outcome of the treatment regimen. Experimental Design: The vaccination regimen was composed of (1) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (2) rV that expresses the B7.1 costimulatory gene (rV-B7.1), and (3) sequential booster vaccinations with recombinant fowlpox virus (rF-) containing the PSA gene (rF- PSA). Patients received GM-CSF with each vaccination. Twenty-eight patients with metastatic AIPC were randomized to receive either vaccine and weekly docetaxel or vaccine alone. Patients on the vaccine alone arm were allowed to cross over to receive docetaxel alone at time of disease progression. The ELISPOT assay was used to monitor immune responses for PSA-specific T cells. Results: The median increase in these T-cell precursors to PSA was 3.33-fold in both arms following 3 months of therapy. In addition, immune responses to other prostate cancer associated tumor antigens were also detected post-vaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median PFS on docetaxel was 6.1 months after receiving vaccine compared with 3.7 months with the same regimen in a historical control. Conclusion: This is the first clinical trial to demonstrate that docetaxel can be administered safely with immunotherapy without inhibiting vaccine specific T-cell responses. Furthermore, patients previously vaccinated with an anticancer vaccine may respond longer to docetaxel compared with a historical control of patients receiving docetaxel alone. Larger prospective clinical studies will be required to validate these findings. PMID:16489082

Burden of Norovirus and Rotavirus in Children After Rotavirus Vaccine Introduction, Cochabamba, Bolivia.

PubMed

McAtee, Casey L; Webman, Rachel; Gilman, Robert H; Mejia, Carolina; Bern, Caryn; Apaza, Sonia; Espetia, Susan; Pajuelo, Mónica; Saito, Mayuko; Challappa, Roxanna; Soria, Richard; Ribera, Jose P; Lozano, Daniel; Torrico, Faustino

2016-01-01

The effectiveness of rotavirus vaccine in the field may set the stage for a changing landscape of diarrheal illness affecting children worldwide. Norovirus and rotavirus are the two major viral enteropathogens of childhood. This study describes the prevalence of norovirus and rotavirus 2 years after widespread rotavirus vaccination in Cochabamba, Bolivia. Stool samples from hospitalized children with acute gastroenteritis (AGE) and outpatients aged 5-24 months without AGE were recruited from an urban hospital serving Bolivia's third largest city. Both viruses were genotyped, and norovirus GII.4 was further sequenced. Norovirus was found much more frequently than rotavirus. Norovirus was detected in 69/201 (34.3%) of specimens from children with AGE and 13/71 (18.3%) of those without diarrhea. Rotavirus was detected in 38/201 (18.9%) of diarrheal specimens and 3/71 (4.2%) of non-diarrheal specimens. Norovirus GII was identified in 97.8% of norovirus-positive samples; GII.4 was the most common genotype (71.4% of typed specimens). Rotavirus G3P[8] was the most prevalent rotavirus genotype (44.0% of typed specimens) and G2P[4] was second most prevalent (16.0% of typed specimens). This community is likely part of a trend toward norovirus predominance over rotavirus in children after widespread vaccination against rotavirus. © The American Society of Tropical Medicine and Hygiene.

The influence of the growth conditions of the plague microbe vaccine strain colonies on the fractal dimension of biospeckles

NASA Astrophysics Data System (ADS)

Ul'yanov, A. S.; Lyapina, A. M.; Ulianova, O. V.; Fedorova, V. A.; Uianov, S. S.

2011-04-01

Specific statistical characteristics of biospeckles, emerging under the diffraction of coherent beams on the bacterial colonies, are studied. The dependence of the fractal dimensions of biospeckles on the conditions of both illumination and growth of the colonies is studied theoretically and experimentally. Particular attention is paid to the fractal properties of biospeckles, emerging under the scattering of light by the colonies of the vaccinal strain of the plague microbe. The possibility in principle to classify the colonies of Yersinia pestis EV NIIEG using the fractal dimension analysis is demonstrated.

Circulating Extracellular Vesicles with Specific Proteome and Liver MicroRNAs Are Potential Biomarkers for Liver Injury in Experimental Fatty Liver Disease

PubMed Central

Povero, Davide; Eguchi, Akiko; Li, Hongying; Johnson, Casey D.; Papouchado, Bettina G.; Wree, Alexander; Messer, Karen; Feldstein, Ariel E.

2014-01-01

Background & Aim Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in both adult and children. Currently there are no reliable methods to determine disease severity, monitor disease progression, or efficacy of therapy, other than an invasive liver biopsy. Design Choline Deficient L-Amino Acid (CDAA) and high fat diets were used as physiologically relevant mouse models of NAFLD. Circulating extracellular vesicles were isolated, fully characterized by proteomics and molecular analyses and compared to control groups. Liver-related microRNAs were isolated from purified extracellular vesicles and liver specimens. Results We observed statistically significant differences in the level of extracellular vesicles (EVs) in liver and blood between two control groups and NAFLD animals. Time-course studies showed that EV levels increase early during disease development and reflect changes in liver histolopathology. EV levels correlated with hepatocyte cell death (r2 = 0.64, p<0.05), fibrosis (r2 = 0.66, p<0.05) and pathological angiogenesis (r2 = 0.71, p<0.05). Extensive characterization of blood EVs identified both microparticles (MPs) and exosomes (EXO) present in blood of NAFLD animals. Proteomic analysis of blood EVs detected various differentially expressed proteins in NAFLD versus control animals. Moreover, unsupervised hierarchical clustering identified a signature that allowed for discrimination between NAFLD and controls. Finally, the liver appears to be an important source of circulating EVs in NAFLD animals as evidenced by the enrichment in blood with miR-122 and 192 - two microRNAs previously described in chronic liver diseases, coupled with a corresponding decrease in expression of these microRNAs in the liver. Conclusions These findings suggest a potential for using specific circulating EVs as sensitive and specific biomarkers for the noninvasive diagnosis and monitoring of NAFLD. PMID:25470250

Electronic structure of layered ferroelectric high-k titanate La2Ti2O7

NASA Astrophysics Data System (ADS)

Atuchin, V. V.; Gavrilova, T. A.; Grivel, J.-C.; Kesler, V. G.

2009-02-01

The electronic structure of binary titanate La2Ti2O7 has been studied by x-ray photoelectron spectroscopy. Spectral features of valence band and all constituent element core levels have been considered. The Auger parameters of titanium and oxygen in La2Ti2O7 are determined as αTi = 872.4 and αO = 1042.3 eV. Chemical bonding effects have been discussed with binding energy (BE) differences ΔTi = (BE O 1s - BE Ti 2p3/2) = 71.6 eV and ΔLa = (BE La 3d5/2 - BE O 1s) = 304.7 eV as key parameters in comparison with those in several titanium- and lanthanum-bearing oxides.

Electronic structure of layered titanate Nd 2Ti 2O 7

NASA Astrophysics Data System (ADS)

Atuchin, V. V.; Gavrilova, T. A.; Grivel, J.-C.; Kesler, V. G.

2008-10-01

The electronic structure of the binary titanate Nd 2Ti 2O 7 has been studied by X-ray photoelectron spectroscopy (XPS). Spectral features of the valence band and all constituent element core levels have been considered. The Auger parameters of titanium and oxygen in Nd 2Ti 2O 7 are determined as αTi = 873.5 and αO = 1042.2 eV. Chemical bonding effects have been discussed with the binding energies differences ΔTi = (BE O 1s - BE Ti 2p 3/2) = 71.5 eV and ΔNd = (BE Nd 3d 5/2 - BE O 1s) = 452.5 eV as key parameters in comparison with those in other titanium- and neodymium-bearing oxides.

Assessment of the HBV vaccine response in a group of HIV-infected children in Morocco.

PubMed

Haban, Houda; Benchekroun, Soumia; Sadeq, Mina; Benjouad, Abdelaziz; Amzazi, Said; Oumzil, Hicham; Elharti, Elmir

2017-09-29

Since its development in the early 1980s, Hepatitis B virus (HBV) vaccine has been proven to be highly protective. However, its immunogenicity may be ineffective among HIV-infected children. In Morocco, HBV vaccine was introduced in 1999, and since then all infants, including vertically HIV-infected infants, have been following the vaccination schedule, implemented by the Moroccan ministry of health. An assessment of the immunization of these children is important to optimize efforts aimed at tackling Hepatitis B coinfection, within the country. Forty-nine HIV-infected children (HIV group) and 112 HIV uninfected children (control group) were enrolled in this study. Samples were tested by Elisa (Monolisa Anti-HBs, Biorad) to quantify the anti-HBs antibodies. The % of lymphocyte subsets i.e. CD4+ T cells, CD8+ T cells, B cells, and NK, was determined by flow cytometry, using CellQuest Pro software (Becton-Dickinson), and for HIV group, HIV viral load was measured by real time PCR assay (Abbott). All variables were statistically compared in the two groups. The median age was 51 ± 35 months for the HIV group and 50 ± 36 months (p > 0.05) for the control group. Female represented 63% and 41% (p = 0.01), among the HIV group and the control group, respectively. Among HIV-infected children, 71.4% (35/49) were under HAART therapy at the enrollment in the study. Seroprotection titer i.e. anti-HBs ≥10mUI/ml among control group was 76% (85/112), and only 29% (14/49) among the perinatally HIV-infected children (p < 0.0001). Lower % of CD4 + T cells was observed in HIV-infected children with a poor anti-HBs response. In this studied group, we have shown that despite the vaccination of HIV-children with HBV vaccine, 71% did not show any seroprotective response. These findings support the need for monitoring HBV vaccine response among HIV-infected children in Morocco, in order to revaccinate non-immunized children.

Human papillomavirus vaccination: assessing knowledge, attitudes, and intentions of college female students in Lebanon, a developing country.

PubMed

Dany, Mohammed; Chidiac, Alissar; Nassar, Anwar H

2015-02-18

Human papillomavirus (HPV) infection is a common cause for genital warts and cervical cancer. Developing countries in the Middle East such as Lebanon are traditionally considered to be conservative societies with low incidence of sexually transmitted infections. However, nowadays, there is an unexpected increase in the incidence of HPV infections among Middle Eastern females. Thus, the objective of this study is to assess the behavioral perceptions of HPV vaccination among female students attending an academic institution in Lebanon. This cross-sectional study invited 512 students to complete a self-administered questionnaire that assessed the knowledge, attitudes, and intentions towards HPV vaccination. Data analysis included the calculation of knowledge scores ranging from 0 to 100, attitude scores ranging from most positive (1) to most negative (5), and intention scores ranging from lowest intention (0) to highest intention (10). With a response rate of n=215 (42%), 36.5% never heard of the vaccine before, and only 16.5% were already HPV vaccinated. The median knowledge score of 52.7% ± 1.71 reflects poor to moderate knowledge. Still, the median attitude score of 2.47 ± 0.05 shows a general positive attitude towards HPV vaccination where most of the participants agreed that female college students in Lebanon have a good chance of contracting HPV (62.1%) and that all gynecologists should recommend the vaccine (76.0%). Students in graduate programs, health related majors, and those who are vaccinated had significantly higher knowledge scores compared with students in undergraduate programs, non-health related majors, and HPV non-vaccinated students, respectively. Finally, the survey helped in increasing the intention to obtain HPV vaccine as the intention score increased significantly from 5.24 ± 0.27 before the students went through the survey to 6.98 ± 0.22 after the students completed the survey. Our study highlights the importance of offering guidance to female college students about HPV and its vaccination in developing countries where the incidence of sexually transmitted infections is on the rise. Copyright © 2015 Elsevier Ltd. All rights reserved.

Clinical characteristics and treatment of severe encephalitis associated with neurogenic pulmonary edema caused by enterovirus 71 in China

PubMed Central

Zhang, Yu-cai; Li, Xing-wang; Zhu, Xiao-dong; Qian, Su-yun; Shang, Yun-xiao; Li, Bi-ru; Liu, Xiao-lin

2010-01-01

BACKGROUND: Hand-foot-mouth disease has become a major public health issue in children in China. In the present prospective study we investigated the clinical characteristics and emergency management of children with severe encephalitis associated with NPE caused by enterovirus 71. METHODS: The study was conducted in 2 pediatric intensive care units (PICUs) over a 2-month period. Clinical records were reviewed of critically ill children with severe encephalitis associated with NPE caused by EV71 who were admitted to PICUs during the period of May to June 2008 in Fuyang. RESULTS: We reviewed the complete records of 36 children, of whom 23 (63.9%) were male and 13 (36.1%) female. Their age ranged from 4 to 48 months, with an average of 15.8 months. All children except one were under 3 years of age. The overall mortality in these children was 19.4%. The average duration of critical life threatening signs and symptoms was 2.1 days (12 hours-5 days). Nervous system diseases included brainstem encephalitis in 27 children (75%), brainstem encephalitis associated with myelitis in 6 children (16.7%), and general encephalitis in 3 chidren (8.3%), respectively. In 12 patients of NPE (33.3%) pink or bloody bubble sputum and asymmetric pulmonary edema or hemorrhage was the primary manifestation but no typical exanthema was observed. Five children died of acute onset of NPE and / or pulmonary hemorrhage with rapid progression of cardiopulmonary failure within hours after admission. Therapeutic management consisted of mechanical ventilation and administration of mannitol, methylprednisolone, intravenous immunoglobulin (IVIG) and vasoactive drugs, associated with the need of fluid volume resuscitation in 9 (25%) of the 36 children. CONCLUSIONS: In children less than 3 years of age found to be affected by severe EV71 encephalitis associated with NPE, one fifth may die. The major organ systems infected by severe EV71 include the central nervous system, the respiratory system, and the cardiovascular system. Early diagnosis and evaluation, respiratory support, treatment of intracranial hypertension, and mainttenance of function of the cardiovascular system are the most important therapeutic measures. PMID:25214951

A high-rate 10B-loaded liquid scintillation detector for parity-violation studies in neutron resonances

NASA Astrophysics Data System (ADS)

Yen, Yi-Fen; Bowman, J. D.; Bolton, R. D.; Crawford, B. E.; Delheij, P. P. J.; Hart, G. W.; Haseyama, T.; Frankle, C. M.; Iinuma, M.; Knudson, J. N.; Masaike, A.; Masuda, Y.; Matsuda, Y.; Mitchell, G. E.; Penttilä, S. I.; Roberson, N. R.; Seestrom, S. J.; Sharapov, E.; Shimizu, H. M.; Smith, D. A.; Stephenson, S. L.; Szymanski, J. J.; Yoo, S. H.; Yuan, V. W.

2000-06-01

We have developed a large-area 10B-loaded liquid scintillation detector for parity-violation studies in neutron resonances with high instantaneous neutron fluxes from the LANSCE short-pulse spallation source. The detector has an efficiency of 95%, 85% and 71% at neutron energies of 10, 100 and 1000 eV, respectively. The neutron mean capture time in the detector is (416±5) ns. We describe the detector and the current-mode signal processing system, that can handle neutron rates up to 500 MHz.

Development of a community pharmacy human papillomavirus vaccine program for underinsured university students along the United States/Mexico border.

PubMed

Navarrete, Jacquelyn P; Padilla, Margie E; Castro, Louise P; Rivera, José O

2014-01-01

To describe the development and implementation of a human papillomavirus (HPV) vaccine patient assistance program (PAP) for university students, and to acquire information on the number who accessed the program and completed the series. University of Texas at El Paso University Student Health Clinic Pharmacy, Fall 2011-Spring 2014. A community pharmacy located within the university student health clinic providing services to an underinsured student population. Existing evidence shows the benefit of using PAP in community pharmacies but is nonspecific regarding the use of PAP for vaccines in an uninsured and underinsured Hispanic student population. The implementation of this unique HPV vaccine program in a community setting aims to increase awareness, access, and rates. Primary measures included results from a needs-assessment questionnaire that were used to implement the HPV vaccine program. After implementation, utilization data were collected on the number of students who qualified and enrolled in the HPV PAP and the number of students who completed the HPV series. The preliminary data from a needs assessment indicated that a majority (72.1%, n = 80) of students did not understand how HPV is transmitted. A total of 89 students qualified for PAP. The majority were women (81%). A total of 71 students (79.8%) received their second dose and 43 (48.3%) completed the series. Although pharmacists continue to provide vaccine services, minorities such as the Hispanic population continue to be underimmunized. Students may not be taking the proper precautions to prevent the acquisition of HPV. For these reasons services such as this HPV vaccine program are warranted. Pharmacists need to continue to educate and advocate on the importance of vaccines and how they prevent disease.

Nursing Case Management, Peer Coaching, and Hepatitis A and B Vaccine Completion Among Homeless Men Recently Released on Parole: Randomized Clinical Trial

PubMed Central

Nyamathi, Adeline; Salem, Benissa E.; Zhang, Sheldon; Farabee, David; Hall, Betsy; Khalilifard, Farinaz; Leake, Barbara

2015-01-01

Background Although hepatitis A virus (HAV) and hepatitis B virus (HBV) infections are vaccine-preventable diseases, few homeless parolees coming out of prisons and jails have received the hepatitis A and B vaccination series. Objectives The study focused on completion of the HAV and HBV vaccine series among homeless men on parole. The efficacy of three levels of peer coaching and nurse-delivered interventions was compared at 12-month follow up: (a) intensive peer coaching and nurse case management (PC-NCM); (b) intensive peer coaching (PC) intervention condition, with minimal nurse involvement; and a (c) usual care (UC) intervention condition, which included minimal PC and nurse involvement. Further, we assessed predictors of vaccine completion among this targeted sample. Methods A randomized control trial was conducted with 600 recently paroled men to assess the impact of the three intervention conditions (PC-NCM vs. PC vs. UC) on reducing drug use and recidivism; of these, 345 seronegative, vaccine-eligible subjects were included in this analysis of completion of the Twinrix HAV/HAB vaccine. Logistic regression was added to assess predictors of completion of the HAV/HBV vaccine series and chi-squared analysis to compare completion rates across the three levels of intervention. Results Vaccine completion rate for the intervention conditions were 75.4% (PC-NCM), 71.8% (PC), and 71.9% (UC) (p =. 78). Predictors of vaccine noncompletion included being Asian and Pacific Islander, experiencing high levels of hostility, positive social support, reporting a history of injection drug use, being released early from California prisons, and being admitted for psychiatric illness. Predictors of vaccine series completion included reporting six or more friends, recent cocaine use, and staying in drug treatment for at least 90 days. Discussion Findings allow greater understanding of factors affecting vaccination completion in order to design more effective programs among the high-risk population of men recently released from prison and on parole. PMID:25932697

Nursing case management, peer coaching, and hepatitis a and B vaccine completion among homeless men recently released on parole: randomized clinical trial.

PubMed

Nyamathi, Adeline; Salem, Benissa E; Zhang, Sheldon; Farabee, David; Hall, Betsy; Khalilifard, Farinaz; Leake, Barbara

2015-01-01

Although hepatitis A virus (HAV) and hepatitis B virus (HBV) infections are vaccine-preventable diseases, few homeless parolees coming out of prisons and jails have received the hepatitis A and B vaccination series. The study focused on completion of the HAV and HBV vaccine series among homeless men on parole. The efficacy of three levels of peer coaching (PC) and nurse-delivered interventions was compared at 12-month follow-up: (a) intensive peer coaching and nurse case management (PC-NCM); (b) intensive PC intervention condition, with minimal nurse involvement; and (c) usual care (UC) intervention condition, which included minimal PC and nurse involvement. Furthermore, we assessed predictors of vaccine completion among this targeted sample. A randomized control trial was conducted with 600 recently paroled men to assess the impact of the three intervention conditions (PC-NCM vs. PC vs. UC) on reducing drug use and recidivism; of these, 345 seronegative, vaccine-eligible subjects were included in this analysis of completion of the Twinrix HAV/HBV vaccine. Logistic regression was added to assess predictors of completion of the HAV/HBV vaccine series and chi-square analysis to compare completion rates across the three levels of intervention. Vaccine completion rate for the intervention conditions were 75.4% (PC-NCM), 71.8% (PC), and 71.9% (UC; p = .78). Predictors of vaccine noncompletion included being Asian and Pacific Islander, experiencing high levels of hostility, positive social support, reporting a history of injection drug use, being released early from California prisons, and being admitted for psychiatric illness. Predictors of vaccine series completion included reporting having six or more friends, recent cocaine use, and staying in drug treatment for at least 90 days. Findings allow greater understanding of factors affecting vaccination completion in order to design more effective programs among the high-risk population of men recently released from prison and on parole.

Quantitative assessment of the impact of partially protective anti-schistosomiasis vaccines

PubMed Central

Ndeffo Mbah, Martial; Galvani, Alison

2017-01-01

Background Mass drug administration (MDA) of praziquantel has been the intervention of choice against schistosomiasis but with limited success in interrupting the transmission. The development of anti-Schistosoma vaccines is underway. Our objective is to quantify the population-level impact of anti-Schistosoma vaccines when administered alone and in combination with mass drug administration (MDA) and determine factors in vaccine design and public health implementation that optimize vaccination role in schistosomiasis control and elimination. Methods and findings We developed a deterministic compartmental model simulation of schistosomiasis transmission in a high-risk Kenyan community, including stratification by age, parasite burden, and vaccination status. The modeled schistosomiasis vaccines differed in terms of vaccine duration of protection (durability) and three biological efficacies. These are vaccine susceptibility effect (SE) of reducing person’s susceptibility to Schistosoma acquisition, vaccine mortality effect (ME) of reducing established worm burden and vaccine fecundity effect (FE) of reducing egg release by mature worms. We quantified the population-level impact of vaccination over two decades under diverse vaccination schemes (childhood vs. mass campaigns), with different age-targeting scenarios, different risk settings, and with combined intervention with MDA. We also assessed the sensitivity of our predictions to uncertainties in model parameters. Over two decades, our base case vaccine with 80% SE, FE, and ME efficacies, 10 years’ durability, provided by mass vaccination every 10 years, reduced host prevalence, mean intensity, incidence, and patent snail prevalence to 31%, 20 eggs/10-ml sample/person, 0.87 worm/person-year, and 0.74%, from endemic-state values of 71%, 152, 3.3, and 0.98%, respectively. Lower impact was found when coverage did not encompass all potential contaminators, and childhood-only vaccination schemes showed delayed and lower impact. In lower prevalence settings, the base case vaccine generated a proportionately smaller impact. A substantially larger vaccine program effect was generated when MDA + mass vaccination was provided every 5 years, which could be achieved by an MDA-only program only if drug was offered annually. Vaccine impact on schistosomiasis transmission was sensitive to a number of parameters including vaccine efficacies, human contact rates with water, human density, patent snails’ rate of patency and lifespan, and force of infection to snails. Conclusions To be successful a vaccine-based control strategy will need a moderately to highly effective formulation combined with early vaccination of potential contaminators and aggressive coverage in repeated rounds of mass vaccination. Compared to MDA-only program, vaccination combined with MDA accelerates and prolongs the impact by reducing the acquisition of new worms and reducing egg release from residual worms. PMID:28410369

Quantitative assessment of the impact of partially protective anti-schistosomiasis vaccines.

PubMed

Alsallaq, Ramzi A; Gurarie, David; Ndeffo Mbah, Martial; Galvani, Alison; King, Charles

2017-04-01

Mass drug administration (MDA) of praziquantel has been the intervention of choice against schistosomiasis but with limited success in interrupting the transmission. The development of anti-Schistosoma vaccines is underway. Our objective is to quantify the population-level impact of anti-Schistosoma vaccines when administered alone and in combination with mass drug administration (MDA) and determine factors in vaccine design and public health implementation that optimize vaccination role in schistosomiasis control and elimination. We developed a deterministic compartmental model simulation of schistosomiasis transmission in a high-risk Kenyan community, including stratification by age, parasite burden, and vaccination status. The modeled schistosomiasis vaccines differed in terms of vaccine duration of protection (durability) and three biological efficacies. These are vaccine susceptibility effect (SE) of reducing person's susceptibility to Schistosoma acquisition, vaccine mortality effect (ME) of reducing established worm burden and vaccine fecundity effect (FE) of reducing egg release by mature worms. We quantified the population-level impact of vaccination over two decades under diverse vaccination schemes (childhood vs. mass campaigns), with different age-targeting scenarios, different risk settings, and with combined intervention with MDA. We also assessed the sensitivity of our predictions to uncertainties in model parameters. Over two decades, our base case vaccine with 80% SE, FE, and ME efficacies, 10 years' durability, provided by mass vaccination every 10 years, reduced host prevalence, mean intensity, incidence, and patent snail prevalence to 31%, 20 eggs/10-ml sample/person, 0.87 worm/person-year, and 0.74%, from endemic-state values of 71%, 152, 3.3, and 0.98%, respectively. Lower impact was found when coverage did not encompass all potential contaminators, and childhood-only vaccination schemes showed delayed and lower impact. In lower prevalence settings, the base case vaccine generated a proportionately smaller impact. A substantially larger vaccine program effect was generated when MDA + mass vaccination was provided every 5 years, which could be achieved by an MDA-only program only if drug was offered annually. Vaccine impact on schistosomiasis transmission was sensitive to a number of parameters including vaccine efficacies, human contact rates with water, human density, patent snails' rate of patency and lifespan, and force of infection to snails. To be successful a vaccine-based control strategy will need a moderately to highly effective formulation combined with early vaccination of potential contaminators and aggressive coverage in repeated rounds of mass vaccination. Compared to MDA-only program, vaccination combined with MDA accelerates and prolongs the impact by reducing the acquisition of new worms and reducing egg release from residual worms.

Seroprevalence of hepatitis B and factors potentially associated in a population-based study in Medellin, Colombia.

PubMed

Cadavid-Betancur, David A; Ospina, Marta C; Hincapié-Palacio, Doracelly; Bernal-Restrepo, Luz M; Buitrago-Giraldo, Seti; Perez-Toro, Olga; Santacruz-Sanmartín, Eduardo; Lenis-Ballesteros, Viviana; Almanza-Payares, Rita; Díaz, Francisco J

2017-09-05

The seroprevalence of hepatitis B (HB) and of potentially associated factors in Medellin, Colombia, were investigated 17years after the start of universal vaccination. Biological and sociodemographic data from a population survey with a multistage random sampling were analyzed in 6-64year old individuals. HB surface antigen, total HB core antibodies and HB surface antibodies, and in some cases IgM antibodies to HB core antigen, were tested in 2077 samples. Factors potentially associated with and natural, and vaccine immunity relative to susceptibility (absence of any marker) were analyzed using a multinomial logistic regression. The prevalence of serological patterns was: chronic infection 0.20% (95% CI 0.11-0.71), vaccine immunity 25.10% (95% CI 21.72-28.83) and natural immunity 2.60% (95% CI 1.80-3.74). No markers were detected in 71.30% (95% CI 67.70-74.83) of the individuals and evidence of recent infection was not detected. Relative to the absence of markers, natural immunity was potentially associated with age (6-17years and 41-64years) and sleeping less than 6 hours, while vaccine immunity was associated with age (6-17years), reporting vaccination against HB, belonging to high socioeconomic strata, home ownership and being obese, after adjusting for other variables. These results may be a population effect of mass vaccination. It is recommended to complete the vaccination schedule and to study in detail, persistence of antibodies and the role of obesity and socioeconomic strata in the vaccine immunity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Detection of serum antibodies against measles, mumps and rubella after primary measles, mumps and rubella (MMR) vaccination in children.

PubMed

Rafiei Tabatabaei, Sedigheh; Esteghamati, Abdoul-Reza; Shiva, Farideh; Fallah, Fatemeh; Radmanesh, Raheleh; Abdinia, Babak; Shamshiri, Ahmad Reza; Khairkhah, Masoumeh; Shekari Ebrahimabad, Hamideh; Karimi, Abdollah

2013-01-01

In Iran, the measles, mumps and rubella vaccine (MMR) is administered in a two-dose protocol where the first dose is scheduled at 12 months of age. This study aims to determine the efficacy of the MMR vaccine by testing IgM and IgG antibody levels 4 - 7 weeks after primary vaccination. A single group cohort study was performed on healthy children, 12 - 15 months of age, who were vaccinated at health centers affiliated with Shahid Beheshti University of Medical Sciences in Tehran, from January to April 2009. Children with negative vaccination and/or clinical history for measles, mumps or rubella were administered the first dose of the MMR live attenuated vaccine. IgG and IgM antibodies were checked by enzyme linked immunoassay (ELISA) in serum samples 4 - 7 weeks after vaccination. A child was considered seropositive if antibody levels were higher than the assay cut-off level set by the ELISA kit. Samples from 240 children were checked for antibodies against measles and rubella. Measles serum IgM level was positive in 71.7% of samples and IgG in 75.8%. The rubella serum IgM level was positive in 71.7% of children and IgG in 73.8%. From 190 blood samples that were checked for mumps antibodies, serum IgM was positive in 68.9% and IgG in 95.3%. No significant relationship was found between seropositivity and age or gender. IgG and IgM antibody levels were below the assay cut-off levels against measles and rubella in approximately one-fourth of the children following primary MMR vaccination. A second dose was necessary to raise the level of protection against measles and rubella.

Time series modeling of pathogen-specific disease probabilities with subsampled data.

PubMed

Fisher, Leigh; Wakefield, Jon; Bauer, Cici; Self, Steve

2017-03-01

Many diseases arise due to exposure to one of multiple possible pathogens. We consider the situation in which disease counts are available over time from a study region, along with a measure of clinical disease severity, for example, mild or severe. In addition, we suppose a subset of the cases are lab tested in order to determine the pathogen responsible for disease. In such a context, we focus interest on modeling the probabilities of disease incidence given pathogen type. The time course of these probabilities is of great interest as is the association with time-varying covariates such as meteorological variables. In this set up, a natural Bayesian approach would be based on imputation of the unsampled pathogen information using Markov Chain Monte Carlo but this is computationally challenging. We describe a practical approach to inference that is easy to implement. We use an empirical Bayes procedure in a first step to estimate summary statistics. We then treat these summary statistics as the observed data and develop a Bayesian generalized additive model. We analyze data on hand, foot, and mouth disease (HFMD) in China in which there are two pathogens of primary interest, enterovirus 71 (EV71) and Coxackie A16 (CA16). We find that both EV71 and CA16 are associated with temperature, relative humidity, and wind speed, with reasonably similar functional forms for both pathogens. The important issue of confounding by time is modeled using a penalized B-spline model with a random effects representation. The level of smoothing is addressed by a careful choice of the prior on the tuning variance. © 2016, The International Biometric Society.

High-Performance Polymer Solar Cells Based on a Wide-Bandgap Polymer Containing Pyrrolo[3,4-f]benzotriazole-5,7-dione with a Power Conversion Efficiency of 8.63.

PubMed

Lan, Liuyuan; Chen, Zhiming; Hu, Qin; Ying, Lei; Zhu, Rui; Liu, Feng; Russell, Thomas P; Huang, Fei; Cao, Yong

2016-09-01

A novel donor-acceptor type conjugated polymer based on a building block of 4,8-di(thien-2-yl) - 6-octyl-2-octyl-5 H- pyrrolo[3,4- f ]benzotriazole-5,7(6 H )-dione (TZBI) as the acceptor unit and 4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)-benzo-[1,2- b :4,5- b' ]dithiophene as the donor unit, named as PTZBIBDT, is developed and used as an electron-donating material in bulk-heterojunction polymer solar cells. The resulting copolymer exhibits a wide bandgap of 1.81 eV along with relatively deep highest occupied molecular orbital energy level of -5.34 eV. Based on the optimized processing conditions, including thermal annealing, and the use of a water/alcohol cathode interlayer, the single-junction polymer solar cell based on PTZBIBDT:PC 71 BM ([6,6]-phenyl-C 71 -butyric acid methyl ester) blend film affords a power conversion efficiency of 8.63% with an open-circuit voltage of 0.87 V, a short circuit current of 13.50 mA cm -2 , and a fill factor of 73.95%, which is among the highest values reported for wide-bandgap polymers-based single-junction organic solar cells. The morphology studies on the PTZBIBDT:PC 71 BM blend film indicate that a fibrillar network can be formed and the extent of phase separation can be mani-pulated by thermal annealing. These results indicate that the TZBI unit is a very promising building block for the synthesis of wide-bandgap polymers for high-performance single-junction and tandem (or multijunction) organic solar cells.

Seroepidemiology of varicella among elementary school children in northern Taiwan.

PubMed

Lin, Ming-Ru; Kuo, Ching-Chia; Hsieh, Yu-Chia; Huang, Ya-Ling; Huang, Yu-Chiau; Hung, Yung-Tai; Huang, Yhu-Chering

2017-06-01

In Taiwan, varicella vaccine was included in the expanded program of immunization since 2004. A seroepidemiologic study in the postvaccine era is helpful to evaluate the efficiency of current varicella vaccination strategies. We used a multistage stratified systematic sampling design to classify 29 administrative districts of New Taipei City into five strata. In 2013, a total of 936 students from 14 primary schools were recruited and had blood drawn for serology tests for varicella-zoster virus-immunoglobulin-G via indirect chemiluminescence immunoassays. A history of clinical varicella and information on varicella vaccination status were obtained. Overall, the seroprevalence was 64.1%. For the five strata, the seropositive rate ranged from 54.2% (Stratum 5) to 71.7% (Stratum 2) with no significant difference. For each participating school, the seropositive rate ranged from 44.4% to 72.9% with a statistically significant difference (p < 0.005). For school children in each grade, seropositive rate increased significantly from 53.2% for Grade 1 to 71.8% for Grade 3 (p = 0.005) and increased steadily from 61.2% for Grade 4 to 71.2% for Grade 6 (p = 0.17). A positive correlation was observed between the seropositive rate and geometric mean titers (p = 0.035). Geometric mean titers and the rate of a history of clinical varicella were positively correlated with increasing class grades. Nine years after the introduction of the varicella vaccine into the expanded program of immunization in Taiwan, around two-thirds of elementary schoolchildren were seropositive for varicella-zoster virus. Further surveillance studies on clinical varicella cases are worthwhile to determine whether a second dose of varicella vaccine is needed in Taiwan. Copyright © 2015. Published by Elsevier B.V.

Ala67Thr mutation in the poliovirus receptor CD155 is a potential risk factor for vaccine and wild-type paralytic poliomyelitis.

PubMed

Kindberg, Elin; Ax, Cecilia; Fiore, Lucia; Svensson, Lennart

2009-05-01

Poliovirus infections can be asymptomatic or cause severe paralysis. Why some individuals develop paralytic poliomyelitis is unknown, but a role for host genetic factors has been suggested. To investigate if a polymorphism, Ala67Thr, in the poliovirus receptor, which has been found to facilitate increased resistance against poliovirus-induced cell lysis and apoptosis, is associated with increased risk of paralytic poliomyelitis, poliovirus receptor genotyping was undertaken among Italian subjects with vaccine-associated (n = 9), or with wild-type paralytic poliomyelitis (n = 6), and control subjects (n = 71), using RFLP-PCR and pyrosequencing. Heterozygous poliovirus receptor Ala67Thr genotype was found in 13.3% of the patients with paresis and in 8.5% of the controls (Odds Ratio = 1.667). The frequency of Ala67Thr among the controls is in agreement with earlier published data. It is concluded that the Ala67Thr mutation in the poliovirus receptor is a possible risk factor for the development of vaccine-associated or paralytic poliomyelitis associated with wild-type virus. Copyright 2009 Wiley-Liss, Inc.

Lithium chloride inhibits early stages of foot-and-mouth disease virus (FMDV) replication in vitro.

PubMed

Zhao, Fu-Rong; Xie, Yin-Li; Liu, Ze-Zhong; Shao, Jun-Jun; Li, Shi-Fang; Zhang, Yong-Guang; Chang, Hui-Yun

2017-11-01

Foot-and-mouth disease virus (FMDV) causes an economically important and highly contagious disease of cloven-hoofed animals such as cattle, swine, and sheep. FMD vaccine is the traditional way to protect against the disease, which can greatly reduce its occurrence. However, the use of FMD vaccines to protect early infection is limited. Therefore, the alternative strategy of applying antiviral agents is required to control the spread of FMDV in outbreak situations. As previously reported, LiCl has obviously inhibition effects on a variety of viruses such as transmissible gastroenteritis virus (TGEV), infectious bronchitis coronavirus (IBV), and pseudorabies herpesvirus and EV-A71 virus. In this study, our findings were the first to demonstrate that LiCl inhibition of the FMDV replication. In this study, BHK-21 cell was dose-dependent with LiCl at various stages of FMDV. Virus titration assay was calculated by the 50% tissue culture infected dose (TCID 50 ) with the Reed and Muench method. The cytotoxicity assay of LiCl was performed by the CCK8 kit. The expression level of viral mRNA was measured by RT-qPCR. The results revealed LiCl can inhibit FMDV replication, but it cannot affect FMDV attachment stage and entry stage in the course of FMDV life cycle. Further studies confirmed that the LiCl affect the replication stage of FMDV, especially the early stages of FMDV replication. So LiCl has potential as an effective anti-FMDV drug. Therefore, LiCl may be an effective drug for the control of FMDV. Based on that, the mechanism of the antiviral effect of LiCl on FMDV infection is need to in-depth research in vivo. © 2017 Wiley Periodicals, Inc.

Awareness and attitudes toward hepatitis B among Malaysian dentists.

PubMed

Razak, I A; Latifah, R J; Nasruddin, J; Esa, R

1991-01-01

A questionnaire was mailed to 1217 dentists whose names appear in the Dentist Register of 1987 in order to assess their awareness and acceptance of hepatitis B vaccine and their pattern of glove usage. Almost all the respondents (99.6%) were aware of the availability of the hepatitis B vaccine yet only 44.8% have received the vaccine. This is in spite of the fact that the majority (61.2%) of the vaccine non-acceptors have no reservations concerning the vaccine. About 71% and 63% of the vaccine-acceptors and non-acceptors respectively believed that the risk of their contracting hepatitis B was high or very high. About 22% of the vaccine non-acceptors never used gloves when treating patients as compared to 9% among vaccine acceptors. Overall, about 78% of the respondents have experienced needleprick injuries in the 3 years preceding the survey.

Isolation and characterization of a new enterovirus F in yak feces in the Qinghai-Tibetan Plateau.

PubMed

He, Huan; Tang, Cheng; Chen, Xinnuo; Yue, Hua; Ren, Yupeng; Liu, Yan; Zhang, Bin

2017-02-01

An enterovirus (EV) strain, designated as SWUN-AB001, was isolated in the Qinghai-Tibetan Plateau from a yak with severe diarrheal disease. The complete genome of strain SWUN-AB001 was 7,382 bp in length and shared 35.1-68.5% nt identities with bovine EVs belonging to a candidate new type EV-F7. Using the sequence difference values in the VP1 gene as a criterion for demarcating a new serotype/genotype in the Enterovirus genus, strain SWUN-AB001 had only a 71.1% nt and a 79.2% aa identity, in the VP1 region, with the most closely matched EV, further indicating that a new type of EV had been identified. Phylogenetic analysis of the nt sequence of the viral polyprotein and of VP1 genes demonstrated that the virus fell within the EV-F cluster, but was located in a unique lineage. Furthermore, a large-scale surveillance study indicated that the prevalence of this EV in yaks was 31.05% (95% CI = 25.5-37.6%) in 235 animals with diarrhea and 24.13% (95% CI = 17.4-32.4%) in 116 healthy yaks. However, there was no significant difference in virus prevalence between diarrheal and healthy samples. Interestingly, in the Tibet region, diarrheal feces had a higher incidence of EVs than feces of healthy yaks (odd ratios = 6.03, 95% CI = 1.93-18.86), indicating that the incidence of EV was potentially correlated with the clinical symptom of diarrhea in yaks.

The influence of the growth conditions of the plague microbe vaccine strain colonies on the fractal dimension of biospeckles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ul'yanov, A S; Lyapina, A M; Ulianova, O V

2011-04-30

Specific statistical characteristics of biospeckles, emerging under the diffraction of coherent beams on the bacterial colonies, are studied. The dependence of the fractal dimensions of biospeckles on the conditions of both illumination and growth of the colonies is studied theoretically and experimentally. Particular attention is paid to the fractal properties of biospeckles, emerging under the scattering of light by the colonies of the vaccinal strain of the plague microbe. The possibility in principle to classify the colonies of Yersinia pestis EV NIIEG using the fractal dimension analysis is demonstrated. (optical technologies in biophysics and medicine)

Genomic characterization of two new enterovirus types, EV-A114 and EV-A121.

PubMed

Deshpande, Jagadish M; Sharma, Deepa K; Saxena, Vinay K; Shetty, Sushmitha A; Qureshi, Tarique Husain I H; Nalavade, Uma P

2016-12-01

Enteroviruses cause a variety of illnesses of the gastrointestinal tract, central nervous system and cardiovascular system. Phylogenetic analysis of VP1 sequences has identified 106 different human enteroviruses classified into four enterovirus species within the genus Enterovirus of the family Picornaviridae. It is likely that not all enterovirus types have been discovered. Between September 2013 and October 2014, stool samples of 6274 apparently healthy children of up to 5 years of age residing in Gorakhpur district, Uttar Pradesh, India were screened for enteroviruses. Virus isolates obtained in RD and Hep-2c cells were identified by complete VP1 sequencing. Enteroviruses were isolated from 3042 samples. A total of 87 different enterovirus types were identified. Two isolates with 71 and 74 % nucleotide sequence similarity to all other known enteroviruses were recognized as novel types. In this paper we report identification and complete genome sequence analysis of these two isolates classified as EV-A114 and EV-A121.

Investigation of electronic structures and optical properties of β -Si3N4 doped with IV A elements: A first-principles simulation

NASA Astrophysics Data System (ADS)

Lu, Xuefeng; Gao, Xu; Ren, Junqiang; Li, Cuixia; Guo, Xin; Wei, Yupeng; La, Peiqing

2018-04-01

Based on first-principles simulations with the generalized gradient approximation (GGA) of the Perdew-Burke-Ernzerhof (PBE) functional, we studied the electronic structures and optical properties of hexagonal silicon nitride (β-Si3N4) doped with IV A elements, C, Ge, Sn and Pb. It was found that the Ge-doped system is characterized by a more stable structure with a lower formation energy of 2.584 eV compared with those of the C-, Sn- and Pb-doped systems of 3.877 eV, 5.249 eV and 7.672 eV, respectively. The band gap (EG) of the Pb-doped system was the lowest at 1.6 eV, displaying semiconducting characteristics. Additionally, there was a transition from a direct band gap to an indirect band gap in the C-doped system. Charge difference density analysis showed that the covalent property of the C-N bonds was enhanced by expansion of the electron-free region and the larger Mulliken population values of 0.71 and 0.86. Furthermore, lower absorption and reflectivity peaks at 11.30 eV were observed for the C-doped system, demonstrating its broader potential for application in photoelectric and microelectronic devices.

Parental perceptions surrounding polio and self-reported non-participation in polio supplementary immunization activities in Karachi, Pakistan: a mixed methods study.

PubMed

Khowaja, Asif Raza; Khan, Sher Ali; Nizam, Naveeda; Omer, Saad Bin; Zaidi, Anita

2012-11-01

To assess parent's knowledge and perceptions surrounding polio and polio vaccination, self-reported participation in polio supplementary immunization activities (SIAs) targeting children aged < 5 years, and reasons for non-participation. The mixed methods study began with a cross-sectional survey in Karachi, Pakistan. A structured questionnaire was administered to assess parental knowledge of polio and participation in polio SIAs conducted in September and October 2011. Additionally, 30 parents of Pashtun ethnicity (a high-risk group) who refused to vaccinate their children were interviewed in depth to determine why. Descriptive and bivariate analyses by ethnic and socioeconomic group were performed for quantitative data; thematic analysis was conducted for qualitative interviews with Pashtun parents. Of 1017 parents surveyed, 412 (41%) had never heard of polio; 132 (13%) did not participate in one SIA and 157 (15.4%) did not participate in either SIA. Among non-participants, 34 (21.6%) reported not having been contacted by a vaccinator; 116 (73.9%) reported having refused to participate, and 7 (4.5%) reported that the child was absent from home when the vaccinator visited. Refusals clustered in low-income Pashtun (43/441; 9.8%) and high-income families of any ethnic background (71/153; 46.4%). Low-income Pashtuns were more likely to not have participated in polio SIAs than low-income non-Pashtuns (odds ratio, OR: 7.1; 95% confidence interval, CI: 3.47-14.5). Reasons commonly cited among Pashtuns for refusing vaccination included fear of sterility; lack of faith in the polio vaccine; scepticism about the vaccination programme, and fear that the vaccine might contain religiously forbidden ingredients. In Karachi, interruption of polio transmission requires integrated and participatory community interventions targeting high-risk populations.

Acellular vaccines for preventing whooping cough in children.

PubMed

Zhang, Linjie; Prietsch, Sílvio Om; Axelsson, Inge; Halperin, Scott A

2011-01-19

Routine use of whole-cell pertussis vaccines was suspended in some countries in the 1970s/1980s because of concerns about adverse effects. There was a resurgence of whooping cough. Acellular pertussis vaccines (containing purified or recombinant Bordetella pertussis antigens) were developed in the hope that they would be as effective but less reactogenic than the whole-cell vaccines. To assess the efficacy and safety of acellular pertussis vaccines in children. We searched the Cochrane Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 2) which contains the Acute Respiratory Infections Group's Specialised Register; MEDLINE (1950 to April week 2 2009) and EMBASE (1974 to April 2009). Double-blind randomised efficacy and safety trials of acellular pertussis vaccines in children up to six years old, with active follow-up of participants and laboratory verification of pertussis cases. Two review authors independently performed data extraction and study quality assessment. Differences in trial design precluded pooling of the efficacy data. The safety data from individual trials were pooled using the Cochrane statistical package Review Manager 5. Six efficacy trials and 52 safety trials were included. The efficacy of multi-component (≥ 3) vaccines varied from 84% to 85% in preventing typical whooping cough, and from 71% to 78% in preventing mild pertussis disease. In contrast, the efficacy of one- and two-component vaccines varied from 59% to 75% against typical whooping cough, and from 13% to 54% against mild pertussis disease. Multi-component acellular vaccines is more effective than low-efficacy whole-cell vaccines, but may be less effective than the highest-efficacy whole-cell vaccines. Most systemic and local adverse events were significantly less common with acellular than with whole-cell pertussis vaccines for the primary series as well as for the booster dose. Multi-component acellular pertussis vaccines are effective, and show less adverse effects than whole-cell pertussis vaccines for the primary series as well as for booster doses.

Reducing Unintended Pregnancies as a Strategy to Avert Zika-Related Microcephaly Births in the United States: A Simulation Study.

PubMed

Ahrens, Katherine A; Hutcheon, Jennifer A; Gavin, Loretta; Moskosky, Susan

2017-05-01

Introduction There is increasing evidence that infection with the Zika virus (ZIKV) during pregnancy can lead to severe brain abnormalities in infants exposed in utero. The objective of our analysis was to estimate the contribution of enhanced contraception access to averting ZIKV-related microcephaly births in the United States, alone and in combination with another possible strategy, anti-ZIKV vaccination. Methods We used Monte Carlo sampling techniques (n = 100,000 simulations) to estimate the number of microcephaly births expected under strategies of enhanced contraception only, vaccination only, both enhanced contraception and vaccination, and status quo (no intervention). Enhanced contraceptive access was assumed to reduce unintended pregnancy rates by 46% and anti-ZIKV vaccination was assumed to be 90% effective. Plausible values for effectiveness of enhanced contraceptive access, ZIKV cumulative incidence, ZIKV-related microcephaly risk, and anti-ZIKV vaccination parameters were derived from the literature or best available knowledge. Results Enhanced contraceptive access alone reduced the median number of ZIKV-related microcephaly births by 16% (95% simulation interval: 5, 23), while the anti-ZIKV vaccine alone reduced these births by 9% (95% SI: 0, 18), 45% (95% SI: 36, 54), and 81% (95% SI: 71, 91), under conservative (10% vaccine uptake), moderate (50% vaccine uptake), and optimistic (90% vaccine uptake) scenarios, respectively. The reduction in ZIKV-related microcephaly births was always greater if both interventions were employed. Discussion Enhanced contraceptive access alone has the ability to produce a meaningful reduction in microcephaly births, and could provide an important adjuvant prevention strategy even following the development of a highly-effective anti-ZIKV vaccine.

Economic evaluation of delivering Haemophilus influenzae type b vaccine in routine immunization services in Kenya.

PubMed

Akumu, Angela Oloo; English, Mike; Scott, J Anthony G; Griffiths, Ulla K

2007-07-01

Haemophilus influenzae type b (Hib) vaccine was introduced into routine immunization services in Kenya in 2001. We aimed to estimate the cost-effectiveness of Hib vaccine delivery. A model was developed to follow the Kenyan 2004 birth cohort until death, with and without Hib vaccine. Incidence of invasive Hib disease was estimated at Kilifi District Hospital and in the surrounding demographic surveillance system in coastal Kenya. National Hib disease incidence was estimated by adjusting incidence observed by passive hospital surveillance using assumptions about access to care. Case fatality rates were also assumed dependent on access to care. A price of US$ 3.65 per dose of pentavalent diphtheria-tetanus-pertussis-hep B-Hib vaccine was used. Multivariate Monte Carlo simulations were performed in order to assess the impact on the cost-effectiveness ratios of uncertainty in parameter values. The introduction of Hib vaccine reduced the estimated incidence of Hib meningitis per 100,000 children aged < 5 years from 71 to 8; of Hib non-meningitic invasive disease from 61 to 7; and of non-bacteraemic Hib pneumonia from 296 to 34. The costs per discounted disability adjusted life year (DALY) and per discounted death averted were US$ 38 (95% confidence interval, CI: 26-63) and US$ 1197 (95% CI: 814-2021) respectively. Most of the uncertainty in the results was due to uncertain access to care parameters. The break-even pentavalent vaccine price--where incremental Hib vaccination costs equal treatment costs averted from Hib disease--was US$ 1.82 per dose. Hib vaccine is a highly cost-effective intervention in Kenya. It would be cost-saving if the vaccine price was below half of its present level.

Development of Mathematical Model for Pneumatic Tire-Soil Interaction in Layered Soils

DTIC Science & Technology

1975-11-01

HI SL E 7 Cli *1) 1XTN J (TFI, j)- - T11 1,J))14 71’ tL~f~iLO, 2 /LPC71F>0 oil -1 + C11 4 IJI .1 1_ 001 F[ A TAi I *JCOIIEITE INTERFACE [FFOIF 7DEPTH...RD4HF10 /LES02200 Oil BE = ALOCG IoS IRAMI /LES02TIJO/ 11 10G iAfMjJ2 I SLF I - TH =P/2 + ARM + 001 /LES0ri2q590 17 /LE`O22I J1 ns10I = PSI/QUW...LES0S780/ 09 W RITE TO 0EV (-ý LUV .GT. 2*ON-F >FALSE 0 F BD I /V1A FORMAT /LE1579t ’N IU/L0305690- 19 FALSE z K <K LU.L. ’Kz 22.10 00S0R7* 03 N

Cost-effectiveness of hepatitis A vaccination in Indonesia.

PubMed

Suwantika, Auliya A; Beutels, Philippe; Postma, Maarten J

2014-01-01

This study aims to assess the cost-effectiveness of hepatitis A immunization in Indonesia, including an explicit comparison between one-dose and two-dose vaccines. An age-structured cohort model based on a decision tree was developed for the 2012 Indonesia birth cohort. Using the model, we made a comparison on the use of two-dose and one-dose vaccines. The model involved a 70-year time horizon with 1-month cycles for children less than 2 years old and annually thereafter. Monte Carlo simulations were used to examine the economic acceptability and affordability of the hepatitis A vaccination. Vaccination would save US$ 3,795,148 and US$ 2,892,920 from the societal perspective, for the two-dose and one-dose vaccine schedules, respectively, in the context of hepatitis A treatment. It also would save 8917 and 6614 discounted quality-adjusted-life-years (QALYs), respectively. With the vaccine price of US$ 3.21 per dose, the implementation of single dose vaccine would yield an incremental cost-effectiveness ratio (ICER) of US$ 4933 per QALY gained versus no vaccination, whereas the two-dose versus one-dose schedule would cost US$ 14 568 per QALY gained. Considering the 2012 gross-domestic-product (GDP) per capita in Indonesia of US$ 3557, the results indicate that hepatitis A vaccination would be a cost-effective intervention, both for the two-dose and one-dose vaccine schedules in isolation, but two-dose vaccination would no longer be cost-effective if one-dose vaccination is a feasible option. Vaccination would be 100% affordable at budgets of US$ 71,408 000 and US$ 37,690,000 for the implementation of the two-dose and one-dose vaccine schedules, respectively. The implementation of hepatitis A vaccination in Indonesia would be a cost-effective health intervention under the market vaccine price. Given the budget limitations, the use of a one-dose-vaccine schedule would be more realistic to be applied than a two-dose schedule. The vaccine price, mortality rate and discount rate were the most influential parameters impacting the ICERs.

Cost-effectiveness of hepatitis A vaccination in Indonesia

PubMed Central

Suwantika, Auliya A; Beutels, Philippe; Postma, Maarten J

2014-01-01

Objective This study aims to assess the cost-effectiveness of hepatitis A immunization in Indonesia, including an explicit comparison between one-dose and two-dose vaccines. Methods An age-structured cohort model based on a decision tree was developed for the 2012 Indonesia birth cohort. Using the model, we made a comparison on the use of two-dose and one-dose vaccines. The model involved a 70-year time horizon with 1-month cycles for children less than 2 years old and annually thereafter. Monte Carlo simulations were used to examine the economic acceptability and affordability of the hepatitis A vaccination. Results Vaccination would save US$ 3 795 148 and US$ 2 892 920 from the societal perspective, for the two-dose and one-dose vaccine schedules, respectively, in the context of hepatitis A treatment. It also would save 8917 and 6614 discounted quality-adjusted-life-years (QALYs), respectively. With the vaccine price of US$ 3.21 per dose, the implementation of single dose vaccine would yield an incremental cost-effectiveness ratio (ICER) of US$ 4933 per QALY gained versus no vaccination, whereas the two-dose versus one-dose schedule would cost US$ 14 568 per QALY gained. Considering the 2012 gross-domestic-product (GDP) per capita in Indonesia of US$ 3557, the results indicate that hepatitis A vaccination would be a cost-effective intervention, both for the two-dose and one-dose vaccine schedules in isolation, but two-dose vaccination would no longer be cost-effective if one-dose vaccination is a feasible option. Vaccination would be 100% affordable at budgets of US$ 71 408 000 and US$ 37 690 000 for the implementation of the two-dose and one-dose vaccine schedules, respectively. Conclusions The implementation of hepatitis A vaccination in Indonesia would be a cost-effective health intervention under the market vaccine price. Given the budget limitations, the use of a one-dose-vaccine schedule would be more realistic to be applied than a two-dose schedule. The vaccine price, mortality rate and discount rate were the most influential parameters impacting the ICERs. PMID:25424941

Estimation of contamination sources of human enteroviruses in a wastewater treatment and reclamation system by PCR-DGGE.

PubMed

Ji, Zheng; Wang, Xiaochang C; Xu, Limei; Zhang, Chongmiao; Funamizu, Naoyuki; Okabe, Satoshi; Sano, Daisuke

2014-06-01

A polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) method was employed to estimate the contamination sources of human enteroviruses and understand how their dominant strains vary in a wastewater treatment and reclamation system consisting of sewage collection, wastewater treatment with membrane bioreactor and open lakes for reclaimed water storage and reuse. After PCR-DGGE using a selected primer set targeting enteroviruses, phylogenetic analysis of acquired enterovirus gene sequences was performed. Enteroviruses identified from the septic tank were much more diverse than those from grey water and kitchen wastewater. Several unique types of enterovirus different from those in wastewater samples were dominant in a biological wastewater treatment unit. Membrane filtration followed by chlorination was proved effective for physically eliminating enteroviruses; however, secondary contamination likely occurred as the reclaimed water was stored in artificial lakes. Enterovirus 71 (EV71), a hand-foot-and-mouth disease (HFMD) viral pathogen, was detected mainly from the artificial lakes, implying that wastewater effluent was not the contamination source of EV71 and that there were unidentified non-point sources of the contamination with the HFMD viral pathogen in the reclaimed water stored in the artificial lakes. The PCR-DGGE targeting enteroviruses provided robust evidence about viral contamination sources in the wastewater treatment and reclamation system.

Left gastric vein-based noninvasive test for esophageal varices: a same-day comparison of portal hemodynamic assessment with endoscopic appearance.

PubMed

Maruyama, Hitoshi; Kobayashi, Kazufumi; Kiyono, Soichiro; Ogasawara, Sadahisa; Ooka, Yoshihiko; Suzuki, Eiichiro; Chiba, Tetsuhiro; Kato, Naoya

2018-05-25

To examine the effect of hemodynamic assessment of the left gastric vein (LGV) as a noninvasive test to diagnose esophageal varices (EV) in cirrhosis patients. This cross-sectional study consisted of 229 cirrhosis patients (62.7 ± 11.8 years; Child-Pugh score 5-14). One hundred fifty-four patients had EV (67.2%; small, 53; medium, 71; large, 30). All patients underwent a blood test and Doppler ultrasound followed by upper gastrointestinal endoscopy on the same day. The diagnostic ability for EV was compared between LGV-related findings and the platelet count/spleen diameter ratio (Plt/Spl). The detectability of the LGV was higher in patients with EV (129/144, 89.6%) than in those without (35/75, 46.7%; p < 0.0001), and was higher in those with large EV (30/30, 100%) than in those without (134/199, 67.3%; p = 0.0002). The positive detection of the LGV showed 100% sensitivity and negative predictive value (NPV) to identify large EV in the whole cohort and compensated group (n = 127). The best cutoff value in the LGV diameter was 5.35 mm to identify large EV, showing 0.753 area under the receiver operating characteristic curve (AUROC) with 90% sensitivity and 96.5% NPV. The Plt/Spl showed 62.1% sensitivity and 87.1% NPV, and the best cutoff value was 442.9 to identify large EV with 0.658 AUROC, which was comparable to LGV-based assessment (p = 0.162). This same-day comparison study demonstrated the value of LGV-based noninvasive test to identify large EV with high sensitivity and NPV in cirrhosis patients at a lower cost.

[Study of combined effects of DES and EV on the proliferation of MCF-7 cells by two experimental designs].

PubMed

Liu, Qian; Lei, Bing-Li; An, Jing; Shang, Yu; Zhong, Yu-Fang; Kang, Jia; Wen, Yu

2013-08-01

The single toxicity of diethylstilbestrol (DES) and beta-estradiol 17-valerate (EV) and the joint toxicity of their binary mixtures in equiconcentration to the proliferation of MCF-7 cells were investigated, respectively. Additive index (AI) method was adopted to evaluate the joint toxicity effect. At the same time, 3 x 3 factorial experimental design was used to verify the joint toxiciy types derived from equiconcentration of DES and EV. The results show that the EC50 values of single EV and DES for 24, 48 and 72 h are 6.02, 0.40 and 0.33 nmol x L(-1) and 5.90, 6.98 and 2.90 nmol x L(-1), respectively. The EC50 values of the binary mixtures of DES and EV for 24, 48 and 72 h are 2.33, 0.71 and 0.39 nmol x L(-1). The binary joint effects of DES and EV for 24 h were synergistic, and the joint effects of DES and EV for 48 and 72 h were antagonistic. But synergistic and antagonistic effects are not strong; their values can be found close to the values of additive effects. Factorial experiment results show that combined effects of DES and EV to proliferation of MCF-7 cells for 24, 48 and 72 h three exposure periods are additive effect types. The consistent joint combined effect types can be drawn from both factorial experimental design and equiconcentration ratio of DES and EV to the proliferation of MCF-7 cells. However, the factorial experimental design is simpler and more convenient, and can avoid unnecessary mistakes due to the derivation of EC50 values.

A simple and highly repeatable viral plaque assay for enterovirus 71.

PubMed

Yin, Yingxian; Xu, Yi; Ou, Zhiying; Su, Ling; Xia, Huimin

2015-04-01

The classic plaque assay is a method for counting infectious viral particles, however its complexity limits its use in a variety of virological experiments. To simplify the operation and to improve the repeatability, we employed an improved plaque assay procedure based on Avicel to make the whole experiment easier and optimize the results on a model of Vero cells infection with Enterovirus 71(EV71). Clear plaques visible to the naked eyes can be formed on a 24-well plate or a 96-well plate without immunostaining. Following further improvement, this plaque assay procedure could be applied to other viruses, being both simple and repeatable. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Host transcriptomic responses to pneumonic plague reveal that Yersinia pestis inhibits both the initial adaptive and innate immune responses in mice.

PubMed

Yang, Huiying; Wang, Tong; Tian, Guang; Zhang, Qingwen; Wu, Xiaohong; Xin, Youqian; Yan, Yanfeng; Tan, Yafang; Cao, Shiyang; Liu, Wanbing; Cui, Yujun; Yang, Ruifu; Du, Zongmin

2017-01-01

Pneumonic plague is the most deadly form of infection caused by Yersinia pestis and can progress extremely fast. However, our understanding on the host transcriptomic response to pneumonic plague is insufficient. Here, we used RNA-sequencing technology to analyze transcriptomic responses in mice infected with fully virulent strain 201 or EV76, a live attenuated vaccine strain lacking the pigmentation locus. Approximately 600 differentially expressed genes (DEGs) were detected in lungs from both 201- and EV76-infected mice at 12h post-infection (hpi). DEGs in lungs of 201-infected mice exceeded 2000 at 48hpi, accompanied by sustained large numbers of DEGs in the liver and spleen; however, limited numbers of DEGs were detected in those organs of EV-infected mice. Remarkably, DEGs in lungs were significantly enriched in critical immune responses pathways in EV76-infected but not 201-infected mice, including antigen processing and presentation, T cell receptor signaling among others. Pathological and bacterial load analyses confirmed the rapid systemic dissemination of 201-infection and the confined EV76-infection in lungs. Our results suggest that fully virulent Y. pestis inhibits both the innate and adaptive immune responses that are substantially stimulated in a self-limited infection, which update our holistic views on the transcriptomic response to pneumonic plague. Copyright © 2016 Elsevier GmbH. All rights reserved.

Long-term Durability of Infrainguinal Endovascular and Open Revascularization for Disabling Claudication.

PubMed

Khan, Sikandar Z; Rivero, Mariel; Cherr, Gregory S; Harris, Linda M; Dryjski, Maciej L; Dosluoglu, Hasan H

2018-05-15

Infrainguinal revascularization for disabling claudication (DC) is frequently performed, but long-term results are still unknown. In this study, we compared clinical outcomes of infrainguinal endovascular (EV) and open interventions for DC after the failure of medical management. One hundred ninety-four patients with DC (Rutherford category 3) who had open (n = 53) or EV (n = 141) interventions were grouped as open-great saphenous vein (GSV) (n = 21), open-prosthetic (n = 32), EV-Trans-Atlantic Inter-Society Consensus II (TASC II) A and B (AB) (n = 48), and EV-TASC II C and D (CD) (n = 93). Patency, primary clinical success (PCS; sustained improvement in symptoms without reintervention), and secondary clinical success (SCS; sustained improvement in symptoms with reintervention) rates were compared. Mean follow-up was 57 ± 33 months. Five-year primary patency was 58% in open-GSV, 40% in open-prosthetic, 72% in EV-AB, and 38% in EV-CD (P < 0.001). Five-year secondary patency was 77% in open-GSV, 50% in open-prosthetic, 96% in EV-AB, and 61% in EV-CD (P < 0.001). Freedom from major adverse limb events was 73% in open-GSV, 77% in EV-AB, 70% in EV-CD, and 67% in open-prosthetic (P = 0.279). Five-year PCS was 46% in open-GSV, 40% in open-prosthetic, 57% in EV-AB, and 44% in EV-CD (P = 0.02). Five-year SCS was 78% in open-GSV, 78% in open-prosthetic, 85% in EV-AB, and 84% in EV-CD (P = 0.732). A total of 116 reinterventions were performed, 10 in 6 limbs (27%) in open-GSV, 18 in 12 limbs (36%) in open-prosthetic, 26 in 15 limbs (24%) in EV-AB, and 62 in 39 limbs (36%) in EV-CD. Reinterventions included 71 (61%) EV and 45 (39%) open procedures. Durability of infrainguinal interventions in claudicants depends mainly on anatomic complexity of disease. Good long-term clinical success can be achieved with both open and EV interventions, albeit with high reintervention rates, especially in patients with TASC II C and D disease. A considerable subset of EV patients will eventually require surgical revascularization to maintain clinical benefit. In this study, almost 20% of patients undergoing EV for TASC II C and D disease eventually required surgical bypass. Copyright © 2018 Elsevier Inc. All rights reserved.

Ontology-Based Vaccine Adverse Event Representation and Analysis.

PubMed

Xie, Jiangan; He, Yongqun

2017-01-01

Vaccine is the one of the greatest inventions of modern medicine that has contributed most to the relief of human misery and the exciting increase in life expectancy. In 1796, an English country physician, Edward Jenner, discovered that inoculating mankind with cowpox can protect them from smallpox (Riedel S, Edward Jenner and the history of smallpox and vaccination. Proceedings (Baylor University. Medical Center) 18(1):21, 2005). Based on the vaccination worldwide, we finally succeeded in the eradication of smallpox in 1977 (Henderson, Vaccine 29:D7-D9, 2011). Other disabling and lethal diseases, like poliomyelitis and measles, are targeted for eradication (Bonanni, Vaccine 17:S120-S125, 1999).Although vaccine development and administration are tremendously successful and cost-effective practices to human health, no vaccine is 100% safe for everyone because each person reacts to vaccinations differently given different genetic background and health conditions. Although all licensed vaccines are generally safe for the majority of people, vaccinees may still suffer adverse events (AEs) in reaction to various vaccines, some of which can be serious or even fatal (Haber et al., Drug Saf 32(4):309-323, 2009). Hence, the double-edged sword of vaccination remains a concern.To support integrative AE data collection and analysis, it is critical to adopt an AE normalization strategy. In the past decades, different controlled terminologies, including the Medical Dictionary for Regulatory Activities (MedDRA) (Brown EG, Wood L, Wood S, et al., Drug Saf 20(2):109-117, 1999), the Common Terminology Criteria for Adverse Events (CTCAE) (NCI, The Common Terminology Criteria for Adverse Events (CTCAE). Available from: http://evs.nci.nih.gov/ftp1/CTCAE/About.html . Access on 7 Oct 2015), and the World Health Organization (WHO) Adverse Reactions Terminology (WHO-ART) (WHO, The WHO Adverse Reaction Terminology - WHO-ART. Available from: https://www.umc-products.com/graphics/28010.pdf ), have been developed with a specific aim to standardize AE categorization. However, these controlled terminologies have many drawbacks, such as lack of textual definitions, poorly defined hierarchies, and lack of semantic axioms that provide logical relations among terms. A biomedical ontology is a set of consensus-based and computer and human interpretable terms and relations that represent entities in a specific biomedical domain and how they relate each other. To represent and analyze vaccine adverse events (VAEs), our research group has initiated and led the development of a community-based ontology: the Ontology of Adverse Events (OAE) (He et al., J Biomed Semant 5:29, 2014). The OAE has been found to have advantages to overcome the drawbacks of those controlled terminologies (He et al., Curr Pharmacol Rep :1-16. doi:10.1007/s40495-016-0055-0, 2014). By expanding the OAE and the community-based Vaccine Ontology (VO) (He et al., VO: vaccine ontology. In The 1st International Conference on Biomedical Ontology (ICBO-2009). Nature Precedings, Buffalo. http://precedings.nature.com/documents/3552/version/1 ; J Biomed Semant 2(Suppl 2):S8; J Biomed Semant 3(1):17, 2009; Ozgur et al., J Biomed Semant 2(2):S8, 2011; Lin Y, He Y, J Biomed Semant 3(1):17, 2012), we have also developed the Ontology of Vaccine Adverse Events (OVAE) to represent known VAEs associated with licensed vaccines (Marcos E, Zhao B, He Y, J Biomed Semant 4:40, 2013).In this book chapter, we will first introduce the basic information of VAEs, VAE safety surveillance systems, and how to specifically query and analyze VAEs using the US VAE database VAERS (Chen et al., Vaccine 12(10):960-960, 1994). In the second half of the chapter, we will introduce the development and applications of the OAE and OVAE. Throughout this chapter, we will use the influenza vaccine Flublok as the vaccine example to launch the corresponding elaboration (Huber VC, McCullers JA, Curr Opin Mol Ther 10(1):75-85, 2008). Flublok is a recombinant hemagglutinin influenza vaccine indicated for active immunization against disease caused by influenza virus subtypes A and type B. On January 16, 2013, Flublok was approved by the FDA for the prevention of seasonal influenza in people 18 years and older in the USA. Now, more than 3 years later, an exploration of the reported AEs associated with this vaccine is urgently needed.

Travel characteristics and yellow fever vaccine usage among US Global TravEpiNet travelers visiting countries with risk of yellow fever virus transmission, 2009-2011.

PubMed

Jentes, Emily S; Han, Pauline; Gershman, Mark D; Rao, Sowmya R; LaRocque, Regina C; Staples, J Erin; Ryan, Edward T

2013-05-01

Yellow fever (YF) vaccine-associated serious adverse events and changing YF epidemiology have challenged healthcare providers to vaccinate only travelers whose risk of YF during travel is greater than their risk of adverse events. We describe the travel characteristics and YF vaccine use among US travelers visiting Global TravEpiNet clinics from January of 2009 to March of 2011. Of 16,660 travelers, 5,588 (34%) had itineraries to areas with risk of YF virus transmission. Of those travelers visiting one country with YF risk (N = 4,517), 71% were vaccinated at the visit, and 20% were presumed to be immune from prior vaccination. However, travelers visiting friends and relatives (odds ratio [OR] = 2.57, 95% confidence interval [95% CI] = 1.27-5.22) or going to Nigeria (OR = 3.01, 95% CI = 1.37-6.62) were significantly more likely to decline vaccination. To optimize YF vaccine use, clinicians should discuss an individual's risk-benefit assessment of vaccination and close knowledge gaps regarding vaccine use among at-risk populations.

Cross-reactivity to highly pathogenic avian influenza H5N1 viruses after vaccination with nonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a potential priming strategy.

PubMed

Stephenson, Iain; Bugarini, Roberto; Nicholson, Karl G; Podda, Audino; Wood, John M; Zambon, Maria C; Katz, Jacqueline M

2005-04-15

Antigenically well-matched vaccines against highly pathogenic avian influenza H5N1 viruses are urgently required. Human serum samples after immunization with MF59 or nonadjuvanted A/duck/Singapore/97 (H5N3) vaccine were tested for antibody to 1997-2004 human H5N1 viruses. Antibody responses to 3 doses of nonadjuvanted vaccine were poor and were higher after MF59-adjuvanted vaccine, with seroconversion rates to A/HongKong/156/97, A/HongKong/213/03, A/Thailand/16/04, and A/Vietnam/1203/04 of 100% (P < .0001), 100% (P < .0001), 71% (P = .0004), and 43% (P = .0128) in 14 subjects, respectively, compared with 27%, 27%, 0%, and 0% in 11 who received nonadjuvanted vaccine. These findings have implications for the rational design of pandemic vaccines against influenza H5.

Major Neutralizing Sites on Vaccinia Virus Glycoprotein B5 Are Exposed Differently on Variola Virus Ortholog B6▿

PubMed Central

Aldaz-Carroll, Lydia; Xiao, Yuhong; Whitbeck, J. Charles; de Leon, Manuel Ponce; Lou, Huan; Kim, Mikyung; Yu, Jessica; Reinherz, Ellis L.; Isaacs, Stuart N.; Eisenberg, Roselyn J.; Cohen, Gary H.

2007-01-01

Immunization against smallpox (variola virus) with Dryvax, a live vaccinia virus (VV), was effective, but now safety is a major concern. To overcome this issue, subunit vaccines composed of VV envelope proteins from both forms of infectious virions, including the extracellular enveloped virion (EV) protein B5, are being developed. However, since B5 has 23 amino acid differences compared with its B6 variola virus homologue, B6 might be a better choice for such a strategy. Therefore, we compared the properties of both proteins using a panel of monoclonal antibodies (MAbs) to B5 that we had previously characterized and grouped according to structural and functional properties. The B6 gene was obtained from the Centers for Disease Control and Prevention, and the ectodomain was cloned and expressed in baculovirus as previously done with B5, allowing us to compare the antigenic properties of the proteins. Polyclonal antibodies to B5 or B6 cross-reacted with the heterologous protein, and 16 of 26 anti-B5 MAbs cross-reacted with B6. Importantly, 10 anti-B5 MAbs did not cross-react with B6. Of these, three have important anti-VV biologic properties, including their ability to neutralize EV infectivity and block comet formation. Here, we found that one of these three MAbs protected mice from a lethal VV challenge by passive immunization. Thus, epitopes that are present on B5 but not on B6 would generate an antibody response that would not recognize B6. Assuming that B6 contains similar variola virus-specific epitopes, our data suggest that a subunit vaccine using the variola virus homologues might exhibit improved protective efficacy against smallpox. PMID:17522205

Major neutralizing sites on vaccinia virus glycoprotein B5 are exposed differently on variola virus ortholog B6.

PubMed

Aldaz-Carroll, Lydia; Xiao, Yuhong; Whitbeck, J Charles; de Leon, Manuel Ponce; Lou, Huan; Kim, Mikyung; Yu, Jessica; Reinherz, Ellis L; Isaacs, Stuart N; Eisenberg, Roselyn J; Cohen, Gary H

2007-08-01

Immunization against smallpox (variola virus) with Dryvax, a live vaccinia virus (VV), was effective, but now safety is a major concern. To overcome this issue, subunit vaccines composed of VV envelope proteins from both forms of infectious virions, including the extracellular enveloped virion (EV) protein B5, are being developed. However, since B5 has 23 amino acid differences compared with its B6 variola virus homologue, B6 might be a better choice for such a strategy. Therefore, we compared the properties of both proteins using a panel of monoclonal antibodies (MAbs) to B5 that we had previously characterized and grouped according to structural and functional properties. The B6 gene was obtained from the Centers for Disease Control and Prevention, and the ectodomain was cloned and expressed in baculovirus as previously done with B5, allowing us to compare the antigenic properties of the proteins. Polyclonal antibodies to B5 or B6 cross-reacted with the heterologous protein, and 16 of 26 anti-B5 MAbs cross-reacted with B6. Importantly, 10 anti-B5 MAbs did not cross-react with B6. Of these, three have important anti-VV biologic properties, including their ability to neutralize EV infectivity and block comet formation. Here, we found that one of these three MAbs protected mice from a lethal VV challenge by passive immunization. Thus, epitopes that are present on B5 but not on B6 would generate an antibody response that would not recognize B6. Assuming that B6 contains similar variola virus-specific epitopes, our data suggest that a subunit vaccine using the variola virus homologues might exhibit improved protective efficacy against smallpox.

Synthesis and properties of nanocrystalline copper indium oxide thin films deposited by Rf magnetron sputtering.

PubMed

Singh, Mandeep; Singh, V N; Mehta, B R

2008-08-01

Nanocrystalline copper indium oxide (CuInO2) thin films with particle size ranging from 25 nm to 71 nm have been synthesized from a composite target using reactive Rf magnetron sputtering technique. X-ray photoelectron spectroscopy (XPS) combined with glancing angle X-ray diffraction (GAXRD) analysis confirmed the presence of delafossite CuInO2 phase in these films. The optical absorption studies show the presence of two direct band gaps at 3.3 and 4.3 eV, respectively. The resistance versus temperature measurements show thermally activated hopping with activation energy of 0.84 eV to be the conduction mechanism.

Determinants of Vaccination Coverage and Consequences for Rabies Control in Bali, Indonesia.

PubMed

Arief, Riana A; Hampson, Katie; Jatikusumah, Andri; Widyastuti, Maria D W; Sunandar; Basri, Chaerul; Putra, Anak A G; Willyanto, Iwan; Estoepangestie, Agnes T S; Mardiana, I W; Kesuma, I K G N; Sumantra, I P; Doherty, Paul F; Salman, M D; Gilbert, Jeff; Unger, Fred

2016-01-01

Maintaining high vaccination coverage is key to successful rabies control, but mass dog vaccination can be challenging and population turnover erodes coverage. Declines in rabies incidence following successive island-wide vaccination campaigns in Bali suggest that prospects for controlling and ultimately eliminating rabies are good. Rabies, however, has continued to circulate at low levels. In the push to eliminate rabies from Bali, high coverage needs to be maintained across all areas of the island. We carried out door-to-door (DTD) questionnaire surveys ( n  = 10,352 dog-owning households) and photographic mark-recapture surveys (536 line transects, 2,597 observations of free-roaming dogs) in 2011-2012 to estimate dog population sizes and assess rabies vaccination coverage and dog demographic characteristics in Bali, Indonesia. The median number of dogs per subvillage unit ( banjar ) was 43 (range 0-307) for owned dogs estimated from the DTD survey and 17 (range 0-83) for unconfined dogs (including both owned and unowned) from transects. Vaccination coverage of owned dogs was significantly higher in adults (91.4%) compared to juveniles (<1 year, 43.9%), likely due to insufficient targeting of pups and from puppies born subsequent to vaccination campaigns. Juveniles had a 10-70 times greater risk of not being vaccinated in urban, suburban, and rural areas [combined odds ratios (ORs): 9.9-71.1, 95% CI: 8.6-96.0]. Free-roaming owned dogs were also 2-3 times more likely to be not vaccinated compared to those confined (combined Ors: 1.9-3.6, 95% CI: 1.4-5.4), with more dogs being confined in urban (71.2%) than in suburban (16.1%) and rural areas (8.0%). Vaccination coverage estimates from transects were also much lower (30.9%) than household surveys (83.6%), possibly due to loss of collars used to identify the vaccination status of free-roaming dogs, but these unconfined dogs may also include dogs that were unowned or more difficult to vaccinate. Overall, coverage levels were high in the owned dog population, but for future campaigns in Bali to have the highest chance of eliminating rabies, concerted effort should be made to vaccinate free-roaming dogs particularly in suburban and rural areas, with advertising to ensure that owners vaccinate pups. Long-lasting, cheap, and quick methods are needed to mark vaccinated animals and reassure communities of the reach of vaccination campaigns.

Determinants of Vaccination Coverage and Consequences for Rabies Control in Bali, Indonesia

PubMed Central

Arief, Riana A.; Hampson, Katie; Jatikusumah, Andri; Widyastuti, Maria D. W.; Sunandar; Basri, Chaerul; Putra, Anak A. G.; Willyanto, Iwan; Estoepangestie, Agnes T. S.; Mardiana, I. W.; Kesuma, I. K. G. N.; Sumantra, I. P.; Doherty, Paul F.; Salman, M. D.; Gilbert, Jeff; Unger, Fred

2017-01-01

Maintaining high vaccination coverage is key to successful rabies control, but mass dog vaccination can be challenging and population turnover erodes coverage. Declines in rabies incidence following successive island-wide vaccination campaigns in Bali suggest that prospects for controlling and ultimately eliminating rabies are good. Rabies, however, has continued to circulate at low levels. In the push to eliminate rabies from Bali, high coverage needs to be maintained across all areas of the island. We carried out door-to-door (DTD) questionnaire surveys (n = 10,352 dog-owning households) and photographic mark–recapture surveys (536 line transects, 2,597 observations of free-roaming dogs) in 2011–2012 to estimate dog population sizes and assess rabies vaccination coverage and dog demographic characteristics in Bali, Indonesia. The median number of dogs per subvillage unit (banjar) was 43 (range 0–307) for owned dogs estimated from the DTD survey and 17 (range 0–83) for unconfined dogs (including both owned and unowned) from transects. Vaccination coverage of owned dogs was significantly higher in adults (91.4%) compared to juveniles (<1 year, 43.9%), likely due to insufficient targeting of pups and from puppies born subsequent to vaccination campaigns. Juveniles had a 10–70 times greater risk of not being vaccinated in urban, suburban, and rural areas [combined odds ratios (ORs): 9.9–71.1, 95% CI: 8.6–96.0]. Free-roaming owned dogs were also 2–3 times more likely to be not vaccinated compared to those confined (combined Ors: 1.9–3.6, 95% CI: 1.4–5.4), with more dogs being confined in urban (71.2%) than in suburban (16.1%) and rural areas (8.0%). Vaccination coverage estimates from transects were also much lower (30.9%) than household surveys (83.6%), possibly due to loss of collars used to identify the vaccination status of free-roaming dogs, but these unconfined dogs may also include dogs that were unowned or more difficult to vaccinate. Overall, coverage levels were high in the owned dog population, but for future campaigns in Bali to have the highest chance of eliminating rabies, concerted effort should be made to vaccinate free-roaming dogs particularly in suburban and rural areas, with advertising to ensure that owners vaccinate pups. Long-lasting, cheap, and quick methods are needed to mark vaccinated animals and reassure communities of the reach of vaccination campaigns. PMID:28119919

Electronic structure of layered ferroelectric high-k titanate Pr2Ti2O7

NASA Astrophysics Data System (ADS)

Atuchin, V. V.; Gavrilova, T. A.; Grivel, J.-C.; Kesler, V. G.; Troitskaia, I. B.

2012-11-01

The spectroscopic parameters and electronic structure of binary titanate Pr2Ti2O7 have been studied by IR-, Raman and X-ray photoelectron spectroscopy (XPS) for the powder sample prepared by solid state synthesis. The spectral features of valence band and all constituent element core levels have been considered. The Auger parameters of titanium and oxygen in Pr2Ti2O7 have been determined as αTi=872.8 and αO=1042.3 eV. Variations of cation-anion bond ionicity have been discussed using binding energy differences ΔTi=(BE O 1s-BE Ti 2p3/2)=71.6 eV and ΔPr=BE(Pr 3d5/2)-BE(O 1s)=403.8 eV as key parameters in comparison with those of other titanium- and praseodymium-bearing oxides.

Catalytic activity of Cu4-cluster to adsorb H2S gas: h-BN nanosheet

NASA Astrophysics Data System (ADS)

Kansara, Shivam; Gupta, Sanjeev K.; Sonvane, Yogesh

2018-05-01

We have investigated the electronic properties, adsorptions strength and charge transfer using first principles calculations using density functional theory (DFT). The hexagonal boron nitride (h-BN) substrate shows metallic behavior, which helps to enhance the absorption process. The adsorption of three different orientations (S, D and T) of the H2S gas molecules to analyze the maximum adsorption strength from them onto a copper cluster (Cu4) based on h-BN nanosheet. The maximum adsorption energy of the H2S gas molecule is -1.50 eV for the S orientation and for D and U, it is -0.71 eV and -0.78 eV, respectively. The results show that Cu4 cluster helps to capture H2S gas from the environment and results are useful for the cleaning environment from the toxic gases.

Characterization of WB/SiC Schottky Barrier Diodes Using I-V-T Method

NASA Astrophysics Data System (ADS)

Aldridge, James; Oder, Tom

2009-04-01

The importance of silicon carbide (SiC) semiconductor for high temperature and high power microelectronic device applications has long been established. We have fabricated SiC Schottky barrier diodes using tungsten boride (WB) as the Schottky contact. The diodes were characterized using the current-voltage-temperature method. The sample was mounted on a heated stage and the temperature varied from about 25 ^oC to 300 ^oC at intervals of 25 ^oC. From the Richardson's plot, we obtained an energy barrier height of 0.96 eV and a Richardson's constant of 71.2 AK-1cm-2. Using the modified Richardson's plot, we obtained a barrier height of 1.01 eV. From the variation of the ideality factor and the temperature, we determined a characteristic energy of 0.02 eV to 0.04 eV across the range of the measurement temperature. This implies that thermionic emission is dominant in the low measurement temperature range. Our results confirm the excellent thermal stability of WB/SiC Schottky barrier diodes.

Smallpox vaccination and adverse reactions. Guidance for clinicians.

PubMed

Cono, Joanne; Casey, Christine G; Bell, David M

2003-02-21

The guidance in this report is for evaluation and treatment of patients with complications from smallpox vaccination in the preoutbreak setting. Information is also included related to reporting adverse events and seeking specialized consultation and therapies for these events. The frequencies of smallpox vaccine-associated adverse events were identified in studies of the 1960s. Because of the unknown prevalence of risk factors among today's population, precise predictions of adverse reaction rates after smallpox vaccination are unavailable. The majority of adverse events are minor, but the less-frequent serious adverse reactions require immediate evaluation for diagnosis and treatment. Agents for treatment of certain vaccine-associated severe adverse reactions are vaccinia immune globulin (VIG), the first-line therapy, and cidofovir, the second-line therapy. These agents will be available under Investigational New Drug (IND) protocols from CDC and the U.S. Department of Defense (DoD). Smallpox vaccination in the preoutbreak setting is contraindicated for persons who have the following conditions or have a close contact with the following conditions: 1) a history of atopic dermatitis (commonly referred to as eczema), irrespective of disease severity or activity; 2) active acute, chronic, or exfoliative skin conditions that disrupt the epidermis; 3) pregnant women or women who desire to become pregnant in the 28 days after vaccination; and 4) persons who are immunocompromised as a result of human immunodeficiency virus or acquired immunodeficiency syndrome, autoimmune conditions, cancer, radiation treatment, immunosuppressive medications, or other immunodeficiencies. Additional contraindications that apply only to vaccination candidates but do not include their close contacts are persons with smallpox vaccine-component allergies, women who are breastfeeding, those taking topical ocular steroid medications, those with moderate-to-severe intercurrent illness, and persons aged < 18 years. In addition, history of Darier disease is a contraindication in a potential vaccinee and a contraindication if a household contact has active disease. In the event of a smallpox outbreak, outbreak-specific guidance will be disseminated by CDC regarding populations to be vaccinated and specific contraindications to vaccination. Vaccinia can be transmitted from a vaccinee's unhealed vaccination site to other persons by close contact and can lead to the same adverse events as in the vaccinee. To avoid transmission of vaccinia virus (found in the smallpox vaccine) from vaccinees to their close contacts, vaccinees should wash their hands with warm soapy water or hand rubs containing > or = 60% alcohol immediately after they touch their vaccination site or change their vaccination site bandages. Used bandages should be placed in sealed plastic bags and can be disposed of in household trash. Smallpox vaccine adverse reactions are diagnosed on the basis of clinical examination and history, and certain reactions can be managed by observation and supportive care. Adverse reactions that are usually self-limited include fever, headache, fatigue, myalgia, chills, local skin reactions, nonspecific rashes, erythema multiforme, lymphadenopathy, and pain at the vaccination site. Other reactions are most often diagnosed through a complete history and physical and might require additional therapies (e.g., VIG, a first-line therapy and cidofovir, a second-line therapy). Adverse reactions that might require further evaluation or therapy include inadvertent inoculation, generalized vaccinia (GV), eczema vaccinatum (EV), progressive vaccinia (PV), postvaccinial central nervous system disease, and fetal vaccinia. Inadvertent inoculation occurs when vaccinia virus is transferred from a vaccination site to a second location on the vaccinee or to a close contact. Usually, this condition is self-limited and no additional care is needed. Inoculations of the eye and eyelid require evaluation by an ophthalmologist and might require therapy with topical antiviral or antibacterial medications, VIG, or topical steroids. GV is characterized by a disseminated maculopapular or vesicular rash, frequently on an erythematous base, which usually occurs 6-9 days after first-time vaccination. This condition is usually self-limited and benign, although treatment with VIG might be required when the patient is systemically ill or found to have an underlying immunocompromising condition. Infection-control precautions should be used to prevent secondary transmission and nosocomial infection. EV occurs among persons with a history of atopic dermatitis (eczema), irrespective of disease severity or activity, and is a localized or generalized papular, vesicular, or pustular rash, which can occur anywhere on the body, with a predilection for areas of previous atopic dermatitis lesions. Patients with EV are often systemically ill and usually require VIG. Infection-control precautions should be used to prevent secondary transmission and nosocomial infection. PV is a rare, severe, and often fatal complication among persons with immunodeficiencies, characterized by painless progressive necrosis at the vaccination site with or without metastases to distant sites (e.g., skin, bones, and other viscera). This disease carries a high mortality rate, and management of PV should include aggressive therapy with VIG, intensive monitoring, and tertiary-level supportive care. Anecdotal experience suggests that, despite treatment with VIG, persons with cell-mediated immune deficits have a poorer prognosis than those with humoral deficits. Infection-control precautions should be used to prevent secondary transmission and nosocomial infection. Central nervous system disease, which includes postvaccinial encephalopathy (PVE) and postvaccinial encephalomyelitis (or encephalitis) (PVEM), occur after smallpox vaccination. PVE is most common among infants aged < 12 months. Clinical symptoms of central nervous system disease indicate cerebral or cerebellar dysfunction with headache, fever, vomiting, altered mental status, lethargy, seizures, and coma. PVE and PVEM are not believed to be a result of replicating vaccinia virus and are diagnoses of exclusion. Although no specific therapy exists for PVE or PVEM, supportive care, anticonvulsants, and intensive care might be required. Fetal vaccinia, resulting from vaccinial transmission from mother to fetus, is a rare, but serious, complication of smallpox vaccination during pregnancy or shortly before conception. It is manifested by skin lesions and organ involvement, and often results in fetal or neonatal death. No known reliable intrauterine diagnostic test is available to confirm fetal infection. Given the rarity of congenital vaccinia among live-born infants, vaccination during pregnancy should not ordinarily be a reason to consider termination of pregnancy. No known indication exists for routine, prophylactic use of VIG in an unintentionally vaccinated pregnant woman; however, VIG should not be withheld if a pregnant woman develops a condition where VIG is needed. Other less-common adverse events after smallpox vaccination have been reported to occur in temporal association with smallpox vaccination, but causality has not been established. Prophylactic treatment with VIG is not recommended for persons or close contacts with contraindications to smallpox vaccination who are inadvertently inoculated or exposed. These persons should be followed closely for early recognition of adverse reactions that might develop, and clinicians are encouraged to enroll these persons in the CDC registry by calling the Clinician Information Line at 877-554-4625. To request clinical consultation and IND therapies for vaccinia-related adverse reactions for civilians, contact your state health department or CDC's Clinician Information Line (877-554-4625). Clinical evaluation tools are available at http.//www.bt.cdc.gov/agent/smallpox/vaccination/clineval. Clinical specimen-collection guidance is available at http://www.bt.cdc.gov/agent/smallpox/vaccination/vaccinia-specimen-collection.asp. Physicians at military medical facilities can request VIG or cidofovir by calling the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) at 301-619-2257 or 888-USA-RIID.

Effects of the introduction of new vaccines in Guinea-Bissau on vaccine coverage, vaccine timeliness, and child survival: an observational study.

PubMed

Fisker, Ane B; Hornshøj, Linda; Rodrigues, Amabelia; Balde, Ibraima; Fernandes, Manuel; Benn, Christine S; Aaby, Peter

2014-08-01

In 2008, the GAVI Alliance funded the introduction of new vaccines (including pentavalent diphtheria-tetanus-pertussis [DTP] plus hepatitis B and Haemophilus influenzae type b antigens) in Guinea-Bissau. The introduction was accompanied by increased vaccination outreach services and a more restrictive wastage policy, including only vaccinating children younger than 12 months. We assessed coverage of all vaccines in the Expanded Program on Immunizations before and after the new vaccines' introduction, and the implications on child survival. This observational cohort study used data from the Bandim Health Project, which has monitored vaccination status and mortality in randomly selected village clusters in Guinea-Bissau since 1990. We assessed the change in vaccination coverage using cohort data from children born in 2007 and 2009; analysed the proportion of children who received measles vaccine after 12 months of age using data from 1999-2006; and compared child mortality after age 12 months in children who had received measles vaccine and those who had not using data from 1999 to 2006. The proportion of children who were fully vaccinated by 12 months of age was 53% (468 of 878) in the 2007 cohort and 53% (467 of 879) in the 2009 cohort (relative risk [RR] 1·00, 95% CI 0·89-1·11). Coverage of DTP-3 and pentavalent-3 increased from 73% (644 of 878) in 2007 to 81% (712 of 879) in 2009 (RR 1·10, 95% CI 1·04 -1·17); by contrast, the coverage of measles vaccination declined from 71% (620 of 878) to 66% (577 of 879; RR 0·93, 0·85-1·01). The effect of the changes was significantly different for DTP-3 coverage compared with measles vaccine coverage (p=0·002). After 12 months of age, the adjusted mortality rate ratio was 0·71 (95% CI 0·56-0·90) for children who had received measles vaccine compared with those who had not (0·59 [0·43-0·80] for girls and 0·87 [0·62-1·23] for boys). The introduction of the new vaccination programme in 2008 was associated with increased coverage of DTP, but decreased coverage of measles vaccine. In 1999-2006, child mortality was higher in children who had not received measles vaccine than in those who had. DANIDA, European Research Council, the Danish Independent Research Council, European Union FP7 via OPTIMUNISE, and Danish National Research Foundation. Copyright © 2014 Fisker et al. Open Access article distributed under the terms of CC BY. Published by .. All rights reserved.

Effect of Spaceflight on Vestibulo-Ocular Reflexes (VORS) During Angular Head Motion

NASA Technical Reports Server (NTRS)

Tomko, David L.; Clifford, James O.; Hargens, Alan R. (Technical Monitor)

1996-01-01

Vestibulo-ocular reflexes (VORs) stabilize the eyes during head motion. During Earth-horizontal (E-H) pitch or roll rotations, canal and otolith stimuli occur together. In Earth-vertical (E-V) pitch or roll rotations, only canal signals occur. In cats and squirrel monkeys, pitch/roll VOR gains during E-H motion have been shown to be larger than during E-V motion, implying that otolith modulation plays a role in producing angular VORs (aVORs). The present experiments replicated this experiment in rhesus monkeys, and examined how spaceflight affected AVOR gain. During yaw, pitch and roll (0.5 - 1.0 Hz, 40-50 deg/s pk) motion, 3-d eye movements were recorded in four Rhesus monkeys using scleral search coils. Mean E-H and E-V pitch VOR gains were 0.85 and 0.71. Torsional VOR gains during E-H and E-V were 0.47 and 0.39. Gains are more compensatory during E-H pitch or roll. Two of the four monkeys flew for 11 days on the COSMOS 2229 Biosatellite. E-H pitch VOR gains were attenuated immediately (72 hrs) post-flight, with similar values to pre-flight E-V pitch gains. Horizontal yaw VOR gains were similar pre- and post-flight.

Mothers' knowledge about EPI and its relation with age-appropriate vaccination of infants in peri-urban Karachi.

PubMed

Siddiqi, Nazish; Siddiqi, Azfar-e-alam; Nisar, Nighat; Khan, Altaf

2010-11-01

To evaluate the relation between the knowledge of mothers about EPI vaccinations and their infant's coverage. Effect of other socio-demographic variables on mothers' knowledge and child's coverage was also assessed. A cross-sectional survey was conducted, utilizing World Health Organization's thirty-cluster sampling strategy. All households with at least one infant were considered eligible. After obtaining verbal consent, the mother was interviewed to assess her knowledge and attitudes towards EPI vaccination. Infant's coverage status was verified by checking EPI card or verbal inquiry. A knowledge score was developed by summing all correct answers. A total of 210 mothers (7 per cluster) were identified and interviewed. The number and proportion of mothers correctly identifying the seven EPI diseases were as follows; Tuberculosis 57 (27.1%), Diphtheria 53 (25.2%), Pertussis 71 (33.8%), Tetanus 70 (33.3%), Measles 85 (40.5%), Polio 91 (43.3%) and Hepatitis B 65 (31.0%). Only ninety four (44.8%) children were appropriately vaccinated for their age. In the multivariate model, mothers' knowledge was not significantly associated with appropriate vaccination of their children (p = 0.22), however, mothers' education was found to be significant (p < 0.001). Mothers' knowledge about EPI vaccination in peri-urban Karachi was quite low and not associated with their children's EPI coverage. Mothers' educational status, however, was significantly associated with Child's coverage. This finding depicts a better health seeking behaviour of a more educated mother.

Do HIV-positive adult immigrants need to be screened for measles-mumps-rubella and varicella zoster virus immunization?

PubMed

Llenas-García, Jara; Rubio, Rafael; Hernando, Asunción; Arrazola, Pilar; Pulido, Federico

2013-08-01

A systematic screening for measles, mumps, rubella (MMR) and varicella zoster virus (VZV) in HIV-positive adult immigrants in Spain was evaluated, and factors associated with MMR and VZV vaccines' indication were studied. Every HIV-positive immigrant was tested for VZV and MMR-IgG. MMR vaccine was indicated to patients with lymphocytes CD4+ >200 cells/mm³ and a negative measles-IgG, a negative mumps-IgG and/or a negative rubella-IgG. VZV vaccine was indicated to every VZV-IgG negative patient with CD4+ >400 cells/mm³. In total, 289 patients were screened; seroprevalence was 95.2%, 92.2%, 70.3% and 89.3% for VZV, measles, mumps and rubella IgG, respectively. Having a negative VZV-IgG was statistically associated with coming from sub-Saharan Africa (prevalence ratio [PR]: 6.52; 95% CI: 1.71-24.84; p=0.006), while having secondary education was a protective factor (PR: 0.25; 95% CI: 0.07-0.97; p=0.045). Fourteen patients (4.8%) had indication of VZV vaccine; vaccination was feasible in 21.4% of them at first visit. Eighty-one patients (29.7%) had indication of MMR vaccine, most of them due to mumps-IgG negative (53.1%) or rubella-IgG negative (24.7%). Age < 30 years at first visit was the only factor statistically associated with MMR vaccine indication (PR: 1.47; 95% CI: 1.02-2.11; p=0.04). According to CD4+ cell counts, vaccination was feasible in 71.6% of patients at first visit. In conclusion, more than a third of HIV-infected immigrant patients are susceptible to at least one easily preventable infectious disease. Especial attention should be given to immigrant women of childbearing age.

Population immunity to measles virus and the effect of HIV-1 infection after a mass measles vaccination campaign in Lusaka, Zambia: a cross-sectional survey.

PubMed

Lowther, Sara A; Curriero, Frank C; Kalish, Brian T; Shields, Timothy M; Monze, Mwaka; Moss, William J

2009-03-21

Measles control efforts are hindered by challenges in sustaining high vaccination coverage, waning immunity in HIV-1-infected children, and clustering of susceptible individuals. Our aim was to assess population immunity to measles virus after a mass vaccination campaign in a region with high HIV prevalence. 3 years after a measles supplemental immunisation activity (SIA), we undertook a cross-sectional survey in Lusaka, Zambia. Households were randomly selected from a satellite image. Children aged 9 months to 5 years from selected households were eligible for enrolment. A questionnaire was administered to the children's caregivers to obtain information about measles vaccination history and history of measles. Oral fluid samples were obtained from children and tested for antibodies to measles virus and HIV-1 by EIA. 1015 children from 668 residences provided adequate specimens. 853 (84%) children had a history of measles vaccination according to either caregiver report or immunisation card. 679 children (67%) had antibodies to measles virus, and 64 (6%) children had antibodies to HIV-1. Children with antibodies to HIV-1 were as likely to have no history of measles vaccination as those without antibodies to HIV-1 (odds ratio [OR] 1.17, 95% CI 0.57-2.41). Children without measles antibodies were more likely to have never received measles vaccine than those with antibodies (adjusted OR 2.50, 1.69-3.71). In vaccinated children, 33 (61%) of 54 children with antibodies to HIV-1 also had antibodies to measles virus, compared with 568 (71%) of 796 children without antibodies to HIV-1 (p=0.1). 3 years after an SIA, population immunity to measles was insufficient to interrupt measles virus transmission. The use of oral fluid and satellite images for sampling are potential methods to assess population immunity and the timing of SIAs.

Parental perceptions surrounding polio and self-reported non-participation in polio supplementary immunization activities in Karachi, Pakistan: a mixed methods study

PubMed Central

Khowaja, Asif Raza; Khan, Sher Ali; Nizam, Naveeda; Omer, Saad Bin

2012-01-01

Abstract Objective To assess parent’s knowledge and perceptions surrounding polio and polio vaccination, self-reported participation in polio supplementary immunization activities (SIAs) targeting children aged < 5 years, and reasons for non-participation. Methods The mixed methods study began with a cross-sectional survey in Karachi, Pakistan. A structured questionnaire was administered to assess parental knowledge of polio and participation in polio SIAs conducted in September and October 2011. Additionally, 30 parents of Pashtun ethnicity (a high-risk group) who refused to vaccinate their children were interviewed in depth to determine why. Descriptive and bivariate analyses by ethnic and socioeconomic group were performed for quantitative data; thematic analysis was conducted for qualitative interviews with Pashtun parents. Findings Of 1017 parents surveyed, 412 (41%) had never heard of polio; 132 (13%) did not participate in one SIA and 157 (15.4%) did not participate in either SIA. Among non-participants, 34 (21.6%) reported not having been contacted by a vaccinator; 116 (73.9%) reported having refused to participate, and 7 (4.5%) reported that the child was absent from home when the vaccinator visited. Refusals clustered in low-income Pashtun (43/441; 9.8%) and high-income families of any ethnic background (71/153; 46.4%). Low-income Pashtuns were more likely to not have participated in polio SIAs than low-income non-Pashtuns (odds ratio, OR: 7.1; 95% confidence interval, CI: 3.47–14.5). Reasons commonly cited among Pashtuns for refusing vaccination included fear of sterility; lack of faith in the polio vaccine; scepticism about the vaccination programme, and fear that the vaccine might contain religiously forbidden ingredients. Conclusion In Karachi, interruption of polio transmission requires integrated and participatory community interventions targeting high-risk populations. PMID:23226894

Update on Rotarix: an oral human rotavirus vaccine.

PubMed

O'Ryan, Miguel; Linhares, Alexandre C

2009-12-01

Worldwide, rotaviruses are the single most important agents of severe gastroenteritis in infants and young children. Globally, it is estimated that every year rotavirus gastroenteritis causes more than 125 million episodes of diarrhea and nearly 527,000 deaths, mainly in developing countries. The development of new effective and safe rotavirus vaccines was recognized as the most effective intervention strategy that could yield a significant impact on the burden of rotavirus disease. Rotarix is an oral live-attenuated human rotavirus vaccine containing a single G1P[8] strain. The first oral dose may be administered as early as 6 weeks of age, with a minimum interval of 4 weeks prior to second dose; the vaccination course should be completed by the age of 24 weeks according to the manufacturer. In the USA, the upper age limit for the second dose has recently been recommended at 32 weeks of age by the Advisory Committee on Immunization Practices. The development program for Rotarix including Phase I, II and III multicenter studies involving over 100,000 infants has been established in Latin America, Europe, Asia and Africa. The vaccine proved to be well tolerated, immunogenic, efficacious, safe and not associated with intussusception. It provided 85-96% protection against severe rotavirus gastroenteritis caused by G1 and non-G1 serotypes in Latin American and European clinical trials; and of public health importance, Rotarix reduced hospitalizations of all-cause gastroenteritis by 40 and 75%, respectively. Efficacy against G2P[4] strains ranged from 41% in Latin America to 81% in Europe. In the former, Rotarix afforded sustained high protection (80.5%; 95% CI: 71.3-87.1) against severe rotavirus gastroenteritis during the first 2 years of life in a region with a changing pattern of wild-type rotavirus circulation. In a recently completed vaccine trial in South Africa and Malawi, Rotarix showed an overall efficacy of 61.2% (95% CI: 44.0-73.2) by 1 year of age. Although these rates are lower than those from developed and middle-income countries, they look promising given the lack of other effective interventions. With the expanding introduction of rotavirus vaccines into national immunization programs, postmarketing surveillance should be conducted to measure the impact of rotavirus vaccination, as well as continued monitoring of circulating rotavirus strains.

A new silicon phase with direct band gap and novel optoelectronic properties

DOE PAGES

Guo, Yaguang; Wang, Qian; Kawazoe, Yoshiyuki; ...

2015-09-23

Due to the compatibility with the well-developed Si-based semiconductor industry, there is considerable interest in developing silicon structures with direct energy band gaps for effective sunlight harvesting. In this paper, using silicon triangles as the building block, we propose a new silicon allotrope with a direct band gap of 0.61 eV, which is dynamically, thermally and mechanically stable. Symmetry group analysis further suggests that dipole transition at the direct band gap is allowed. Additionally, this new allotrope displays large carrier mobility (~10 4 cm/V · s) at room temperature and a low mass density (1.71 g/cm 3), making it amore » promising material for optoelectronic applications.« less

Development of Procedures for Nondestructive Testing of Concrete Structures. Report 2. Feasibility of Sonic Pulse-Echo Technique

DTIC Science & Technology

1980-04-01

7Z F be dm trvt w i T .3 71`ý EV ~ 0 0 1-0 houws for Ofce, Che oF Engineecu, U. S. A~my WuLngo ’D. C. 20314 Uawo Work Units 31553 and 31138 CD .80 𔄀...PAGE BEFORE CO.MPLETING FORM 1ýRýRý 2. GAýOVT ACCESSION No. 3. RECIPIENT’S CATALOG NUMBER Miscellaneous ~ape -77-11 D444 4, ULE.m ,.bIftI• . 5 ...NUMBERS Structures Laboratory Work Units .. )3 and 31138 P. 0. Box 631, Vicksburg, Miss. 39180 I 1 CONTROLLING OFFICE NAME AND ADDRESS Office, Chief of

Coxsackievirus B4 as a Causative Agent of Diabetes Mellitus Type 1: Is There a Role of Inefficiently Treated Drinking Water and Sewage in Virus Spreading?

PubMed

El-Senousy, Waled M; Abdel-Moneim, Adel; Abdel-Latif, Mahmoud; El-Hefnawy, Mohamed H; Khalil, Rehab G

2018-03-01

This study proposed to detect the enterovirus (EV) infection in children with type 1 diabetes mellitus (T1D) and to assess the role of insufficiently treated water and sewage as sources of viral spreading. Three hundred and eighty-two serum specimens of children with T1D, one hundred serum specimens of children who did not suffer from T1D as control, and forty-eight water and sewage samples were screened for EV RNA using nested RT-PCR. The number of genome copies and infectious units of EVs in raw and treated sewage and water samples were investigated using real-time (RT)-PCR and plaque assay, respectively. T1D markers [Fasting blood glucose (FBG), HbA1c, and C-peptide], in addition to anti-Coxsackie A & B viruses (CVs A & B) IgG, were measured in control, T1D-negative EV (T1D-EV - ), and T1D-positive EV (T1D-EV + ) children specimens. The prevalence of EV genome was significantly higher in diabetic children (26.2%, 100 out of 382) than the control children (0%, 0 out of 100). FBG and HbA1c in T1D-EV - and T1D-EV + children specimens were significantly higher than those in the control group, while c-peptide in T1D-EV - and T1D-EV + children specimens was significantly lower than that in the control (n = 100; p < 0.001). Positivity of anti-CVs A & B IgG was 70.7, 6.7, and 22.9% in T1D-EV + , T1D-EV - , and control children specimens, respectively. The prevalence of EV genome in drinking water and treated sewage samples was 25 and 33.3%, respectively. The prevalence of EV infectious units in drinking water and treated sewage samples was 8.5 and 25%, respectively. Quantification assays were performed to assess the capabilities of both wastewater treatment plants (WWTPs) and water treatment plants (WTPs) to remove EV. The reduction of EV genome in Zenin WWTP ranged from 2 to 4 log 10 , while the reduction of EV infectious units ranged from 1 to 4 log 10 . The reduction of EV genome in El-Giza WTP ranged from 1 to 3 log 10 , while the reduction of EV infectious units ranged from 1 to 2 log 10 . This capability of reduction did not prevent the appearance of infectious EV in treated sewage and drinking water. Plaque purification was performed for isolation of separate EV isolates from treated and untreated water and sewage samples. Characterization of the EV amplicons by RT-PCR followed by sequencing of these isolates revealed high homology (97%) with human coxsackievirus B4 (CV B4) in 60% of the isolates, while the rest of the isolates belonged to poliovirus type 1 and type 2 vaccine strains. On the other hand, characterization of the EV amplicons by RT-PCR followed by sequencing for T1D-EV + children specimens indicated that all samples contained CV B4 with the same sequence characterized in the environmental samples. CV B4-contaminated drinking water or treated sewage may play a role as a causative agent of T1D in children.

Prediction of linear B-cell epitopes of hepatitis C virus for vaccine development

PubMed Central

2015-01-01

Background High genetic heterogeneity in the hepatitis C virus (HCV) is the major challenge of the development of an effective vaccine. Existing studies for developing HCV vaccines have mainly focused on T-cell immune response. However, identification of linear B-cell epitopes that can stimulate B-cell response is one of the major tasks of peptide-based vaccine development. Owing to the variability in B-cell epitope length, the prediction of B-cell epitopes is much more complex than that of T-cell epitopes. Furthermore, the motifs of linear B-cell epitopes in different pathogens are quite different (e. g. HCV and hepatitis B virus). To cope with this challenge, this work aims to propose an HCV-customized sequence-based prediction method to identify B-cell epitopes of HCV. Results This work establishes an experimentally verified dataset comprising the B-cell response of HCV dataset consisting of 774 linear B-cell epitopes and 774 non B-cell epitopes from the Immune Epitope Database. An interpretable rule mining system of B-cell epitopes (IRMS-BE) is proposed to select informative physicochemical properties (PCPs) and then extracts several if-then rule-based knowledge for identifying B-cell epitopes. A web server Bcell-HCV was implemented using an SVM with the 34 informative PCPs, which achieved a training accuracy of 79.7% and test accuracy of 70.7% better than the SVM-based methods for identifying B-cell epitopes of HCV and the two general-purpose methods. This work performs advanced analysis of the 34 informative properties, and the results indicate that the most effective property is the alpha-helix structure of epitopes, which influences the connection between host cells and the E2 proteins of HCV. Furthermore, 12 interpretable rules are acquired from top-five PCPs and achieve a sensitivity of 75.6% and specificity of 71.3%. Finally, a conserved promising vaccine candidate, PDREMVLYQE, is identified for inclusion in a vaccine against HCV. Conclusions This work proposes an interpretable rule mining system IRMS-BE for extracting interpretable rules using informative physicochemical properties and a web server Bcell-HCV for predicting linear B-cell epitopes of HCV. IRMS-BE may also apply to predict B-cell epitopes for other viruses, which benefits the improvement of vaccines development of these viruses without significant modification. Bcell-HCV is useful for identifying B-cell epitopes of HCV antigen to help vaccine development, which is available at http://e045.life.nctu.edu.tw/BcellHCV. PMID:26680271

New genetic associations detected in a host response study to hepatitis B vaccine.

PubMed

Davila, S; Froeling, F E M; Tan, A; Bonnard, C; Boland, G J; Snippe, H; Hibberd, M L; Seielstad, M

2010-04-01

The immune response to hepatitis B vaccination differs greatly among individuals, with 5-10% of healthy people failing to produce protective levels of antibodies. Several factors have been implicated in determining this response, chiefly individual genetic variation and age. Aiming to identify genes involved in the response to hepatitis B vaccination, a two-stage investigation of 6091 single-nucleotide polymorphisms (SNPs) in 914 immune genes was performed in an Indonesian cohort of 981 individuals showing normal levels of anti-HBs versus 665 individuals displaying undetectable levels of anti-HBs 18 months after initial dose of the vaccine. Of 275 SNPs identified in the first stage (476 normal/372 nonresponders) with P<0.05, significant associations were replicated for 25 polymorphisms in 15 genes (503 normal/295 nonresponders). We validated previous findings (HLA-DRA, rs5000563, P-value combined=5.57 x 10(-10); OR (95%CI)=0.61 (0.52-0.71)). In addition, we detected a new association outside of the human leukocyte antigen loci region that passed correction for multiple testing. This SNP is in the 3' downstream region of FOXP1, a transcription factor involved in B-cell development (P-value combined=9.2 x 10(-6); OR (95%CI)=1.38 (1.2-1.6)).These findings might help to understand the biological reasons behind vaccine failure and other aspects of variation in the immune responses of healthy individuals.

Factors that influence parental vaccination decisions for adolescents, 13 to 17 years old: National Immunization Survey-Teen, 2010.

PubMed

Dorell, Christina; Yankey, David; Kennedy, Allison; Stokley, Shannon

2013-02-01

We aim to describe factors that influence parental decisions to vaccinate their adolescents. Data from the July to December 2010 National Immunization Survey-Teen Parental Concerns Module were analyzed to determine factors that influence parental decisions to vaccinate their adolescents. Parents reported that their adolescent's health care provider recommended tetanus toxoid/tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Td/Tdap; 74.4%), meningococcal conjugate (MenACWY; 60.3%), and human papillomavirus (HPV; 71.3%). Vaccination coverage estimates were significantly higher among parents who reported receiving a provider recommendation: 85.2% versus 76.7% (Td/Tdap), 77.3% versus 49.7% (MenACWY), and 62.2% versus 21.5% (HPV). Compared with Td/Tdap and MenACWY, fewer HPV vaccination conversations included recommendations for vaccination. Other than health care providers, school requirements (46.1%), news coverage (31.2%), and family (31.0%) were most frequently reported influences on parental vaccination decisions. Many factors influence parental decisions to vaccinate their adolescents; one of the most important factors is the provider recommendation. Missed opportunities for vaccination persist when strong vaccination recommendations are not given or are delayed.

Travel Characteristics and Yellow Fever Vaccine Usage Among US Global TravEpiNet Travelers Visiting Countries with Risk of Yellow Fever Virus Transmission, 2009–2011

PubMed Central

Jentes, Emily S.; Han, Pauline; Gershman, Mark D.; Rao, Sowmya R.; LaRocque, Regina C.; Staples, J. Erin; Ryan, Edward T.

2013-01-01

Yellow fever (YF) vaccine-associated serious adverse events and changing YF epidemiology have challenged healthcare providers to vaccinate only travelers whose risk of YF during travel is greater than their risk of adverse events. We describe the travel characteristics and YF vaccine use among US travelers visiting Global TravEpiNet clinics from January of 2009 to March of 2011. Of 16,660 travelers, 5,588 (34%) had itineraries to areas with risk of YF virus transmission. Of those travelers visiting one country with YF risk (N = 4,517), 71% were vaccinated at the visit, and 20% were presumed to be immune from prior vaccination. However, travelers visiting friends and relatives (odds ratio [OR] = 2.57, 95% confidence interval [95% CI] = 1.27–5.22) or going to Nigeria (OR = 3.01, 95% CI = 1.37–6.62) were significantly more likely to decline vaccination. To optimize YF vaccine use, clinicians should discuss an individual's risk–benefit assessment of vaccination and close knowledge gaps regarding vaccine use among at-risk populations. PMID:23458961

Influenza vaccination program for elderly outpatients.

PubMed

Knoell, K R; Leeds, A L

1991-02-01

The effect of pharmacist interventions on the rate at which elderly outpatients were offered influenza vaccination was studied. Pharmacists at a university-based ambulatory-care facility reviewed the medical records of a random sample of control patients over the age of 65 who had been seen during the influenza vaccination months in 1987 or 1988 or both years. The purpose was to estimate the percentage of patients who had been documented as being offered influenza vaccination. In 1989 an intervention program was undertaken consisting of inservice presentations to the facility's nursing staff, dissemination of influenza information sheets to patients upon check-in, placement of wall posters, placement of reminders in patient charts, and institution and advertisement of a vaccination clinic. At the end of the 1989 vaccination season, the records of a random sample of intervention group patients were reviewed to determine the proportion of patients who had been offered influenza virus vaccine. Of the 280 control group patients, 47% were offered influenza vaccination during 1987 and 1988. A significantly higher proportion of the 153 intervention group patients, 71%, was offered influenza vaccine during 1989. A combination of pharmacist-initiated interventions significantly increased the number of elderly patients who were offered vaccinations during scheduled clinic visits.

Active surveillance for intussusception in a phase III efficacy trial of an oral monovalent rotavirus vaccine in India.

PubMed

John, Jacob; Kawade, Anand; Rongsen-Chandola, Temsunaro; Bavdekar, Ashish; Bhandari, Nita; Taneja, Sunita; Antony, Kalpana; Bhatnagar, Veereshwar; Gupta, Arun; Kabra, Madhulika; Kang, Gagandeep

2014-08-11

Post licensure studies have identified an increased risk of intussusception following vaccination with currently licensed rotavirus vaccines, raising safety concerns generic to all rotavirus vaccines. We describe the surveillance for intussusception in a phase III clinical trial with an oral monovalent rotavirus vaccine developed from the neonatal 116E strain. Using broad screening criteria and active surveillance, the incidence of intussusception between 6 weeks and 2 years of age was measured in 4532 children who received three doses of vaccine and 2267 children who received a placebo in the clinical trial. Possible intussusceptions were evaluated with a screening ultrasonogram. An independent intussusception case adjudication committee reviewed all intussusceptions and graded them on Brighton Collaboration criteria for diagnostic certainty. We identified twenty-three intussusceptions on ultrasound from 1361 evaluated sentinel events. Eleven were of level 1 diagnostic certainty as determined by the independent intussusception case adjudication committee. None required surgical intervention, and the earliest identified intussusception was at 36 days following the third dose in a placebo recipient. Among vaccine recipients the first event of intussusception occurred 112 days after the third dose. The incidence of ultrasound-diagnosed intussusception was 200/100,000 child-years (95% CI, 120, 320) among those receiving the vaccine and 141/100,000 child-years (95% CI, 50, 310) among those receiving the placebo. The incidence rate of confirmed intussusception among vaccine recipients was 94/100,000 child-years (95% CI, 41, 185) and 71/100,000 child-years (95% CI, 15, 206) among those receiving the placebo. In this licensure study, 23 cases of intussusception were identified through an active surveillance system, but there was no temporal association with rotavirus vaccination. The use of active surveillance with broad criteria intended for ensuring safety of children participating in a trial, identified several transient intussusceptions that were of doubtful clinical significance. Copyright © 2014. Published by Elsevier Ltd.

Effectiveness and safety of immunization with live-attenuated and inactivated vaccines for pediatric liver transplantation recipients.

PubMed

Kawano, Yoshihiko; Suzuki, Michio; Kawada, Jun-ichi; Kimura, Hiroshi; Kamei, Hideya; Ohnishi, Yasuharu; Ono, Yasuyuki; Uchida, Hiroo; Ogura, Yasuhiro; Ito, Yoshinori

2015-03-17

Liver transplantation recipients are at high risk for severe complications due to infections because of being treated with immunosuppressive drugs that affect the immune system. Vaccination for liver transplantation candidates is generally recommended before surgery, but the opportunities for vaccination prior to transplantation in pediatric candidates are often limited by severe disease conditions. The participants in this study comprised 39 pediatric recipients of living donor liver transplantation performed between 2005 and 2013. Criteria for administering live-attenuated (measles, rubella, mumps, and varicella) and inactivated (hepatitis B, pertussis, and Japanese encephalitis) vaccines were as follows: (1) >1 year after transplantation; (2) no use of systemic steroids to treat acute rejection within the last 6 months; (3) serum trough concentration of tacrolimus <5 ng/mL; (4) no severe immunosuppression according to blood examinations; and (5) provision of written informed consent. Median age at transplantation was 17 months, and median period from transplantation to the beginning of immunization was 18 months. Seroprotection rates for measles, rubella, mumps, varicella, hepatitis B, pertussis, and Japanese encephalitis after post-transplant immunization were 44% (11/25), 70% (19/27), 48% (12/25), 32% (6/19), 83% (19/23), 87% (13/15), and 88% (7/8), respectively. Seroprotection rates for measles, rubella, mumps, and varicella after second vaccination for recipients with primary vaccine failure after first vaccination were 100% (8/8), 50% (1/2), 71% (5/7), and 50% (5/10), respectively. While four recipients contracted mumps and eight contracted varicella before immunization, one recipient developed varicella after immunization. No serious systemic adverse events were observed in vaccinated recipients. Seroprotection rates for measles, mumps, and varicella appeared low in children after the first post-transplantation vaccination. Immunizations with four live-attenuated and three inactivated vaccines were safe and effective for pediatric liver transplantation recipients who were not severely immunosuppressed. Copyright © 2015. Published by Elsevier Ltd.

Modeling The Economic Burden Of Adult Vaccine-Preventable Diseases In The United States.

PubMed

Ozawa, Sachiko; Portnoy, Allison; Getaneh, Hiwote; Clark, Samantha; Knoll, Maria; Bishai, David; Yang, H Keri; Patwardhan, Pallavi D

2016-11-01

Vaccines save thousands of lives in the United States every year, but many adults remain unvaccinated. Low rates of vaccine uptake lead to costs to individuals and society in terms of deaths and disabilities, which are avoidable, and they create economic losses from doctor visits, hospitalizations, and lost income. To identify the magnitude of this problem, we calculated the current economic burden that is attributable to vaccine-preventable diseases among US adults. We estimated the total remaining economic burden at approximately $9 billion (plausibility range: $4.7-$15.2 billion) in a single year, 2015, from vaccine-preventable diseases related to ten vaccines recommended for adults ages nineteen and older. Unvaccinated individuals are responsible for almost 80 percent, or $7.1 billion, of the financial burden. These results not only indicate the potential economic benefit of increasing adult immunization uptake but also highlight the value of vaccines. Policies should focus on minimizing the negative externalities or spillover effects from the choice not to be vaccinated, while preserving patient autonomy. Project HOPE—The People-to-People Health Foundation, Inc.

Perceptions and Attitudes of Patients About Adult Vaccination and Their Vaccination Status: Still a Long Way to Go?

PubMed

Ozisik, Lale; Calik Basaran, Nursel; Oz, S Gul; Sain Guven, Gulay; Durusu Tanriover, Mine

2017-06-29

BACKGROUND Immunization is one of the most effective public health measures to prevent disease, but vaccination rates in adult populations still remain below the targets. Patient and physician attitudes about vaccination are important for adult vaccination. In this study, we aimed to determine patient attitudes and perceptions about vaccination and the vaccination coverage rates of adult patients in a university hospital in Turkey. MATERIAL AND METHODS A survey was conducted between October 2014 and May 2015 at the Internal Medicine Outpatient Clinics of a university hospital. Adult patients were asked to fill out a questionnaire on their perceptions and attitudes about vaccination and their vaccination status. RESULTS We interviewed 512 patients ages 19-64 years. Eighty percent of the study population thought that adults should be vaccinated, while only 36.1% of the patients stated that vaccination was ever recommended to them in their adult life. Forty-eight percent of the patients stated that they were vaccinated at least once in their adulthood. The most commonly received vaccine was tetanus vaccine in general, while influenza vaccine was the leading vaccine among patients with chronic medical conditions. While 71.4% of the patients to whom vaccination was recommended received the vaccine, 34.9% of the patients received a vaccine without any recommendation. CONCLUSIONS Although the vaccine coverage rates among adults in this survey were low, the perceptions of patients about adult vaccination were mainly positive and of many of them positively reacted when their physician recommended a vaccine.

Safety and immunogenicity of adjuvanted inactivated split-virion and whole-virion influenza A (H5N1) vaccines in children: a phase I-II randomized trial.

PubMed

Wu, Jiang; Liu, Shu-Zhen; Dong, Shan-Shan; Dong, Xiao-Ping; Zhang, Wu-Li; Lu, Min; Li, Chang-Gui; Zhou, Ji-Chen; Fang, Han-Hua; Liu, Yan; Liu, Li-Ying; Qiu, Yuan-Zheng; Gao, Qiang; Zhang, Xiao-Mei; Chen, Jiang-Ting; Zhong, Xiang; Yin, Wei-Dong; Feng, Zi-Jian

2010-08-31

Highly pathogenic avian influenza A virus H5N1 has the potential to cause a pandemic. Many prototype pandemic influenza A (H5N1) vaccines had been developed and well evaluated in adults in recent years. However, data in children are limited. Herein we evaluate the safety and immunogenicity of adjuvanted split-virion and whole-virion H5N1 vaccines in children. An open-labelled phase I trial was conducted in children aged 3-11 years to receive aluminum-adjuvated, split-virion H5N1 vaccine (5-30 microg) and in children aged 12-17 years to receive aluminum-adjuvated, whole-virion H5N1 vaccine (5-15 microg). Safety of the two formulations was assessed. Then a randomized phase II trial was conducted, in which 141 children aged 3-11 years received the split-virion vaccine (10 or 15 microg) and 280 children aged 12-17 years received the split-virion vaccine (10-30 microg) or the whole-virion vaccine (5 microg). Serum samples were collected for hemagglutination-inhibition (HI) assays. 5-15 microg adjuvated split-virion vaccines were well tolerated in children aged 3-11 years and 5-30 microg adjuvated split-virion vaccines and 5 microg adjuvated whole-virion vaccine were well tolerated in children aged 12-17 years. Most local and systemic reactions were mild or moderate. Before vaccination, all participants were immunologically naïve to H5N1 virus. Immune responses were induced after the first dose and significantly boosted after the second dose. In 3-11 years children, the 10 and 15 microg split-virion vaccine induced similar responses with 55% seroconversion and seroprotection (HI titer >or=1:40) rates. In 12-17 years children, the 30 microg split-virion vaccine induced the highest immune response with 71% seroconversion and seroprotection rates. The 5 microg whole-virion vaccine induced higher response than the 10 microg split-virion vaccine did. The aluminum-adjuvanted, split-virion prototype pandemic influenza A (H5N1) vaccine showed good safety and immunogenicity in children and 30 microg dose induced immune response complying with European Union licensure criteria. (c) 2010 Elsevier Ltd. All rights reserved.

Streptococcus pyogenes strains in Sao Paulo, Brazil: molecular characterization as a basis for StreptInCor coverage capacity analysis.

PubMed

Freschi de Barros, Samar; De Amicis, Karine Marafigo; Alencar, Raquel; Smeesters, Pierre Robert; Trunkel, Ariel; Postól, Edilberto; Almeida Junior, João Nóbrega; Rossi, Flavia; Pignatari, Antonio Carlos Campos; Kalil, Jorge; Guilherme, Luiza

2015-08-05

Several human diseases are caused by Streptococcus pyogenes, ranging from common infections to autoimmunity. Characterization of the most prevalent strains worldwide is a useful tool for evaluating the coverage capacity of vaccines under development. In this study, a collection of S. pyogenes strains from Sao Paulo, Brazil, was analyzed to describe the diversity of strains and assess the vaccine coverage capacity of StreptInCor. Molecular epidemiology of S. pyogenes strains was performed by emm-genotyping the 229 isolates from different clinical sites, and PCR was used for superantigen profile analysis. The emm-pattern and tissue tropism for these M types were also predicted and compared based on the emm-cluster classification. The strains were fit into 12 different emm-clusters, revealing a diverse phylogenetic origin and, consequently, different mechanisms of infection and escape of the host immune system. Forty-eight emm-types were distinguished in 229 samples, and the 10 most frequently observed types accounted for 69 % of all isolates, indicating a diverse profile of circulating strains comparable to other countries under development. A similar proportion of E and A-C emm-patterns were observed, whereas pattern D was less frequent, indicating that the strains of this collection primarily had a tissue tropism for the throat. In silico analysis of the coverage capacity of StreptInCor, an M protein-conserved regionally based vaccine candidate developed by our group, had a range of 94.5 % to 59.7 %, with a mean of 71.0 % identity between the vaccine antigen and the predicted amino acid sequence of the emm-types included here. This is the first report of S. pyogenes strain characterization in Sao Paulo, one of the largest cities in the world; thus, the strain panel described here is a representative sample for vaccine coverage capacity analysis. Our results enabled evaluation of StreptInCor candidate vaccine coverage capacity against diverse M-types, indicating that the vaccine candidate likely would induce protection against the diverse strains worldwide.

International Travelers' Sociodemographic, Health, and Travel Characteristics: An Italian Study.

PubMed

Troiano, Gianmarco; Mercone, Astrid; Bagnoli, Alessandra; Nante, Nicola

Approximately the 8% of travelers requires medical care, with the diagnosis of a vaccine-preventable disease. The aim of our study was to analyze the socio-demographic, health and travel characteristics of the Italian international travelers. We conducted a cross sectional study from January 2015 to June 2016, at the Travel Medicine Clinic of Siena, asking the doctor to interview patients who attended the Clinic, recording socio-demographic and travel information, malaria prophylaxis, vaccinations. The data were organized in a database and processed by software Stata®. We collected 419 questionnaires. Patients chose 71 countries for their travels; the favorite destinations were: India (6.31%), Thailand (6.31%), and Brazil (5.10%). The mean length of stay was 36.17 days. Italians, students, and freelancers tended to stay abroad for a longer time (mean: 36.4 days, 59.87 days and 64.16 days respectively). 33.17% of our sample used drugs for malaria chemoprophylaxis: 71.9% of them used Atovaquone/Proguanil (Malarone®), 26.6% used Mefloquine (Lariam®), 1.5% other drugs. The vaccinations that travelers mostly got in our study were to prevent hepatitis A (n = 264), the typhoid fever (n = 187), the Tetanus + Diphtheria + Pertussis (n = 165), the Yellow fever (n = 118) and the cholera (n = 78). Twenty-eight (6.68%) refused some recommended vaccinations. The vaccines mostly refused were for Typhoid fever (n = 20), hepatitis a (n = 9), and cholera (n = 9). Our results demonstrated that Italian international travelers are at-risk because of their poor vaccinations adherence. This implies that pre-travel counseling is fundamental to increase the knowledge of the risks and the compliance of future travelers. Copyright © 2016 Icahn School of Medicine at Mount Sinai. Published by Elsevier Inc. All rights reserved.

Safety and immunogenicity of the M72/AS01E candidate tuberculosis vaccine in adults with tuberculosis: A phase II randomised study.

PubMed

Gillard, Paul; Yang, Pan-Chyr; Danilovits, Manfred; Su, Wei-Juin; Cheng, Shih-Lung; Pehme, Lea; Bollaerts, Anne; Jongert, Erik; Moris, Philippe; Ofori-Anyinam, Opokua; Demoitié, Marie-Ange; Castro, Marcela

2016-09-01

Previous studies have shown that the M72/AS01E candidate tuberculosis vaccine is immunogenic with a clinically acceptable safety profile in healthy and Mycobacterium tuberculosis-infected adults. This phase II, observer-blind, randomised study compared the safety, reactogenicity, and immunogenicity of M72/AS01E in 3 cohorts: tuberculosis-naïve adults (n = 80), adults previously treated for tuberculosis (n = 49), and adults who have completed the intensive phase of tuberculosis treatment (n = 13). In each cohort, 18-59-year-old adults were randomised (1:1) to receive two doses of M72/AS01E (n = 71) or placebo (n = 71) and followed-up until six months post-dose 2. Safety and reactogenicity were assessed as primary objective. Recruitment in the study ended prematurely because of a high incidence of large injection site redness/swelling reactions in M72/AS01E-vaccinated adults undergoing tuberculosis treatment. No additional clinically relevant adverse events were observed, except one possibly vaccine-related serious adverse event (hypersensitivity in a tuberculosis-treated-M72/AS01E participant). Robust and persistent M72-specific humoral and polyfunctional CD4(+) T-cell-mediated immune responses were observed post-M72/AS01E vaccination in each cohort. In conclusion, the M72/AS01E vaccine was immunogenic in adults previously or currently treated for tuberculosis, but further analyses are needed to explain the high local reactogenicity in adults undergoing tuberculosis treatment. ClinicalTrials.gov: NCT01424501. Copyright © 2016 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd.. All rights reserved.

Public awareness regarding children vaccination in Jordan.

PubMed

Masadeh, Majed M; Alzoubi, Karem H; Al-Azzam, Sayer I; Al-Agedi, Hassan S; Abu Rashid, Baraa E; Mukattash, Tariq L

2014-01-01

Immunization can contribute to a dramatic reduction in number of vaccine-preventable diseases among children. The aim of this study is to investigate mothers' awareness about child vaccines and vaccination in Jordan. This study was a community-based, cross-sectional study that was performed at public places in Irbid City. Data was collected from 506 mothers. After verbal approval, mothers were interviewed to assess their knowledge, attitudes, and practice toward vaccination. Results show that majority of mothers had acceptable knowledge and positive attitude toward vaccination. Most of mothers (94.7-86.8%) were able to identify vaccines that are mandatory as per the national vaccination program. Lower knowledge was observed among mothers (71.6%) for HIB vaccination being mandatory. Most mothers (97.2%) had vaccination card for their baby form the national vaccination programs. Vaccination delay was reported by about 36.6% of mothers and was shown to be associated with significantly (P = 0.001) lower vaccination knowledge/attitude score. Additionally, mothers who reported to be regularly offered information about vaccination during visits and those who identified medical staff members as their major information source had significantly higher vaccination knowledge/attitude score (P = 0.002). In conclusion, vaccination coverage rate is high; however, some aspects of knowledge, attitudes, and practice of vaccination need to be improved. Knowledge and attitudes of mothers were directly associated with their practice of vaccination. Medical staff education about vaccination during each visit seems to be the most effective tool that directly reflects on better practice of vaccination such as reducing the possibility for vaccination delay.

Public awareness regarding children vaccination in Jordan

PubMed Central

Masadeh, Majed M; Alzoubi, Karem H; Al-Azzam, Sayer I; Al-Agedi, Hassan S; Abu Rashid, Baraa E; Mukattash, Tariq L

2014-01-01

Immunization can contribute to a dramatic reduction in number of vaccine-preventable diseases among children. The aim of this study is to investigate mothers’ awareness about child vaccines and vaccination in Jordan. This study was a community-based, cross-sectional study that was performed at public places in Irbid City. Data was collected from 506 mothers. After verbal approval, mothers were interviewed to assess their knowledge, attitudes, and practice toward vaccination. Results show that majority of mothers had acceptable knowledge and positive attitude toward vaccination. Most of mothers (94.7–86.8%) were able to identify vaccines that are mandatory as per the national vaccination program. Lower knowledge was observed among mothers (71.6%) for HIB vaccination being mandatory. Most mothers (97.2%) had vaccination card for their baby form the national vaccination programs. Vaccination delay was reported by about 36.6% of mothers and was shown to be associated with significantly (P = 0.001) lower vaccination knowledge/attitude score. Additionally, mothers who reported to be regularly offered information about vaccination during visits and those who identified medical staff members as their major information source had significantly higher vaccination knowledge/attitude score (P = 0.002). In conclusion, vaccination coverage rate is high; however, some aspects of knowledge, attitudes, and practice of vaccination need to be improved. Knowledge and attitudes of mothers were directly associated with their practice of vaccination. Medical staff education about vaccination during each visit seems to be the most effective tool that directly reflects on better practice of vaccination such as reducing the possibility for vaccination delay. PMID:24732060

Parents’ perceptions of provider communication regarding adolescent vaccines

PubMed Central

Dempsey, Amanda F.; Pyrzanowski, Jennifer; Lockhart, Steven; Campagna, Elizabeth; Barnard, Juliana; O'Leary, Sean T.

2016-01-01

ABSTRACT Strong provider recommendations for adolescent vaccines are critical for achieving high vaccination levels.  However, little is known about parents’ preferred provider communication strategies for adolescent vaccines in general, and for human papillomavirus (HPV) vaccines specifically. We performed a cross-sectional survey of 800 parents of 9-14 year olds in April 2014 to assess current adolescent vaccine communication practices by providers, parents’ preferred HPV vaccine-specific communication strategies, and the association of these two outcomes with experiential, attitudinal and demographic characteristics.  Among the 356 parents in the study (response rate 48%), HPV vaccines were reported as less likely to have been “very strongly” recommended by their adolescent’s provider (39%) than other adolescent-targeted vaccines (45%-59%, <0.05 for all comparisons).  Receiving a very strong recommendation for HPV vaccines was associated with a higher likelihood of vaccine receipt (71% versus 39%, p<0.001), or among those not yet vaccinated, increased likelihood of positive vaccination intentions (82% vs. 60%, p = 0.015).  Nearly all parents (87%) reported that, if available, they would use a website providing personalized HPV vaccine-related materials before their adolescent’s next check-up, and other technology-based communications were also endorsed by the majority of parents.   From these data we conclude that parents received weaker recommendations for HPV vaccines than other adolescent vaccines, and that most parents want additional HPV vaccine-related materials, preferably delivered using a variety of technology-based modalities which is not their providers’ current practice. PMID:27078515

Estimates of Pandemic Influenza Vaccine Effectiveness in Europe, 2009–2010: Results of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) Multicentre Case-Control Study

PubMed Central

Valenciano, Marta; Kissling, Esther; Cohen, Jean-Marie; Oroszi, Beatrix; Barret, Anne-Sophie; Rizzo, Caterina; Nunes, Baltazar; Pitigoi, Daniela; Larrauri Cámara, Amparro; Mosnier, Anne; Horvath, Judith K.; O'Donnell, Joan; Bella, Antonino; Guiomar, Raquel; Lupulescu, Emilia; Savulescu, Camelia; Ciancio, Bruno C.; Kramarz, Piotr; Moren, Alain

2011-01-01

Background A multicentre case-control study based on sentinel practitioner surveillance networks from seven European countries was undertaken to estimate the effectiveness of 2009–2010 pandemic and seasonal influenza vaccines against medically attended influenza-like illness (ILI) laboratory-confirmed as pandemic influenza A (H1N1) (pH1N1). Methods and Findings Sentinel practitioners swabbed ILI patients using systematic sampling. We included in the study patients meeting the European ILI case definition with onset of symptoms >14 days after the start of national pandemic vaccination campaigns. We compared pH1N1 cases to influenza laboratory-negative controls. A valid vaccination corresponded to >14 days between receiving a dose of vaccine and symptom onset. We estimated pooled vaccine effectiveness (VE) as 1 minus the odds ratio with the study site as a fixed effect. Using logistic regression, we adjusted VE for potential confounding factors (age group, sex, month of onset, chronic diseases and related hospitalizations, smoking history, seasonal influenza vaccinations, practitioner visits in previous year). We conducted a complete case analysis excluding individuals with missing values and a multiple multivariate imputation to estimate missing values. The multivariate imputation (n = 2902) adjusted pandemic VE (PIVE) estimates were 71.9% (95% confidence interval [CI] 45.6–85.5) overall; 78.4% (95% CI 54.4–89.8) in patients <65 years; and 72.9% (95% CI 39.8–87.8) in individuals without chronic disease. The complete case (n = 1,502) adjusted PIVE were 66.0% (95% CI 23.9–84.8), 71.3% (95% CI 29.1–88.4), and 70.2% (95% CI 19.4–89.0), respectively. The adjusted PIVE was 66.0% (95% CI −69.9 to 93.2) if vaccinated 8–14 days before ILI onset. The adjusted 2009–2010 seasonal influenza VE was 9.9% (95% CI −65.2 to 50.9). Conclusions Our results suggest good protection of the pandemic monovalent vaccine against medically attended pH1N1 and no effect of the 2009–2010 seasonal influenza vaccine. However, the late availability of the pandemic vaccine and subsequent limited coverage with this vaccine hampered our ability to study vaccine benefits during the outbreak period. Future studies should include estimation of the effectiveness of the new trivalent vaccine in the upcoming 2010–2011 season, when vaccination will occur before the influenza season starts. Please see later in the article for the Editors' Summary PMID:21379316

[Invasive infections caused by Haemophilus influenzae type b after the institution of the conjugated vaccine on the expanded programm on immunization in Chile].

PubMed

Cruces R, Pablo; Donoso F, Alejandro; Camacho A, Jorge; Llorente H, Marcela

2006-03-01

After almost a decade since the introduction of Haemophilus influenzae type b (Hib) conjugate vaccines in Chile (in a 2-4-6 month schedule), Hib invasive infections have dramatically decreased, albeit they remain to occasionally produce disease in pediatric patients. We report our experience with children whom developed Hib invasive disease in children since 2000 to 2004. Medical records of children with Hib were reviewed in order to describe the epidemiology, main clinical and laboratory findings, management and complications. Twenty three patients (17 male), between 1 and 71 months (median 30 months) were identified: pneumonia (7), meningitis (4), pleuropneumonia (2), empyema (2), sepsis (2), cellulitis (2), meningitis and pleuropneumonia (1), purpura fulminans (1), miositis (1) and epiglottitis (1). No deaths were observed and four patients presented severe sequelae at hospital discharge. Twenty patients were considered vaccine failures. Hib remains as a sporadic cause of severe disease in Chile and thus for physicians should still keep it in mind. Case analysis and active surveillance are necessary to monitor the current immunization regimen.

Development of a bait and baiting system for delivery of oral rabies vaccine to free-ranging African wild dogs (Lycaon pictus).

PubMed

Knobel, D L; du Toit, J T; Bingham, J

2002-04-01

The objective of the study was to develop a bait and baiting system capable of delivering one effective dose of oral rabies vaccine to each member of a free-ranging African wild dog (Lycaon pictus) pack. Trials were conducted between June and October 2000. The results of cafeteria-style bait preference trials testing seven candidate baits in captive wild dogs revealed a significant preference for chicken heads (June trials: P = 0.023, September trials: P = 0.021). Trials using a topical biomarker (rhodamine B) showed that chicken head baits were sufficiently chewed on most occasions to rupture the vaccine container. Free-ranging wild dogs and young pups ingested chicken head baits. Significant dominance of bait intake by a single individual was seen in four of six study packs and in the three packs in which an alpha pair could be distinguished, the dominant feeder was an alpha animal. Pattern of bait distribution and degree of satiation had no effect on pack coverage (proportion of pack ingesting at least one bait). Pack coverage was significantly related to trial number (r = 0.71, P < 0.001), with pack coverage increasing with increased exposure of the pack to the baits. During 46 hr of diurnal observations of free-ranging wild dogs only two baits were lost to non-target species. A baiting system for the oral vaccination of captive and free-ranging wild dogs is proposed.

Influence of condition of growth of bacterial colonies on fractal dimension of bacterial speckle patterns

NASA Astrophysics Data System (ADS)

Ulyanov, Alexander S.; Lyapina, Anna M.; Ulianova, Onega V.; Feodorova, Valentina A.

2010-10-01

New field of application of fractal dimensions is proposed. A technique, based on the calculation of fractal dimension, was used for express-diagnostics and identification of bacteria of the vaccine strain Yersinia pestis EV line NIIEG. Purpose of this study was the experimental investigation of properties of speckle patterns, formed under laser illumination of a single colony of the strain that was grown on different agars.

Influence of condition of growth of bacterial colonies on fractal dimension of bacterial speckle patterns

NASA Astrophysics Data System (ADS)

Ulyanov, Alexander S.; Lyapina, Anna M.; Ulianova, Onega V.; Feodorova, Valentina A.

2011-03-01

New field of application of fractal dimensions is proposed. A technique, based on the calculation of fractal dimension, was used for express-diagnostics and identification of bacteria of the vaccine strain Yersinia pestis EV line NIIEG. Purpose of this study was the experimental investigation of properties of speckle patterns, formed under laser illumination of a single colony of the strain that was grown on different agars.

Impact of changing the measles vaccine vial size on Niger's vaccine supply chain: a computational model

PubMed Central

2011-01-01

Background Many countries, such as Niger, are considering changing their vaccine vial size presentation and may want to evaluate the subsequent impact on their supply chains, the series of steps required to get vaccines from their manufacturers to patients. The measles vaccine is particularly important in Niger, a country prone to measles outbreaks. Methods We developed a detailed discrete event simulation model of the vaccine supply chain representing every vaccine, storage location, refrigerator, freezer, and transport device (e.g., cold trucks, 4 × 4 trucks, and vaccine carriers) in the Niger Expanded Programme on Immunization (EPI). Experiments simulated the impact of replacing the 10-dose measles vial size with 5-dose, 2-dose and 1-dose vial sizes. Results Switching from the 10-dose to the 5-dose, 2-dose and 1-dose vial sizes decreased the average availability of EPI vaccines for arriving patients from 83% to 82%, 81% and 78%, respectively for a 100% target population size. The switches also changed transport vehicle's utilization from a mean of 58% (range: 4-164%) to means of 59% (range: 4-164%), 62% (range: 4-175%), and 67% (range: 5-192%), respectively, between the regional and district stores, and from a mean of 160% (range: 83-300%) to means of 161% (range: 82-322%), 175% (range: 78-344%), and 198% (range: 88-402%), respectively, between the district to integrated health centres (IHC). The switch also changed district level storage utilization from a mean of 65% to means of 64%, 66% and 68% (range for all scenarios: 3-100%). Finally, accounting for vaccine administration, wastage, and disposal, replacing the 10-dose vial with the 5 or 1-dose vials would increase the cost per immunized patient from $0.47US to $0.71US and $1.26US, respectively. Conclusions The switch from the 10-dose measles vaccines to smaller vial sizes could overwhelm the capacities of many storage facilities and transport vehicles as well as increase the cost per vaccinated child. PMID:21635774

Indirect oral immunization of captive vampires, Desmodus rotundus.

PubMed

Almeida, Marilene F; Martorelli, Luzia F A; Aires, Caroline C; Sallum, P C; Massad, Eduardo

2005-07-01

A vaccinia-rabies glycoprotein recombinant virus (V-RG) vaccine was tested in hematophagous bats (Desmodus rotundus) kept in captivity. The vaccine was applied in a neutral vehicle (Vaseline) spread on the back of one or two vector bats, which were then reintroduced into their groups. Our hypothesis was that, as in the case of vampire bat control by vampiricide paste, the administration of V-RG vaccine through paste to one bat could indirectly protect other bats from the same group. Eight groups were tested. The rabies virus strain used to challenge the bats was isolated from a naturally infected hematophagous bat (Desmodus rotundus). The survival proportion after the virus challenge ranged between 42.8 and 71.4%. The results are encouraging because a significant number of bats that did not receive the vaccine survived the challenge. The vaccine was shown to be safe and immunogenic to hematophagous bats. No adverse effects to vaccinia virus were observed.

Four two-dimensional ternary selenides based on group 13 and 14 metals: Syntheses, crystal structures, and electrochemical properties

NASA Astrophysics Data System (ADS)

Wang, Jingrui; Li, Peng; Cai, Ting; Yang, Dan-Dan; Xiong, Wei-Wei

2018-07-01

A series of two-dimensional ternary selenides, [NH4]2[Ga2Sn2Se8] (1), [NH4]2[In2Ge2Se8] (2), [NH4]2[In2Sn2Se8] (3), [NH4]2[Ga2Ge2Se8] (4), have been solvothermally synthesized and characterized by single crystal X-ray diffraction, energy dispersive X-ray (EDX) spectroscopy, solid-state UV-Vis diffuse reflectance spectroscopy, and thermogravimetric analyses. The solid-state optical absorption spectra indicated that these compounds were semiconductors with band gaps of 1.71 eV for 1, 1.95 eV for 2, 1.85 eV for 3, and 1.83 eV for 4. In addition, compound 2 was employed as an anode material for lithium ion battery application, which exhibited a high specific capacity of 479 mA h g-1 over 200 cycles at a current density of 200 mA g-1, and an excellent rate capability of 425.2 mA h g-1 at a current density of 1000 mA g-1. Our results suggest that crystalline chalcogenides could be an alternative anode material for high performance LIBs application.

Relativistic Many-Body Calculations of n=2 States for the Beryllium Isoelectronic Sequence

NASA Astrophysics Data System (ADS)

Safronova, M. S.; Johnson, W. R.; Safronova, U. I.

1996-05-01

Energies of the ten (2l2l') states of ions of the beryllium isoelectronic sequence are determined to second-order in relativistic many-body perturbation theory. Both the second-order Coulomb interaction and the second-order Breit-Coulomb interaction are included. Corrections for the frequency-dependent Breit interaction are taken in account in lowest order only. The effect of the Lamb shift is also estimated and included. Comparisons with other calculations and with experiment are made. Our theoretical results for the 2s-2p_3/2 transitions in U^88+ and Th^86+ (4501.60 eV and 4069.02 eV, resp.) differ only by 0.12 eV for U^88+ and 0.55 eV for Th^86+ from experimental data obtained at the SUPER-EBIT in LLNL.(P. Beiersdorfer, D. Knapp, R.E. Marrs, S.R. Elliot and M.H. Chen, Phys. Rev. Lett. 71), 3939 (1993); P. Beiersdorfer, A. Osterheld, S.R. Elliot, M.H. Chen, D. Knapp, and K. Reed, Phys. Rev. A52, 2693 (1995). Excellent agreement with experimental results for the splitting of ^3 P terms is found.

Predictors of seasonal influenza vaccination behaviour among nurses and implications for interventions to increase vaccination uptake: A cross-sectional survey.

PubMed

Kan, Ting; Ai, Jiaqi; Zhang, Jing; Liu, Xiaohong

2018-03-01

Vaccination has been proven the most effective method to prevent seasonal influenza. Nurses' vaccination can provide protection against influenza not only for themselves but also for patients they take care of. However, vaccination coverage of nurses is suboptimal worldwide, especially in China. The influencing factors need to be explored so as to develop specific, workable strategies to improve nurses' vaccination behaviour. To explore predictors of their vaccination behaviour, identify the motivators and barriers of vaccination, and provide implications for future interventions. A cross-sectional convenience sampling questionnaire survey. Nine hospitals including five tertiary hospitals, two secondary hospitals, and two primary hospitals in Shanghai, China. A total of 1000 nurses from the nine hospitals were invited to participate in this survey. Among them, 921 nurses responded and 895 returned valid questionnaires that were used in data analysis. The Chinese version of the King's Nurses' Influenza Vaccination Questionnaire was used as the survey instrument and distributed to the participants during February-November 2012. Descriptive statistics, univariate analyses, and multivariate analyses were conducted to explore the predictors of nurses' vaccination behaviour. Overall, 8.8% of the respondents received seasonal influenza vaccination in the past influenza season (2011/2012 season). Nurses had averagely received 0.38 ± 0.71 influenza vaccines during the past five influenza seasons (2007/2008 to 2011/2012 season). Predictors of nurses' vaccination status were clinical specialty, knowledge about influenza vaccination [1.331 (1.102, 1.608), p = 0.003], internal health locus of control [0.910 (0.845, 0.980), p = 0.013], chance health locus of control [1.075 (1.023, 1.130), p = 0.004]and powerful others health of locus control [1.166 (1.083, 1.255), p < 0.001]. Predictors of their vaccination times were hospital level, clinical specialty, and knowledge about influenza vaccination [1.458 (1.242, 1.711), p < 0.001]. Self-protection was the most common cited reason for getting vaccinated, and "no need" was cited as the most common refusal reason. This is the first well-designed study conducted in mainland China to explore nurses' vaccination behaviour against seasonal influenza. Vaccination coverage in this population was suboptimal. Mandatory vaccination policy should be implemented and attempts of multi-faceted interventions including specific education might also be needed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Self-reported hepatitis A vaccination as a predictor of hepatitis A virus antibody protection in U.S. adults: National Health and Nutrition Examination Survey 2007-2012.

PubMed

Denniston, Maxine M; Monina Klevens, R; Jiles, Ruth B; Murphy, Trudy V

2015-07-31

To estimate the predictive value of self-reported hepatitis A vaccine (HepA) receipt for the presence of hepatitis A virus (HAV) antibody (anti-HAV) from either past infection or vaccination, as an indicator of HAV protection. Using 2007-2012 National Health and Nutrition Examination Survey data, we assigned participants to 4 groups based on self-reported HepA receipt and anti-HAV results. We compared characteristics across groups and calculated three measures of agreement between self-report and serologic status (anti-HAV): percentage concordance, and positive (PPV) and negative (NPV) predictive values. Using logistic regression we investigated factors associated with agreement between self-reported vaccination status and serological results. Demographic and other characteristics varied significantly across the 4 groups. Overall agreement between self-reported HepA receipt and serological results was 63.6% (95% confidence interval [CI] 61.9-65.2); PPV and NPV of self-reported vaccination status for serological result were 47.0% (95% CI 44.2-49.8) and 69.4% (95% CI 67.0-71.8), respectively. Mexican American and foreign-born adults had the highest PPVs (71.5% [95% CI 65.9-76.5], and 75.8% [95% CI 71.4-79.7]) and the lowest NPVs (21.8% [95% CI 18.5-25.4], and 20.0% [95% CI 17.2-23.1]), respectively. Young (ages 20-29 years), US-born, and non-Hispanic White adults had the lowest PPVs (37.9% [95% CI 34.5-41.5], 39.1% [95% CI, 36.0-42.3], and 39.8% [36.1-43.7]), and the highest NPVs (76.9% [95% CI 72.2-81.0, 78.5% [95% CI 76.5-80.4)], and 80.6% [95% CI 78.2-82.8), respectively. Multivariate logistic analyses found age, race/ethnicity, education, place of birth and income to be significantly associated with agreement between self-reported vaccination status and serological results. When assessing hepatitis A protection, self-report of not having received HepA was most likely to identify persons at risk for hepatitis A infection (no anti-HAV) among young, US-born and non-Hispanic White adults, and self-report of HepA receipt was least likely to be reliable among adults with the same characteristics. Copyright © 2015. Published by Elsevier Ltd.

A clinical trial of WRL 105 strain live attenuated influenza vaccine comparing four methods of intranasal vaccination.

PubMed Central

Freestone, D. S.; Bowker, C. H.; Letley, E.; Ferris, R. D.; White, W. G.; Barnes, G. M.

1976-01-01

A single intranasal dose of 10(7-0) EID50 recombinant WRL 105 strain live attenuated influenza vaccine was administered intranasally to 193 volunteers either as nose drops or by one of three spray devices which produced sprays of differing physical characteristics. In volunteers with homologous haemagglutinating inhibiting antibody titres of less than or equal to 20 before vaccination, seroconversion rates varied widely from 80% following the administration of drops to 71%, 57% and 28% with the three spray devices. In the week following vaccination 16 (22%) of 74 volunteers who were found to show a fourfold or greater antibody response to took analgesics to control symptoms in comparison with 4 (7%) of 58 volunteers who exhibited no serological response to vaccination (P less than 0-05). However, neither the occurrence of upper respiratory nor systemic symptoms were significantly different in these two groups and the degree of attenuation of the recombinant WRL 105 strain appears to be acceptable for future use. PMID:1064672

The effectiveness of shingles vaccine among Albertans aged 50 years or older: A retrospective cohort study.

PubMed

McDonald, Bruce M; Dover, Douglas C; Simmonds, Kimberley A; Bell, Christopher A; Svenson, Lawrence W; Russell, Margaret L

2017-12-15

We assessed the effectiveness of shingles vaccine in preventing incident shingles among Alberta residents aged 50 years or older over the period 2009 - 2015, using administrative health data. The cohort comprised of Albertans from the Alberta Health Care Insurance Plan Registry (AHCIP) as of June 30, 2009 and aged 50 years or older. Those who received shingles vaccine were identified from the provincial pharmaceutical information network. The occurrence of incident shingles was identified through both inpatient and outpatients/community care data. Incident shingles was defined as the earliest dated record of ICD 9-CM 053 or ICD-10-CA B02. Starting on November 1, 2009, individuals with no history of shingles or shingles vaccination were followed until Nov 1, 2015 (6 years), or until shingles incidence, death, or AHCIP cancellation (including leaving Alberta). Vaccine effectiveness (VE) was estimated as the inverse of the relative risk of developing incident shingles in each year following vaccination compared to time at risk without vaccination, while adjusting for age, sex, income quintile, and immune compromising conditions (identified from physician claims, inpatient, and cancer registry data). There were 1,094,236 individuals in the cohort, with 85,439 (7.80%) vaccinated individuals. The shingles incidence rate was 9.03 [95% CI: 8.95, 9.11] cases per 1,000 person years (49,243 cases). Adjusted VE in the first year following immunization was 50.02% [95% CI: 44.71%, 54.83%] against incident shingles, decreasing to no effect by the fifth year (VE = 14.00% [95% CI: -20.99%, 38.88%]). Our findings are consistent with observations from other population based studies and provide population level data for policy-makers to review when making decisions related to public funding of shingles vaccine. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Dose response of CRM197 and tetanus toxoid-conjugated Haemophilus influenzae type b vaccines.

PubMed

Huebner, Robin E; Nicol, Mark; Mothupi, Rosalia; Käyhty, Helena; Mbelle, Nontombi; Khomo, Esther; Klugman, Keith P

2004-12-21

High vaccine cost has limited use of conjugate vaccines in the developing world where the disease burden is greatest. Fixed fractional doses of Haemophilus influenzae type b (Hib) vaccines have been shown to be immunogenic, but dose responses of these vaccines in humans are needed to determine the lowest immunogenic dose as an option for lowering vaccine cost. We randomized children to receive one of five doses (0.625, 1.25, 2.5, 5.0 and 10 microg) of either a diphtheria CRM197 or tetanus toxoid-conjugated Hib vaccine. The children received a primary three-dose series at 6, 10, and 14 weeks of age and a booster dose at 9 months. Anti-PRP IgG antibodies were measured at each vaccination, at 18 weeks, and at one week following the booster dose. Concentrations of > or =1.25 microg of HibCRM197 vaccine produced mean anti-PRP responses at 18 weeks of > or =5.72 microg/ml and > or =0.15 microg/ml was achieved in >98% of the children with at least 79% reaching anti-PRP concentrations of > or =1.0 microg/ml. Concentrations of > or =1.25 microg of Hib-tetanus vaccine produced mean anti-PRP responses at 18 weeks of > or =8.63 microg/ml and > or =0.15 microg/ml was achieved in 100% of the children with at least 88.9% reaching anti-PRP concentrations of > or =1.0 microg/ml. While mean antibody concentrations after either vaccine decreased over time, the proportion of children with antibody levels of > or =0.15 microg/ml had not changed significantly at the 9 month measurement. Immunologic memory was demonstrated by significant increases in mean antibody concentrations one week after the booster dose for doses > or =1.25 microg of HibCRM197 and Hib-tetanus to mean concentrations > or =37.71 and 16.07 microg/ml, respectively. There were no differences in antibody responses for vaccine doses > or =1.25 microg of the same vaccine or between the same concentrations of the two different vaccines. Our data suggest that doses of these vaccines of > or =1.25 microg may be sufficient to stimulate an immune response that offers both short and longer term protection from invasive Hib disease.

Opportunity for catch-up HPV vaccination in young women after first delivery.

PubMed

Rama, Cristina Helena; Villa, Luisa L; Pagliusi, Sonia; Andreoli, Maria A; Costa, Maria C; Thomann, Patricia; Alves, Venancio A F; Longatto-Filho, Adhemar; Eluf-Neto, Jose

2010-07-01

Early age at first delivery has been identified as a risk factor for high-risk HPV-type infection and cervical cancer development. A cross-sectional study was carried out in a large public maternity hospital in São Paulo, Brazil. During June 2006 to February 2007, 301 women aged 15-24 years who gave birth to their first child were recruited between 43 and 60 days after delivery. Detection of HPV DNA in cervical specimens was performed using a standardised PCR protocol with PGMY09/11 primers. The association of selected factors with HPV infection was assessed by using a Generalised Linear Model. HPV DNA was detected in 58.5% (95% CI 52.7% to 64.0%) of the enrolled young women. The most common types of HPV found were: HPV16, HPV51, HPV52, HPV58 and HPV71. The overall prevalence of HPV types targeted by the HPV prophylactic vaccines was: HPV 16-12.0%, HPV 18- 2.3% and HPV 6 and 11 4.3%. In the multivariate analysis, only age (inversely, p for trend=0.02) and smoking habits were independently associated with HPV infection. The findings show that these young primiparous women had high cervical HPV prevalence, suggesting that this is a high-risk group for cervical cancer development. Nevertheless, 17.3% were positive for any of the four HPV types included in HPV vaccines (HPV6, 11, 16 or 18), with 13.3% positive for HPV 16 or 18 and only 1.0% having both vaccine related-oncogenic HPV types. Thus, young primiparous women could benefit from catch-up HPV vaccination programmes.

Influencers and preference predictors of HPV vaccine uptake among US male and female young adult college students.

PubMed

LaJoie, A Scott; Kerr, Jelani C; Clover, Richard D; Harper, Diane M

2018-06-01

The purpose of the study was to assess the knowledge, attitudes and beliefs of male and female college students in Kentucky about HPV associated diseases and vaccines, and to determine which parameters predicted self-reported uptake of HPV vaccination. A self-selected cross-sectional sample of college students completed an evidence-based online survey. Of approximately 1200 potential respondents, 585 completed the survey. The average age was 20.6 (SD 3.15) and 78% were female; 84% of the population had had one or more sexual partners. Concern for HPV vaccine safety and potential need for boosters did not significantly deter vaccine uptake. Likewise, knowledge about HPV associated cancers was not predictive of vaccine uptake. On the other hand, parental influence for vaccination was a strong predictor for vaccine uptake (aOR = 5.32, 2.71-13.03), and free vaccine nearly doubled the likelihood of being vaccinated (aOR 1.90, 1.05-3.41). In addition, the strong preference for the respondent's partner to be HPV vaccinated predicted vaccine uptake (aOR = 4.04, 95% CI: 2.31-7.05), but the lack of preference for partner vaccination predicted an unvaccinated self (aOR = 0.50, 0.27-0.93). HPV vaccination has been successful in young adult college students in Kentucky. Young adults prefer their partners to be HPV vaccinated regardless of whether they themselves are vaccinated. Parental influence and free vaccine were positive predictors for vaccine uptake in this population. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Vaccination Coverage Cluster Surveys in Middle Dreib – Akkar, Lebanon: Comparison of Vaccination Coverage in Children Aged 12-59 Months Pre- and Post-Vaccination Campaign

PubMed Central

Assaad, Ramia; Rebeschini, Arianna; Hamadeh, Randa

2016-01-01

Introduction With the high proportion of refugee population throughout Lebanon and continuous population movement, it is sensible to believe that, in particular vulnerable areas, vaccination coverage may not be at an optimal level. Therefore, we assessed the vaccination coverage in children under 5 in a district of the Akkar governorate before and after a vaccination campaign. During the vaccination campaign, conducted in August 2015, 2,509 children were vaccinated. Materials and Methods We conducted a pre- and post-vaccination campaign coverage surveys adapting the WHO EPI cluster survey to the Lebanese MoPH vaccination calendar. Percentages of coverage for each dose of each vaccine were calculated for both surveys. Factors associated with complete vaccination were explored. Results Comparing the pre- with the post-campaign surveys, coverage for polio vaccine increased from 51.9% to 84.3%, for Pentavalent from 49.0% to 71.9%, for MMR from 36.2% to 61.0%, while the percentage of children with fully updated vaccination calendar increased from 32.9% to 53.8%. While Lebanese children were found to be better covered for some antigens compared to Syrians at the first survey, this difference disappeared at the post-campaign survey. Awareness and logistic obstacles were the primary reported causes of not complete vaccination in both surveys. Discussion Vaccination campaigns remain a quick and effective approach to increase vaccination coverage in crisis-affected areas. However, campaigns cannot be considered as a replacement of routine vaccination services to maintain a good level of coverage. PMID:27992470

Diarrhoea-related hospitalizations in children before and after implementation of monovalent rotavirus vaccination in Mexico

PubMed Central

Esparza-Aguilar, Marcelino; Sánchez-Uribe, Edgar; Desai, Rishi; Parashar, Umesh D; Richardson, Vesta; Patel, Manish

2014-01-01

Abstract Objective To assess, by socioeconomic setting, the effect of nationwide vaccination against species A rotavirus (RVA) on childhood diarrhoea-related hospitalizations in Mexico. Methods Data on children younger than 5 years who were hospitalized for diarrhoea in health ministry hospitals between 1 January 2003 and 31 December 2011 were collected from monthly discharge reports. Human development indexes were used to categorize the states where hospitals were located as having generally high, intermediate or low socioeconomic status. Annual rates of hospitalization for diarrhoea – per 10 000 hospitalizations for any cause – were calculated. Administrative data were used to estimate vaccine coverage. Findings In the states with high, intermediate and low socioeconomic status, coverage with a two-dose monovalent RVA vaccine – among children younger than 5 years – had reached 93%, 86% and 71%, respectively, by 2010. The corresponding median annual rates of hospitalization for diarrhoea – per 10 000 admissions – fell from 1001, 834 and 1033 in the “prevaccine” period of 2003–2006, to 597, 497 and 705 in the “postvaccine” period from 2008 to 2011, respectively. These decreases correspond to rate reductions of 40% (95% confidence interval, CI: 38–43), 41% (95% CI: 38–43) and 32% (95% CI: 29–34), respectively. Nationwide, RVA vaccination appeared to have averted approximately 16 500 hospitalizations for childhood diarrhoea in each year of the postvaccine period. Conclusion Monovalent RVA vaccination has substantially reduced childhood diarrhoea-related hospitalizations for four continuous years in discretely different socioeconomic populations across Mexico. PMID:24623905

A locally initiated and executed measles outbreak response immunization campaign in the nylon health district, Douala Cameroon 2011.

PubMed

Sume, Gerald Etapelong; Fouda, André Arsène Bita; Kobela, Marie; Nguelé, Salomé; Emah, Irène; Atem, Peter

2013-03-16

The Cameroon health system is divided into central, intermediate and peripheral levels. Of the 43 health districts with a measles outbreak in Cameroon in 2011, only the Nylon Health District organized a documented outbreak response immunization. We present the methods and results of the response campaign solely shouldered by the district and intermediate level. The risk group, targets and neighborhoods to be vaccinated were identified after a detailed analysis of initial cases. The intermediate level defined strategies, provided logistics, capacity building and 41% of the operational budget while 59% was completed by the peripheral level. Microsoft Office Excel 2007 was used to estimate coverage rates and to draw an epidemic curve. The response immunization campaign was organized on the 14th epidemiological week, 10 weeks after the onset of the outbreak which ended 11 weeks thereafter. A total of 15867(108.5%) children aged 9-59 months were vaccinated in five health areas at a direct cost (vaccines excluded) of 71.34FCFA ($0.143) per vaccinated child. An additional 824 children aged 9-59 months were vaccinated around the residence of notified cases in neighborhoods which were not involved in the response campaign. The number of cases after the response campaign was lower than before. Once vaccines are available, prompt outbreak response campaigns can be organized at operational level to obtain commendable results instead of depending solely on international organizations or central levels. Decision makers at the intermediate and operational levels should redeploy available funds during emergencies to prevent the development of extreme public health conditions.

Serum antibody titres to canine parvovirus, adenovirus and distemper virus in dogs in the UK which had not been vaccinated for at least three years.

PubMed

Böhm, M; Thompson, H; Weir, A; Hasted, A M; Maxwell, N S; Herrtage, M E

2004-04-10

Antibody titres to canine distemper (CDV), canine parvovirus (CPV) and canine adenovirus (CAV) were measured in 144 adult dogs that had not been vaccinated for between three and 15 years. Protective antibodies to CPV were present in 95 per cent of the population, to CDV in 71.5 per cent and to CAV in 82 per cent. The prevalence of protective titres did not decrease with increasing time interval from the last vaccination for any of the three diseases studied. Booster vaccination increased the dogs CAV titres. For comparative purposes, 199 puppies were sampled at the time of their first and second vaccination. In the case of CPV and CAV a significantly higher proportion of the adult dogs were protected than of the puppies immediately after they were vaccinated. Natural CPV boosting was strongly suspected because the dogs had significantly higher titres three years after their primary vaccination than two weeks after it and three unvaccinated dogs had acquired protective antibody levels uneventfully. There was no evidence of natural exposure to CDV.

Effectiveness of Varicella Vaccination Program in Preventing Laboratory-Confirmed Cases in Children in Seoul, Korea.

PubMed

Lee, Young Hwa; Choe, Young June; Cho, Sung Il; Kang, Cho Ryok; Bang, Ji Hwan; Oh, Myoung Don; Lee, Jong Koo

2016-12-01

A universal one-dose varicella vaccination program was introduced in 2005 in Republic of Korea. However, the incidence of varicella in Korea has tripled over the last decade. We conducted a community based 1:1 matched case-control study to assess the effectiveness of one MAV strain-based vaccine and three Oka strain-based vaccines licensed for use in Korea. All cases were children in Seoul, Korea with varicella who were reported to the National Notifiable Disease Surveillance System in Seoul during 2013. The controls were age-matched children with mumps or scarlet fever but no history of varicella. We included 537 cases and 537 controls. The overall effectiveness of one dose of varicella vaccination was 13% (95% confidence interval [CI], -17.3-35.6). Of the four licensed varicella vaccines, only one was highly effective (88.9%; 95% CI, 52.1-97.4). The vaccine effectiveness for the other vaccines were 71.4% (95% CI, -37.5-94.1), -5% (95% CI, -61.9-31.9), and -100% (95% CI, -700-50.0). The overall effectiveness of vaccination was 75.8% (95% CI, 22.8-92.4) in the first year after vaccination and decreased thereafter; the effectiveness became -7.2% (95% CI, -130.9-59.2) in the fourth year after vaccination. Further studies are warranted to investigate reduced effectiveness of varicella vaccines in Korea.

Non-polio enteroviruses serotypes circulating in Nigeria.

PubMed

Oyero, O G; Adu, F D

2010-12-01

Enteroviruses is one of the most common group of human pathogens, causing a wide range of acute symptoms involving the cardiac and skeletal muscles, central nervous system, pancreas,skin and mucous membranes. In spite of the success recorded in polio eradication globally, infections with other enteroviruses remain frequent and sometimes very serious, requiring hospitalization. In this study we determined the various circulating serotypes of non-polio enteroviruses (NPEVs) with a view to providing information on the activity of these viruses among the Nigerian children, who usually are the most affected. Stool samples were obtained from hospitalized children at two major secondary community hospitals in Ibadan and acute flaccid paralysis (AFP) cases from 26 states ofNigeria. A presumptive identification of NPEVs was based on growth in RD cells. Isolates were identified by neutralization assay using sera obtained from the Institute for Public Health and the Environment, the Netherlands. The problems associated with this assay prompted the use of genotypic method developed at the Centers for Disease Control, Atlanta, USA for the final identification of isolates. Neutralization assay identified the 138 isolates into echoviruses (43.5%), coxsackie B viruses (29.7%) and untypeable isolates (26.8%). Finally genotyping identified echoviruses (E3, E6, E7, E11, E12, E13, E14, E19, E20, E21, E24, E29, E30, E33), coxsackieviruses (CVA3, CVA4, CVA6, CVA17, CVB3, CVB5, CVB6) and enteroviruses (EV69, EV71). The causal association of isolates with different diseases was also established. Majority of the isolates belonged to the human enterovirus gropup B (HEV-B) specie, followed by 4 and 1 in the HEV-A and HEV-C species respectively. This study forms the basis of molecular epidemiology of NPEVs being established for the first time in Nigeria. The implication of the presence of neurotropic serotypes (E3, E6, E7, E11, E14, E20, E24, E29, E30, EV71, CVB3 and CVB5) is that AFP may still be prevalent following polio eradication.

Local measles vaccination gaps in Germany and the role of vaccination providers.

PubMed

Eichner, Linda; Wjst, Stephanie; Brockmann, Stefan O; Wolfers, Kerstin; Eichner, Martin

2017-08-14

Measles elimination in Europe is an urgent public health goal, yet despite the efforts of its member states, vaccination gaps and outbreaks occur. This study explores local vaccination heterogeneity in kindergartens and municipalities of a German county. Data on children from mandatory school enrolment examinations in 2014/15 in Reutlingen county were used. Children with unknown vaccination status were either removed from the analysis (best case) or assumed to be unvaccinated (worst case). Vaccination data were translated into expected outbreak probabilities. Physicians and kindergartens with statistically outstanding numbers of under-vaccinated children were identified. A total of 170 (7.1%) of 2388 children did not provide a vaccination certificate; 88.3% (worst case) or 95.1% (best case) were vaccinated at least once against measles. Based on the worst case vaccination coverage, <10% of municipalities and <20% of kindergartens were sufficiently vaccinated to be protected against outbreaks. Excluding children without a vaccination certificate (best case) leads to over-optimistic views: the overall outbreak probability in case of a measles introduction lies between 39.5% (best case) and 73.0% (worst case). Four paediatricians were identified who accounted for 41 of 109 unvaccinated children and for 47 of 138 incomplete vaccinations; GPs showed significantly higher rates of missing vaccination certificates and unvaccinated or under-vaccinated children than paediatricians. Missing vaccination certificates pose a severe problem regarding the interpretability of vaccination data. Although the coverage for at least one measles vaccination is higher in the studied county than in most South German counties and higher than the European average, many severe and potentially dangerous vaccination gaps occur locally. If other federal German states and EU countries show similar vaccination variability, measles elimination may not succeed in Europe.

A Neonatal Murine Model of Coxsackievirus A6 Infection for Evaluation of Antiviral and Vaccine Efficacy

PubMed Central

Zhang, Zhenjie; Dong, Zhaopeng; Wei, Qingjuan; Carr, Michael J.; Li, Juan; Ding, Shujun; Tong, Yigang

2017-01-01

ABSTRACT Hand, foot, and mouth disease (HFMD) is a global health concern. Family Picornaviridae members, particularly enterovirus A71 (EVA71) and coxsackievirus A16 (CVA16), are the primary etiological agents of HFMD; however, a third enterovirus A species, CVA6, has been recently associated with epidemic outbreaks. Study of the pathogenesis of CVA6 infection and development of antivirals and vaccines are hindered by a lack of appropriate animal models. We have developed and characterized a murine model of CVA6 infection that was employed to evaluate the antiviral activities of different drugs and the protective efficacies of CVA6-inactivated vaccines. Neonatal mice were susceptible to CVA6 infection via intramuscular inoculation, and the susceptibility of mice to CVA6 infection was age and dose dependent. Five-day-old mice infected with 105.5 50% tissue culture infective doses of the CVA6 WF057R strain consistently exhibited clinical signs, including reduced mobility, lower weight gain, and quadriplegia with significant pathology in the brain, hind limb skeletal muscles, and lungs of the infected mice in the moribund state. Immunohistochemical analysis and quantitative reverse transcription-PCR (qRT-PCR) analyses showed high viral loads (11 log10/mg) in skeletal muscle, and elevated levels of interleukin-6 (IL-6; >2,000 pg/ml) were associated with severe viral pneumonia and encephalitis. Ribavirin and gamma interferon administered prophylactically diminished CVA6-associated pathology in vivo, and treatment with IL-6 accelerated the death of neonatal mice. Both specific anti-CVA6 serum and maternal antibody play important roles in controlling CVA6 infection and viral replication. Collectively, these findings indicate that this neonatal murine model will be invaluable in future studies to develop CVA6-specific antivirals and vaccines. IMPORTANCE Although coxsackievirus A6 (CVA6) infections are commonly mild and self-limiting, a small proportion of children may have serious complications, such as encephalitis, acute flaccid paralysis, and neurorespiratory syndrome, leading to fatalities. We have established a mouse model of CVA6 infection by inoculation of neonatal mice with a CVA6 clinical isolate that produced consistent pathological outcomes. Here, using this model of CVA6 infection, we found that high levels of IL-6 were associated with severe viral pneumonia and encephalitis, as in an evaluation of antiviral efficacy in vivo, IL-6 had no protective effect and instead accelerated death in neonatal mice. We demonstrated that, as antiviral drugs, both gamma interferon and ribavirin played important protective roles in the early stages of infection, with increased survival in treated neonatal mice challenged with CVA6. Moreover, active and passive immunization with the inactivated vaccines and anti-CVA6 serum also protected mice against homologous challenge infections. PMID:28250116

First-in-human safety and immunogenicity investigations of three adjuvanted reduced dose inactivated poliovirus vaccines (IPV-Al SSI) compared to full dose IPV Vaccine SSI when given as a booster vaccination to adolescents with a history of IPV vaccination at 3, 5, 12months and 5years of age.

PubMed

Lindgren, Line M; Tingskov, Pernille N; Justesen, Annette H; Nedergaard, Bettina S; Olsen, Klaus J; Andreasen, Lars V; Kromann, Ingrid; Sørensen, Charlotte; Dietrich, Jes; Thierry-Carstensen, Birgit

2017-01-23

There is a demand of affordable IPV in the World. Statens Serum Institut (SSI) has developed three reduced dose IPV formulations adsorbed to aluminium hydroxide; 1/3 IPV-Al, 1/5 IPV-Al and 1/10 IPV-Al SSI, and now report the results of the first investigations in humans. 240 Danish adolescents, aged 10-15years, and childhood vaccinated with IPV were booster vaccinated with 1/3 IPV-Al, 1/5 IPV-Al, 1/10 IPV-Al or IPV Vaccine SSI. The booster effects (GMTRs) of the three IPV-Al SSI were compared to IPV Vaccine SSI, and evaluated for non-inferiority. The pre-vaccination GMTs were similar across the groups; 926 (type 1), 969 (type 2) and 846 (type 3) in the total trial population. The GMTRs by poliovirus type and IPV formulation were: Type 1: 17.0 (1/3 IPV-Al), 13.0 (1/5 IPV-Al), 7.1 (1/10 IPV-Al) and 42.2 (IPV Vaccine SSI). Type 2: 12.5 (1/3 IPV-Al), 13.1 (1/5 IPV-Al), 7.6 (1/10 IPV-Al) and 47.8 (IPV Vaccine SSI). Type 3: 14.5 (1/3 IPV-Al), 16.2 (1/5 IPV-Al), 8.9 (1/10 IPV-Al) and 62.4 (IPV Vaccine SSI) Thus, the three IPV-Al formulations were highly immunogenic, but inferior to IPV Vaccine SSI, in this booster vaccination trial. No SAE and no AE of severe intensity occurred. 59.2% of the subjects reported at least one AE. Injection site pain was the most frequent AE in all groups; from 24.6% to 43.3%. Injection site redness and swelling frequencies were<5% in most and<10% in all groups. The most frequent systemic AEs were fatigue (from 8.2% to 15.0%) and headache (from 15.0% to 28.3%). Most AEs were of mild intensity. In conclusion, the three IPV-Al SSI were safe in adolescents and the booster effects were satisfactory. ClinicalTrials.gov registration number: NCT02280447. Copyright © 2016. Published by Elsevier Ltd.

Vaccination rate and seroepidemiology of hepatitis a in chronic-hepatitis-B-infected individuals in the korean army.

PubMed

Shin, Dong Hyuk; Han, Sang Kuk; Choi, Pil Cho; Lim, Seong Woo; Kim, Kyung Mook; Sinn, Dong Hyun

2010-06-01

Vaccination against hepatitis A virus (HAV) is recommended for patients with chronic hepatitis B (CHB), since they are potentially at an increased risk of HAV-related morbidity and mortality. However, little is known about the adherence to these recommendations in the community. This study evaluated the current vaccination status and immunity against HAV among Korean military soldiers with CHB. We performed a prospective study of Korean military soldiers from August 2008 to January 2009. We enrolled 96 soldiers with CHB on a consecutive basis. We assessed their vaccination history and the presence of anti-HAV immunoglobulin G (IgG). The HAV vaccination rate of the soldiers enrolled in our study was 2% (2 of the 96 soldiers). The seroprevalence rates of anti-HAV IgG among military soldiers without a vaccination history were 0%, 50%, and 100% for those aged 19-29 years (n=71), 30-39 years (n=8), and 40 years or older (n=15), respectively (p<0.001). The HAV vaccination rate is very low among military soldiers. Public health efforts aimed at raising awareness about HAV vaccination in patients with CHB should be strongly encouraged.

Association of infectious mononucleosis with multiple sclerosis. A population-based study.

PubMed

Ramagopalan, Sreeram V; Valdar, William; Dyment, David A; DeLuca, Gabriele C; Yee, Irene M; Giovannoni, Gavin; Ebers, George C; Sadovnick, A Dessa

2009-01-01

Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. Several studies have attempted to correlate exposure to viral illness with the subsequent development of MS. Here in a population-based Canadian cohort, we investigate the relationship between prior clinical infection or vaccination and the risk of MS. Using the longitudinal Canadian database, 14,362 MS index cases and 7,671 spouse controls were asked about history of measles, mumps, rubella, varicella and infectious mononucleosis as well as details about vaccination with measles, mumps, rubella, hepatitis B and influenza vaccines. Comparisons were made between cases and spouse controls. Spouse controls and stratification by sex appear to correct for ascertainment bias because with a single exception we found no significant differences between cases and controls for all viral exposures and vaccinations. However, 699 cases and 165 controls reported a history of infectious mononucleosis (p < 0.001, corrected odds ratio 2.06, 95% confidence interval 1.71-2.48). Females were more aware of disease history than males (p < 0.001). The data further confirms a reporting distortion between males and females. Historically reported measles, mumps, rubella, varicella and vaccination for hepatitis B, influenza, measles, mumps and rubella are not associated with increased risk of MS later in life. A clinical history of infectious mononucleosis is conspicuously associated with increased MS susceptibility. These findings support studies implicating Epstein-Barr virus in MS disease susceptibility, but a co-association between MS susceptibility and clinically apparent infectious mononucleosis cannot be excluded.

Detection and differentiation of field and vaccine strains of canine distemper virus using reverse transcription followed by nested real time PCR (RT-nqPCR) and RFLP analysis.

PubMed

Fischer, Cristine Dossin Bastos; Ikuta, Nilo; Canal, Cláudio Wageck; Makiejczuk, Aline; Allgayer, Mariangela da Costa; Cardoso, Cristine Hoffmeister; Lehmann, Fernanda Kieling; Fonseca, André Salvador Kazantzi; Lunge, Vagner Ricardo

2013-12-01

Canine distemper virus (CDV) is the cause of a severe and highly contagious disease in dogs. Practical diagnosis of canine distemper based on clinical signs and laboratory tests are required to confirm CDV infection. The present study aimed to develop a molecular assay to detect and differentiate field and vaccine CDV strains. Reverse transcription followed by nested real time polymerase chain reaction (RT-nqPCR) was developed, which exhibited analytical specificity (all the samples from healthy dogs and other canine infectious agents were not incorrectly detected) and sensitivity (all replicates of a vaccine strain were positive up to the 3125-fold dilution - 10(0.7) TCID50). RT-nqPCR was validated for CDV detection on different clinical samples (blood, urine, rectal and conjunctival swabs) of 103 animals suspected to have distemper. A total of 53 animals were found to be positive based on RT-nqPCR in at least one clinical sample. Blood resulted in more positive samples (50 out of 53, 94.3%), followed by urine (44/53, 83.0%), rectal (38/53, 71%) and conjunctival (27/53, 50.9%) swabs. A commercial immunochromatography (IC) assay had detected CDV in only 30 conjunctival samples of these positive dogs. Nucleoprotein (NC) gene sequencing of 25 samples demonstrated that 23 of them were closer to other Brazilian field strains and the remaining two to vaccine strains. A single nucleotide sequences difference, which creates an Msp I restriction enzyme digestion, was used to differentiate between field and vaccine CDV strains by restriction fragment length polymorphism (RFLP) analysis. The complete assay was more sensitive than was IC for the detection of CDV. Blood was the more frequently positive specimen and the addition of a restriction enzyme step allowed the differentiation of vaccine and Brazilian field strains. Copyright © 2013 Elsevier B.V. All rights reserved.

Parental Attitudes and Factors Associated With Varicella Vaccination in Preschool and Schoolchildren in Hong Kong: A Cross-Sectional Study.

PubMed

Tam, Wilson W S; Chan, Johnny; Lo, Kenneth K H; Lee, Albert; Chan, Paul K S; Chan, Denise; Nelson, E Anthony S

2015-09-01

This study investigates parental attitudes and factors associated with varicella vaccination among preschool and schoolchildren prior to introduction of the vaccine into Hong Kong's universal Childhood Immunization Program.Fourteen kindergartens and 5 primary schools in Hong Kong were randomly selected in 2013. Parents of the students were invited to answer the self-administered questionnaires. Acquired information included demographic characteristics and socioeconomic statuses of families, children's history of chickenpox infection and vaccination, and reasons for getting children vaccinated. Logistic regression was applied to examine the factors associated with vaccination.From the 3484 completed questionnaires, the calculated rates of varicella infection and vaccination were 20.7% and 69.0%, respectively. Barriers to vaccination included parental uncertainties about vaccine effectiveness, lack of recommendation from the government, and concerns on adverse effects. Overall, 71.8%, 69.0%, and 45.7% of the parents rated family doctors, specialists, and the government, respectively, as very important motivators of vaccination. Higher parental educational level and family income, better perceived knowledge of varicella and chance of infection, discussion with a family doctor, and positive health belief towards vaccination were associated with vaccination (all P < 0.05).The rate of vaccination in Hong Kong was higher than that of some other countries that also did not include the vaccine in their routine immunization programs. More positive parental attitudes, higher socioeconomic status, and discussion with a family doctor are associated with greater vaccination rates. The important roles that health professionals and the government play in promoting varicella vaccination were emphasized.

Parental Attitudes and Factors Associated With Varicella Vaccination in Preschool and Schoolchildren in Hong Kong

PubMed Central

Tam, Wilson W.S.; Chan, Johnny; Lo, Kenneth K.H.; Lee, Albert; Chan, Paul K.S.; Chan, Denise; Nelson, E. Anthony S.

2015-01-01

Abstract This study investigates parental attitudes and factors associated with varicella vaccination among preschool and schoolchildren prior to introduction of the vaccine into Hong Kong's universal Childhood Immunization Program. Fourteen kindergartens and 5 primary schools in Hong Kong were randomly selected in 2013. Parents of the students were invited to answer the self-administered questionnaires. Acquired information included demographic characteristics and socioeconomic statuses of families, children's history of chickenpox infection and vaccination, and reasons for getting children vaccinated. Logistic regression was applied to examine the factors associated with vaccination. From the 3484 completed questionnaires, the calculated rates of varicella infection and vaccination were 20.7% and 69.0%, respectively. Barriers to vaccination included parental uncertainties about vaccine effectiveness, lack of recommendation from the government, and concerns on adverse effects. Overall, 71.8%, 69.0%, and 45.7% of the parents rated family doctors, specialists, and the government, respectively, as very important motivators of vaccination. Higher parental educational level and family income, better perceived knowledge of varicella and chance of infection, discussion with a family doctor, and positive health belief towards vaccination were associated with vaccination (all P < 0.05). The rate of vaccination in Hong Kong was higher than that of some other countries that also did not include the vaccine in their routine immunization programs. More positive parental attitudes, higher socioeconomic status, and discussion with a family doctor are associated with greater vaccination rates. The important roles that health professionals and the government play in promoting varicella vaccination were emphasized. PMID:26356725

Molecular epidemiology of enterovirus and parechovirus infections according to patient age over a 4-year period in Spain.

PubMed

Cabrerizo, María; Díaz-Cerio, María; Muñoz-Almagro, Carmen; Rabella, Núria; Tarragó, David; Romero, María Pilar; Pena, María José; Calvo, Cristina; Rey-Cao, Sonia; Moreno-Docón, Antonio; Martínez-Rienda, Inés; Otero, Almudena; Trallero, Gloria

2017-03-01

The epidemiology and clinical association of enterovirus (EV) and parechovirus (HPeV) infections, as well as the type-distribution-according-to-age, were determined during a 4-year study period in Spain. During 2010-2013, a total of 21,832 clinical samples were screened for EV and the detection frequency was 6.5% (1,430). Of the total EV-negative samples, only 1,873 samples from 2011 to 2013 were available for HPeV testing. HPeV was detected in 42 (2%) of them. Positive samples were genotyped using PCR and sequencing. EV infections occurred in all age groups of patients: neonates (17%), children 28 days to 2 years (29%), children 2-14 years (40%), and adults (14%). Thirty-four different EV types were identified. HPeV infections were detected exclusively in infants <8 m (70% neonates, P < 0.05). All but one HPeV were HPeV-3. Differences in type frequency detection were found according to age and clinical manifestation. Coxsackievirus (CV)-B4 (61%), CV-B5 (83%), and HPeV-3 (64%) were more frequent in neonates than in older patients (P < 0.05). Echovirus (E)-3 (60%), E-18 (47%), E-25 (62%), CV-A6 (61%), CV-A16 (72%), and EV-71 (75%) were mainly detected in children 28 days to 2 years (P < 0.05), whereas, E-6 (79%), E-20 (88%), and E-30 (85%) were predominant in children >2 years and adults (P < 0.05). Clinically, meningitis was associated with EV (P < 0.01) whereas, encephalitis was more frequent in HPeV-infected patients. CV-B types were associated with myocarditis (90%; P < 0.05) and EV species A with hand-foot-mouth-disease/atypical exanthema (88%; P < 0.05). J. Med. Virol. 89:435-442, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Community vaccine perceptions and its role on vaccination uptake among children aged 12-23 months in the Ileje District, Tanzania: a cross section study

PubMed Central

Chambongo, Pai Elia; Nguku, Patrick; Wasswa, Peter; Semali, Innocent

2016-01-01

Introduction Underutilization of vaccines still remains a challenge in many regions across the world. Ileje district is one of the districts in Tanzania with consistently low pentavalent vaccine uptake (69%) and with drop out of 15%. We determined the vaccination completion with regard to Oral Polio virus, Measles, Bacillus Calmette-Guérin, and pentavalent vaccines and its association with community perceptions on vaccines. Methods We conducted a cross sectional study in Ileje district from October to December 2013. We sampled 380 mothers using a multistage random sampling technique. We analysed data using EPI INFO. We summarized descriptive variables using mean and standard deviation and categorical variables using proportions. We conducted bivariate and multivariate logistic regression to identify factors influencing vaccination uptake, statistical significance was assessed at 95% confidence interval. Results Mean age of the mothers was 27 years (SD 6.5 years) while that of their children was 16 months (SD 3.6 months). Fully vaccinated children were 71.1% and partially vaccinated were 28.9%, 99.2% were vaccinated with BCG vaccine and 73.4% were vaccinated with all OPV vaccine. Predictors of vaccination completion included negative perception on the vaccine provider-client relationship (AOR 1.86, 95%CI1.03-3.35), Perceived satisfaction with vaccination services (AOR 2.63, 95%CI 1.1 - 6.3). Others include child being born in the health facility (AOR 13.8 95% CI 8.04-25.8) and younger age of a child (AOR 0.51, 95%CI 0.29-0.9). Conclusion Improving quality of vaccination services, promoting health education and sensitizing community on health facility delivery will improve child vaccination completion in the district PMID:27303578

Community vaccine perceptions and its role on vaccination uptake among children aged 12-23 months in the Ileje District, Tanzania: a cross section study.

PubMed

Chambongo, Pai Elia; Nguku, Patrick; Wasswa, Peter; Semali, Innocent

2016-01-01

Underutilization of vaccines still remains a challenge in many regions across the world. Ileje district is one of the districts in Tanzania with consistently low pentavalent vaccine uptake (69%) and with drop out of 15%. We determined the vaccination completion with regard to Oral Polio virus, Measles, Bacillus Calmette-Guérin, and pentavalent vaccines and its association with community perceptions on vaccines. We conducted a cross sectional study in Ileje district from October to December 2013. We sampled 380 mothers using a multistage random sampling technique. We analysed data using EPI INFO. We summarized descriptive variables using mean and standard deviation and categorical variables using proportions. We conducted bivariate and multivariate logistic regression to identify factors influencing vaccination uptake, statistical significance was assessed at 95% confidence interval. Mean age of the mothers was 27 years (SD 6.5 years) while that of their children was 16 months (SD 3.6 months). Fully vaccinated children were 71.1% and partially vaccinated were 28.9%, 99.2% were vaccinated with BCG vaccine and 73.4% were vaccinated with all OPV vaccine. Predictors of vaccination completion included negative perception on the vaccine provider-client relationship (AOR 1.86, 95%CI1.03-3.35), Perceived satisfaction with vaccination services (AOR 2.63, 95%CI 1.1 - 6.3). Others include child being born in the health facility (AOR 13.8 95% CI 8.04-25.8) and younger age of a child (AOR 0.51, 95%CI 0.29-0.9). Improving quality of vaccination services, promoting health education and sensitizing community on health facility delivery will improve child vaccination completion in the district.

Direct Identification of Enteroviruses in Cerebrospinal Fluid of Patients with Suspected Meningitis by Nested PCR Amplification.

PubMed

Krasota, Alexandr; Loginovskih, Natalia; Ivanova, Olga; Lipskaya, Galina

2016-01-06

Enteroviruses, the most common human viral pathogens worldwide, have been associated with serous meningitis, encephalitis, syndrome of acute flaccid paralysis, myocarditis and the onset of diabetes type 1. In the future, the rapid identification of the etiological agent would allow to adjust the therapy promptly and thereby improve the course of the disease and prognosis. We developed RT-nested PCR amplification of the genomic region coding viral structural protein VP1 for direct identification of enteroviruses in clinical specimens and compared it with the existing analogs. One-hundred-fifty-nine cerebrospinal fluids (CSF) from patients with suspected meningitis were studied. The amplification of VP1 genomic region using the new method was achieved for 86 (54.1%) patients compared with 75 (47.2%), 53 (33.3%) and 31 (19.5%) achieved with previously published methods. We identified 11 serotypes of the Enterovirus species B in 2012, including relatively rare echovirus 14 (E-14), E-15 and E-32, and eight serotypes of species B and 5 enteroviruses A71 (EV-A71) in 2013. The developed method can be useful for direct identification of enteroviruses in clinical material with the low virus loads such as CSF.

Direct Identification of Enteroviruses in Cerebrospinal Fluid of Patients with Suspected Meningitis by Nested PCR Amplification

PubMed Central

Krasota, Alexandr; Loginovskih, Natalia; Ivanova, Olga; Lipskaya, Galina

2016-01-01

Enteroviruses, the most common human viral pathogens worldwide, have been associated with serous meningitis, encephalitis, syndrome of acute flaccid paralysis, myocarditis and the onset of diabetes type 1. In the future, the rapid identification of the etiological agent would allow to adjust the therapy promptly and thereby improve the course of the disease and prognosis. We developed RT-nested PCR amplification of the genomic region coding viral structural protein VP1 for direct identification of enteroviruses in clinical specimens and compared it with the existing analogs. One-hundred-fifty-nine cerebrospinal fluids (CSF) from patients with suspected meningitis were studied. The amplification of VP1 genomic region using the new method was achieved for 86 (54.1%) patients compared with 75 (47.2%), 53 (33.3%) and 31 (19.5%) achieved with previously published methods. We identified 11 serotypes of the Enterovirus species B in 2012, including relatively rare echovirus 14 (E-14), E-15 and E-32, and eight serotypes of species B and 5 enteroviruses A71 (EV-A71) in 2013. The developed method can be useful for direct identification of enteroviruses in clinical material with the low virus loads such as CSF. PMID:26751470

Electronic and transport properties of fluorite structure of La2Ce2O7

NASA Astrophysics Data System (ADS)

Mahida, H. R.; Singh, Deobrat; Gupta, Sanjeev K.; Sonvane, Yogesh; Thakor, P. B.

2017-05-01

In this paper, we have symmetrically investigated the structural, electronic and transport properties of fluorite structure of lanthanum cerate oxide (La2Ce2O7) using density functional theory (DFT). The electronic band structure of La2Ce2O7 show semiconducting in nature with band gap of 1.54 eV (indirect at R-X points) and 1.71 eV (direct at R points). We have also calculated the susceptibility, hall resistance, electrical, and thermal conductivity by using Boltztrap equation. The electrical conductivity decreases where as thermal conductivity increases with increase in the temperature. Our result shows that La2Ce2O7 has application in Proton exchange membrane (PEM) fuel cells applications.

Protective Effect of Maternal Influenza Vaccination on Influenza in Their Infants: A Prospective Cohort Study.

PubMed

Ohfuji, Satoko; Deguchi, Masaaki; Tachibana, Daisuke; Koyama, Masayasu; Takagi, Tetsu; Yoshioka, Takayuki; Urae, Akinori; Ito, Kazuya; Kase, Tetsuo; Maeda, Akiko; Kondo, Kyoko; Fukushima, Wakaba; Hirota, Yoshio

2018-03-05

Infants <6 months of age are too young to receive influenza vaccine, despite being at high risk for severe influenza-related complications. To examine the effectiveness of maternal influenza vaccination in preventing influenza in their infants, we conducted a prospective cohort study of 3441 infants born at participating hospitals before the 2013-2014 influenza season. At the time of recruitment, their mothers completed a questionnaire about influenza vaccination status for the 2013-2014 season. A follow-up survey was conducted after the end of the 2013-2014 season to collect information regarding influenza diagnosis and hospitalization among infants. During the 2013-2014 influenza season, 71 infants (2%) had influenza diagnosed, and 13 infants (0.4%) were hospitalized with influenza. Maternal influenza vaccination (especially prenatal vaccination) decreased the odds of influenza among infants. The effectiveness of prenatal vaccination was 61% (95% confidence interval, 16%-81%), whereas that of postpartum vaccination was 53% (-28%-83%). Although maternal influenza vaccination was also associated with a decreased odds of influenza-related hospitalization among infants, vaccine effectiveness (73%) did not reach statistical significance, owing to the limited number of infants hospitalized because of influenza. The present findings indicated that pregnant women and postpartum women should receive influenza vaccination to protect their infants. © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Knowledge and concerns related to the human papillomavirus vaccine among underserved Latina women.

PubMed

Wu, Justine P; Porch, Emily; McWeeney, Michelle; Ohman-Strickland, Pamela; Levine, Jeffrey P

2010-07-01

This study's purpose was to assess knowledge and concerns related to the human papillomavirus (HPV) vaccine among underserved Latina women and Latina mothers of female adolescents and to explore differences between those in the vaccinated and those in the unvaccinated groups. We conducted cross-sectional written surveys of 206 Latina women at an urban health center in central New Jersey. Participants included vaccine-eligible women and mothers of vaccine-eligible adolescents. We calculated descriptive statistics, Fisher exact tests, and corresponding risk ratios (RRs) with 95% CIs. Of those who had heard of HPV (71%), 80% knew that HPV is a sexually transmitted infection. Fewer understood the causative link between HPV and cervical cancer (58%) and genital warts (45%). Vaccine safety was the most frequently cited concern. Unvaccinated women and mothers of unvaccinated daughters were more worried that the vaccine could promote risky sexual behavior (RR = 1.6, 95% CI = 1.2-2.1) and more likely to believe that they or their daughters were not at risk for HPV infection (RR = 1.2, 95% CI = 1.1-1.4). To maximize HPV vaccination rates among underserved Latinas, concerns about vaccine safety, potential effects on sexual behavior, and self-perceptions of risk for HPV infection must be addressed.

Human papillomavirus vaccine knowledge and hypothetical acceptance among women in Appalachia Ohio

PubMed Central

Hade, Erinn M.; Gorsline, Melissa R.; DeGraffinreid, Cecilia R.; Katz, Mira L.; Kobrin, Sarah C.; Paskett, Electra D.

2013-01-01

Objective To assess hypothetical acceptance of the human papillomavirus (HPV) vaccine for themselves and a daughter age 9–12 years among Appalachia Ohio women. Methods Women with an abnormal Pap smear and randomly selected women with a normal Pap smear from 17 clinics completed an interview in 2006–2008. Results From 1131 original study participants, 807 (71%) completed a survey about the HPV vaccine for their daughters and themselves. Nearly half, 380 (47%), of the participants had heard of a vaccine to prevent cancer, and 362 (95%) of respondents had heard of HPV. The participants were then told that the FDA had approved a vaccine to prevent HPV. Only 379 (38%) participants identified girls ages 9–12 years as a group who should get the vaccine. After being given the official HPV vaccine recommendation statement, 252 (31%) wanted the vaccine; 198 (25%) were “not sure”; and 353 (44%) did not want the vaccine for themselves. With respect to giving the HPV vaccine to a daughter ages 9–12 years, participants responded “yes” 445 (55%); “not sure” 163 (20%); or “no” 185 (23%). Numerous reasons were provided supporting and opposing vaccine acceptance for themselves and for a daughter. Their physician’s recommendation for the HPV vaccine increased vaccine acceptance to 86% for themselves and 90% for a daughter. Conclusion Knowledge, acceptance, and barriers about the HPV vaccine vary among women living in Appalachia Ohio. Physician recommendation is a key facilitator for vaccine diffusion in this region. PMID:22749839

Vaccines for preventing enterotoxigenic Escherichia coli (ETEC) diarrhoea.

PubMed

Ahmed, Tanvir; Bhuiyan, Taufiqur R; Zaman, K; Sinclair, David; Qadri, Firdausi

2013-07-05

Infection with enterotoxigenic Escherichia coli (ETEC) bacteria is a common cause of diarrhoea in adults and children in developing countries and is a major cause of 'travellers' diarrhoea' in people visiting or returning from endemic regions. A killed whole cell vaccine (Dukoral®), primarily designed and licensed to prevent cholera, has been recommended by some groups to prevent travellers' diarrhoea in people visiting endemic regions. This vaccine contains a recombinant B subunit of the cholera toxin that is antigenically similar to the heat labile toxin of ETEC. This review aims to evaluate the clinical efficacy of this vaccine and other vaccines designed specifically to protect people against diarrhoea caused by ETEC infection. To evaluate the efficacy, safety, and immunogenicity of vaccines for preventing ETEC diarrhoea. We searched the Cochrane Infectious Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, and http://clinicaltrials.gov up to December 2012. Randomized controlled trials (RCTs) and quasi-RCTs comparing use of vaccines to prevent ETEC with use of no intervention, a control vaccine (either an inert vaccine or a vaccine normally given to prevent an unrelated infection), an alternative ETEC vaccine, or a different dose or schedule of the same ETEC vaccine in healthy adults and children living in endemic regions, intending to travel to endemic regions, or volunteering to receive an artificial challenge of ETEC bacteria. Two authors independently assessed each trial for eligibility and risk of bias. Two independent reviewers extracted data from the included studies and analyzed the data using Review Manager (RevMan) software. We reported outcomes as risk ratios (RR) with 95% confidence intervals (CI). We assessed the quality of the evidence using the GRADE approach. Twenty-four RCTs, including 53,247 participants, met the inclusion criteria. Four studies assessed the protective efficacy of oral cholera vaccines when used to prevent diarrhoea due to ETEC and seven studies assessed the protective efficacy of ETEC-specific vaccines. Of these 11 studies, seven studies presented efficacy data from field trials and four studies presented efficacy data from artificial challenge studies. An additional 13 trials contributed safety and immunological data only. Cholera vaccinesThe currently available, oral cholera killed whole cell vaccine (Dukoral®) was evaluated for protection of people against 'travellers' diarrhoea' in a single RCT in people arriving in Mexico from the USA. We did not identify any statistically significant effects on ETEC diarrhoea or all-cause diarrhoea (one trial, 502 participants, low quality evidence).Two earlier trials, one undertaken in an endemic population in Bangladesh and one undertaken in people travelling from Finland to Morocco, evaluated a precursor of this vaccine containing purified cholera toxin B subunit rather than the recombinant subunit in Dukoral®. Short term protective efficacy against ETEC diarrhoea was demonstrated, lasting for around three months (RR 0.43, 95% CI 0.26 to 0.71; two trials, 50,227 participants). This vaccine is no longer available. ETEC vaccinesAn ETEC-specific, killed whole cell vaccine, which also contains the recombinant cholera toxin B-subunit, was evaluated in people travelling from the USA to Mexico or Guatemala, and from Austria to Latin America, Africa, or Asia. We did not identify any statistically significant differences in ETEC-specific diarrhoea or all-cause diarrhoea (two trials, 799 participants), and the vaccine was associated with increased vomiting (RR 2.0, 95% CI 1.16 to 3.45; nine trials, 1528 participants). The other ETEC-specific vaccines in development have not yet demonstrated clinically important benefits. There is currently insufficient evidence from RCTs to support the use of the oral cholera vaccine Dukoral® for protecting travellers against ETEC diarrhoea. Further research is needed to develop safe and effective vaccines to provide both short and long-term protection against ETEC diarrhoea.

Knowledge, attitudes and practices of South African healthcare workers regarding the prevention and treatment of influenza among HIV-infected individuals.

PubMed

Duque, Jazmin; Gaga, Sisanda; Clark, David; Muller, Madeleine; Kuwane, Bulenani; Cohen, Cheryl; Walaza, Sibongile; Tempia, Stefano; Ramatoboe, Puleng; Furumele, Tsakani; Widdowson, Marc-Alain; McMorrow, Meredith L; Cohen, Adam L

2017-01-01

The South African Department of Health (DOH) publishes annual guidelines identifying priority groups, including immunosuppressed individuals and healthcare workers (HCW), for influenza vaccination and treatment. How these guidelines have impacted HCW and their patients, particularly those infected with HIV, remains unknown. We aimed to describe the knowledge, attitudes and practices regarding influenza and the vaccine among South African HCW. Surveys were distributed by two local non-governmental organizations in public health clinics and hospitals in 21 districts/municipalities (5 of 9 provinces). There were 1164 respondents; median age 41 years; 978/1126 (87%) female; 801/1122 (71%) nurses. One-third (34%) of HCW reported getting influenza vaccine 2013/2014 and most (94%) recommended influenza vaccine to patients infected with HIV. Ability to get vaccine free of charge (aOR 1.69; 95% CI 1.21-2.37) and having received influenza government training (aOR 1.50; 95% CI 1.04-2.15) were significantly associated with self-reported vaccination in 2013/2014. Self-reported 2013/2014 vaccination (aOR 3.76; 95% CI 1.28-11.03) and availability of influenza vaccine during the healthcare visit (aOR 2.56; 95% CI 1.18-5.57) were significantly associated with recommending influenza vaccine to patients infected with HIV/AIDS. Only one-third of participants were vaccinated in 2013-2014 but those who were vaccinated were more likely to recommend vaccination to their patients. Free and close access to influenza vaccine were associated with a higher likelihood of getting vaccinated in 2013/2014. HCW who reported getting the influenza vaccine themselves, had vaccine to offer during the patient consult and were familiar with DOH guidelines/trainings were more likely to recommend vaccine to HIV-infected patients.

HPV Vaccination among Adolescent Males: Results from the National Immunization Survey-Teen

PubMed Central

Reiter, Paul L.; Gilkey, Melissa B.; Brewer, Noel T.

2013-01-01

US guidelines provided a permissive recommendation forHPV vaccine for males in 2009, with an updated recommendation for routine vaccination in 2011. Dataon vaccine uptake among males, however, remain sparse. We analyzed 2010–2011 data (collected mostlyprior to the recommendation for routine vaccination) from the National Immunization Survey-Teen for a nationally representative sample of adolescent males ages 13–17 (n=22,365). We examined HPV vaccine initiation( receipt of at least one doseba sed on healthcare provider records) as the primary outcome. Analyses used weighted logistic regression. HPV vaccine initiation increased from 1.4% in 2010 to 8.3% in 2011. Parents who reported receiving a healthcare provider recommendation to get their sons HPV vaccine were much more likely to have vaccinated sons (OR=19.02, 95% CI: 14.36–25.19). Initiation was also higher among sons who were Hispanic (OR=1.83, 95% CI: 1.24–2.71) or who were eligible for the Vaccines for Children program (OR=1.53, 95% CI: 1.01–2.31). Only31.0% of parents with unvaccinated sons indicatedtheir sons were “somewhat likely” or “very likely” to receive HPV vaccine in the next year. The most common main reasons for parents not intending to vaccinate were believing vaccination is not needed or not necessary (24.5%), not having received a provider recommendation (22.1%), and lack of knowledge (15.9%). HPV vaccination is low among adolescent males in the US, and provider recommendation for vaccination is likely keyto improv ingvaccine uptake. Given the updated recommendation for routine vaccination and the changes in health insurance coverage that are likely to follow, continued efforts are needed to monitor HPV vaccination among males. PMID:23602667

The mature virion of ectromelia virus, a pathogenic poxvirus, is capable of intrahepatic spread and can serve as a target for delayed therapy.

PubMed

Ma, Xueying; Xu, Ren-Huan; Roscoe, Felicia; Whitbeck, J Charles; Eisenberg, Roselyn J; Cohen, Gary H; Sigal, Luis J

2013-06-01

Orthopoxviruses (OPVs), which include the agent of smallpox (variola virus), the zoonotic monkeypox virus, the vaccine and zoonotic species vaccinia virus, and the mouse pathogen ectromelia virus (ECTV), form two types of infectious viral particles: the mature virus (MV), which is cytosolic, and the enveloped virus (EV), which is extracellular. It is believed that MVs are required for viral entry into the host, while EVs are responsible for spread within the host. Following footpad infection of susceptible mice, ECTV spreads lymphohematogenously, entering the liver at 3 to 4 days postinfection (dpi). Afterwards, ECTV spreads intrahepatically, killing the host. We found that antibodies to an MV protein were highly effective at curing mice from ECTV infection when administered after the virus reached the liver. Moreover, a mutant ECTV that does not make EV was able to spread intrahepatically and kill immunodeficient mice. Together, these findings indicate that MVs are sufficient for the spread of ECTV within the liver and could have implications regarding the pathogenesis of other OPVs, the treatment of emerging OPV infections, as well as strategies for preparedness in case of accidental or intentional release of pathogenic OPVs.

Factors associated with dog rabies vaccination in Bhol, Philippines: results of a cross-sectional cluster survey conducted following the island-wide rabies elimination campaign.

PubMed

Davlin, S; Lapiz, S M; Miranda, M E; Murray, K

2013-11-01

The Philippines has a long history of rabies control efforts in their dog populations; however, long-term success of such programmes and the goal of rabies elimination have not yet been realized. The Bohol Rabies Prevention and Elimination Program was developed as an innovative approach to canine rabies control in 2007. The objective of this study was to assess canine rabies vaccination coverage in the owned-dog population in Bohol and to describe factors associated with rabies vaccination 2 years after implementation of the programme. We utilized a cross-sectional cluster survey based on the World Health Organization's Expanded Programme on Immunization coverage survey technique. We sampled 460 households and collected data on 539 dogs residing within these households. Seventy-seven per cent of surveyed households reported owning at least one dog. The human-to-dog ratio was approximately 4 : 1, and the mean number of dogs owned per household was 1.6. Based on this ratio, we calculated an owned-dog population of almost 300 000. Overall, 71% of dogs were reported as having been vaccinated for rabies at some time in their lives; however, only 64% of dogs were reported as having been recently vaccinated. Dogs in our study were young (median age = 24 months). The odds of vaccination increased with increasing age. Dogs aged 12-23 months had 4.6 times the odds of vaccination compared to dogs aged 3-11 months (95% CI 1.8-12.0; P = 0.002). Confinement of the dog both day and night was also associated with increased odds of vaccination (OR = 2.1; 95% CI 0.9-4.9; P = 0.07), and this result approached statistical significance. While the programme is on track to meet its goal of 80% vaccination coverage, educational efforts should focus on the need to confine dogs and vaccinate young dogs. © 2012 Blackwell Verlag GmbH.

Combined approaches to flexible fitting and assessment in virus capsids undergoing conformational change☆

PubMed Central

Pandurangan, Arun Prasad; Shakeel, Shabih; Butcher, Sarah Jane; Topf, Maya

2014-01-01

Fitting of atomic components into electron cryo-microscopy (cryoEM) density maps is routinely used to understand the structure and function of macromolecular machines. Many fitting methods have been developed, but a standard protocol for successful fitting and assessment of fitted models has yet to be agreed upon among the experts in the field. Here, we created and tested a protocol that highlights important issues related to homology modelling, density map segmentation, rigid and flexible fitting, as well as the assessment of fits. As part of it, we use two different flexible fitting methods (Flex-EM and iMODfit) and demonstrate how combining the analysis of multiple fits and model assessment could result in an improved model. The protocol is applied to the case of the mature and empty capsids of Coxsackievirus A7 (CAV7) by flexibly fitting homology models into the corresponding cryoEM density maps at 8.2 and 6.1 Å resolution. As a result, and due to the improved homology models (derived from recently solved crystal structures of a close homolog – EV71 capsid – in mature and empty forms), the final models present an improvement over previously published models. In close agreement with the capsid expansion observed in the EV71 structures, the new CAV7 models reveal that the expansion is accompanied by ∼5° counterclockwise rotation of the asymmetric unit, predominantly contributed by the capsid protein VP1. The protocol could be applied not only to viral capsids but also to many other complexes characterised by a combination of atomic structure modelling and cryoEM density fitting. PMID:24333899

[Acceptability of human papillomavirus vaccine in mothers from Valencia (Spain)].

PubMed

Navarro-Illana, P; Caballero, P; Tuells, J; Puig-Barberá, J; Diez-Domingo, J

2015-11-01

In October 2008, Valencian Community started its human papillomavirus (HPV) vaccination schedules for 14 year-old girls. The aim of this study is to assess knowledge about HPV infection and its vaccine among the mothers of these girls, and to identify factors associated with the willingness to vaccinate their daughters. Cross-sectional study by means of a questionnaire to mothers of girls born in 1995, and attending secondary schools in the province of Valencia during 2010-2011. Cluster stratified random sample (n=1279). percentages, confidence intervals, OR, Chi-squared and multivariate logistic regression contrasts. A total of 833 (65.1%) questionnaires were completed. The results obtained showed that, 76.6% of mothers had vaccinated their daughters against HPV; 93.8% knew about the vaccine, particularly through television (71.5%); and 78.5% received positive advice from a health professional which increased the vaccination of their daughters (OR: 2.4). There was low overall knowledge about HPV infection and vaccination. Confidence of the mothers in vaccines as a preventative method increases the HPV vaccination (OR: 3.8). The first reason for refusal was the fear of adverse events (45.6%). Apparently, the media does not influence the willingness to vaccinate. It would be desirable to minimize the perception of risk of the vaccine. Positive health advice from a health professional can have a positive effect on vaccination. There is a gap between the level of knowledge and decision-making to vaccinate. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

Financial Issues and Adult Immunization: Medicare Coverage and the Affordable Care Act

PubMed Central

Hurley, Laura P.; Lindley, Megan C.; Allison, Mandy A.; Crane, Lori A.; Brtnikova, Michaela; Beaty, Brenda L.; Snow, Megan; Bridges, Carolyn B.; Kempe, Allison

2017-01-01

Background Financial barriers to adult vaccination are poorly understood. Our objectives were to assess among general internists (GIM) and family physicians (FP) shortly after Affordable Care Act (ACA) implementation: 1) proportion of adult patients deferring or refusing vaccines because of cost and frequency of physicians not recommending vaccines for financial reasons; 2) satisfaction with reimbursement for vaccine purchase and administration by payer type; 3) knowledge of Medicare coverage of vaccines; and 4) awareness of vaccine-specific provisions of the ACA. Methods We administered an Internet and mail survey from June to October 2013 to national networks of 438 GIMs and 401 FPs. Results Response rates were 72% (317/438) for GIM and 59% (236/401) for FP. Among physicians who routinely recommended vaccines, up to 24% of GIM and 30% of FP reported adult patients defer or refuse certain vaccines for financial reasons most of the time. Physicians reported not recommending vaccines because they thought the patient’s insurance would not cover it (35%) or the patient could be vaccinated more affordably elsewhere (38%). Among physicians who saw patients with this insurance, dissatisfaction (‘very dissatisfied’) was highest for payments received from Medicaid (16 % vaccine purchase, 14 % vaccine administration) and Medicare Part B (11 % vaccine purchase, 11 % vaccine administration). Depending on the vaccine, 36–71% reported not knowing how Medicare covered the vaccine. Thirty-seven percent were ‘not at all aware’ and 19% were ‘a little aware’ of vaccine-specific provisions of the ACA. Conclusions Patients are refusing and physicians are not recommending adult vaccinations for financial reasons. Increased knowledge of private and public insurance coverage for adult vaccinations might position physicians to be more likely to recommend vaccines and better enable them to refer patients to other vaccine providers when a particular vaccine or vaccines are not offered in the practice. PMID:28024954

A new modified live porcine reproductive and respiratory syndrome vaccine improves growth performance in pigs under field conditions.

PubMed

Park, Changhoon; Seo, Hwi Won; Kang, Ikjae; Jeong, Jiwoon; Choi, Kyuhyung; Chae, Chanhee

2014-09-01

The change in growth performance resulting from a new modified live porcine reproductive and respiratory syndrome (PRRS) vaccine was evaluated under field conditions for registration with the government as guided by the Republic of Korea's Animal and Plant Quarantine Agency. Three farms were selected based on their history of PRRS-associated respiratory diseases. On each farm, a total of 45 3-week-old pigs were randomly allocated to one of two treatment groups, (i) vaccinated (n = 25) or (ii) control (n = 20) animals. A new modified live PRRSV vaccine increased market weight by 1.26 kg/pig (104.71 kg versus 103.45 kg; P < 0.05) and decreased mortality by 17% (1.33% versus 18.33%; P < 0.05). Pathological examination indicated that vaccination effectively reduced microscopic lung lesions compared with control animals on the 3 farms. Thus, the new modified live PRRS vaccine improved growth performance and decreased mortality and lung lesions when evaluated under field conditions. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Paediatric Active Enhanced Disease Surveillance inaugural annual report, 2014.

PubMed

Zurynski, Yvonne A; McRae, Jocelynne E; Quinn, Helen E; Wood, Nicholas J; Macartney, Kristine K

2016-09-30

The Paediatric Active Enhanced Disease Surveillance (PAEDS) network is a hospital-based active surveillance system employing prospective case ascertainment of selected uncommon vaccine preventable diseases and potential adverse events following immunisation (AEFI). PAEDS enhances other Australian surveillance systems by providing prospective detailed clinical and laboratory data for the same child. Specialist surveillance nurses screen hospital admissions, emergency department records, laboratory and other data, to prospectively identify hospitalised children aged under 15 years in 5 paediatric tertiary referral hospitals in New South Wales, Victoria, South Australia, Western Australia and Queensland. Standardised protocols and case definitions are used across all sites. Conditions under surveillance include vaccine preventable diseases: acute flaccid paralysis, varicella, pandemic and seasonal influenza and pertussis, and potential AEFIs: febrile seizures and intussusception. PAEDS also conducts surveillance for acute childhood encephalitis. Since August 2007, PAEDS has recruited a total of 6,227 hospitalised cases in total, for all conditions. From January to December 2014, there were 1,220 cases recruited across all conditions. Key outcomes include: enhanced acute flaccid paralysis surveillance to reach World Health Organization targets; supporting varicella and influenza vaccination in children; confirmation of a known low risk of febrile seizures following the 1st dose of measles-mumps-rubella vaccine but no increased risk of febrile seizures after measles-mumps-rubella-varicella vaccine, and a slightly increased risk of developing intussusception 1-7 days after rotavirus vaccination in infants aged less than 3 months. Acute childhood encephalitis data facilitated rapid investigation and response to the enterovirus 71 outbreak in 2013-2014. PAEDS provides unique policy-relevant data. This is the first of planned PAEDS annual reports to Communicable Diseases Intelligence.

A locally initiated and executed measles outbreak response immunization campaign in the nylon health district, Douala Cameroon 2011

PubMed Central

2013-01-01

The Cameroon health system is divided into central, intermediate and peripheral levels. Of the 43 health districts with a measles outbreak in Cameroon in 2011, only the Nylon Health District organized a documented outbreak response immunization. We present the methods and results of the response campaign solely shouldered by the district and intermediate level. The risk group, targets and neighborhoods to be vaccinated were identified after a detailed analysis of initial cases. The intermediate level defined strategies, provided logistics, capacity building and 41% of the operational budget while 59% was completed by the peripheral level. Microsoft Office Excel 2007 was used to estimate coverage rates and to draw an epidemic curve. The response immunization campaign was organized on the 14th epidemiological week, 10 weeks after the onset of the outbreak which ended 11 weeks thereafter. A total of 15867(108.5%) children aged 9-59 months were vaccinated in five health areas at a direct cost (vaccines excluded) of 71.34FCFA ($0.143) per vaccinated child. An additional 824 children aged 9-59 months were vaccinated around the residence of notified cases in neighborhoods which were not involved in the response campaign. The number of cases after the response campaign was lower than before. Once vaccines are available, prompt outbreak response campaigns can be organized at operational level to obtain commendable results instead of depending solely on international organizations or central levels. Decision makers at the intermediate and operational levels should redeploy available funds during emergencies to prevent the development of extreme public health conditions. PMID:23497712

Surface exciton emission of MgO crystals

NASA Astrophysics Data System (ADS)

Kuang, Wen-Jian; Li, Qing; Chen, Yu-Xiang; Hu, Kai; Wang, Ning-Hui; Xing, Fang-Li; Yan, Qun; Sun, Shuai-Shuai; Huang, Yan; Tao, Ye; Tolner, Harm

2013-09-01

MgO crystals have been exposed to vacuum ultraviolet (VUV) radiation from a synchrotron, with energies up to 9 eV, and the emitted light, at wavelengths above 200 nm, was observed. It is concluded that bulk excitons, play an important role in the diffusion of energy inside MgO crystals, resulting in 5.85 eV (212 nm) emission from the MgO terraces of large (0.2-2 µm) MgO : F crystals. In the case of aliovalent impurity doping, then the bulk exciton energy is also transferred to the Vk centres and 5.3 eV (235 nm) light is emitted. Both fluorine and silicon doping appear to promote UV surface emission, acting similarly to an ns2 ion inside MgO, while strong scandium doping is killing the surface emission completely. The 212 nm surface UV emission and the 235 nm bulk UV emission can be excited only at the bandgap edge. Broadband visible light, centred around 400 nm, is also emitted. Contrary to the UV emission, this is not generated when excited at the bandgap edge; instead, we find that it is only excited at sub-bandgap energies, with a maximum at the 5C surface excitation energy of 5.71 eV (217 nm) for the MgO terraces.

Proof-of-principle evaluation of the efficacy of fewer than three doses of a bivalent HPV16/18 vaccine.

PubMed

Kreimer, Aimée R; Rodriguez, Ana Cecilia; Hildesheim, Allan; Herrero, Rolando; Porras, Carolina; Schiffman, Mark; González, Paula; Solomon, Diane; Jiménez, Silvia; Schiller, John T; Lowy, Douglas R; Quint, Wim; Sherman, Mark E; Schussler, John; Wacholder, Sholom

2011-10-05

Three-dose regimens for human papillomavirus (HPV) vaccines are expensive and difficult to complete, especially in settings where the need for cervical cancer prevention is greatest. We evaluated the vaccine efficacy of fewer than three doses of the HPV16/18 vaccine Cervarix in our Costa Rica Vaccine Trial. Women were randomly assigned to receive three doses of the HPV16/18 vaccine or to a control vaccine and were followed for incident HPV16 or HPV18 infection that persisted in visits that were 10 or more months apart (median follow-up 4.2 years). After excluding women who had no follow-up or who were HPV16 and HPV18 DNA positive at enrollment, 5967 women received three vaccine doses (2957 HPV vaccine vs 3010 control vaccine), 802 received two doses (422 HPV vs. 380 control), and 384 received one dose (196 HPV vs. 188 control). Reasons for receiving fewer doses and other pre- and post-randomization characteristics were balanced within each dosage group between women receiving the HPV and control vaccines. Incident HPV16 or HPV18 infections that persisted for 1 year were unrelated to dosage of the control vaccine. Vaccine efficacy was 80.9% for three doses of the HPV vaccine (95% confidence interval [CI] = 71.1% to 87.7%; 25 and 133 events in the HPV and control arms, respectively), 84.1% for two doses (95% CI = 50.2% to 96.3%; 3 and 17 events), and 100% for one dose (95% CI = 66.5% to 100%; 0 and 10 events). Four years after vaccination of women who appeared to be uninfected, this nonrandomized analysis suggests that two doses of the HPV16/18 vaccine, and maybe even one dose, are as protective as three doses.

[Public health service prescriptions of vaccines not included in systematic vaccination programs in Valencian community, Spain, during the period 2004-2009].

PubMed

Ruiz Palacio, Ana; Pastor Villalba, Eliseo; Martín Ivorra, Rosa; Alguacil Ramos, Ana María; Portero Alonso, Antonio; Lluch Rodrigo, José Antonio

2011-06-01

In the context of the policies of rational use of medicine, and in order to achieve an efficient management of the vaccinations programs, we expect to know the number of packings and cost of prescribed vaccines not included in the vaccination programs of Valencian Community and its departments during 2009 and to analyze its evolution since 2004, focusing on an analysis of Heptavalent pneumococcal conjugate vaccine in children under two years old. Retrospective descriptive study to analyze the prescriptions of vaccines in Valencian Community during 2009 and its evolution since 2004. vaccine availability, number of packings, group of beneficiary (actives/pensioners), department, and cost of prescriptions. Gestor de Prestación Farmacéutica (GAIA) and Sistema Información Poblacional (SIP). In 2009 prescribed vaccines on official national health system prescription forms that are not included in vaccination programs, supposed a cost of 683.445,71 € corresponding to 17.353 packings (87% of the total prescribed vaccines). Heptavalent pneumococcal conjugate vaccine generated 72% of the total cost of vaccines not included in the vaccination programs. The trend from 2004 to 2009 shows an increase in expenditure of 735.334 € (24,66%) in 2005 from which there takes place a marked and gradual decrease that reaches 1.562.650,67 € (-228.64%). The cost by departments of prescriptions per 1000 children under two years old of pneumococcal conjugate vaccine ranges between 17.377 and 324 €. The declining trend of prescriptions, mainly of pneumococcal conjugate vaccines, continues during 2009. A great interdepartmental variability is observed, nevertheless, in rates of prescription that should be corrected.

Reporting of adverse events following immunizations in Ghana - Using disproportionality analysis reporting ratios.

PubMed

Ankrah, Daniel N A; Darko, Delese M; Sabblah, George; Mantel-Teeuwisse, Aukje; Leufkens, Hubert M G

2018-01-02

Timely reporting of safety information post vaccination is pivotal for the success of any vaccination program. Reports of adverse events following immunization (AEFI) of 6 different vaccinations from Ghana were analysed for signals. De-identified data from active surveillance for AEFIs after 2009 AH1N1 influenza, yellow fever, meningitis, measles-rubella, pneumococcal-rotavirus and human papilloma virus vaccinations were used. All vaccinations occurred between January 2010 and December 2013. The ten most occurring events for each vaccination were captured and arranged using Medical Dictionary for Regulatory Authorities (MedDRA) Preferred Term (PT) and System Organ Classification (SOC) codes. Adverse event incidence rates were calculated for each vaccine type, and signals were generated using proportional reporting ratios (PRR). A total number of 5,141 reports were analysed ranging from 33 (human papilloma virus) to 1958 (measles-rubella). Between 22% and 55% of all AEFIs per vaccine type were collected on the day of vaccination. For each vaccine type, at least 87% of all reported AEFIs occurred in the first 7 days post-vaccination. Multiple reports were received per vaccine type. For the MR vaccine, urticarial recorded the highest attack rate of 6.6 (95% CI 6.2, 7.1) per 100,000 vaccines. The AEFI with the highest PRR for both human papilloma and measles-rubella vaccines was abdominal pain, recording a PRR of 8.15 (95% CI 3.46, 19.23) and 43.75 (95% CI 17.81, 107.45) respectively. These results underscore the competency of public health systems in sub-Saharan African countries (like Ghana) to identify most frequently occurring and important vaccine related safety issues.

Should I or shouldn't I: decision making, knowledge and behavioral effects of quadrivalent HPV vaccination in men who have sex with men.

PubMed

Thomas, Emily A; Goldstone, Stephen E

2011-01-10

Prior to FDA licensure in men, a surgical practice (SG) offered the quadrivalent HPV vaccine (qHPV) off-label to men who have sex with men (MSM). We administered a written or telephone survey to MSM to elicit drivers and barriers to vaccination, sexual behavior changes post-vaccination, and knowledge. 191 subjects enrolled: 68 refused qHPV, 71 received qHPV <1 year ago, and 52 received qHPV >1 year ago. History of HPV infection (86%, n=164) and level of HPV and qHPV knowledge were high, with a mean of 10.8 of 13 knowledge questions correct. Ninety-seven percent of participants understood that qHPV does not cure present infection or disease. MSM refused qHPV for reasons including cost and not FDA approved; prevention of future HPV infection was the paramount driver for immunization. Vaccination did not affect sexual behavior. Copyright © 2010 Elsevier Ltd. All rights reserved.

Evolution of antimicrobial resistance and serotype distribution of Streptococcus pneumoniae isolated from children with invasive and noninvasive pneumococcal diseases in Algeria from 2005 to 2012

PubMed Central

Ramdani-Bouguessa, N.; Ziane, H.; Bekhoucha, S.; Guechi, Z.; Azzam, A.; Touati, D.; Naim, M.; Azrou, S.; Hamidi, M.; Mertani, A.; Laraba, A.; Annane, T.; Kermani, S.; Tazir, M.

2015-01-01

Pneumococcal infections are a major cause of morbidity and mortality in developing countries. The introduction of pneumococcal conjugate vaccines (PCVs) has dramatically reduced the incidence of pneumococcal diseases. PCVs are not currently being used in Algeria. We conducted a prospective study from 2005 to 2012 in Algeria to determine antimicrobial drug resistance and serotype distribution of Streptococcus pneumoniae from children with pneumococcal disease. Among 270 isolated strains from children, 97 (36%) were invasive disease; of these, 48% were not susceptible to penicillin and 53% not susceptible to erythromycin. A high rate of antimicrobial nonsusceptibility was observed in strains isolated from children with meningitis. The serotype distribution from pneumococci isolated from children with invasive infections was (by order of prevalence): 14, 1, 19F, 19A, 6B, 5, 3, 6A and 23F. Multidrug resistance was observed in serotypes 14, 19F, 19A and 6B. The vaccine coverage of serotypes isolated from children aged <5 years was 55.3% for PCV7, 71.1% for PCV10 and 86.8% for PCV13. Our results highlight the burden of pneumococcal disease in Algeria and the increasing S. pneumoniae antibiotic resistance. The current pneumococcal vaccines cover a high percentage of the circulating strains. Therefore, vaccination would reduce the incidence of pneumococcal disease in Algeria. PMID:26106481

Estimating the critical immunity threshold for preventing hepatitis A outbreaks in men who have sex with men.

PubMed

Regan, D G; Wood, J G; Benevent, C; Ali, H; Smith, L Watchirs; Robertson, P W; Ferson, M J; Fairley, C K; Donovan, B; Law, M G

2016-05-01

Several outbreaks of hepatitis A in men who have sex with men (MSM) were reported in the 1980s and 1990s in Australia and other countries. An effective hepatitis A virus (HAV) vaccine has been available in Australia since 1994 and is recommended for high-risk groups including MSM. No outbreaks of hepatitis A in Australian MSM have been reported since 1996. In this study, we aimed to estimate HAV transmissibility in MSM populations in order to inform targets for vaccine coverage in such populations. We used mathematical models of HAV transmission in a MSM population to estimate the basic reproduction number (R 0) and the probability of an HAV epidemic occurring as a function of the immune proportion. We estimated a plausible range for R 0 of 1·71-3·67 for HAV in MSM and that sustained epidemics cannot occur once the proportion immune to HAV is greater than ~70%. To our knowledge this is the first estimate of R 0 and the critical population immunity threshold for HAV transmission in MSM. As HAV is no longer endemic in Australia or in most other developed countries, vaccination is the only means of maintaining population immunity >70%. Our findings provide impetus to promote HAV vaccination in high-risk groups such as MSM.

Vaccination against Neisseria meningitidis using three variants of the lipoprotein GNA1870.

PubMed

Masignani, Vega; Comanducci, Maurizio; Giuliani, Marzia Monica; Bambini, Stefania; Adu-Bobie, Jeannette; Arico, Beatrice; Brunelli, Brunella; Pieri, Alessandro; Santini, Laura; Savino, Silvana; Serruto, Davide; Litt, David; Kroll, Simon; Welsch, Jo Anne; Granoff, Dan M; Rappuoli, Rino; Pizza, Mariagrazia

2003-03-17

Sepsis and meningitis caused by serogroup B meningococcus are devastating diseases of infants and young adults, which cannot yet be prevented by vaccination. By genome mining, we discovered GNA1870, a new surface-exposed lipoprotein of Neisseria meningitidis that induces high levels of bactericidal antibodies. The antigen is expressed by all strains of N. meningitidis tested. Sequencing of the gene in 71 strains representative of the genetic and geographic diversity of the N. meningitidis population, showed that the protein can be divided into three variants. Conservation within each variant ranges between 91.6 to 100%, while between the variants the conservation can be as low as 62.8%. The level of expression varies between strains, which can be classified as high, intermediate, and low expressors. Antibodies against a recombinant form of the protein elicit complement-mediated killing of the strains that carry the same variant and induce passive protection in the infant rat model. Bactericidal titers are highest against those strains expressing high yields of the protein; however, even the very low expressors are efficiently killed. The novel antigen is a top candidate for the development of a new vaccine against meningococcus.

Global Impact of Rotavirus Vaccination on Childhood Hospitalizations and Mortality From Diarrhea.

PubMed

Burnett, Eleanor; Jonesteller, Christine L; Tate, Jacqueline E; Yen, Catherine; Parashar, Umesh D

2017-06-01

In 2006, 2 rotavirus vaccines were licensed. We summarize the impact of rotavirus vaccination on hospitalizations and deaths from rotavirus and all-cause acute gastroenteritis (AGE) during the first 10 years since vaccine licensure, including recent evidence from countries with high child mortality. We used standardized guidelines (PRISMA) to identify observational evaluations of rotavirus vaccine impact among children <5 years of age that presented at least 12 months of pre- and post-vaccine introduction surveillance data. We identified 57 articles from 27 countries. Among children <5 years of age, the median percentage reduction in AGE hospitalizations was 38% overall and 41%, 30%, and 46% in countries with low, medium, and high child mortality, respectively. Hospitalizations and emergency department visits due to rotavirus AGE were reduced by a median of 67% overall and 71%, 59%, and 60% in countries with low, medium, and high child mortality, respectively. Implementation of rotavirus vaccines has substantially decreased hospitalizations from rotavirus and all-cause AGE. Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Evaluation of the effect of chickenpox vaccination on shingles epidemiology using agent-based modeling.

PubMed

Rafferty, Ellen; McDonald, Wade; Qian, Weicheng; Osgood, Nathaniel D; Doroshenko, Alexander

2018-01-01

Biological interactions between varicella (chickenpox) and herpes zoster (shingles), two diseases caused by the varicella zoster virus (VZV), continue to be debated including the potential effect on shingles cases following the introduction of universal childhood chickenpox vaccination programs. We investigated how chickenpox vaccination in Alberta impacts the incidence and age-distribution of shingles over 75 years post-vaccination, taking into consideration a variety of plausible theories of waning and boosting of immunity. We developed an agent-based model representing VZV disease, transmission, vaccination states and coverage, waning and boosting of immunity in a stylized geographic area, utilizing a distance-based network. We derived parameters from literature, including modeling, epidemiological, and immunology studies. We calibrated our model to the age-specific incidence of shingles and chickenpox prior to vaccination to derive optimal combinations of duration of boosting (DoB) and waning of immunity. We conducted paired simulations with and without implementing chickenpox vaccination. We computed the count and cumulative incidence rate of shingles cases at 10, 25, 50, and 75 years intervals, following introduction of vaccination, and compared the difference between runs with vaccination and without vaccination using the Mann-Whitney U-test to determine statistical significance. We carried out sensitivity analyses by increasing and lowering vaccination coverage and removing biological effect of boosting. Chickenpox vaccination led to a decrease in chickenpox cases. The cumulative incidence of chickenpox had dropped from 1,254 cases per 100,000 person-years pre chickenpox vaccination to 193 cases per 100,000 person-years 10 years after the vaccine implementation. We observed an increase in the all-ages shingles cumulative incidence at 10 and 25 years post chickenpox vaccination and mixed cumulative incidence change at 50 and 75 years post-vaccination. The magnitude of change was sensitive to DoB and ranged from an increase of 22-100 per 100,000 person-years at 10 years post-vaccination for two and seven years of boosting respectively ( p < 0.001). At 75 years post-vaccination, cumulative incidence ranged from a decline of 70 to an increase of 71 per 100,000 person-years for two and seven years of boosting respectively ( p < 0.001). Sensitivity analyses had a minimal impact on our inferences except for removing the effect of boosting. Our model demonstrates that over the longer time period, there will be a reduction in shingles incidence driven by the depletion of the source of shingles reactivation; however in the short to medium term some age cohorts may experience an increase in shingles incidence. Our model offers a platform to further explore the relationship between chickenpox and shingles, including analyzing the impact of different chickenpox vaccination schedules and cost-effectiveness studies.

Biological reference materials for extracellular vesicle studies.

PubMed

Valkonen, S; van der Pol, E; Böing, A; Yuana, Y; Yliperttula, M; Nieuwland, R; Laitinen, S; Siljander, P R M

2017-02-15

Extracellular vesicles (EVs) mediate normal physiological homeostasis and pathological processes by facilitating intercellular communication. Research of EVs in basic science and clinical settings requires both methodological standardization and development of reference materials (RM). Here, we show insights and results of biological RM development for EV studies. We used a three-step approach to find and develop a biological RM. First, a literature search was done to find candidates for biological RMs. Second, a questionnaire was sent to EV researchers querying the preferences for RM and their use. Third, a biological RM was selected, developed, characterized, and evaluated. The responses to the survey demonstrated a clear and recognized need for RM optimized for the calibration of EV measurements. Based on the literature, naturally occurring and produced biological RM, such as virus particles and liposomes, were proposed as RM. However, none of these candidate RMs have properties completely matching those of EVs, such as size and refractive index distribution. Therefore, we evaluated the use of nanoerythrosomes (NanoE), vesicles produced from erythrocytes, as a potential biological RM. The strength of NanoE is their resemblance to EVs. Compared to the erythrocyte-derived EVs (eryEVs), NanoE have similar morphology, a similar refractive index (1.37), larger diameter (70% of the NanoE are over 200nm), and increased positive staining for CD235a and lipids (Di-8-ANEPPS) (58% and 67% in NanoE vs. 21% and 45% in eryEVs, respectively). Altogether, our results highlight the general need to develop and validate new RM with similar physical and biochemical properties as EVs to standardize EV measurements between instruments and laboratories. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Self-reported hepatitis A vaccination as a predictor of hepatitis A virus antibody protection in U.S. adults: National Health and Nutrition Examination Survey 2007–2012

PubMed Central

Denniston, Maxine M.; Klevens, R. Monina; Jiles, Ruth B.; Murphy, Trudy V.

2015-01-01

Objectives To estimate the predictive value of self-reported hepatitis A vaccine (HepA) receipt for the presence of hepatitis A virus (HAV) antibody (anti-HAV) from either past infection or vaccination, as an indicator of HAV protection. Methods Using 2007–2012 National Health and Nutrition Examination Survey data, we assigned participants to 4 groups based on self-reported HepA receipt and anti-HAV results. We compared characteristics across groups and calculated three measures of agreement between self-report and serologic status (anti- HAV): percentage concordance, and positive (PPV) and negative (NPV) predictive values. Using logistic regression we investigated factors associated with agreement between self-reported vaccination status and serological results. Results Demographic and other characteristics varied significantly across the 4 groups. Overall agreement between self-reported HepA receipt and serological results was 63.6% (95% confidence interval [CI] 61.9–65.2); PPV and NPV of self-reported vaccination status for serological result were 47.0% (95% CI 44.2–49.8) and 69.4% (95% CI 67.0–71.8), respectively. Mexican American and foreign-born adults had the highest PPVs (71.5% [95% CI 65.9–76.5], and 75.8% [95% CI 71.4–79.7]) and the lowest NPVs (21.8% [95% CI 18.5–25.4], and 20.0% [95% CI 17.2–23.1]), respectively. Young (ages 20–29 years), US-born, and non-Hispanic White adults had the lowest PPVs (37.9% [95% CI 34.5–41.5], 39.1% [95% CI, 36.0–42.3], and 39.8% [36.1–43.7]), and the highest NPVs (76.9% [95% CI 72.2–81.0, 78.5% [95% CI 76.5–80.4)], and 80.6% [95% CI 78.2–82.8), respectively. Multivariate logistic analyses found age, race/ethnicity, education, place of birth and income to be significantly associated with agreement between self-reported vaccination status and serological results. Conclusions When assessing hepatitis A protection, self-report of not having received HepA was most likely to identify persons at risk for hepatitis A infection (no anti-HAV) among young, US-born and non-Hispanic White adults, and self-report of HepA receipt was least likely to be reliable among adults with the same characteristics. PMID:26116252

Mutual interference on the immune response to yellow fever vaccine and a combined vaccine against measles, mumps and rubella.

PubMed

Nascimento Silva, Juliana Romualdo; Camacho, Luiz Antonio B; Siqueira, Marilda M; Freire, Marcos de Silva; Castro, Yvone P; Maia, Maria de Lourdes S; Yamamura, Anna Maya Y; Martins, Reinaldo M; Leal, Maria de Luz F

2011-08-26

A randomized trial was conducted to assess the immunogenicity and reactogenicity of yellow fever vaccines (YFV) given either simultaneously in separate injections, or 30 days or more after a combined measles-mumps-rubella (MMR) vaccine. Volunteers were also randomized to YFV produced from 17DD and WHO-17D-213 substrains. The study group comprised 1769 healthy 12-month-old children brought to health care centers in Brasilia for routine vaccination. The reactogenicity was of the type and frequency expected for the vaccines and no severe adverse event was associated to either vaccine. Seroconversion and seropositivity 30 days or more after vaccination against yellow fever was similar across groups defined by YFV substrain. Subjects injected YFV and MMR simultaneously had lower seroconversion rates--90% for rubella, 70% for yellow fever and 61% for mumps--compared with those vaccinated 30 days apart--97% for rubella, 87% for yellow fever and 71% for mumps. Seroconversion rates for measles were higher than 98% in both comparison groups. Geometric mean titers for rubella and for yellow fever were approximately three times higher among those who got the vaccines 30 days apart. For measles and mumps antibodies GMTs were similar across groups. MMR's interference in immune response of YFV and YFV's interference in immune response of rubella and mumps components of MMR had never been reported before but are consistent with previous observations from other live vaccines. These results may affect the recommendations regarding primary vaccination with yellow fever vaccine and MMR. Copyright © 2011 Elsevier Ltd. All rights reserved.

Human papillomavirus vaccine acceptability among parents of adolescent girls: obstacles and challenges in Mysore, India.

PubMed

Madhivanan, Purnima; Li, Tan; Srinivas, Vijaya; Marlow, Laura; Mukherjee, Soumyadeep; Krupp, Karl

2014-07-01

Worldwide, 530,000 women are diagnosed with cervical cancer and 275,000 die annually. India bears the greatest burden of the disease with 132,000 cases and 74,000 deaths yearly. Widespread uptake of human papillomavirus (HPV) vaccine could reduce incidence and mortality by two-thirds. This study explored obstacles and facilitators of parental acceptability of HPV vaccine. In 2010, questionnaires were sent home with a random sample of 800 girls attending 12 schools in Mysore city to be completed by a parent. Data were analyzed using multivariable logistic regression with generalized estimating equation to account for potential clustering by school. Of the 797 completed surveys; 71% reported willingness to accept HPV vaccine for their daughters. The adjusted odds of acceptance was higher among participants who received recommendation from their parents, perceived cervical cancer as a serious disease, believed that HPV vaccine was safe, or felt that vaccination was a good way to protect against cervical cancer. Parents who had concerns about vaccine side-effects or thought that it would cause pain had lower odds of acceptance. Future promotion of vaccine should emphasize safety of immunization and involve promotion to the extended family, so that they actively recommend immunization of young adolescent girls. Copyright © 2014. Published by Elsevier Inc.

The effects of convenience and quality on the demand for vaccination: Results from a discrete choice experiment.

PubMed

Guo, Na; Zhang, Guojie; Zhu, Dawei; Wang, Jian; Shi, Luwen

2017-05-15

Vaccination is an effective way to prevent infectious diseases. Most studies analysed people's vaccine decisions, but few studies have analysed the effects of convenience such as immunisation schedule and distance and the quality of vaccination service on vaccination uptake. The aim of this paper was to investigate adults' preferences for convenience and quality of vaccination service, calculate the private economic benefit from convenience (vaccination schedule and distance) and quality, and predict the uptake rate for different vaccine scenarios. In our study, we interviewed 266 adults in 2 counties of Shandong province in China. The discrete choice experiment (DCE) was employed to analyse the preference for hepatitis B virus (HBV) vaccination, and a mixed logit model was used to estimate respondent preferences for vaccination attributes included in the DCE. The protection rate against hepatitis B (HB), duration of protection, risk of side effects, vaccination cost, schedule, and vaccination sites were proved to influence adults' preferences for HBV vaccination. The estimated willingness to pay (WTP) for 1 dose schedule instead of 3 doses and for a third-level vaccination site instead of a first-level site was almost equal (19 RMB). However, if the protection duration of the vaccination programme changed from 5years to 20years, the adults were willing to pay 35.05 RMB, and WTP for a 99% protection rate instead of a 79% rate was 67.71 RMB. The predicted uptake rate is almost 43% for the base case of HBV vaccination. Adults made trade-offs between vaccination schedules, vaccination sites, and other characteristics of HBV vaccine. The impact of attributes of the vaccine itself, especially protection rate against HB, duration of protection, and risk of side-effects, is more dramatic than convenience and quality of vaccination service. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Comparison of the immunogenicity and safety of the conventional subunit, MF59-adjuvanted, and intradermal influenza vaccines in the elderly.

PubMed

Seo, Yu Bin; Choi, Won Suk; Lee, Jacob; Song, Joon Young; Cheong, Hee Jin; Kim, Woo Joo

2014-07-01

The influenza vaccination is known as the most effective method for preventing influenza infection and its complications in the elderly. Conventional subunit (Agrippal S1; Novartis), MF59-adjuvanted (Fluad; Novartis), and intradermal (IDflu15; Sanofi Pasteur) influenza vaccines are widely used throughout South Korea. However, few comparative studies evaluating the safety and immunogenicity of these vaccines are available. Prior to the beginning of the 2011-2012 influenza season, 335 healthy elderly volunteers randomly received one of three seasonal trivalent influenza vaccines, the conventional subunit, MF59-adjuvanted, or intradermal influenza vaccine. Serum hemagglutination-inhibiting antibody levels were measured at the time of vaccination and at 1 and 6 months after vaccination. Adverse events were recorded prospectively. A total of 113 conventional subunit, 111 MF59-adjuvanted, and 111 intradermal influenza vaccine volunteers were followed up during a 6-month postvaccination period. One month after vaccination, all three vaccines satisfied Committee for Medical Products for Human Use (CHMP) immunogenicity criteria for the A/H1N1 and A/H3N2 strains but not for the B strain. Compared with the subunit vaccine, the intradermal vaccine exhibited noninferiority, while the MF59-adjuvanted vaccine exhibited superiority. Furthermore, the MF59-adjuvanted vaccine was more immunogenic against the A/H3N2 strain than was the subunit vaccine up to 6 months postvaccination. The most common local and systemic reactions to the conventional subunit, MF59-adjuvanted, and intradermal influenza vaccines were pain at the injection site (7.1%, 10.8%, and 6.3%, respectively) and generalized myalgia (0.9%, 8.1%, and 5.4%, respectively). Local and systemic reactions were similar among the three vaccine groups. MF59-adjuvanted vaccine exhibited superior immunogenicity compared with a conventional subunit vaccine and had a comparable safety profile. For older adults, the MF59-adjuvanted vaccine is preferable for providing superior immunogenicity. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

The varicella vaccination pattern among children under 5 years old in selected areas in China.

PubMed

Yue, Chenyan; Li, Yan; Wang, Yamin; Liu, Yan; Cao, Linsheng; Zhu, Xu; Martin, Kathryn; Wang, Huaqing; An, Zhijie

2017-07-11

Vaccine is the most effective way to protect susceptible children from varicella. Few published literature or reports on varicella vaccination of Chinese children exist. Thus, in order to obtain specific information on varicella vaccination of this population, we conducted this survey. We first used purposive sampling methods to select 6 provinces 10 counties from eastern, middle and western parts of China with high quality of Immunization Information Management System (IIMS), and then randomly select children from population in the IIMS, then we checked vaccination certificate on-site. Based on the varicella vaccination information collected from 481 children's vaccination certificates from all ten selected counties in China, overall coverage of the first dose of varicella vaccine was 73.6%. There is a positive linear correlation between per capita GDP and vaccine coverage at county level (r=0.929, P < 0.01). The cumulative vaccine coverage among children at 1 year, 2 years and ≥3 years old were 67.6%, 71.9% and 73.6% respectively (X2=4.53, P =0.10). The age of vaccination was mainly concentrated in 12-17 months. The coverage rate of the first dose of varicella vaccine in selected areas was lower than that recommended by WHO position paper. The coverage rate was relatively low in areas of low social-economic status. The cumulative coverage had no significant statistical difference among different age group. Most children received varicella vaccine before 3 years old. We suggest introducing the varicella vaccine into routine immunization program, to ensure universal high coverage among children in China. We also suggest that varicella vaccination information should be checked before entering school, in order to control and prevent varicella outbreaks in schools.

Changes in parents' perceptions of infant influenza vaccination over two years.

PubMed Central

Nowalk, Mary Patricia; Lin, Chyongchiou J.; Zimmerman, Richard K.; Ko, Feng-Shou; Hoberman, Alejandro; Zoffel, Lisa; Kearney, Diana H.

2007-01-01

BACKGROUND: Inner-city health centers serving large proportions of low-income and minority children participated in a study to introduce influenza vaccination among healthy infants in 2002-2003 and 2003-2004. METHODS: Following the 2002-2003 and 2003-2004 influenza vaccination seasons, a short, low-literacy level survey was mailed to parents of vaccine-eligible children. Factors related to vaccination status were determined using Chi-squared and logistic regression procedures. In 2003, 436 of 1000 surveys were returned and in 2004, 274 of 583 surveys were returned. RESULTS: Influenza vaccination rate by parental report was 56% in 2003 and 45% in 2004. The most important factors related to immunization were doctor's recommendation (OR = 10.5, 95% CI: 6.2-17.7; P < 0.001), receiving a reminder (OR = 1.6, 95% CI: 1.01-2.6; P = 0.047) and parental belief that the child should be vaccinated (OR = 7.1, 95% CI: 4.3-11.6; P < 0.001). From 2003-2004, nonphysician social influences to have infants vaccinated against influenza increased overall, and perceived positive consequences of vaccination increased among parents of vaccinated children. CONCLUSIONS: Social support for influenza vaccination of healthy infants increased over the two years of the encouragement period, suggesting that information regarding this vaccine was reaching the general public. The most important facilitators of influenza immunization were physician recommendation, parental support and reminders. This suggests that reminders from physicians should specifically state that the doctor recommends influenza vaccine and address common misperceptions about influenza vaccine. These findings may have broader applications as the age groups for whom influenza vaccination is recommended continue to expand. PMID:17595932

[Efficacy and safety of vaccination against hepatitis A and B in patients with chronic liver disease].

PubMed

de Artaza Varasa, Tomás; Sánchez Ruano, Juan José; García Vela, Almudena; Gómez Rodríguez, Rafael; Romero Gutiérrez, Marta; de la Cruz Pérez, Gema; Gómez Moreno, Ana Zaida; Carrobles Jiménez, José María

2009-01-01

Vaccination to protect against hepatitis A and B should be part of the routine management of patients with chronic liver disease (CLD). To evaluate the efficacy and safety of hepatitis A virus (HAV) and hepatitis B virus (HBV) vaccination in a group of patients with CLD and to assess the presence of factors predictive of response. We performed a prospective, single-center study in 194 patients (123 men, 71 women; mean age, 48.9+/-10.7 years) with CLD: 107 with chronic hepatitis (CH) and 87 with hepatic cirrhosis (HC), all Child-Pugh class A. The most frequent causes of CLD were HCV infection and alcohol. Patients negative for anti-HAV IgG received the HAV vaccination (1440 ELISA units in two doses) and those with negative HBV serology received the HBV vaccination ( three 20 microg doses). Patients with inadequate response to the latter vaccine received an additional double dose. Thirty patients received a combination vaccine (three doses). Sixty patients (31%) received the HAV vaccine and 150 (77%) patients received the HBV vaccine. Seroconversion was achieved by 91.6% of patients for HAV and by 57% of the patients for HBV. After the additional dose, the response increased to 74%. Efficacy was similar between CH and HC. HBV vaccination was less effective in HC than in CH and the seroconversion rate was significantly lower in patients with HC and previous decompensation. The combination vaccine (30 patients) was highly immunogenic. No adverse effects were registered. HAV vaccination has high efficacy in patients with CLD. Patients with HC respond weakly to HBV vaccination compared with those with CH and especially if there is prior decompensation. The combination vaccine seems particularly effective in patients with CLD. The three vaccines are safe.

Vaccination of bovines against Schistosomiasis japonica with highly irradiated schistosomula in China

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hsue, S.Y.; Xu, S.T.; He, Y.X.

1984-09-01

Vaccination of Chinese bovines (cattle and buffaloes) against Schistosomiasis japonica with 36 kR gamma-irradiated schistosomula was done for laboratory challenge and for field trials in China. Altogether, 61 bovines were used. All experimental animals were vaccinated 2-3 times with 10,000 irradiated schistosomula per time. For the laboratory challenge, all experimental and control cattle were challenged with 500 normal cercariae and each buffalo, with 2,000 cercariae. The laboratory-challenged bovines were killed after 54-57 days of challenge; the bovines for the field trial in the lightly endemic area, after 5 months in the field; and the bovines for the field trial inmore » the heavily endemic area, after 58-63 days. When the animals were killed, the number of mature worms in the vaccinated (experimental) and non-vaccinated (control) animals was recorded and the percentage of worm reduction in each group was calculated. The first group, consisting of three vaccinated and three non-vaccinated cattle, was given a laboratory challenge; the worm reduction was 71.6%. The second group, consisting of two vaccinated and three non-vaccinated buffaloes, was also given a laboratory challenge; the worm reduction was 74.4%. The third group, consisting of seven vaccinated and eight non-vaccinated buffaloes, was utilized in a field trial in a lightly endemic area; the worm reduction was 75.6%. The fourth group, consisting of eight vaccinated and nine non-vaccinated cattle, and the fifth group, consisting of nine vaccinated and nine non-vaccinated buffaloes, were pastured in a heavily endemic area. The worm reduction was 65.1% in the fourth group and 75.7% in the fifth group.« less

Does BCG vaccine prevent tuberculous meningitis?

PubMed Central

Thilothammal, N; Krishnamurthy, P V; Runyan, D K; Banu, K

1996-01-01

The reported efficacy of BCG vaccine in preventing pulmonary tuberculosis varies from 0-80%; however, its efficacy in preventing tuberculous meningitis ranges from 52%-84%. A case-control study was conducted to assess the efficacy of BCG in preventing tuberculous meningitis in children. New cases of tuberculous meningitis, confirmed bacteriologically, were registered as cases. Controls were children suffering from febrile convulsions attending the same hospital. A total of 107 cases and 321 controls, block matched for age, were registered. Vaccination status was determined from the history reported by the mother and by BCG scar reading. Data regarding socioeconomic status, crowding, and nutritional status were collected. Using multiple logistic regression analysis the odds ratio obtained for the presence of BCG scar was 0.23 (95% confidence interval (CI) 0.14 to 0.37) and the protective efficacy of BCG vaccine in preventing tuberculous meningitis in children was found to be 77% (95% CI 71 to 83%). PMID:8660078

Low uptake of influenza vaccine among university students: evaluating predictors beyond cost and safety concerns.

PubMed

Bednarczyk, Robert A; Chu, Samantha L; Sickler, Heather; Shaw, Jana; Nadeau, Jessica A; McNutt, Louise-Anne

2015-03-30

Annual influenza vaccine coverage for young adults (including college students) remains low, despite a 2011 US recommendation for annual immunization of all people 6 months and older. College students are at high risk for influenza morbidity given close living and social spaces and extended travel during semester breaks when influenza circulation typically increases. We evaluated influenza vaccine uptake following an on-campus vaccine campaign at a large, public New York State university. Consecutive students visiting the University Health Center were recruited for a self-administered, anonymous, written survey. Students were asked about recent influenza vaccination, barriers to influenza vaccination, and willingness to get vaccinated to protect other vulnerable individuals they may encounter. Frequencies and proportions were evaluated. Of 653 students approached, 600 completed surveys (92% response proportion); respondents were primarily female (61%) and non-Hispanic white (59%). Influenza vaccine coverage was low (28%). Compared to coverage among non-Hispanic white students (30%), coverage was similar among Hispanic (30%) and other race/ethnicity students (28%) and lowest among non-Hispanic black students (17%). Among the unvaccinated, the most commonly selected vaccination barriers were "Too lazy to get the vaccine" (32%) and "Don't need the vaccine because I'm healthy" (29%); 6% of unvaccinated students cited cost as a barrier. After being informed that influenza vaccination of young, healthy people can protect other vulnerable individuals (e.g., infants, elderly), 71% of unvaccinated students indicated this would increase their willingness to get vaccinated. Influenza vaccine uptake among college students is very low. While making vaccine easily obtained may increase vaccine uptake, college students need to be motivated to get vaccinated. Typically healthy students may not perceive a need for influenza vaccine. Education about vaccinating healthy individuals to prevent the spread of influenza to close contacts, such as vulnerable family members, may provide this motivation to get vaccinated. Copyright © 2015 Elsevier Ltd. All rights reserved.