Midthun, K; Greenberg, H B; Hoshino, Y; Kapikian, A Z; Wyatt, R G; Chanock, R M
A series of reassortants was isolated from coinfection of cell cultures with a wild-type animal rotavirus and a "noncultivatable" human rotavirus. Wild-type bovine rotavirus (UK strain) was reassorted with human rotavirus strains D, DS-1, and P; wild-type rhesus rotavirus was reassorted with human rotavirus strains D and DS-1. The D, DS-1, and P strains represent human rotavirus serotypes 1, 2, and 3, respectively. Monospecific antiserum (to bovine rotavirus, NCDV strain) or a set of monoclonal antibodies to the major outer capsid neutralization glycoprotein, VP7 (of the rhesus rotavirus), was used to select for reassortants with human rotavirus neutralization specificity. This selection technique yielded many reassortants which received only the gene segment coding for the major neutralization protein from the human rotavirus parent, whereas the remaining genes were derived from the animal rotavirus parent. Single human rotavirus gene substitution reassortants of this sort represent potential live vaccine strains. Images PMID:2983101
Live oral candidate rotavirus vaccines of bovine (RIT 4237) or rhesus (RRV-1) origin and reassortants of RRV-1 expressing human serotype 1 (DxRRV) or serotype 2 (DS1xRRV) VP7 protein were evaluated for clinical efficacy in young children in successive trials from 1983 to 1989. In each study, the vaccinations were given before a rotavirus epidemic season and the follow-up of vaccinees covered two rotavirus epidemic seasons lasting up to 2-3 years of age. Serotype 1 rotavirus was predominant in each season. Protection rates against all rotavirus-associated diarrhoea ranged from 0 to 67% but were higher, up to 100%, against more severe rotavirus disease. All tested vaccines also showed efficacy for diarrhoea not apparently associated with rotavirus; therefore the clinical benefit of the vaccinations was greater than could be deduced from efficacy rates for rotavirus-associated diarrhoea alone. Each of the candidate vaccines could significantly reduce severe diarrhoea in Finnish children in the first 2 to 3 years of life. For optimal efficacy, the vaccines should be administered in the autumn before the regular epidemic season of rotavirus.
Yen, Catherine; Tate, Jacqueline E; Hyde, Terri B; Cortese, Margaret M; Lopman, Benjamin A; Jiang, Baoming; Glass, Roger I; Parashar, Umesh D
Rotavirus is the leading cause of severe diarrhea among children <5 years worldwide. Currently licensed rotavirus vaccines have been efficacious and effective, with many countries reporting substantial declines in diarrheal and rotavirus-specific morbidity and mortality. However, the full public health impact of these vaccines has not been realized. Most countries, including those with the highest disease burden, have not yet introduced rotavirus vaccines into their national immunization programs. Research activities that may help inform vaccine introduction decisions include (1) establishing effectiveness, impact, and safety for rotavirus vaccines in low-income settings; (2) identifying potential strategies to improve performance of oral rotavirus vaccines in developing countries, such as zinc supplementation; and (3) pursuing alternate approaches to oral vaccines, such as parenteral immunization. Policy- and program-level barriers, such as financial implications of new vaccine introductions, should be addressed to ensure that countries are able to make informed decisions regarding rotavirus vaccine introduction. PMID:24755452
... including a severe allergy to latex. Babies with "severe combined immunodeficiency" (SCID) should not get rotavirus vaccine. Babies who have had a type of bowel blockage called "intussusception" should not get ... with moderate or severe diarrhea or vomiting. Check with your doctor if ...
Rongsen-Chandola, Temsunaro; Strand, Tor A; Goyal, Nidhi; Flem, Elmira; Rathore, Sudeep Singh; Arya, Alok; Winje, Brita Askeland; Lazarus, Robin; Shanmugasundaram, Elango; Babji, Sudhir; Sommerfelt, Halvor; Vainio, Kirsti; Kang, Gagandeep; Bhandari, Nita
Interference from transplacental and breast milk antibodies may impede the performance of oral live vaccines. The effect of breastfeeding on the immunogenicity of Rotarix, a two-dose oral monovalent rotavirus vaccine, was examined in a community-based trial in New Delhi, India. Four hundred mother-infant pairs were randomized into two equal groups. Infants were aged 6-7 weeks at enrollment. Mothers were encouraged to either breastfeed or to withhold breastfeeding during the 30 min prior to and after each vaccine dose was administered. We collected blood specimens from infants at enrollment and 4 weeks after the second vaccine dose. Blood and breast milk specimens were obtained from mothers at baseline and breast milk specimens were collected at the time of the second vaccine dose. Seroconversion was defined as infant serum anti-VP6 IgA antibody level of ≥20 IU/mL 4 weeks after the second vaccine dose and a ≥4-fold rise from baseline. There was no difference in the proportion who seroconverted between the two groups (26% vs 27%; p=0.92). The levels of infant serum IgA, maternal serum and breast milk IgA and IgG anti-rotavirus antibodies predicted the anti-rotavirus IgA level in infants at end-study and explained approximately 10% of the variability of the immune response (r(2)=0.10, p<0.001). In this population, the immune response to Rotarix was not enhanced by withholding breastfeeding around the time of vaccination. Maternal anti-rotavirus antibodies explained little of the variability in the immune response to the vaccine. Factors other than maternal anti-rotavirus antibodies probably explain why infants in low-and middle-income settings respond poorly to live oral rotavirus vaccines.
Rotaviruses discovered in 1973 are the most common cause of severe diarrheal disease in infants and young children world-wide. Annually rotavirus infections are estimated to cause the deaths of more than 600,000 children under the age of 5 years with more than 90% of fatalities occurring in developing countries. In 2006 two live oral attenuated rotavirus vaccines were licensed: the monovalent human rotavirus vaccine (RotarixT) and the pentavalent bovine-human, reassortant vaccine (RotaTeqT). Both vaccines demonstrated excellent safety and protective effectiveness in large pre-licensing trials conducted in Europe, the United States and Latin America. Several countries in Latin and Central America have already decided to include rotavirus vaccines into their national immunization program. African and Asiatic countries have postponed their decisions pending the results of further studies.
... Resources Related Links Vaccines & Immunizations Rotavirus and the Vaccine (Drops) to Prevent It Language: English Español (Spanish) ... vaccine. Why should my child get the rotavirus vaccine? The rotavirus vaccine: Protects your child from rotavirus, ...
Kuate Defo, Zenas; Lee, Byong
Rotavirus is the leading cause of severe dehydrating diarrhea worldwide, and affects primarily developing nations, in large part because of the inaccessibility of vaccines and high rates of mortality present therein. At present, there exist two oral rotaviral vaccines, Rotarix™ and RotaTeq™. These vaccines are generally effective in their actions: however, associated costs often stymie their effectiveness, and they continue to be associated with a slight risk of intussusception. While different programs are being implemented worldwide to enhance vaccine distribution and monitor vaccine administration for possible intussusception in light of recent WHO recommendation, another major problem persists: that of the reduced efficacy of the existing rotaviral vaccines in developing countries over time. The development of new oral rotavirus vaccine classes - live-attenuated vaccines, virus-like particles, lactic acid bacteria-containing vaccines, combination therapy with immunoglobulins, and biodegradable polymer-encapsulated vaccines - could potentially circumvent these problems.
Patel, Niraj C.; Hertel, Paula M.; Estes, Mary K.; de la Morena, Maite; Petru, Ann M.; Noroski, Lenora M.; Revell, Paula A.; Celine Hanson, I.; Paul, Mary E.; Rosenblatt, Howard M.; Abramson, Stuart L.
SUMMARY Live pentavalent human–bovine reassortant rotavirus vaccine is recommended in the United States for routine immunization of infants. We describe three infants, two with failure to thrive, who had dehydration and diarrhea within 1 month after their first or second rotavirus immunization and subsequently received a diagnosis of severe combined immunodeficiency. Rotavirus was detected, by means of reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay, in stool specimens obtained from all three infants, and gene-sequence analysis revealed the presence of vaccine rotavirus. These infections raise concerns regarding the safety of rotavirus vaccine in severely immunocompromised patients. PMID:20107217
... Vaccine Information Statement (VIS): www.cdc.gov/vaccines/hcp/vis/vis-statements/rotavirus.pdf . CDC review information ... known reason for it. www.cdc.gov/vaccines/hcp/vis/vis-statements/rotavirus.pdf Problems that could ...
Tissera, Marion S; Cowley, Daniel; Bogdanovic-Sakran, Nada; Hutton, Melanie L; Lyras, Dena; Kirkwood, Carl D; Buttery, Jim P
Rotavirus gastroenteritis is a leading global cause of mortality and morbidity in young children due to diarrhea and dehydration. Over 85% of deaths occur in developing countries. In industrialised countries, 2 live oral rotavirus vaccines licensed in 2006 quickly demonstrated high effectiveness, dramatically reducing severe rotavirus gastroenteritis admissions in many settings by more than 90%. In contrast, the same vaccines reduced severe rotavirus gastroenteritis by only 30-60% in developing countries, but have been proven life-saving. Bridging this "efficacy gap" offers the possibility to save many more lives of children under the age of 5. The reduced efficacy of rotavirus vaccines in developing settings may be related to differences in transmission dynamics, as well as host luminal, mucosal and immune factors. This review will examine strategies currently under study to target the issue of reduced efficacy and effectiveness of oral rotavirus vaccines in developing settings.
Rotavirus vaccines are at an advanced stage of development but there are as yet no WHO recommendations on production and quality control to provide regulatory guidance. A meeting of experts was convened by WHO and PAHO/AMRO to review the scientific basis for production and quality control of rotavirus vaccines, and to discuss specific measures to assure the safety and efficacy of rotavirus vaccines. The meeting was attended by 25 experts from 14 countries, drawn from academia, public health, national regulatory authorities and vaccine producers. It was agreed that existing guidance for other live virus vaccines provides a very good basis for product characterization, especially for source materials and control of production. The basis for attenuation of current vaccines or vaccine candidates is not known but, at least for the vaccines based on the Jennerian approach of using animal (bovine) rotaviruses, is likely to be multigenic. The risk of intussusception in humans is influenced by genetic background and age. Recent analyzes of large vaccine safety trials found that certain strains of vaccine virus were not associated with intussusception, although in these trials the first dose of vaccine was not administered to children over 3 months of age. Since age is a risk factor for intussusception, this may suggest that early delivery of the first dose of vaccine is desirable. However, maternal antibodies may mitigate against early delivery of the first vaccine dose. Factors which could affect vaccine efficacy or safety include strain diversity, malnutrition, other enteric infections, parasitic infection or immune suppression. It was concluded that data from clinical trials conducted in one part of the world would not necessarily be predictive of vaccine efficacy in other places. It was agreed that in nonclinical evaluations there was a need to use oral dosing for toxicity studies and, because rotavirus is non-neurovirulent, that there was no need for an animal
Kamiya, Hajime; Suga, Shigeru; Nagao, Mizuho; Ichimi, Ryoji; Fujisawa, Takao; Umemoto, Masakazu; Tanaka, Takaaki; Ito, Hiroaki; Tanaka, Shigeki; Ido, Masaru; Taniguchi, Koki; Ihara, Toshiaki; Nakano, Takashi
Background Rotavirus vaccines were introduced in Japan in November 2011. We evaluated the subsequent reduction of the health-care burden of rotavirus gastroenteritis. Methods We conducted active surveillance for rotavirus gastroenteritis among children under 5 years old before and after the vaccine introduction. We surveyed hospitalization rates for rotavirus gastroenteritis in children in Tsu City, Mie Prefecture, Japan, from 2007 to 2015 and surveyed the number of outpatient visits at a Tsu City clinic from 2010 to 2015. Stool samples were obtained for rotavirus testing and genotype investigation. We assessed rotavirus vaccine coverage for infants living in Tsu City. Results In the pre-vaccine years (2007–2011), hospitalization rates for rotavirus gastroenteritis in children under 5 years old were 5.5, 4.3, 3.1 and 3.9 cases per 1000 person-years, respectively. In the post-vaccine years (2011–2015), the rates were 3.0, 3.5, 0.8 and 0.6 cases per 1000 person-years, respectively. The hospitalization rate decreased significantly in the 2013–2014 and 2014–2015 seasons compared to the average of the seasons before vaccine introduction (P < 0.0001). In one pre-vaccine year (2010–2011), the number of outpatient visits due to the rotavirus infection was 66. In the post-vaccine years (2011–2015), the numbers for each season was 23, 23, 7 and 5, respectively. The most dominant rotavirus genotype shifted from G3P to G1P and to G2P. The coverage of one dose of rotavirus vaccine in Tsu City was 56.5% in 2014. Conclusion After the vaccine introduction, the hospitalization rates and outpatient visits for rotavirus gastroenteritis greatly decreased. PMID:28246579
Esona, Mathew D; Gautam, Rashi
Group A rotavirus (RVA) is the major cause of acute gastroenteritis (AGE) in young children worldwide. Introduction of two live, attenuated rotavirus vaccines, Rotarix® and RotaTeq®, has dramatically reduced RVA-associated AGE and mortality. High-throughput, sensitive and specific techniques are required to rapidly diagnose and characterize rotavirus strains in stool samples for proper patient treatment and to monitor circulating vaccine and wild-type rotavirus strains. New molecular assays are rapidly developed that are more sensitive and specific than the conventional assays for detection, genotyping and full genome characterization of circulating rotavirus wild-type and vaccine (Rotarix® and RotaTeq®) strains causing AGE.
Mameli, Chiara; Fabiano, Valentina; Zuccotti, Gian Vincenzo
Rotavirus vaccines have shown to be effective and well tolerated in clinical trials. However it’s crucial to point out that immunization occurs in “real-word” conditions different from ideal clinical trial settings. Thus, the impact of rotavirus vaccines in terms of effectiveness and safety needs to be evaluated in real-world conditions. Post-licensure data regarding vaccine impact, effectiveness and safety under routine use are now available and provide a “real-world view.” PMID:22699445
Tate, Jacqueline E; Parashar, Umesh D
Rotavirus infection is the most common cause of severe gastroenteritis in children <5 years of age globally. Since 2009, the WHO has recommended inclusion of rotavirus vaccine in the national immunization programs of all countries. Data regarding rotavirus vaccine impact and effectiveness under conditions of routine use are important for encouraging countries to implement vaccination programs. In the absence of a national rotavirus vaccination program in France, the IVANHOE study was initiated to determine the real-world impact and effectiveness of rotavirus vaccine following introduction in a limited geographic area. This study found a twofold reduction in rotavirus hospitalizations among children <2 years of age who were age-eligible to receive rotavirus vaccine and a 98% vaccine effectiveness, highlighting the health benefits of a vaccination program.
Wu, Weilin; Orr-Burks, Nichole; Karpilow, Jon; Tripp, Ralph A.
Rotavirus is a major cause of severe gastroenteritis among very young children. In developing countries, rotavirus is the major cause of mortality in children under five years old, causing up to 20% of all childhood deaths in countries with high diarrheal disease burden, with more than 90% of these deaths occurring in Africa and Asia. Rotavirus vaccination mimics the first infection without causing illness, thus inducing strong and broad heterotypic immunity against prospective rotavirus infections. Two live vaccines are available, Rotarix and RotaTeq, but vaccination efforts are hampered by high production costs. Here, we present a dataset containing a genome-wide RNA interference (RNAi) screen that identified silencing events that enhanced rotavirus replication. Evaluated against several rotavirus vaccine strains, hits were validated in a Vero vaccine cell line as well as CRISPR/Cas9 generated cells permanently and stably lacking the genes that affect RV replication. Knockout cells were dramatically more permissive to RV replication and permitted an increase in rotavirus replication. These data show a means to improve manufacturing of rotavirus vaccine. PMID:28248921
Martinón-Torres, Federico; Aramburo, Angela; Martinón-Torres, Nazareth; Cebey, Miriam; Seoane-Pillado, María Teresa; Redondo-Collazo, Lorenzo; Martinón-Sánchez, Jose Maria
In 2010, and due to a quality problem identified in the vaccine manufacture, the rotavirus (RV) vaccination was withheld in Spain during 5 months. Our study aimed to evaluate the impact that this sudden cease had on rotavirus acute gastroenteritis (RAGE) hospitalizations. An increase in RAGE hospitalization was observed in parallel to the drop in vaccine coverage. Here, we report the first reverse evidence of rotavirus vaccine impact. PMID:23836258
Martinón-Torres, Federico; Aramburo, Angela; Martinón-Torres, Nazareth; Cebey, Miriam; Seoane-Pillado, María Teresa; Redondo-Collazo, Lorenzo; Martinón-Sánchez, Jose Maria
In 2010, and due to a quality problem identified in the vaccine manufacture, the rotavirus (RV) vaccination was withheld in Spain during 5 months. Our study aimed to evaluate the impact that this sudden cease had on rotavirus acute gastroenteritis (RAGE) hospitalizations. An increase in RAGE hospitalization was observed in parallel to the drop in vaccine coverage. Here, we report the first reverse evidence of rotavirus vaccine impact.
... PARENT S | DISEASES and the VACCINES THAT PREVENT THEM | Rotavirus and the Vaccine (Drops) to Prevent It Last ... February 2014 The best way to protect against rotavirus is by getting the rotavirus vaccine. Doctors recommend ...
Grimwood, Keith; Lambert, Stephen B; Milne, Richard J
Rotaviruses are the most common cause of severe gastroenteritis in children. By 5 years of age virtually every child worldwide will have experienced at least one rotavirus infection. This leads to an enormous disease burden, where every minute a child dies because of rotavirus infection and another four are hospitalized, at an annual societal cost in 2007 of $US2 billion. Most of the annual 527 000 deaths are in malnourished infants living in rural regions of low and middle income countries. In contrast, most measurable costs arise from medical expenses and lost parental wages in high income countries. Vaccines are the only public health prevention strategy likely to control rotavirus disease. They were developed to mimic the immunity following natural rotavirus infection that confers protection against severe gastroenteritis and consequently reduces the risk of primary healthcare utilization, hospitalization and death. The two currently licensed vaccines--one a single human strain rotavirus vaccine, the other a multiple strain human-bovine pentavalent reassortant rotavirus vaccine--are administered to infants in a two- or three-dose course, respectively, with the first dose given at 6-14 weeks of age. In various settings they are safe, immunogenic and efficacious against many different rotavirus genotypes. In high and middle income countries, rotavirus vaccines confer 85-100% protection against severe disease, while in low income regions of Africa and Asia, protection is less, at 46-77%. Despite this reduced efficacy in low income countries, the high burden of diarrheal disease in these regions means that proportionately more severe cases are prevented by vaccination than elsewhere. Post-licensure effectiveness studies show that rotavirus vaccines not only reduce rotavirus activity in infancy but they also decrease rates of rotavirus diarrhea in older and unimmunized children. A successful rotavirus vaccination program will rely upon sustained vaccine efficacy
Aliabadi, N; Tate, J E; Parashar, U D
Rotavirus vaccines have demonstrated significant impact in reducing the burden of morbidity and mortality from childhood diarrhoea in countries that have implemented routine vaccination to date. Despite this success, in many countries, rotavirus vaccine coverage remains lower than that of other routine childhood vaccines. Several issues may potentially affect vaccine uptake, namely safety concerns related to intussusception with consequent age restrictions on rotavirus vaccination, contamination with porcine circovirus, vaccine-derived reassortant strains and hospitalization in newborn nurseries at time of administration of live oral rotavirus vaccine. In addition to these safety concerns, other factors may also affect uptake, including lower vaccine efficacy in the developing world, potential emergence of strains escaping from vaccine protection resulting in lower overall impact of a vaccination programme and sustainable vaccine financing. Although further work is needed to address some of these concerns, global policy bodies have reaffirmed that the benefits of rotavirus vaccination outweigh the risks, and vaccine use is recommended globally.
Hawthorn, Rachael L; Watts, Brook; Singer, Mendel E
Objectives To examine the public health impact of mass vaccination with live attenuated human rotavirus vaccine (RIX4414) in a birth cohort in India, and to estimate the cost effectiveness and affordability of such a programme. Design Decision analytical Markov model encompassing all direct medical costs. Infection risk and severity depended on age, number of previous infections, and vaccination history; probabilities of use of inpatient and outpatient health services depended on symptom severity. Data sources Published clinical, epidemiological, and economic data. When possible, parameter estimates were based on data specific for India. Population Simulated Indian birth cohort followed for five years. Main outcome measures Decrease in rotavirus gastroenteritis episodes (non-severe and severe), deaths, outpatient visits, and admission to hospital; incremental cost effectiveness ratio of vaccination expressed as net cost in 2007 rupees per life year saved. Results In the base case, vaccination prevented 28 943 (29.7%) symptomatic episodes, 6981 (38.2%) severe episodes, 164 deaths (41.0%), 7178 (33.3%) outpatient visits, and 812 (34.3%) admissions to hospital per 100 000 children. Vaccination cost 8023 rupees (about £100, €113, $165) per life year saved, less than India’s per capita gross domestic product, a common criterion for cost effectiveness. The net programme cost would be equivalent to 11.6% of the 2006-7 budget of the Indian Department of Health and Family Welfare. Model results were most sensitive to variations in access to outpatient care for those with severe symptoms. If this parameter was increased to its upper limit, the incremental cost effectiveness ratio for vaccination still fell between one and three times the per capita gross domestic product, meeting the World Health Organization’s criterion for “cost effective” interventions. Uncertainty analysis indicated a 94.7% probability that vaccination would be cost effective according to
Constenla, Dagna O.; Linhares, Alexandre C.; Rheingans, Richard D.; Antil, Lynn R.; Waldman, Eliseu A.; da Silva, Luiz J.
The study was done to evaluate the cost-effectiveness of a national rotavirus vaccination programme in Brazilian children from the healthcare system perspective. A hypothetical annual birth-cohort was followed for a five-year period. Published and national administrative data were incorporated into a model to quantify the consequences of vaccination versus no vaccination. Main outcome measures included the reduction in disease burden, lives saved, and disability-adjusted life-years (DALYs) averted. A rotavirus vaccination programme in Brazil would prevent an estimated 1,804 deaths associated with gastroenteritis due to rotavirus, 91,127 hospitalizations, and 550,198 outpatient visits. Vaccination is likely to reduce 76% of the overall healthcare burden of rotavirus-associated gastroenteritis in Brazil. At a vaccine price of US$ 7-8 per dose, the cost-effectiveness ratio would be US$ 643 per DALY averted. Rotavirus vaccination can reduce the burden of gastroenteritis due to rotavirus at a reasonable cost-effectiveness ratio. PMID:19069617
Gagneur, Arnaud; Nowak, Emmanuel; Lemaitre, Thomas; Segura, Jean-Francois; Delaperrière, Nadège; Abalea, Lydie; Poulhazan, Elise; Jossens, Anne; Auzanneau, Lucie; Tran, Adissa; Payan, Christopher; Jay, Nadine; de Parscau, Loic; Oger, Emmanuel
The aim of the IVANHOE study was to determine the real-world impact of the rotavirus vaccine, controlling for epidemic-to-epidemic variation in disease burden. A population-based prospective cohort study was conducted in Brest City and 7 suburban districts (CUB area), North-western Brittany, France (210,000 inhabitants; 5500 births per year). The vaccination program started in May 2007 for a 2-year period for all infants born in the Brest birth zone through pediatricians, public outpatient clinics and general practitioners. To determine vaccine impact we monitored trends in hospitalizations for rotavirus-specific diarrhea using an active hospital-based surveillance system initiated 5 years before vaccine introduction. The number of hospitalizations for rotavirus-specific diarrhea during the 2008/2009 epidemic in infants less than 2 years of age whose parents lived within the CUB area was modelled as a function of (1) the number of hospitalizations in infants 2-5 years of age to control for epidemic-to-epidemic variation and (2) vaccine introduction. A total of 4684 infants received at least one dose. Of these, 2635 lived within the CUB area. Vaccine coverage for a complete schedule in the CUB area was 47.1%. Poisson modelling revealed a reduction by a factor of 2.04 (1.56-2.66) in the number of hospitalizations during the last epidemic season (2008/2009), the number of observed cases being equal to 30, against an expected number of 61. Relative risk reduction for hospitalizations for rotavirus diarrhea was 98% (95% CI: 83-100%). We observed a noticeable impact of vaccination on rotavirus diarrhea hospitalizations within 2 years of vaccine introduction integrating for the first time rotavirus epidemics variation. The trial is registered with ClinicalTrials.gov, number, NCT00740935.
Nowak, Emmanuel; Le Gal, Grégoire; Lemaitre, Thomas; Oger, Emmanuel; Poulhazan, Elise; Giroux, Jean-Dominique; Garenne, Armelle; Gagneur, Arnaud
Infants born preterm are at a higher risk of complications and hospitalization in cases of rotavirus diarrhea than children born at term. We evaluated the impact of a rotavirus vaccination campaign (May 2007 to May 2010) on hospitalizations for rotavirus gastroenteritis in a population of children under 3 years old born prematurely (before 37 weeks of gestation) in the Brest University Hospital birth zone. Active surveillance from 2002 to 2006 and a prospective collection of hospitalizations for rotavirus diarrhea were initiated in the pediatric units of Brest University Hospital until May 2010. Numbers of hospitalizations for rotavirus diarrhea among the population of children born prematurely, before and after the start of the vaccination program, were compared using a Poisson regression model controlling for epidemic-to-epidemic variation. A total of 217 premature infants were vaccinated from 2007 to 2010. Vaccine coverage for a complete course of three doses was 41.9%. The vaccine safety in premature infants was similar to that in term infants. The vaccination program led to a division by a factor of 2.6 (95% confidence interval [CI], 1.3 to 5.2) in the number of hospitalizations for rotavirus diarrhea during the first two epidemic seasons following vaccine introduction and by a factor of 11 (95% CI, 3.5 to 34.8) during the third season. We observed significant effectiveness of the pentavalent rotavirus vaccine on the number of hospitalizations in a population of prematurely born infants younger than 3 years of age. A multicenter national study would provide better assessment of this impact. (This study [Impact of Systematic Infants Vaccination Against Rotavirus on Gastroenteritis Hospitalization: a Prospective Study in Brest District, France (IVANHOE)] has been registered at ClinicalTrials.gov under registration no. NCT00740935.) PMID:25080553
Roué, Jean-Michel; Nowak, Emmanuel; Le Gal, Grégoire; Lemaitre, Thomas; Oger, Emmanuel; Poulhazan, Elise; Giroux, Jean-Dominique; Garenne, Armelle; Gagneur, Arnaud
Infants born preterm are at a higher risk of complications and hospitalization in cases of rotavirus diarrhea than children born at term. We evaluated the impact of a rotavirus vaccination campaign (May 2007 to May 2010) on hospitalizations for rotavirus gastroenteritis in a population of children under 3 years old born prematurely (before 37 weeks of gestation) in the Brest University Hospital birth zone. Active surveillance from 2002 to 2006 and a prospective collection of hospitalizations for rotavirus diarrhea were initiated in the pediatric units of Brest University Hospital until May 2010. Numbers of hospitalizations for rotavirus diarrhea among the population of children born prematurely, before and after the start of the vaccination program, were compared using a Poisson regression model controlling for epidemic-to-epidemic variation. A total of 217 premature infants were vaccinated from 2007 to 2010. Vaccine coverage for a complete course of three doses was 41.9%. The vaccine safety in premature infants was similar to that in term infants. The vaccination program led to a division by a factor of 2.6 (95% confidence interval [CI], 1.3 to 5.2) in the number of hospitalizations for rotavirus diarrhea during the first two epidemic seasons following vaccine introduction and by a factor of 11 (95% CI, 3.5 to 34.8) during the third season. We observed significant effectiveness of the pentavalent rotavirus vaccine on the number of hospitalizations in a population of prematurely born infants younger than 3 years of age. A multicenter national study would provide better assessment of this impact. (This study [Impact of Systematic Infants Vaccination Against Rotavirus on Gastroenteritis Hospitalization: a Prospective Study in Brest District, France (IVANHOE)] has been registered at ClinicalTrials.gov under registration no. NCT00740935.).
Panozzo, Catherine A; Becker-Dreps, Sylvia; Pate, Virginia; Jonsson Funk, Michele; Stürmer, Til; Weber, David J; Brookhart, M Alan
Rotavirus vaccines are highly effective at preventing gastroenteritis in young children and are now universally recommended for infants in the US. We studied patterns of use of rotavirus vaccines among US infants with commercial insurance. We identified a large cohort of infants in the MarketScan Research Databases, 2006-2010. The analysis was restricted to infants residing in states without state-funded rotavirus vaccination programs. We computed summary statistics and used multivariable regression to assess the association between patient-, provider-, and ecologic-level variables of rotavirus vaccine receipt and series completion. Approximately 69% of 594,117 eligible infants received at least one dose of rotavirus vaccine from 2006-2010. Most infants received the rotavirus vaccines at the recommended ages, but more infants completed the series for monovalent rotavirus vaccine than pentavalent rotavirus vaccine or a mix of the vaccines (87% versus 79% versus 73%, P<0.001). In multivariable analyses, the strongest predictors of rotavirus vaccine series initiation and completion were receipt of the diphtheria, tetanus and acellular pertussis vaccine (Initiation: RR = 7.91, 95% CI = 7.69-8.13; Completion: RR = 1.26, 95% CI = 1.23-1.29), visiting a pediatrician versus family physician (Initiation: RR = 1.51, 95% CI = 1.49-1.52; Completion: RR = 1.13, 95% CI = 1.11-1.14), and living in a large metropolitan versus smaller metropolitan, urban, or rural area. We observed rapid diffusion of the rotavirus vaccine in routine practice; however, approximately one-fifth of infants did not receive at least one dose of vaccine as recently as 2010. Interventions to increase rotavirus vaccine coverage should consider targeting family physicians and encouraging completion of the vaccine series.
Immergluck, Lilly Cheng; Held, Melissa; Jain, Shabnam; Chan, Trisha; Grizas, Alexandra P.; Khizer, Saadia; Barrett, Carol; Quaye, Osbourne; Mijatovic-Rustempasic, Slavica; Gautam, Rashi; Bowen, Michael D.; Moore, Jessica; Tate, Jacqueline E.; Parashar, Umesh D.; Vázquez, Marietta
OBJECTIVE: Previous US evaluations have not assessed monovalent rotavirus vaccine (RV1, a G1P human rotavirus strain) effectiveness, because of its later introduction (2008). Using case-control methodology, we measured the vaccine effectiveness (VE) of the 2-dose RV1 and 3-dose pentavalent vaccine (RV5) series against rotavirus disease resulting in hospital emergency department or inpatient care. METHODS: Children were eligible for enrollment if they presented to 1 of 5 hospitals (3 in Georgia, 2 in Connecticut) with diarrhea of ≤10 days’ duration during January through June 2010 or 2011, and were born after RV1 introduction. Stools were collected; immunization records were obtained from providers and state electronic immunization information system (IIS). Case-subjects (children testing rotavirus antigen-positive) were compared with 2 control groups: children testing rotavirus negative and children selected from IIS. RESULTS: Overall, 165 rotavirus-case subjects and 428 rotavirus-negative controls were enrolled. Using the rotavirus-negative controls, RV1 VE was 91% (95% confidence interval [CI] 80 to 95) and RV5 VE was 92% (CI 75 to 97) among children aged ≥8 months. The RV1 VE against G2P disease was high (94%, CI 78 to 98), as was that against G1P disease (89%, CI 70 to 96). RV1 effectiveness was sustained among children aged 12 through 23 months (VE 91%; CI 75 to 96). VE point estimates using IIS controls were similar to those using rotavirus-negative controls. CONCLUSIONS: RV1 and RV5 were both highly effective against severe rotavirus disease. RV1 conferred sustained protection during the first 2 years of life and demonstrated high effectiveness against G2P (heterotypic) disease. PMID:23776114
... HUMAN SERVICES Centers for Disease Control and Prevention Proposed Vaccine Information Materials for Rotavirus Vaccine AGENCY: Centers for Disease Control and Prevention (CDC), Department of Health and Human Services (HHS). ACTION: Notice with comment period. SUMMARY: Under the National Childhood Vaccine...
... including a severe allergy to latex. Babies with “severe combined immunodeficiency” (SCID) should not get rotavirus vaccine. Babies who have had a type of bowel blockage called “intussusception” should not get ... moderate or severe diarrhea or vomiting. Check with your doctor if ...
Seheri, L Mapaseka; Page, Nicola A; Mawela, Mothahadini P B; Mphahlele, M Jeffrey; Steele, A Duncan
Diarrhoeal diseases are ranked the third major cause of childhood mortality in South African children less than 5 years, where the majority of deaths are among black children. Acute severe dehydrating rotavirus diarrhoea remains an important contributor towards childhood mortality and morbidity and has been well documented in South Africa. As the preventive strategy to control rotavirus diarrhoea, South Africa became the first country in the WHO African Region to adopt the rotavirus vaccine in the national childhood immunisation programme in August 2009. The rotavirus vaccine in use, Rotarix, GSK Biologicals, is given at 6 and 14 weeks of age, along with other vaccines as part of Expanded Programme on Immunisation (EPI). Studies which facilitated the introduction of rotavirus vaccine in South Africa included the burden of rotavirus disease and strain surveillance, economic burden of rotavirus infection and clinical trials to assess the safety and efficacy of vaccine candidates. This paper reviews the epidemiology of rotavirus in South Africa, outlines some of the steps followed to introduce rotavirus vaccine in the EPI, and highlights the early positive impact of vaccination in reducing the rotavirus burden of disease based on the post-marketing surveillance studies at Dr George Mukhari hospital, a sentinel site at University of Limpopo teaching hospital in Pretoria, South Africa, which has conducted rotavirus surveillance for >20 years.
Heaton, Penny M; Ciarlet, Max
Twenty-five years passed between the discovery of the parent strain (WC3) of the pentavalent human-bovine reassortant rotavirus vaccine (PRV) in 1981 and the licensure of PRV in 2006. This orally administered liquid vaccine, which is given as a 3-dose series, is indicated for the prevention of rotavirus gastroenteritis, caused by the G serotypes contained in the vaccine, in infants and children. PRV is recommended by the Advisory Committee on Immunization Practices and the American Academy of Pediatrics for administration to all infants in the United States. These recommendations are supported by the results of the phase III studies, which demonstrated that PRV is well tolerated and efficacious. PRV reduced rotavirus-related hospitalizations by 96% and was not associated with an increased incidence of serious adverse events, including intussusception. This report focuses on the safety and efficacy data from the late-phase studies of PRV and discusses plans for providing this vaccine to the developing world.
García-López, Rodrigo; Pérez-Brocal, Vicente; Diez-Domingo, Javier; Moya, Andrés
To assess the effect that the rotavirus vaccine RotaTeq may have on the gut microbiota, this study searched for differences in intestinal bacterial composition between vaccinated and unvaccinated children. Bacterial diversity in fecal samples was evaluated by pyrosequencing of the 16S rRNA gene and taxonomic analyses using bioinformatics tools. No evidence of such differences was observed.
Libster, Romina; McNeal, Monica; Walter, Emmanuel B.; Shane, Andi L.; Winokur, Patricia; Cress, Gretchen; Berry, Andrea A.; Kotloff, Karen L.; Sarpong, Kwabena; Turley, Christine B.; Harrison, Christopher J.; Pahud, Barbara A.; Marbin, Jyothi; Dunn, John; El-Khorazaty, Jill; Barrett, Jill
BACKGROUND AND OBJECTIVES: Although both licensed rotavirus vaccines are safe and effective, it is often not possible to complete the schedule by using the same vaccine formulation. The goal of this study was to investigate the noninferiority of the immune responses to the 2 licensed rotavirus vaccines when administered as a mixed schedule compared with administering a single vaccine formulation alone. METHODS: Randomized, multicenter, open-label study. Healthy infants (6–14 weeks of age) were randomized to receive rotavirus vaccines in 1 of 5 different schedules (2 using a single vaccine for all doses, and 3 using mixed schedules). The group receiving only the monovalent rotavirus vaccine received 2 doses of vaccine and the other 4 groups received 3 doses of vaccine. Serum for immunogenicity testing was obtained 1 month after the last vaccine dose and the proportion of seropositive children (rotavirus immunoglobulin A ≥20 U/mL) were compared in all the vaccine groups. RESULTS: Between March 2011 and September 2013, 1393 children were enrolled and randomized. Immune responses to all the sequential mixed vaccine schedules were shown to be noninferior when compared with the 2 single vaccine reference groups. The proportion of children seropositive to at least 1 vaccine antigen at 1 month after vaccination ranged from 77% to 96%, and was not significantly different among all the study groups. All schedules were well tolerated. CONCLUSIONS: Mixed schedules are safe and induced comparable immune responses when compared with the licensed rotavirus vaccines given alone. PMID:26823540
Rotaviruses are the cause of acute gastroenteritis, and disease is widespread amongst infants and young children throughout the world. Also, rotavirus is associated with significant mortality in developing countries with more than 500 000 children dying each year as a result of the severe dehydration associated with rotavirus disease. Efforts have been ongoing for more than 30 years to develop a safe and effective rotavirus vaccine. Currently, two vaccines, RotaRix and RotaTeq, have been licensed for use in many countries throughout the world following comprehensive safety and efficiency trials. Monitoring their effectiveness after licensure has confirmed that their incorporation into early childhood vaccination schedules can significantly prevent severe rotavirus diarrhoea, which would have resulted in hospitalizations, emergency room visits or increased diarrhoea-related mortality. Although the efficacy of both vaccines is lower at approximately 40-59% in developing countries, their use could significantly reduce the mortality associated with rotavirus disease that is concentrated in these countries.
Suarez-Castaneda, Eduardo; Burnett, Eleanor; Elas, Miguel; Baltrons, Rafael; Pezzoli, Lorenzo; Flannery, Brendan; Kleinbaum, David; de Oliveira, Lucia Helena; Danovaro-Holliday, M Carolina
Rotavirus vaccine was introduced in El Salvador in 2006 and is recommended to be given concomitantly with DTP-HepB-Haemophilus influenzae type b (pentavalent) vaccine at ages 2 months (upper age limit 15 weeks) and 4 months (upper age limit 8 months) of age. However, rotavirus vaccination coverage continues to lag behind that of pentavalent vaccine, even in years when national rotavirus vaccine stock-outs have not occurred. We analyzed factors associated with receipt of oral rotavirus vaccine among children who received at least 2 doses of pentavalent vaccine in a stratified cluster survey of children aged 24-59 months conducted in El Salvador in 2011. Vaccine doses included were documented on vaccination cards (94.4%) or in health facility records (5.6%). Logistic regression and survival analysis were used to assess factors associated with vaccination status and age at vaccination. Receipt of pentavalent vaccine by age 15 weeks was associated with rotavirus vaccination (OR: 5.1; 95% CI 2.7, 9.4), and receipt of the second pentavalent dose by age 32 weeks was associated with receipt of two rotavirus vaccine doses (OR: 5.0; 95% CI 2.1-12.3). Timely coverage with the first pentavalent vaccine dose was 88.2% in the 2007 cohort and 91.1% in the 2008 cohort (p=0.04). Children born in 2009, when a four-month national rotavirus vaccine stock-out occurred, had an older median age of receipt of rotavirus vaccine and were less likely to receive rotavirus on the same date as the same dose of pentavalent vaccine than children born in 2007 and 2008. Upper age limit recommendations for rotavirus vaccine administration contributed to suboptimal vaccination coverage. Survey data suggest that late rotavirus vaccination and co-administration with later doses of pentavalent vaccine among children born in 2009 helped increase rotavirus vaccine coverage following shortages.
Patel, Manish; Shane, Andi L.; Parashar, Umesh D.; Jiang, Baoming; Gentsch, Jon R.; Glass, Roger I.
Rotavirus vaccines hold promise to decrease the burden of severe diarrhea in the poorest countries, where 85% of deaths due to rotavirus occur. However, the potency of live oral vaccines is lower in these challenging settings than in middle- and upper-income countries. Many hypotheses have been suggested to explain these differences that could provide clues to improve the ultimate success of these novel vaccines. Although introduction today of even moderately effective vaccines will decrease the morbidity and mortality associated with rotavirus in low-income settings, research is urgently needed to understand why these differences in efficacy occur and what could be done to improve vaccine performance to maximize the life-saving benefits of vaccination. PMID:19817613
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
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 was the most prevalent rotavirus genotype (44.0% of typed specimens) and G2P 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.
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
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 was the most prevalent rotavirus genotype (44.0% of typed specimens) and G2P 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
Peláez-Carvajal, Dioselina; Cotes-Cantillo, Karol; Paternina-Caicedo, Angel; Gentsch, Jon; de la Hoz-Restrepo, Fernando; Patel, Manish
Strain monitoring for emergence of novel strains after the introduction of rotavirus vaccine is an integral component of routine rotavirus immunization programs. Using a laboratory based strain surveillance system between 2008 and 2012, a wide variation in strain pattern in Colombia was founded both before and after the introduction of a monovalent rotavirus vaccine in 2009. G2P, a strain fully heterotypic to the vaccine was predominant before vaccine introduction in 2008 (47%) and after vaccine introduction in 2010 (54%), 2011 (86%), and 2012 (32%). The presence of this strain before the introduction of vaccine and decreasing prevalence during the most recent surveillance year suggests secular variation rather than vaccine pressure as a cause for this fluctuation. While strain monitoring can be valuable after vaccine introduction, these surveillance data alone without information on disease incidence or strain specific vaccine effectiveness can be prone to misinterpretation with regard to the role of vaccine pressure on emergence of new or persistent strains.
Al-Areqi, Lina; Mujally, Abulatif; Alkarshy, Fawzya; Nasser, Arwa; Jumaan, Aisha O.
The study aims to assess the impact of rotavirus vaccine introduction on diarrheal diseases hospitalization and to identify the rotavirus genotypes most prevalent before and after vaccine introduction among children ≤ 5 years of age. Rotarix™ ® rotavirus vaccine is currently licensed for infants in Yemen and was introduced in 2012. The vaccination course consists of two doses. The first dose is administrated at 6 weeks of age and the second dose is completed by 10 weeks. Based on a longitudinal observational study, we assessed the impact of vaccination on rotavirus hospitalization before and after vaccination among children ≤ 5 years of age at the Yemeni-Swedish Hospital (YSH) in Taiz, Yemen. Prevaccination covered January 2009–July 2012 during which 2335 fecal samples were collected from children ≤ 5 years old. Postvaccination covered January 2013–December 2014 during which 1114 fecal samples were collected. Rotavirus was detected by Enzyme Linkage Immunosorbent Assay (ELISA). The incidence of rotavirus hospitalization decreased from 43.79% in 2009 to 10.54% in 2014. Hospitalization due to rotavirus diarrhea was reduced by 75.93%. Vaccine coverage increased from 23% in 2012 to 72% in 2014. Also, the results showed that the most predominant genotypes in prevaccination period were G2P (55.0%), followed by G1P (15.0%), while in postvaccination period G1P (31%) was the predominant genotype, followed by G9P (27.5%). In conclusion, rotavirus vaccination in Yemen resulted in sharp reduction in diarrheal hospitalization. A successful rotavirus vaccination program in Yemen will rely upon efficient vaccine delivery systems and sustained vaccine efficacy against diverse and evolving rotavirus strains. PMID:27437161
Parashar, U. D.; Bresee, J. S.; Gentsch, J. R.; Glass, R. I.
Rotavirus, the most common diarrheal pathogen in children worldwide, causes approximately one third of diarrhea-associated hospitalizations and 800,000 deaths per year. Because natural infection reduces the incidence and severity of subsequent episodes, rotavirus diarrhea might be controlled through vaccination. Serotypespecific immunity may play a role in protection from disease. Tetravalent rhesus-human reassortant rotavirus vaccine (RRV-TV) (which contains a rhesus rotavirus with serotype G3 specificity and reassortant rhesus-human rotaviruses with G1, G2, and G4 specificity) provides coverage against the four common serotypes of human rotavirus. In clinical trials in industrialized countries, RRV-TV conferred 49% to 68% protection against any rotavirus diarrhea and 61% to 100% protection against severe disease. This vaccine was licensed by the U.S. Food and Drug Administration on August 31, 1998, and should be cost-effective in reducing diarrheal diseases in industrialized countries. The vaccine's efficacy and cost-effectiveness in developing countries should be evaluated. PMID:9866732
Iwata, Satoshi; Nakata, Shuji; Ukae, Susumu; Koizumi, Yoshitugu; Morita, Yasuyuki; Kuroki, Haruo; Tanaka, Yoshiyuki; Shizuya, Toshiyuki; Schödel, Florian; Brown, Michelle L; Lawrence, Jody
Rotavirus is the most common cause of severe gastroenteritis in children under 5 y of age. Estimates of disease burden in Japan suggest that between 26,500 and 78,000 children in this age group need hospitalization each year, resulting in a direct medical cost of 10 to 24 billion Yen. Since being introduced in routine infant immunization schedules in the United States in 2006, the oral live pentavalent rotavirus vaccine RV5 (RotaTeq™) has contributed to dramatic reductions in the incidence of rotavirus gastroenteritis (RVGE) and in health care resource utilization. This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of a 3-dose regimen of RV5 in healthy infants, age 6 to 12 weeks, at 32 sites across Japan. The results indicate that RV5 was significantly efficacious in preventing any severity [74.5% (95% confidence interval [CI]: 39.9%, 90.6%; p < 0.001)], moderate-to-severe [80.2% (95% CI: 47.4%, 94.1%)], and severe [100% (95% CI: 55.4%, 100%)] RVGE caused by viruses with serotypes contained in the vaccine. The observed cases of RVGE included rotavirus types G1 (n = 19), G3 (n = 9), G9 (n = 5) and one unspecified G serotype with P1A. No G2 or G4 RVGE cases were observed, and this study was not powered to evaluate efficacy against individual serotypes. RV5 was generally safe and well tolerated in Japanese infants. These results are comparable to those observed in clinical studies conducted in other developed countries. Introduction of the vaccine in Japan may reduce disease burden and associated health care costs. PMID:23732903
Rheingans, Richard; Anderson, John D; Anderson, Benjamin; Chakraborty, Poulomy; Atherly, Deborah; Pindolia, Deepa
India accounts for 23% of global rotavirus mortality in under-five children, with more than 100,000 deaths from rotavirus annually. Introduction of a vaccine in India is considered to be the most effective intervention for preventing rotavirus mortality. Recent research suggests that there is considerable variation in rotavirus mortality burden across regional, gender and socio-economic subpopulations within India. In addition, there is potential variability in who would likely receive rotavirus vaccine if introduced. We use available household data to estimate heterogeneity in rotavirus mortality risk, vaccination benefits, and cost-effectiveness across geographic and socio-economic groups within India. We account for heterogeneity by modeling estimated three-dose routine vaccinations as a proxy for a generalized rotavirus vaccine, and mortality for subpopulations of children aggregated by region and state, socio-economic status and sex, separately. Results are presented for six geographic regions and for Bihar, Uttar Pradesh, and Madhya Pradesh, three high mortality states accounting for 56% of national mortality estimates. Impact estimates accounting for disparities predict rotavirus vaccine introduction will prevent 35,000 deaths at an average cost of $118/DALY averted (7292 INR/DALY averted). Rotavirus vaccines are most cost-effective for the poor living in high mortality regions and states. Reductions in geographic and socio-economic disparities based on regional estimates could prevent an additional 9400 deaths annually, while reductions in socio-economic disparities in the three highest morality states alone could prevent an additional 10,600 deaths annually. Understanding the impact of heterogeneity can help improve strategies to maximize the benefits of rotavirus vaccination introduction, leading to fewer lives lost as a result of rotavirus disease.
Benhafid, Mohammed; Elomari, Nezha; Azzouzi Idrissi, Meryem; Rguig, Ahmed; Gentsch, Jon R; Parashar, Umesh; Elaouad, Rajae
Rotarix(TM) vaccine was introduced into the National Program of Immunization of Morocco in October 2010, reaching quickly 87% of the target population of children nationally. The incidence of rotavirus gastroenteritis and the prevalence of circulating rotavirus strains has been monitored in three sentinel hospitals since June 2006. The average percentage of rotavirus positive cases among all children under 5 years old hospitalized for gastroenteritis during the pre-vaccine period (2006-2010) was 44%. This percentage dropped to 29%, 15% and 24% in the 3 years post vaccine introduction (2011, 2012 and 2013), which is a decline of 34%, 66%, and 45%, respectively. Declines in prevalence were greatest among children 0-1 years of age (53%) and were most prominent during the winter and autumn rotavirus season. The prevalence of the G2P and G9P genotype sharply increased in the post vaccine period (2011-2013) compared to the previous seasons (2006-2010). Rotavirus vaccines have reduced greatly the number of children hospitalized due to rotavirus infection at the three sentinel hospitals; it is however unclear if the predominance of G2P and G9P genotypes is related to the vaccine introduction, or if this is attributable to normal genotype fluctuations. Continued surveillance will be pivotal to answer this question in the future.
Castilla, Jesús; Beristain, Xabier; Martínez-Artola, Víctor; Navascués, Ana; García Cenoz, Manuel; Alvarez, Nerea; Polo, Isabel; Mazón, Ana; Gil-Setas, Alberto; Barricarte, Aurelio
Two rotavirus vaccines have been available since 2006. This study evaluates the effectiveness of these vaccines using a test-negative case-control design in Navarre, Spain. We included children 3-59 months of age who sought medical care for gastroenteritis and for whom stool samples were taken between January 2008 and June 2011. About 9% had received the pentavalent vaccine (RotaTeq) and another 8% received the monovalent vaccine (Rotarix). Cases were the 756 children with confirmed rotavirus and controls were the 6036 children who tested negative for rotavirus. Thirty-five percent of cases and 9% of controls had required hospitalization (p<0.0001). The adjusted effectiveness of complete vaccination was 78% (95% CI: 68-85%) in preventing rotavirus gastroenteritis and 83% (95% CI: 65-93%) in preventing hospitalization for rotavirus gastroenteritis. No differences between the two vaccines were detected (p=0.4523). Both vaccines were highly effective in preventing cases and hospital admissions in children due to rotavirus gastroenteritis.
Wen, Xiaobo; Cao, Dianjun; Jones, Ronald W.; Li, Jianping; Szu, Shousun; Hoshino, Yasutaka
Two currently licensed live oral rotavirus vaccines (Rotarix® and RotaTeq®) are highly efficacious against severe rotavirus diarrhea. However, the efficacy of such vaccines in selected low-income African and Asian countries is much lower than that in middle or high-income countries. Additionally, these two vaccines have recently been associated with rare case of intussusception in vaccinated infants. We developed a novel recombinant subunit parenteral rotavirus vaccine which may be more effective in low-income countries and also avert the potential problem of intussusception. Truncated recombinant VP8* (ΔVP8*) protein of human rotavirus strain Wa P, DS-1 P or 1076 P expressed in E. coli was highly soluble and was generated in high yield. Guinea pigs hyperimmunized intramuscularly with each of the ΔVP8* proteins (i.e., (P, P or P) developed high levels of homotypic as well as variable levels of heterotypic neutralizing antibodies. Moreover, the selected ΔVP8* proteins when administered to mice at a clinically relevant dosage, route and schedule, elicited high levels of serum anti-VP8* IgG and/or neutralizing antibodies. Our data indicated that the ΔVP8* proteins may be a plausible additional candidate as new parenteral rotavirus vaccines. PMID:22885016
Wen, Xiaobo; Cao, Dianjun; Jones, Ronald W; Li, Jianping; Szu, Shousun; Hoshino, Yasutaka
Two currently licensed live oral rotavirus vaccines (Rotarix® and RotaTeq®) are highly efficacious against severe rotavirus diarrhea. However, the efficacy of such vaccines in selected low-income African and Asian countries is much lower than that in middle or high-income countries. Additionally, these two vaccines have recently been associated with rare case of intussusception in vaccinated infants. We developed a novel recombinant subunit parenteral rotavirus vaccine which may be more effective in low-income countries and also avert the potential problem of intussusception. Truncated recombinant VP8* (ΔVP8*) protein of human rotavirus strain Wa P, DS-1 P or 1076 P expressed in Escherichia coli was highly soluble and was generated in high yield. Guinea pigs hyperimmunized intramuscularly with each of the ΔVP8* proteins (i.e., P, P or P) developed high levels of homotypic as well as variable levels of heterotypic neutralizing antibodies. Moreover, the selected ΔVP8* proteins when administered to mice at a clinically relevant dosage, route and schedule, elicited high levels of serum anti-VP8* IgG and/or neutralizing antibodies. Our data indicated that the ΔVP8* proteins may be a plausible additional candidate as new parenteral rotavirus vaccines.
Giménez Sánchez, F; Martinón Torres, F; Bernaola Iturbe, E; Baca Cots, M; de Juan Martín, F; Díez Delgado, J; Garcés Sánchez, M; Gómez Campderá, J A; Picazo, J; Pineda Solas, V
Rotavirus is the leading cause of diarrhea in infants. In developed countries, this infection leads to considerable morbidity with a high number of hospitalizations and medical interventions in the winter season, giving rise to substantial medical and social costs. In developing countries, rotavirus is a major cause of mortality in infants due to dehydration, with an estimated 600.000 deaths or more per year worldwide. A vaccine that is easy administrated, safe and with high efficacy would be the ideal means to reduce the burden of this disease and its high economic and social cost and to decrease the number of deaths in low-income countries. Recently, the results of two well-designed clinical trials with a large number of subjects have been reported. Both studies, which used different vaccines, reported high efficacy in the prevention of severe gastroenteritis and hospitalizations caused by rotavirus. When these vaccines become available in Europe, a reduction in hospitalizations, medical consultations, and days of work lost can be expected.
Kumar, Arun; Goel, Manish K; Jain, Ram Bilas; Khanna, Pardeep; Vibha, Vibha
Globally, rotavirus diarrhea results in 453,000 deaths in children younger than 5 y—37% of deaths attributable to diarrhea and 5% of all deaths in children younger than 5 y. India alone accounts for 22% (~100,000 deaths) of all deaths attributable to rotavirus infection. Two oral rotavirus vaccines are available: Rotarix, a monovalent P1A G1 vaccine (GlaxoSmithKline), and RotaTeq, a pentavalent bovine-human reassortant vaccine (Merck). Rotarix is administered in a 2-dose schedule with the first and second doses of DTP (DTP1, DTP2). RotaTeq requires a 3-dose schedule with DTP1, DTP2 and DTP3 with an interval of 4–10 weeks between doses. The first dose of either vaccine should be administered to infants aged 6–15 weeks irrespective of the history of previous rotavirus infection, and the maximum age for administering the last dose of either vaccine should be 32 weeks. Although India would require funding from international health organizations/GAVI until new indigenous rotavirus vaccine candidates are developed at a cheaper price, introduction of vaccination into the national immunization program would be a cost-effective step toward control of the rotavirus diarrhea-related morbidity and mortality in India.
Zhen, Shan-Shan; Li, Yue; Wang, Song-Mei; Zhang, Xin-Jiang; Hao, Zhi-Yong; Chen, Ying; Wang, Dan; Zhang, Yan-Hong; Zhang, Zhi-Yong; Ma, Jing-Chen; Zhou, Peng; Zhang, Zhen; Jiang, Zhi-Wei; Zhao, Yu-Liang; Wang, Xuan-Yi
A universal rotavirus (RV) immunization program is a potentially cost-effective measure for preventing RV infection in China. However, the efficacy of the only licensed RV vaccine (Lanzhou lamb rotavirus vaccine, LLR), which is made by a domestic manufacturer, has not been proven by a properly designed clinical trial. In October 2011 to March 2012, to measure the potential protection provided by LLR, a case-control study nested in a population-based active diarrhea surveillance study of children <5 years of age was conducted in rural Zhengding county. During the study period, 308 episodes of diarrhea were identified as being caused by RV infection, resulting in an incidence rate of 48.0/1000 people/year. The predominant RV serotype was G3 (61.5%), followed by G1 (15.2%), and G9 (6.5%). Overall, a protection of 35.0% (95% confidence interval (CI), 13.0%-52.0%) was identified, and higher protection was found among moderate RV gastroenteritis cases caused by the serotype G3 (52.0% 95% CI: 2.0%-76.1%). A concurrently conducted case-control study comparing non-RV viral diarrheal cases with non-diarrheal controls in the same population found that the RV vaccine offered no protection against non-RV diarrhea. Even under a less ideal immunization schedule, the oral LLR conferred a certain level of protection against RV gastroenteritis. However, further studies are needed to understand the full characteristics of the LLR, including its efficacy when administered following the optimal regimen, the potential risk of inducing intussusception, and the direct and indirect protective effects of LLR.
Gurgel, Ricardo Q.; Alvarez, Alberto De Juan; Rodrigues, Alda; Ribeiro, Robergson R.; Dolabella, Sílvio S.; Da Mota, Natanael L.; Santos, Victor S.; Iturriza-Gomara, Miren; Cunliffe, Nigel A.; Cuevas, Luis E.
Background and Aims Rotavirus causes severe diarrhoea and Brazil introduced the Rotarix G1P vaccine in 2006. We aimed to describe changes in rotavirus incidence and diarrhoea epidemiology before and after vaccine introduction. Methods Design: (i) hospital-based survey of children with diarrhoea (2006–2012); (ii) diarrhea-mortality and hospitalization surveillance (1999–2012). Setting (i) Aracaju and (ii) state and national level. Results 1841 children were enrolled and 231 (12.5%) had rotavirus. Rotavirus was less frequent from January-June than from July-December (9.4% versus 20.9%, p<0.01), but the seasonal variation was less defined after 2009. Very few rotavirus cases (8–3.9%) were detected in 2011, with an increase in 2012 (13–18.5%). In 2006, unvaccinated children were more likely to have rotavirus, but thereafter unvaccinated and vaccinated children had equally low incidence. Older children and those with rotavirus were more likely to have severe diarrhea episodes. The most frequent genotype from 2006 to 2010 was G2P; except in 2009, when most cases were G1P. Very few G2P were detected from 2011 and 50% cases in 2012 were G8P. Diarrhoea-hospitalizations decreased nationally from 89,934 (2003) to 53,705 (2012; 40.3% reduction) and in the state from 1729 to 748 (56.7% reduction). Diarrhoea-deaths decreased nationally from 4368 in 1999 to 697 in 2012 (84% reduction, p<0.001) and in the state from 132 to 18 (86% reduction). These changes were much larger after vaccine introduction. Conclusions The vaccine was associated with substantial reductions in rotavirus incidence and diarrhoea-hospitalizations and deaths. The G2P genotype predominance disappeared over time and may be replaced by other heterotypic genotypes. PMID:25360784
Montenegro, Fernanda Maria Ulisses; Falbo, Ana Rodrigues; Germano, Eliane Mendes; Correia, Nancy Barros; Souza, Edvaldo da Silva; Nakagomi, Osamu; Nakagomi, Toyoko; Cuevas, Luis E; Cunliffe, Nigel A; Correia, Jailson B
Rotavirus vaccination was introduced in Brazil in March 2006. We describe the distribution of rotavirus genotypes in children with acute gastroenteritis in a hospital in Recife, Brazil, during pre- and post-vaccination periods. There was a 43.8% reduction in the proportion of diarrhea episodes due to rotavirus. Nevertheless, we observed a sustained predominance of G2P as the main genotype identified in the post-vaccination period.
... the recombinant influenza vaccine (RIV). The nasal spray flu vaccine (live attenuated influenza vaccine or LAIV) should NOT ... to your doctor or pharmacist about the best flu vaccine option for you or your family.
Gosselin, Virginie; Généreux, Mélissa; Gagneur, Arnaud; Petit, Geneviève
ABSTRACT In 2011, the monovalent rotavirus vaccine was introduced into a universal immunization program in Quebec (Canada). This retrospective cohort study assessed vaccine effectiveness (VE) in preventing acute gastroenteritis (AGE) and rotavirus gastroenteritis (RVGE) hospitalizations among children <3 y living in the Quebec Eastern Townships region according to socioeconomic status (SES). Data were gathered from a tertiary hospital database paired with a regional immunization registry. Three cohorts of children were followed: (1) vaccinated children born in post-universal vaccination period (2011–2013, n = 5,033), (2) unvaccinated children born in post-universal vaccination period (n = 1,239), and (3) unvaccinated children born in pre-universal vaccination period (2008–2010, n = 6,436). In each cohort, AGE and RVGE hospitalizations were identified during equivalent follow-up periods to calculate VE globally and according to neighborhood-level SES. Using multivariable logistic regression, adjusted odds ratios (OR) were computed to obtain VE (1-OR). Adjusted VE of 2 doses was 62% (95% confidence interval [CI]: 37%–77%) and 94% (95%CI: 52%–99%) in preventing AGE and RVGE hospitalization, respectively. Stratified analyses according to SES showed that children living in neighborhoods with higher rates of low-income families had significantly lower VE against AGE hospitalizations compared to neighborhoods with lower rates of low-income families (30% vs. 78%, p = 0.027). Our results suggest that the rotavirus vaccine is highly effective in preventing severe gastroenteritis in young children, particularly among the most well-off. SES seems to influence rotavirus VE, even in a high-income country like Canada. Further studies are needed to determine factors related to lower rotavirus VE among socioeconomically disadvantaged groups. PMID:27367155
Matthijnssens, J; Zeller, M; Heylen, E; De Coster, S; Vercauteren, J; Braeckman, T; Van Herck, K; Meyer, N; Pirçon, J-Y; Soriano-Gabarro, M; Azou, M; Capiau, H; De Koster, J; Maernoudt, A-S; Raes, M; Verdonck, L; Verghote, M; Vergison, A; Van Damme, P; Van Ranst, M
The overall vaccine effectiveness of the monovalent rotavirus vaccine in an observational, prospective, multicentre, hospital-based case-control study in Belgium (RotaBel) was 90%. However, rotavirus genotype and co-infecting pathogens are important parameters to take into account when assessing vaccine effectiveness. In this study we specifically investigated the effect of rotavirus genotypes and co-infecting pathogens on vaccine effectiveness of the monovalent vaccine. In addition, we also investigated the effect of co-infecting pathogens on disease severity. From February 2008 to June 2010 stool samples of rotavirus gastroenteritis cases of a random sample of 39 Belgian hospitals were collected and subsequently genotyped. Fisher's exact tests were performed to investigate the relationships between rotavirus genotype, co-infecting pathogens and disease severity. The vaccine effectiveness of a full series of the monovalent rotavirus vaccine against hospitalized rotavirus gastroenteritis caused by G1P rotavirus strains was 95% (95% CI 77.5-98.7). Against G2P, the vaccine effectiveness was 85% (95% CI: 63.7-93.8). G4P- and G3P-specific vaccine effectiveness was 90% (95% CI 19.2-98.7) and 87% (95% CI -5.2 to 98.4), respectively. A post-hoc analysis showed that the genotype distribution was significantly related to the vaccination status (p <0.001), whereby G2P strains were proportionally more prevalent in vaccinated cases than in unvaccinated cases. No statistical associations were found between co-infection status and vaccination status, Vesikari severity score or rotavirus genotype. The high vaccine effectiveness against the individual genotypes implies robust protection of the monovalent rotavirus vaccine against hospitalized rotavirus gastroenteritis caused by the major human rotavirus genotypes. The prevalence of G2P requires continued monitoring.
Patel, Manish M; Glass, Roger; Desai, Rishi; Tate, Jacqueline E; Parashar, Umesh D
Rotavirus is the most common cause of fatal and severe childhood diarrhoea worldwide. Two new rotavirus vaccines have shown efficacy against severe rotavirus disease in large clinical trials. Between 2006 and 2010, 27 countries introduced rotavirus vaccination into national immunisation programmes and, subsequently, the burden of severe rotavirus disease in these countries has decreased substantially in both vaccinated and unvaccinated children. Rotavirus vaccination has led to large, sustained declines in childhood deaths from diarrhoea in Brazil and Mexico, which supports estimates that rotavirus was the leading cause of diarrhoeal deaths in these countries. Studies after licensing have provided new insights into these vaccines, such as the duration of protection, relative effectiveness in poor populations, and strain evolution after vaccine introduction. The challenge for policy makers worldwide is to analyse the effect of vaccination in early adopter countries and to assess whether the benefits outweigh the costs and encourage wider dissemination of these vaccines.
Hull, Brynley P; Menzies, Robert; Macartney, Kristine; McIntyre, Peter B
Strict age limits for receipt of rotavirus vaccines and simultaneous use of vaccines requiring two (Rotarix(®)) and three (RotaTeq(®)) doses in Australia may impact on coverage and timeliness of other vaccines in the infant schedule. Using data from the Australian Childhood Immunisation Register (ACIR), coverage and timeliness of rotavirus vaccines and changes in timeliness of other infant vaccines following rotavirus vaccine introduction was examined, with particular emphasis on Indigenous infants in whom coverage is less optimal. Final dose rotavirus coverage reached 83% within 21 months of program commencement but remained 7% lower than other vaccines due in infancy. Coverage was 11-17% lower in Indigenous infants. Adherence to the first dose upper age limits for rotavirus vaccine was high with >97% of children vaccinated by the recommended age, but for subsequent rotavirus doses, receipt beyond the upper age limits was more common, especially in Indigenous children. Following rotavirus vaccine introduction, there were improvements in timeliness of receipt of all doses of DTPa-containing and 7-valent pneumococcal conjugate vaccines. High population coverage can be attained with rotavirus vaccines, even with adherence to strict upper age restrictions for vaccine dose administration. Rotavirus vaccine introduction appears to have impacted upon the timeliness of other concomitantly scheduled vaccines. These factors should be considered when rotavirus programs are introduced.
Trang, Nguyen V; Braeckman, Tessa; Lernout, Tinne; Hau, Vu T B; Anh, Le T K; Luan, Le T; Van Damme, Pierre; Anh, Dang D
Rotavirus (RV) is the most common cause of childhood diarrhea worldwide, and several vaccines have been successfully developed to reduce the burden of disease. However, lower vaccine immunogenicity and efficacy in developing countries might be related to the virus-neutralizing activity of breast milk. We examined possible differences in breast milk antibody levels (total IgA antibody, RV-specific antibodies, and RV-neutralizing antibodies) between healthy mothers living in a rural area (n = 145) and mothers living in an urban area (n = 147) of Vietnam. Total IgA concentration was significantly higher in samples from mothers in the rural region than in samples from mothers in the urban region, whereas urban mothers had significantly higher RV-specific IgA antibody titers than did rural mothers. Neutralizing antibodies against RV strain G1P were undetected in nearly one-half of the breast milk samples (45–48%), whereas the majority of the remaining samples had low antibody titers (2–16). Despite these low titers, the breast milk still reduced vaccine strain titers (2 × 106 plaque forming units/mL) up to 80% or more, even at a milk-to-virus ratio of 1:8. An increase in neutralizing anti-G1P antibody titers (P < 0.05) in rural infants over time suggests a continuous exposure to circulating RV. These results contribute to the understanding of the potential interference of breast milk with RV vaccine efficacy and immunogenicity in Vietnamese infants. PMID:25668672
Trang, Nguyen V; Braeckman, Tessa; Lernout, Tinne; Hau, Vu T B; Anh, Le T K; Luan, Le T; Van Damme, Pierre; Anh, Dang D
Rotavirus (RV) is the most common cause of childhood diarrhea worldwide, and several vaccines have been successfully developed to reduce the burden of disease. However, lower vaccine immunogenicity and efficacy in developing countries might be related to the virus-neutralizing activity of breast milk. We examined possible differences in breast milk antibody levels (total IgA antibody, RV-specific antibodies, and RV-neutralizing antibodies) between healthy mothers living in a rural area (n=145) and mothers living in an urban area (n=147) of Vietnam. Total IgA concentration was significantly higher in samples from mothers in the rural region than in samples from mothers in the urban region, whereas urban mothers had significantly higher RV-specific IgA antibody titers than did rural mothers. Neutralizing antibodies against RV strain G1P were undetected in nearly one-half of the breast milk samples (45-48%), whereas the majority of the remaining samples had low antibody titers (2-16). Despite these low titers, the breast milk still reduced vaccine strain titers (2×10(6) plaque forming units/mL) up to 80% or more, even at a milk-to-virus ratio of 1:8. An increase in neutralizing anti-G1P antibody titers (P<0.05) in rural infants over time suggests a continuous exposure to circulating RV. These results contribute to the understanding of the potential interference of breast milk with RV vaccine efficacy and immunogenicity in Vietnamese infants.
Yin, Shi; Liubao, Peng; Chongqing, Tan; Xiaomin, Wan
Kawasaki disease (KD) after rotavirus and hepatitis A vaccination has not previously been reported in a baby in China. Herein, we describe a 20-month-old child who developed Kawasaki disease after receiving her second dose of Lanzhou lamb rotavirus vaccine (LLR) and her first dose of freeze-dried live attenuated hepatitis A vaccine. The case report was conducted by collecting and analyzing the hospital in-patient medical records and reviewing both the domestic and foreign pertinent literature. These findings will be important to note this possible side effect and to further investigate the association between the above 2 vaccines and Kawasaki disease.
Mousavi Jarrahi, Yasaman; Zahraei, Seyed Mohsen; Sadigh, Nader; Esmaeelpoor Langeroudy, Keyhan; Khodadost, Mahmoud; Ranjbaran, Mehdi; Sanjari Moghaddam, Ali; Besharat, Mehdi; Mosavi Jarrahi, Alireza
ABSTRACT Rotavirus is the most common cause of severe diarrhea leading to hospitalization or disease-specific death among young children. Effective vaccines have recently been approved and successful vaccination program implemented. The aim of this study was to evaluate the cost effectiveness of mass rotavirus vaccination program in Iran. We developed a Markov model that reflects key features of rotavirus natural history. Parameters of the model were assessed by field study or developed through literature search and published data. We applied the model to the 2009 Iranian birth cohort and evaluated the cost-effectiveness of including the rotavirus vaccine (Rotarix®) into Iranian expanded immunization program (EPI). With an estimated hospitalization rate of 0.05 and outpatient rate of 0.23 cases per person-year, vaccinating cohort of 1231735 infants in Iran with 2 doses of (Rotarix®), would prevent 32092 hospitalizations, 158750 outpatient visits, and 1591 deaths during 5 y of follow-up. Under base-case assumption of $10 cost per course of vaccine, the vaccination would incur an extra cost of $1,019,192 from health care perspective and would avert 54680 DALYs. From societal perspective, there would be $15,192,568 saving for the society with the same averted DALYs. The incremental cost effectiveness ratio showed a cost of $19 US dollars per averted DALY from health care perspective and a saving of $278 US dollars for each averted DALY from societal perspective. Introducing rotavirus vaccine into EPI program would be highly cost-effective public health intervention in Iran. PMID:26360331
Chang, Millie R.; Velapatiño, Grace; Campos, Miguel; Chea-Woo, Elsa; Baiocchi, Nelly; Cleary, Thomas G.; Ochoa, Theresa J.
We evaluated the monthly distribution of rotavirus diarrhea in a cohort of children 12–24 months of age followed as part of a diarrhea clinical trial in a peri-urban community of Lima. We observed a peak of rotavirus diarrhea in the winter months and a decrease in rotavirus prevalence after the introduction of the rotavirus vaccine in Peru. PMID:25778507
Wang, Yuhuan; Vlasova, Anastasia; Velasquez, Daniel E.; Saif, Linda J.; Kandasamy, Sukumar; Kochba, Efrat; Levin, Yotam; Jiang, Baoming
Live-attenuated oral rotavirus (RV) vaccines have lower efficacy in low income countries, and additionally are associated with a rare but severe adverse event, intussusception. We have been pursuing the development of an inactivated rotavirus vaccine (IRV) using the human rotavirus strain CDC-9 (G1P) through parenteral immunization and previously demonstrated dose sparing and enhanced immunogenicity of intradermal (ID) unadjuvanted IRV using a coated microneedle patch in comparison with intramuscular (IM) administration in mice. The aim of this study was to evaluate the immune response and protection against RV infection and diarrhea conferred by the administration of the ID unadjuvanted IRV using the microneedle device MicronJet600® in neonatal gnotobiotic (Gn) piglets challenged with virulent Wa G1P human RV. Three doses of 5 μg IRV when administered intradermally and 5 μg IRV formulated with aluminum hydroxide [Al(OH)3] when administered intramuscularly induced comparable rotavirus-specific antibody titers of IgA, IgG, IgG avidity index and neutralizing activity in sera of neonatal piglets. Both IRV vaccination regimens protected against RV antigen shedding in stools, and reduced the cumulative diarrhea scores in the piglets. This study demonstrated that the ID and IM administrations of IRV are immunogenic and protective against RV-induced diarrhea in neonatal piglets. Our findings highlight the potential value of an adjuvant sparing effect of the IRV ID delivery route. PMID:27824918
Wang, Yuhuan; Vlasova, Anastasia; Velasquez, Daniel E; Saif, Linda J; Kandasamy, Sukumar; Kochba, Efrat; Levin, Yotam; Jiang, Baoming
Live-attenuated oral rotavirus (RV) vaccines have lower efficacy in low income countries, and additionally are associated with a rare but severe adverse event, intussusception. We have been pursuing the development of an inactivated rotavirus vaccine (IRV) using the human rotavirus strain CDC-9 (G1P) through parenteral immunization and previously demonstrated dose sparing and enhanced immunogenicity of intradermal (ID) unadjuvanted IRV using a coated microneedle patch in comparison with intramuscular (IM) administration in mice. The aim of this study was to evaluate the immune response and protection against RV infection and diarrhea conferred by the administration of the ID unadjuvanted IRV using the microneedle device MicronJet600® in neonatal gnotobiotic (Gn) piglets challenged with virulent Wa G1P human RV. Three doses of 5 μg IRV when administered intradermally and 5 μg IRV formulated with aluminum hydroxide [Al(OH)3] when administered intramuscularly induced comparable rotavirus-specific antibody titers of IgA, IgG, IgG avidity index and neutralizing activity in sera of neonatal piglets. Both IRV vaccination regimens protected against RV antigen shedding in stools, and reduced the cumulative diarrhea scores in the piglets. This study demonstrated that the ID and IM administrations of IRV are immunogenic and protective against RV-induced diarrhea in neonatal piglets. Our findings highlight the potential value of an adjuvant sparing effect of the IRV ID delivery route.
Karafillakis, Emilie; Hassounah, Sondus; Atchison, Christina
Prior to the introduction of rotavirus vaccines in 2006, rotavirus was the leading cause of severe gastroenteritis among European children <5 years of age. We conducted a systematic review of the published literature to examine the effectiveness and impact of rotavirus vaccines in Europe following the first eight years of routine use. Four publication databases were searched, yielding 276 unique citations from February 1st, 2006 to July 31st, 2014. Twenty four studies on effectiveness (n=9) and impact (n=15) met the inclusion criteria. Across Europe, vaccine effectiveness against rotavirus-related healthcare utilisation ranged from 68% to 98%, consistent with efficacy data from clinical trials. Reductions in rotavirus hospitalisations ranged from 65% to 84%, consistent with findings from post-marketing studies from the US and Latin America. We confirm the significant public health benefit of rotavirus vaccination in Europe and provide further evidence to support implementation of universal rotavirus vaccination in all European countries.
Schweitzer, A.; Pessler, F.; Akmatov, M. K.
ABSTRACT We examined the coverage and timing of rotavirus vaccination and the impact of rotavirus vaccine introduction on coverage and timing of the pentavalent vaccine. We used data from the Demographic and Health Surveys in Honduras (2011/2012) and Peru (2012). The samples were divided into 2 subcohorts: children born before and after the introduction of rotavirus vaccine. We compared coverage and timing of the pentavalent vaccine in the aforementioned subcohorts. Coverage with the first and second doses of rotavirus vaccination was 95% (95% confidence intervals: 93–97%) and 91% (89–95%) in Honduras and 79% (77–82%) and 72% (69–75%) in Peru, respectively. Coverage increased in both countries over the years. The proportion of children vaccinated according to age-appropriate vaccination schedules varied between 67% (second dose of rotavirus vaccinations in Peru) and 89% (first dose of rotavirus vaccination in Honduras). Coverage with the first and second doses of pentavalent vaccination remained constant over the years in Honduras, while in Peru there was a significant increase in coverage over the years (p for trend, <0.0001). In both countries, timing of pentavalent vaccination was better in post-rota-cohorts than in pre-rota-cohorts. Since its introduction, coverage of rotavirus vaccination has improved over time in both countries. An introduction of rotavirus vaccination in both countries appears to have improved the coverage and timing of other similarly scheduled vaccinations. PMID:26833132
Hungerford, D; Read, J M; Cooke, R P D; Vivancos, R; Iturriza-Gómara, M; Allen, D J; French, N; Cunliffe, N
The impact of routine rotavirus vaccination on community-acquired (CA) and healthcare-associated (HA) rotavirus gastroenteritis (RVGE) at a large paediatric hospital, UK, was investigated over a 13-year period. A total of 1644 hospitalized children aged 0-15 years tested positive for rotavirus between July 2002 and June 2015. Interrupted time-series analysis demonstrated that, post vaccine introduction (July 2013 to June 2015), CA- and HA-RVGE hospitalizations were 83% [95% confidence interval (CI): 72-90%) and 83% (95% CI: 66-92%] lower than expected, respectively. Rotavirus vaccination has rapidly reduced the hospital rotavirus disease burden among both CA- and HA-RVGE cases.
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Parashar, Umesh D; Cortese, Margaret M; Payne, Daniel C; Lopman, Benjamin; Yen, Catherine; Tate, Jacqueline E
In 1999, the first rhesus-human reassortant rotavirus vaccine licensed in the United States was withdrawn within a year of its introduction after it was linked with intussusception at a rate of ∼1 excess case per 10,000 vaccinated infants. While clinical trials of 60,000-70,000 infants of each of the two current live oral rotavirus vaccines, RotaTeq (RV5) and Rotarix (RV1), did not find an association with intussusception, post-licensure studies have documented a risk in several high and middle income countries, at a rate of ∼1-6 excess cases per 100,000 vaccinated infants. However, considering this low risk against the large health benefits of vaccination that have been observed in many countries, including in countries with a documented vaccine-associated intussusception risk, policy makers and health organizations around the world continue to support the routine use of RV1 and RV5 in national infant immunization programs. Because the risk and benefit data from affluent settings may not be directly applicable to developing countries, further characterization of any associated intussusception risk following rotavirus vaccination as well as the health benefits of vaccination is desirable for low income settings.
Parashar, Umesh D; Cortese, Margaret M; Payne, Daniel C; Lopman, Benjamin; Yen, Catherine; Tate, Jacqueline E
In 1999, the first rhesus-human reassortant rotavirus vaccine licensed in the U.S. was withdrawn within a year of its introduction after it was linked with intussusception at a rate of ~1 excess case per 10,000 vaccinated infants. While clinical trials of 60,000-70,000 infants of each of the two current live oral rotavirus vaccines, RotaTeq (RV5) and Rotarix (RV1), did not find an association with intussusception, post-licensure studies have documented a risk in several high and middle income countries, at a rate of ~1-6 excess cases per 100,000 vaccinated infants. However, considering this low risk against the large health benefits of vaccination that have been observed in many countries, including in countries with a documented vaccine-associated intussusception risk, policy makers and health organizations around the world continue to support the routine use of RV1 and RV5 in national infant immunization programs. Because the risk and benefit data from affluent settings may not be directly applicable to developing countries, further characterization of any associated intussusception risk following rotavirus vaccination as well as the health benefits of vaccination is desirable for low income settings.
Yen, Catherine; Figueroa, Jesùs Reyna; Uribe, Edgar Sánchez; Carmen-Hernández, Luz Del; Tate, Jacqueline E; Parashar, Umesh D; Patel, Manish M; Richardson López-Collado, Vesta
After the introduction of monovalent rotavirus vaccine (RV1) in Mexico in 2006-2007, diarrhea mortality and morbidity declined substantially among Mexican children under 5 years of age. In January 2010, surveillance identified the emergence of a novel G9P rotavirus strain nationwide. We conducted a case-control study to assess the field effectiveness of RV1 against severe rotavirus gastroenteritis caused by this unusual strain and to determine whether the G9P emergence was related to vaccine failure or failure to vaccinate. RV1 was 94% effective (95% confidence interval, 16%-100%) against G9P rotavirus-related hospitalization, indicating that its emergence was likely unrelated to vaccine pressure.
Parashar, Umesh D; Johnson, Hope; Steele, A Duncan; Tate, Jacqueline E
Two rotavirus vaccines have been licensed in >100 countries worldwide since 2006. As of October 2105, these vaccines have been implemented in the national immunization programs of 79 countries, including 36 low-income countries that are eligible for support for vaccine purchase from Gavi, the Vaccine Alliance. Rotavirus vaccines were initially introduced in Australia and countries of the Americas and Europe after completion of successful clinical trials in these regions, and the impact of routine vaccination in reducing the health burden of severe childhood gastroenteritis in these regions has been well documented. Because of concerns around the performance of orally administered rotavirus vaccines in developing countries, vaccine implementation in these settings only began after additional clinical trials were completed and the World Health Organization issued a global recommendation for use of rotavirus vaccines in 2009. This supplementary issue of Clinical Infectious Diseases includes a collection of articles describing the impact and effectiveness of routine rotavirus vaccination in developing countries that were among the early adopters of rotavirus vaccine. The data highlight the benefits of vaccination and should provide valuable evidence to sustain vaccine use in these countries and encourage other countries to adopt routine rotavirus vaccination to reduce the health burden of severe childhood gastroenteritis.
Pérez-Vilar, Silvia; Díez-Domingo, Javier; Puig-Barberà, Joan; Gil-Prieto, Ruth; Romio, Silvana
Studies have shown high intussusception rates in Spain. We performed a hospital-based retrospective observational study of the intussusception risk following rotavirus vaccinations among infants in Valencia, a region of Spain with an annual birth cohort of approximately 48,000 children, during 2007–2011, using a self-controlled case series design. We performed medical record review of all cases using Brighton Collaboration´s case definition and assessed the positive predictive value (PPV) of the intussusception diagnosis code. Among 151 hospitalized cases discharged as intussusception, we confirmed 136 as Brighton Collaboration's Levels 1 or 2, resulting in a PPV of 93% (95% CI: 87%–96%). Three confirmed cases occurred within days 1–7 following the first rotavirus vaccination. The incidence rate ratio was 9.0 (95% CI: 0.9–86.5) (crude) and 4.7 (95% CI:0.3–74.1)(age adjusted). In this first study in Europe, the intussusception risk point estimate was comparable to other studies, although results were not statistically significant, maybe due to limited power. The high PPV found will facilitate implementation of a larger study without requiring medical record review. Our finding of very few vaccinated cases despite a thorough 5-year investigation in a country that, according to previous studies, may have a large background rate of intussusception is reassuring and should contribute to deliberations about the need to include rotavirus vaccines in the official Spanish calendars. PMID:26083707
Background Acute diarrhea is the second leading cause of mortality among children under 5 years of age in developing countries. The pathogen most strongly associated with diarrhea is rotavirus followed by enteric pathogens such as bacteria, helminthes and protozoan. Adequate sanitation and water supply contribute to decrease acute diarrhea incidence of most etiologic agents, although vaccination remains the most important intervention to control rotavirus acute diarrhea. This study aimed to describe environmental conditions and analyze spatially the acute diarrhea and intestinal infection among rotavirus vaccinated infants from Laranjeiras-Sergipe, Brazil. Methods Children were enrolled between 2 and 11 months of age and followed through 12 months. Demographic, socioeconomic and environmental data were obtained from a questionnaire, and immunization data were obtained from children vaccination card. Children stool samples were collected each month in order to run laboratory analyses. The household spatial localization was obtained by using a Global Positioning System (GPS). Spatial analysis was performed using the TerraView computer program and Kernel intensity estimation. Results A total of 1,113 stool samples were collected with 80 being diarrhea associated. Diarrhea incidence rate was 0.5 ± 1.0 episodes/child/year. The overall infection rates by Ascaris lumbricoides, Endolimax nana, Giardia lamblia and rotavirus were 5.1%, 3.0%, 0.9% and 2.6%, respectively. 3.8% of diarrhea-associated stool samples were positive for rotavirus and 11.3% were positive for helminths and protozoans. There were some changes on spatial distribution of intestinal infections and diarrhea episodes along the four trimesters evaluated. Conclusions The studied infants live equally in precarious conditions of sanitation which probably explain the significant rates of parasitic infections appearing in early life. The low acute diarrhea incidence in the studied rotavirus vaccinated
Sindhu, Kuladaipalayam Natarajan C; Cunliffe, Nigel; Peak, Matthew; Turner, Mark; Darby, Alistair; Grassly, Nicholas; Gordon, Melita; Dube, Queen; Babji, Sudhir; Praharaj, Ira; Verghese, Valsan; Iturriza-Gómara, Miren; Kang, Gagandeep
Introduction Gastroenteritis is the leading cause of morbidity and mortality among young children living in resource-poor settings, majority of which is attributed to rotavirus. Rotavirus vaccination can therefore have a significant impact on infant mortality. However, rotavirus vaccine efficacy in Sub-Saharan Africa and Southeast Asia is significantly lower than in high-income countries. Maternally derived antibodies, infant gut microbiota and concomitant oral polio vaccination have been proposed as potential reasons for poor vaccine performance in low-income settings. The overall aim of this study is to compare the role of maternally derived antibodies and infant gut microbiota in determining immune response to rotavirus vaccine in high-income and low-income settings, using the same vaccine and a similar study protocol. Methods and analysis The study is an observational cohort in three countries—Malawi, India and UK. Mothers will be enrolled in third trimester of pregnancy and followed up, along with infants after delivery, until the infant completes two doses of oral rotavirus vaccine (along with routine immunisation). The levels of prevaccination maternally derived rotavirus-specific antibodies (IgG) will be correlated with infant seroconversion and antibody titres, 4 weeks after the second dose of rotavirus vaccine. Both within-country and between-country comparisons of gut microbiome will be carried out between children who seroconvert and those who do not. The impact of oral polio vaccine coadministration on rotavirus vaccine response will be studied in Indian infants. Ethics and dissemination Ethical approvals have been obtained from Integrated Research Application System (IRAS, NHS ethics) in UK, College of Medicine Research and Ethics Committee (COMREC) in Malawi and Institutional Review Board (IRB), Christian Medical College, Vellore in India. Participant recruitment and follow-up is ongoing at all three sites. Analysis of data, followed by
McGrath, Eric J.; Thomas, Ron; Duggan, Christopher; Asmar, Basim I.
Objectives Pentavalent rotavirus vaccine (RV5) has been shown to be well-tolerated and efficacious in preventing rotavirus gastroenteritis in healthy infants. Safety and immunogenicity of RV5 in infants with surgical gastrointestinal disease have not been studied. The aim of the present study was to evaluate the safety and immunogenicity of RV5 in infants with a history of congenital or acquired intestinal disease requiring resection compared with healthy infants. Methods Infants with intestinal resection were matched by gestational age and chronological age to healthy infants (controls). Dose 1 of RV5 was given at 10 to 12 weeks of chronological age. Doses 2 and 3 were given at intervals of 4 to 10 weeks, with all 3 doses given by 32 weeks. All infants were monitored for adverse events (AEs) by telephone calls, clinic visits, and parental written reports during the first 42 days after each dose and monthly thereafter by telephone for 12 months. Serum anti-rotavirus immunoglobulin A (IgA) titers were measured prevaccination and 2 weeks after dose 3. Results A total of 5 infants with surgical gastrointestinal disease and 3 control subjects were enrolled. All participants (100%) mounted a 3-fold increase in serum anti-rotavirus IgA geometric mean titer postvaccination. RV5 administration to surgical infants was well tolerated with a majority of AEs being attributed to the underlying medical condition. Conclusions Postvaccination serum anti-rotavirus IgA levels indicate that RV5 is immunogenic in infants with a history of bowel resection, despite varying lengths of residual bowel. RV5 was well tolerated with few vaccine-related AEs. PMID:24614127
Giménez Sánchez, Francisco; Nogueira, Esperanza Jiménez; Sánchez Forte, Miguel; Ibáñez Alcalde, Mercedes; Cobo, Elvira; Angulo, Raquel; Garrido Fernández, Pablo
ABSTRACT Rotavirus is the leading cause of hospitalization due to acute gastroenteritis (AGE) in infants and toddlers. However, rotavirus vaccination has been associated with a decline in hospitalization rates due to rotavirus AGE. A descriptive retrospective study was conducted to analyze the impact of rotavirus vaccination on the rate of hospitalizations due to AGE among children ≤2 years old in 2 areas of the province of Almería, Spain. After eight years of rotavirus vaccination, rates of hospitalizations due to rotavirus AGE are diminished. This decline is closely related to vaccine coverage in the studied areas. PMID:26810147
Giménez Sánchez, Francisco; Nogueira, Esperanza Jiménez; Sánchez Forte, Miguel; Ibáñez Alcalde, Mercedes; Cobo, Elvira; Angulo, Raquel; Garrido Fernández, Pablo
Rotavirus is the leading cause of hospitalization due to acute gastroenteritis (AGE) in infants and toddlers. However, rotavirus vaccination has been associated with a decline in hospitalization rates due to rotavirus AGE. A descriptive retrospective study was conducted to analyze the impact of rotavirus vaccination on the rate of hospitalizations due to AGE among children ≤2 years old in 2 areas of the province of Almería, Spain. After eight years of rotavirus vaccination, rates of hospitalizations due to rotavirus AGE are diminished. This decline is closely related to vaccine coverage in the studied areas.
Kuter, Barbara J; Dallas, Michael J; Heaton, Penny
The Rotavirus Efficacy and Safety Trial (REST) was a blinded, placebo-controlled study of the live pentavalent human-bovine vaccine, RotaTeq® (Merck & Co. Inc., West Point, PA). REST was noteworthy because its primary objective was to evaluate the safety of RotaTeq® with regard to intussusception, a rare intestinal illness that occurs with a background incidence of approximately 50 cases per 100 000 infant years. The study involved approximately 70 000 infants at over 500 study sites in 11 countries. The study demonstrated that the risk of intussusception was similar in vaccine and placebo recipients and that the vaccine prevented rotavirus gastroenteritis, ameliorated the severity of disease in those who had any disease, and substantially reduced rotavirus-associated hospitalizations and other health care contacts. This report provides an in-depth review of the background, statistical and regulatory considerations, and execution of REST. We describe the rationale and methods used for sample size, continuous safety monitoring, group sequential design, and detailed study execution. The results of the study have been reported elsewhere. The design and conduct of this study may serve as a useful model for planning other future large-scale clinical trials, especially those evaluating uncommon adverse events. PMID:18375651
Wen, Xiaobo; Cao, Dianjun; Jones, Ronald W; Hoshino, Yasutaka; Yuan, Lijuan
The two currently available live oral rotavirus vaccines, Rotarix® and RotaTeq®, are highly efficacious in the developed countries. However, the efficacy of such vaccines in resource deprived countries in Africa and Southeast Asia is low. We reported previously that a bacterially-expressed rotavirus P2-P ΔVP8* subunit vaccine candidate administered intramuscularly elicited high-titers of neutralizing antibodies in guinea pigs and mice and significantly shortened the duration of diarrhea in neonatal gnotobiotic pigs upon oral challenge with virulent human rotavirus Wa strain. To further improve its vaccine potential and provide wider coverage against rotavirus strains of global and regional epidemiologic importance, we constructed 2 tandem recombinant VP8* proteins, P2-P ΔVP8*-P ΔVP8* and P2-P ΔVP8*-P ΔVP8* based on Escherichia coli expression system. The two resulting recombinant tandem proteins were highly soluble and P2-P ΔVP8*-P ΔVP8* was generated with high yield. Moreover, guinea pigs immunized intramuscularly by 3 doses of the P2-P ΔVP8*-P ΔVP8* or P2-P ΔVP8*-P ΔVP8* vaccine with aluminum phosphate adjuvant developed high titers of homotypic and heterotypic neutralizing antibodies against human rotaviruses bearing G1-G4, G8, G9 and G12 with P, P or P combination. The results suggest that these 2 subunit vaccines in monovalent or bivalent formulation can provide antigenic coverage to almost all the rotavirus G (VP7) types and major P (VP4) types of global as well as regional epidemiologic importance. PMID:26091081
Kannan Kutty, P; Pathmanathan, G; Salleh, N M
Rotavirus vaccine is available as an optional vaccine in Malaysia. The counselling of optional vaccines is considered an integral part of the health services offered in a private paediatric clinic. While ensuring that all babies are up-todate with their compulsory immunization, counselling of optional vaccines like the rotavirus vaccine could give parents the choice to make an informed decision on the acceptance of this vaccine. Over a period of two years, we counselled the parents regarding diarrhoea caused by rotavirus disease and the rotavirus vaccine. In this study, the factors that were significantly associated with the acceptance of the rotavirus vaccine were the gender of the baby, the mother's age, the mother's occupation, the mode of payment for the vaccine, the number of previous visits to the clinic by the parents, the number of counselling sessions given to the parents and the pre-counselling awareness or knowledge of rotavirus disease and rotavirus vaccine. It is hoped that these findings may assist busy clinicians in their continuous efforts to provide health education and vaccination counselling to the parents of their patients.
Braeckman, Tessa; Van Herck, Koen; Meyer, Nadia; Pirçon, Jean-Yves; Soriano-Gabarró, Montse; Heylen, Elisabeth; Zeller, Mark; Azou, Myriam; Capiau, Heidi; De Koster, Jan; Maernoudt, Anne-Sophie; Raes, Marc; Verdonck, Lutgard; Verghote, Marc; Vergison, Anne; Matthijnssens, Jelle; Van Ranst, Marc
Objective To evaluate the effectiveness of rotavirus vaccination among young children in Belgium. Design Prospective case-control study. Setting Random sample of 39 Belgian hospitals, February 2008 to June 2010. Participants 215 children admitted to hospital with rotavirus gastroenteritis confirmed by polymerase chain reaction and 276 age and hospital matched controls. All children were of an eligible age to have received rotavirus vaccination (that is, born after 1 October 2006 and aged ≥14 weeks). Main outcome measure Vaccination status of children admitted to hospital with rotavirus gastroenteritis and matched controls. Results 99 children (48%) admitted with rotavirus gastroenteritis and 244 (91%) controls had received at least one dose of any rotavirus vaccine (P<0.001). The monovalent rotavirus vaccine accounted for 92% (n=594) of all rotavirus vaccine doses. With hospital admission as the outcome, the unadjusted effectiveness of two doses of the monovalent rotavirus vaccine was 90% (95% confidence interval 81% to 95%) overall, 91% (75% to 97%) in children aged 3-11 months, and 90% (76% to 96%) in those aged ≥12 months. The G2P genotype accounted for 52% of cases confirmed by polymerase chain reaction with eligible matched controls. Vaccine effectiveness was 85% (64% to 94%) against G2P and 95% (78% to 99%) against G1P. In 25% of cases confirmed by polymerase chain reaction with eligible matched controls, there was reported co-infection with adenovirus, astrovirus and/or norovirus. Vaccine effectiveness against co-infected cases was 86% (52% to 96%). Effectiveness of at least one dose of any rotavirus vaccine (intention to vaccinate analysis) was 91% (82% to 95%). Conclusions Rotavirus vaccination is effective for the prevention of admission to hospital for rotavirus gastroenteritis among young children in Belgium, despite the high prevalence of G2P and viral co-infection. PMID:22875947
Pérez-Rubio, Alberto; Luquero, Francisco Javier; Eiros Bouza, Jose María; Castrodeza Sanz, Jose Javier; Bachiller Luque, Maria Rosario; de Lejarazu, Raúl Ortiz; Sánchez Porto, Antonio
Rotavirus is one of the main causes of acute gastroenteritis in infants and young children. Furthermore, rotavirus is the leading cause of hospitalization and death from acute gastroenteritis among infants and young children worldwide. Although death due to rotavirus is rare in industrialized regions such as Spain, the rotavirus disease burden and its economic impact is severe. This study aims to assess systematic vaccination against rotavirus economically and socially in a Spanish region. Economic cost-effectiveness and cost-benefit assessment through a choice tree was designed. We estimated health provider costs, economic costs and quality-adjusted life years (QALYs) lost due to rotavirus infections. The study includes a fictitious cohort of 100,000 children from Castilla y Leon who were also administered the rotavirus vaccine together with diphtheria and tetanus toxoids and pertussis (DTP) . The study adopted a society and health care system perspective. A sensitivity analysis was developed to assess the uncertainty of some variables. According to the estimated incidence rate for children in Castilla y Leon, rotavirus immunization is projected to prevent 45% of cases with RotaTeq and 57% with Rotarix. The respective cost per QALY is about Euro 75,000 and 50,000 from the perspective of the health care system. Routine infant vaccination in Castilla y Leon using either rotavirus vaccine is not profitable from the payer's perspective and is not cost-effective under basic case assumptions unless the vaccine is available at a lower cost.
Liu, Fangning; Wen, Ke; Li, Guohua; Yang, Xingdong; Kocher, Jacob; Bui, Tammy; Jones, Dorothy; Pelzer, Kevin; Clark-Deener, Sherrie; Yuan, Lijuan
Objectives To examine dose effects of Lactobacillus acidophilus NCFM (LA) ™ strain on rotavirus-specific antibody and B cell responses in gnotobiotic pigs vaccinated with an oral attenuated human rotavirus (AttHRV). Methods Pigs were inoculated with AttHRV vaccine in conjunction with high dose LA (14 doses, total 2.2×109 colony forming units [CFU]), intermediate dose LA (9 doses, total 3.2×106 CFU), low dose LA (5 doses, total 2.1×106 CFU) or without LA feeding. Protection against rotavirus shedding and diarrhea was assessed upon challenge with a virulent HRV. Rotavirus-specific IgA and IgG antibodies in serum and rotavirus-specific IgA and IgG antibody-secreting cells (ASC) and memory B cells in ileum, spleen and blood of the pigs were measured and compared among treatment groups. Results The intermediate dose LA (MidLA), but not high or low dose LA, significantly reduced rotavirus diarrhea (MidLA only group) and significantly improved the protection conferred by AttHRV vaccine (MidLA+AttHRV group). Associated with the increased protection, MidLA significantly enhanced rotavirus-specific antibody, ASC and memory B cell responses to AttHRV vaccine. High or low dose LA did not enhance virus-specific antibody and ASC responses, hence did not improve the vaccine efficacy. Conclusions These findings highlight the importance of dose selection and indicate that certain specific lactobacilli strains at the appropriate dose have the dual function of reducing rotavirus diarrhea and enhancing the immunogenicity and protective efficacy of rotavirus vaccines. PMID:24126832
Rodríguez-Limas, William A; Pastor, Ana Ruth; Esquivel-Soto, Ernesto; Esquivel-Guadarrama, Fernando; Ramírez, Octavio T; Palomares, Laura A
Rotavirus is the most common cause of severe diarrhea in many animal species of economic interest. A simple, safe and cost-effective vaccine is required for the control and prevention of rotavirus in animals. In this study, we evaluated the use of Saccharomyces cerevisiae extracts containing rotavirus-like particles (RLP) as a vaccine candidate in an adult mice model. Two doses of 1mg of yeast extract containing rotavirus proteins (between 0.3 and 3 μg) resulted in an immunological response capable of reducing the replication of rotavirus after infection. Viral shedding in all mice groups diminished in comparison with the control group when challenged with 100 50% diarrhea doses (DD50) of murine rotavirus strain EDIM. Interestingly, when immunizing intranasally protection against rotavirus infection was observed even when no increase in rotavirus-specific antibody titers was evident, suggesting that cellular responses were responsible of protection. Our results indicate that raw yeast extracts containing rotavirus proteins and RLP are a simple, cost-effective alternative for veterinary vaccines against rotavirus.
Lopman, Ben A; Payne, Daniel C; Tate, Jacqueline E; Patel, Manish M; Cortese, Margaret M; Parashar, Umesh D
Rotavirus causes one-third to one-half of severe diarrheal disease in children under the age of five years worldwide. In 2006 two rotavirus vaccines became available and, in the intervening years, approximately thirty countries have introduced them into their immunization programs, primarily in high-income and middle-income settings. Major reductions in rotavirus hospitalizations have been observed in a number of these locations, and in select countries, there have been impacts on gastroenteritis mortality associated with rotavirus vaccine introduction. In addition to these direct health benefits, reduced gastroenteritis risk has been documented in unvaccinated groups, including older children and adults, suggesting indirect benefits (i.e. herd immunity). In this paper, we summarize what has been learned from programs studying post-licensure vaccine effectiveness, impact on health-care utilization and death, safety issues (namely, intussception and the detection of adventitious viruses) and the potential selective pressure of vaccination on the diversity of rotavirus genotypes.
Luchs, Adriana; Timenetsky, Maria do Carmo Sampaio Tavares
ABSTRACT This article provides a review of immunity, diagnosis, and clinical aspects of rotavirus disease. It also informs about the changes in epidemiology of diarrheal disease and genetic diversity of circulating group A rotavirus strains following the introduction of vaccines. Group A rotavirus is the major pathogen causing gastroenteritis in animals. Its segmented RNA genome can lead to the emergence of new or unusual strains in human populations via interspecies transmission and/or reassortment events. PMID:27462899
Lopman, Benjamin A.; Pitzer, Virginia E.; Sarkar, Rajiv; Gladstone, Beryl; Patel, Manish; Glasser, John; Gambhir, Manoj; Atchison, Christina; Grenfell, Bryan T.; Edmunds, W. John; Kang, Gagandeep; Parashar, Umesh D.
Introduction Rotavirus vaccine efficacy ranges from >90% in high socio-economic settings (SES) to 50% in low SES. With the imminent introduction of rotavirus vaccine in low SES countries, understanding reasons for reduced efficacy in these settings could identify strategies to improve vaccine performance. Methods We developed a mathematical model to predict rotavirus vaccine efficacy in high, middle and low SES based on data specific for each setting on incidence, protection conferred by natural infection and immune response to vaccination. We then examined factors affecting efficacy. Results Vaccination was predicted to prevent 93%, 86% and 51% of severe rotavirus gastroenteritis in high, middle and low SES, respectively. Also predicted was that vaccines are most effective against severe disease and efficacy declines with age in low but not high SES. Reduced immunogenicity of vaccination and reduced protection conferred by natural infection are the main factors that compromise efficacy in low SES. Discussion The continued risk of severe disease in non-primary natural infections in low SES is a key factor underpinning reduced efficacy of rotavirus vaccines. Predicted efficacy was remarkably consistent with observed clinical trial results from different SES, validating the model. The phenomenon of reduced vaccine efficacy can be predicted by intrinsic immunological and epidemiological factors of low SES populations. Modifying aspects of the vaccine (e.g. improving immunogenicity in low SES) and vaccination program (e.g. additional doses) may bring improvements. PMID:22879893
Clark, H Fred; Lawley, Diane; Mallette, Laura A; DiNubile, Mark J; Hodinka, Richard L
A pentavalent rotavirus vaccine for infants became available in the United States in February 2006. By 2007, vaccination rates nationwide were estimated to be approximately 50%. We studied the effectiveness of the vaccine in a real-world setting outside of a clinical trial. All children presenting to The Children's Hospital of Philadelphia with acute gastroenteritis have been monitored for the presence of rotavirus antigen in the stool by enzyme-linked immunosorbent assay (ELISA [followed by genotyping if ELISA positive]) since the 1994-1995 epidemic season, presenting a unique opportunity to assess the impact of the recently introduced vaccine. The annual number of community-acquired cases over the preceding 13 years had approached or exceeded 100, with 271 cases in 2005 to 2006 and 167 cases in 2006 to 2007. In the 2007-2008 season, only 36 community-acquired cases were identified, representing an 87% reduction from the same period in 2005 to 2006. G3 was the predominant serotype, accounting for 15 community cases (42%). Our study is limited by its observational design using historical comparisons. Nonetheless, the abrupt decline in rotavirus gastroenteritis cases during the 2007-2008 season likely resulted from vaccination. Because protection rates appeared to have exceeded vaccination rates, herd immunity may have contributed to some degree to the effectiveness of the vaccine.
Chung, Ju-Young; Kim, Min-Sung; Jung, Tae Woong; Kim, Seong Joon; Kang, Jin-Han; Han, Seung Beom; Kim, Sang Yong; Rhim, Jung Woo; Kim, Hwang-Min; Park, Jae Hong; Jo, Dae Sun; Ma, Sang Hyuk; Jeong, Hye-Sook; Cheon, Doo-Sung; Kim, Jong-Hyun
Rotavirus (RV) is one of the most important viral etiologic agents of acute gastroenteritis (AGE) in children. Although effective RV vaccines (RVVs) are now used worldwide, novel genotypes and outbreaks resulting from rare genotype combinations have emerged. This study documented RV genotypes in a Korean population of children with AGE 5 yr after the introduction of RVV and assessed potential genotype differences based on vaccination status or vaccine type. Children less than 5-yr-old diagnosed with AGE between October 2012 and September 2013 admitted to 9 medical institutions from 8 provinces in Korea were prospectively enrolled. Stool samples were tested for RV by enzyme immunoassay and genotyped by multiplex reverse-transcription polymerase chain reaction. In 346 patients, 114 (32.9%) were RV-positive. Among them, 87 (76.3%) patients were infected with RV alone. Eighty-six of 114 RV-positive stool samples were successfully genotyped, and their combinations of genotypes were G1P (36, 41.9%), G2P (12, 14.0%), and G3P (6, 7.0%). RV was detected in 27.8% of patients in the vaccinated group and 39.8% in the unvaccinated group (P=0.035). Vaccination history was available for 67 of 86 cases with successfully genotyped RV-positive stool samples; RotaTeq (20, 29.9%), Rotarix (7, 10.4%), unvaccinated (40, 59.7%). The incidence of RV AGE is lower in the RV-vaccinated group compared to the unvaccinated group with no evidence of substitution with unusual genotype combinations.
Durmaz, Riza; Kalaycioglu, Atila Taner; Acar, Sumeyra; Bakkaloglu, Zekiye; Karagoz, Alper; Korukluoglu, Gulay; Ertek, Mustafa; Torunoglu, Mehmet Ali
Background Group A rotaviruses are the most common causative agent of acute gastroenteritis among children less than 5 years of age throughout the world. This sentinel surveillance study was aimed to obtain baseline data on the rotavirus G and P genotypes across Turkey before the introduction of a universal rotavirus vaccination program. Methods Rotavirus antigen-positive samples were collected from 2102 children less than 5 years of age who attended hospitals participating in the Turkish Rotavirus Surveillance Network. Rotavirus antigen was detected in the laboratories of participating hospitals by commercial serological tests such as latex agglutination, immunochromatographic test or enzyme immunoassay. Rotavirus G and P genotypes were determined by reverse transcription polymerase chain reaction (RT-PCR) using consensus primers detecting the VP7 and VP4 genes, followed by semi-nested type-specific multiplex PCR. Results RT-PCR found rotavirus RNA in 1644 (78.2%) of the samples tested. The highest rate of rotavirus positivity (38.7%) was observed among children in the 13 to 24 month age group, followed by children in the age group of 25 to 36 months (28.3%). A total of eight different G types, six different P types, and 42 different G–P combinations were obtained. Four common G types (G1, G2, G3, and G9) and two common P types (P and P) accounted for 95.1% and 98.8% of the strains, respectively. G9P was the most common G/P combination found in 40.5% of the strains followed by G1P (21.6%), G2P (9.3%), G2P (6.5%), G3P (3.5%), and finally, G4P (3.4%). These six common genotypes included 83.7% of the strains tested in this study. The rate of uncommon genotypes was 14%. Conclusion The majority of the strains analyzed belonged to the G1–G4 and G9 genotypes, suggesting high coverage of current rotavirus vaccines. This study also demonstrates a dramatic increase in G9 genotype across the country. PMID:25437502
Pitzer, Virginia E; Bilcke, Joke; Heylen, Elisabeth; Crawford, Forrest W; Callens, Michael; De Smet, Frank; Van Ranst, Marc; Zeller, Mark; Matthijnssens, Jelle
Vaccination can place selective pressures on viral populations, leading to changes in the distribution of strains as viruses evolve to escape immunity from the vaccine. Vaccine-driven strain replacement is a major concern after nationwide rotavirus vaccine introductions. However, the distribution of the predominant rotavirus genotypes varies from year to year in the absence of vaccination, making it difficult to determine what changes can be attributed to the vaccines. To gain insight in the underlying dynamics driving changes in the rotavirus population, we fitted a hierarchy of mathematical models to national and local genotype-specific hospitalization data from Belgium, where large-scale vaccination was introduced in 2006. We estimated that natural- and vaccine-derived immunity was strongest against completely homotypic strains and weakest against fully heterotypic strains, with an intermediate immunity amongst partially heterotypic strains. The predominance of G2P infections in Belgium after vaccine introduction can be explained by a combination of natural genotype fluctuations and weaker natural and vaccine-induced immunity against infection with strains heterotypic to the vaccine, in the absence of significant variation in strain-specific vaccine effectiveness against disease. However, the incidence of rotavirus gastroenteritis is predicted to remain low despite vaccine-driven changes in the distribution of genotypes.
Background Rotavirus is the most common cause of gastroenteritis in young children worldwide. The aim of the study was to assess the health outcomes and the economic impact of a universal rotavirus vaccination programme with RotaTeq, the pentavalent rotavirus vaccine, versus no vaccination programme in Spain. Methods A birth cohort was followed up to the age of 5 using a cohort model. Epidemiological parameters were taken from the REVEAL study (a prospective epidemiological study conducted in Spain, 2004-2005) and from the literature. Direct and indirect costs were assessed from the national healthcare payer and societal perspectives by combining health care resource utilisation collected in REVEAL study and unit costs from official sources. RotaTeq per protocol efficacy data was taken from a large worldwide rotavirus clinical trial (70,000 children). Health outcomes included home care cases, General Practioner (GP)/Paediatrician, emergency department visits, hospitalisations and nosocomial infections. Results The model estimates that the introduction of a universal rotavirus vaccination programme with RotaTeq (90% coverage rate) would reduce the rotavirus gastroenteritis (RVGE) burden by 75% in Spain; 53,692 home care cases, 35,187 GP/Paediatrician visits, 34,287 emergency department visits, 10,987 hospitalisations and 2,053 nosocomial infections would be avoided. The introduction of RotaTeq would avoid about 76% of RVGE-related costs from both perspectives: €22 million from the national health system perspective and €38 million from the societal perspective. Conclusions A rotavirus vaccination programme with RotaTeq would reduce significantly the important medical and economic burden of RVGE in Spain. PMID:20698958
Panda, Samiran; Das, Aritra; Samanta, Saheli
The debate on the relevance of rotavirus vaccine to immunization program in India, where 27 million children are born every year, rages on. We synthesized the issues raised during these debates and reviewed the current literature to identify themes that could inform public health policy decision. The paradigm we used integrated disease burden data, host and environmental factors, vaccine efficacy, immunization program issues, and economic considerations. Our synthesis reveals that substantive country specific information on disease burden and economic impact of rotavirus illness in India is constrained by lack of public discussion and qualitative studies on mothers' perceptions of the vaccine in concern. The need to improve the performance of current immunization program against six major vaccine preventable diseases (tuberculosis, diphtheria, tetanus, pertussis, polio, and measles) is often cited as a priority over introduction of rotavirus vaccine. Health in India being a state subject, we emphasize that the states which are in a position to reap the benefit of rotavirus vaccine, due to their good immunization program performance, should not be restrained from doing so. Meanwhile, the poorly performing states should step up their vaccination program and increase immunization coverage. Scientific, ethical and societal concerns captured through multiple sources indicate that the introduction of rotavirus vaccine would be a good investment for India.
Chilengi, Roma; Simuyandi, Michelo; Beach, Lauren; Mwila, Katayi; Becker-Dreps, Sylvia; Emperador, Devy M.; Velasquez, Daniel E.; Bosomprah, Samuel; Jiang, Baoming
Introduction Live attenuated oral vaccines against rotavirus (RV) have been shown to be less efficacious in children from developing countries. Reasons for this disparity are not fully understood. We assessed the role of maternal factors including breast milk RV-specific IgA, transplacentally acquired infant serum RV-specific IgG and maternal HIV status in seroconversion among Zambian infants routinely immunized with Rotarix™ (RV1). Methods 420 mother-child pairs were recruited at infant age 6–12 weeks in Lusaka. Clinical information and samples were collected at baseline and at one month following the second dose of RV1. Determination of breast milk RV-specific IgA and serum RV-specific IgA and IgG was done using standardized ELISA. Seroconversion was defined as a ≥ 4 fold rise in serum IgA titre from baseline to one-month post RV1 dose 2, while seropositivity of IgA was defined as serum titre ≥ 40 and antibody variables were modelled on log-base 2. Logistic regression was used to identify predictors of the odds of seroconversion. Results Baseline infant seropositivity was 25.5% (91/357). The seroconversion frequency was 60.2% (130/216). Infants who were IgA seropositive at baseline were less likely to seroconvert compared to their seronegative counterparts (P = 0.04). There was no evidence of an association between maternal HIV status and seroconversion (P = 0.25). Higher titres of breast milk rotavirus-specific IgA were associated with a lower frequency of seroconverson (Nonparametric test for trend Z = -2.84; P<0.01): a two-fold increase in breast milk RV-specific IgA titres was associated with a 22% lower odds of seroconversion (OR = 0.80; 95% CI = 0.68–0.94; P = 0.01). There was seasonal variation in baseline breast milk rotavirus-specific IgA titres, with significantly higher GMTs during the cold dry months (P = 0.01). Conclusion Low immunogenicity of RV1 vaccine could be explained in part by exposure to high antibody titres in breast milk and
Nelson, E Anthony S; de Quadros, Ciro A; Santosham, Mathuram; Parashar, Umesh D; Steele, Duncan
Despite a WHO recommendation in 2009, reaffirmed in 2013, that all countries should consider introducing rotavirus vaccines into their National Immunization Programs, as of June 2013 only 45 have done so. One major consideration appears to have been the costs of the vaccine to countries. Of concern, is that Asian countries have been slow to introduce rotavirus vaccines despite having robust data that could inform the decision-making process. Although decisions on new vaccine introduction are very complex and vary by country and region, economic evaluations are often pivotal once vaccine efficacy and safety has been established, and disease burden documented and communicated. Unfortunately, with private sector list prices of vaccines often used in economic evaluations, rather than a potential public health sector pricing structure, policy-makers may defer decisions on rotavirus vaccine introduction based on the belief that "the vaccine price is too high," even though this might be based on erroneous data. The Pan American Health Organization's Revolving Fund provides one example of how vaccine price can be made more competitive and transparent through a regional tendering process. Other mechanisms, such as tiered pricing and UNICEF procurement, also exist that could help Asian and other countries move forward more quickly with rotavirus vaccine introduction.
Nelson, E Anthony S; de Quadros, Ciro A; Santosham, Mathuram; Parashar, Umesh D; Steele, A Duncan
Despite a WHO recommendation in 2009, reaffirmed in 2013, that all countries should consider introducing rotavirus vaccines into their National Immunization Programs, as of June 2013 only 45 have done so. One major consideration appears to have been the costs of the vaccine to countries. Of concern, is that Asian countries have been slow to introduce rotavirus vaccines despite having robust data that could inform the decision-making process. Although decisions on new vaccine introduction are very complex and vary by country and region, economic evaluations are often pivotal once vaccine efficacy and safety has been established, and disease burden documented and communicated. Unfortunately, with private sector list prices of vaccines often used in economic evaluations, rather than a potential public health sector pricing structure, policy-makers may defer decisions on rotavirus vaccine introduction based on the belief that “the vaccine price is too high,” even though this might be based on erroneous data. The Pan American Health Organization’s Revolving Fund provides one example of how vaccine price can be made more competitive and transparent through a regional tendering process. Other mechanisms, such as tiered pricing and UNICEF procurement, also exist that could help Asian and other countries move forward more quickly with rotavirus vaccine introduction. PMID:23955246
Snodgrass, D R; Nagy, L K; Sherwood, D; Campbell, I
Twenty-four pregnant cows were vaccinated intramuscularly with K99 extract from enterotoxigenic Escherichia coli and inactivated rotavirus as follows: six cows were injected with 2 ml of oil-adjuvanted vaccine; six cows were injected with 0.5 ml of oil-adjuvanted vaccine; six cows were injected with 4 ml of aluminum hydroxide-adjuvanted vaccine twice with a four-week interval; and six cows were unvaccinated as controls. Calves born to these cows were challenged with enterotoxigenic E. coli at 6 to 18 h after birth. Serum and milk antibodies to K99 and rotavirus in cows vaccinated with either dose of oil vaccine were significantly increased until at least 28 days after calving. In cows vaccinated with alhydrogel vaccine, there was a significant K99 antibody increase in serum and in colostrum but not in milk and a significant rotavirus antibody increase only in colostrum. Five of six calves born to unvaccinated cows developed enterotoxic colibacillosis after challenge, and all excreted the challenge strain of enterotoxigenic E. coli. None of the 18 calves in the three vaccinated groups developed clinical colibacillosis, and fecal excretion of the challenge organism was reduced. A combined enterotoxigenic E. coli-rotavirus vaccine may prove useful in preventing some outbreaks of calf diarrhea. PMID:6288567
Cunliffe, Nigel A; Witte, Desiree; Ngwira, Bagrey M; Todd, Stacy; Bostock, Nancy J; Turner, Ann M; Chimpeni, Philips; Victor, John C; Steele, A Duncan; Bouckenooghe, Alain; Neuzil, Kathleen M
Rotavirus gastroenteritis is a major cause of morbidity and mortality among African infants and young children. A phase III, placebo-controlled, multi-centre clinical trial of a live, oral G1P human rotavirus vaccine (RIX4414) undertaken in Malawi and South Africa significantly reduced the incidence of severe rotavirus gastroenteritis in the first year of life. We now report on vaccine efficacy in the Malawi cohort of children who were followed into the second year of life. A total of 1773 healthy infants were enrolled in Blantyre, Malawi into three groups. Two groups received three doses of RIX4414 or placebo at age 6, 10, and 14 weeks and the third group received placebo at 6 weeks and RIX4414 at age 10 and 14 weeks. Subjects were followed by weekly home visits for episodes of gastroenteritis until 1 year of age, and were then re-consented for further follow-up to 18-24 months of age. Severity of gastroenteritis episodes was graded according to the Vesikari scoring system. Seroconversion for anti-rotavirus IgA was determined on a subset of children by using ELISA on pre- and post-vaccine blood samples. Rotavirus VP7 (G) and VP4 (P) genotypes were determined by RT-PCR. A total of 70/1030 (6.8%, 95% CI 5.3-8.5) subjects in the pooled (2 dose plus 3 dose) RIX4414 group compared with 53/483 (11.0%, 8.3-14.1) subjects in the placebo group developed severe rotavirus gastroenteritis in the entire follow-up period (vaccine efficacy 38.1% (9.8-57.3)). The point estimate of efficacy in the second year of life (17.6%; -59.2 to 56.0) was lower than in the first year of life (49.4%; 19.2-68.3). There were non-significant trends towards a higher efficacy in the second year of life among children who received the three-dose schedule compared with the two-dose schedule, and a higher anti-rotavirus IgA seroresponse rate in the three-dose RIX4414 group. Rotavirus strains detected included genotype G12 (31%); G9 (23%); and G8 (18%); only 18% of strains belonged to the G1P[8
Muñoz M, Alma; Abarca V, Katia; Luchsinger F, Vivian; Valenzuela B, M Teresa; Jiménez de la J, Jorge
The article briefly reviews the epidemiology of rotavirus infection and the scientific information of the rotavirus vaccines: Rotashield, withdrawn from the market due to its association with intussusception, Rotateq currently in an advanced phase of development, and Rotarix, recently licensed in Chile. Considering the available information, the Consultive Committee of Immunizations of the Chilean Society of Infectious Diseases, summarizes its conclusions and makes recommendations for infants vaccination against rotavirus in our country.
Manish M Patel, Alan P Janssen, Richard Tardif, Mark Herring, Umesh Parashar
In 2006, a new rotavirus vaccine (RotaTeq) was licensed in the US and recommended for routine immunization of all US infants. Because a previously licensed vaccine (Rotashield) was withdrawn from the US for safety concerns, identifying barriers to uptake of RotaTeq will help develop strategies to broaden vaccine coverage. Our qualitative assessment provides complementary data to recent quantitative surveys and suggests that physicians and parents are likely to adopt the newly licensed rotavirus vaccine. Increasing parental awareness of the rotavirus disease burden and providing physicians with timely post-marketing surveillance data will be integral to a successful vaccination program.
Alkoshi, Salem; Maimaiti, Namaitijiang; Dahlui, Maznah
Background Rotavirus infection is a major cause of childhood diarrhea in Libya. The objective of this study is to evaluate the cost-effectiveness of rotavirus vaccination in that country. Methods We used a published decision tree model that has been adapted to the Libyan situation to analyze a birth cohort of 160,000 children. The evaluation of diarrhea events in three public hospitals helped to estimate the rotavirus burden. The economic analysis was done from two perspectives: health care provider and societal. Univariate sensitivity analyses were conducted to assess uncertainty in some values of the variables selected. Results The three hospitals received 545 diarrhea patients aged≤5 with 311 (57%) rotavirus positive test results during a 9-month period. The societal cost for treatment of a case of rotavirus diarrhea was estimated at US$ 661/event. The incremental cost-effectiveness ratio with a vaccine price of US$ 27 per course was US$ 8,972 per quality-adjusted life year gained from the health care perspective. From a societal perspective, the analysis shows cost savings of around US$ 16 per child. Conclusion The model shows that rotavirus vaccination could be economically a very attractive intervention in Libya. PMID:25499622
Meier, Anita F.; Suter, Mark; Schraner, Elisabeth M.; Humbel, Bruno M.; Tobler, Kurt; Ackermann, Mathias; Laimbacher, Andrea S.
Rotaviruses (RVs) are important enteric pathogens of newborn humans and animals, causing diarrhea and in rare cases death, especially in very young individuals. Rotavirus vaccines presently used are modified live vaccines that lack complete biological safety. Previous work from our laboratory suggested that vaccines based on in situ produced, non-infectious rotavirus-like particles (RVLPs) are efficient while being entirely safe. However, using either vaccine, active mucosal immunization cannot induce protective immunity in newborns due to their immature immune system. We therefore hypothesized that offspring from vaccinated dams are passively immunized either by transfer of maternal antibodies during pregnancy or by taking up antibodies from milk. Using a codon optimized polycistronic gene expression cassette packaged into herpesvirus particles, the simultaneous expression of the RV capsid genes led to the intracellular formation of RVLPs in various cell lines. Vaccinated dams developed a strong RV specific IgG antibody response determined in sera and milk of both mother and pups. Moreover, sera of naïve pups nursed by vaccinated dams also had RV specific antibodies suggesting a lactogenic transfer of antibodies. Although full protection of pups was not achieved in this mouse model, our observations are important for the development of improved vaccines against RV in humans as well as in various animal species. PMID:28212334
Meier, Anita F; Suter, Mark; Schraner, Elisabeth M; Humbel, Bruno M; Tobler, Kurt; Ackermann, Mathias; Laimbacher, Andrea S
Rotaviruses (RVs) are important enteric pathogens of newborn humans and animals, causing diarrhea and in rare cases death, especially in very young individuals. Rotavirus vaccines presently used are modified live vaccines that lack complete biological safety. Previous work from our laboratory suggested that vaccines based on in situ produced, non-infectious rotavirus-like particles (RVLPs) are efficient while being entirely safe. However, using either vaccine, active mucosal immunization cannot induce protective immunity in newborns due to their immature immune system. We therefore hypothesized that offspring from vaccinated dams are passively immunized either by transfer of maternal antibodies during pregnancy or by taking up antibodies from milk. Using a codon optimized polycistronic gene expression cassette packaged into herpesvirus particles, the simultaneous expression of the RV capsid genes led to the intracellular formation of RVLPs in various cell lines. Vaccinated dams developed a strong RV specific IgG antibody response determined in sera and milk of both mother and pups. Moreover, sera of naïve pups nursed by vaccinated dams also had RV specific antibodies suggesting a lactogenic transfer of antibodies. Although full protection of pups was not achieved in this mouse model, our observations are important for the development of improved vaccines against RV in humans as well as in various animal species.
Cardellino, Anna; Khawaja, Shazia; Sánchez Cruz, Edmundo; Mast, T Christopher
The screening method is a surveillance tool to evaluate vaccine effectiveness (VE) using coverage data on cases and available administrative estimates of vaccine coverage in the population. The aim of this analysis was to evaluate the utility and limitations of using the screening methodology to estimate VE, particularly in a developing world country with a high coverage rate, and to compare it with the VE estimates from 2 case-control studies. Using data from 2008, the screening method employed in this study estimated that VE for 3 doses of RV5 among children<12 mo of age to prevent wild-type severe disease, resulting in hospitalization or emergency department visits, was 92% (95% confidence interval [CI]: 78-100%). Additional sensitivity analysis demonstrated that the point estimates of VE against severe disease ranged from 72% (95% CI: 62-83%) to 92% (95% CI: 78-100%); this range of VE estimates, although wide, is relatively consistent with results reported from 2 case-control studies in Nicaragua for the same time period. When the infrastructure is in place to collect reasonably robust case data, the use of the screening method to estimate VE is possible in the developing world setting. Cases of severe wild-type rotavirus gastroenteritis were obtained through an observational, hospital-based, prospective, surveillance program to assess rotavirus acute gastroenteritis. The proportion of cases vaccinated was estimated using the child's vaccination card or health record. The proportion of the population vaccinated was estimated using administrative population-based vaccination coverage estimates provided by the Nicaraguan Ministry of Health.
Rivera, Rosario; Forney, Kristen; Castro, Maria René; Rebolledo, Paulina A.; Mamani, Nataniel; Patzi, Maritza; Halkyer, Percy; Leon, Juan S.; Iñiguez, Volga
Summary Objectives Rotavirus is the most important etiology of severe diarrhea in Bolivia. The monovalent attenuated human oral rotavirus vaccine Rotarix® was introduced in Bolivia in 2008. We describe the molecular epidemiology of circulating rotavirus strains before vaccine introduction. Methods Two thousand one hundred thirty-five diarrheal samples were collected from hospitals in four Bolivian cities during 2007–2008. Forty-three percent (445 of 1030 rotavirus-positive samples) were analyzed for G and P genotypes. Among those, 331 were electropherotyped by polyacrylamide gel electrophoresis. Disease severity was quantified using a modified Vesikari scale. Results Among the 445 samples, five genotypes were found to be prevalent: G9P (33%), G1P (17%), G2P (13%), G9P (12%), and G1P (4%). Co-infections with two or more strains accounted for 14% of samples. The most prevalent strain, G9, showed greater electropherotype diversity compared to other serogroups. Strain G1P generally infected younger children and peaked later in the year than other strains. No particular genotype was associated with a higher severity score, though there was a significant difference in the duration of diarrhea between genotypes. Conclusions During the 2-year pre-vaccine period, substantial diversity of rotavirus co-circulating strains was observed. These data constitute a baseline against which changes in circulating strains post-vaccine introduction can be monitored. PMID:23688547
Dubin, Gary; Toussaint, Jean-François; Cassart, Jean-Pol; Howe, Barbara; Boyce, Donna; Friedland, Leonard; Abu-Elyazeed, Remon; Poncelet, Sylviane; Han, Htay Htay; Debrus, Serge
In January 2010, porcine circovirus type 1 (PCV1) DNA was unexpectedly detected in the oral live-attenuated human rotavirus vaccine, Rotarix™ (GlaxoSmithKline [GSK] Vaccines) by an academic research team investigating a novel, highly sensitive analysis not routinely used for adventitious agent screening. GSK rapidly initiated an investigation to confirm the source, nature and amount of PCV1 in the vaccine manufacturing process and to assess potential clinical implications of this finding. The investigation also considered the manufacturer’s inactivated poliovirus (IPV)-containing vaccines, since poliovirus vaccine strains are propagated using the same cell line as the rotavirus vaccine strain. Results confirmed the presence of PCV1 DNA and low levels of PCV1 viral particles at all stages of the Rotarix™ manufacturing process. PCV type 2 DNA was not detected at any stage. When tested in human cell lines, productive PCV1 infection was not observed. There was no immunological or clinical evidence of PCV1 infection in infants who had received Rotarix™ in clinical trials. PCV1 DNA was not detected in the IPV-containing vaccine manufacturing process beyond the purification stage. Retrospective testing confirmed the presence of PCV1 DNA in Rotarix™ since the initial stages of its development and in vaccine lots used in clinical studies conducted pre- and post-licensure. The acceptable safety profile observed in clinical trials of Rotarix™ therefore reflects exposure to PCV1 DNA. The investigation into the presence of PCV1 in Rotarix™ could serve as a model for risk assessment in the event of new technologies identifying adventitious agents in the manufacturing of other vaccines and biological products. PMID:24056737
De la Hoz, Fernando; Alvis, Nelson; Narváez, Javier; Cediel, Natalia; Gamboa, Oscar; Velandia, Martha
A complete economic study was carried out to assess the economical impact of two rotavirus vaccine in Colombia. A Markov decision model was built to assess the health outcomes from birth to 24 months of age for three hypothetical cohorts: one unvaccinated, one vaccinated with 2 doses of Rotarix and the third, with 3 doses of Rotateq. Without vaccination, the annual number of medical visits by diarrhea in children under 2 years would be 1,293,159 cases, with 105,378 medical visits and 470 deaths (IC95% 295-560) related to rotavirus. Without vaccination, rotavirus disease would cost around USD$8 millions including direct and indirect costs. Assuming a cost per dose of USD$7.5, average cost-effectiveness ratio would be USD$663/DALY with Rotarix and USD$1391 with Rotateq. When price per dose falls below USD$7 both vaccines yield a similar average cost-effectiveness ratio (USD$1063/DALY). Incremental cost-effectiveness ratio of Rotateq versus Rotarix was USD$7787/DALY. Cost-effectiveness ratio was influenced mainly by vaccine cost and cost per case hospitalized. Other programmatic aspects such as number of doses to be applied, likelihood of completing vaccination schedule with shorter versus longer schedules, and storage space within the chain cold should be considered to make decisions on which vaccine should be introduced. In conclusion, vaccinating against rotavirus in Colombia with either vaccine would be very cost effective. If cost per vaccinated children falls below USD$3 per dose vaccination would be cost saving.
Vieira, Sarah Cristina Fontes; Gurgel, Ricardo Queiroz; Kirby, Andrew; Barreto, Isis Pinheiro; Souza, Liane Desiderio de; Oliveira, Oderlan Carvalho; Correia, Jailson de Barros; Dove, Winifred; Cunliffe, Nigel A; Cuevas, Luis E
Rotavirus is an important cause of childhood diarrhoea. A monovalent rotavirus vaccine (Rotarix®) was introduced into the Immunization Program of Brazil in 2006. In this study, we describe the incidence and burden of disease of rotavirus diarrhoea in two cohorts of children (vaccinated and unvaccinated). We followed two groups of 250 children under one year old, who were enrolled in December 2006 from a low-income residential area in Northeast Brazil. The children were monitored every two weeks for two years. Stool samples from children with diarrhoea were examined for the presence of rotavirus. Rotaviruses were genotyped using real time-polymerase chain reaction. The mean numbers of all-cause diarrhoea episodes/child (adjusted for age) in the first year were 0.87 and 0.84, in vaccinated and unvaccinated children, respectively. During the second year, the number of episodes/child decreased to 0.52 and 0.42. Only 16 (4.9%) of 330 stool samples were rotavirus-positive (10 vaccinated and 6 unvaccinated children) and only PG2 rotaviruses were identified. All-cause diarrhoea episodes were more severe in unvaccinated children in the first year of age (p < 0.05), while vaccinated children had more severe episodes 18 months after vaccination. Rotavirus diarrhoea incidence was very low in both groups.
Steele, A. Duncan; Madhi, Shabir A.; Cunliffe, Nigel A.; Vesikari, Timo; Phua, Kong Boo; Lim, Fong Seng; Nelson, E. Anthony S.; Lau, Yu-Lung; Huang, Li-Min; Karkada, Naveen; Debrus, Serge; Han, Htay Htay; Benninghoff, Bernd
ABSTRACT Variability in rotavirus gastroenteritis (RVGE) epidemiology can influence the optimal vaccination schedule. We evaluated regional trends in the age of RVGE episodes in low- to middle- versus high-income countries in three continents. We undertook a post-hoc analysis based on efficacy trials of a human rotavirus vaccine (HRV; Rotarix™, GSK Vaccines), in which 1348, 1641, and 5250 healthy infants received a placebo in Europe (NCT00140686), Africa (NCT00241644), and Asia (NCT00197210, NCT00329745). Incidence of any/severe RVGE by age at onset was evaluated by active surveillance over the first two years of life. Severity of RVGE episodes was assessed using the Vesikari-scale. The incidence of any RVGE in Africa was higher than in Europe during the first year of life (≤2.78% vs. ≤2.03% per month), but much lower during the second one (≤0.86% versus ≤2.00% per month). The incidence of severe RVGE in Africa was slightly lower than in Europe during the first year of life. Nevertheless, temporal profiles for the incidence of severe RVGE in Africa and Europe during the first (≤1.00% and ≤1.23% per month) and second (≤0.53% and ≤1.13% per month) years of life were similar to those of any RVGE. Any/severe RVGE incidences peaked at younger ages in Africa vs. Europe. In high-income Asian regions, severe RVGE incidence (≤0.31% per month) remained low during the study. The burden of any RVGE was higher earlier in life in children from low- to middle- compared with high-income countries. Differing rotavirus vaccine schedules are likely warranted to maximize protection in different settings. PMID:27260009
Steele, A Duncan; Madhi, Shabir A; Cunliffe, Nigel A; Vesikari, Timo; Phua, Kong Boo; Lim, Fong Seng; Nelson, E Anthony S; Lau, Yu-Lung; Huang, Li-Min; Karkada, Naveen; Debrus, Serge; Han, Htay Htay; Benninghoff, Bernd
Variability in rotavirus gastroenteritis (RVGE) epidemiology can influence the optimal vaccination schedule. We evaluated regional trends in the age of RVGE episodes in low- to middle- versus high-income countries in three continents. We undertook a post-hoc analysis based on efficacy trials of a human rotavirus vaccine (HRV; Rotarix™, GSK Vaccines), in which 1348, 1641, and 5250 healthy infants received a placebo in Europe (NCT00140686), Africa (NCT00241644), and Asia (NCT00197210, NCT00329745). Incidence of any/severe RVGE by age at onset was evaluated by active surveillance over the first two years of life. Severity of RVGE episodes was assessed using the Vesikari-scale. The incidence of any RVGE in Africa was higher than in Europe during the first year of life (≤2.78% vs. ≤2.03% per month), but much lower during the second one (≤0.86% versus ≤2.00% per month). The incidence of severe RVGE in Africa was slightly lower than in Europe during the first year of life. Nevertheless, temporal profiles for the incidence of severe RVGE in Africa and Europe during the first (≤1.00% and ≤1.23% per month) and second (≤0.53% and ≤1.13% per month) years of life were similar to those of any RVGE. Any/severe RVGE incidences peaked at younger ages in Africa vs. Europe. In high-income Asian regions, severe RVGE incidence (≤0.31% per month) remained low during the study. The burden of any RVGE was higher earlier in life in children from low- to middle- compared with high-income countries. Differing rotavirus vaccine schedules are likely warranted to maximize protection in different settings.
Patzi, Maritza; Pastor, Desiree; Nina, Aleida; Roca, Yelin; Alvarez, Leovigildo; Iniguez, Volga; Rivera, Rosario; Tam, Ka Ian; Quaye, Osbourne; Bowen, Michael; Parashar, Umesh; De Oliveira, Lucia Helena
Objective To evaluate the effectiveness of two doses of a monovalent rotavirus vaccine (RV1) against hospital admission for rotavirus in Bolivia. Design Case-control study. Setting Six hospitals in Bolivia, between March 2010 and June 2011. Participants 400 hospital admissions for rotavirus, 1200 non-diarrhea hospital controls, and 718 rotavirus negative hospital controls. Main outcome measures Odds of antecedent vaccination between case patients and controls; effectiveness of vaccination ((1–adjusted odds ratio)×100), adjusted for age and other confounders; and stratified effectiveness by dose, disease severity, age group, and serotype. Results In comparison with non-diarrhea controls, case patients were more likely to be male and attend day care but less likely to have chronic underlying illness, higher level maternal education, and telephones and computers in their home. Rotavirus negative controls were somewhat more similar to case patients but also were more likely to be male and attend day care and less likely to have higher level maternal education and computers in their homes. The adjusted effectiveness of RV1 against hospital admission for rotavirus was 69% (95% confidence interval 54% to 79%) with rotavirus negative controls and 77% (65% to 84%) with non-diarrhea controls. The effectiveness of one dose of RV1 was 36% and 56%, respectively. With both control groups, protection was sustained through two years of life, with similar efficacy against hospital admission among children under 1 year (64% and 77%) and over 1 year of age (72% and 76%). RV1 provided significant protection against diverse serotypes, partially and fully heterotypic to the G1P vaccine. Effectiveness using the two control groups was 80% and 85% against G9P, 74% and 93%% against G3P, 59% and 69% against G2P, and 80% and 87% against G9P strains. Conclusion The monovalent rotavirus vaccine conferred high protection against hospital admission for diarrhea due to rotavirus
He, Qing; Wang, Ming; Xu, Jianxiong; Zhang, Chunhuan; Wang, Hui; Zhu, Wei; Fu, Chuanxi
Objective We aimed to estimate the Lanzhou lamb rotavirus (LLR) vaccination coverage (VC) and timeliness among children aged 2 to 59 months in Guangzhou, China. Methods An electronic system-based VC survey was conducted using stratified cluster random sampling. Results We reported an overall Lanzhou lamb rotavirus vaccine coverage of 25.3% among children aged 2-59 months (2-8 months, 2.6%) in Guangzhou, China. Conclusion Great efforts should be taken to increase LLR VC in eligible children in Guangzhou, China. PMID:23840828
Giaquinto, Carlo; Dominiak-Felden, Geraldine; Van Damme, Pierre; Myint, Tin Tin Htar; Maldonado, Yvonne A; Spoulou, Vana; Mast, T Christopher; Staat, Mary Allen
The pentavalent rotavirus (RV) vaccine RotaTeq™ has been available in industrialized countries since 2006. Several studies have been conducted to evaluate the benefit of RV vaccination under routine conditions of use. A systematic review of all publicly available data from RotaTeq™ vaccine-effectiveness and vaccination-impact studies in the USA, Europe and Australia between 2006 and February 2010 was undertaken. Depending on the population studied, effectiveness of up to 100% (95% confidence interval 85-100%) associated with decreased hospitalizations for RV gastroenteritis (RVGE) was seen. Vaccination-impact studies demonstrated that the burden of RVGE has been reduced significantly since the introduction of RV vaccination. Evidence included reductions in healthcare utilization due to RVGE (hospitalizations and emergency-department visits reduced by up to 90%), reductions in the magnitude and duration of the RV season as assessed by laboratory testing for RV, and the possible induction of herd immunity.
Imaz, Iñaki; Rubio, Beltrán; Cornejo, Ana M; González-Enríquez, Jesús
Rotavirus is not included in the Spanish mass infant vaccination schedule but has also not been economically evaluated for its inclusion. We analysed cost-utility of the universal infant rotavirus vaccination using RotaTeq® versus no vaccination in Spain. We also carried out a budget impact analysis and determined the effect on results of different variables introduced in the model. A deterministic Markov model was built considering loss of quality of life for children and their parents, and introducing direct and indirect costs updated to 2011. The introduction of the vaccination using RotaTeq® as a universal infant vaccination would increase the annual health care budget in 10.43 million euro and would result in a gain of an additional Quality Adjusted Life Year at a cost of 280,338€ from the healthcare system perspective and 210,167€ from the societal perspective. The model was stable to variable modifications. To sum up, according to our model and estimates, the introduction of a universal infant rotavirus vaccination with RotaTeq® in Spain would cause a large impact on the health care budget and would not be efficient unless significant variations in vaccine price, vaccine efficacy and/or utilities took place.
Kidane, Teklay; Chirwa, Geoffrey; Tesfaye, Neghist; Prescott, Marta R; Scotney, Soleine T; Valle, Moussa; Abebe, Sintayehu; Tambuli, Adija; Malewezi, Bridget; Mohammed, Tahir; Kobayashi, Emily; Wootton, Emily; Wong, Renee; Dosani, Rahima; Subramaniam, Hamsa; Joseph, Jessica; Yavuz, Elif; Apple, Aliza; Le Tallec, Yann; Kang’ethe, Alice
Understanding post-launch demand for new vaccines can help countries maximize the benefits of immunization programmes. In particular, low- and middle-income countries (LMICs) should ensure adequate resource planning with regards to stock consumption and service delivery for new vaccines, whereas global suppliers must produce enough vaccines to meet demand. If a country underestimates the number of children seeking vaccination, a stock-out of commodities will create missed opportunities for saving lives. We describe the post-launch demand for the first dose of pneumococcal conjugate vaccine (PCV1) in Ethiopia and Malawi and the first dose of rotavirus vaccine (Rota1) in Malawi, with focus on the new birth cohort and the ‘backlog cohort’, comprised of older children who are still eligible for vaccination at the time of launch. PCV1 and Rota1 uptake were compared with the demand for the first dose of pentavalent vaccine (Penta1), a routine immunization that targets the same age group and immunization schedule. In the first year, the total demand for PCV1 was 37% greater than that of Penta1 in Ethiopia and 59% greater in Malawi. In the first 6 months, the demand of Rota1 was only 5.9% greater than Penta1 demand in Malawi. Over the first three post-introduction months, 70.7% of PCV1 demand in Ethiopia and 71.5% of demand in Malawi came from children in the backlog cohort, whereas only 28.0% of Rota1 demand in Malawi was from the backlog cohort. The composition of demand was impacted by time elapsed since vaccine introduction and age restrictions. Evidence suggests that countries’ plans should account for the impact of backlog demand, especially in the first 3 months post-introduction. LMICs should request for higher stock volumes when compared with routine needs, plan social mobilization activities to reach the backlog cohort and allocate human resources and cold chain capacity to accommodate high demand following vaccine introduction. PMID:26856361
Lappalainen, Suvi; Blazevic, Vesna; Malm, Maria; Vesikari, Timo
Rotavirus (RV) is the leading cause of severe gastroenteritis (GE) in young children, but RVGE has drastically been reduced with the introduction of live oral RV vaccines into childhood immunization program in many countries. Serum IgA antibody is a marker of clinical protection against severe RVGE after RV infection and vaccination. This study investigated VP6-specificity of anti-RV IgA antibody levels in Finnish children aged 6-23 months before and after introduction of RotaTeq® into national immunization program. Although RV inner capsid protein VP6 is considered as antigenic target in clinical and seroepidemiological studies, at present VP6 protein is not commonly employed as a primary ELISA-antigen. Thus, sera from 20 unvaccinated and 19 vaccinated children were examined in ELISA with recombinant VP6 (rVP6) protein, and the VP6-specific responses were compared to responses observed with human RV Wa and bovine RV WC3 cell culture antigens. Moreover, fecal antibodies were tested with rVP6 and Wa cell culture antigen. Equal levels of serum anti-RV IgA antibodies were detected by the three antigens. Fecal IgA titers against rVP6 and Wa antigen showed a correlation with the corresponding serum levels. The results suggest that the IgA response measured by virus-capture ELISA is mainly directed to VP6 protein, supporting the usage of rVP6 in detection of anti-RV IgA antibodies. Natural RV infections and vaccinations induced similar levels of serum VP6-specific IgA antibodies. Serum IgA antibodies after RotaTeq® vaccination showed sustained levels up to two years of age in line with long term protection. J. Med. Virol. 89:239-245, 2017. © 2016 Wiley Periodicals, Inc.
O'Ryan, Miguel; Giaquinto, Carlo; Benninghoff, Bernd
A decade after licensure of the human rotavirus vaccine (HRV), a wealth of evidence supports a reduction of rotavirus (RV) gastroenteritis-associated mortality and hospitalizations following HRV inclusion in national immunization programs. Nevertheless, the majority of real-world data has been generated in high- or middle-income settings. Clinical efficacy trials previously indicated RV vaccine performance may be lower in less-developed countries compared with wealthier counterparts. Using recently published data from Africa, we examine the effectiveness and impact of HRV in resource-deprived areas, exploring whether vaccine performance differs by socioeconomic setting and the potential underlying factors. HRV vaccine effectiveness in early adopting African countries has proven to be similar or even superior to the efficacy results observed in pre-licensure studies.
Strina, Agostino; Rodrigues, Laura C; Cairncross, Sandy; Ferrer, Suzana R; Fialho, Alexandre Madi; Leite, Jose Paulo G; Ribeiro, Hugo C; Barreto, Mauricio L
A case-control study, aimed at identifying factors associated with rotavirus diarrhoea cases presenting to health facilities, was conducted in children from low-income and middle-low-income families in Brazil. Cases were 390 children with diarrhoea and rotavirus in stools; controls were 1674 children without diarrhoea presenting to the same facilities. Data were collected by questionnaire and observations during home visits. Explanatory variables were grouped according to a conceptual model of causation. The ORs by non-conditional logistic regression and population-attributable fractions were calculated. Socioeconomic factors contributed a third of cases, followed by contact with diarrhoea cases and by not being breast fed. In cases aged <1 year, not being breast fed was the main determinant, followed by socioeconomic factors, and crowding and contact outside the home; in older children, socioeconomic factors followed by contact inside and outside the home were the main determinants. Environmental and sanitation variables were not associated with diarrhoea in the final model, and socioeconomic factors were only partly mediated by proximal variables. Transmission of rotavirus appears to be mostly by person-to-person contact, and shows marked social differentials not explained by the biological factors studied. The rotavirus vaccine is unlikely to protect against the full range of circulating genotypes of rotavirus, and understanding rotavirus epidemiology remains essential to the development of control policies.
Valencia-Mendoza, Atanacio; Bertozzi, Stefano M; Gutierrez, Juan-Pablo; Itzler, Robbin
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 $15 per dose, the cost per life-year saved is estimated to be lower than one GNP per capita and hence highly cost effective by the WHO Commission on Macroeconomics and Health criteria. The cost-effectiveness estimates are highly dependent upon the mortality in the absence of the vaccine, which suggests that the vaccine is likely to be
Patel, Hiten D.; Roberts, Eric T.; Constenla, Dagna O.
Background Rotavirus gastroenteritis places a significant health and economic burden on Pakistan. To determine the public health impact of a national rotavirus vaccination program, we performed a cost-effectiveness study from the perspective of the health care system. Methods A decision tree model was developed to assess the cost-effectiveness of a national vaccination program in Pakistan. Disease and cost burden with the program were compared to the current state. Disease parameters, vaccine-related costs, and medical treatment costs were based on published epidemiological and economic data, which were specific to Pakistan when possible. An annual birth cohort of children was followed for 5 years to model the public health impact of vaccination on health-related events and costs. The cost-effectiveness was assessed and quantified in cost (2012 US$) per disability-adjusted life-year (DALY) averted and cost per death averted. Sensitivity analyses were performed to assess the robustness of the incremental cost-effectiveness ratios (ICERs). Results The base case results showed vaccination prevented 1.2 million cases of rotavirus gastroenteritis, 93,000 outpatient visits, 43,000 hospitalizations, and 6,700 deaths by 5 years of age for an annual birth cohort scaled from 6% current coverage to DPT3 levels (85%). The medical cost savings would be US$1.4 million from hospitalizations and US$200,000 from outpatient visit costs. The vaccination program would cost US$35 million at a vaccine price of US$5.00. The ICER was US$149.50 per DALY averted or US$4,972 per death averted. Sensitivity analyses showed changes in case-fatality ratio, vaccine efficacy, and vaccine cost exerted the greatest influence on the ICER. Conclusions Across a range of sensitivity analyses, a national rotavirus vaccination program was predicted to decrease health and economic burden due to rotavirus gastroenteritis in Pakistan by ~40%. Vaccination was highly cost-effective in this context. As
On July 24, 2013, the Secretary of Health and Human Services (the Secretary) published in the Federal Register a Notice of Proposed Rulemaking (NPRM) proposing changes to the regulations governing the National Vaccine Injury Compensation Program (VICP). Specifically, the Secretary proposed revisions to the Vaccine Injury Table (Table). The basis for this change is consistent with the Secretary's findings that intussusceptions can reasonably be determined in some circumstances to be caused by rotavirus vaccines. The Secretary is now making this amendment to the Table and to the Qualifications and Aids to Interpretation (QAI), described below under Background Information, as proposed in the NPRM. These regulations will apply only to petitions for compensation under the VICP filed after this final rule becomes effective.
Zeller, Mark; Donato, Celeste; Trovão, Nídia Sequeira; Cowley, Daniel; Heylen, Elisabeth; Donker, Nicole C; McAllen, John K; Akopov, Asmik; Kirkness, Ewen F; Lemey, Philippe; Van Ranst, Marc; Matthijnssens, Jelle; Kirkwood, Carl D
Rotaviruses are the most important etiological agent of acute gastroenteritis in young children worldwide. Among the first countries to introduce rotavirus vaccines into their national immunization programs were Belgium (November 2006) and Australia (July 2007). Surveillance programs in Belgium (since 1999) and Australia (since 1989) offer the opportunity to perform a detailed comparison of rotavirus strains circulating pre- and postvaccine introduction. G1P rotaviruses are the most prominent genotype in humans, and a total of 157 G1P rotaviruses isolated between 1999 and 2011 were selected from Belgium and Australia and their complete genomes were sequenced. Phylogenetic analysis showed evidence of frequent reassortment among Belgian and Australian G1P rotaviruses. Although many different phylogenetic subclusters were present before and after vaccine introduction, some unique clusters were only identified after vaccine introduction, which could be due to natural fluctuation or the first signs of vaccine-driven evolution. The times to the most recent common ancestors for the Belgian and Australian G1P rotaviruses ranged from 1846 to 1955 depending on the gene segment, with VP7 and NSP4 resulting in the most recent estimates. We found no evidence that rotavirus population size was affected after vaccine introduction and only six amino acid sites in VP2, VP3, VP7, and NSP1 were identified to be under positive selective pressure. Continued surveillance of G1P strains is needed to determine long-term effects of vaccine introductions, particularly now rotavirus vaccines are implemented in the national immunization programs of an increasing number of countries worldwide.
Becker-Dreps, Sylvia; Meléndez, Marlon; Liu, Lan; Enrique Zambrana, Luis; Paniagua, Margarita; Weber, David J.; Hudgens, Michael G.; Cáceres, Mercedes; Källeståll, Carina; Morgan, Douglas R.; Espinoza, Félix; Peña, Rodolfo
We estimated the incidence of watery diarrhea in the community before and after introduction of the pentavalent rotavirus vaccine in León, Nicaragua. A random sample of households was selected before and after rotavirus vaccine introduction. All children < 5 years of age in selected households were eligible for inclusion. Children were followed every 2 weeks for watery diarrhea episodes. The incidence rate was estimated as numbers of episodes per 100 child-years of exposure time. A mixed effects Poisson regression model was fit to compare incidence rates in the pre-vaccine and vaccine periods. The pre-vaccine cohort (N = 726) experienced 36 episodes per 100 child-years, and the vaccine cohort (N = 826) experienced 25 episodes per 100 child-years. The adjusted incidence rate ratio was 0.60 (95% confidence interval [CI] 0.40, 0.91) during the vaccine period versus the pre-vaccine period, indicating a lower incidence of watery diarrhea in the community during the vaccine period. PMID:23817336
Bucardo, Filemón; Rippinger, Christine M.; Svensson, Lennart; Patton, John T.
Rotavirus (RV) vaccination programs have been established in several countries using the human-attenuated G1P monovalent vaccine Rotarix™ (GlaxoSmithKline) and/or the human-bovine reassortant G1, G2, G3, G4, P pentavalent vaccine RotaTeq™ (Merck). The efficacy of both vaccines is high (~90%) in developed countries, but can be remarkably lower in developing countries. For example, a vaccine efficacy against severe diarrhea of only 58% was observed in a 2007–2009 Nicaraguan study using RotaTeq. To gain insight into the significant level of vaccine failure in this country, we sequenced the genomes of RVs recovered from vaccinated Nicaraguan children with gastroenteritis. The results revealed that all had genotype specificities typical for human RVs (11 G1P, 1 G3P) and that the sequences and antigenic epitopes of the outer capsid proteins (VP4 and VP7) of these viruses were similar to those reported for RVs isolated elsewhere in the world. As expected, nine of the G1P viruses and the single G3P virus had genome constellations typical of human G1P and G3P RVs: G1/3-P-I1-R1-C1-M1-A1-N1-T1-E1-H1. However, two of the G1P viruses had atypical constellations, G1-P-I1-R1-C1-M1-A1-N2-T1-E1-H1, due to the presence of a genotype-2 NSP2 (N2) gene. The sequence of the N2 NSP2 gene was identical to the bovine N2 NSP2 gene of RotaTeq, indicating that the two atypical viruses originated via reassortment of human G1P RVs with RotaTeq viruses. Together, our data suggest that the high level of vaccine failure in Nicaraguan is probably not due to antigenic drift of commonly circulating virus strains nor the emergence of new antigenetically distinct virus strains. Furthermore, our data suggests that the widespread use of the RotaTeq vaccine has led to the introduction of vaccine genes into circulating human RVs. PMID:22487061
Ang, Li; Arboleya, Silvia; Lihua, Guo; Chuihui, Yuan; Nan, Qin; Suarez, Marta; Solís, Gonzalo; de los Reyes-Gavilán, Clara G.; Gueimonde, Miguel
The microbial colonization of the intestine during the first months of life constitutes the most important process for the microbiota-induced host-homeostasis. Alterations in this process may entail a high-risk for disease in later life. However, the potential factors affecting this process in the infant are not well known. Moreover, the potential impact of orally administered vaccines upon the establishing microbiome remains unknown. Here we assessed the intestinal microbiome establishment process and evaluated the impact of rotavirus vaccination upon this process. Metagenomic, PCR-DGGE and faecal short chain fatty acids analyses were performed on faecal samples obtained from three infants before and after the administration of each dose of vaccine. We found a high inter-individual variability in the early life gut microbiota at microbial composition level, but a large similarity between the infants' microbiomes at functional level. Rotavirus vaccination did not show any major effects upon the infant gut microbiota. Thus, the individual microbiome establishment and development process seems to occur in a defined manner during the first stages of life and rotavirus vaccination appears to be inconsequential for this process. PMID:25491920
GRDADOLNIK, Urška; SOČAN, Maja
Background Socio-economic inequalities may have an impact on the uptake of selfpaid vaccines. The aim of the study was to identify the effect of some socio economic determinants on vaccination rates with self-paid human papilloma virus (HPV) and rotavirus (RV) vaccines. Methods Vaccination coverage data, available in electronic database cepljenje.net (administered by the National Institute of Public Health), were collected at administrative unit level. The socio-economic determinants (the average gross pay in euros, the unemployment rate, the educational and households structure, the population density, the number of inhabitants, the number of children aged from 0 to 4, the number of women aged from 15 to 30) were extracted from Statistical Office of the Republic of Slovenia web page. The strength of the correlation between socioeconomic variables and self-paid HPV and RV vaccination rates was determined. Results Rotavirus vaccination rates show a slight negative correlation with the number of residents per administrative unit (ρ=−0.29, p=0.04), and no correlation with other socio-economic variables. Likewise, no correlation has been found between HPV vaccination rates and the selected socio-economic variables. Conclusion Ecological study did not reveal any correlations between socio economic variables and vaccination rates with RV and HPV self-paid vaccines on administrative unit level. PMID:27647088
Han, Htay Htay; Karkada, Naveen; Jayadeva, Girish; Dubin, Gary
ABSTRACT In 2010, porcine circovirus type 1 (PCV1) material was unexpectedly detected in the oral live-attenuated human rotavirus (RV) vaccine, Rotarix™ (GSK Vaccines, Belgium). An initial study (NCT01511133) found no immunologic response against PCV1 in 40 vaccinated infants. As a follow-up, the current study (NCT02153333), searched for evidence of post-vaccination serologic response to PCV1 in a larger number of archived serum samples. Unlike the previous study, serum anti-PCV1 antibodies were assessed with an adapted Immuno Peroxidase Monolayer Assay (IPMA) using a Vero-adapted PCV1 strain. Samples from 596 infants who participated in clinical trials of the human RV vaccine were randomly selected and analyzed. The observed anti-PCV1 antibody seropositivity rate 1–2 months post-dose 2 was approximately 1% [90% Confidence Interval (CI): 0.3–2.6] (3/299 samples) in infants who received the human RV vaccine and 0.3% [90% CI: 0.0–1.6] (1/297 samples) in those who received placebo; the difference between the groups was −0.66 [90% CI: −2.16–0.60]. One subject in the vaccinated group was also seropositive before vaccination. Notably, the seropositivity rate observed in vaccinated subjects was below that observed during assay qualification in samples from unvaccinated subjects outside of this study (2.5%; 5/200 samples). No serious adverse events had been reported in any of the 4 subjects providing anti-PCV1 positive samples during the 31-day post-vaccination follow-up period in the original studies. In conclusion, the presence of PCV1 in the human RV vaccine is considered to be a manufacturing quality issue and does not appear to pose a safety risk to vaccinated infants. PMID:27657348
Yen, Catherine; Healy, Kelly; Tate, Jacqueline E; Parashar, Umesh D; Bines, Julie; Neuzil, Kathleen; Santosham, Mathuram; Steele, A Duncan
As of January 2016, 80 countries have introduced rotavirus vaccines into their national immunization programs. Many have documented significant declines in rotavirus-specific and all-cause diarrheal illnesses following vaccine introduction. Two globally licensed rotavirus vaccines have been associated with a low risk of intussusception in several studies. In July 2014, the Rotavirus Organization of Technical Allies Council convened a meeting of research and advocacy organizations, public health experts, funders, and vaccine manufacturers to discuss post-marketing intussusception surveillance and rotavirus vaccine impact data. Meeting objectives were to evaluate updated data, identify and prioritize research gaps, discuss best practices for intussusception monitoring in lower-income settings and risk communication, and provide insight to country-level stakeholders on best practices for intussusception monitoring and communication. Meeting participants agreed with statements from expert bodies that the benefits of vaccination with currently available rotavirus vaccines outweigh the low risk of vaccination-associated intussusception. However, further research is needed to better understand the relationship of intussusception to wild-type rotavirus and rotavirus vaccines and delineate potential etiologies and mechanisms of intussusception. Additionally, evidence from research and post-licensure evaluations should be presented with evidence of the benefits of vaccination to best inform policymakers deciding on vaccine introduction or vaccination program sustainability.
Yen, Catherine; Healy, Kelly; Tate, Jacqueline E.; Parashar, Umesh D.; Bines, Julie; Neuzil, Kathleen; Santosham, Mathuram; Steele, A. Duncan
ABSTRACT As of January 2016, 80 countries have introduced rotavirus vaccines into their national immunization programs. Many have documented significant declines in rotavirus-specific and all-cause diarrheal illnesses following vaccine introduction. Two globally licensed rotavirus vaccines have been associated with a low risk of intussusception in several studies. In July 2014, the Rotavirus Organization of Technical Allies Council convened a meeting of research and advocacy organizations, public health experts, funders, and vaccine manufacturers to discuss post-marketing intussusception surveillance and rotavirus vaccine impact data. Meeting objectives were to evaluate updated data, identify and prioritize research gaps, discuss best practices for intussusception monitoring in lower-income settings and risk communication, and provide insight to country-level stakeholders on best practices for intussusception monitoring and communication. Meeting participants agreed with statements from expert bodies that the benefits of vaccination with currently available rotavirus vaccines outweigh the low risk of vaccination-associated intussusception. However, further research is needed to better understand the relationship of intussusception to wild-type rotavirus and rotavirus vaccines and delineate potential etiologies and mechanisms of intussusception. Additionally, evidence from research and post-licensure evaluations should be presented with evidence of the benefits of vaccination to best inform policymakers deciding on vaccine introduction or vaccination program sustainability. PMID:27322835
Rodríguez, Mabel; Wood, Christopher; Sanchez-López, Rosana; Castro-Acosta, Ricardo M; Ramírez, Octavio T; Palomares, Laura A
Rotavirus VP6 nanotubes are an attractive option for a recombinant vaccine against rotavirus disease. Protection against rotavirus infection and an adjuvant effect have been observed upon immunization with VP6 nanotubes. However, little information exists on how VP6 nanotubes interact with cells and trigger an immune response. In this work, the interaction between VP6 nanotubes and different cell lines was characterized. VP6 nanotubes were not cytotoxic to any of the animal or human cell lines tested. Uptake of nanotubes into cells was cell-line-dependent, as only THP1 and J774 macrophage cells internalized them. Moreover, the size and spatial arrangement of VP6 assembled into nanotubes allowed their uptake by macrophages, as double-layered rotavirus-like particles also displaying VP6 in their surface were not taken up. The internalization of VP6 nanotubes was inhibited by methyl-β-cyclodextrin, but not by genistein, indicating that nanotube entry is specific, depends on the presence of cholesterol in the plasma membrane, and does not require the activity of tyrosine kinases. The information generated here expands our understanding of the interaction of protein nanotubes with cells, which is useful for the application of VP6 nanotubes as a vaccine.
Li, Jin-Tao; Fei, Lei; Mou, Zhi-Rong; Wei, Jing; Tang, Yan; He, Hai-Yang; Wang, Li; Wu, Yu-Zhang
Major efforts have been put forth for the development of effective rotavirus vaccines including transgenic plant vaccines. Previous studies have reported that rotavirus VP7 maintains its neutralizing immunity when it is transformed into the potato genome. The present study was aimed at investigating the hereditary stability of VP7-transformed potatoes over fifty generations. The VP7 gene was stably transcribed and expressed in potato cells as detected by RT-PCR and Western blotting. Humeral and mucosal responses were successfully induced in BALB/c mice fed with the fiftieth generation transformed potato tubers. There were no significant differences in serum IgG and fecal IgA between the mice fed with the first and fiftieth generation potatoes (P>0.05). Profiles of cytokines such as IFN-gamma, IL-2, IL-4, IL-5 and TGF-beta in immunized mice showed a naive T-cells bias to Th1 and Th3 polarization. Moreover, specific CTL responses were also detected in C57BL/6 mice fed with transformed potatoes. This research represents a significant step towards the development of rotavirus vaccines derived from a transgenic plant that can be obtained by long-term and large-scale vegetative reproduction. To our knowledge, this is the first finding regarding vaccines derived from plants that can be propagated for many generations.
Wen, Xiaobo; Wen, Ke; Cao, Dianjun; Li, Guohua; Jones, Ronald W.; Li, Jianping; Szu, Shousun; Hoshino, Yasutaka; Yuan, Lijuan
Currently available live oral rotavirus vaccines, Rotarix® and RotaTeq®, are highly efficacious in developed countries. However, the immunogenicity and efficacy of such vaccines in some developing countries are low. We reported previously that bacterially-expressed rotavirus ΔVP8* subunit vaccine candidates with P, P or P specificity elicited high-titer virus neutralizing antibodies in animals immunized intramuscularly. Of note was the finding that antibodies induced with the PΔVP8* vaccine neutralized both homotypic P and heterotypic P rotavirus strains to high titer. To further improve its vaccine potential, a tetanus toxoid universal CD4+ T cell epitope P2 was introduced into P or PΔVP8* construct. The resulting recombinant fusion proteins expressed in Escherichia coli were of high solubility and were produced with high yield. Two doses (10 or 20μg/dose) of the P2-PΔVP8* vaccine or P2-PΔVP8* vaccine with aluminum phosphate adjuvant elicited significantly higher geometric mean homologous neutralizing antibody titers than the vaccines without P2 in intramuscularly immunized guinea pigs. Interestingly, high levels of neutralizing antibody responses induced in guinea pigs with 3 doses of the P2-PΔVP8* vaccine persisted for at least 6 months. Furthermore, in the gnotobiotic piglet challenge study, three intramuscular doses (50μg/dose) of the P2-PΔVP8* vaccine with aluminum phosphate adjuvant significantly delayed the onset of diarrhea and significantly reduced the duration of diarrhea and the cumulative diarrhea score after oral challenge with virulent human rotavirus Wa (G1P) strain. The P2-PΔVP8* vaccine induced serum virus neutralizing antibody and VP4-specific IgG antibody production prechallenge, and primed the pigs for higher antibody and intestinal and systemic virus-specific IFN-γ producing CD4+ T cell responses postchallenge. These two subunit vaccines could be used at a minimum singly or preferably in
Background The aim of the study was to evaluate the effects of universal mass vaccination (UMV) against rotavirus (RV) on the hospitalization rates, nosocomial RV infections and RV-gastroenteritis (GE)-associated secondary blood stream infections (BSI). Methods The retrospective evaluation (2002–2009) by chart analysis included all clinically diagnosed and microbiologically confirmed RV-GE cases in a large tertiary care hospital in Austria. The pre-vaccination period (2002–2005) was compared with the recommended and early funded (2006–2007) and the funded (2008–2009) vaccination periods. Primary outcomes were RV-GE-associated hospitalizations, secondary outcomes nosocomial RV disease, secondary BSI and direct hospitalization costs for children and their accompanying persons. Results In 1,532 children with RV-GE, a significant reduction by 73.9% of hospitalized RV-GE cases per year could be observed between the pre-vaccination and the funded vaccination period, which was most pronounced in the age groups 0–11 months (by 87.8%), 6–10 years (by 84.2%) and 11–18 years (88.9%). In the funded vaccination period, a reduction by 71.9% of nosocomial RV-GE cases per year was found compared to the pre-vaccination period. Fatalities due to nosocomial RV-GE were only observed in the pre-vaccination period (3 cases). Direct costs of hospitalized, community-acquired RV-GE cases per year were reduced by 72.7% in the funded vaccination period. The reduction of direct costs for patients (by 86.9%) and accompanying persons (86.2%) was most pronounced in the age group 0–11 months. Conclusions UMV may have contributed to the significant decrease of RV-GE-associated hospitalizations, to a reduction in nosocomial RV infections and RV-associated morbidity due to secondary BSI and reduced direct hospitalization costs. The reduction in nosocomial cases is an important aspect considering severe disease courses in hospitalized patients with co-morbidities and death due to
Ducharme, Robin; Rosella, Laura C.; Benchimol, Eric I.; Wilson, Kumanan; Crowcroft, Natasha S.; Halperin, Scott A.; Desai, Shalina; Naus, Monika; Sanford, Carolyn J.; Mahmud, Salah M.; Deeks, Shelley L.
ABSTRACT Background: Intussusception has been identified as a rare adverse event following rotavirus immunization. We sought to determine the incidence of intussusception among infants in Canada both before and after introduction of rotavirus immunization programs. Methods: We used Canadian Institute for Health Information (CIHI) Discharge Abstract Database (DAD) to identify infants under 1 y of age who were admitted to a Canadian hospital, which the exception of Quebec, which does not submit data to CIHI, with a diagnosis of intussusception (ICD-10 code K56.1, and ICD-9 code 560) between January 1st, 2003 and December 31, 2013. We compared rates of intussusception hospitalization before and after rotavirus vaccine program introduction. Rates were adjusted for calendar year, age (in months), sex and region using Poisson regression models. Denominator data for infants under 1 year, stratified by age in months, were obtained from Statistics Canada. Results: Annual intussusception hospitalization rates ranged from 20-30 per 100,000 infants over the study period, with no evidence of a trend over time. Intussusception hospitalization rates were highest in infants 4 to <8 months and lowest in those under 2 months or between 10 and <12 months. Males had higher rates than females both overall and within each age group. The rate of intussusception hospitalization after rotavirus vaccine program introduction was 22.4 (95% CI: 18.3, 27.4) compared to 23.4 (95% CI: 21.5, 25.4) per 100,000 before program introduction. Conclusions: We have described baseline intussusception hospitalization rates for infants in Canada and have found no evidence of a change in rate after implementation of routine rotavirus immunization programs. PMID:27835525
Heylen, Elisabeth; Tamim, Sana; McAllen, John K.; Kirkness, Ewen F.; Akopov, Asmik; De Coster, Sarah; Van Ranst, Marc; Matthijnssens, Jelle
G1P rotaviruses are responsible for the majority of human rotavirus infections worldwide. The effect of universal mass vaccination with rotavirus vaccines on circulating G1P rotaviruses is still poorly understood. Therefore we analyzed the complete genomes of the Rotarix™ vaccine strain, and 70 G1P rotaviruses, detected between 1999 and 2010 in Belgium (36 before and 34 after vaccine introduction) to investigate the impact of rotavirus vaccine introduction on circulating G1P strains. All rotaviruses possessed a complete Wa-like genotype constellation, but frequent intra-genogroup reassortments were observed as well as multiple different cluster constellations circulating in a single season. In addition, identical cluster constellations were found to circulate persistently over multiple seasons. The Rotarix™ vaccine strain possessed a unique cluster constellation that was not present in currently circulating G1P strains. At the nucleotide level, the VP6, VP2 and NSP2 gene segments of Rotarix™ were relatively distantly related to any Belgian G1P strain, but other gene segments of Rotarix™ were found in clusters also containing circulating Belgian strains. At the amino acid level, the genetic distance between Rotarix™ and circulating Belgian strains was considerably lower, except for NSP1. When we compared the Belgian G1P strains collected before and after vaccine introduction a reduction in the proportion of strains that were found in the same cluster as the Rotarix™ vaccine strain was observed for most gene segments. The reduction in the proportion of strains belonging to the same cluster may be the result of the vaccine introduction, although natural fluctuations cannot be ruled out. PMID:28070453
Zeller, Mark; Heylen, Elisabeth; Tamim, Sana; McAllen, John K; Kirkness, Ewen F; Akopov, Asmik; De Coster, Sarah; Van Ranst, Marc; Matthijnssens, Jelle
G1P rotaviruses are responsible for the majority of human rotavirus infections worldwide. The effect of universal mass vaccination with rotavirus vaccines on circulating G1P rotaviruses is still poorly understood. Therefore we analyzed the complete genomes of the Rotarix™ vaccine strain, and 70 G1P rotaviruses, detected between 1999 and 2010 in Belgium (36 before and 34 after vaccine introduction) to investigate the impact of rotavirus vaccine introduction on circulating G1P strains. All rotaviruses possessed a complete Wa-like genotype constellation, but frequent intra-genogroup reassortments were observed as well as multiple different cluster constellations circulating in a single season. In addition, identical cluster constellations were found to circulate persistently over multiple seasons. The Rotarix™ vaccine strain possessed a unique cluster constellation that was not present in currently circulating G1P strains. At the nucleotide level, the VP6, VP2 and NSP2 gene segments of Rotarix™ were relatively distantly related to any Belgian G1P strain, but other gene segments of Rotarix™ were found in clusters also containing circulating Belgian strains. At the amino acid level, the genetic distance between Rotarix™ and circulating Belgian strains was considerably lower, except for NSP1. When we compared the Belgian G1P strains collected before and after vaccine introduction a reduction in the proportion of strains that were found in the same cluster as the Rotarix™ vaccine strain was observed for most gene segments. The reduction in the proportion of strains belonging to the same cluster may be the result of the vaccine introduction, although natural fluctuations cannot be ruled out.
Yang, Xingdong; Wen, Ke; Tin, Christine; Li, Guohua; Wang, Haifeng; Kocher, Jacob; Pelzer, Kevin; Ryan, Elizabeth; Yuan, Lijuan
Rice bran (RB) contains a distinct stoichiometry of phytochemicals that can promote gut mucosal immune responses against enteric pathogens. The effects of RB on rotavirus diarrhea and immunogenicity of an attenuated human rotavirus (HRV) vaccine were evaluated in gnotobiotic pigs. The four treatment groups studied were RB plus vaccine, vaccine only, RB only, and mock control. Pigs in the RB groups were fed the amount of RB that replaced 10% of the pigs' total daily calorie intake from milk starting from 5 days of age until they were euthanized. Pigs in the vaccine groups were orally inoculated with two doses of the attenuated HRV vaccine. A subset of pigs from each group was orally challenged with the homologous virulent HRV on postinoculation day 28. Diarrhea and virus shedding were monitored daily from postchallenge day 0 to day 7. RB feeding significantly protected against diarrhea upon virulent HRV challenge and enhanced the protective rate of the vaccine against rotavirus diarrhea. Consistent with protection, RB significantly increased gamma interferon (IFN-γ)-producing CD4(+) and CD8(+) T cell responses in intestinal and systemic lymphoid tissues. Furthermore, RB also increased the number of total IgM- and IgA-secreting cells, total serum IgM, IgG, and IgA titers, and HRV-specific IgA titers in intestinal contents. RB reduced the numbers of intestinal and systemic HRV-specific IgA and IgG antibody-secreting cells and reduced serum HRV-specific IgA and IgG antibody titers before the challenge. These results demonstrate clear beneficial effects of RB in protection against rotavirus diarrhea and stimulation of nonspecific and HRV-specific immune responses, as well as its biased Th1-type adjuvant effect for the vaccine.
Background In 2010, researchers using novel laboratory techniques found that US-licensed rotavirus vaccines contain DNA or DNA fragments from Porcine circovirus (PCV), a virus common among pigs but not believed to cause illness in humans. We sought to understand pediatricians' and mothers' perspectives on this finding. Methods We conducted three iterations of focus groups for pediatricians and non-vaccine hesitant mothers in Seattle, WA, Cincinnati, OH, and Rochester, NY. Focus groups explored perceptions of rotavirus disease, rotavirus vaccination, and attitudes about the detection of PCV material in rotavirus vaccines. Results Pediatricians understood firsthand the success of rotavirus vaccines in preventing severe acute gastroenteritis among infants and young children. They measured this benefit against the theoretical risk of DNA material from PCV in rotavirus vaccines, determining overall that the PCV finding was of no clinical significance. Particularly influential was the realization that the large, randomized clinical trials that found both vaccines to be highly effective and safe were conducted with DNA material from PCV already in the vaccines. Most mothers supported the ideal of full disclosure regarding vaccination risks and benefits. However, with a scientific topic of this complexity, simplified information regarding PCV material in rotavirus vaccines seemed frightening and suspicious, and detailed information was frequently overwhelming. Mothers often remarked that if they did not understand a medical or technical topic regarding their child's health, they relied on their pediatrician's guidance. Many mothers and pediatricians were also concerned that persons who abstain from pork consumption for religious or personal reasons may have unsubstantiated fears of the PCV finding. Conclusions Pediatricians considered the detection of DNA material from PCV in rotavirus vaccines a "non-issue" and reported little hesitation in continuing to recommend the
Linhares, A. C.; Gabbay, Y. B.; Mascarenhas, J. D.; de Freitas, R. B.; Oliveira, C. S.; Bellesi, N.; Monteiro, T. A.; Lins-Lainson, Z.; Ramos, F. L.; Valente, S. A.
A tetravalent rhesus-human reassortant rotavirus (RRV-TV) vaccine (4 x 10(4) plaque-forming units/dose) was evaluated for safety, immunogenicity and efficacy in a prospective, randomized, double-blind, placebo-controlled trial involving 540 Brazilian infants. Doses of vaccine or placebo were given at ages 1, 3 and 5 months. No significant differences were noted in the occurrence of diarrhoea or vomiting in vaccine and placebo recipients following each dose. Low-grade fever occurred on days 3-5 in 2-3% of vaccinees after the first dose, but not after the second or third doses of vaccine. An IgA antibody response to rhesus rotavirus (RRV) occurred in 58% of vaccinees and 33% of placebo recipients. Neutralizing antibody responses to individual serotypes did not exceed 20% when measured by fluorescent focus reduction, but exceeded 40% when assayed by plaque reduction neutralization. There were 91 cases of rotavirus diarrhoea among the 3-dose (vaccine or placebo) recipients during two years of follow-up, 36 of them among children given the vaccine. Overall vaccine efficacy was 8% (P = 0.005) against any diarrhoea and 35% (P = 0.03) against any rotavirus diarrhoea. Protection during the first year of follow-up, when G serotype 1 rotavirus predominated, was 57% (P = 0.008), but fell to 12% in the second year. Similar results were obtained when analysis was restricted to episodes in which rotavirus was the only identified pathogen. There was a tendency for enhanced protection by vaccine against illness associated with an average of 6 or more stools per day. These results are sufficiently encouraging to warrant further studies of this vaccine in developing countries using a higher dosage in an attempt to improve its immunogenicity and efficacy. PMID:9002329
Patel, Manish M; Janssen, Alan P; Tardif, Richard R; Herring, Mark; Parashar, Umesh D
Background In 2006, a new rotavirus vaccine (RotaTeq) was licensed in the US and recommended for routine immunization of all US infants. Because a previously licensed vaccine (Rotashield) was withdrawn from the US for safety concerns, identifying barriers to uptake of RotaTeq will help develop strategies to broaden vaccine coverage. Methods We explored beliefs and attitudes of parents (n = 57) and providers (n = 10) towards rotavirus disease and vaccines through a qualitative assessment using focus groups and in-depth interviews. Results All physicians were familiar with safety concerns about rotavirus vaccines, but felt reassured by RotaTeq's safety profile. When asked about likelihood of using RotaTeq on a scale of one to seven (1 = "absolutely not;" 7 = "absolutely yes") the mean score was 5 (range = 3–6). Physicians expressed a high likelihood of adopting RotaTeq, particularly if recommended by their professional organizations and expressed specific interest in post-marketing safety data. Similarly, consumers found the RotaTeq safety profile to be favorable and would rely on their physician's recommendation for vaccination. However, when asked to rank likelihood of having their child vaccinated against rotavirus (1 = "definitely not get;" 7 = "definitely get"), 29% ranked 1 or 2, 36% 3 or 4, and 35% 5 to 7. Conclusion Our qualitative assessment provides complementary data to recent quantitative surveys and suggests that physicians and parents are likely to adopt the newly licensed rotavirus vaccine. Increasing parental awareness of the rotavirus disease burden and providing physicians with timely post-marketing surveillance data will be integral to a successful vaccination program. PMID:17945010
Chattha, Kuldeep S.; Kandasamy, Sukumar; Vlasova, Anastasia N.; Saif, Linda J.
Rotaviruses (RV) are a major cause of gastroenteritis in children. Widespread vitamin A deficiency is associated with reduced efficacy of vaccines and higher incidence of diarrheal infections in children in developing countries. We established a vitamin A deficient (VAD) gnotobiotic piglet model that mimics subclinical vitamin A deficiency in children to study its effects on an oral human rotavirus (HRV) vaccine and virulent HRV challenge. Piglets derived from VAD and vitamin A sufficient (VAS) sows were orally vaccinated with attenuated HRV or mock, with/without supplemental vitamin A and challenged with virulent HRV. Unvaccinated VAD control piglets had significantly lower hepatic vitamin A, higher severity and duration of diarrhea and HRV fecal shedding post-challenge as compared to VAS control pigs. Reduced protection coincided with significantly higher innate (IFNα) cytokine and CD8 T cell frequencies in the blood and intestinal tissues, higher pro-inflammatory (IL12) and 2-3 fold lower anti-inflammatory (IL10) cytokines, in VAD compared to VAS control pigs. Vaccinated VAD pigs had higher diarrhea severity scores compared to vaccinated VAS pigs, which coincided with lower serum IgA HRV antibody titers and significantly lower intestinal IgA antibody secreting cells post-challenge in the former groups suggesting lower anamnestic responses. A trend for higher serum HRV IgG antibodies was observed in VAD vs VAS vaccinated groups post-challenge. The vaccinated VAD (non-vitamin A supplemented) pigs had significantly higher serum IL12 (PID2) and IFNγ (PID6) compared to vaccinated VAS groups suggesting higher Th1 responses in VAD conditions. Furthermore, regulatory T-cell responses were compromised in VAD pigs. Supplemental vitamin A in VAD pigs did not fully restore the dysregulated immune responses to AttHRV vaccine or moderate virulent HRV diarrhea. Our findings suggest that that VAD in children in developing countries may partially contribute to more severe
Gyrd-Hansen, Dorte; Olsen, Kim Rose
The literature on cost-effectiveness of oral vaccination against rotavirus infection in high-income European countries is assessed in order to show which parameters are important for evaluation results and recommendations on inclusion in child immunization programs. There is a high degree of variation in results due to variation in country specific incidence rates, unit costs and assumed price of the vaccination. A determining factor is whether only costs to the health care system are included or whether a broader approach to costing is applied. A Danish discussion on this issue is pivotal.
Panozzo, Catherine A; Becker-Dreps, Sylvia; Pate, Virginia; Weber, David J; Jonsson Funk, Michele; Stürmer, Til; Brookhart, M Alan
We demonstrate how direct, indirect, total, and overall effectiveness estimates and absolute benefits of rotavirus vaccines vary through the years following vaccine introduction. Privately insured US children in a large claims database were followed from age 8 months until they 1) experienced a hospitalization for rotavirus or acute gastroenteritis; 2) lost continuous health plan enrollment; 3) turned 20 months of age; or 4) reached the end of the study period. Vaccine effectiveness estimates in preventing rotavirus and acute gastroenteritis hospitalizations were estimated using Cox proportional hazards regression, stratified by calendar year and adjusted for birth month. Incidence rate differences were estimated to determine the absolute number of gastroenteritis hospitalizations prevented in the cohort. Among 905,718 children, 51%, 66%, 80%, and 86% received 1 or more doses of rotavirus vaccine in each year from 2007 to 2010. The direct vaccine effectiveness of 1 or more doses of rotavirus vaccine in preventing rotavirus gastroenteritis hospitalizations ranged from 87% to 92% each year. Accounting for indirect protection increased estimates of vaccine effectiveness by an additional 3%-8% among those vaccinated. Failing to account for population-level vaccine benefits in 2010, when circulation of rotavirus was low, could underestimate the sustained impact of the vaccine program.
González, Rosabel; Franco, Manuel; Sarmiento, Luis; Romero, Milagros; Schael, Irene Pérez
To directly compare serum rotavirus specific IgA as a marker of protection in children vaccinated with the RRV-TV (Rotashield) vaccine and in naturally infected children, we studied pre-existing rotavirus IgA antibodies by ELISA assays in these groups of children within the first 5 days after the onset of a diarrhea episode, due or not to rotavirus. In immunized children, rotavirus IgA titers were similar between infected and non-RV infected children. In non-immunized children, the proportion with rotavirus IgA titers was significantly greater in non-RV infected children (58%) than in infected children (31%). Additionally, a titer >/=1:800 was associated with 68% protection. Thus, in this study serum rotavirus IgA showed a good correlation with protection in children pre-exposed to natural infection but not in those immunized with the RRV-TV vaccine.
Ali, Zainab; Harastani, Houda; Hammadi, Moza; Reslan, Lina; Ghanem, Soha; Hajar, Farah; Sabra, Ahmad; Haidar, Amjad; Inati, Adlette; Rajab, Mariam; Fakhouri, Hassan; Ghanem, Bassam; Baasiri, Ghassan; Gerbaka, Bernard; Zaraket, Hassan; Matar, Ghassan M.; Dbaibo, Ghassan
Introduction Globally, rotavirus (RV) is the leading cause of gastroenteritis (GE) in children. Longitudinal data about changes in RV genotype distribution and vaccine effectiveness (VE) are scarce. This study was conducted in Lebanon over 3 consecutive RV seasons to estimate the rate of RVGE hospitalization, identify RV genotypes, determine the seasonal and geographical variations, and calculate RV VE. Materials and Methods This prospective, multicenter, hospital-based surveillance study was conducted between 2011 and 2013 and enrolled children (<5 years) admitted for GE. Socio-demographic and clinical data about the current episode of GE at admission were collected. Genotypes were determined from stool samples testing positive for RV by PCR. Results Of 1,414 cases included in the final analysis, 83% were <2 years old and 55.6% were boys. Median duration of hospitalization was 4 days and 91.6% of GE cases were severe (Vesikari score ≥11). PCR testing showed that 30.3% of subjects were RV-positive of which 62.1% had fever versus 71.1% of RV-negative subjects (P = 0.001). RV was predominantly detected in the cold season from November till March (69.9%). G and P genotype pairs for all RV-positive stool specimens showed a predominance of G1P in 36% (n = 154) of specimens, G9P in 26.4% (n = 113), and G2P in 17.8% (n = 76). RV-negative subjects were more likely to be RV-vaccinated (21%) compared to the RV-positive subjects (11.3%) (P<0.001), with a vaccine breakthrough rate of 18.8%. The ratio of RV1-vaccinated for each RV5-vaccinated subject was 7.8 and VE against RV disease was 68.4% (95%CI, 49.6%-80.2%). Conclusion RV is a major cause of GE requiring hospitalization of children under 5 years of age in Lebanon. A few genotypes predominated over the three RV seasons studied. Mass RV vaccination will likely decrease the burden of hospitalization due to RV. VE is similar to what has been observed for other middle-income countries. PMID:27571515
Guerra, Sylvia F S; Linhares, Alexandre C; Mascarenhas, Joana D'Arc P; Oliveira, Alessilva; Justino, Maria Cleonice A; Soares, Luana S; Müller, Elza Caroline; Brasil, Patrícia; Tuboi, Suely; Ortega-Barria, Eduardo; Colindres, Rómulo
The monovalent human rotavirus (RV) vaccine, RIX4414 (Rotarix™, GlaxoSmithKline Biologicals) was introduced into Brazil's Expanded Program on Immunization in March 2006. One year after vaccine introduction, the G2P strain was found to be predominant, with an apparent extinction of many non-G2 strains. This study investigated the diversity of circulating strains in the three years following RIX4414 introduction. Between May 2008 and May 2011, stool samples were collected from children aged ≥12 weeks who were hospitalized for severe lab confirmed RV-gastroenteritis (≥3 liquid or semi-liquid motions over a 24-h period for <14 days, requiring ≥1 overnight hospital stay and intravenous rehydration therapy) in Belém, Brazil. RV-gastroenteritis was detected by ELISA and the G- and P-types were determined by RT-PCR assays. During the first year of surveillance nucleotide sequencing was used for typing those samples not previously typed by RT-PCR. A total of 1,726 of 10,030 severe gastroentertis hospitalizations (17.2%) were due to severe RVGE. G2P was detected in 57.2% of circulating strains over the whole study period, however it predominated during the first 20 months from May 2008 to January 2009. G1P increased in the last part of the study period from May 2010 to May 2011 and represented 36.6% (112/306) of the circulating strains. G2P was the predominant RV strain circulating during the first 20 months of the study, followed by G1P. These findings probably reflect a natural fluctuation in RV strains over time, rather than a vaccine-induced selective pressure.
Schwartz, Jason L
Context Vaccination in the United States is a frequent source of controversy, with critics alleging failures by public health officials to adequately identify, monitor, and respond to risks associated with vaccines. In response to these charges, the case of RotaShield, a vaccine withdrawn in 1999 following confirmation of a serious adverse event associated with its use, is regularly invoked as evidence of the effectiveness of current vaccine safety activities. Methods This article examines the history of RotaShield, with particular attention paid to decision making regarding its use in the United States and internationally. I reviewed and analyzed federal advisory committee meeting transcripts, international conference reports, government and scientific publications, media coverage, and other primary and secondary source materials. I also conducted six semistructured interviews with former senior officials and advisory committee members at the U.S. Centers for Disease Control and Prevention who participated in decisions regarding the vaccine. Findings Decision making regarding RotaShield, including the ultimate withdrawal of its recommendation for use, was shaped significantly by government health officials’ concern for preserving public confidence in overall U.S. vaccination efforts amid several unrelated vaccine risk controversies ongoing at that time. This attention to public perception and external pressures occurred in tandem with the evaluation of the quantitative evidence regarding the magnitude and severity of the risk associated with the vaccine. The decisions made in the United States resulted in foreseen but unintended consequences for international use of the vaccine, including in nations where the profile of risks and potential benefits was dramatically different. Conclusions As enthusiasm for evidence-based decision making grows throughout medicine and public health, greater explicit attention should be directed to the processes by which decision
Chattha, Kuldeep S; Vlasova, Anastasia N; Kandasamy, Sukumar; Esseili, Malak A; Siegismund, Christine; Rajashekara, Gireesh; Saif, Linda J
Breast milk (colostrum [col]/milk) components and gut commensals play important roles in neonatal immune maturation, establishment of gut homeostasis and immune responses to enteric pathogens and oral vaccines. We investigated the impact of colonization by probiotics, Lactobacillus rhamnosus GG (LGG) and Bifidobacterium lactis Bb12 (Bb12) with/without col/milk (mimicking breast/formula fed infants) on B lymphocyte responses to an attenuated (Att) human rotavirus (HRV) Wa strain vaccine in a neonatal gnotobiotic pig model. Col/milk did not affect probiotic colonization in AttHRV vaccinated pigs. However, unvaccinated pigs fed col/milk shed higher numbers of probiotic bacteria in feces than non-col/milk fed colonized controls. In AttHRV vaccinated pigs, col/milk feeding with probiotic treatment resulted in higher mean serum IgA HRV antibody titers and intestinal IgA antibody secreting cell (ASC) numbers compared to col/milk fed, non-colonized vaccinated pigs. In vaccinated pigs without col/milk, probiotic colonization did not affect IgA HRV antibody titers, but serum IgG HRV antibody titers and gut IgG ASC numbers were lower, suggesting that certain probiotics differentially impact HRV vaccine responses. Our findings suggest that col/milk components (soluble mediators) affect initial probiotic colonization, and together, they modulate neonatal antibody responses to oral AttHRV vaccine in complex ways. PMID:23453730
Chattha, Kuldeep S; Vlasova, Anastasia N; Kandasamy, Sukumar; Esseili, Malak A; Siegismund, Christine; Rajashekara, Gireesh; Saif, Linda J
Breast milk (colostrum [col]/milk) components and gut commensals play important roles in neonatal immune maturation, establishment of gut homeostasis and immune responses to enteric pathogens and oral vaccines. We investigated the impact of colonization by probiotics, Lactobacillus rhamnosus GG (LGG) and Bifidobacterium lactis Bb12 (Bb12) with/without col/milk (mimicking breast/formula fed infants) on B lymphocyte responses to an attenuated (Att) human rotavirus (HRV) Wa strain vaccine in a neonatal gnotobiotic pig model. Col/milk did not affect probiotic colonization in AttHRV vaccinated pigs. However, unvaccinated pigs fed col/milk shed higher numbers of probiotic bacteria in feces than non-col/milk fed colonized controls. In AttHRV vaccinated pigs, col/milk feeding with probiotic treatment resulted in higher mean serum IgA HRV antibody titers and intestinal IgA antibody secreting cell (ASC) numbers compared to col/milk fed, non-colonized vaccinated pigs. In vaccinated pigs without col/milk, probiotic colonization did not affect IgA HRV antibody titers, but serum IgG HRV antibody titers and gut IgG ASC numbers were lower, suggesting that certain probiotics differentially impact HRV vaccine responses. Our findings suggest that col/milk components (soluble mediators) affect initial probiotic colonization, and together, they modulate neonatal antibody responses to oral AttHRV vaccine in complex ways.
Lernout, Tinne; Theeten, Heidi; Leuridan, Elke; Van Damme, Pierre
Since their introduction and widespread use, vaccines have been very successful in reducing morbidity and mortality of the diseases they target, at an individual level and through herd immunity. The impact on the mortality has been rapid and easy to measure for some diseases, such as diphtheria, pertussis and measles. For other diseases, including hepatitis B and human papillomavirus infections, deaths averted occur many years after vaccination, and it takes years until the full potential of the vaccine can be established. Finally, in middle and high income countries, the impact of vaccination against some diseases, like invasive pneumococcal disease and rotavirus gastro-enteritis, is measured by decrease in incidence of the disease and reduction in hospitalization rather than impact on mortality. But in the countries with the highest incidence of these diseases, mortality remains high due to low availability of these vaccines, and millions of deaths could be averted by optimal use of vaccines in these regions. Major challenges for vaccination programmes are to maintain and strengthen trust in the benefits of vaccination and adapt immunization schedules according to the changing epidemiological landscape.
Jalilvand, Somayeh; Marashi, Sayed Mahdi; Shoja, Zabihollah
Rotavirus (RV) structural proteins VP4 and VP7, located on the surface of viral particles, elicit neutralizing antibodies (Abs) and are therefore considered to be important components of RV vaccines. However, despite inducing neutralizing Abs, limits of cross-neutralizing activity and lack of full correlation with protection limit the usefulness of these proteins as protective agents against RV disease. VP6 protein, which forms the middle layer of RV particles, is discussed as an alternative vaccine candidate since it can induce cross-protective immune responses against different RV strains although the Ab raised is not neutralizing. This report reviews different functions of VP6 that can lead to considering it as an alternative vaccine against RV disease.
Paulke-Korinek, Maria; Kundi, Michael; Rendi-Wagner, Pamela; de Martin, Alfred; Eder, Gerald; Schmidle-Loss, Birgit; Vecsei, Andreas; Kollaritsch, Herwig
Austria was the first country in Europe implementing a universal mass vaccination program against rotavirus gastroenteritis (RV-GE) for all infants nationwide. Epidemiological data from a hospital based surveillance system show that incidence rates of children hospitalized with RV-GE decreased in 2009 compared to 2008 and compared to the prevaccination period 2001-2005. Decreasing hospitalization-rates from RV-GE were observed in children of all age groups, even in those not eligible for vaccination according to their age, suggesting herd immunity induced by universal mass vaccination against RV-GE. In 2009 the disease burden was highest in children below three months of age stressing the importance of the early start of the immunization course.
Yuan, Lijuan; Wen, Ke; Azevedo, Marli S P; Gonzalez, Ana M; Zhang, Wei; Saif, Linda J
We examined rotavirus-specific IFN-gamma producing CD4+, CD8+ and CD4+CD8+ T cell responses in gnotobiotic pigs infected with a virulent human rotavirus (VirHRV) or vaccinated with an attenuated (Att) HRV vaccine (AttHRV3x or AttHRV2x) or an AttHRV oral priming and 2/6-virus-like particle (VLP) intranasal boosting (AttHRV-2/6VLP) regimen. In VirHRV infected pigs, HRV-specific IFN-gamma producing T cells reside primarily in ileum. AttHRV-2/6VLP induced similar frequencies of intestinal IFN-gamma producing T cells as the VirHRV, whereas AttHRV3x or 2x vaccines were less effective. Protection rates against rotavirus diarrhea upon VirHRV challenge significantly correlated (r=0.97-1.0, p<0.005) with frequencies of intestinal IFN-gamma producing T cells, suggesting their role in protective immunity.
Li, Rong-cheng; Huang, Teng; Li, Yan-Ping; Luo, Dong; Tao, Junhui; Fu, Botao; Si, Guoai; Nong, Yi; Mo, Zhao-Jun; Liao, Xue-Yan; Luan, Ivy; Tang, Haiwen; Rathi, Niraj; Karkada, Naveen; Han, Htay Htay
Rotaviruses (RV) are a major cause of severe gastroenteritis (GE) in children aged <5 y. For the first time in China, we assessed the efficacy of two oral doses of the human rotavirus vaccine (RIX4414) in infants during the first two years of life (113808/NCT01171963). Healthy infants aged 6–16 weeks were randomized (1:1) to receive two oral doses of either the RIX4414 vaccine/placebo according to a 0, 1 month schedule. Vaccine efficacy (VE) against severe RVGE was assessed from two weeks post-Dose 2 up until the end of the second RV season and calculated with its 95% confidence intervals (CI). The primary efficacy objective was met if the lower limit of the 95% CI on VE was ≥10%. Unsolicited symptoms reported during the 31-d post-vaccination follow-up period and serious adverse events (SAEs) reported throughout the study were assessed. Of 3333 enrolled infants, 3148 were included in the according-to-protocol efficacy cohort. Over two consecutive RV seasons, fewer severe RVGE episodes were reported in the RIX4414 group (n = 21) vs. the placebo group (n = 75). VE against severe RVGE was 72% (95% CI: 54.1–83.6); the lower limit of the 95% CI on VE was >10%. The number of unsolicited symptoms and SAEs reported was similar between both groups. Thirteen deaths (RIX4414 = 6; placebo = 7) occurred during the study. All SAEs and deaths in the RIX4414 group were considered unrelated to vaccination. Two oral doses of RIX4414 vaccine provided a substantial level of protection against severe RVGE in Chinese children during the first two years of life. PMID:24013441
Luchs, Adriana; Timenetsky, Maria do Carmo Sampaio Tavares
ABSTRACTThis article provides a review of immunity, diagnosis, and clinical aspects of rotavirus disease. It also informs about the changes in epidemiology of diarrheal disease and genetic diversity of circulating group A rotavirus strains following the introduction of vaccines. Group A rotavirus is the major pathogen causing gastroenteritis in animals. Its segmented RNA genome can lead to the emergence of new or unusual strains in human populations via interspecies transmission and/or reassortment events.RESUMOEste artigo fornece uma revisão sobre imunidade, diagnóstico e aspectos clínicos da doença causada por rotavírus. Também aponta as principais mudanças no perfil epidemiológico da doença diarreica e na diversidade genética das cepas circulantes de rotavírus do grupo A, após a introdução vacinal. O rotavírus do grupo A é o principal patógeno associado à gastroenterite em animais. Seu genoma RNA segmentado pode levar ao surgimento de cepas novas ou incomuns na população humana, por meio de transmissão entre espécies e eventos de rearranjo.
Background Neutralizing antibodies in breast milk may adversely influence the immune response to live oral vaccines. Withholding breastfeeding around the time of vaccine administration has been suggested for improving vaccine performance. However, we do not know whether mothers find withholding breastfeeding around the time of vaccination acceptable and how they perceive this recommendation. Methods In a clinical study designed to examine predictors of poor immune response to rotavirus vaccine in infants in India, Rotarix® was administered to infants at 6 and 10 weeks with other childhood vaccines. For the study, 400 mother–infant pairs were randomized into two groups in a 1:1 ratio. Mothers were either recommended to withhold breastfeeding or were encouraged to breastfeed half an hour before and after administration of Rotarix®. The mother–infant pairs were observed and the breastfeeding intervals were recorded during this period. Mothers were administered a questionnaire about their perception of the intervention after the infants received the second dose of Rotarix®. Results Almost 98% (391/400) of the infants received both doses of Rotarix®. Adherence to the recommendations was high in both groups. All mothers in the group who were asked to withhold breastfeeding did so, except one who breastfed her infant before the recommended time after the first dose of Rotarix®. Of the mothers, 4% (7/195) reported that the recommendation to withhold breastfeeding was difficult to follow. All mothers in this group reported that they would withhold breastfeeding at the time of vaccination if they were asked to by a health-care provider. Only one mother responded that withholding breastfeeding would be a reason for not giving rotavirus vaccine to her infant. Conclusions Withholding breastfeeding half an hour before and after vaccination appears to be acceptable to mothers in this setting. If withholding breastfeeding produces an improvement in the performance of the
Ali, Asad; Kazi, Abdul Momin; Cortese, Margaret M.; Fleming, Jessica A.; Moon, SungSil; Parashar, Umesh D.; Jiang, Baoming; McNeal, Monica M.; Steele, Duncan; Bhutta, Zulfiqar; Zaidi, Anita K. M.
Background Breast milk contains anti-rotavirus IgA antibodies and other innate immune factors that inhibit rotavirus replication in vitro. These factors could diminish the immunogenicity of oral rotavirus vaccines, particularly if breastfeeding occurs close to the time of vaccine administration. Methods Between April 2011 and November 2012, we conducted an open label, randomized trial to compare the immunogenicity of Rotarix (RV1) in infants whose breastfeeding was withheld one hour before through one hour after vaccination with that in infants breastfed at the time of vaccination. The trial was conducted in the peri-urban area of Ibrahim Hyderi in Karachi, Pakistan. Both groups received three doses of RV1 at 6, 10 and 14 weeks of age. Seroconversion (anti-rotavirus IgA antibodies ≥20 U/mL in subjects seronegative at 6 weeks of age) following three vaccine doses (6, 10 and 14 weeks) was determined at 18 weeks of age (primary objective) and seroconversion following two doses (6 and 10 weeks) was determined at 14 weeks of age (secondary objective). Results Four hundred eligible infants were randomly assigned in a 1:1 ratio between the withholding breastfeeding and immediate breastfeeding arms. Overall, 353 (88.3%) infants completed the study according to protocol; 181 in the withholding breastfeeding group and 172 in the immediate breastfeeding group. After three RV1 doses, anti-rotavirus IgA antibody seroconversion was 28.2% (95% CI: 22.1; 35.1) in the withholding arm and 37.8% (95% CI: 30.9; 45.2) in the immediate breastfeeding arm (difference: -9.6% [95% CI: -19.2; 0.2] p=0.07). After two doses of RV1, seroconversion was 16.6% (95% CI: 11.9; 22.7) in the withholding arm and 29.1% (95% CI: 22.8, 36.3) in the immediate breastfeeding arm (difference: -12.5% [95% CI: -21.2,-3.8] p=0.005). Conclusions Withholding breastfeeding around the time of RV1 vaccine administration did not lead to increased anti-rotavirus IgA seroconversion compared with that seen with a
Becker-Dreps, Sylvia; Bucardo, Filemon; Vilchez, Samuel; Zambrana, Luis Enrique; Liu, Lan; Weber, David J.; Peña, Rodolfo; Barclay, Leslie; Vinjé, Jan; Hudgens, Michael G.; Nordgren, Johan; Svensson, Lennart; Morgan, Douglas R.; Espinoza, Félix; Paniagua, Margarita
Background Nicaragua was the first developing nation to implement routine immunization with the pentavalent rotavirus vaccine (RV5). In this RV5-immunized population, understanding infectious etiologies of childhood diarrhea is necessary to direct diarrhea treatment and prevention efforts. Methods We followed a population-based sample of children less than 5 years in León, Nicaragua for diarrhea episodes through household visits. Information was obtained on RV5 history and sociodemographics. Stool samples collected during diarrhea episodes and among healthy children underwent laboratory analysis for viral, bacterial, and parasitic enteropathogens. Detection frequency and incidence of each enteropathogen was calculated. Results The 826 children in the cohort experienced 677 diarrhea episodes during 607.5 child-years of exposure time (1.1 episodes per child-year). At least one enteropathogen was detected among 61.1% of the 337 diarrheal stools collected. The most common enteropathogens among diarrheal stools were: norovirus (20.4%), sapovirus (16.6%), enteropathogenic Escherichia coli (EPEC, 11.3%), Entamoeba histolytica/dispar (8.3%), Giardia lamblia (8.0%), and enterotoxigenic E.coli (ETEC, 7.7%), with rotavirus detected among 5.3% of diarrheal stools. EPEC and ETEC were frequently detected among stools from healthy children. Among children with diarrhea, norovirus was more commonly detected among younger children (< 2 years) and G. lamblia was more commonly detected among older children (2-4 years). The mean age of rotavirus detection was 34.6 months. Conclusions In this Central American community following RV5 introduction, rotavirus was not commonly detected among children with diarrhea. Prevention and appropriate management of norovirus and sapovirus should be considered to further reduce the burden of diarrheal disease. PMID:24879131
... will be protected from severe rotavirus disease. Most vaccinated children will not get sick from rotavirus at all. ... does not cover vaccines for your child, the Vaccines for Children (VFC) Program may be able to help. This ...
van Hoek, Albert Jan; Ngama, Mwanajuma; Ismail, Amina; Chuma, Jane; Cheburet, Samuel; Mutonga, David; Kamau, Tatu; Nokes, D. James
Background Diarrhoea is an important cause of death in the developing world, and rotavirus is the single most important cause of diarrhoea associated mortality. Two vaccines (Rotarix and RotaTeq) are available to prevent rotavirus disease. This analysis was undertaken to aid the decision in Kenya as to which vaccine to choose when introducing rotavirus vaccination. Methods Cost-effectiveness modelling, using national and sentinel surveillance data, and an impact assessment on the cold chain. Results The median estimated incidence of rotavirus disease in Kenya was 3015 outpatient visits, 279 hospitalisations and 65 deaths per 100,000 children under five years of age per year. Cumulated over the first five years of life vaccination was predicted to prevent 34% of the outpatient visits, 31% of the hospitalizations and 42% of the deaths. The estimated prevented costs accumulated over five years totalled US$1,782,761 (direct and indirect costs) with an associated 48,585 DALYs. From a societal perspective Rotarix had a cost-effectiveness ratio of US$142 per DALY (US$5 for the full course of two doses) and RotaTeq US$288 per DALY ($10.5 for the full course of three doses). RotaTeq will have a bigger impact on the cold chain compared to Rotarix. Conclusion Vaccination against rotavirus disease is cost-effective for Kenya irrespective of the vaccine. Of the two vaccines Rotarix was the preferred choice due to a better cost-effectiveness ratio, the presence of a vaccine vial monitor, the requirement of fewer doses and less storage space, and proven thermo-stability. PMID:23115650
Zaman, K.; Fleming, Jessica A.; Victor, John C.; Yunus, Mohammad; Bari, Tajul Islam A.; Azim, Tasnim; Rahman, Mustafizur; Mowla, Syed Mohammad Niaz; Bellini, William J.; McNeal, Monica; Icenogle, Joseph P.; Lopman, Ben; Parashar, Umesh; Cortese, Margaret M.; Steele, A. Duncan; Neuzil, Kathleen M.
Background. The burden of rotavirus morbidity and mortality is high in children aged <5 years in developing countries, and evaluations indicate waning protection from rotavirus immunization in the second year. An additional dose of rotavirus vaccine may enhance the immune response and lengthen the period of protection against disease, but coadministration of this dose should not interfere with immune responses to concurrently given vaccines. Methods. A total of 480 9-month-old participants from Matlab, Bangladesh, were enrolled in a study with a primary objective to establish noninferiority of concomitant administration of measles-rubella vaccine (MR) and a third dose of human rotavirus vaccine (HRV; MR + HRV), compared with MR given alone. Secondary objectives included noninferiority of rubella antibody seroconversion and evaluating rotavirus IgA/IgG seroresponses in MR + HRV recipients. Results. Two months after vaccination, 75.3% and 74.3% of MR + HRV and MR recipients, respectively, had seroprotective levels of measles virus antibodies; 100.0% and 99.6%, respectively, showed anti–rubella virus immunoglobulin G (IgG) seroprotection. In the MR + HRV group, antirotavirus immunoglobulin A and IgG seropositivity frequencies before vaccination (52.7% and 66.3%, respectively) increased to 69.6% and 88.3% after vaccination. Conclusions. Vaccine-induced measles and rubella antibody responses are not negatively affected by concomitant administration of HRV. The HRV dose increases antirotavirus serum antibody titers and the proportion of infants with detectable antirotavirus antibody. Clinical Trials Registration. NCT01700621. PMID:26823338
Tennant, Sharon M.; Levine, Myron M.
Salmonella enterica serovar Typhi produces significant morbidity and mortality worldwide despite the fact that there are licensed S. Typhi vaccines available. This is primarily due to the fact that these vaccines are not used in the countries that most need them. There is growing recognition that an effective invasive Salmonella vaccine formulation must also prevent infection due to other Salmonella serovars. We anticipate that a multivalent vaccine that targets the following serovars will be needed to control invasive Salmonella infections worldwide: S. Typhi, S. Paratyphi A, S. Paratyphi B (currently uncommon but may become dominant again), S. Typhimurium, S. Enteritidis and S. Choleraesuis (as well as other Group C Salmonella). Live attenuated vaccines are an attractive vaccine formulation for use in developing as well as developed countries. Here, we describe the methods of attenuation that have been used to date to create live attenuated Salmonella vaccines and provide an update on the progress that has been made on these vaccines. PMID:25902362
Tennant, Sharon M; Levine, Myron M
Salmonella enterica serovar Typhi produces significant morbidity and mortality worldwide despite the fact that there are licensed Salmonella Typhi vaccines available. This is primarily due to the fact that these vaccines are not used in the countries that most need them. There is growing recognition that an effective invasive Salmonella vaccine formulation must also prevent infection due to other Salmonella serovars. We anticipate that a multivalent vaccine that targets the following serovars will be needed to control invasive Salmonella infections worldwide: Salmonella Typhi, Salmonella Paratyphi A, Salmonella Paratyphi B (currently uncommon but may become dominant again), Salmonella Typhimurium, Salmonella Enteritidis and Salmonella Choleraesuis (as well as other Group C Salmonella). Live attenuated vaccines are an attractive vaccine formulation for use in developing as well as developed countries. Here, we describe the methods of attenuation that have been used to date to create live attenuated Salmonella vaccines and provide an update on the progress that has been made on these vaccines.
Neves, Mayara A O; Pinheiro, Helder H C; Silva, Rita S U; Linhares, Alexandre C; Silva, Luciana D; Gabbay, Yvone B; Silva, Mônica C M; Loureiro, Edvaldo C B; Soares, Luana S; Mascarenhas, Joana D'Arc P
The present study aimed to provide a molecular characterization of circulating rotavirus (RVA) strains in Rio Branco, Acre, in the post-rotavirus vaccination period, particularly with regard to the emerging, increasingly prevalent G12P genotype. A total of 488 fecal specimens from diarrheic and non-diarrheic children were obtained between January and December 2012. RVA detection was initially performed using enzyme-linked immunosorbent assay (ELISA) method, followed by reverse-transcription polymerase chain reaction (RT-PCR) using specific primers. RVA was detected in 18.3% (44/241) of the children with acute diarrhea and in 1.2% (3/247) of the non-diarrheic children (P < 0.001), with overall RVA-positivity of 9.6% (47/488). The most common genotype was G2P with 43.2% (19/44) of the diarrheic cases, followed by G12P (27.3%, 12/44), G3P (18.2%, 8/44), G3P (4.5%, 2/44), and G12P (2.3%, 1/44). G12 samples belonged to lineage III and were from children aged 4-52 months. All of these children had acute diarrhea associated with fever (83.3%, 10/12) and vomiting (66.7%, 8/12). Most of the cases occurred in August (58.3%, 7/12), 75% (9/12) of which having received the full vaccination scheme with Rotarix™. For the first time G12 was reported at relative high prevalence in Brazil. Our findings warrant further monitoring studies on the molecular characterization of circulating RVA strains after rotavirus vaccine introduction in Brazil and elsewhere, since the occurrence of either unusual our emerging genotypes may pose a challenge to vaccination strategies.
Wen, Xiaobo; Wei, Xiaoman; Ran, Xuhua; Ni, Hongbo; Cao, Si; Zhang, Yao
Currently, commercial porcine rotavirus vaccines remain varied limitations. The objective of this study is to develop an alternative porcine rotavirus subunit vaccine candidate by parenteral administration, which enables to elicit robust immune responses against most prevalence porcine rotavirus strains. The bacterially-expressed porcine rotavirus P- or P-specific truncated VP8* (aa 64-223) recombinant protein with or without a universal tetanus toxoid CD4(+) T cell epitope P2 was generated. All the recombinant subunit proteins △VP8*s or P2-△VP8*s were of high solubility and high yields. The immunogenicity of each purified △VP8* and P2-△VP8* was evaluated in mice (10 μg/dose) or guinea pigs (20 μg/dose) immunized IM with 600 μg aluminum hydroxide three times at 2-week interval. The introduction of P2T cell epitope to P-△VP8* elicited significantly higher IgG titer in mice than its absence. Comparatively, P2 epitope slightly enhanced the immunogenicity of P-△VP8*. P2-P△VP8* elicited high titer of neutralizing antibody against heterotypic P-specific rotaviruses with varied G type combination. Our data indicated that two subunit vaccines could be plausible bivalent rotavirus vaccine candidate to provide antigenic coverage of porcine rotavirus strains of global or regional importance.
Michael-Meese, M; Klie, H; Schöll, W
Immunisation of pregnant sows prior to parturition has long proved to be a good method to forestall coli dysentery in piglets before weaning. Inactivated vaccines of the pathogenetically important E. coli serogroups with and without adjuvant so far were primarily used at international level. A vaccine of that kind has become available in the GDR more than eight years ago. Its name is Coliporc "Dessau". A live vaccine has been developed from two R-mutants at the authors' institute. The effectiveness of that live vaccine on laboratory animals and in field experiments is reported in this paper together with possibilities of differential diagnosis to distinguish wild strains from the mutants. The live vaccine was commercially registered under the name of Suicolpex "Dessau", in spring 1976.
Bowen, Michael D.; Mijatovic-Rustempasic, Slavica; Esona, Mathew D.; Teel, Elizabeth N.; Gautam, Rashi; Sturgeon, Michele; Azimi, Parvin H.; Baker, Carol J.; Bernstein, David I.; Boom, Julie A.; Chappell, James; Donauer, Stephanie; Edwards, Kathryn M.; Englund, Janet A.; Halasa, Natasha B.; Harrison, Christopher J.; Johnston, Samantha H.; Klein, Eileen J.; McNeal, Monica M.; Moffatt, Mary E.; Rench, Marcia A.; Sahni, Leila C.; Selvarangan, Rangaraj; Staat, Mary A.; Szilagyi, Peter G.; Weinberg, Geoffrey A.; Wikswo, Mary E.; Parashar, Umesh D.; Payne, Daniel C.
Background Group A rotaviruses (RVA) are a significant cause of pediatric gastroenteritis worldwide. The New Vaccine Surveillance Network (NVSN) has conducted active surveillance for RVA at pediatric hospitals and emergency departments at 3–7 geographically diverse sites in the United States since 2006. Methods Over 6 consecutive years, from 2008 to 2013, 1523 samples from NVSN sites that were tested positive by a Rotaclone enzyme immunoassay were submitted to the Centers for Disease Control and Prevention for genotyping. Results In the 2009, 2010, and 2011 seasons, genotype G3P was the predominant genotype throughout the network, with a 46%–84% prevalence. In the 2012 season, G12P replaced G3P as the most common genotype, with a 70% prevalence, and this trend persisted in 2013 (68.0% prevalence). Vaccine (RotaTeq; Rotarix) strains were detected in 0.6%–3.4% of genotyped samples each season. Uncommon and unusual strains (eg, G8P, G3P, G2P, G3P, G3P, G24P, G4P, and G9P) were detected sporadically over the study period. Year, study site, and race were found to be significant predictors of genotype. Conclusions Continued active surveillance is needed to monitor RVA genotypes in the United States and to detect potential changes since vaccine licensure. PMID:27302190
... is taken in its entirety from the CDC Influenza Live, Intranasal Flu Vaccine Information Statement (VIS): www.cdc.gov/vaccines/ ... flulive.html . CDC review information for Live, Intranasal Influenza VIS: Vaccine Information Statement Influenza Page last reviewed: ...
Esparza-Aguilar, Marcelino; Sánchez-Uribe, Edgar; Desai, Rishi; Parashar, Umesh D; Richardson, Vesta; Patel, Manish
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
Dube, E.; Bettinger, J. A.; Halperin, B.; Bradet, R.; Lavoie, F.; Sauvageau, C.; Gilca, V.; Boulianne, N.
Rotavirus disease is a common cause of health care utilization and almost all children are affected by the age of 5 years. In Canada, at the time of this survey (2008-09), immunization rates for rotavirus were less than 20%. We assessed the determinants of a parent's acceptance to have their child immunized against rotavirus. The survey…
Saif, L J; Smith, K L; Landmeier, B J; Bohl, E H; Theil, K W; Todhunter, D A
Fifteen pregnant Holstein cows were freely assigned to 3 experimental groups (5 cows in each group). Cows in group I were inoculated IM and intramammarily (IMm) with Ohio Agricultural Research and Development Center (OARDC) tissue culture-propagated modified-live Nebraska calf diarrhea bovine rotavirus with added adjuvant (OARDC vaccine-immunized cows). Group II cows were given IM injections of a commercial modified-live rotavirus-coronavirus vaccine (commercial vaccine-immunized cows), and the remaining 5 cows were noninoculated controls (group III). Rotavirus antibody in colostrum and milk was mainly associated with immunoglobulin (Ig)G1, and less so with IgG2, IgA, and IgM, as analyzed by the enzyme-linked immunosorbent assay (ELISA), using monospecific anti-bovine IgG1, IgG2, IgM, and IgA sera. In serum, the rotavirus antibody was distributed almost equally between IgG1 and IgG2. The same relationships appeared in both immunized and nonvaccinated cows. All OARDC vaccine-injected cows had virus-neutralization (VN) and ELISA IgG1 rotavirus antibody titers in serum and mammary secretions at significantly increased levels (at least 100-fold; P less than 0.05) compared with the titers in groups II (commercial vaccine-immunized cows) and III (controls). Serum, colostrum, and milk antibody titers from these latter 2 groups did not differ statistically. The ELISA IgG2, IgA, and IgM rotavirus antibody titers also were significantly greater in mammary secretions from OARDC vaccine-immunized cows than in groups II and III cows. There was a high correlation between ELISA IgG1 and VN rotavirus antibody titers for all samples tested (r = 0.97, P less than 0.001), but ELISA IgG1 antibody titers were consistently higher than VN titers. The ELISA IgG1 and VN antibody titers of milk samples collected from cows 30 days after parturition were higher from the OARDC vaccine-immunized cows (ELISA IgG1, geometric mean titer (GMT) = 3,511; VN GMT = 1,689) than were titers from the
For centuries, acute diarrhea has been a major worldwide cause of death in young children, and until 1973, no infectious agents could be identified in about 80% of patients admitted to hospital with severe dehydrating diarrhea. In 1973 Ruth Bishop, Geoffrey Davidson, Ian Holmes, and Brian Ruck identified abundant particles of a 'new' virus (rotavirus) in the cytoplasm of mature epithelial cells lining duodenal villi and in feces, from such children admitted to the Royal Children's Hospital, Melbourne. Rotaviruses have now been shown to cause 40-50% of severe acute diarrhea in young children worldwide in both developing and developed countries, and > 600 000 young children die annually from rotavirus disease, predominantly in South-East Asia and sub-Saharan Africa. Longitudinal surveillance studies following primary infection in young children have shown that rotavirus reinfections are common. However the immune response that develops after primary infection is protective against severe symptoms on reinfection. This observation became the basis for development of live oral rotavirus vaccines. Two safe and effective vaccines are now licensed in 100 countries and in use in 17 countries (including Australia). Rotarix (GSK) is a single attenuated human rotavirus, representative of the most common serotype identified worldwide (G1P). RotaTeq (Merck) is a pentavalent mixture of naturally attenuated bovine/human rotavirus reassortants representing G1, G2, G3, G4, and P(8) serotypes. Preliminary surveillance of the numbers of children requiring hospitalization for severe diarrhea, in USA, Brazil, and Australia, after introduction of these vaccines, encourages the hope that rotavirus infection need no longer be a threat to young children worldwide.
Matthijnssens, Jelle; Joelsson, Daniel B.; Warakomski, Donald J.; Zhou, Tingyi; Mathis, Pamela K.; Maanen, Marc-Henri van; Ranheim, Todd S.; Ciarlet, Max
RotaTeq (registered) is a pentavalent rotavirus vaccine that contains five human-bovine reassortant strains (designated G1, G2, G3, G4, and P1) on the backbone of the naturally attenuated tissue culture-adapted parental bovine rotavirus (BRV) strain WC3. The viral genomes of each of the reassortant strains were completely sequenced and compared pairwise and phylogenetically among each other and to human rotavirus (HRV) and BRV reference strains. Reassortants G1, G2, G3, and G4 contained the VP7 gene from their corresponding HRV parent strains, while reassortants G1 and G2 also contained the VP3 gene (genotype M1) from the HRV parent strain. The P1 reassortant contained the VP4 gene from the HRV parent strain and all the other gene segments from the BRV WC3 strain. The human VP7s had a high level of overall amino acid identity (G1: 95-99%, G2: 94-99% G3: 96-100%, G4: 93-99%) when compared to those of representative rotavirus strains of their corresponding G serotypes. The VP4 of the P1 reassortant had a high identity (92-97%) with those of serotype P1A HRV reference strains, while the BRV VP7 showed identities ranging from 91% to 94% to those of serotype G6 HRV strains. Sequence analyses of the BRV or HRV genes confirmed that the fundamental structure of the proteins in the vaccine was similar to those of the HRV and BRV references strains. Sequences analyses showed that RotaTeq (registered) exhibited a high degree of genetic stability as no mutations were identified in the material of each reassortant, which undergoes two rounds of replication cycles in cell culture during the manufacturing process, when compared to the final material used to fill the dosing tubes. The infectivity of each of the reassortant strains of RotaTeq (registered) , like HRV strains, did not require the presence of sialic acid residues on the cell surface. The molecular and biologic characterization of RotaTeq (registered) adds to the significant body of clinical data supporting the
We aimed to investigate epidemiology and host- and pathogen-related factors associated with clinical severity of acute gastroenteritis (AGE) in children after rotavirus vaccination introduction. Factors assessed included age, co-infection with more than 2 viruses, and virus-toxigenic Clostridium difficile co-detection. Fecal samples and clinical information, including modified Vesikari scores, were collected from hospitalized children with AGE. The presence of enteric viruses and bacteria, including toxigenic C. difficile, was detected by polymerase chain reaction (PCR). Among the 415 children included, virus was detected in stool of 282 (68.0%) children. Co-infection with more than 2 viruses and toxigenic C. difficile were found in 24 (8.5%) and 26 (9.2%) children with viral AGE, respectively. Norovirus (n = 130) infection, including norovirus-associated co-infection, was the most frequent infection, especially in children aged < 24 months (P < 0.001). In the severity-related analysis, age < 24 months was associated with greater diarrheal severity (P < 0.001) and modified Vesikari score (P = 0.001), after adjustment for other severity-related factors including rotavirus status. Although the age at infection with rotavirus was higher than that for other viruses (P = 0.001), rotavirus detection was the most significant risk factor for all severity parameters, including modified Vesikari score (P < 0.001). Viral co-infection and toxigenic C. difficile co-detection were not associated with any severity-related parameter. This information will be helpful in the management of childhood AGE in this era of rotavirus vaccination and availability of molecular diagnostic tests, which often lead to the simultaneous detection of multiple pathogens. PMID:28145650
LUCHS, Adriana; CILLI, Audrey; MORILLO, Simone Guadagnucci; CARMONA, Rita de Cássia Compagnoli; TIMENETSKY, Maria do Carmo Sampaio Tavares
SUMMARY Regarding public health in Brazil, a new scenario emerged with the establishment of universal rotavirus (RV) vaccination programs. Herein, the data from the five years of surveillance (2007-2012) of G- and P-type RV strains isolated from individuals with acute gastroenteritis in Brazil are reported. A total of 6,196 fecal specimens were investigated by ELISA and RT-PCR. RVs were detected in 19.1% (1,181/6,196). The peak of RV incidence moved from June-August to September. RV was detected less frequently (19.5%) among children ≤ 5 years than in older children and adolescents (6-18 years) (40.6%). Genotype distribution showed a different profile for each year: G2P strains were most prevalent during 2007-2010, G9P in 2011, and G12P in 2012. Mixed infections (G1+G2P, G2+G3P+P, G2+G12P), unusual combinations (G1P, G2P), and rare strains (G3P) were also identified throughout the study period. Widespread vaccination may alter the RV seasonal pattern. The finding of RV disease affecting older children and adolescents after vaccine implementation has been reported worldwide. G2P emergence most likely follows a global trend seemingly unrelated to vaccination, and G12, apparently, is emerging in the Brazilian population. The rapidly changing RV genotype patterns detected during this study illustrate a dynamic population of co-circulating wildtype RVs in Brazil. PMID:26422154
... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Rabies Vaccine, Live Virus. 113.312... Virus Vaccines § 113.312 Rabies Vaccine, Live Virus. Rabies Vaccine shall be prepared from virus-bearing..., safe and immunogenic shall be used for preparing the production seed virus for vaccine production....
... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Rabies Vaccine, Live Virus. 113.312... Virus Vaccines § 113.312 Rabies Vaccine, Live Virus. Rabies Vaccine shall be prepared from virus-bearing..., safe and immunogenic shall be used for preparing the production seed virus for vaccine production....
... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Rabies Vaccine, Live Virus. 113.312... Virus Vaccines § 113.312 Rabies Vaccine, Live Virus. Rabies Vaccine shall be prepared from virus-bearing..., safe and immunogenic shall be used for preparing the production seed virus for vaccine production....
... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Rabies Vaccine, Live Virus. 113.312... Virus Vaccines § 113.312 Rabies Vaccine, Live Virus. Rabies Vaccine shall be prepared from virus-bearing..., safe and immunogenic shall be used for preparing the production seed virus for vaccine production....
... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Rabies Vaccine, Live Virus. 113.312... Virus Vaccines § 113.312 Rabies Vaccine, Live Virus. Rabies Vaccine shall be prepared from virus-bearing..., safe and immunogenic shall be used for preparing the production seed virus for vaccine production....
MedImmune Vaccines (formerly Aviron) has developed a cold-adapted live influenza virus vaccine [FluMist] that can be administered by nasal spray. FluMist is the first live virus influenza vaccine and also the first nasally administered vaccine to be marketed in the US. The vaccine will be formulated to contain live attenuated (att) influenza virus reassortants of the strains recommended by the US Public Health Service for each 'flu season. The vaccine is termed cold-adapted (ca) because the virus has been adapted to replicate efficiently at 25 degrees C in the nasal passages, which are below normal body temperature. The strains used in the seasonal vaccine will also be made temperature sensitive (ts) so that their replication is restricted at 37 degrees C (Type B strains) and 39 degrees C (Type A strains). The combined effect of the antigenic properties and the att, ca and ts phenotypes of the influenza strains contained in the vaccine enables the viruses to replicate in the nasopharynx to produce protective immunity. The original formulation of FluMist requires freezer storage throughout distribution. Because many international markets do not have distribution channels well suited to the sale of frozen vaccines, Wyeth and MedImmune are collaborating to develop a second generation, refrigerator-stable, liquid trivalent cold-adapted influenza vaccine (CAIV-T), which is in phase III trials. Initially, the frozen formulation will only be available in the US. For the 2003-2004 season, FluMist will contain A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2) (A/Moscow/10/99-like) and B/Hong Kong/330/2001. Aviron was acquired by MedImmune on 15 January 2002. Aviron is now a wholly-owned subsidiary of MedImmune and is called MedImmune Vaccines. Aviron acquired FluMist in March 1995 through a Co-operative Research and Development Agreement (CRADA) with the US NIAID, and a licensing agreement with the University of Michigan, Ann Arbor, USA. In June 2000, the CRADA was
The decision to add a new vaccine to the immunization schedule is a complex and multidisciplinary process based on the risk-benefit balance and, increasingly, on the cost- effectiveness ratio. Such decisions now use mathematical models that can predict the indirect, and potentially detrimental, effects of mass vaccination on the epidemiology of the target disease. The adjunction of an economic component to the modeling process ensures that vaccination represents an efficient allocation of available financial resources in an increasingly constrained environment.
Chattha, Kuldeep S.; Vlasova, Anastasia N.; Kandasamy, Sukumar; Rajashekara, Gireesh; Saif, Linda J.
Rotaviruses (RVs) are a leading cause of childhood diarrhea. Current oral vaccines are not effective in impoverished countries where the vaccine is needed most. Therefore, alternative affordable strategies are urgently needed. Probiotics can alleviate diarrhea in children and enhance specific systemic and mucosal Ab responses, but the T cell responses are undefined. In this study, we elucidated the T cell and cytokine responses to attenuated human RV (AttHRV) and virulent human RV (HRV) in gnotobiotic pigs colonized with probiotics (Lactobacillus rhamnosus strain GG [LGG] and Bifidobacterium lactis Bb12 [Bb12]), mimicking gut commensals in breastfed infants. Neonatal gnotobiotic pigs are the only animal model susceptible to HRV diarrhea. Probiotic colonized and nonvaccinated (Probiotic) pigs had lower diarrhea and reduced virus shedding postchallenge compared with noncolonized and nonvaccinated pigs (Control). Higher protection in the Probiotic group coincided with higher ileal T regulatory cells (Tregs) before and after challenge, and higher serum TGF-β and lower serum and biliary proinflammatory cytokines postchallenge. Probiotic colonization in vaccinated pigs enhanced innate serum IFN-α, splenic and circulatory IFN-γ−producing T cells, and serum Th1 cytokines, but reduced serum Th2 cytokines compared with noncolonized vaccinated pigs (Vac). Thus, LGG+Bb12 induced systemic Th1 immunostimulatory effects on oral AttHRV vaccine that coincided with lower diarrhea severity and reduced virus shedding postchallenge in Vac+Pro compared with Vac pigs. Previously unreported intestinal CD8 Tregs were induced in vaccinated groups postchallenge. Thus, probiotics LGG+Bb12 exert divergent immunomodulating effects, with enhanced Th1 responses to oral AttHRV vaccine, whereas inducing Treg responses to virulent HRV. PMID:23918983
Bucardo, Filemón; Lindgren, Per-Eric; Svensson, Lennart; Nordgren, Johan
Rotavirus (RV) and norovirus (NoV) are major causes of pediatric diarrhea and are altogether associated with approximately 800,000 deaths in young children every year. In Nicaragua, national RV vaccination program using the pentavalent RV5 vaccine from Merck was implemented in October 2006. To determine whether RV vaccination decreased the overall number of RV infections, we investigated the occurrence of RV and NoV in wastewater in the city of León from July 2007 to July 2008 and compared these data with pre-vaccination data. The major finding was the low prevalence of RV compared to NoV in all sampling points (11% vs 44%, p<0.05), and that RV concentration was lower as compared to NoV. RV was observed mainly during the rainy season (July–September), and the majority of all RV detected (6/9) belonged to subgroup (SG) I. The partial VP7-gene obtained from one RV positive sample was similar (99% nt identity) to a G6 VP7-gene of bovine origin and similar to the corresponding gene of the vaccine strain (98%). Furthermore RV G-types 2 and 4 were found in the incoming wastewater. NoV strains were detected throughout the year, of which a majority (20/21) were of genotype GII.4. We conclude that the introduction of RV vaccination reduced the transmission of RV in the community in Nicaragua. However, the burden of diarrhea in the country remains high, and the high prevalence of NoVs in hospital and municipal wastewater is noteworthy. This study highlights the need for further assessment of NoV following RV vaccine introduction. PMID:22016794
Chattha, Kuldeep S; Vlasova, Anastasia N; Kandasamy, Sukumar; Rajashekara, Gireesh; Saif, Linda J
Rotaviruses (RVs) are a leading cause of childhood diarrhea. Current oral vaccines are not effective in impoverished countries where the vaccine is needed most. Therefore, alternative affordable strategies are urgently needed. Probiotics can alleviate diarrhea in children and enhance specific systemic and mucosal Ab responses, but the T cell responses are undefined. In this study, we elucidated the T cell and cytokine responses to attenuated human RV (AttHRV) and virulent human RV (HRV) in gnotobiotic pigs colonized with probiotics (Lactobacillus rhamnosus strain GG [LGG] and Bifidobacterium lactis Bb12 [Bb12]), mimicking gut commensals in breastfed infants. Neonatal gnotobiotic pigs are the only animal model susceptible to HRV diarrhea. Probiotic colonized and nonvaccinated (Probiotic) pigs had lower diarrhea and reduced virus shedding postchallenge compared with noncolonized and nonvaccinated pigs (Control). Higher protection in the Probiotic group coincided with higher ileal T regulatory cells (Tregs) before and after challenge, and higher serum TGF-β and lower serum and biliary proinflammatory cytokines postchallenge. Probiotic colonization in vaccinated pigs enhanced innate serum IFN-α, splenic and circulatory IFN-γ-producing T cells, and serum Th1 cytokines, but reduced serum Th2 cytokines compared with noncolonized vaccinated pigs (Vac). Thus, LGG+Bb12 induced systemic Th1 immunostimulatory effects on oral AttHRV vaccine that coincided with lower diarrhea severity and reduced virus shedding postchallenge in Vac+Pro compared with Vac pigs. Previously unreported intestinal CD8 Tregs were induced in vaccinated groups postchallenge. Thus, probiotics LGG+Bb12 exert divergent immunomodulating effects, with enhanced Th1 responses to oral AttHRV vaccine, whereas inducing Treg responses to virulent HRV.
Redondo, Olga; Cano, Rosa; Simón, Lorena
Rotavirus is a major burden on the Spanish Healthcare System. Rotarix® and RotaTeq® were simultaneously commercialized in Spain by February, 2007. The objective is to analyze the incidence and seasonality of rotavirus hospitalizations (RH) in Castile-La Mancha (CLM), following the first 3 y of commercialization. A cross-sectional study of the hospital discharge registry's Minimum Basic Data Set (MBDS) in CLM between 2003 and 2009 was performed. We used the Poisson regression model to quantify the percentage of change in the rotavirus incidence rate (IR) for 2007–09 vs. 2003–05, adjusting for age, sex, and province. To analyze changes between epidemic seasons the chi-square test was used. The median IR in 2003–09 was 224.71 per 105 [interquartile range (IQR): 185.24–274.70], which represents 60% of hospital admissions due to infectious acute gastroenteritis. The median rate in 2007–09 decreased [incidence rate ratio (IRR): 0.86, 95% CI: 0.78–0.96], significantly in Toledo (IRR: 0.54, 95% CI: 0.39–0.75). An incipient decline at the beginning of the last cold season was observed, preceded by a significant decrease of 68% in the autumn season of 2009. Despite its limited coverage, the rotavirus vaccine may have contributed to decrease RH in CLM. PMID:25644531
Xia, Ming; Wei, Chao; Wang, Leyi; Cao, Dianjun; Meng, Xiang-Jin; Jiang, Xi; Tan, Ming
Hepatitis E virus (HEV), rotavirus (RV), and astrovirus (AstV) are important pathogens that transmit through a common fecal-oral route, causing hepatitis (HEV) and gastroenteritis (RV and AstV) respectively in humans. In this study, we developed and evaluated two subunit vaccine candidates that consisted of the same protruding or spike protein antigens of the three viruses in two formats, a fusion of the three antigens into one molecule (fused vaccine) vs. a mixture of the three free antigens together (mixed vaccine). Both vaccines were easily made via E. coli expression system. Mouse immunization experiments showed that the fused vaccine elicited significantly higher antibody responses against the three viral antigens than those induced by the mixed vaccine. In addition, the mouse post-immune antisera of the fused vaccine revealed significantly higher neutralizing titers against HEV infection in cell culture, as well as significantly higher 50% blocking titers (BT50) against RV VP8-HBGA receptor interactions than those of the post-immune antisera after immunization of the mixed vaccine. Thus, the fused vaccine is a promising trivalent vaccine candidate against HEV, RV, and AstV, which is worth for further development. PMID:27194006
Karmann, Alexander; Jurack, Andrea; Lukas, Daniel
The objective of this study was to assess the budget impact and health effects of introducing rotavirus (RV) vaccination in Saxony, Germany, from a health insurance perspective. Special emphasis is given to the herd effect. We analyzed direct medical and non-medical costs of RV infection for Social Health Insurance between 2007 and 2010 based on 360,000 routine data observations from the AOK PLUS for children below 5 years of age. We compared the actual annual number of RV cases (vaccination scenario) with the number derived from 2005 (no vaccination, base case scenario). The vaccination coverage rate has increased from 5% to 61% between 2007 and 2010. The number of RV cases decreased by 21% from 32,274 in 2007 to 25,614 in 2010. Based on vaccination coverage, the total cost savings per 1,000 children due to RV vaccination was estimated to be 39,686 Euros. The overall share of outpatient costs was 60%. Mean gross cost savings were expected to be 304 Euros per avoided case. The net cost savings were expected to be 19 Euros per avoided case. About 59% of total savings was due to herd protection resulting from increasing vaccine rates. The herd effect per avoided case increased with increasing vaccine coverage. Incidence of RV cases, vaccination costs and days absent from work were sensitive parameters. This retrospective analysis showed that the increase in RV vaccination coverage in Saxony has been budget neutral if not cost saving for sick funds.
Dudareva-Vizule, Sandra; Koch, Judith; an der Heiden, Matthias; Oberle, Doris; Keller-Stanislawski, Brigitte; Wichmann, Ole
In Germany, routine RV-vaccination is not adopted into the national immunization schedule as of 2012. Because RV-vaccines were already on the market since 2006, in 2010 a moderate (58%) and low (22%) vaccine uptake was observed in the 5 eastern federal states (EFS) and the 11 western federal states (WFS), respectively. To assess the impact of RV-vaccination, we compared the incidence rates (IR) of RV-related hospitalizations before (2004‒2006) and in seasons after (2008/09–2010/11) RV-vaccine introduction in Germany by utilizing data from the national mandatory disease reporting system. In the EFS, the IR was significantly reduced in age-groups < 18 mo in 2008/09 and in age-groups < 24 mo in 2009/10–2010/11. In the WFS an IR-reduction was observed only in age-groups < 12 mo in 2008/09 and in age-groups < 18 mo in 2009/10–2010/11. Overall IR-reduction in age-groups < 24 mo comparing 2008–11 with 2004–06 was 36% and 25% in EFS and WFS, respectively. In addition, we computed IR-ratios (IRR) in the seasons after mid-2006 with negative binomial regression. The effect of vaccination was independent from the geographic region. Vaccination was associated with a significant reduction in RV-related hospitalizations in the age-groups 6–23 mo. Most prominently, vaccination of 50% of infants led to an estimated decrease in age group 6–11 mo by 42%. No significant reduction was observed in age-groups ≥ 24 mo. In conclusion, in the German setting with low to moderate vaccine uptake, RV-related hospitalization incidence decreased substantially depending on the achieved vaccination coverage, but only in the first two years of life. PMID:22960495
Zaman, K; Yunus, M; El Arifeen, Shams; Azim, Tasnim; Faruque, A S G; Huq, Ehsanul; Hossain, Ilias; Luby, Stephen P; Victor, John C; Dallas, Michael J; Lewis, Kristen D C; Rivers, Stephen B; Steele, A Duncan; Neuzil, Kathleen M; Ciarlet, Max; Sack, David A
An efficacy clinical trial with pentavalent rotavirus vaccine (PRV), RotaTeq(®), was conducted at Matlab field site of ICDDR,B, Bangladesh from March 2007 to March 2009. The methodology, including operation logistics, and lessons-learned are described in this report. Vaccination was organized at 41 fixed-site clinics twice/month. A total of 1136 infants were randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6-, 10-, and 14-weeks of age with routine vaccines of the Expanded Programme on Immunization (EPI) schedule. Twelve field-workers routinely visited study participants for safety and efficacy follow-up. The study was conducted following good clinical practices and maintaining cold-chain requirements. There were no temperature deviations of clinical vaccine supplies. Data entry was done using the source documents to a central database developed by the sponsor which was linked to web. Among enrolled infants, 1128 (99.3%) received 3 doses of PRV/placebo and efficacy follow-up was conducted for a median of 554 days. For the evaluation of immunogenicity, blood samples were collected from 150 participants predose 1 and from 147 (98%) of the same participants post dose 3. Stool samples were collected from 778 (99.9%) acute gastroenteritis episodes among children who reported to diarrhoea treatment centres. Thirty-nine serious adverse events, including 6 deaths, occurred among study participants. The efficacy of PRV against severe rotavirus gastroenteritis was 42.7% through the entire follow-up period; serum anti-rotavirus IgA response was 78.1%. Inclement weather, difficult transportation, and movement of study participants were some of the challenges identified. This is the first vaccine trial in rural Bangladesh with online data entry. The study was well accepted in the community and was completed successfully.
Pastor, Ana Ruth; Rodríguez-Limas, William A; Contreras, Martha A; Esquivel, Ernesto; Esquivel-Guadarrama, Fernando; Ramírez, Octavio T; Palomares, Laura A
Viral protein assemblies have shown to be superior immunogens used in commercial vaccines. However, little is known about the effect of protein assembly structure in immunogenicity and the protection conferred by a vaccine. In this work, rotavirus VP6, a polymorphic protein that assembles into nanotubes, icosahedra (dlRLP) or trimers was used to compare the immune response elicited by three different assemblies. VP6 is the most antigenic and abundant rotavirus structural protein. It has been demonstrated that antibodies against VP6 interfere with the replication cycle of rotavirus, making it a vaccine candidate. Groups of mice were immunized with either nanotubes, dlRLP or trimers and the humoral response (IgG and IgA titers) was measured. Immunized mice were challenged with EDIM rotavirus and protection against rotavirus infection, measured as viral shedding, was evaluated. Immunization with nanotubes resulted in the highest IgG titers, followed by immunization with dlRLP. While immunization with one dose of nanotubes was sufficient to reduce viral shedding by 70%, two doses of dlRLP or trimers were required to obtain a similar protection. The results show that the type of assembly of VP6 results in different humoral responses and protection efficacies against challenge with live virus. This information is important for the design of recombinant vaccines in general.
Nelson, E A S; Bresee, J S; Parashar, U D; Widdowson, M-A; Glass, R I
Availability of new rotavirus vaccines has highlighted the need to collect local disease and economic burden data to aid decision makers at global, regional and country level. The World Health Organization and the GAVI Alliance recommended that generic protocols be used and that regional surveillance networks be established to collect these data, thereby helping to fast-track the introduction of these new vaccines into developing countries. Nine countries and regions participated in the first phase of the Asian Rotavirus Surveillance Network (ARSN), which collected data over a 2-year period during 2001-2003. Overall 45% of diarrhoea admissions in the region were positive for rotavirus, which was higher than had been anticipated. Significant rotavirus strain diversity was noted during the surveillance period. Data collection for a second phase of the ARSN commenced in 2004 and included a greater proportion of poorer countries that would in future be eligible for funding support for rotavirus immunization from GAVI. Limited economic evaluations in Asia have demonstrated the potential for new rotavirus vaccines to be cost-effective but more local analyses are required. Despite the ARSN's comprehensive data from a mix of developed and developing countries, Asia has lagged the Americas in terms of the introduction of rotavirus vaccines into National Immunization Programmes (NIPs). Lack on rotavirus vaccine efficacy data in Asia, particularly in poorer populations, will have contributed to this delay. Thus ensuring that all global regions are simultaneously involved in the evaluation of new vaccines from the beginning and also encouraging more regional collaborations of Ministry of Health representatives could help to accelerate the introduction of new vaccines into NIPs.
Desai, Rishi; Oliveira, Lucia Helena de; Parashar, Umesh D; Lopman, Benjamin; Tate, Jacqueline E; Patel, Manish M
Countries in Latin America were among the first to implement routine vaccination against species A rotavirus (RVA). We evaluate data from Latin America on reductions in gastroenteritis and RVA disease burden following the introduction of RVA vaccine. Published literature was reviewed to identify case-control studies of vaccine effectiveness and population-based studies examining longitudinal trends of diarrhoeal disease reduction after RVA vaccine introduction in Latin American countries. RVA vaccine effectiveness and impact on gastroenteritis mortality and hospitalization rates and RVA hospitalization rates are described. Among middle-income Latin American countries with published data (Mexico, Brazil, El Salvador and Panama), RVA vaccine contributed to a gastroenteritis-associated mortality reduction of 22-41%, a gastroenteritis-associated hospitalization reduction of 17-51% and a RVA hospitalization reduction of 59-81% among children younger than five years of age. In Brazil and El Salvador, case-control studies demonstrated that a full RVA vaccination schedule was 76-85% effective against RVA hospitalization; a lower effectiveness of 46% was seen in Nicaragua, the only low-income country with available data. A growing body of literature offers convincing evidence of "real world" vaccine program successes in Latin American settings, which may be expanded as more countries in the region include RVA vaccine in their immunization programs.
Broor, Shobha; Ghosh, Dhrubaa; Mathur, Purva
] was reported from Bangalore. G10P strains also have a high prevalence in calves with diarrhoea, in India. The occurrence of these unusual rotavirus strains which are natural reassortants of human and bovine rotaviruses, suggests that reassortment may be an important mechanism for generation of rotavirus strains of newborns. This is catalyzed by the age old traditions of calves and humans living in the same household and socio-economic conditions in India. The diversity of rotavirus strains and the high prevalence of mixed infections in India are unique features of rotavirus epidemiology in India and emphasizes that vaccines should be formulated against a broad range of strains. Another important aspect is that vaccines in India should also target G9 strains. Since neonates acquiring rotavirus infection are protected against severe diarrhoea, neonatal rotavirus strains can be effective potential vaccine candidates and vaccines based on these neonatal strains are being indigenously developed in India.
Harris, Vanessa C.; Armah, George; Fuentes, Susana; Korpela, Katri E.; Parashar, Umesh; Victor, John C.; Tate, Jacqueline; de Weerth, Carolina; Giaquinto, Carlo; Wiersinga, Willem Joost; Lewis, Kristen D. C.; de Vos, Willem M.
Background. Rotavirus (RV) is the leading cause of diarrhea-related death in children worldwide and 95% of RV-associated deaths occur in Africa and Asia where RV vaccines (RVVs) have lower efficacy. We hypothesize that differences in intestinal microbiome composition correlate with the decreased RVV efficacy observed in poor settings. Methods. We conducted a nested, case-control study comparing prevaccination, fecal microbiome compositions between 6-week old, matched RVV responders and nonresponders in rural Ghana. These infants' microbiomes were then compared with 154 age-matched, healthy Dutch infants' microbiomes, assumed to be RVV responders. Fecal microbiome analysis was performed in all groups using the Human Intestinal Tract Chip. Results. We analyzed findings in 78 Ghanaian infants, including 39 RVV responder and nonresponder pairs. The overall microbiome composition was significantly different between RVV responders and nonresponders (FDR, 0.12), and Ghanaian responders were more similar to Dutch infants than nonresponders (P = .002). RVV response correlated with an increased abundance of Streptococcus bovis and a decreased abundance of the Bacteroidetes phylum in comparisons between both Ghanaian RVV responders and nonresponders (FDR, 0.008 vs 0.003) and Dutch infants and Ghanaian nonresponders (FDR, 0.002 vs 0.009). Conclusions. The intestinal microbiome composition correlates significantly with RVV immunogenicity and may contribute to the diminished RVV immunogenicity observed in developing countries. PMID:27803175
Bucardo, Filemón; Reyes, Yaoska; Svensson, Lennart; Nordgren, Johan
Background Despite significant reduction of rotavirus (RV) infections following implementation of RotaTeq vaccination in Nicaragua, a large burden of patients with diarrhea persists. Methods We conducted a community- and hospital-based study of the burden of RV, norovirus (NV) and sapovirus (SV) infections as cause of sporadic acute gastroenteritis (GE) among 330 children ≤ 5 years of age between September 2009 and October 2010 in two major cities of Nicaragua with a RotaTeq coverage rate of 95%. Results We found that NV, SV and RV infections altogether accounted for 45% of cases of GE. Notably, NV was found in 24% (79/330) of the children, followed by SV (17%, 57/330) and RV (8%, 25/330). The detection rate in the hospital setting was 27%, 15% and 14% for NV, SV and RV respectively, whereas in the community setting the detection rate of RV was < 1%. Among each of the investigated viruses one particular genogroup or genotype was dominant; GII.4 (82%) for NV, GI (46%) for SV and G1P (64%) in RV. These variants were also found in higher proportions in the hospital setting compared to the community setting. The GII.4.2006 Minerva strain circulating globally since 2006 was the most common among genotyped NV in this study, with the GII.4-2010 New Orleans emerging in 2010. Conclusions This study shows that NV has become the leading viral cause of gastroenteritis at hospital and community settings in Nicaragua after implementation of RV vaccination. PMID:24849288
Intellectual property rights and challenges for development of affordable human papillomavirus, rotavirus and pneumococcal vaccines: Patent landscaping and perspectives of developing country vaccine manufacturers.
Chandrasekharan, Subhashini; Amin, Tahir; Kim, Joyce; Furrer, Eliane; Matterson, Anna-Carin; Schwalbe, Nina; Nguyen, Aurélia
The success of Gavi, the Vaccine Alliance depends on the vaccine markets providing appropriate, affordable vaccines at sufficient and reliable quantities. Gavi's current supplier base for new and underutilized vaccines, such as the human papillomavirus (HPV), rotavirus, and the pneumococcal conjugate vaccine is very small. There is growing concern that following globalization of laws on intellectual property rights (IPRs) through trade agreements, IPRs are impeding new manufacturers from entering the market with competing vaccines. This article examines the extent to which IPRs, specifically patents, can create such obstacles, in particular for developing country vaccine manufacturers (DCVMs). Through building patent landscapes in Brazil, China, and India and interviews with manufacturers and experts in the field, we found intense patenting activity for the HPV and pneumococcal vaccines that could potentially delay the entry of new manufacturers. Increased transparency around patenting of vaccine technologies, stricter patentability criteria suited for local development needs and strengthening of IPRs management capabilities where relevant, may help reduce impediments to market entry for new manufacturers and ensure a competitive supplier base for quality vaccines at sustainably low prices.
Commercially available attenuated strains of Mycoplasma gallisepticum (MG) are commonly used within the layer industry to control MG-induced mycoplasmosis. Among these are two live MG vaccines derived from the moderately pathogenic MG “chick F” strain. In the present study, the commercially availa...
Niu, M T; Erwin, D E; Braun, M M
The Vaccine Adverse Event Reporting System (VAERS) is the US passive surveillance system monitoring vaccine safety. A major limitation of VAERS is the lack of denominator data (number of doses of administered vaccine), an element necessary for calculating reporting rates. Empirical Bayesian data mining, a data analysis method, utilizes the number of events reported for each vaccine and statistically screens the database for higher than expected vaccine-event combinations signaling a potential vaccine-associated event. This is the first study of data mining in VAERS designed to test the utility of this method to detect retrospectively a known side effect of vaccination-intussusception following rotavirus (RV) vaccine. From October 1998 to December 1999, 112 cases of intussusception were reported. The data mining method was able to detect a signal for RV-intussusception in February 1999 when only four cases were reported. These results demonstrate the utility of data mining to detect significant vaccine-associated events at early date. Data mining appears to be an efficient and effective computer-based program that may enhance early detection of adverse events in passive surveillance systems.
Becker-Dreps, Sylvia; Paniagua, Margarita; Zambrana, Luis Enrique; Bucardo, Filemon; Hudgens, Michael G.; Weber, David J.; Morgan, Douglas R.; Espinoza, Félix
Nicaragua was the first developing nation to implement universal infant rotavirus immunization with the pentavalent rotavirus vaccine (RV5). Initial studies of vaccine effectiveness in Nicaragua and other developing nations have focused on the prevention of hospitalizations and severe rotavirus diarrhea. However, rotavirus diarrhea is more commonly treated in the primary care setting, with only 1–3% of rotavirus cases receiving hospital care. We measured the prevalence of rotavirus infection in primary care clinics in León, Nicaragua, after introduction of the immunization program. In the post-vaccine period, 3.5% (95% confidence interval = 1.9–5.8) of children seeking care for diarrhea tested positive for rotavirus. A high diversity of rotavirus genotypes was encountered among the few positive samples. In conclusion, rotavirus was an uncommon cause of childhood diarrhea in this primary care setting after implementation of a rotavirus immunization program. PMID:22049057
Martinelli, D; Fortunato, F; Cappelli, M G; Gallone, M S; Tafuri, S; Prato, R
Recommendations for vaccination against rotavirus (RV) were issued in Apulia in 2006; the vaccine was free of charge to children who entered day care or nursery school by 1 year of age or those affected by chronic diseases for which diarrhea caused by rotavirus can increase the risk of complications and hospitalization. In 2014, vaccination became available to all healthy children with only a copayment. However, there has not been a significant increase in vaccination coverage. On April 17, 2015, Apulian public health physicians and paediatricians met to share strategies to promote the RV vaccine indications provided in the regional immunization schedule. During the meeting, presentation of data reports were interspersed with discussions that were led with a "bottom-up" approach. The discussants responded to pre-planned questions raised by the participants and encouraged by the discussion.
Wang, Shifeng; Curtiss, Roy
Streptococcus pneumoniae still causes severe morbidity and mortality worldwide, especially in young children and the elderly. Much effort has been dedicated to developing protein-based universal vaccines to conquer the current shortcomings of capsular vaccines and capsular conjugate vaccines, such as serotype replacement, limited coverage and high costs. A recombinant live vector vaccine delivering protective antigens is a promising way to achieve this goal. In this review, we discuss the researches using live recombinant vaccines, mainly live attenuated Salmonella and lactic acid bacteria, to deliver pneumococcal antigens. We also discuss both the limitations and the future of these vaccines. PMID:25309747
Borges, Ana Maria Tavares; Dias e Souza, Menira; Fiaccadori, Fabíola Souza; Cardoso, Divina das Dores de Paula
The epidemiological features of rotavirus A (RVA) infection differ between children from developing and developed countries which could result in differences in vaccine efficacy around the world. To evaluate the impact of Rotarix™ on RVA prevalence, we monitored RVA genotypes circulating in Goiânia by monitoring virus in faecal samples from children that had or had not been previously vaccinated. From February-November of 2008, 220 faecal samples were collected from children in seven day-care centres. RVA detection was performed by two methodologies and the results were confirmed by polyacrylamide gel electrophoresis. From the 220 samples, eight were RVA-positive (3.6%) and five were from children that had received either one or two doses of the vaccine. All positive samples were collected from children with diarrhoea during August and September. Genotyping of the RVA characterised five of the viral samples as genotype G2P and one as G8P, suggesting that G2P was the predominant circulating genotype in Goiânia during the study. The fact that vaccinated children were also infected by RVA suggests that the vaccine does not fully protect against infection by the G2[P4] RVA genotype.
da Silva, Adilson José; Zangirolami, Teresa Cristina; Novo-Mansur, Maria Teresa Marques; Giordano, Roberto de Campos; Martins, Elizabeth Angélica Leme
Genetically attenuated microorganisms, pathogens, and some commensal bacteria can be engineered to deliver recombinant heterologous antigens to stimulate the host immune system, while still offering good levels of safety. A key feature of these live vectors is their capacity to stimulate mucosal as well as humoral and/or cellular systemic immunity. This enables the use of different forms of vaccination to prevent pathogen colonization of mucosal tissues, the front door for many infectious agents. Furthermore, delivery of DNA vaccines and immune system stimulatory molecules, such as cytokines, can be achieved using these special carriers, whose adjuvant properties and, sometimes, invasive capacities enhance the immune response. More recently, the unique features and versatility of these vectors have also been exploited to develop anti-cancer vaccines, where tumor-associated antigens, cytokines, and DNA or RNA molecules are delivered. Different strategies and genetic tools are constantly being developed, increasing the antigenic potential of agents delivered by these systems, opening fresh perspectives for the deployment of vehicles for new purposes. Here we summarize the main characteristics of the different types of live bacterial vectors and discuss new applications of these delivery systems in the field of vaccinology. PMID:25763014
Malnutrition levels among vaccinated and unvaccinated children between 2 and 3 years of age following enrollment in a randomized clinical trial with the pentavalent rotavirus vaccine (PRV) in Bangladesh.
Feller, Andrea J; Zaman, K; Lewis, Kristen D C; Hossain, Ilias; Yunus, M; Sack, David A
A double-masked, individually randomized Phase 3 clinical trial to assess the efficacy, safety and immunogenicity of the pentavalent rotavirus vaccine (PRV), RotaTeq™, was conducted in rural Matlab, Bangladesh (NCT00362648). A total of 1136 infants were enrolled and randomized to receive either vaccine or placebo in a 1:1 ratio administered with the standard EPI vaccines at a mean age of approximately 8, 12, and 16 weeks. Weight was collected at four time points (study vaccine doses 1, 2, and 3, and a close-out visit in March 2009 at 15-26 months of age), and birth weight was retrospectively collected from information contained on the mother's health card when available. Approximately one year following trial completion a separate study was conducted to collect anthropometry measurements, including weight and height. These measurements were linked with Phase 3 trial data and a post hoc analysis was conducted to assess the effects of rotavirus vaccination on malnutrition among enrolled children who could be located when they were between 27 and 38 months old. Among the 1033 (91%) children located, and measured, for this analysis height-for-age and weight-for-height Z scores were calculated and compared between vaccine and placebo recipients at the anthropometry follow-up 1-year post-trial, and weight-for-age Z scores were calculated at four trial time points in addition to the anthropometry follow-up. The data indicated that there was no effect of rotavirus vaccination on malnutrition in this population at any of the measured time points. PRV, estimated to have about 43% efficacy against severe rotavirus gastroenteritis in this population, may not reduce the overall burden of diarrheal illness sufficiently among all vaccinees to appreciably measure impact on growth compared with non-vaccinees. Regardless of the impact on malnutrition indicators, rotavirus vaccines are an important intervention for reducing morbidity and mortality in children in developing
Dennehy, Penelope H
Rotavirus infection is the most common cause of severe diarrhea disease in infants and young children worldwide. Vaccination is the only control measure likely to have a significant impact on the incidence of severe disease. Rotavirus vaccines have reduced the burden of disease in the United States and Europe and vaccine programs are being introduced in Asia and Africa where it is hoped that vaccine will have significant impact on severe infection. Long-term monitoring and strain surveillance are needed to assess the effects of rotavirus immunization programs and to determine whether changes in strain ecology will affect rotavirus vaccine effectiveness.
Nokes, D. James; Abwao, John; Pamba, Allan; Peenze, Ina; Dewar, John; Maghenda, J. Kamino; Gatakaa, Hellen; Bauni, Evasius; Scott, J. Anthony G; Maitland, Kathryn; Williams, Thomas N
Background Rotavirus, predominantly of group A, is a major cause of severe diarrhoea worldwide, with the greatest burden falling on young children living in less-developed countries. Vaccines directed against this virus have shown promise in recent trials, and are undergoing effectiveness evaluation in sub-Saharan Africa. In this region limited childhood data are available on the incidence and clinical characteristics of severe group A rotavirus disease. Advocacy for vaccine intervention and interpretation of effectiveness following implementation will benefit from accurate base-line estimates of the incidence and severity of rotavirus paediatric admissions in relevant populations. The study objective was to accurately define the incidence and severity of group A rotavirus disease in a resource-poor setting necessary to make informed decisions on the need for vaccine prevention. Methods and Findings Between 2002 and 2004 we conducted prospective surveillance for group A rotavirus infection at Kilifi District Hospital in coastal Kenya. Children < 13 y of age were eligible as “cases” if admitted with diarrhoea, and “controls” if admitted without diarrhoea. We calculated the incidence of hospital admission with group A rotavirus using data from a demographic surveillance study of 220,000 people in Kilifi District. Of 15,347 childhood admissions 3,296 (22%) had diarrhoea, 2,039 were tested for group A rotavirus antigen and, of these, 588 (29%) were positive. 372 (63%) rotavirus-positive cases were infants. Of 620 controls 19 (3.1%, 95% confidence interval [CI] 1.9–4.7) were rotavirus positive. The annual incidence (per 100,000 children) of rotavirus-positive admissions was 1,431 (95% CI 1,275–1,600) in infants and 478 (437–521) in under-5-y-olds, and highest proximal to the hospital. Compared to children with rotavirus-negative diarrhoea, rotavirus-positive cases were less likely to have coexisting illnesses and more likely to have acidosis (46% versus 17
Muhsen, Khitam; Rubenstein, Uri; Kassem, Eias; Goren, Sophy; Schachter, Yaakov; Kremer, Adi; Shulman, Lester M; Ephros, Moshe; Cohen, Dani
Universal rotavirus vaccination with RotaTeq was introduced in Israel in December 2010. We examined hospitalization rates of children under 5 years of age due to all-cause and rotavirus gastroenteritis, both before and 3 years after universal introduction of the vaccination. An ongoing hospital-based surveillance network that was established in November 2007, accessed information regarding hospitalization of children due to gastroenteritis (n = 6205) in 3 hospitals in northern Israel, with an annual average of about 60,000 children under 5 years of age living in the catchment area of these hospitals. Stool samples were tested for rotavirus by immunochromatography. Compared to the period preceding implementation of the universal rotavirus vaccination (2008–2010), hospitalizations due to rotavirus gastroenteritis in children <5 years of age decreased significantly, by 55% (95% CI 43%-67%) during the period of universal vaccination (2011–2013), a decrease that was sustained throughout the 3 year period. This reduction was greater in children aged 0–23 months (60–61%) than in toddlers aged 24–59 months (36%). A 32% (95% CI 21%-45%) decrease in the incidence of all-cause gastroenteritis was also observed. During the period preceding universal vaccination, rotavirus diarrhea showed typical winter seasonality, with highest incidence in December. However, the winter peak was substantially blunted during the period of universal immunization. Surveillance of rotavirus gastroenteritis should continue to assess the long-term impact of such a program. Our findings are of relevance to high and middle-income countries considering the introduction of a universal rotavirus immunization program. PMID:26212174
Muhsen, Khitam; Rubenstein, Uri; Kassem, Eias; Goren, Sophy; Schachter, Yaakov; Kremer, Adi; Shulman, Lester M; Ephros, Moshe; Cohen, Dani
Universal rotavirus vaccination with RotaTeq was introduced in Israel in December 2010. We examined hospitalization rates of children under 5 years of age due to all-cause and rotavirus gastroenteritis, both before and 3 years after universal introduction of the vaccination. An ongoing hospital-based surveillance network that was established in November 2007, accessed information regarding hospitalization of children due to gastroenteritis (n = 6205) in 3 hospitals in northern Israel, with an annual average of about 60,000 children under 5 years of age living in the catchment area of these hospitals. Stool samples were tested for rotavirus by immunochromatography. Compared to the period preceding implementation of the universal rotavirus vaccination (2008-2010), hospitalizations due to rotavirus gastroenteritis in children <5 years of age decreased significantly, by 55% (95% CI 43%-67%) during the period of universal vaccination (2011-2013), a decrease that was sustained throughout the 3 year period. This reduction was greater in children aged 0-23 months (60-61%) than in toddlers aged 24-59 months (36%). A 32% (95% CI 21%-45%) decrease in the incidence of all-cause gastroenteritis was also observed. During the period preceding universal vaccination, rotavirus diarrhea showed typical winter seasonality, with highest incidence in December. However, the winter peak was substantially blunted during the period of universal immunization. Surveillance of rotavirus gastroenteritis should continue to assess the long-term impact of such a program. Our findings are of relevance to high and middle-income countries considering the introduction of a universal rotavirus immunization program.
Kandasamy, Sukumar; Chattha, Kuldeep S; Vlasova, Anastasia N; Saif, Linda J
Vitamin A deficiency (VAD) is associated with increased childhood mortality and morbidity in impoverished Asian and African countries, but the impact of VAD on rotavirus (RV) vaccine or infection is poorly understood. We assessed effects of gestational and dietary induced pre- and post-natal VAD and vitamin A supplementation on immune responses to a pentavalent rotavirus vaccine, RotaTeq(®) in a neonatal gnotobiotic pig model. Vaccine efficacy was assessed against virulent G1P human rotavirus (HRV) challenge. VAD and vitamin A sufficient (VAS) piglets were derived from dietary VAD and VAS sows, respectively. VAD piglets had significantly lower levels of hepatic vitamin A compared to that of VAS piglets. RotaTeq(®)-vaccinated VAD piglets had 350-fold higher fecal virus shedding titers compared to vaccinated VAS piglets post-challenge. Only 25% of vaccinated non-vitamin A supplemented VAD piglets were protected against diarrhea compared with 100% protection rate in vaccinated non-supplemented VAS piglets post-challenge. Intestinal HRV specific immune responses were compromised in VAD piglets. Vaccinated VAD piglets had significantly lower ileal HRV IgG antibody secreting cell (ASC) responses (pre-challenge) and duodenal HRV IgA ASC responses (post-challenge) compared to vaccinated VAS piglets. Also, intestinal HRV IgA antibody titers were 11-fold lower in vaccinated VAD compared to vaccinated VAS piglets post-challenge. Persistently elevated levels of IL-8, a pro-inflammatory mediator, and lower IL-10 responses (anti-inflammatory) in vaccinated VAD compared to VAS piglets suggest more severe inflammatory responses in VAD piglets post-challenge. Moreover higher IFN-γ responses pre-challenge were observed in VAD compared to VAS piglets. The impaired vaccine-specific intestinal antibody responses and decreased immunoregulatory cytokine responses coincided with reduced protective efficacy of the RV vaccine against virulent HRV challenge in VAD piglets. In
Gautam, Rashi; Esona, Mathew D; Mijatovic-Rustempasic, Slavica; Ian Tam, Ka; Gentsch, Jon R; Bowen, Michael D
Group A rotaviruses (RVA) are the leading cause of severe diarrhea in young children worldwide. Two live-attenuated RVA vaccines, Rotarix(®) and RotaTeq(®) are recommended by World Health Organization (WHO) for routine immunization of all infants. Rotarix(®) and RotaTeq(®) vaccines have substantially reduced RVA associated mortality but occasionally have been associated with acute gastroenteritis (AGE) cases identified in vaccinees and their contacts. High-throughput assays are needed to monitor the prevalence of vaccine strains in AGE cases and emergence of new vaccine-derived strains following RVA vaccine introduction. In this study, we have developed quantitative real-time RT-PCR (qRT-PCR) assays for detection of Rotarix(®) and RotaTeq(®) vaccine components in stool samples. Real-time RT-PCR assays were designed for vaccine specific targets in the genomes of Rotarix(®) (NSP2, VP4) and RotaTeq(®) (VP6, VP3-WC3, VP3-human) and validated on sequence confirmed stool samples containing vaccine strains, wild-type RVA strains, and RVA-negative stools. For quantification, standard curves were generated using dsRNA transcripts derived from RVA gene segments. Rotarix(®) NSP2 and VP4 qRT-PCR assays exhibited 92-100% sensitivity, 99-100% specificity, 94-105% efficiency, and a limit of detection of 2-3 copies per reaction. RotaTeq(®) VP6, VP3-WC3, and VP3-human qRT-PCR assays displayed 100% sensitivity, 94-100% specificity, 91-102% efficiency and limits of detection of 1 copy, 2 copies, and 140 copies, respectively. These assays permit rapid identification of Rotarix(®) and RotaTeq(®) vaccine components in stool samples from clinical and surveillance studies and will be helpful in determining the frequency of vaccine strain-associated AGE.
Background This study aims to critically review available cost-effectiveness models for rotavirus vaccination, compare their designs using a standardized approach and compare similarities and differences in cost-effectiveness outcomes using a uniform set of input parameters. Methods We identified various models used to estimate the cost-effectiveness of rotavirus vaccination. From these, results using a standardized dataset for four regions in the world could be obtained for three specific applications. Results Despite differences in the approaches and individual constituting elements including costs, QALYs Quality Adjusted Life Years and deaths, cost-effectiveness results of the models were quite similar. Differences between the models on the individual components of cost-effectiveness could be related to some specific features of the respective models. Sensitivity analysis revealed that cost-effectiveness of rotavirus vaccination is highly sensitive to vaccine prices, rotavirus-associated mortality and discount rates, in particular that for QALYs. Conclusions The comparative approach followed here is helpful in understanding the various models selected and will thus benefit (low-income) countries in designing their own cost-effectiveness analyses using new or adapted existing models. Potential users of the models in low and middle income countries need to consider results from existing studies and reviews. There will be a need for contextualization including the use of country specific data inputs. However, given that the underlying biological and epidemiological mechanisms do not change between countries, users are likely to be able to adapt existing model designs rather than developing completely new approaches. Also, the communication established between the individual researchers involved in the three models is helpful in the further development of these individual models. Therefore, we recommend that this kind of comparative study be extended to other areas
Wang, Zhen; Wu, Qingmin
Brucella spp. are facultative intracellular bacteria that cause brucellosis, which is a globally occurring zoonotic disease that is characterized by abortion in domestic animals and undulant fever, arthritis, endocarditis, and meningitis in humans. There are currently no licensed vaccines against brucellosis for human use, and only a few licensed live Brucella vaccines are available for use in animals. However, the available animal vaccines may cause abortion and are associated with lower protection rates in animals and higher virulence in humans. Much research has been performed recently to develop novel Brucella vaccines for the prevention and control of animal brucellosis. This article discusses the approaches and strategies for novel live attenuated vaccine development.
Al-Ayed, Mohammed Saeed Zayed; Asaad, Ahmed Morad; Qureshi, Mohamed Ansar; Hawan, Ali Abdullah
This study aimed to investigate the prevalence of group A rotavirus (RVA) gastroenteritis and the distribution of the RVA genotypes as well as to determine a possible change in the age of occurrence of the RVA infection in the first 2 years after Rotarix® vaccine introduction in Saudi Arabia. This descriptive study included 850 hospitalized children <5 years of age with acute gastroenteritis (AG) between October 2013 and September 2015. Overall, 78 (9.2%) children were positive for RVA during the study period with a positivity rate ranging from 11.3% in the first year of the study to 6.8% in the second year. G1 (47.4%) was the predominant G type, followed by G2 (28.2%) and G9 (10.3%). The most common P type was P (69.2%) followed by P (25.6%). The decrease in the prevalence of G1P from 51% to 37.1% was associated with an increase in the prevalence of G2P from 21.6% to 33.3% during the 2-year study period. This study demonstrated a significant decrease in the prevalence of RVA-AG cases in the first 2-year period after vaccine introduction, especially in the age group between 1 and 12 months, and a reduction in the circulation of G1P. The parallel rise and spread of G2P in post-vaccination period might pose an impact to long-term vaccine efficacy. Continued surveillance studies in different Saudi regions are crucial to document the effectiveness of Rotarix® vaccine and evaluate the potential emergence of rare/novel RVA genotypes. J. Med. Virol. 89:429-434, 2017. © 2016 Wiley Periodicals, Inc.
Yazbak, F Edward; Yazbak, Kathleen
Vaccination of women with live virus vaccines around conception has always been contraindicated by the Center for Disease Control and Prevention (CDC) and the vaccine manufacturer because of potential risks to the fetus. Nevertheless this dangerous practice occurs and is associated with maternal health problems and a very high incidence of early-onset autism in the children. Postpartum vaccination with live virus vaccines has been recommended by the CDC, and described as 'convenient' by the vaccine manufacturer. This 'routine practice' may lead to health and is also associated with many health and obstetrical problems in the recipient, and is frequently associated with autism in both current and future children. Re-vaccination often fails to produce immunity, the very reason for which it was recommended.
Matthijnssens, Jelle; Nuyts, Valerie; Heylen, Elisabeth; De Coster, Sarah; Conceição-Neto, Nádia; Van Ranst, Marc; Matthijnssens, Jelle
The introduction of Rotarix into the Belgian immunization program in June 2006 coincided with an increase of the relative prevalence of G2P strains. However, the genetic composition of these persistent G2P strains has not been investigated. Therefore, we have investigated the NSP4 gene of 89 Belgian G2P strains detected between 1999 and 2013, covering both pre- and post-vaccination periods. The NSP4 genes were divided over seven separate clusters of which six were more closely related to animal than to human strains. The NSP4 genes that clustered more closely to animal DS-1-like strains were isolated after 2004–2005 and were found throughout multiple seasons. Complete genome sequencing of 28 strains identified several other gene segments that clustered more closely to animal than to human DS-1-like strains. These findings suggest that frequent interspecies reassortments may have played a role in the spread of G2P rotaviruses in the post-vaccination period in Belgium. PMID:27841357
Galen, James E.; Curtiss, Roy
Contemporary vaccine development relies less on empirical methods of vaccine construction, and now employs a powerful array of precise engineering strategies to construct immunogenic live vaccines. In this review, we will survey various engineering techniques used to create attenuated vaccines, with an emphasis on recent advances and insights. We will further explore the adaptation of attenuated strains to create multivalent vaccine platforms for immunization against multiple unrelated pathogens. These carrier vaccines are engineered to deliver sufficient levels of protective antigens to appropriate lymphoid inductive sites to elicit both carrier-specific and foreign antigen-specific immunity. Although many of these technologies were originally developed for use in Salmonella vaccines, application of the essential logic of these approaches will be extended to development of other enteric vaccines where possible. A central theme driving our discussion will stress that the ultimate success of an engineered vaccine rests on achieving the proper balance between attenuation and immunogenicity. Achieving this balance will avoid over-activation of inflammatory responses, which results in unacceptable reactogenicity, but will retain sufficient metabolic fitness to enable the live vaccine to reach deep tissue inductive sites and trigger protective immunity. The breadth of examples presented herein will clearly demonstrate that genetic engineering offers the potential for rapidly propelling vaccine development forward into novel applications and therapies which will significantly expand the role of vaccines in public health. PMID:24370705
Galen, James E; Curtiss, Roy
Contemporary vaccine development relies less on empirical methods of vaccine construction, and now employs a powerful array of precise engineering strategies to construct immunogenic live vaccines. In this review, we will survey various engineering techniques used to create attenuated vaccines, with an emphasis on recent advances and insights. We will further explore the adaptation of attenuated strains to create multivalent vaccine platforms for immunization against multiple unrelated pathogens. These carrier vaccines are engineered to deliver sufficient levels of protective antigens to appropriate lymphoid inductive sites to elicit both carrier-specific and foreign antigen-specific immunity. Although many of these technologies were originally developed for use in Salmonella vaccines, application of the essential logic of these approaches will be extended to development of other enteric vaccines where possible. A central theme driving our discussion will stress that the ultimate success of an engineered vaccine rests on achieving the proper balance between attenuation and immunogenicity. Achieving this balance will avoid over-activation of inflammatory responses, which results in unacceptable reactogenicity, but will retain sufficient metabolic fitness to enable the live vaccine to reach deep tissue inductive sites and trigger protective immunity. The breadth of examples presented herein will clearly demonstrate that genetic engineering offers the potential for rapidly propelling vaccine development forward into novel applications and therapies which will significantly expand the role of vaccines in public health.
Lactobacilli and Bifidobacteria enhance mucosal B cell responses and differentially modulate systemic antibody responses to an oral human rotavirus vaccine in a neonatal gnotobiotic pig disease model.
Kandasamy, Sukumar; Chattha, Kuldeep S; Vlasova, Anastasia N; Rajashekara, Gireesh; Saif, Linda J
B cells play a key role in generation of protective immunity against rotavirus infection, a major cause of gastroenteritis in children. Current RV vaccines are less effective in developing countries compared to developed countries. Commensals/probiotics influence mucosal immunity, but the role of early gut colonizing bacteria in modulating intestinal B cell responses to RV vaccines is largely unknown. We co-colonized neonatal gnotobiotic pigs, the only animal model susceptible to HRV diarrhea, with 2 dominant bacterial species present in the gut of breastfed infants, Lactobacillus rhamnosus strain GG and Bifidobacterium animalis lactis Bb12 to evaluate their impact on B cell responses to an attenuated (Att) human rotavirus (HRV) Wa strain vaccine. Following HRV challenge, probiotic-colonized, AttHRV vaccinated piglets had significantly lower fecal scores and reduced HRV shedding titers compared to uncolonized, AttHRV vaccinated pigs. The reduction in HRV diarrhea was significantly correlated with higher intestinal IgA HRV antibody titers and intestinal HRV-specific IgA antibody secreting cell (ASC) numbers in probiotic-colonized, AttHRV vaccinated pigs compared to uncolonized, vaccinated pigs. The significantly higher small intestinal HRV IgA antibody responses coincided with higher IL-6, IL-10 and APRIL responses of ileal mononuclear cells (MNCs) and the immunomodulatory effects of probiotics genomic DNA on TGF-β and IL-10 responses. However, serum RV IgG antibody titers and total IgG titers were significantly lower in probiotic-colonized, AttHRV vaccinated pigs compared to uncolonized, vaccinated pigs, both pre- and post-challenge. In summary, LGG and Bb12 beneficially modulated intestinal B cell responses to HRV vaccine.
Kandasamy, Sukumar; Chattha, Kuldeep S; Vlasova, Anastasia N; Rajashekara, Gireesh; Saif, Linda J
B cells play a key role in generation of protective immunity against rotavirus infection, a major cause of gastroenteritis in children. Current RV vaccines are less effective in developing countries compared to developed countries. Commensals/probiotics influence mucosal immunity, but the role of early gut colonizing bacteria in modulating intestinal B cell responses to RV vaccines is largely unknown. We co-colonized neonatal gnotobiotic pigs, the only animal model susceptible to HRV diarrhea, with 2 dominant bacterial species present in the gut of breastfed infants, Lactobacillus rhamnosus strain GG and Bifidobacterium animalis lactis Bb12 to evaluate their impact on B cell responses to an attenuated (Att) human rotavirus (HRV) Wa strain vaccine. Following HRV challenge, probiotic-colonized, AttHRV vaccinated piglets had significantly lower fecal scores and reduced HRV shedding titers compared to uncolonized, AttHRV vaccinated pigs. The reduction in HRV diarrhea was significantly correlated with higher intestinal IgA HRV antibody titers and intestinal HRV-specific IgA antibody secreting cell (ASC) numbers in probiotic-colonized, AttHRV vaccinated pigs compared to uncolonized, vaccinated pigs. The significantly higher small intestinal HRV IgA antibody responses coincided with higher IL-6, IL-10 and APRIL responses of ileal mononuclear cells (MNCs) and the immunomodulatory effects of probiotics genomic DNA on TGF-β and IL-10 responses. However, serum RV IgG antibody titers and total IgG titers were significantly lower in probiotic-colonized, AttHRV vaccinated pigs compared to uncolonized, vaccinated pigs, both pre- and post-challenge. In summary, LGG and Bb12 beneficially modulated intestinal B cell responses to HRV vaccine. PMID:25483333
... diphtheria, mumps, measles, pertussis (whooping cough), meningitis, and polio. Many of these infections can cause serious or ... MMR - vaccine Pneumococcal conjugate vaccine Pneumococcal polysaccharide ... (vaccine) Rotavirus vaccine Tdap vaccine Tetanus - vaccine
Tretyakova, Irina; Lukashevich, Igor S; Glass, Pamela; Wang, Eryu; Weaver, Scott; Pushko, Peter
DNA vaccines combine remarkable genetic and chemical stability with proven safety and efficacy in animal models, while remaining less immunogenic in humans. In contrast, live-attenuated vaccines have the advantage of inducing rapid, robust, long-term immunity after a single-dose vaccination. Here we describe novel iDNA vaccine technology that is based on an infectious DNA platform and combines advantages of DNA and live attenuated vaccines. We applied this technology for vaccination against infection with Venezuelan equine encephalitis virus (VEEV), an alphavirus from the Togaviridae family. The iDNA vaccine is based on transcription of the full-length genomic RNA of the TC-83 live-attenuated virus from plasmid DNA in vivo. The in vivo-generated viral RNA initiates limited replication of the vaccine virus, which in turn leads to efficient immunization. This technology allows the plasmid DNA to launch a live-attenuated vaccine in vitro or in vivo. Less than 10 ng of pTC83 iDNA encoding the full-length genomic RNA of the TC-83 vaccine strain initiated replication of the vaccine virus in vitro. In order to evaluate this approach in vivo, BALB/c mice were vaccinated with a single dose of pTC83 iDNA. After vaccination, all mice seroconverted with no adverse reactions. Four weeks after immunization, animals were challenged with the lethal epidemic strain of VEEV. All iDNA-vaccinated mice were protected from fatal disease, while all unvaccinated controls succumbed to infection and died. To our knowledge, this is the first example of launching a clinical live-attenuated vaccine from recombinant plasmid DNA in vivo.
Sá, Ana Caroline C; Gómez, Mariela M; Lima, Ila Fernanda N; Quetz, Josiane S; Havt, Alexandre; Oriá, Reinaldo B; Lima, Aldo A; Leite, José Paulo G
Group A rotaviruses (RVA) and noroviruses (NoV) are the leading cause of acute gastroenteritis (AGE) worldwide. Childhood diarrhea deaths and hospital admissions have declined since the introduction of the monovalent (G1P) vaccine (Rotarix(®) [RV1]) in the National Immunization Program in Brazil in 2006. This study aims to investigate the epidemiological profile of NoV and RVA infections from children with AGE in the Northeastern region of Brazil in the post vaccine season. Two-hundred fecal samples collected from children up to 10 years old in Fortaleza, Ceará between 2008-2009 were screened for the presence of RVA and NoV. Positive samples were genotyped and sequenced. The RVA screening revealed 12% prevalence and all RVA strains belonged to G2P genotype. Phylogenetic analysis based on the 11 RVA genome segments sequenced from eight samples revealed a DS-1-like genotype constellation: I2-R2-C2-M2-A2-N2-T2-E2-H2. For NoV screening, the prevalence observed was 17% and the following genotypes were detected: GII.4 (59%), GII.12 (17%), GII.6 (9%), GII.3 (6%), and GII.? (9%). At least four different NoVs genotypes and two RVA G2P variants were identified circulating in the Northeastern region of Brazil. RVA phylogenetic analysis suggests that the RVA G2P strains might have originated from intragenogroup reassortment events. Whether the genetic modifications observed in these contemporary G2P RVA strains may impact the long-term effectiveness of the current vaccination programs remains to be explored. These data reinforce the importance of surveillance for monitoring the emergence of new strains of RVA and NoV and their impact on cases of acute gastroenteritis.
Terpstra, C; Kroese, A H
This paper reviews various aspects of efficacy, and methods for assaying the potency of modified live viral vaccines. The pros and cons of parametric versus non-parametric methods for analysis of potency assays are discussed and critical levels of protection, as determined by the target(s) of vaccination, are exemplified. Recommendations are presented for designing potency assays on master virus seeds and vaccine batches.
Terpstra, C; Kroese, A H
This paper reviews various aspects of efficacy, and methods for assaying the potency of modified live viral vaccines. The pros and cons of parametric versus non-parametric methods for analysis of potency assays are discussed and critical levels of protection, as determined by the target(s) of vaccination, are exemplified. Recommendations are presented for designing potency assays on master virus seeds and vaccine batches.
Epidemiological trends for hospital admissions for acute rotavirus gastroenteritis in Belgium following the introduction of routine rotavirus vaccination and the subsequent switch from lyophilized to liquid formulation of Rotarix™.
Raes, M; Strens, D; Kleintjens, J; Biundo, E; Morel, T; Vyse, A
This study describes epidemiological trends for acute rotavirus gastroenteritis (RVGE) in Belgium in children aged ⩽5 years during the period June 2007 to May 2014 after the introduction of routine rotavirus (RV) vaccination. This period encompassed the switch from lyophilized to the liquid formulation of Rotarix™ (GlaxoSmithKline, Belgium) in August 2011. Uptake of RV vaccine remained consistently high throughout the study period with Rotarix the brand most often used. RV was present in 9% (1139/12 511) of hospitalized cases with acute gastroenteritis included in the study. Epidemiological trends for hospital admissions for RVGE remained consistent throughout the study period, with no evidence of any change associated with the switch from lyophilized to liquid formulation of Rotarix. This suggests both formulations perform similarly, with the liquid formulation not inferior regarding ability to reduce hospital admissions for acute RVGE in children aged ⩽5 years. A strong seasonal effect was observed with most RVGE occurring in the winter months but with some variability in intensity, with highest incidence found in those aged 6-24 months. The main observation was the decreased number of hospital admissions for RVGE in Belgium that occurred during winter 2013/2014.
Xu, Zhi-Yi; Wang, Xuan-Yi
Two live, attenuated hepatitis A vaccines, H 2 and LA-1 virus strains, were developed through serial passages of the viruses in cell cultures at 32 °C and 35 °C respectively. Both vaccines were safe and immunogenic, providing protection against clinical hepatitis A in 95% of the vaccinees, with a single dose by subcutaneous injection. The vaccine recipients were not protected from asymptomatic, subclinical hepatitis A virus (HAV) infection, which induced a similar antibody response as for unvaccinated subjects. A second dose caused anamnestic response and can be used for boosting. Oral immunization of human with H 2 vaccine or of marmoset with LA-1 vaccine failed, and no evidence was found for person-to-person transmission of the H 2 strain or for marmoset-to-marmoset transmission of LA-1 strain, by close contact. H 2 strain was genetically stable when passaged in marmosets, humans or cell cultures at 37 °C; 3 consecutive passages of the virus in marmosets did not cause virulence mutation. The live vaccines offer the benefits of low cost, single dose injection, long- term protection, and increased duration of immunity through subclinical infection. Improved sanitation and administration of 150 million doses of the live vaccines to children had led to a 90% reduction in the annual national incidence rate of hepatitis A in China during the 16-year period, from 1991 to 2006. Hepatitis A immunization with both live and inactivated HA vaccines was implemented in the national routine childhood immunization program in 2008 and around 92% of the 16 million annual births received the affordable live, attenuated vaccines at 18 months of age. Near elimination of the disease was achieved in China for 14 years following introduction of the H 2 live vaccine into the Expanded Immunization Program (EPI) in 1992.
In 2001, in anticipation of rotavirus vaccine licensure and introduction, the World Health Organization (WHO) and partners established regional laboratory surveillance networks for rotavirus detection and strain type monitoring among hospitalized children aged <5 years. In 2006, two WHO-prequalified oral rotavirus vaccines were licensed: a 2-dose, single-strain vaccine (Rotarix, GlaxoSmithKline Biologicals) and a 3-dose, multistrain vaccine (RotaTeq, Merck). Both vaccines provide protection against a range of rotavirus strain types, generally classified as G and P types based on specific viral proteins. Based on results of clinical trial data, disease burden data from surveillance networks, and findings from vaccine impact studies, WHO recommends that all countries include rotavirus vaccination in national immunization programs. Vaccination is recommended to help reduce the morbidity and mortality associated with rotavirus, a leading cause of diarrhea in children aged <5 years that was responsible for approximately 450,000 deaths in 2008. This report describes the expansion of the regional rotavirus laboratory surveillance networks to a global surveillance network, the implementation of data quality assurance measures to ensure quality laboratory data reporting to support rotavirus surveillance activities, and data reporting through the surveillance network. Timely, quality surveillance data can provide baseline estimates of rotavirus disease burden to inform decisions regarding rotavirus vaccine introduction in national immunization programs and can help monitor the impact of vaccine introduction on disease trends.
Rotavirus is a virus that causes gastroenteritis. Symptoms include severe diarrhea, vomiting, fever, and dehydration. Almost all ... the U.S. are likely to be infected with rotavirus before their 5th birthday. Infections happen most often ...
Rocchi, G.; Ragona, G.; Piga, C.; Pelosio, A.; Volpi, A.; Vella, S.; Legniti, N.; de Felici, A.
Immunization procedures with live attenuated and inactivated vaccines were carried out on a group of young recruits at the beginning of an outbreak of infection due to an A/Victoria/3/75-related virus strain, which occurred in February 1977 in a military camp. A retrospective investigation on protection from clinical influenza was then performed in order to investigate whether immunization with live virus vaccines, administered at the beginning of an epidemic, could provide early protection from the disease. In the course of the two weeks following vaccination, laboratory-confirmed clinical influenza cases occurred in 4 subjects among the 110 volunteers of the control group which received placebo, and in 8, 7 and 4 subjects respectively of the 3 groups of about 125 individuals, each of which received one of the following vaccine preparations: (a), live attenuated A/Victoria/3/75 influenza virus oral vaccine, grown on chick embryo kidney culture; (b), live attenuated nasal vaccine, a recombinant of A/Puerto Rico/8/34 with A/Victoria/3/75 virus; and (c), inactivated A/Victoria/3/75 virus intramuscular vaccine. These data do not support the hypothesis that, during an epidemic of infection, early protection from clinical influenza can be achieved through immunization with live attenuated or inactivated influenza virus vaccines, in spite of the high immunizing capability of the vaccine preparations. PMID:512351
Immunogenicity, reactogenicity and safety of the human rotavirus vaccine RIX4414 (Rotarix™) oral suspension (liquid formulation) when co-administered with expanded program on immunization (EPI) vaccines in Vietnam and the Philippines in 2006-2007.
Anh, D D; Carlos, C C; Thiem, D V; Hutagalung, Y; Gatchalian, S; Bock, H L; Smolenov, I; Suryakiran, P V; Han, H H
Evaluation of immunogenicity and safety of a 2-dose liquid formulation of human rotavirus vaccine, RIX4414 following WHO's Expanded Program on Immunization (EPI) schedule (0, 1, and 2 months; Month 0 indicates day of enrollment) in Vietnam and the Philippines. Infants aged 6-10 (mean=8.7 ± 1.07 weeks Vietnam) and 5-10 weeks (mean=6.6 ± 1.03 weeks Philippines) received two doses of RIX4414 vaccine (V) and one dose of placebo (PL) or three placebo doses concomitantly with commercially available diphtheria-tetanus-whole-cell pertussis, hepatitis B and oral poliovirus vaccines. The vaccination schedules were: V-V-PL, V-PL-V and PL-PL-PL (Vietnam); PL-V-V, V-PL-V and PL-PL-PL (Philippines). Anti-rotavirus seroconversion rate was assessed pre-vaccination and post-vaccination (ELISA cut-off=20 U/ml). 375 infants were enrolled in each country. Seroconversion rates at one month post-Dose 2 of RIX4414 were Vietnam 63.3% (95% CI: 54.3-71.6) in V-V-PL group and 81.5% (95% CI: 73.4-88) in V-PL-V group; Philippines 70% (95% CI: 61-78) in PL-V-V group and 59.2% (95% CI: 49.8-68) in V-PL-V group. Frequencies of solicited (8-day post-each dose) and unsolicited symptoms (31-day post-each dose) were similar. Two-doses of rotavirus vaccine administered within the WHO EPI offer flexibility in existing schedule, though both schedules provides good immune responses.
Weise, William J; Hermance, Meghan E; Forrester, Naomi; Adams, A Paige; Langsjoen, Rose; Gorchakov, Rodion; Wang, Eryu; Alcorn, Maria D H; Tsetsarkin, Konstantin; Weaver, Scott C
Mayaro virus (MAYV) is an emerging, mosquito-borne alphavirus that causes a dengue-like illness in many regions of South America, and which has the potential to urbanize. Because no specific treatment or vaccine is available for MAYV infection, we capitalized on an IRES-based approach to develop a live-attenuated MAYV vaccine candidate. Testing in infant, immunocompetent as well as interferon receptor-deficient mice demonstrated a high degree of attenuation, strong induction of neutralizing antibodies, and efficacy against lethal challenge. This vaccine strain was also unable to infect mosquito cells, a major safety feature for a live vaccine derived from a mosquito-borne virus. Further preclinical development of this vaccine candidate is warranted to protect against this important emerging disease.
Weise, William J.; Hermance, Meghan E.; Forrester, Naomi; Adams, A. Paige; Langsjoen, Rose; Gorchakov, Rodion; Wang, Eryu; Alcorn, Maria D. H.; Tsetsarkin, Konstantin; Weaver, Scott C.
Mayaro virus (MAYV) is an emerging, mosquito-borne alphavirus that causes a dengue-like illness in many regions of South America, and which has the potential to urbanize. Because no specific treatment or vaccine is available for MAYV infection, we capitalized on an IRES-based approach to develop a live-attenuated MAYV vaccine candidate. Testing in infant, immunocompetent as well as interferon receptor-deficient mice demonstrated a high degree of attenuation, strong induction of neutralizing antibodies, and efficacy against lethal challenge. This vaccine strain was also unable to infect mosquito cells, a major safety feature for a live vaccine derived from a mosquito-borne virus. Further preclinical development of this vaccine candidate is warranted to protect against this important emerging disease. PMID:25101995
Rosch, Jason W
The pneumococcus is a remarkably adaptable pathogen whose disease manifestations range from mucosal surface infections such as acute otitis media and pneumonia to invasive infections such as sepsis and meningitis. Currently approved vaccines target the polysaccharide capsule, of which there are over 90 distinct serotypes, leading to rapid serotype replacement in vaccinated populations. Substantial progress has been made in the development of a universal pneumococcal vaccine, with efforts focused on broadly conserved and protective protein antigens. An area attracting considerable attention is the potential application of live attenuated vaccines to confer serotype-independent protection against mucosal and systemic infection. On the basis of recent work to understand the mucosal and systemic responses to nasal administration of pneumococci and to develop novel attenuation strategies, the prospect of a practical and protective live vaccine remains promising.
Cuffia, Valeria I; Díaz Ariza, María Del Carmen; Silvera, Alejandro; Sabini, Liliana I; Cordoba, Patricia A
A massive vaccination in Argentina was implemented recently. The antigenic dominants of VP7 in G9 and G1 rotavirus strains, circulating in La Rioja, Argentina with strain vaccines were compared. From 2000 to 2010 in several attention centers of La Rioja, at northwestern Argentina, 418 stool samples from children younger than 5 years old were collected. Ninety were positive by immunochromatography and 51 were genotyped by reverse transcriptase-polymerase chain reaction followed by nested-multiplex polymerase chain reaction (PCR) with type-specific primers. Six G9 strains and four G1 strains were sequenced by MACROGEN Korea. The phylogenetic analysis was conducted in MEGA 6.0. The 940 bp were aligned using CLUSTALW and the tree was inferred using the UPGMA method. The antigenic dominants of VP7, 7-1a, 7-1b, and 7-2 were studied using BioEdit, 7.2.5. In the comparison between G9-lineage III d rotavirus (RV) strains circulating in La Rioja with ROTAVAC vaccine strain, three differences were detected corresponding to 100, 211, and 145 positions. In the comparison between G1-Lineage 1 strains and G1 Rotarix and G1 RotaTeq, three differences were observed in 94, 123, and 217 positions. All these positions were important for the escape to neutralization for study with monoclonal antibody. In conclusion, the differences between the G1 strains in La Rioja, Argentina and the G1 components of the RotaTeq and Rotarix vaccine strains are few, but important for the escape immunologic, and need to be monitored for appropriate evaluation of long-term impact of vaccine used in Argentina. Nevertheless, the VP7 antigenic regions of G9 RV strains circulating in La Rioja and ROTAVAC vaccine strains are different to other zones of Argentina and could play an important role in the failure of vaccine response in these regions and Argentina.
Reis, Thaís Aparecida Vieira; Assis, Andrêssa Silvino Ferreira; do Valle, Daniel Almeida; Barletta, Vívian Honorato; de Carvalho, Iná Pires; Rose, Tatiana Lundgren; Portes, Silvana Augusta Rodrigues; Leite, José Paulo Gagliardi; da Rosa e Silva, Maria Luzia
distribution. These data indicate the significant involvement of HAdV-F type 41 in the etiology of ADD in Minas Gerais, which demonstrates the importance of other viral agents in the development of the disease after the introduction of rotavirus vaccine immunization. PMID:26887251
Aballéa, Samuel; Millier, Aurélie; Quilici, Sibilia; Caroll, Stuart; Petrou, Stavros; Toumi, Mondher
Two licensed vaccines are available to prevent RVGE in infants. A worldwide critical review of economic evaluations of these vaccines was conducted. The objective was to describe differences in methodologies, assumptions and inputs and determine the key factors driving differences in conclusions. 68 economic evaluations were reviewed. RV vaccination was found to be cost-effective in developing countries, while conclusions varied between studies in developed countries. Many studies found that vaccination was likely to be cost-effective under some scenarios, such as lower prices scenarios, inclusion of herd protection, and/or adoption of a societal perspective. Other reasons for variability included uncertainty around healthcare visits incidence and lack of consensus on quality of life (QoL) valuation for infants and caregivers. New evidence on the vaccination effectiveness in real-world, new ways of modeling herd protection and assessments of QoL in children could help more precisely define the conditions under which RV vaccination would be cost-effective in developed countries. PMID:23571226
Tao, J; Zhang, J; Liu, X; Jin, H; Jiang, C; Yin, Y
Rotavirus infection is the most frequent cause of infantile gastroenteritis worldwide and a significant cause of death in infants and young children, following severe diarrhea and dehydration. Rotavirus vaccines are considered the most effective way to prevent rotavirus infections. In the process of developing rotavirus vaccines, it is crucial to establish a reliable and standardized method to determine vaccine titer. In this study, we developed an indirect immunofluorescence assay (IFA) to determine the infectious titer of Lanzhou lamb rotavirus (LLR) vaccine grown in MA104 cells. The activating concentration of trypsin was 1 µg/ml for healthy monolayers of MA104 cells at 100% confluence. After incubation for 18 hr, a rabbit anti-SA11 polyclonal antibody, diluted at 1:800 in PBS, was added to all wells, followed by an Alexa-488-conjugated secondary antibody diluted at 1:500 in PBS. Cells were examined with a fluorescence microscope. Our results show that IFA was more reproducible, more sensitive, simpler, and more rapid than the log 50% cell culture infectious dose-ELISA (lgCCID50-ELISA) in measuring the rotavirus vaccines. IFA provided a reliable basis for the qualitative and quantitative analysis of rotavirus, and the certification of rotavirus vaccine production.
... Old Feeding Your 1- to 2-Year-Old Rotavirus KidsHealth > For Parents > Rotavirus Print A A A ... Call the Doctor en español El rotavirus About Rotavirus Almost all kids have had a rotavirus infection ...
Li, Rong-cheng; Huang, Teng; Li, Yanping; Wang, Lao-Hong; Tao, Junhui; Fu, Botao; Si, Guoai; Nong, Yi; Mo, Zhaojun; Liao, XueYan; Luan, Ivy; Tang, Haiwen; Rathi, Niraj; Karkada, Naveen; Han, Htay Htay
Abstract This study evaluated the immunogenicity of the human rotavirus (RV) vaccine (RIX4414) when co-administered with routine childhood vaccines in Chinese infants (NCT01171963). Healthy infants aged 6–16 weeks received 2 doses of either RIX4414 or placebo according to a 0, 1-month schedule. Infants received routine diphtheria-tetanus-acellular pertussis (DTPa) and oral poliovirus (OPV) vaccines either separately from or concomitantly with RIX4414/placebo (separate and co-administration cohorts, respectively). Anti-RV IgA seroconversion rates (one month post-dose-2) and seropositivity rates (at one year of age) were measured using ELISA. Immune responses against the DTPa and OPV antigens were measured one month post-DTPa dose-3 in the co-administration cohort. Solicited local and general symptoms were recorded for 8-days post-vaccination (total cohort). The according-to-protocol immunogenicity population included 511 infants in the separate cohort and 275 in the co-administration cohort. One month post-RIX4414 dose-2, anti-RV IgA seroconversion rates were 74.7% (95% confidence interval [CI]: 68.9–79.9) and 64.2% (95% CI: 55.4–72.3) in the separate and co-administration cohorts; seropositivity rates at one year of age were 71.5% (95% CI: 65.5–77.1) and 50.0% (95% CI: 40.9–59.1), respectively. One month post-DTPa dose-3, all infants in the co-administration cohort were seroprotected against diphtheria and tetanus, and seropositive for pertussis toxoid, pertactin and filamentous haemaglutinin. Two months post-OPV dose-3, seroprotection rates against anti-poliovirus types 1, 2 and 3 were >99% in the co-administration cohort. Reactogenicity profiles were similar in both cohorts. RIX4414 was immunogenic and well-tolerated in Chinese infants and did not appear to interfere with the immunogenicity and reactogenicity of co-administered routine childhood vaccines. PMID:27149266
CAMPILLO-SAINZ, C; ORNELAS HERNANDEZ, A; DE MUCHA MACIAS, J; NAVA, S E
Campillo-Sainz, C. (Instituto Nacional de Virología de la S.S.A., México, D.F.), A. Ornelas Hernandez, J. de Mucha Macías, and S. E. Nava. Immunization of newborn children with living oral trivalent poliovirus vaccine. J. Bacteriol. 84:446-450. 1962.-The serological response to one dose of living oral trivalent polio-virus vaccine was compared in two groups of children, 49 vaccinated at birth and 44 vaccinated at the age of 4 months. Of those vaccinated at birth, 44 (90%) responded to the vaccine strains of type 1 and type 3 and 30 (61%) to the type 2 strain. Of those vaccinated at 4 months of age; 64% responded to type 1, 52% to type 2, and 82% to type 3. The difference between the responses of the two groups, which for type 1 is significant, may result from the interference of other enteric viruses in the 4-month-old children. A second dose of vaccine, administered to the children vaccinated at birth when they reached the age of 4 months, increased the over-all immunological response to 100% for types 1 and 3 and 96% for type 2, and showed that no immunological tolerance had been developed. The vaccine produced no undesirable effects in any of the children, and no paralytic poliomyelitis occurred among them. The observation of other investigators, that a high titer of maternal antibody inhibits immunological response to vaccination, was confirmed, but breast feeding apparently had no unfavorable effect on response.
Diseases, Bacteriology Division, 425 Porter St, Frederick , MD 21702-5011. Dr Brittingham is the recipient of the National Research Council Fellowship...tularemia vaccine strain) infection by the sera of human recipients of the live tula- remia vaccine. Am J Med Sci 1994;308:83-7. 10. Herzberg VL
Fujii, Yoshiki; Nakagomi, Toyoko; Nishimura, Naoko; Noguchi, Atsuko; Miura, Sinobu; Ito, Hisato; Doan, Yen Hai; Takahashi, Tsutomu; Ozaki, Takao; Katayama, Kazuhiko; Nakagomi, Osamu
Rotavirus is a major cause of severe gastroenteritis in children <5 years of age worldwide, and two, live attenuated rotavirus vaccines are globally available. As rotavirus vaccines are introduced into national immunization programs, there is an increasing need to monitor circulating wild-type strains. However, few studies have systematically examined their full genotype constellation. This study was therefore undertaken to characterize the whole genotype constellation of circulating rotavirus strains in three widely-separated locations in Japan during the 2012 rotavirus season when rotavirus vaccines became available in the country for the first time. Of 107 rotavirus-positive specimens, 50 (46.7%) strains collected from all three locations possessed an unusual G1-P-I2-R2-C2-M2-A2-N2-T2-E2-H2 constellation in which a typical G2P strain appeared to have acquired its two surface protein genes from the most common G1P strain. These G1P double-reassortant strains were shown to possess the 11 genome segments virtually indistinguishable from each other in their nucleotide sequences and phylogenetic lineages except for two strains that underwent further intra-genotype reassortment. Successful spread to and predominance in broad locations across Japan of novel rotavirus strains possessing a genotype constellation that was previously thought not to be preferred suggests unexpected genomic flexibility of the genotype constellation.
... vaccines. 113.300 Section 113.300 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE... REQUIREMENTS Live Virus Vaccines § 113.300 General requirements for live virus vaccines. When prescribed in an applicable Standard Requirement or in the filed Outline of Production, a live virus vaccine shall meet...
... vaccines. 113.300 Section 113.300 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE... REQUIREMENTS Live Virus Vaccines § 113.300 General requirements for live virus vaccines. When prescribed in an applicable Standard Requirement or in the filed Outline of Production, a live virus vaccine shall meet...
... 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...
... 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...
... vaccines. 113.300 Section 113.300 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE... REQUIREMENTS Live Virus Vaccines § 113.300 General requirements for live virus vaccines. When prescribed in an applicable Standard Requirement or in the filed Outline of Production, a live virus vaccine shall meet...
... 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...
... 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...
... 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...
da Silva Medeiros, Thais Neris; Lorenzetti, Elis; Alfieri, Alice Fernandes; Alfieri, Amauri Alcindo
The aim of this study was to perform the molecular characterization of the eleven genes of a G6P bovine group A rotavirus (RVA) strain detected in a diarrhea outbreak from a vaccinated beef cattle herd. The outbreak affected 80 % of calves between 15-30 days old. RVA was identified by RT-PCR in 12 (70.6 %) out of 17 diarrheic fecal samples evaluated. The rotavirus wild-type strain had the genotype constellation G6(IV)-P(IX)-I2c-R2-C2-M2-A3-N2-T6-E2e-H3a. This study confirms the importance of homotypic immunity against the bovine RVA P genotype in neonatal diarrhea in cattle herds that are regularly vaccinated against rotaviruses.
Wen, Ke; Li, Guohua; Bui, Tammy; Liu, Fangning; Li, Yanru; Kocher, Jacob; Lin, Lin; Yang, Xingdong; Yuan, Lijuan
Background Strain-specific effects of probiotics in pro- or anti-inflammatory immune responses have been well recognized. Several proinflammatory Lactobacillus strains have been shown to act as adjuvants to enhance the immunogenicity of vaccines. However, dose effects of probiotics in modulating immune responses are not clearly understood. This study examined the dose effects of Lactobacillus acidophilus (LA) NCFM strain on T cell immune responses to rotavirus vaccination in a gnotobiotic (Gn) pig model. Methods Frequencies of IFN-γ producing CD4+ and CD8+ T cell and IL-10 and TGF-β producing CD4+CD25+ and CD4+CD25- regulatory T (Treg) cell responses were determined in the intestinal and systemic lymphoid tissues of Gn pigs vaccinated with an oral human rotavirus vaccine in conjunction with low dose (5 feedings; up to 106 colony forming units [CFU]/dose) or high dose (14 feedings; up to 109 CFU/dose) or without LA feeding. Results Low dose LA significantly promoted IFN-γ producing T cell responses and down-regulated Treg cell responses and their TGF-β and IL-10 productions in all the tissues compared to the high dose LA and control groups. To the contrary, high dose LA increased the frequencies of Treg cells in most of the tissues compared to the control groups. The dose effects of LA on IFN-γ producing T cell and CD4+CD25- Treg cell immune responses were similar in the intestinal and systemic lymphoid tissues and were independent from the vaccination. Conclusion Thus the same probiotic strain in different doses can either promote or suppress IFN-γ producing T cell or Treg cell immune responses. These findings have significant implications in the use of probiotic lactobacilli as immunostimulatory versus immunoregulatory agents. Probiotics can be ineffective or even detrimental if not used at the optimal dosage for the appropriate purposes. PMID:22178726
Zhang, Shunxian; Yin, Jianwen; Yang, Jinhui; Tian, Liguang; Li, Dandi; Zhang, Qing; Chen, Jiaxu; Xu, Wen; Zhou, Xiaonong
Group A rotavirus (RVA) is one of the leading cause of acute diarrhea worldwide, the RVA-related disease burden and the genotypes of RVA is important reference to introduce RVA variance to national immunisation programmes, 1,121 diarrhea cases and 319 healthy controls were recruited from four sentinel hospital outpatient from July 2014 to June 2015. The prevalence of RVA was 244 (21.8%) in gastroenteritis cases and in 12 (3.8%) in healthy controls across all age group (OR = 7.12, 95%CI = 3.93-12.89); the detection rate of RVA in diarrhea patients under 5 years was more higher than in diarrhea cases over 5 years (26.1%, 222/850; 8.1%, 22/271, respectively, P = 0.000). Of 244 RVA strains isolated from acute diarrhea cases, G9 (66.4%) was predominant G genotype, followed by G3 (18.7%), G1 (8.9%), and G1G3 (3.8%); P was the overwhelming prevalence P genotype, followed by P (4.7%); G9P (54.9%) was most common G and P Combination, followed by G3P (17.6%) and G1 (8.6%). The conclusion of the study was important to provide reference for introducing the RVA vaccine to prevent and control RVA-associated disease burden. J. Med. Virol. 89:71-78, 2017. © 2016 Wiley Periodicals, Inc.
Luchs, Adriana; Cilli, Audrey; Morillo, Simone Guadagnucci; Ribeiro, Cibele Daniel; Carmona, Rita de Cassia Compagnoli; Timenetsky, Maria do Carmo Sampaio Tavares
World group A rotavirus (RVA) surveillance data provides useful estimates of the disease burden, however, indigenous population might require special consideration. The aim of this study was to describe the results of G- and P-types from Brazilian native children ≤ 3 years. Furthermore, selected strains have been analyzed for the VP7, VP6, VP4, and NSP4 encoding genes in order to gain insight into genetic variability of Brazilian strains. A total of 149 samples, collected during 2008-2012, were tested for RVA using ELISA and PAGE, following by RT-PCR and sequencing. RVA infection was detected in 8.7% of samples (13/149). Genotype G2P was detected in 2008 and 2010, G8P in 2009, and G3P in 2011. The phylogenetic analysis of the VP7 and VP4 genes grouped the Brazilian G2P and G3P strains within the lineages currently circulating in humans worldwide. However, the phylogenetic analysis of the VP6 and NSP4 from the Brazilian G2P strains, and the VP7 and NSP4 from the Brazilian G3P strains suggest a distant common ancestor with different animal strains (bovine, caprine, and porcine). The epidemiological and genetic information obtained in the present study is expected to provide an updated understanding of RVA genotypes circulating in the native infant population, and to formulate policies for the use of RVA vaccines in indigenous Brazilian people. Moreover, these results highlight the great diversity of human RVA strains circulating in Brazil, and an in-depth surveillance of human and animal RVA will lead to a better understanding of the complex dynamics of RVA evolution.
Protection against dengue virus by non-replicating and live attenuated vaccines used together in a prime boost vaccination strategy Monika Simmons a...Dengue DNA Punfied inacdvared virus Uvc artenuatcd virus Jlnmc boost A new vaccination strategy for dengue virus (DENV) was eval uated in rhesus...region (TDNA) then boosting 2 months l,ltcr with a tetravalent live aucnuated virus (TLAV) vaccine . Both vaccine combinations elicited virus
Stanfield, Brent; Kousoulas, Konstantin Gus
Herpes simplex virus type-1 (HSV-1) and its closely related type-2 (HSV-2) viruses cause important clinical manifestations in humans including acute ocular disease and genital infections. These viruses establish latency in the trigeminal ganglionic and dorsal root neurons, respectively. Both viruses are widespread among humans and can frequently reactivate from latency causing disease. Currently, there are no vaccines available against herpes simplex viral infections. However, a number of promising vaccine approaches are being explored in pre-clinical investigations with few progressing to early phase clinical trials. Consensus research findings suggest that robust humoral and cellular immune responses may partially control the frequency of reactivation episodes and reduce clinical symptoms. Live-attenuated viral vaccines have long been considered as a viable option for generating robust and protective immune responses against viral pathogens. Varicella zoster virus (VZV) belongs to the same alphaherpesvirus subfamily with herpes simplex viruses. A live-attenuated VZV vaccine has been extensively used in a prophylactic and therapeutic approach to combat primary and recurrent VZV infection indicating that a similar vaccine approach may be feasible for HSVs. In this review, we summarize pre-clinical approaches to HSV vaccine development and current efforts to test certain vaccine approaches in human clinical trials. Also, we discuss the potential advantages of using a safe, live-attenuated HSV-1 vaccine strain to protect against both HSV-1 and HSV-2 infections.
Buchholz, Ursula J; Nagashima, Kunio; Murphy, Brian R; Collins, Peter L
Human metapneumovirus (HMPV) was first described in 2001 and has quickly become recognized as an important cause of respiratory tract disease worldwide, especially in the pediatric population. A vaccine against HMPV is required to prevent severe disease associated with infection in infancy. The primary strategy is to develop a live-attenuated virus for intranasal immunization, which is particularly well suited against a respiratory virus. Reverse genetics provides a means of developing highly characterized 'designer' attenuated vaccine candidates. To date, several promising vaccine candidates have been developed, each using a different mode of attenuation. One candidate involves deletion of the G glycoprotein, providing attenuation that is probably based on reduced efficiency of attachment. A second candidate involves deletion of the M2-2 protein, which participates in regulating RNA synthesis and whose deletion has the advantageous property of upregulating transcription and increasing antigen synthesis. A third candidate involves replacing the P protein gene of HMPV with its counterpart from the related avian metapneumovirus, thereby introducing attenuation owing to its chimeric nature and host range restriction. Another live vaccine strategy involves using an attenuated parainfluenza virus as a vector to express HMPV protective antigens, providing a bivalent pediatric vaccine. Additional modifications to provide improved vaccines will also be discussed.
Hansen, L J J; Daoussi, R; Vervaet, C; Remon, J-P; De Beer, T R M
Freeze-drying is the preferred method for stabilizing live, attenuated virus vaccines. After decades of research on several aspects of the process like the stabilization and destabilization mechanisms of the live, attenuated viruses during freeze-drying, the optimal formulation components and process settings are still matter of research. The molecular complexity of live, attenuated viruses, the multiple destabilization pathways and the lack of analytical techniques allowing the measurement of physicochemical changes in the antigen's structure during and after freeze-drying mean that they form a particular lyophilization challenge. The purpose of this review is to overview the available information on the development of the freeze-drying process of live, attenuated virus vaccines, herewith focusing on the freezing and drying stresses the viruses can undergo during processing as well as on the mechanisms and strategies (formulation and process) that are used to stabilize them during freeze-drying.
Mossad, Sherif B
FluMist--a cold-adapted, live-attenuated, trivalent, intranasal influenza virus vaccine approved by the US Food and Drug Administration on June 17, 2003--has been shown to be safe and effective, but its role in the general prevention of influenza is yet to be defined. Intranasal administration is expected to be more acceptable than parenteral, particularly in children, but the potential for the shedding of live virus may pose a risk to anyone with a compromised immune system.
Selle, Martina; Hertlein, Tobias; Oesterreich, Babett; Klemm, Theresa; Kloppot, Peggy; Müller, Elke; Ehricht, Ralf; Stentzel, Sebastian; Bröker, Barbara M; Engelmann, Susanne; Ohlsen, Knut
The pathogen Staphylococcus aureus causes a broad range of severe diseases and is feared for its ability to rapidly develop resistance to antibiotic substances. The increasing number of highly resistant S. aureus infections has accelerated the search for alternative treatment options to close the widening gap in anti-S. aureus therapy. This study analyses the humoral immune response to vaccination of Balb/c mice with sublethal doses of live S. aureus. The elicited antibody pattern in the sera of intravenously and intramuscularly vaccinated mice was determined using of a recently developed protein array. We observed a specific antibody response against a broad set of S. aureus antigens which was stronger following i.v. than i.m. vaccination. Intravenous but not intramuscular vaccination protected mice against an intramuscular challenge infection with a high bacterial dose. Vaccine protection was correlated with the strength of the anti-S. aureus antibody response. This study identified novel vaccine candidates by using protein microarrays as an effective tool and showed that successful vaccination against S. aureus relies on the optimal route of administration.
Selle, Martina; Hertlein, Tobias; Oesterreich, Babett; Klemm, Theresa; Kloppot, Peggy; Müller, Elke; Ehricht, Ralf; Stentzel, Sebastian; Bröker, Barbara M.; Engelmann, Susanne; Ohlsen, Knut
The pathogen Staphylococcus aureus causes a broad range of severe diseases and is feared for its ability to rapidly develop resistance to antibiotic substances. The increasing number of highly resistant S. aureus infections has accelerated the search for alternative treatment options to close the widening gap in anti-S. aureus therapy. This study analyses the humoral immune response to vaccination of Balb/c mice with sublethal doses of live S. aureus. The elicited antibody pattern in the sera of intravenously and intramuscularly vaccinated mice was determined using of a recently developed protein array. We observed a specific antibody response against a broad set of S. aureus antigens which was stronger following i.v. than i.m. vaccination. Intravenous but not intramuscular vaccination protected mice against an intramuscular challenge infection with a high bacterial dose. Vaccine protection was correlated with the strength of the anti-S. aureus antibody response. This study identified novel vaccine candidates by using protein microarrays as an effective tool and showed that successful vaccination against S. aureus relies on the optimal route of administration. PMID:27103319
Wigfall, L T; Bynum, S A; Brandt, H M; Hébert, J R
Cervical cancer risk is increased among women living with HIV (WLH). Human papillomavirus (HPV) vaccination has been shown to be safe and immunogenic among WLH. We examined HPV vaccine awareness and HPV knowledge among WLH. This cross-sectional study collected data from 145 WLH between March 2011 and April 2012. An interviewer-administered survey assessed HPV vaccine awareness and knowledge. Stata/IC 13 was used to perform chi-square tests and multivariate logistic regression analyses. Our sample was 90 % non-Hispanic black and 64 % earned <$10,000/year. Few (38 %) had heard of the HPV vaccine. Half (50 %) knew that HPV caused cervical cancer. HPV vaccine awareness was ten times higher among WLH who knew HPV caused cervical cancer (OR = 10.17; 95 % CI 3.82-27.06). HPV vaccine awareness is low among WLH. Cancer prevention efforts aimed at raising awareness about the HPV vaccine and increasing knowledge about HPV are necessary first steps in reducing cervical cancer disparities among WLH.
Jacobson, Robert M
Rates of reported adverse events are remarkably low. VAERS identifies an adverse event rate approximating 11.4 reports per 100,000 vaccine doses. Approximately 15% of these reports represent SAEs, but less than 2% involve death; in most cases, reviews have shown no causal relation between the events and the vaccine. Across the spectrum of vaccines in use (including those directed against influenza and hepatitis B virus), many claims of adverse events regarding vaccines represent typical reactions to vaccinations. These reactions can be thought of as foreign-body reactions and predominate among the inactivated vaccines. In controlled studies, the adverse event rates that occur with vaccination resemble those that occur with placebo injections. Typical reactions associated with live viral and bacterial vaccines, such as MMR and varicella vaccines, may resemble attenuated forms of the disease for which the vaccine is directed. Other claims against vaccines represent chance-coincidence or misunderstood data; further studies of claims have vindicated the overall safety of the vaccines in most cases. Two documented safety concerns with vaccines, however, have demonstrated that vaccines (like other biologics and pharmacologic) can result in harm (eg, rotavirus and OPV vaccines). The denouement with these vaccines indicates the broad postmarketing data collection and evaluation that extends efforts made with prelicensure study to balance the benefits from vaccination with the risk for harm. Overall, measures including prelicensure study and postlicensure surveillance, such as VAERS, the Vaccine Safety Datalink Project, and the Clinical Immunization Safety Assessment Centers, have resulted in an exceptional safety profile for the vaccines in use.
Hungerford, Daniel; Vivancos, Roberto; Read, Jonathan M; Pitzer, Virginia E; Cunliffe, Nigel; French, Neil; Iturriza-Gómara, Miren
The EuroRotaNet surveillance network has conducted rotavirus genotype surveillance since 2007 in 16 European countries. Using epidemiological and microbiological data from 39,786 genotyped rotavirus-positive specimens collected between September 2007 and August 2013, we assessed genotype distribution and age distribution of rotavirus gastroenteritis (RVGE) cases in and out of peak season in 12 countries which were yet to implement routine rotavirus vaccination. In multinomial multivariate logistic regression, adjusting for year, country and age, the odds of infection caused by genotype-constellation 2 DS-1-like stains (adjusted multinomial odds ratio (aM-OR) = 1.25; 95% confidence interval (CI): 1.13-1.37; p < 0.001), mixed or untypable genotypes (aM-OR = 1.55; 95% CI: 1.40-1.72; p < 0.001) and less common genotypes (aM-OR = 2.11; 95% CI:1.78-2.51; p < 0.001) increased out of season relative to G1P. Age varied significantly between seasons; the proportion of RVGE cases younger than 12 months in the United Kingdom increased from 34% in season to 39% out of season (aM-OR = 1.66; 95% CI: 1.20-2.30), and the proportion five years and older increased from 9% in season to 17% out of season (aM-OR = 2.53; 95% CI: 1.67-3.82). This study provides further understanding of the rotavirus ecology before vaccine introduction, which will help interpret epidemiological changes in countries introducing or expanding rotavirus vaccination programmes.
Information concerning the disease burden of rotavirus, particularly in developing countries, has important implications for the use and for monitoring the impact of rotavirus vaccines. Although rotavirus has been recognized as the most frequent cause of hospitalization in the world, national estimates and specific information about the incidence of hospitalization for rotavirus gastroenteritis are very limited. Consequently, estimates of the incidence of hospitalization among children during the first 2 years of life in Venezuela were determined by extrapolation of data from a community-based study carried out in Caracas.
... bacterial vaccines. 113.64 Section 113.64 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION... STANDARD REQUIREMENTS Live Bacterial Vaccines § 113.64 General requirements for live bacterial vaccines... bacterial vaccine shall meet the requirements in this section. (a) Purity test. Final container samples...
... bacterial vaccines. 113.64 Section 113.64 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION... STANDARD REQUIREMENTS Live Bacterial Vaccines § 113.64 General requirements for live bacterial vaccines... bacterial vaccine shall meet the requirements in this section. (a) Purity test. Final container samples...
... bacterial vaccines. 113.64 Section 113.64 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION... STANDARD REQUIREMENTS Live Bacterial Vaccines § 113.64 General requirements for live bacterial vaccines... bacterial vaccine shall meet the requirements in this section. (a) Purity test. Final container samples...
Seheri, L M; Mwenda, J M; Page, N
The 7th African Rotavirus Symposium was held in Cape Town, South Africa, on the 8th November 2012 as a Satellite Symposium at the First International African Vaccinology Conference. Over 150 delegates participated in this symposium including scientists, clinicians, health officials, policymakers and vaccine manufacturers from across Africa. Key topics discussed included rotavirus surveillance, rotavirus vaccine introduction, post rotavirus vaccine impact analysis and intussusception data and surveillance in Africa. The symposium provided early rotavirus vaccine adopter countries in Africa (South Africa, Ghana and Botswana) an opportunity to share up-to-date information on vaccine introduction, and allowed colleagues to share experiences in establishing routine rotavirus surveillance (Tanzania, Niger and Rwanda). Overall, the symposium highlighted the high burden of rotavirus in Africa, and the need to continue to strengthen efforts in preventing rotavirus diarrhoea in Africa.
Kashirina, O S; Vasil'ev, Iu M
Comparative evaluation of live attenuated and inactivated influenza vaccines based on data from direct comparative studies is necessary for ensuring the most effective and safe vaccination against influenza. Analysis of direct comparative preclinical and clinical studies of inactivated and live cold-adapted (ca) influenza vaccines showed that published data are inconsistent and limited for some population groups. Live ca vaccines may be promising as an alternative or addition to inactivated vaccines especially for mass vaccination against influenza in children as well as in the elderly when combined with inactivated vaccines. Further studies of inactivated and live ca influenza vaccines in direct comparative studies that control the administration route and vaccine strain production as well as development and confirmation of objective criteria of live attenuated influenza vaccine effectiveness evaluation are necessary.
Neumann, Eric J; Grinberg, Alex; Bonistalli, Kathryn N; Mack, Hamish J; Lehrbach, Philip R; Gibson, Nicole
Infection with Erysipelothrix rhusiopathiae has a significant economic impact on pig production systems worldwide. Both inactivated and attenuated vaccines are available to prevent development of clinical signs of swine erysipelas. The ability of a live attenuated E. rhusiopathiae strain to become persistently established in pigs after intranasal exposure and its potential to cause clinical signs consistent with swine erysipelas after being administered directly into the nasopharynx of healthy pigs was evaluated. Five, E. rhusiopathiae-negative pigs were vaccinated by deep intranasal inoculation then followed for 14 days. Nasal swabs were collected daily for 5 days and clinical observations were made daily for 14 days post-vaccination. Nasal swabs were cultured for E. rhusiopathiae with the intent of back-passaging any recovered organisms into subsequent replicates. No organism was recovered from nasal swabs in the first vaccination replicate. A second replicate including 10 pigs was initiated and followed in an identical manner to that described above. Again, no E. rhusiopathiae was recovered from any pigs. No pigs in either replicate showed any signs of clinical swine erysipelas. The live attenuated E. rhusiopathiae strain evaluated in this study did not appear to become persistently established in pigs post-vaccination, did not cause any local or systemic signs consistent with swine erysipelas, and was therefore unlikely to revert to a virulent state when used in a field setting.
Cliquet, Florence; Picard-Meyer, Evelyne; Mojzis, Miroslav; Dirbakova, Zuzana; Muizniece, Zita; Jaceviciene, Ingrida; Mutinelli, Franco; Matulova, Marta; Frolichova, Jitka; Rychlik, Ivan; Celer, Vladimir
Although rabies incidence has fallen sharply over the past decades in Europe, the disease is still present in Eastern Europe. Oral rabies immunization of wild animal rabies has been shown to be the most effective method for the control and elimination of rabies. All rabies vaccines used in Europe are modified live virus vaccines based on the Street Alabama Dufferin (SAD) strain isolated from a naturally-infected dog in 1935. Because of the potential safety risk of a live virus which could revert to virulence, the genetic composition of three commercial attenuated live rabies vaccines was investigated in two independent laboratories using next genome sequencing. This study is the first one reporting on the diversity of variants in oral rabies vaccines as well as the presence of a mix of at least two different variants in all tested batches. The results demonstrate the need for vaccine producers to use new robust methodologies in the context of their routine vaccine quality controls prior to market release. PMID:26509266
Cliquet, Florence; Picard-Meyer, Evelyne; Mojzis, Miroslav; Dirbakova, Zuzana; Muizniece, Zita; Jaceviciene, Ingrida; Mutinelli, Franco; Matulova, Marta; Frolichova, Jitka; Rychlik, Ivan; Celer, Vladimir
Although rabies incidence has fallen sharply over the past decades in Europe, the disease is still present in Eastern Europe. Oral rabies immunization of wild animal rabies has been shown to be the most effective method for the control and elimination of rabies. All rabies vaccines used in Europe are modified live virus vaccines based on the Street Alabama Dufferin (SAD) strain isolated from a naturally-infected dog in 1935. Because of the potential safety risk of a live virus which could revert to virulence, the genetic composition of three commercial attenuated live rabies vaccines was investigated in two independent laboratories using next genome sequencing. This study is the first one reporting on the diversity of variants in oral rabies vaccines as well as the presence of a mix of at least two different variants in all tested batches. The results demonstrate the need for vaccine producers to use new robust methodologies in the context of their routine vaccine quality controls prior to market release.
Roh, J-H; Kang, M; Wei, B; Yoon, R-H; Seo, H-S; Bahng, J-Y; Kwon, J-T; Cha, S-Y; Jang, H-K
The production performance, efficacy, and safety of two types of vaccines for infectious bursal disease virus (IBDV) were compared with in-ovo vaccination of Cobb 500 broiler chickens for gross and microscopic examination of the bursa of Fabricius, bursa/body weight (b/B) ratio, flow cytometry, and serologic response to Newcastle disease virus (NDV) vaccination. One vaccine was a recombinant HVT-IBD vector vaccine (HVT as for herpesvirus of turkeys) and the other was an intermediate plus live IBDV vaccine. A significant difference was detected at 21 d. Eight of 10 chickens that received the IBDV live vaccine had severe bursal lesions and a relatively low b/B ratio of 0.95, and an inhibited NDV vaccine response. On the other hand, the HVT-IBD vector vaccine resulted in mild bursal lesions and a b/B ratio of 1.89. Therefore, the live vaccine had lower safety than that of the HVT-IBD vector vaccine. To determine the protective efficacy, chickens were intraocularly challenged at 24 d. Eight of 10 chickens in the IBDV live vaccination group showed gross and histological lesions characterized by hemorrhage, cyst formation, lymphocytic depletion, and a decreased b/B ratio. In contrast, the HVT-IBD vector vaccinated chickens showed mild gross and histological lesions in three of 10 chickens with a b/B ratio of 1.36, which was similar to that of the unchallenged controls. Vaccinated chickens showed a significant increase in IBDV antibody titers, regardless of the type of vaccine used. In addition, significantly better broiler flock performance was observed with the HVT-IBD vector vaccine compared to that of the live vaccine. Our results revealed that the HVT-IBD vector vaccine could be used as an alternative vaccine to increase efficacy, and to have an improved safety profile compared with the IBDV live vaccine using in-ovo vaccination against the Korean very virulent IBDV in commercial broiler chickens.
Chakrabarti, B K; Maitra, R K; Ma, X Z; Kestler, H W
The recent discovery of long term AIDS nonprogressors who harbor nef-attenuated HIV suggests that a naturally occurring live vaccine for AIDS may already exist. Animal models have shown that a live vaccine for AIDS, attenuated in nef, is the best candidate vaccine. There are considerable risks, real and perceived, with the use of live HIV vaccines. We have introduced a conditional lethal genetic element into HIV-1 and simian immunodeficiency virus (SIV) molecular clones deleted in nef. The antiviral strategy we employed targets both virus replication and the survival of the infected cell. The suicide gene, herpes simplex virus thymidine kinase (tk), was expressed and maintained in HIV over long periods of time. Herpes simplex virus tk confers sensitivity to the antiviral activity of acyclic nucleosides such as ganciclovir (GCV). HIV-tk and SIV-tk replication were sensitive to GCV at subtoxic concentrations, and virus-infected cells were eliminated from tumor cell lines as well as primary cell cultures. We found the HIV-tk virus to be remarkably stable even after being cultured in media containing a low concentration of GCV and then challenged with the higher dose and that while GCV resistant escape mutants did arise, a significant fraction of the virus remained sensitive to GCV. Images Fig. 1 Fig. 5 PMID:8790413
... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Detection of viable bacteria and fungi except in live vaccine. 113.26 Section 113.26 Animals and Animal Products ANIMAL AND PLANT HEALTH... in live vaccine. Each serial and subserial of biological product except live vaccines shall be...
... bacteria and fungi in live vaccines. 113.27 Section 113.27 Animals and Animal Products ANIMAL AND PLANT... bacteria and fungi in live vaccines. Unless otherwise specified by the Administrator or elsewhere exempted in this part, each serial and subserial of live vaccine and each lot of Master Seed Virus and...
... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Detection of viable bacteria and fungi except in live vaccine. 113.26 Section 113.26 Animals and Animal Products ANIMAL AND PLANT HEALTH... in live vaccine. Each serial and subserial of biological product except live vaccines shall be...
... bacteria and fungi in live vaccines. 113.27 Section 113.27 Animals and Animal Products ANIMAL AND PLANT... bacteria and fungi in live vaccines. Unless otherwise specified by the Administrator or elsewhere exempted in this part, each serial and subserial of live vaccine and each lot of Master Seed Virus and...
... bacteria and fungi in live vaccines. 113.27 Section 113.27 Animals and Animal Products ANIMAL AND PLANT... bacteria and fungi in live vaccines. Unless otherwise specified by the Administrator or elsewhere exempted in this part, each serial and subserial of live vaccine and each lot of Master Seed Virus and...
... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Detection of viable bacteria and fungi except in live vaccine. 113.26 Section 113.26 Animals and Animal Products ANIMAL AND PLANT HEALTH... in live vaccine. Each serial and subserial of biological product except live vaccines shall be...
... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Detection of viable bacteria and fungi except in live vaccine. 113.26 Section 113.26 Animals and Animal Products ANIMAL AND PLANT HEALTH... in live vaccine. Each serial and subserial of biological product except live vaccines shall be...
... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Detection of viable bacteria and fungi except in live vaccine. 113.26 Section 113.26 Animals and Animal Products ANIMAL AND PLANT HEALTH... in live vaccine. Each serial and subserial of biological product except live vaccines shall be...
Becker, Pablo D; Hervouet, Catherine; Mason, Gavin M; Kwon, Sung-Yun; Klavinskis, Linda S
A simple dissolvable microneedle array (MA) platform has emerged as a promising technology for vaccine delivery, due to needle-free injection with a formulation that preserves the immunogenicity of live viral vectored vaccines dried in the MA matrix. While recent studies have focused largely on design parameters optimized to induce primary CD8(+) T cell responses, the hallmark of a vaccine is synonymous with engendering long-lasting memory. Here, we address the capacity of dried MA vaccination to programme phenotypic markers indicative of effector/memory CD8(+) T cell subsets and also responsiveness to recall antigen benchmarked against conventional intradermal (ID) injection. We show that despite a slightly lower frequency of dividing T cell receptor transgenic CD8(+) T cells in secondary lymphoid tissue at an early time point, the absolute number of CD8(+) T cells expressing an effector memory (CD62L(-)CD127(+)) and central memory (CD62L(+)CD127(+)) phenotype during peak expansion were comparable after MA and ID vaccination with a recombinant human adenovirus type 5 vector (AdHu5) encoding HIV-1 gag. Similarly, both vaccination routes generated CD8(+) memory T cell subsets detected in draining LNs for at least two years post-vaccination capable of responding to secondary antigen. These data suggest that CD8(+) T cell effector/memory generation and long-term memory is largely unaffected by physical differences in vaccine delivery to the skin via dried MA or ID suspension.
Uchiyama-Nakamura, Fukumi; Sugata-Tsubaki, Aiko; Yamada, Yutaka; Uno, Kenji; Kasahara, Kei; Maeda, Koichi; Konishi, Mitsuru; Mikasa, Keiichi
Abstract The purpose of this study was to examine the efficacy rendered with a single dose of live attenuated measles, rubella, mumps, and varicella containing vaccine. We inoculated healthcare workers (HCWs) with a single dose of vaccine to a disease lacking in antibody titer for those not meeting the criteria of our hospital (measles: <16.0 (IgG enzyme immunoassay (EIA)), rubella: ≤1:32 (hemagglutination-inhibition), mumps: <4.0 (IgG EIA), and varicella: <4.0 (IgG EIA)). At 28–60 days after vaccination, the antibody titer was tested again. We included 48 HCWs. A total of 32, 15, 31, and 10 individuals were inoculated with a single dose of measles-containing, rubella-containing, mumps, or varicella vaccine, respectively, and showed significant antibody elevation (9.2 ± 12.3 to 27.6 ± 215.6, p<0.001; 8 ± 1.2 to 32 ± 65.5, p<0.001; 3.0 ± 1.0 to 13.1 ± 8.6, p<0.05; and 2.6 ± 1.3 to 11.8 ± 8.1, p<0.001, respectively). Major side effects were not observed. In a limited population, a single dose of live attenuated vaccine showed elevation of antibody titer without any severe adverse reactions. However, whether the post-vaccination response rate criteria of our university was fulfilled could not be determined owing to limited sample size. PMID:28352840
Gilbert, Amy; Greenberg, Lauren; Moran, David; Alvarez, Danilo; Alvarado, Marlon; Garcia, Daniel L; Peruski, Leonard
Vampire bat rabies is a public and animal health concern throughout Latin America. As part of an ecological study of vampire bat depredation on cattle in southern Guatemala, we conducted a vaccine seroconversion study among three dairy farms. The main objectives of this cross sectional and cohort study were to understand factors associated with bat bites among cattle, to determine whether unvaccinated cattle had evidence of rabies virus exposure and evaluate whether exposure was related to bat bite prevalence, and to assess whether cattle demonstrate adequate seroconversion to two commercial vaccines used in Guatemala. In 2012, baseline blood samples were collected immediately prior to intramuscular inoculation of cattle with one of two modified live rabies vaccines. Post vaccination blood samples were collected 13 and 393 days later. Sera were tested for rabies virus neutralizing antibodies (rVNA) by the rapid fluorescent focus inhibition test (RFFIT). Across two years of study, 36% (254/702) of inspected cattle presented gross evidence of vampire bat bites. Individual cattle with a bat bite in 2012 were more likely have a bat bite in 2013. Prior to vaccination, 12% (42/350) of cattle sera demonstrated rVNA, but bite status in 2012 was not associated with presence of rVNA. Vaccine brand was the only factor associated with adequate rVNA response of cattle by day 13. However, vaccine brand and rVNA status at day 13 were associated with an adequate rVNA titer on day 393, with animals demonstrating an adequate titer at day 13 more likely to have an adequate titer at day 393. Our findings support stable levels of vampire bat depredation and evidence of rVNA in unvaccinated cattle. Brand of vaccine may be an important consideration impacting adequate rVNA response and long-term maintenance of rVNA in cattle. Further, the results demonstrate that initial response to vaccination is associated with rVNA status over one year following vaccination.
Precioso, Alexander Roberto; Palacios, Ricardo; Thomé, Beatriz; Mondini, Gabriella; Braga, Patrícia; Kalil, Jorge
Butantan Institute is a public Brazilian biomedical research-manufacturer center affiliated to the São Paulo State Secretary of Health. Currently, Butantan is one of the main public producers of vaccines, antivenoms, and antitoxins in Latin America. The partnership between Butantan and the National Institutes of Health (NIH) of the United Sates has been one of the longest and most successful partnerships in the development and manufacturing of new vaccines. Recently, Butantan Institute has developed and manufactured a lyophilized tetravalent live attenuated dengue vaccine with the four dengue viruses attenuated and licensed from the Laboratory of Infectious Diseases at The National Institutes of Allergy and Infectious Diseases (LID/NIAID/NIH). The objective of this paper is to describe the clinical evaluation strategies of a live attenuated tetravalent dengue vaccine (Butantan-DV) developed and manufactured by Butantan Institute. These clinical strategies will be used to evaluate the Butantan-DV Phase III trial to support the Butantan-DV licensure for protection against any symptomatic dengue caused by any serotype in people aged 2 to 59 years.
Minor, Philip D.
Live attenuated vaccines against human viral diseases have been amongst the most successful cost effective interventions in medical history. Smallpox was declared eradicated in 1980; poliomyelitis is nearing global eradication and measles has been controlled in most parts of the world. Vaccines function well for acute diseases such as these but chronic infections such as HIV are more challenging for reasons of both likely safety and probable efficacy. The derivation of the vaccines used has in general not been purely rational except in the sense that it has involved careful clinical trials of candidates and subsequent careful follow up in clinical use; the identification of the candidates is reviewed. - Highlights: • Live vaccines against human diseases caused by viruses have been very successful. • They have been developed by empirical clinical studies and problems identified in later use. • It can be difficult to balance ability to cause disease and ability to immunise for a strain. • There is currently no reliable basis for predicting success from pure virological studies. • Vaccinia, which eradicated smallpox, is the paradigm for all successes and issues.
Gendon, Iu Z
Published data related with comparison studies of safety, efficiency and some other properties of cold-adapted live influenza vaccine (LIV) and of inactivated influenza vaccine (IIV) are analyzed. LIV and IIV do not differ by systemic reactions after administration; however, it is not ruled out that there can be unfavorable reactions in vaccination of persons with allergy to the chicken-embryo proteins as well as in cases of persistence/reversion of cold-adapted strain observed in vaccination of persons with primary impairments of the immune system. There are no convincing data, up to now, on that LIV is superior to IIV in coping with influenza pandemics. The efficiency of LIV and IIV for children aged 3 years and more and for healthy adults is virtually identical. Additional controllable field comparative studies of LIV and IIV efficiency in immunization of elderly persons are needed. Limited data on LIV efficiency for children aged 2 months and more were obtained. The need in a 2-stage vaccination of all age group with the aim of ensuring responses to all 3 LIV components is, certainly, a LIV disadvantage. In case of IIV, the 2-stage vaccination is needed only for persons who were not ill with influenza. The intranasal LIV administration has, from the practical and psychological standpoints, an advantage before the IIV administration by syringe. The ability of LIV to protect from the drift influenza-virus variations could be its advantage before IIV; still, more research is needed to verify it. Transplantable cell lines meeting the WHO requirements could be an optimal substrate for the production of LIV and IIV. Children are the optimal age group for influenza prevention by cold-adapted LIV, whereas, IIV fits better for vaccination of adults and elderly persons.
Live attenuated virus vaccines have shown the greatest potential to protect against simian immunodeficiency virus (SIV) infection, a model for human immunodeficiency virus (HIV). Immunity against the vaccine virus is thought to mediate protection. However, it is shown computationally that the opposite might be true. According to the model, the initial growth of the challenge strain, its peak load, and its potential to be pathogenic is higher if immunity against the vaccine virus is stronger. This is because the initial growth of the challenge strain is mainly determined by virus competition rather than immune suppression. The stronger the immunity against the vaccine strain, the weaker its competitive ability relative to the challenge strain, and the lower the level of protection. If the vaccine virus does protect the host against a challenge, it is because the competitive interactions between the viruses inhibit the initial growth of the challenge strain. According to these arguments, an inverse correlation between the level of attenuation and the level of protection is expected, and this has indeed been observed in experimental data. PMID:18586297
Harrison, J A; Villarreal-Ramos, B; Mastroeni, P; Demarco de Hormaeche, R; Hormaeche, C E
Live attenuated salmonella vaccines generally confer better protection than killed vaccines. The immune responses in BALB/c mice elicited by immunization with a live attenuated Aro Salmonella typhimurium vaccine given orally, intravenously or subcutaneously were compared with those elicited by killed whole-cell vaccines (acetone or heat-treated) given subcutaneously. Live vaccines given by all routes elicited higher interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) responses in spleen cells against an alkali-treated whole-cell salmonella lysate than did killed vaccines. Live and killed vaccines elicited high total antibody levels to smooth lipopolysaccharide (LPS) (enzyme-linked immunosorbent assay), but all live vaccine regimes elicited higher IgG2a, suggesting a Th1 response. Oral and intravenous vaccination with live organisms elicited IgA against smooth LPS which subcutaneous vaccination with live or killed salmonellae failed to evoke. Western blots using rough whole-cell lysates showed that all vaccines elicited a varied anti-protein response; however, all groups immunized with live organisms recognized three unidentified bands of MW 52,000, 46,000 and 18,000 which were consistently absent in groups immunized with killed organisms. The results indicate that immunization with live aroA salmonellae elicited a Th1 type of response, including bystander T-cell help to LPS, and a response to proteins not seen in mice that received killed vaccines. Images Figure 6 PMID:9176117
Guerrero, Carlos A; Acosta, Orlando
Rotaviruses are the single leading cause of life-threatening diarrhea affecting children under 5 years of age. Rotavirus entry into the host cell seems to occur by sequential interactions between virion proteins and various cell surface molecules. The entry mechanisms seem to involve the contribution of cellular molecules having binding, chaperoning and oxido-reducing activities. It appears to be that the receptor usage and tropism of rotaviruses is determined by the species, cell line and rotavirus strain. Rotaviruses have evolved functions which can antagonize the host innate immune response, whereas are able to induce endoplasmic reticulum (ER) stress, oxidative stress and inflammatory signaling. A networking between ER stress, inflammation and oxidative stress is suggested, in which release of calcium from the ER increases the generation of mitochondrial reactive oxygen species (ROS) leading to toxic accumulation of ROS within ER and mitochondria. Sustained ER stress potentially stimulates inflammatory response through unfolded protein response pathways. However, the detailed characterization of the molecular mechanisms underpinning these rotavirus-induced stressful conditions is still lacking. The signaling events triggered by host recognition of virus-associated molecular patterns offers an opportunity for the development of novel therapeutic strategies aimed at interfering with rotavirus infection. The use of N-acetylcysteine, non-steroidal anti-inflammatory drugs and PPARγ agonists to inhibit rotavirus infection opens a new way for treating the rotavirus-induced diarrhea and complementing vaccines. PMID:27175349
Classical Swine Fever, caused by Classical Swine Fever Virus (CSFV), is a highly contagious disease affecting swine worldwide. The two main strategies for disease control are prophylactic vaccination and non-vaccination “stamping out” policies. In a vaccination-to-live strategy, marker vaccines coul...
Flannery, Brendan; Thompson, Mark G.; Gaglani, Manjusha; Jackson, Michael L.; Monto, Arnold S.; Nowalk, Mary Patricia; Talbot, H. Keipp; Treanor, John J.; Belongia, Edward A.; Murthy, Kempapura; Jackson, Lisa A.; Petrie, Joshua G.; Zimmerman, Richard K.; Griffin, Marie R.; McLean, Huong Q.; Fry, Alicia M.
BACKGROUND: Few observational studies have evaluated the relative effectiveness of live attenuated (LAIV) and inactivated (IIV) influenza vaccines against medically attended laboratory-confirmed influenza. METHODS: We analyzed US Influenza Vaccine Effectiveness Network data from participants aged 2 to 17 years during 4 seasons (2010–2011 through 2013–2014) to compare relative effectiveness of LAIV and IIV against influenza-associated illness. Vaccine receipt was confirmed via provider/electronic medical records or immunization registry. We calculated the ratio (odds) of influenza-positive to influenza-negative participants among those age-appropriately vaccinated with either LAIV or IIV for the corresponding season. We examined relative effectiveness of LAIV and IIV by using adjusted odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression. RESULTS: Of 6819 participants aged 2 to 17 years, 2703 were age-appropriately vaccinated with LAIV (n = 637) or IIV (n = 2066). Odds of influenza were similar for LAIV and IIV recipients during 3 seasons (2010–2011 through 2012–2013). In 2013–2014, odds of influenza were significantly higher among LAIV recipients compared with IIV recipients 2 to 8 years old (OR 5.36; 95% CI, 2.37 to 12.13). Participants vaccinated with LAIV or IIV had similar odds of illness associated with influenza A/H3N2 or B. LAIV recipients had greater odds of illness due to influenza A/H1N1pdm09 in 2010–2011 and 2013–2014. CONCLUSIONS: We observed lower effectiveness of LAIV compared with IIV against influenza A/H1N1pdm09 but not A(H3N2) or B among children and adolescents, suggesting poor performance related to the LAIV A/H1N1pdm09 viral construct. PMID:26738884
... Feline Leukemia Vaccine, Live Canarypox Vector AGENCY: Animal and Plant Health Inspection Service, USDA... testing, and then to field test, an unlicensed Feline Leukemia Vaccine, Live Canarypox Vector. The... field testing of this vaccine, examines the potential effects that field testing this veterinary...
Vesikari, Timo; Karvonen, Aino; Borrow, Ray; Kitchin, Nick; Baudin, Martine; Thomas, Stéphane; Fiquet, Anne
RotaTeq (Merck & Co. Inc./Sanofi Pasteur MSD) is a three-dose, oral pentavalent rotavirus vaccine for the immunization of infants from 6 weeks of age for the prevention of rotavirus gastroenteritis. The primary objective of the present trial was to demonstrate that RotaTeq can be coadministered with meningococcal serogroup C conjugate vaccine (MenCC; NeisVac-C; Baxter Healthcare) to healthy infants without impairing the protective immune responses to MenCC. This was an open-label, randomized, comparative study conducted in Finland. The study was designed to assess concomitant versus sequential administration of RotaTeq and MenCC on the immune response to both vaccines. Healthy infants (n = 247), aged 6 to 7 weeks, were recruited. Coadministration of MenCC with RotaTeq was noninferior to sequential administration for the seroprotection rate against meningococcal serogroup C (the proportion of infants with a serum bactericidal antibody titer using baby rabbit complement of ≥8 was 100% in both groups). The other responses to MenCC (titer of ≥1:128, ≥4-fold increase in titer, and geometric mean titers [GMTs]) and the responses to RotaTeq (IgA and SNA response to G1 to G4 and P1A, GMTs, and ≥3-fold increase in titer) were comparable between groups, including a ≥3-fold IgA increase in >96% of the infants in both groups. Concomitant administration of the first doses of MenCC, diphtheria and tetanus toxoids and acellular pertussis vaccine, inactivated poliovirus vaccine, and Haemophilus influenzae type b conjugate vaccine (DTaP-IPV-Hib), and RotaTeq was associated with a higher rate of vomiting and diarrhea than concomitant administration of MenCC and DTaP-IPV-Hib, but that was not observed after the second concomitant administration. The convenience of concomitant administration of RotaTeq and MenCC may, however, outweigh the additive effect of mostly mild adverse events reported after the individual administration of each vaccine. These results support the
Coelingh, Kathleen L; Luke, Catherine J; Jin, Hong; Talaat, Kawsar R
Avian and animal influenza viruses can sporadically transmit to humans, causing outbreaks of varying severity. In some cases, further human-to-human virus transmission does not occur, and the outbreak in humans is limited. In other cases, sustained human-to-human transmission occurs, resulting in worldwide influenza pandemics. Preparation for future pandemics is an important global public health goal. A key objective of preparedness is to gain an understanding of how to design, test, and manufacture effective vaccines that could be stockpiled for use in a pandemic. This review summarizes results of an ongoing collaboration to produce, characterize, and clinically test a library of live attenuated influenza vaccine strains (based on Ann Arbor attenuated Type A strain) containing protective antigens from influenza viruses considered to be of high pandemic potential.
Fumian, Tulio Machado; Leite, José Paulo Gagliardi; Rose, Tatiana Lundgreen; Prado, Tatiana; Miagostovich, Marize Pereira
Rotavirus specie A (RVA) infection is the leading cause of severe acute diarrhea among young children worldwide. To reduce this major RVA health impact, the Rotarix® vaccine (GlaxoSmithKline, Rixensart, Belgium) was introduced in the Brazilian Expanded Immunization Program in March 2006 and became available to the entire birth cohort. The aim of this study was to evaluate the spread of RVA in the environment after the introduction of Rotarix® in Brazil. For this purpose, a Wastewater Treatment Plant (WTP) in Rio de Janeiro was monitored for one year to detect, characterize and discriminate RVA genotypes and identify possible circulation of vaccine strains. Using TaqMan® quantitative PCR (qPCR), RVA was detected in 100% (mean viral loads from 2.40×10(5) to 1.16×10(7) genome copies (GC)/L) of sewage influent samples and 71% (mean viral loads from 1.35×10(3) to 1.64×10(5)GC/L) of sewage effluent samples. The most prevalent RVA genotypes were P, P and G2, based on VP4 and VP7 classification. Direct nucleotide sequencing (NSP4 fragment) and restriction enzyme digestion (NSP3) analysis did not detect RVA vaccine-like strains from the sewage samples. These data on RVA detection, quantification and molecular characterization highlight the importance of environmental monitoring as a tool to study RVA epidemiology in the surrounding human population and may be useful on ongoing vaccine monitoring programs, since sewage may be a good screening option for a rapid and economical overview of the circulating genotypes.
Pant, Neha; Marcotte, Harold; Brüssow, Harald; Svensson, Lennart; Hammarström, Lennart
Background Rotavirus is a worldwide cause of infectious infantile diarrhea that claims over 600,000 lives annually. Recently, two new vaccine candidates have been developed but their efficacy in developing countries, still remains to be proven. Oral delivery of specific immunoglobulins provides passive immunity and is a fast acting treatment for rotavirus diarrhea. Probiotic bacteria have also gained considerable attention lately as treatment for rotavirus diarrhea. Here we report an evaluation of the therapeutic potential of different probiotics and their combination with anti – rotavirus antibodies in a mouse model of rotavirus diarrhea. Results Of the six probiotic bacteria tested, Lactobacillus rhamnosus strain GG had the strongest influence in reducing prevalence, duration and severity of diarrhea and was therefore chosen for combination treatment with immunoglobulins. The combination treatment reduced the diarrhea outcome measures significantly, prevented histopathological changes and reduced the virus load in the intestines. Conclusion The advantages associated with immunoglobulins and probiotics based therapy is that the treatment provides a rapid therapeutic effect and is cost efficient. These components do not require special storage conditions and could potentially complement the rehydration therapy that is currently used. PMID:17900343
Castrucci, G; Ferrari, M; Frigeri, F; Traldi, V; Angelillo, V
This review summarizes the results of a study on rotaviruses isolated from calves affected by neonatal diarrhea. The results indicated that rotavirus infection is widespread and supported the evidence for an etiologic role of these viruses in neonatal diarrhea. Differences in virulence among bovine rotaviruses appeared also to be confirmed. Conventionally reared calves were fully susceptible to the experimental infection induced by rotaviruses originating from heterologous hosts, i.e. monkeys, pigs and rabbits. When rotavirus strains of bovine, simian and rabbit origin were compared by cross neutralization tests, it was found the simian and porcine strains were indistinguishable and both appeared to relate antigenically to the bovine strain. Finally, it was proven that feeding newborn calves with colostrum and first milk of their dams, previously vaccinated with an inactivated adjuvanted rotavirus vaccine, could prevent the neonatal diarrhea from occurring.
Hoshino, Y; Kapikian, A Z; Chanock, R M
Group A human rotavirus strains D, Wa, DS-1, and P were originally recovered from children with diarrhea. In an attempt to attenuate virulent, wild-type human rotaviruses of major epidemiological importance for use in a live oral vaccine, two reference rotavirus strains, D and DS-1, and two laboratory-generated reassortants, Wa x DS-1 and Wa x P, were subjected to cold adaptation. Collectively, these viruses provide antigenic coverage for both of the clinically important rotavirus VP4 antigens and three of the four important rotavirus VP7 antigens. Mutants of each of these rotaviruses were selected during successive serial passage in primary African green monkey kidney cells at progressively lower suboptimal temperatures (30, 28, and 26 degrees C). The genotype of each mutant appeared to be indistinguishable from that of its wild-type, parental virus. The mutants recovered after 10 serial passages at 30 degrees C exhibited both temperature sensitivity of plaque formation (i.e., a ts phenotype) and the ability to form plaques efficiently at suboptimal temperature (i.e., a cold adaptation [ca] phenotype), in contrast to parental wild-type rotavirus. The succeeding set of 10 serial passages at 28 degrees C selected mutants that exhibited an increased degree of cold adaptation, and three of the mutants exhibited an associated increase in temperature sensitivity. Finally, in the case of three of the strains, the third successive serial passage series, which was performed at 26 degrees C, selected for mutants with an even greater degree of cold adaptation than the previous series and was associated with greater temperature sensitivity in one instance. It appeared that each of the viruses sustained a minimum of four to five mutations during the total selection procedure. The ultimate identification of candidate vaccine viruses that exhibit the desired level of attenuation, immunogenicity, and protective efficacy needed for immunoprophylaxis will require evaluation of
Cunliffe, N. A.; Kilgore, P. E.; Bresee, J. S.; Steele, A. D.; Luo, N.; Hart, C. A.; Glass, R. I.
Rapid progress towards the development of rotavirus vaccines has prompted a reassessment of the disease burden of rotavirus diarrhoea in developing countries and the possible impact of these vaccines in reducing diarrhoeal morbidity and mortality among infants and young children. We examined the epidemiology and disease burden of rotavirus diarrhoea among hospitalized and clinic patients in African countries through a review of 43 published studies of the etiology of diarrhoea. The studies were carried out from 1975 through 1992, and only those in which a sample of more than 100 patients with diarrhoea were specifically screened for rotavirus by using an established diagnostic test were included. Rotavirus was detected in a median of 24% of children hospitalized for diarrhoea and in 23% who were treated as outpatients; 38% of the hospitalized patients with rotavirus were < 6 months and 81% were < 1 year of age. Rotavirus was detected year-round in nearly every country and generally exhibited distinct seasonal peaks during the dry months. In 5 countries where rotavirus strains had been G-typed, 74% of strains were of one of the four common serotypes (G1 to G4), G1 was the predominant serotype, and 26% were non-typeable. This cumulative experience from 15 African countries suggests that rotavirus is the most important cause of severe diarrhoea in African children and that most strains in circulation today belong to common G types that are included in reassortant vaccines. Wherever large numbers of cases of rotavirus diarrhoea occur early in infancy, immunization at birth may protect the children before their first symptomatic infection. PMID:9868844
The avian rotaviruses are members of the Reoviridae family, which is characterized by virions that contain 10-12 linear double-stranded RNA (dsRNA) segments. The Reoviridae consists of 15 genera which can be placed into two recognized subfamilies based upon the presence or absence of structural “tur...
Velázquez, F Raúl
Rotavirus is a ubiquitous infection that is the leading cause of severe diarrhea worldwide. Severe infections are most commonly observed in the first 2 years of life. Rotavirus-induced diarrhea is associated with substantial morbidity and mortality rates and socioeconomic costs with adverse outcomes particularly prevalent in developing countries. The natural history of rotavirus infection can provide guidance for the development and optimization of an effective vaccine. Epidemiologic studies have demonstrated that children who acquire natural rotavirus infections develop immunity to subsequent infections, with the protective effect increasing with each natural infection. Natural infections also decrease the severity of any subsequent rotavirus infections. Notably, asymptomatic infections provide protection similar to that induced by symptomatic infections. Data also suggest that the antibody response to natural infection is heterotypic, and therefore may provide protection against multiple serotypes. These data suggest that the development of a vaccine that produces asymptomatic infection at an optimal time point may provide effective immunity. An effective vaccine should mimic protection provided by natural infection and provide protection against the most common rotavirus serotypes (ie, G1, G2, G3, G4, G9) and be able to decrease disease severity, reduce hospitalizations, and decrease disease-related costs.
West Nile virus has become an important epidemiological problem attracting significant attention of health authorities, mass media, and the public. Although there are promising advancements toward addressing the vaccine need, the perspectives of the commercial availability of the vaccine remain uncertain. To a large extent this is due to lack of a sustained interest for further commercial development of the vaccines already undergoing the preclinical and clinical development, and a predicted insignificant cost effectiveness of mass vaccination. There is a need for a safe, efficacious and cost effective vaccine, which can improve the feasibility of a targeted vaccination program. In the present report, we summarize the background, the rationale, and the choice of the development pathway that we selected for the design of a live attenuated human West Nile vaccine in a novel infectious DNA format.
Cliquet, Florence; Robardet, Emmanuelle; Picard Meyer, Evelyne
In Europe, the main reservoir and vector of rabies has been the red fox (Vulpes vulpes). Oral immunization of foxes with live vaccines, using attenuated rabies strains (SAD B19, SAD Bern), apathogenic mutants of an attenuated strain (SAG2) and the vaccinia-rabies glycoprotein recombinant virus vaccine (V-RG), has been shown to be the most effective method for the control and elimination of rabies. Among all vaccines currently used for wildlife oral vaccination, one vaccine (marketed as SAD Bern strain) has been widely used in Europe since 1992 with the distribution of 17million of baits in 2011. Because of the potential environmental safety risk of a live virus which could revert to virulence, the full genome sequencing of this vaccine was undertaken and the sequence was characterized and compared with those of referenced rabies viruses. The vaccine showed higher similarity to the strains belonging to the SAD B19 vaccine virus strains than to the SAD Bern vaccines. This study is the first one reporting on virus strain identity changes in this attenuated vaccine.
Abstract Q fever and chlamydiosis often affect ovine and caprine flocks simultaneously or successively. Combination vaccines effective against these 2 diseases would be of great value in veterinary medicine. Unfortunately, the current effective vaccines are a live vaccine for chlamydiosis and killed vaccine for Q fever. Vaccination of mice with live chlamydiosis vaccine 1B and killed phase I vaccine against Q fever at 2 points on the back at the same time produced good protection against chlamydial abortion. This suggests that it may be possible to vaccinate ewes and goats against chlamydiosis and Q fever simultaneously. PMID:15352550
Nan, Xiao; Jinyuan, Wu; Yan, Zhou; Maosheng, Sun; Hongjun, Li
under cool, dry conditions. However, the presence of rotavirus in low-latitude provinces likely indicates living habits, living environments, and education level influencethe precautions and vaccine utilization rate. The traditional subtypes are the rotavirus G- and P-subtypes, thus allowing for the development of vaccines. In China, the treatments that are primarily used to combat the infection are integrative medicines combining a variety of nursing and adjuvant therapies. PMID:25668671
Ilyushina, Natalia A.; Haynes, Brenda C.; Hoen, Anne G.; Khalenkov, Alexey M.; Housman, Molly L.; Brown, Eric P.; Ackerman, Margaret E.; Treanor, John J.; Luke, Catherine J.; Subbarao, Kanta; Wright, Peter F.
Background. Live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) are available for children. Local and systemic immunity induced by LAIV followed a month later by LAIV and IIV followed by LAIV were investigated with virus recovery after LAIV doses as surrogates for protection against influenza on natural exposure. Methods. Fifteen children received IIV followed by LAIV, 13 an initial dose of LAIV, and 11 a second dose of LAIV. The studies were done during autumn 2009 and autumn 2010 with the same seasonal vaccine (A/California/07/09 [H1N1], A/Perth/16/09 [H3N2], B/Brisbane/60/08). Results. Twenty-eight of 39 possible influenza viral strains were recovered after the initial dose of LAIV. When LAIV followed IIV, 21 of 45 viral strains were identified. When compared to primary LAIV infection, the decreased frequency of shedding with the IIV-LAIV schedule was significant (P = .023). With LAIV-LAIV, the fewest viral strains were recovered (3/33)—numbers significantly lower (P < .001) than shedding after initial LAIV and after IIV-LAIV (P < .001). Serum hemagglutination inhibition antibody responses were more frequent after IIV than LAIV (P = .02). In contrast, more mucosal immunoglobulin A responses were seen with LAIV. Conclusions. LAIV priming induces greater inhibition of virus recovery on LAIV challenge than IIV priming. The correlate(s) of protection are the subject of ongoing analysis. Clinical Trials Registration. NCT01246999. PMID:25165161
Souriau, A; Bosseray, N; Rodolakis, A; Lantier, F; Plommet, M
Live attenuated vaccines against Chlamydia psittaci var ovis, Brucella melitensis and Salmonella abortus ovis have previously been shown to be compatible in mice by subcutaneous administration. Immunity against challenge with virulent chlamydia was, however, slightly decreased in associations including the B melitensis Rev 1 vaccine. The chlamydia strain 1B vaccine was administered to four- to five-month-old female lambs, either alone or in combination with the B melitensis Rev1 and the S abortus ovis Rv6 vaccines. Clinical, serological and bacteriological observations demonstrated the compatibility of the three vaccines. Control, singly and triply vaccinated ewes were challenged with a virulent strain of chlamydia during their second pregnancy, 15 months after vaccination. Five of the 12 control ewes lambed normally and 10 of them were infected, as shown by the excretion of the challenge chlamydia in genital secretions. Sixteen of the 17 ewes in the triple vaccine group lambed normally and none was infected. All 12 in the single vaccine group lambed normally and three of the 12 were infected. In spite of this unusually poor protection by the single vaccine, antichlamydial immunity was clearly not decreased by the association with the two other vaccines.
Yu, Xing; Mishra, Rahul; Holloway, Gavan; von Itzstein, Mark; Coulson, Barbara S; Blanchard, Helen
Rotavirus-cell binding is the essential first step in rotavirus infection. This binding is a major determinant of rotavirus tropism, as host cell invasion is necessary to initiate infection. Initial rotavirus-cell interactions are mediated by carbohydrate-recognizing domain VP8* of the rotavirus capsid spike protein VP4. Here, we report the first observation of significant structural rearrangement of VP8* from human and animal rotavirus strains upon glycan receptor binding. The structural adaptability of rotavirus VP8* delivers important insights into how human and animal rotaviruses utilize the wider range of cellular glycans identified as VP8* binding partners. Furthermore, our studies on rotaviruses with atypical genetic makeup provide information expected to be critical for understanding the mechanisms of animal rotavirus gene emergence in humans and support implementation of epidemiologic surveillance of animal reservoirs as well as future vaccination schemes.
Ferguson-Noel, N M; Williams, S M
The efficacy of a live Mycoplasma gallisepticum (MG) vaccine candidate (K-strain) was compared to commercially available vaccines in broiler-type chickens (Trial 1) and layer-type chickens (Trial 2). In Trial 1, three-week-old broiler-type chickens were vaccinated via aerosol with K-strain or an F-strain vaccine. The vaccinated chickens and 10 non-vaccinated controls were subsequently challenged with virulent R-strain via aerosol at six weeks post vaccination; both K-strain and F-strain vaccination resulted in significant protection from air sac and tracheal lesions, as well as R-strain colonization (P ≤ 0.05). In Trial 2, commercial layer-type chickens were vaccinated with ts-11 (via eye drop) or K-strain (via aerosol) at 12 weeks of age. At 25 weeks of age these birds were challenged with R-strain via aerosol. The ts-11 and K-strain vaccinated groups both had significantly lower air sac lesion scores and a lower prevalence of ovarian regression after challenge as compared to non-vaccinated chickens (P ≤ 0.05). K-strain vaccination also prevented significant tracheal lesions and R-strain colonization (P ≤ 0.05). K-strain shows great potential as a highly efficacious live MG vaccine in broiler and layer-type chickens for protection of the respiratory and reproductive systems as well as prevention of infection with field strains.
Price, Kayla R; Freeman, Megan; Van-Heerden, Kobus; Barta, John R
Hatching, processing and transportation result in inevitable delays before chicks are placed into brooding and receive their first feed and drinking water after hatching. To determine if delayed access to feed for different durations following live Eimeria vaccination affected initial shedding of vaccine progeny, replacement layer chicks (480, Lohmann-LSL Lite) aged approximately 6h after hatch were administered a commercial live Eimeria vaccine. Vaccinated chicks were divided randomly into groups and were provided access to feed immediately (0 h) or after a delay of 6, 12, or 24 h (4 treatments × 6 replicates per treatment × 20 pullets per replicate). All pullets were provided drinking water immediately following vaccination. Fecal oocysts shed per gram of feces for each cage replicate was determined daily from 4 to 9 days post inoculation. Chicks provided feed immediately had peak oocyst shedding at 5 days post-inoculation but delayed access to feed for 24h was associated with a 2 days delay in peak oocyst shedding to 7 days post-inoculation. Chicks with delays in access to feed of intermediate duration (i.e. 6 or 12h) had peak oocyst shedding at 6 days post-inoculation. Overall oocyst shedding was not affected. Live Eimeria vaccination success may be measured by evaluating initial shedding of oocysts at some pre-established time after vaccine application, usually by a single fecal collection conducted at 5, 6 or 7 days post-inoculation. Recognizing that withholding feed following live Eimeria vaccination shifts the time of the resultant peak oocyst shedding complicates the assessment of vaccine application; if delayed access to feed is not taken into account, it is possible that false conclusions could be drawn regarding the relative success of vaccine administration.
Riedmann, Eva M
Infant rotavirus vaccination provides for herd immunity Nonreplicating sporozoite vaccine protects humans against malaria Personalized brain cancer vaccine enters phase 2 trial Novel implantable therapeutic cancer vaccine to be tested in humans Clostridium difficile vaccine candidate successful in phase 1 CDC reports strong uptake of HPV vaccine in boys Whooping cough outbreak in Texas.
Li, Rong-Cheng; Li, Yan-Ping; Mo, Zhao-Jun; Luo, Dong; Huang, Teng; Kong, Ji-Lian; Wang, Lao-Hong; Song, Ning-Sheng; Liu, Aixue; Zhang, Helen; Liao, Xueyan; Karkada, Naveen; Han, Htay Htay
We report the findings of three randomized, double-blind, placebo-controlled Phase I studies undertaken to support licensure of the liquid formulation of the human G1P rotavirus (RV) vaccine (RIX4414; GlaxoSmithKline Biologicals SA) in China. Healthy adults aged 18-45 y (n=48) and children aged 2-6 y (n=50) received a single dose of the human RV vaccine or placebo. Healthy infants (n=50) aged 6-16 weeks at the time of first vaccination received two oral doses of the human RV vaccine or placebo according to a 0, 1 mo schedule. In infants, blood samples were collected prior to vaccination and one month post-dose 2 to assess anti-RV IgA antibody concentrations using ELISA. Stool samples were collected from all infants on the day of each vaccination, at 7 and 15 d after each vaccination and one month post-dose 2. Stool samples were analyzed by ELISA for detection of RV antigen to assess RV antigen excretion. The reactogenicity profile of the human RV vaccine was found to be comparable to that of placebo in all age groups studied. The anti-RV IgA antibody seroconversion rate in infants after two vaccine doses was 86.7% (95% CI: 59.5-98.3). Vaccine take in infants who received the liquid human RV vaccine was 86.7% (95% CI: 59.5-98.3). A Phase III efficacy study of the human RV vaccine in the infant population in China has now been completed (ROTA-075/NCT01171963).
Estes, M K; Cohen, J
Knowledge of the structure and function of the genes and proteins of the rotaviruses has expanded rapidly. Information obtained in the last 5 years has revealed unexpected and unique molecular properties of rotavirus proteins of general interest to virologists, biochemists, and cell biologists. Rotaviruses share some features of replication with reoviruses, yet antigenic and molecular properties of the outer capsid proteins, VP4 (a protein whose cleavage is required for infectivity, possibly by mediating fusion with the cell membrane) and VP7 (a glycoprotein), show more similarities with those of other viruses such as the orthomyxoviruses, paramyxoviruses, and alphaviruses. Rotavirus morphogenesis is a unique process, during which immature subviral particles bud through the membrane of the endoplasmic reticulum (ER). During this process, transiently enveloped particles form, the outer capsid proteins are assembled onto particles, and mature particles accumulate in the lumen of the ER. Two ER-specific viral glycoproteins are involved in virus maturation, and these glycoproteins have been shown to be useful models for studying protein targeting and retention in the ER and for studying mechanisms of virus budding. New ideas and approaches to understanding how each gene functions to replicate and assemble the segmented viral genome have emerged from knowledge of the primary structure of rotavirus genes and their proteins and from knowledge of the properties of domains on individual proteins. Localization of type-specific and cross-reactive neutralizing epitopes on the outer capsid proteins is becoming increasingly useful in dissecting the protective immune response, including evaluation of vaccine trials, with the practical possibility of enhancing the production of new, more effective vaccines. Finally, future analyses with recently characterized immunologic and gene probes and new animal models can be expected to provide a basic understanding of what regulates the
Dimitrov, D H; Estes, M K; Rangelova, S M; Shindarov, L M; Melnick, J L; Graham, D Y
Antigenically distinct rotaviruses, i.e., viruses morphologically identical to conventional rotaviruses by electron microscopy, yet lacking the common group antigen(s) detected by an enzyme-linked immunosorbent assay, were found in 2 of 51 fecal samples from Bulgarian infants with rotavirus gastroenteritis. These antigenically distinct viruses contained 11 segments of double-stranded RNA, but they demonstrated a unique RNA migration profile after electrophoresis of the genome RNA in polyacrylamide gels. This report confirms the presence of a new group of rotaviruses in humans. The significance of these viruses is currently unknown, and specific diagnostic tests must be developed for epidemiological studies to determine their role as human and veterinary pathogens and to evaluate their impact on proposed vaccine development programs. Images PMID:6307873
Vlasova, Anastasia N.; Kandasamy, Sukumar; Chattha, Kuldeep S.; Rajashekara, Gireesh; Saif, Linda J.
Different probiotic strains of Lactobacillus and Bifidobacterium genera possess significant and widely acknowledged health-promoting and immunomodulatory properties. They also provide an affordable means for prevention and treatment of various infectious, allergic and inflammatory conditions as demonstrated in numerous human and animal studies. Despite the ample evidence of protective effects of these probiotics against rotavirus (RV) infection and disease, the precise immune mechanisms of this protection remain largely undefined, because of limited mechanistic research possible in humans and investigated in the majority of animal models. Additionally, while most human clinical probiotic trials are well-standardized using the same strains, uniform dosages, regimens of the probiotic treatments and similar host age, animal studies often lack standardization, have variable experimental designs, and non-uniform and sometime limited selection of experimental variables or observational parameters. This review presents selected data on different probiotic strains of lactobacilli and bifidobacteria and summarizes the knowledge of their immunomodulatory properties and the associated protection against RV disease in diverse host species including neonates. PMID:26809484
Vlasova, Anastasia N; Kandasamy, Sukumar; Chattha, Kuldeep S; Rajashekara, Gireesh; Saif, Linda J
Different probiotic strains of Lactobacillus and Bifidobacterium genera possess significant and widely acknowledged health-promoting and immunomodulatory properties. They also provide an affordable means for prevention and treatment of various infectious, allergic and inflammatory conditions as demonstrated in numerous human and animal studies. Despite the ample evidence of protective effects of these probiotics against rotavirus (RV) infection and disease, the precise immune mechanisms of this protection remain largely undefined, because of limited mechanistic research possible in humans and investigated in the majority of animal models. Additionally, while most human clinical probiotic trials are well-standardized using the same strains, uniform dosages, regimens of the probiotic treatments and similar host age, animal studies often lack standardization, have variable experimental designs, and non-uniform and sometime limited selection of experimental variables or observational parameters. This review presents selected data on different probiotic strains of lactobacilli and bifidobacteria and summarizes the knowledge of their immunomodulatory properties and the associated protection against RV disease in diverse host species including neonates.
The study evaluated the efficacy of an oral live-attenuated Edwardsiella ictaluri vaccine against enteric septicemia of catfish in 20 full-sib fingerling channel catfish families. Each family was split into vaccinated and non-vaccinated groups. The vaccine was delivered orally by feeding fish diet...
Luchs, Adriana; Cilli, Audrey; Morillo, Simone Guadagnucci; Gregório, Debora de Souza; de Souza, Karen Aparecida Farias; Vieira, Heloísa Rosa; Fernandes, Adeline de Mira; Carmona, Rita de Cássia Compagnoli; Timenetsky, Maria do Carmo Sampaio Tavares
The continuum characterization of rotavirus (RVA) genotypes is essential to understand how vaccine introduction could impact virus epidemiology. In the present study, an unexpected rapid changing pattern of RVA genotypes distribution in Brazilian population during three followed seasons is described. From January/2012 to December/2014, a total of 3441 fecal specimens were collected from collaborating centers across Southern, Southeastern and Midwest of Brazil. All specimens were screened for RVA using ELISA, and genotyped by RT-PCR. Differences in proportions were tested using Chi-Squares. A p-value of less than 0.05 was considered statistically significant. RVA was detected in 19.7% (677/3441). Among RVA positive cases (n=677), a total of 652 (96.3%) samples were successfully amplified by RT-PCR. G3P remained prevalent in 2012 (37.6%, 69/185) and 2013 (40.1%, 74/186) (χ(2)=0.107, p=0.743), but declined markedly in 2014 (3.5%, 10/281) (χ(2)=71.770, p=0.000). G12P was second highest strain in 2012 (22.7%, 42/185), decrease rapidly in 2013 (2.7%, 5/186) (χ(2)=26.224, p=0.000) and re-emerged as the predominant genotype in 2014 (86.6%, 243/281) (χ(2)=118.299, p=0.000). From July/2014, G12P was the single genotype detected in all regions studied. The sudden emergence, spread and predominance of G12P strain in Brazil, raised the hypothesis of a possible G12 outbreak being in progress. Nationally, the long term decline in gastroenteritis hospitalization observed in the country after RVA vaccine introduction was confirmed. Nevertheless, the sharp increase in diarrhea hospitalization prevalence from 2013 to 2014 observed in Southern and Southeastern regions is consistent with what appears to be an outbreak of G12P. Continued surveillance is needed to verify the effectiveness of the RotarixTM vaccine in Brazil together with potential emergence of unusual genotypes.
Silva, Marcelle Figueira Marques da; Rose, Tatiana Lundgren; Gómez, Mariela Martínez; Carvalho-Costa, Filipe Anibal; Fialho, Alexandre Madi; Assis, Rosane Maria Santos de; Andrade, Juliana da Silva Ribeiro de; Volotão, Eduardo de Mello; Leite, José Paulo Gagliardi
Epidemiological data on species A rotavirus (RVA) infections have demonstrated the genetic diversity of strains circulating worldwide. Many G and P genotype combinations have been described over the years, varying regionally and temporally, especially in developing countries. However, the most common G and P genotype combinations identified in RVA human strains worldwide are G1P, G2P, G3P, G4P and G9P. RVA genotype G1P strains are responsible for more than 50% of child infections worldwide and component of the two vaccines (Rotarix® [RV1] and RotaTeq® [RV5]) licensed globally. For a better understanding of the evolutionary mechanisms of this genotype in Brazil, phylogenetic analyses based on the 11 RVA genome segments (genomic constellation) from 90 G1P RVA strains collected in two eras - (i) pre-vaccination with RV1 (1996-February 2006); (ii) post-vaccination (March 2006-2013) - in different Brazilian states were performed. The results showed the Wa-like genomic constellation of the Brazilian G1P strains with a I1-R1-C1-M1-A1-N1-T1-E1-H1 specificity, except for two strains (rj14055-07 and ba19030-10) that belong to a I1-R1-C1-M1-A1-N1-T3-E1-H1 genomic constellation, evidencing the occurrence of reassortment (Wa-like×AU-1-like) of the NSP3 gene. Reassortment events were also demonstrated between Brazilian G1P strains and the RV1 vaccine strain in some genes in vaccinated and unvaccinated children. VP7 and VP8* antigenic site analysis showed that the amino acid substitutions observed in samples collected after the introduction of RV1 in Brazil were already detected in samples collected in the 1980s and 1990s, suggesting that mass Brazilian RV1 vaccination had no impact on the diversity observed inside antigenic sites for these two proteins.
Evaluation of reproductive protection against bovine viral diarrhea virus and bovine herpesvirus-1 afforded by annual revaccination with modified-live viral or combination modified-live/killed viral vaccines after primary vaccination with modified-live viral vaccine.
Walz, Paul H; Givens, M Daniel; Rodning, Soren P; Riddell, Kay P; Brodersen, Bruce W; Scruggs, Daniel; Short, Thomas; Grotelueschen, Dale
The objective of this study was to compare reproductive protection in cattle against bovine viral diarrhea virus (BVDV) and bovine herpesvirus 1 (BoHV-1) provided by annual revaccination with multivalent modified-live viral (MLV) vaccine or multivalent combination viral (CV) vaccine containing temperature-sensitive modified-live BoHV-1 and killed BVDV when MLV vaccines were given pre-breeding to nulliparous heifers. Seventy-five beef heifers were allocated into treatment groups A (n=30; two MLV doses pre-breeding, annual revaccination with MLV vaccine), B (n=30; two MLV doses pre-breeding, annual revaccination with CV vaccine) and C (n=15; saline in lieu of vaccine). Heifers were administered treatments on days 0 (weaning), 183 (pre-breeding), 366 (first gestation), and 738 (second gestation). After first calving, primiparous cows were bred, with pregnancy assessment on day 715. At that time, 24 group A heifers (23 pregnancies), 23 group B heifers (22 pregnancies), and 15 group C heifers (15 pregnancies) were commingled with six persistently infected (PI) cattle for 16days. Ninety-nine days after PI removal, cows were intravenously inoculated with BoHV-1. All fetuses and live offspring were assessed for BVDV and BoHV-1. Abortions occurred in 3/23 group A cows, 1/22 group B cows, and 11/15 group C cows. Fetal infection with BVDV or BoHV-1 occurred in 4/23 group A offspring, 0/22 group B offspring, and 15/15 group C offspring. This research demonstrates efficacy of administering two pre-breeding doses of MLV vaccine with annual revaccination using CV vaccine to prevent fetal loss due to exposure to BVDV and BoHV-1.
Kirkwood, Carl D; Roczo-Farkas, Suzie
The Australian Rotavirus Surveillance Program, together with collaborating laboratories Australia-wide, reports the rotavirus genotypes responsible for the hospitalisation of children with acute gastroenteritis. During the survey period of 1 January to 31 December 2014, 1,022 faecal samples were referred for rotavirus G and P genotype analysis, and of these 733 were confirmed as rotavirus positive. A total of 480 specimens were collected from children under 5 years of age, while 253 were from older children and adults. Genotype analysis of the 733 rotavirus samples collected from both children and adults revealed that G12P was the dominant genotype in this reporting period, identified in 29.6% of strains nationally. Genotype G1P was the 2nd most common strain nationally, representing 22.9% of samples, followed by genotype G3P (14.9%). This report highlights the continued significance of G12P strains as the major cause of disease in this population. The genotype distribution was slightly altered when the analysis was restricted to samples collected from children under 5 years of age, with G1P being the dominant genotype (29%) followed by G12P as the 2nd most common genotype (26%). Fluctuations in genotype distribution were also observed based on the vaccine type in use. Genotype G12P was more common in states and territories using RotaTeq, while G1P was more common in the locations using Rotarix. This survey highlights the yearly fluctuations in rotavirus genotypes observed since vaccine introduction. The continuation of G12P as the dominant genotype further illustrates the dynamic and diversity present in the wild-type rotavirus population evident in the Australian population since vaccine introduction.
Kirkwood, Carl D; Roczo-Farkas, Susie
This report from the Australian Rotavirus Surveillance Program, together with collaborating laboratories Australia-wide, describes the rotavirus genotypes responsible for the hospitalisation of children with acute gastroenteritis during the period 1 January to 31 December 2013. During the survey period, 1,035 faecal samples were referred for rotavirus G and P genotype analysis. Of these 828 were confirmed as rotavirus positive. A total of 503 specimens were collected from children under 5 years of age, while 325 were from older children and adults. Genotype analysis of the 828 rotavirus samples collected from both children and adults revealed that G12P was the dominant genotype in this reporting period, identified in 33% of strains nationally. Genotype G3P was the second most common strain nationally, representing 31% of samples, followed by genotype G2P (14%). This represents the first report where G12P strains are the major cause of disease in this population. The genotype distribution was slightly altered when the analysis was restricted to samples collected from children under 5 years of age, with G3P being the dominant genotype (39.2%) followed by G12P as the second most common genotype (31%). Fluctuations in genotype distribution were also observed based on the vaccine type in use. Genotype G12P was more common in states and territories using RotaTeq, while G3P was more common in the locations using Rotarix. This survey highlights the yearly fluctuations in rotavirus genotypes observed since vaccine introduction, with changes in dominant genotypes an annual event. The emergence of G12P as the dominant genotype further illustrates the ongoing changes in the wild type rotavirus population evident in the Australian population since vaccine introduction.
Coelingh, Kathleen; Olajide, Ifedapo Rosemary; MacDonald, Peter; Yogev, Ram
Evidence of high efficacy of live attenuated influenza vaccine (LAIV) from randomized controlled trials is strong for children 2-6 years of age, but fewer data exist for older school-age children. We reviewed the published data on efficacy and effectiveness of LAIV in children ≥5 years. QUOSA (Elsevier database) was searched for articles published from January 1990 to June 2014 that included 'FluMist', 'LAIV', 'CAIV', 'cold adapted influenza vaccine', 'live attenuated influenza vaccine', 'live attenuated cold adapted' or 'flu mist'. Studies evaluated included randomized controlled trials, effectiveness and indirect protection studies. This review demonstrates that LAIV has considerable efficacy and effectiveness in school-age children.
Crafford, J E; Lourens, C W; Smit, T K; Gardner, I A; MacLachlan, N J; Guthrie, A J
African horse sickness (AHS) is typically a highly fatal disease in susceptible horses and vaccination is currently used to prevent the occurrence of disease in endemic areas. Similarly, vaccination has been central to the control of incursions of African horse sickness virus (AHSV) into previously unaffected areas and will likely play a significant role in any future incursions. Horses in the AHSV-infected area in South Africa are vaccinated annually with a live-attenuated (modified-live virus [MLV]) vaccine, which includes a cocktail of serotypes 1, 3, 4 (bottle 1) and 2, 6-8 (bottle 2) delivered in two separate doses at least 21 days apart. In this study, the neutralising antibody response of foals immunized with this polyvalent MLV AHSV vaccine was evaluated and compared to the response elicited to monovalent MLV AHSV serotypes. Naïve foals were immunized with either the polyvalent MLV AHSV vaccine, or a combination of monovalent MLV vaccines containing individual AHSV serotypes 1, 4, 7 or 8. There was a marked and consistent difference in the immunogenicity of individual virus serotypes contained in the MLV vaccines. Specifically, foals most consistently seroconverted to AHSV-1 and responses to other serotypes were highly variable, and often weak or not detected. The serotype-specific responses of foals given the monovalent MLV vaccines were similar to those of foals given the polyvalent MLV preparation suggesting that there is no obvious enhanced immune response through the administration of a monovalent vaccine as opposed to the polyvalent vaccine.
Yuan, L; Ward, L A; Rosen, B I; To, T L; Saif, L J
Neonatal gnotobiotic pigs orally inoculated with virulent (intestinal-suspension) Wa strain human rotavirus (which mimics human natural infection) developed diarrhea, and most pigs which recovered (87% protection rate) were immune to disease upon homologous virulent virus challenge at postinoculation day (PID) 21. Pigs inoculated with cell culture-attenuated Wa rotavirus (which mimics live oral vaccines) developed subclinical infections and seroconverted but were only partially protected against challenge (33% protection rate). Isotype-specific antibody-secreting cells (ASC were enumerated at selected PID in intestinal (duodenal and ileal lamina propria and mesenteric lymph node [MLN]) and systemic (spleen and blood) lymphoid tissues by using enzyme-linked immunospot assays. At challenge (PID 21), the numbers of virus-specific immunoglobulin A (IgA) ASC, but not IgG ASC, in intestines and blood were significantly greater in virulent-Wa rotavirus-inoculated pigs than in attenuated-Wa rotavirus-inoculated pigs and were correlated (correlation coefficients: for duodenum and ileum, 0.9; for MLN, 0.8; for blood, 0.6) with the degree of protection induced. After challenge, the numbers of IgA and IgG virus-specific ASC and serum-neutralizing antibodies increased significantly in the attenuated-Wa rotavirus-inoculated pigs but not in the virulent-Wa rotavirus-inoculated pigs (except in the spleen and except for IgA ASC in the duodenum). The transient appearance of IgA ASC in the blood mirrored the IgA ASC responses in the gut, albeit at a lower level, suggesting that IgA ASC in the blood of humans could serve as an indicator for IgA ASC responses in the intestine after rotavirus infection. To our knowledge, this is the first report to study and identify intestinal IgA ASC as a correlate of protective active immunity in an animal model of human-rotavirus-induced disease. PMID:8627786
Gastanaduy, Paul A.; Islam, Khaleda; Rahman, Mahmudur; Rahman, Mustafizur; Luby, Stephen P.; Heffelfinger, James D.; Parashar, Umesh D.; Gurley, Emily S.
Background: In anticipation of introduction of a rotavirus vaccine into the national immunization program of Bangladesh, active hospital-based surveillance was initiated to provide prevaccine baseline data on rotavirus disease. Methods: Children 5 years of age and younger admitted with acute gastroenteritis (AGE) (≥3 watery or looser-than-normal stools or ≥1 episode of forceful vomiting) at 7 hospitals throughout Bangladesh were identified. Clinical information and stool specimens were collected from every 4th patient. Specimens were tested for rotavirus antigen by enzyme immunoassays; 25% of detected rotaviruses were genotyped. Results: From July 2012 to June 2015, rotavirus was detected in 2432 (64%) of 3783 children hospitalized for AGE. Eight enrolled children died, including 4 (50%) who were rotavirus positive. Rotavirus was detected year-round in Bangladesh with peak detection rates of >80% during November–February. Most (86%) rotavirus AGE cases were 6–23 months of age. Sixty-nine percent of children with rotavirus had severe disease (Vesikari score, ≥11). Among 543 strains genotyped, G1P (31%) and G12P (29%) were the most common. Conclusions: Rotavirus is a major cause of morbidity in Bangladeshi children, accounting for nearly two-thirds of AGE hospitalizations. These data highlight the potential value of rotavirus vaccination in Bangladesh, and will be the key for future measurement of vaccine impact. PMID:27798545
Sánchez-Valdéz, Fernando J; Pérez Brandán, Cecilia; Ferreira, Arturo; Basombrío, Miguel Ángel
Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. This illness is now becoming global, mainly due to congenital transmission, and so far, there are no prophylactic or therapeutic vaccines available to either prevent or treat Chagas disease. Therefore, different approaches aimed at identifying new protective immunogens are urgently needed. Live vaccines are likely to be more efficient in inducing protection, but safety issues linked with their use have been raised. The development of improved protozoan genetic manipulation tools and genomic and biological information has helped to increase the safety of live vaccines. These advances have generated a renewed interest in the use of genetically attenuated parasites as vaccines against Chagas disease. This review discusses the protective capacity of genetically attenuated parasite vaccines and the challenges and perspectives for the development of an effective whole-parasite Chagas disease vaccine.
Ng, Tony W; Saavedra-Ávila, Noemí A; Kennedy, Steven C; Carreño, Leandro J; Porcelli, Steven A
The development of more effective vaccines against Mycobacterium tuberculosis (Mtb) remains a major goal in the effort to reduce the enormous global burden of disease caused by this pathogen. Whole-cell vaccines based on live mycobacteria with attenuated virulence represent an appealing approach, providing broad antigen exposure and intrinsic adjuvant properties to prime durable immune responses. However, designing vaccine strains with an optimal balance between attenuation and immunogenicity has proven to be extremely challenging. Recent basic and clinical research efforts have broadened our understanding of Mtb pathogenesis and created numerous new vaccine candidates that have been designed to overcome different aspects of immune evasion by Mtb. In this review, we provide an overview of the current efforts to create improved vaccines against tuberculosis based on modifications of live attenuated mycobacteria. In addition, we discuss the use of such vaccine strains as vectors for stimulating protective immunity against other infectious diseases and cancers.
Rao, Sameer; Mao, J. S.; Motlekar, Salman; Fangcheng, Zhuang; Kadhe, Ganesh
ABSTRACT Changing epidemiology of Hepatitis A virus (HAV) has led to an increased susceptibility of adolescents and adults to the infection. Vaccination can remarkably reduce the incidence and associated morbidity of HAV infection. This review is focused on the safety and efficacy of H2 strain derived live attenuated Hepatitis A vaccine. We found the vaccine to be highly immunogenic with minimal or negligible safety issues. Moreover, a single dose of live attenuated vaccine persists a long term immune response and can be a preferred option for developing countries. In 2014, Indian Academy of Paediatrics (IAP) also updated their recommendations for H2 vaccine as a single dose as against the previous 2 dose schedule. A focused approach to include the vaccine in national immunization program should be explored. PMID:27532370
Lee, Hsiang-Chi; Butler, Michael; Wu, Suh-Chin
Dramatic increases in dengue (DEN) incidence and disease severity have been reported, in great part due to the geographic expansion of Aedes aegypti and Aedes albopictus mosquitoes. One result is the expanded co-circulation of all dengue 1-4 serotype viruses (DENV) in urban areas worldwide, especially in South and South-East Asia, and South America. DEN disease severity ranges from asymptomatic infections to febrile dengue fevers (DF) to life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). There is an urgent need for a safe and effective tetravalent DEN vaccine. Several live attenuated, tetravalent DEN vaccine candidates have been generated by recombinant DNA technology; these candidates are capable of providing immunity to all four DENV serotypes. In this paper we review (a) recombinant live-attenuated DEN vaccine candidates in terms of deletion, antigen chimerization, and the introduction of adaptive mutations; (b) strategies for improving tetravalent vaccine attenuation; and (c) live-attenuated DENV vaccine development.
Kaufmann, Judith R; Miller, Roger; Cheyne, James
In the next decade, at least twelve additional vaccines that target such diseases as typhoid, malaria, and dengue will become available to lower- and middle-income countries. These vaccines must travel along what are called supply chains, which include all personnel, systems, equipment, and activities involved in ensuring that vaccines are effectively delivered from the point of production to the people who need them. But for various reasons, supply chains are already strained in many developing countries, and the potential inability to distribute new vaccines will place lives at risk. Among the many steps needed to strengthen the global vaccine supply chain, we suggest that the international community pursue improved coordination between organizations that donate and ship vaccines and the host-country officials who receive and distribute the vaccines, as well as better training for supply-chain managers.
Kolibab, Kristopher; Derrick, Steven C; Jacobs, William R; Morris, Sheldon L
The viability of BCG vaccine has traditionally been monitored using a colony-forming unit (CFU) assay. Despite its widespread use, results from the CFU assay can be highly variable because of the characteristic clumping of mycobacteria, their requirement for complex growth media, and the three week incubation period needed to cultivate slow-growing mycobacteria. In this study, we evaluated whether an ATP luminescence assay (which measures intracellular ATP content) could be used to rapidly estimate the viability of lyophilized and/or frozen preparations of six different BCG vaccine preparations - Danish, Tokyo, Russia, Brazil, Tice, and Pasteur - and two live attenuated mycobacterial vaccine candidates - a ΔlysAΔpanCD M. tuberculosis strain and a ΔmmaA4 BCG vaccine mutant. For every vaccine tested, a significant correlation was observed between intracellular ATP concentrations and the number of viable attenuated bacilli. However, the extractable intracellular ATP levels detected per cell among the different live vaccines varied suggesting that validated ATP luminescence assays with specific appropriate standards must be developed for each individual live attenuated vaccine preparation. Overall, these data indicate that the ATP luminescence assay is a rapid, sensitive, and reliable alternative method for quantifying the viability of varying live attenuated mycobacterial vaccine preparations.
Yazbak, F Edward; Diodati, Catherine J M
Pregnant rubella-susceptible women are often revaccinated during the postpartum period with the Measles, Mumps, and Rubella vaccine (MMR). It is known that the rubella virus from vaccine is secreted in breast milk and persists in the nose and throat for up to 28 days but it is not known whether the measles and mumps viruses are similarly secreted. It is probable the measles virus from vaccine is.
Dömök, I.; Balayan, M. S.; Fayinka, O. A.; Škrtić, N.; Soneji, A. D.; Harland, P. S. E. G.
A virologically controlled field trial was conducted with live monovalent type 1 poliovirus vaccine in children aged 3-30 months living in a rural area of Uganda, in an attempt to find out the reason for the poor efficacy of such vaccine often observed in countries with a warm climate. Groups of breast-fed and of artificially fed infants received the vaccine orally, either alone or mixed with horse serum prepared against partly purified human gamma-globulin. Irrespective of the diet, the “take rate”—measured by the rates of vaccine virus excretion and of antibody conversion—was found to be poor when the vaccine was given alone but satisfactory when it was given together with the horse antiserum. However, the extent and duration of vaccine virus multiplication in the intestinal tract proved to be limited and the mean antibody level elicited by the vaccination, irrespective of the schedule of vaccine administration, was low. These results, besides indicating that breast-feeding does not influence the efficacy of vaccination in the age groups studied, revealed the presence of an inhibitor in the alimentary tract. This inhibitor acts against the multiplication of vaccine virus, which may be blocked by antibodies in the horse antiserum for a limited period at the time of vaccination. Interference between the enteroviruses and the vaccine strain was also found to be responsible for decreasing the efficacy of vaccination, though its role was secondary to that of the inhibitor. Revaccination experiments showed that the effects of both inhibitor and interference may be overcome by repeated administration of the vaccine. PMID:4142936
Live attenuated vaccines (LAVs) are commonly utilized to protect commercial table egg producers from economic losses associated with challenges by the respiratory pathogen Mycoplasma gallisepticum (MG). Currently there are four MG LAVs commercially available within the United States. Consistent am...
Issa, Nicolas C; Marty, Francisco M; Leblebjian, Houry; Galar, Alicia; Shea, Margaret M; Antin, Joseph H; Soiffer, Robert J; Baden, Lindsey R
Hematopoietic stem cell transplantation (HSCT) recipients are at risk for varicella-zoster virus (VZV) reactivation. Vaccination may help restore VZV immunity; however, the available live attenuated VZV vaccine (Zostavax) is contraindicated in immunocompromised hosts. We report our experience with using a single dose of VZV vaccine in 110 adult autologous and allogeneic HSCT recipients who were about 2 years after transplantation, free of graft-versus-host disease, and not receiving immunosuppression. One hundred eight vaccine recipients (98.2%) had no clinically apparent adverse events with a median follow-up period of 9.5 months (interquartile range, 6 to 16; range, 2 to 28). Two vaccine recipients (1.8%) developed a skin rash (one zoster-like rash with associated pain, one varicella-like) within 42 days post-vaccination that resolved with antiviral therapy. We could not confirm if these rashes were due to vaccine (Oka) or wild-type VZV. No other possible cases of VZV reactivation have occurred with about 1178 months of follow-up. Live attenuated zoster vaccine appears generally safe in this population when vaccinated as noted; the overall vaccination risk needs to be weighed against the risk of wild-type VZV disease in this high-risk population.
Sirinonthanawech, Naraporn; Surichan, Somchaiya; Namsai, Aphinya; Puthavathana, Pilaipan; Auewarakul, Prasert; Kongchanagul, Alita
Formulation and quality control of trivalent live-attenuated influenza vaccine requires titration of infectivity of individual strains in the trivalent mix. This is usually performed by selective neutralization of two of the three strains and titration of the un-neutralized strain in cell culture or embryonated eggs. This procedure requires standard sera with high neutralizing titer against each of the three strains. Obtaining standard sera, which can specifically neutralize only the corresponding strain of influenza viruses and is able to completely neutralize high concentration of virus in the vaccine samples, can be a problem for many vaccine manufacturers as vaccine stocks usually have very high viral titers and complete neutralization may not be obtained. Here an alternative approach for titration of individual strain in trivalent vaccine without the selective neutralization is presented. This was done by detecting individual strains with specific antibodies in an end-point titration of a trivalent vaccine in cell culture. Similar titers were observed in monovalent and trivalent vaccines for influenza A H3N2 and influenza B strains, whereas the influenza A H1N1 strain did not grow well in cell culture. Viral interference among the vaccine strains was not observed. Therefore, providing that vaccine strains grow well in cell culture, this assay can reliably determine the potency of individual strains in trivalent live-attenuated influenza vaccines.
Kirkwood, Carl D; Roczo-Farkas, Susie; Bishop, Ruth F; Barnes, Graeme L
This report from the Australian Rotavirus Surveillance Program, together with collaborating laboratories Australia-wide, describes the rotavirus genotypes responsible for the hospitalisation of children with acute gastroenteritis during the period 1 January to 31 December 2012. During the survey period, 1,300 faecal samples were referred to the centre for rotavirus G and P genotype analysis, and of these 748 were confirmed as rotavirus positive. A total of 491 specimens were collected from children under 5 years of age, while 257 were from older children and adults. Genotype analysis revealed that G1P was the dominant type in this reporting period, identified in 35% of strains nationally. Genotype G2P was the second most common strain nationally, representing 28% of samples, followed by genotype G12P (23%). This represents the first report where G12P strains are a major cause of disease in this community. Fluctuations in genotype distribution were also observed based on the vaccine type in use. Genotype G2P was more common in states and territories using Rotarix while G1P was more common in states using RotaTeq. This survey of rotavirus strains circulating in 2012 highlights the continued fluctuations in rotavirus genotypes, with an annual change in dominant genotypes as well as emergence of a previously rare genotype, suggesting a dynamic wild-type population.
Wüthrich, Marcel; Krajaejun, Theerapong; Shearn-Bochsler, Valerie; Bass, Chris; Filutowicz, Hanna I; Legendre, Alfred M; Klein, Bruce S
Blastomycosis is a severe, commonly fatal infection caused by the dimorphic fungus Blastomyces dermatitidis in dogs that live in the United States, Canada, and parts of Africa. The cost of treating an infection can be expensive, and no vaccine against this infection is commercially available. A genetically engineered live-attenuated strain of B. dermatitidis lacking the major virulence factor BAD-1 successfully vaccinates against lethal experimental infection in mice. Here we studied the safety, toxicity, and immunogenicity of this strain as a vaccine in dogs, using 25 beagles at a teaching laboratory and 78 foxhounds in a field trial. In the beagles, escalating doses of live vaccine ranging from 2 × 10⁴ to 2 × 10⁷ yeast cells given subcutaneously were safe and did not disseminate to the lung or induce systemic illness, but a dose of < 2 × 10⁶ yeast cells induced less fever and local inflammation. A vaccine dose of 10⁵ yeast cells was also well tolerated in vaccinated foxhounds who had never had blastomycosis; however, vaccinated dogs with prior infection had more local reactions at the vaccine site. The draining lymph node cells and peripheral blood lymphocytes from vaccinated dogs demonstrated gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and granulocyte-macrophage colony-stimulating factor (GM-CSF) specifically in response to stimulation with Blastomyces antigens. Thus, the live-attenuated vaccine against blastomycosis studied here proved safe, well tolerated, and immunogenic in dogs and merits further studies of vaccine efficacy.
Abdel-Moneim, Ahmed S; Al-Malky, Mater I R; Alsulaimani, Adnan A A; Abuelsaad, Abdelaziz S A; Mohamed, Imad; Ismail, Ayman K
Group A rotavirus is responsible for inducing severe diarrhea in young children worldwide. Rotavirus vaccines are used to control the disease in many countries. In the current study, the sequences of human rotavirus G and P types in Saudi Arabia are reported and compared to different relevant published sequences. In addition, the VP4 and VP7 genes of the G1P strains are compared to different antigenic epitopes of the rotavirus vaccines. Stool samples were collected from children under 2 years suffering from severe diarrhea. Screening of the rotavirus-positive samples was performed with rapid antigen detection kit. RNA was amplified from rotavirus-positive samples by reverse transcriptase polymerase chain reaction assay for both VP4 and VP7 genes. Direct sequencing of the VP4 and VP7 genes was conducted and the obtained sequences were compared to each other and to the rotavirus vaccines. Both G1P G1P genotypes were detected. Phylogenetic analysis revealed that the detected strains belong to G1 lineage 1 and 2, P lineage 3, and to P lineage 5. Multiple amino acid substitutions were detected between the Saudi RVA strains and the commonly used vaccines. The current findings emphasize the importance of the continuous surveillance of the circulating rotavirus strains, which is crucial for monitoring virus evolution and helping in predicting the protection level afforded by rotavirus vaccines.
Rudd, Cheryl; Mwenda, Jason; Chilengi, Roma
The 8th African Rotavirus Symposium was held in Livingstone, Zambia from the 12-13 June 2014. Over 130 delegates from 35 countries - 28 from African nations - participated in this symposium, which included scientists, clinicians, immunisation managers, public health officials, policymakers and vaccine manufacturers. The theme for the symposium was Rotavirus Landscape in Africa-Towards Prevention and Control. At the time of the symposium, a total of 21 African countries had introduced the rotavirus vaccine into their national immunisation schedules. This meeting was particularly timely and relevant to review early data on vaccine adoption and impact from these countries. The concluding panel discussion proposed several recommendations for areas of focus moving forward in rotavirus advocacy and research.
Huang, Yu-Liang; Deng, Ming-Chung; Wang, Fun-In; Huang, Chin-Cheng; Chang, Chia-Yi
Classical swine fever (CSF) is an economically important, highly contagious disease of swine worldwide. CSF is caused by classical swine fever virus (CSFV), and domestic pigs and wild boars are its only natural hosts. The two main strategies used to control CSF epidemic are systematic prophylactic vaccination and a non-vaccination stamping-out policy. This review compares the protective efficacy of the routinely used modified live vaccine (MLV) and E2 subunit vaccines and summarizes the factors that influence the efficacy of the vaccines and the challenges that both vaccines face to CSF control. Although MLV provide earlier and more complete protection than E2 subunit vaccines, it has the drawback of not allowing differentiation between infected and vaccinated animals (DIVA). The marker vaccine of E2 protein with companion discriminatory test to detect antibodies against E(rns) allows DIVA and is a promising strategy for future control and eradication of CSF. Maternal derived antibody (MDA) is the critical factor in impairing the efficacy of both MLV and E2 subunit vaccines, so the well-designed vaccination programs of sows and piglets should be considered together. Because of the antigen variation among various genotypes of CSFV, antibodies raised by either MLV or subunit vaccine neutralize genotypically homologous strains better than heterologous ones. However, although this is not a major concern for MLV as the induced immune responses can protect pigs against the challenge of various genotypes of CSFVs, it is critical for E2 subunit vaccines. It is thus necessary to evaluate whether the E2 subunit vaccine can completely protect against the current prevalent strains in the field. An ideal new generation of vaccine should be able to maintain the high protective efficiency of MLV and overcome the problem of antigenic variations while allowing for DIVA.
Zhou, Peifu; Xie, Jianping
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains a major threat to global public health. A new TB vaccine affording superior immune protection to M. bovis Bacillus Calmette-Guérin (BCG) is imperative. The advantage of a live attenuated vaccine is that it can mimic the bona fide pathogen, elicit immune responses similar to natural infection, and potentially provide more protection than other vaccines. BCG, the only vaccine and a live attenuated vaccine that is the result of cumulative mutations by serial passage of M. bovis, has provided clues for the construction of novel improved vaccines. A strategy is put forward for identifying a new live attenuated TB vaccine generated by cumulative mutation based on M.tb. Given the important role of the M.tb signaling network consisting of a two-component system, eukaryotic-like Ser/Thr protein kinase system and sigma factor system based on comparisons among M.tb H37Rv, M. bovis, and BCG, we have put a premium on this signaling circuit as the starting point for the generation of an attenuated TB vaccine.
Pandey, Aseem; Cabello, Ana; Akoolo, Lavoisier; Rice-Ficht, Allison; Arenas-Gamboa, Angela; McMurray, David; Ficht, Thomas A.; de Figueiredo, Paul
Vaccination of humans and animals with live attenuated organisms has proven to be an effective means of combatting some important infectious diseases. In fact, the 20th century witnessed tremendous improvements in human and animal health worldwide as a consequence of large-scale vaccination programs with live attenuated vaccines (LAVs). Here, we use the neglected zoonotic diseases brucellosis and bovine tuberculosis (BTb) caused by Brucella spp. and Mycobacterium bovis (M. bovis), respectively, as comparative models to outline the merits of LAV platforms with emphasis on molecular strategies that have been pursued to generate LAVs with enhanced vaccine safety and efficacy profiles. Finally, we discuss the prospects of LAV platforms in the fight against brucellosis and BTb and outline new avenues for future research towards developing effective vaccines using LAV platforms. PMID:27537413
Li, Jieqiong; Chen, Hui; Wu, Na; Fan, Dongying; Liang, Guodong; Gao, Na; An, Jing
Vaccination is the most effective countermeasure for protecting individuals from Japanese encephalitis virus (JEV) infection. There are two types of JEV vaccines currently used in China: the Vero cell-derived inactivated vaccine and the live attenuated vaccine. In this study, we characterized the immune response and protective efficacy induced in mice by the inactivated vaccine, live attenuated vaccine and the DNA vaccine candidate pCAG-JME, which expresses JEV prM-E proteins. We found that the live attenuated vaccine conferred 100% protection and resulted in the generation of high levels of specific anti-JEV antibodies and cytokines. The pCAG-JME vaccine induced protective immunity as well as the live attenuated vaccine. Unexpectedly, immunization with the inactivated vaccine only induced a limited immune response and partial protection, which may be due to the decreased activity of dendritic cells and the expansion of CD4+CD25+Foxp3+ regulatory T cells observed in these mice. Altogether, our results suggest that the live attenuated vaccine is more effective in providing protection against JEV infection than the inactivated vaccine and that pCAG-JME will be a potential JEV vaccine candidate.
Roczo-Farkas, Susie; Kirkwood, Carl D; Bines, Julie E
The Australian Rotavirus Surveillance Program, together with collaborating laboratories Australia-wide, reports the rotavirus genotypes responsible for the hospitalisation of children with acute gastroenteritis during the period 1 January to 31 December 2015. During the survey period, 1,383 faecal samples were referred for rotavirus G and P genotype analysis, and of these, 1,031 were confirmed as rotavirus positive. A total of 634 specimens had been collected from children under 5 years of age, while 397 were from older children and adults. Genotype analysis of samples from both children and adults revealed that G12P was the dominant genotype in this reporting period, identified in 48.2% of strains nationally. Genotype G3P was the second most common strain nationally, representing 22.8% of samples, followed by G2P and G1P (9% and 8% respectively). G3P was further divided as equine-like G3P (13.2% of all strains) and other wild-type G3P (9.6%). This report highlights the continued predominance of G12P strains as the major cause of disease in this population. Genotype distribution was distinct between jurisdictions using RotaTeq and Rotarix vaccines. Genotype G12P was more common in states using RotaTeq, while equine-like G3P and G2P were more common in the states and territories using Rotarix. This survey highlights the dynamic change in rotavirus genotypes observed since vaccine introduction, including the emergence of a novel equine-like G3P as a major strain. The prolonged dominance of G12P for a 4th consecutive year further illustrates the unexpected trends in the wild type rotaviruses circulating in the Australian population since vaccine introduction.
Genetic and antigenic diversity within H1 influenza A virus (IAV) subtypes circulating in swine is increasing. The need for cross-protective influenza vaccines in swine is necessary as the virus becomes more diverse. This study compared the humoral and cell-mediated immune response of modified live ...
Muñoz-González, Sara; Perez-Simó, Marta; Muñoz, Marta; Bohorquez, José Alejandro; Rosell, Rosa; Summerfield, Artur; Domingo, Mariano; Ruggli, Nicolas; Ganges, Llilianne
Classical swine fever (CSF) causes major losses in pig farming, with various degrees of disease severity. Efficient live attenuated vaccines against classical swine fever virus (CSFV) are used routinely in endemic countries. However, despite intensive vaccination programs in these areas for more than 20 years, CSF has not been eradicated. Molecular epidemiology studies in these regions suggests that the virus circulating in the field has evolved under the positive selection pressure exerted by the immune response to the vaccine, leading to new attenuated viral variants. Recent work by our group demonstrated that a high proportion of persistently infected piglets can be generated by early postnatal infection with low and moderately virulent CSFV strains. Here, we studied the immune response to a hog cholera lapinised virus vaccine (HCLV), C-strain, in six-week-old persistently infected pigs following post-natal infection. CSFV-negative pigs were vaccinated as controls. The humoral and interferon gamma responses as well as the CSFV RNA loads were monitored for 21 days post-vaccination. No vaccine viral RNA was detected in the serum samples and tonsils from CSFV postnatally persistently infected pigs for 21 days post-vaccination. Furthermore, no E2-specific antibody response or neutralising antibody titres were shown in CSFV persistently infected vaccinated animals. Likewise, no of IFN-gamma producing cell response against CSFV or PHA was observed. To our knowledge, this is the first report demonstrating the absence of a response to vaccination in CSFV persistently infected pigs.
controlled studies. Vaccine 2012; 30:886–92. 11. Piedra PA, Gaglani MJ, Kozinetz CA, et al. Trivalent live attenuated intranasal influenza vaccine...120:e553–64. 12. Halloran ME, Piedra PA, Longini IM Jr, et al. Efficacy of trivalent, cold-adapted, influenza virus vaccine against influenza A (Fujian
Sudheesh, Ponnerassery S; Cain, Kenneth D
This study was aimed at optimizing the efficacy of a recently developed live attenuated immersion vaccine (B.17-ILM) as a promising vaccine against bacterial coldwater disease (BCWD) caused by Flavobacterium psychrophilum in salmonids. Rainbow trout (RBT) fry were vaccinated by immersion, and different parameters affecting vaccination such as fish size, vaccine delivery time, dose, duration of protection, booster regimes and vaccine growth incubation time were optimized. Specific anti-F. psychrophilum immune response was determined by ELISA. Protective efficacy was determined by challenging with a virulent strain of F. psychrophilum (CSF-259-93) and calculating cumulative percent mortality (CPM) and relative percent survival (RPS). All vaccinated fish developed significantly higher levels of serum antibody titers by week 8 when compared to their respective controls. Immersion vaccination for 3, 6 and 30 min produced significant protection with comparable RPS values of 47%, 53% and 52%, respectively. This vaccine provided significant protection for fish as small as 0.5 g with an RPS of 55%; larger fish of 1 g and 2 g yielded slightly higher RPS values of 59% and 60%, respectively. Fish vaccinated with higher vaccine doses of ∼10(10) and 10(8) colony forming units mL(-1) (cfu ml(-1)) were strongly protected out to at least 24 weeks with RPS values up to 70%. Fish vaccinated with lower doses (∼10(6) and 10(5) cfu mL(-1)) had good protection out to 12 weeks, but RPS values dropped to 36% and 34%, respectively by 24 weeks. Vaccine efficacy was optimum when the primary vaccination was followed by a single booster (week 12 challenge RPS = 61%) rather than two boosters (week 12 challenge RPS = 48%). Vaccination without a booster resulted in a lower RPS (13%) indicating the necessity of a single booster vaccination to maximize efficacy. This study presents key findings that demonstrate the efficacy and commercial potential for this live attenuated BCWD
Hashizume, Masahiro; Nakagomi, Toyoko; Nakagomi, Osamu
Rotavirus is a leading cause of severe acute gastroenteritis in children worldwide, and globally licensed vaccines are available. To expedite the introduction of rotavirus vaccines in the national immunisation programme, a simple, ecological method to monitor changes in the burden of rotavirus disease may be of great help. Here, we report an application of a time-series analysis on a publicly-available dataset in Japan on the weekly number of laboratory-confirmed rotavirus-positive samples over the last 5 year period between the 36th week of 2009 and the 35th week of 2014 during which rotavirus vaccines became marketed in Japan and presumed to reach an uptake rate of at least 39% as a national average. Compared with the expected number of rotavirus detection based on the preceding four rotavirus seasons, the number of rotavirus detection during the 2013–2014 season was 42.9% (95% CI: 38.6, 47.8). This suggests that the use of rotavirus vaccine had a positive impact on reducing the burden of rotavirus diarrhoea in Japan. This method, because of its simplicity and little cost, should be applicable to early detection of the impact of rotavirus vaccine even in resource-poor countries where the World Health Organization funded and implemented the sentinel surveillance programmes of laboratory-confirmed rotavirus cases. PMID:26543393
De Grazia, Simona; Dóró, Renáta; Bonura, Floriana; Marton, Szilvia; Cascio, Antonio; Martella, Vito; Bányai, Krisztián; M Giammanco, Giovanni
G12 rotaviruses are globally emergent rotaviruses causing severe childhood gastroenteritis. Little is known about the evolution and diversity of G12P rotaviruses and the possible role that widespread vaccine use, globally, has had on their emergence. In Sicily, Italy, surveillance activity for rotaviruses has been conducted uninterruptedly since 1985, thus representing a unique observatory for the study of human rotaviruses in the pre- and post-vaccine era. G12 rotaviruses were first detected only in 2012 and between 2012 and 2014 they accounted for 8.7% of all rotavirus-associated infections among children, with peaks of 27.8% in 2012/2013 and 21% in 2014. We determined and analyzed the full-genome of 22 G12P rotaviruses collected during the 2012-2014. Although all G12P rotaviruses exhibited a typical Wa-like genotype constellation (G12P-I1-R1-C1-M1-A1-N1-T1-E1-H1), phylogenetic analysis allowed distinguishing either two or three (sub)lineages in each genome segment. On the basis of the segregation patterns into lineages/sublineages, 20 G12P rotaviruses could be grouped into three stable major genomic sub-constellations, whilst two strains displayed unique genome architectures, likely due to ressortment with co-circulating strains. Altogether, these findings indicate that the onset and prolonged circulation of G12 rotaviruses was due to repeated introductions of different G12 rotaviruses circulating globally. Importantly, as regional rotavirus vaccination was initiated in 2012 reaching a 45% coverage in newborns in 2014, a correlation between the appearance and spread of G12 rotaviruses and the enacted vaccination program could not be drawn. Constant epidemiologic surveillance remains important to monitor the epidemiological dynamics of human rotaviruses.
Renukaradhya, Gourapura J; Meng, Xiang-Jin; Calvert, Jay G; Roof, Michael; Lager, Kelly M
Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) was reported in the late 1980s. PRRS still is a huge economic concern to the global pig industry with a current annual loss estimated at one billion US dollars in North America alone. It has been 20 years since the first modified live-attenuated PRRSV vaccine (PRRSV-MLV) became commercially available. PRRSV-MLVs provide homologous protection and help in reducing shedding of heterologous viruses, but they do not completely protect pigs against heterologous field strains. There have been many advances in understanding the biology and ecology of PRRSV; however, the complexities of virus-host interaction and PRRSV vaccinology are not yet completely understood leaving a significant gap for improving breadth of immunity against diverse PRRS isolates. This review provides insights on immunization efforts using infectious PRRSV-based vaccines since the 1990s, beginning with live PRRSV immunization, development and commercialization of PRRSV-MLV, and strategies to overcome the deficiencies of PRRSV-MLV through use of replicating viral vectors expressing multiple PRRSV membrane proteins. Finally, powerful reverse genetics systems (infectious cDNA clones) generated from more than 20 PRRSV isolates of both genotypes 1 and 2 viruses have provided a great resource for exploring many innovative strategies to improve the safety and cross-protective efficacy of live PRRSV vaccines. Examples include vaccines with diminished ability to down-regulate the immune system, positive and negative marker vaccines, multivalent vaccines incorporating antigens from other porcine pathogens, vaccines that carry their own cytokine adjuvants, and chimeric vaccine viruses with the potential for broad cross-protection against heterologous strains. To combat this devastating pig disease in the future, evaluation and commercialization of such improved live PRRSV vaccines is a shared goal among PRRSV researchers, pork
Galen, James E.; Pasetti, Marcela F.; Tennant, Sharon; Olveira-Ruiz, Patricia; Sztein, Marcelo B.; Levine, Myron M.
Attenuated bacterial vaccine strains hold great promise as live vectors for presentation of foreign antigens from unrelated bacterial, viral, and parasitic pathogens to the immune system. While this approach has proven quite successful in experimental animal models for eliciting antigen-specific mucosal, humoral, and cellular responses, results have been disappointing for clinical trials carried out thus far. We hypothesize that the paucity of human responses to foreign antigens delivered by live vectors suggests that the strains and genetic approaches used to date have resulted in over-attenuated vaccine strains with severely reduced immunogenicity. However, remarkable advances have now been made in the genetics of foreign antigen expression, understanding mechanisms of live vector immunity, and refining immunization strategies. The time has now come for development of multivalent live vectors in which stable antigen expression is balanced with metabolic fitness to create highly immunogenic vaccines. PMID:19417771
Bányai, K; Sas, Yvette; Varga, L; Szucs, G
In anticipation of a future vaccination program against rotavirus disease, a longitudinal survey has been set up to evaluate the epidemiologic features of rotavirus infections. In this report hospitalisation data and serotyping results are compiled from an epidemiologic survey conducted in Baranya County, Hungary. It was found that rotavirus-associated hospitalisation constituted a major part of infectious gastroenteritis cases (range, 14.9% to 28.5%). A higher proportion of rotavirus-positive cases was recorded when the serotype of predominant strains changed from G1 (1996-1999) to G4 (1999-2000), however, due to the short time period it was not possible to demonstrate a firm association between serotype prevalence and rotavirus-associated hospitalisation rate. In the future, such studies might help to understand if serotype-specific immunity against rotavirus infection plays an important role at the population level and if (re-)emerging rotavirus strains make an impact on the annual disease burden.
Zhang, Junbo; Yin, Shuanghong; Guo, Fei; Meng, Ren; Chen, Chuangfu; Zhang, Hui; Li, Zhiqiang; Fu, Qiang; Shi, Huijun; Hu, Shengwei; Ni, Wei; Li, Tiansen; Zhang, Ke
Brucellosis is a globally distributed zoonotic disease that causes animal and human diseases. However, the current Brucella abortus vaccines (S19 and RB51) are deficient; they can cause abortion in pregnant animals. Moreover, when the vaccine S19 is used, tests cannot differentiate natural from vaccinated infection. Therefore, a safer and more potent vaccine is needed. A Brucella abortus 2308 ery promoter mutant (Δery) was constructed to overcome these drawbacks. The growth of the Δery mutant was significantly attenuated in macrophages and mice and induced high protective immunity in mice. Moreover, Δery induced an anti-Brucella-specific IgG (immunoglobulin G) response and stimulated the expression of interferon-gamma (INF-γ) and interleukin-4 (IL-4). Furthermore, the expression of EryA antigen allowed for the serological differentiation between natural and vaccinated infection in mice. These results indicate that the Δery mutant is a potential attenuated live vaccine candidate against virulent Brucella abortus 2308 (S2308) infection.
Tompkins, D. M.; Ramsey, D. S. L.; Cross, M. L.; Aldwell, F. E.; de Lisle, G. W.; Buddle, B. M.
Bovine tuberculosis (Tb) caused by Mycobacterium bovis has proved refractory to eradication from domestic livestock in countries with wildlife disease reservoirs. Vaccination of wild hosts offers a way of controlling Tb in livestock without wildlife culling. This study was conducted in a Tb-endemic region of New Zealand, where the introduced Australian brushtail possum (Trichosurus vulpecula) is the main wildlife reservoir of Tb. Possums were trapped and vaccinated using a prototype oral-delivery system to deliver the Tb vaccine bacille Calmette–Guerin. Vaccinated and control possums were matched according to age, sex and location, re-trapped bimonthly and assessed for Tb status by palpation and lesion aspiration; the site was depopulated after 2 years and post-mortem examinations were conducted to further identify clinical Tb cases and subclinical infection. Significantly fewer culture-confirmed Tb cases were recorded in vaccinated possums (1/51) compared with control animals (12/71); the transition probability from susceptible to infected was significantly reduced in both males and females by vaccination. Vaccine efficacy was estimated at 95 per cent (87–100%) for females and 96 per cent (82–99%) for males. Hence, this trial demonstrates that orally delivered live bacterial vaccines can significantly protect wildlife against natural disease exposure, indicating that wildlife vaccination, along with existing control methods, could be used to eradicate Tb from domestic animals. PMID:19493904
Sasaki, Sanae; Holmes, Tyson H.; Albrecht, Randy A.; García-Sastre, Adolfo; Dekker, Cornelia L.; He, Xiao-Song; Greenberg, Harry B.
Background. The immunological bases for the efficacies of the 2 currently licensed influenza vaccines, live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV), are not fully understood. The goal of this study was to identify specific B-cell responses correlated with the known efficacies of these 2 vaccines. Methods. We compared the B-cell and antibody responses after immunization with 2010/2011 IIV or LAIV in young adults, focusing on peripheral plasmablasts 6–8 days after vaccination. Results. The quantities of vaccine-specific plasmablasts and plasmablast-derived polyclonal antibodies (PPAbs) in IIV recipients were significantly higher than those in LAIV recipients. No significant difference was detected in the avidity of vaccine-specific PPAbs between the 2 vaccine groups. Proportionally, LAIV induced a greater vaccine-specific immunoglobulin A plasmablast response, as well as a greater plasmablast response to the conserved influenza nuclear protein, than IIV. The cross-reactive plasmablast response to heterovariant strains, as indicated by the relative levels of cross-reactive plasmablasts and the cross-reactive PPAb binding reactivity, was also greater in the LAIV group. Conclusions. Distinct quantitative and qualitative patterns of plasmablast responses were induced by LAIV and IIV in young adults; a proportionally greater cross-reactive response was induced by LAIV. PMID:24676204
Liang, Yan; Ma, Jingchen; Li, Changgui; Chen, Yuguo; Liu, Longding; Liao, Yun; Zhang, Ying; Jiang, Li; Wang, Xuan-Yi; Che, Yanchun; Deng, Wei; Li, Hong; Cui, Xiaoyu; Ma, Na; Ding, Dong; Xie, Zhongping; Cui, Pingfang; Ji, Qiuyan; Wang, Jingjing; Zhao, Yuliang; Wang, Junzhi; Li, Qihan
Background: Mumps, a communicable, acute and previously well-controlled disease, has had recent and occasional resurgences in some areas. Methods: A randomized, double-blind, controlled and multistep phase I study of an F-genotype attenuated mumps vaccine produced in human diploid cells was conducted. A total of 300 subjects were enrolled and divided into 4 age groups: 16–60 years, 5–16 years, 2–5 years and 8–24 months. The groups were immunized with one injection per subject. Three different doses of the F-genotype attenuated mumps vaccine, A (3.5 ± 0.25 logCCID50), B (4.25 ± 0.25 logCCID50) and C (5.0 ± 0.25 logCCID50), as well as a placebo control and a positive control of a licensed A-genotype vaccine (S79 strain) were used. The safety and immunogenicity of this vaccine were compared with those of the controls. Results: The safety evaluation suggested that mild adverse reactions were observed in all groups. No serious adverse event (SAE) was reported throughout the trial. The immunogenicity test showed a similar seroconversion rate of the neutralizing and ELISA antibody in the 2- to 5-year-old and 8- to 24-month-old groups compared with the seroconversion rate in the positive control. The GMT of the neutralizing anti-F-genotype virus antibodies in the vaccine groups was slightly higher than that in the positive control group. Conclusions: The F-genotype attenuated mumps vaccine evaluated in this clinical trial was demonstrated to be safe and have effective immunogenicity vs. control. PMID:24614759
Bajolet, O; Chippaux-Hyppolite, C
Rotaviruses represent 80% of recognized viral etiologies and 140 million cases of diarrhea per year. They strike young children with similar frequency throughout the world, but the mortality rate is high in developing countries only, with some 870,000 deaths per year (WHO, 1997). Rotaviruses belong to the family of Reoviridae; they are segmented bicatenary RNA viruses, which explains their genetic variability, the presence of mixed infections, the establishment for some time already of a molecular epidemiology by electrophore types. The viruses are "naked" and thus resistant to the outside environment; their massive elimination, 10(8) to 10(10)viral particles per gram of faeces, begins with the first day of diarrhea. They are found in used water and can also be concentrated by shellfish; the environment thus constitutes a notable reservoir for the virus. Oral-faecal transmission is facilitated by deficient sanitary conditions. The 11 fragments of the genome each codify for 1 viral protein; 2 surface proteins, VP4 and VP7, bring about the formation of neutralizing antibodies, which are important for the protection and determination of different serotypes. A non structural protein--NSP4--would seem to intervene in the cytopathogenic effect and may act as a veritable viral enterotoxine. Numerous animal species are infected by rotaviruses which are district from the human ones. The pathology as it affects animals is of economic importance and of interest as an experimental and vaccinal model. Between human and animal rotaviruses there can be genetic rematchings and the VP6 protein is an antigen common to the group. The description of the other viruses responsible for diarrhea has benefited from widespread use of electronic microscopes from the very first years of study of rotaviruses. These other viruses belong to 6 different types: adenovirus, calcivirus, astrovirus, Norwalk agent and related viruses, coronavirus, enterovirus. They therefore have a structural and
Yin, Yuebang; Bijvelds, Marcel; Dang, Wen; Xu, Lei; van der Eijk, Annemiek A; Knipping, Karen; Tuysuz, Nesrin; Dekkers, Johanna F; Wang, Yijin; de Jonge, Jeroen; Sprengers, Dave; van der Laan, Luc J W; Beekman, Jeffrey M; Ten Berge, Derk; Metselaar, Herold J; de Jonge, Hugo; Koopmans, Marion P G; Peppelenbosch, Maikel P; Pan, Qiuwei
Despite the introduction of oral vaccines, rotavirus still kills over 450,000 children under five years of age annually. The absence of specific treatment prompts research aiming at further understanding of pathogenesis and the development of effective antiviral therapy, which in turn requires advanced experimental models. Given the intrinsic limitations of the classical rotavirus models using immortalized cell lines infected with laboratory-adapted strains in two dimensional cultures, our study aimed to model infection and antiviral therapy of both experimental and patient-derived rotavirus strains using three dimensional cultures of primary intestinal organoids. Intestinal epithelial organoids were successfully cultured from mouse or human gut tissues. These organoids recapitulate essential features of the in vivo tissue architecture, and are susceptible to rotavirus. Human organoids are more permissive to rotavirus infection, displaying an over 10,000-fold increase in genomic RNA following 24h of viral replication. Furthermore, infected organoids are capable of producing infectious rotavirus particles. Treatment of interferon-alpha or ribavirin inhibited viral replication in organoids of both species. Importantly, human organoids efficiently support the infection of patient-derived rotavirus strains and can be potentially harnessed for personalized evaluation of the efficacy of antiviral medications. Therefore, organoids provide a robust model system for studying rotavirus-host interactions and assessing antiviral medications.
Wang, Yali; Dong, Duo; Cheng, Gang; Zuo, Shuyan; Liu, Dawei; Du, Xiaoxi
Japanese encephalitis (JE) is the most severe form of viral encephalitis in Asia and no specific treatment is available. Vaccination provides an effective intervention to prevent JE. In this paper, surveillance data for adverse events following immunization (AEFI) related to SA-14-14-2 live-attenuated Japanese encephalitis vaccine (Chengdu Institute of Biological Products) was presented. This information has been routinely generated by the Chinese national surveillance system for the period 2009-2012. There were 6024 AEFI cases (estimated reported rate 96.55 per million doses). Most common symptoms of adverse events were fever, redness, induration and skin rash. There were 70 serious AEFI cases (1.12 per million doses), including 9 cases of meningoencephalitis and 4 cases of death. The post-marketing surveillance data add the evidence that the Chengdu institute live attenutated vaccine has a reasonable safety profile. The relationship between encephalitis and SA-14-14-2 vaccination should be further studied.
Ramsay, Edward; Sadler, Ryan; Rush, Robert; Seimon, Tracie; Tomaszewicz, Ania; Fleetwood, Ellen A; McAloose, Denise; Wilkes, Rebecca P
Three methods for delivering a live attenuated canine distemper virus (CDV) vaccine to domestic cats ( Felis catus ) were investigated, as models for developing vaccination protocols for tigers (Panthera tigris). Twenty domestic cats were randomly divided into four treatment groups: saline injection (negative controls); and oral, intranasal, and subcutaneous vaccinates. Cats were injected with saline or a CDV vaccine (Nobivac DP, Merck) at wk 0 and 4. Blood and nasal swabs were collected at wk 0 (prior to the initial vaccination) and weekly thereafter for 9 wk. Urine samples were collected on wk 1 to 9 after initial vaccination. Forty-nine weeks following the initial vaccination series, three cats from the subcutaneous group and three cats from the intranasal group were revaccinated. Blood was collected immediately prior, and 7 and 21 days subsequent to revaccination. Nasal swabs and urine samples were collected from each cat prior to wk 49 revaccination and daily for 7 days thereafter. Nasal swabs and urine were analyzed by quantitative PCR for vaccine virus presence. Sera were tested for CDV antibodies by virus neutralization. All cats were sero-negative for CDV antibodies at the beginning of the study, and saline-injected cats remained sero-negative throughout the study. A dramatic anamnestic response was seen following wk 4 subcutaneous vaccinations, with titers peaking at wk 6 (geometric mean = 2,435.5). Following wk 49 revaccination, subcutaneous vaccinates again mounted impressive titers (wk 52 geometric mean = 2,048). Revaccination of the intranasal group cats at wk 49 produced a small increase in titers (wk 52 geometric mean = 203). CDV viral RNA was detected in six nasal swabs but no urine samples, demonstrating low viral shedding postvaccination. The strong antibody response to subcutaneous vaccination and the lack of adverse effects suggest this vaccine is safe and potentially protective against CDV infection in domestic cats.
Maiztegui, J I; McKee, K T; Barrera Oro, J G; Harrison, L H; Gibbs, P H; Feuillade, M R; Enria, D A; Briggiler, A M; Levis, S C; Ambrosio, A M; Halsey, N A; Peters, C J
Argentine hemorrhagic fever (AHF), caused by the arenavirus Junin, is a major public health problem among agricultural workers in Argentina. A prospective, randomized, double-blind, placebo-controlled, efficacy trial of Candid 1, a live attenuated Junin virus vaccine, was conducted over two consecutive epidemic seasons among 6500 male agricultural workers in the AHF-endemic region. Twenty-three men developed laboratory-confirmed AHF during the study; 22 received placebo and 1 received vaccine (vaccine efficacy 95%; 95% confidence interval [CI], 82%-99%). Three additional subjects in each group developed laboratory-confirmed Junin virus infection associated with mild illnesses that did not fulfill the clinical case definition for AHF, yielding a protective efficacy for prevention of any illness associated with Junin virus infection of 84% (95% CI, 60%-94%). No serious adverse events were attributed to vaccination. Candid 1, the first vaccine for the prevention of illness caused by an arenavirus, is safe and highly efficacious.
Periaswamy, Balamurugan; Maier, Lisa; Vishwakarma, Vikalp; Slack, Emma; Kremer, Marcus; Andrews-Polymenis, Helene L.; McClelland, Michael; Grant, Andrew J.; Suar, Mrutyunjay; Hardt, Wolf-Dietrich
Live attenuated vaccines are of great value for preventing infectious diseases. They represent a delicate compromise between sufficient colonization-mediated adaptive immunity and minimizing the risk for infection by the vaccine strain itself. Immune defects can predispose to vaccine strain infections. It has remained unclear whether vaccine safety could be improved via mutations attenuating a vaccine in immune-deficient individuals without compromising the vaccine's performance in the normal host. We have addressed this hypothesis using a mouse model for Salmonella diarrhea and a live attenuated Salmonella Typhimurium strain (ssaV). Vaccination with this strain elicited protective immunity in wild type mice, but a fatal systemic infection in immune-deficient cybb−/−nos2−/− animals lacking NADPH oxidase and inducible NO synthase. In cybb−/−nos2−/− mice, we analyzed the attenuation of 35 ssaV strains carrying one additional mutation each. One strain, Z234 (ssaV SL1344_3093), was >1000-fold attenuated in cybb−/−nos2−/− mice and ≈100 fold attenuated in tnfr1−/− animals. However, in wt mice, Z234 was as efficient as ssaV with respect to host colonization and the elicitation of a protective, O-antigen specific mucosal secretory IgA (sIgA) response. These data suggest that it is possible to engineer live attenuated vaccines which are specifically attenuated in immuno-compromised hosts. This might help to improve vaccine safety. PMID:23029007
Species-specific but not genotype-specific primary and secondary isotype-specific NSP4 antibody responses in gnotobiotic calves and piglets infected with homologous host bovine (NSP4[A]) or porcine (NSP4[B]) rotavirus.
Yuan, Lijuan; Honma, Shinjiro; Ishida, Shin-Ichi; Yan, Xiao-Yi; Kapikian, Albert Z; Hoshino, Yasutaka
Using recombinant baculoviruses expressing rotavirus NSP4 [A], [B], [C], and [D] genotypes of bovine, porcine, human, simian, or murine origin, we analyzed serum antibody responses to NSP4s in gnotobiotic calves and piglets infected by the oral/alimentary or intraamniotic route with bovine (NSP4[A]) (Wyatt, R.G., Mebus, C.A., Yolken, R.H., Kalica, A.R., James, H.D., Jr., Kapikian, A.Z., Chanock, R.M., 1979. Rotaviral immunity in gnotobiotic calves: heterologous resistance to human virus induced by bovine virus. Science 203(4380), 548-550) or porcine (NSP4[B]) (Hoshino, Y., Saif, L.J., Sereno, M.M., Chanock, R.M., Kapikian, A.Z., 1988. Infection immunity of piglets to either VP3 or VP7 outer capsid protein confers resistance to challenge with a virulent rotavirus bearing the corresponding antigen. J. Virol. 62(3), 744-748) rotaviruses. Following primary infection and challenge with virulent rotaviruses, the animals developed higher or significantly higher antibody titers to homologous host homotypic NSP4s than to heterologous host homotypic or heterologous host heterotypic NSP4s, indicating that antibody responses were species specific rather than genotype specific. Antibody responses to NSP4s corresponded closely with the phylogenetic relationships of NSP4s within a species-specific region of amino acids (aa) 131-141. In contrast, NSP4 genotypes determined by amino acid full-length sequence identity predicted poorly their "serotypes". In piglets, antibodies to NSP4 induced by previous oral infection failed to confer protection against challenge from a porcine rotavirus bearing serotypically different VP4 and VP7 but essentially identical NSP4 to the porcine rotavirus in primary infection. Thus, in an approach to immunization with a live oral rotavirus vaccine, the NSP4 protein does not appear to play an important role in protection against rotavirus disease and infection.
This review covers comprehensive data accumulated during the long history of using monkeys in the determination of neurovirulence activity and safety of live poliomyelitis, flaviviral, smallpox and mumps vaccines, as well as newly developed transgenic mouse and molecular-biological tests. The review also analyzes processes caused by some of these viruses in infant rodents (mice, rats) and evaluates the role of these processes in vaccine safety control. Recommendations resulting from this analysis are presented.
Glass, Roger I.; Parashar, Umesh; Patel, Manish; Tate, Jacqueline; Jiang, Baoming; Gentsch, Jon
Since 2006, two new vaccines have been licensed to prevent rotavirus, the cause of 20% to 50% of severe acute gastroenteritis in young children worldwide. These vaccines have been implemented in national immunization programs in about 30 high- and middle-income countries, including the United States, and vaccine use has led to substantial decreases in diarrhea-related health care visits. In addition to reductions in diarrhea burden in vaccinated children, decreases have been observed in older, unvaccinated age groups in many settings, suggesting indirect benefits (i.e., herd immunity) from vaccination. Although the efficacy of these oral rotavirus vaccines is expectedly lower in developing countries in Asia and Africa, the public health benefits of vaccination in these settings, where more than 90% of the estimated 453,000 annual deaths from rotavirus occur, are likely to be substantial. Efforts continue to develop alternative rotavirus vaccines that could have a better efficacy and safety profile and may be less expensive. PMID:23303967
Whitehead, Stephen S
Dengue is caused by four serotype-distinct dengue viruses (DENVs), and developing a multivalent vaccine against dengue has not been straightforward since partial immunity to DENV may predispose to more severe disease upon subsequent DENV infection. The vaccine that is furthest along in development is CYD™, a live attenuated tetravalent vaccine (LATV) produced by Sanofi Pasteur. Although the multi-dose vaccine demonstrated protection against severe dengue, its overall efficacy was limited by DENV serotype, serostatus at vaccination, region and age. The National Institute of Allergy and Infectious Diseases has developed the LATV dengue vaccines TV003/TV005. A single dose of either TV003 or TV005 induced seroconversion to four DENV serotypes in 74-92% (TV003) and 90% (TV005) of flavivirus seronegative adults and elicited near-sterilizing immunity to a second dose of vaccine administered 6-12 months later. The important differences in the structure, infectivity and immune responses to TV003/TV005 are compared with CYD™.
Ogawa, Yohsuke; Oishi, Eiji; Muneta, Yoshihiro; Sano, Akiyuki; Hikono, Hirokazu; Shibahara, Tomoyuki; Yagi, Yukio; Shimoji, Yoshihiro
Erysipelothrix rhusiopathiae Koganei 65-0.15 strain, the live swine erysipelas vaccine for subcutaneous injection, has been shown to colonize the tonsils of pigs after oral inoculation. We thus evaluated the possible use of the strain as a vector for oral vaccination against mycoplasmal pneumonia of swine. Recombinant E. rhusiopathiae strains expressing the C-terminal domain of the P97 adhesin of Mycoplasma hyopneumoniae were constructed and examined for vaccine efficacy in mice and pigs. Mice subcutaneously inoculated with the recombinant strains were protected from challenge exposure to a virulent E. rhusiopathiae. Administration of milk replacer containing recombinant E. rhusiopathiae expressing the M. hyopneumoniae protein protected pigs from death after exposure to E. rhusiopathiae and significantly reduced the severity of pneumonic lung lesions caused by infection with M. hyopneumoniae.
Effective and easy to administer cholera vaccines are in need more than ever, for at risk populations and travellers alike. In many parts of the world cholera is still endemic, causing outbreaks and constituting repeatedly serious public health problems. The oral live cholera vaccine CVD 103-HgR (Orochol, Mutachol), the first genetically modified organism (GMO) used as vaccine, was in its time (launched 1993, Switzerland) the ideal cholera vaccine: single-dose, protective efficacy of 80-100% against moderate to severe cholera, acting within 8 days and exhibiting excellent safety, indiscernible from placebo. However, there were strong headwinds: In the 1990s the indication for cholera vaccines was generally downplayed by experts and in 1997 the European Commission called for a moratorium of GMOs which blocked the registration in the European Union. Thus, demand for this vaccine remained low and in 2003 it was taken off the market for economic reasons. After a decade in obscurity it (Vaxchora) has resurfaced again, now produced in the U.S. and equipped with a U.S. FDA license (June 10, 2016). What had happened? This commentary gives a critical account of an almost unbelievable string of misadventures, emerging adverse circumstances and man-made failures which nearly killed this single-dose live oral cholera vaccine. The good news is that patience and persistence lead to success in the end, allowing good science to prevail for the benefit of those in need.
Shearer, William T.; Fleisher, Thomas A.; Buckley, Rebecca H.; Ballas, Zuhair; Ballow, Mark; Blaese, R. Michael; Bonilla, Francisco A.; Conley, Mary Ellen; Charlotte-Cunningham-Rundles; Filipovich, Alexandra H.; Fuleihan, Ramsay; Gelfand, Erwin W.; Hernandez-Trujillo, Vivian; Holland, Steven M.; Hong, Richard; Lederman, Howard M.; Malech, Harry L.; Miles, Stephen; Notarangelo, Luigi D.; Ochs, Hans D.; Orange, Jordan S.; Puck, Jennifer M.; Routes, John M.; Stiehm, E. Richard; Sullivan, Kathleen; Torgerson, Troy; Winkelstein, Jerry
The present uncertainty of which live viral or bacterial vaccines may be given to immune deficient patients and the growing neglect of societal adherence to routine immunizations has prompted the Medical Advisory Committee of the Immune Deficiency Foundation to issue recommendations based upon published literature and the collective experience of the committee members. These recommendations address the concern for immunodeficient patients acquiring infections from healthy individuals who have not been immunized or who are shedding live vaccine-derived viral or bacterial organisms. Such transmission of infectious agents may occur within the hospital, clinic, home, or at any public gathering. Collectively, we define this type transmission as close-contact spread of infectious disease that is particularly relevant in patients with impaired immunity who may develop infection when exposed to individuals carrying vaccine-preventable infectious diseases or who have recently received a live vaccine. Immunodeficient patients who have received therapeutic hematopoietic stem transplantation are also at risk during the time when immune reconstitution is incomplete or while they are on immunosuppressive agents to prevent or treat graft-versus-host disease. This review recommends the general education of what is known about vaccine-preventable or vaccine-derived diseases being spread to immunodeficient patients at risk for close-contact spread of infection, and describes the relative risks for a child with severe immunodeficiency. The review also recommends a balance between the need to protect vulnerable individuals with their social needs to integrate into society, attend school, and benefit from peer education. PMID:24582311
Hayami, Masanori; Horiuchi, Reii
A great effort for developing AIDS vaccine has been carried out in the world, designed by various new ideas based on basic research information obtained in recent virology and immunology. Withall it, to obtain effective AIDS vaccine is considered skeptical. One of the reasons of its difficulty is a lack of experimental animals susceptible to HIV-1. In our laboratory, we have succeeded in developing chimeric SIV having 3' half of HIV-1 genome including env (SHIV), which is infectious to macaque monkeys. One of SHIVs has been proved nonpathogenic in monkeys from various aspects and it afforded protective immunity to monkeys against pathogenic SHIV challenge infection. Now, we are trying to develop anti-HIV live attenuated vaccines using the nonpathogenic SHIV as a starting material. In the history of virus vaccine, live attenuated vaccines have been proved most effective in measles and polio-myelitis. However, it is not clear whether nonpathogenic HIV exists or not. Futhermore, even if nonpathogenic HIV could be obtained, there is possibility that it will easily mutate to pathogenic one. Therefore, to develop live attenuated AIDS vaccine is considered dangerous. In this article, We will introduce our research on SHIV pathogenicity using monkeys and hypothesize possibility to obtain nonpathogenic HIV which is speculated from the origin and evolution of HIV/SIV. To clarify virulence and nonvirulence of HIV and to obtain nonpathogenic virus are not only applied research but also basic science to dissolve the fundemental question why HIV can induce the disease.
Blaney, Joseph E; Hanson, Christopher T; Firestone, Cai-Yen; Hanley, Kathryn A; Murphy, Brian R; Whitehead, Stephen S
Three novel recombinant dengue type 3 (DEN3) virus vaccine candidates have been generated from a DEN3 virus isolated from a mild outbreak of dengue fever in the Sleman area of central Java in Indonesia in 1978. Antigenic chimeric viruses were prepared by replacing the membrane precursor and envelope (ME) proteins of recombinant DEN4 (rDEN4) virus with those from DEN3 Sleman/78 in the presence (rDEN3/4Delta30(ME)) and the absence (rDEN3/4(ME)) of the Delta30 mutation, a previously described 30-nucleotide deletion in the 3' untranslated region. In addition, a full-length infectious cDNA clone was generated from the DEN3 isolate and used to produce rDEN3 virus and the vaccine candidate rDEN3Delta30. The chimeric viruses rDEN3/4(ME) and rDEN3/4Delta30(ME) appear to be acceptable vaccine candidates since they were restricted in replication in severe combined immune deficiency mice transplanted with human hepatoma cells, in rhesus monkeys, and in Aedes and Toxorynchites mosquitoes, and each was protective in rhesus monkeys against DEN3 virus challenge. The rDEN3/4(ME) and rDEN3/4Delta30(ME) viruses were comparable in all parameters evaluated, indicating that antigenic chimerization resulted in the observed high level of attenuation. Surprisingly, rDEN3Delta30 was not attenuated in any model tested when compared with wild-type rDEN3 and therefore, is not a vaccine candidate at present. Thus, the rDEN3/4(ME) and rDEN3/4Delta30(ME) antigenic chimeric viruses can be considered for evaluation in humans and for inclusion in a tetravalent dengue vaccine.
Matson, D O; O'Ryan, M L; Pickering, L K; Chiba, S; Nakata, S; Raj, P; Estes, M K
Knowledge of the immune response to rotavirus is crucial for vaccine development. We compared an epitope-blocking assay (EBA) that uses VP7-specific monoclonal antibodies with neutralization assays (NAs) with polyclonal antisera for detecting serum antibody responses after natural rotavirus infection in children. Twenty-six serum pairs from children living in an orphanage with and without symptoms during two rotavirus outbreaks were evaluated for VP7 type 1-, 2-, 3-, and 4-specific antibody responses. In the first outbreak, which was caused by a VP7 type 3 strain, homotypic antibody responses were detected in 11 of 11 symptomatic children by NA and in 10 of 11 symptomatic children by EBA. Heterotypic antibody responses were detected more frequently (12 of 15 children) by NA than by EBA, and the heterotypic epitope-blocking antibody responses occurred in children older than 14 months of age. Antibody responses in asymptomatic children were more commonly detected by EBA than by NA. EBA results from the sera of children in the second outbreak indicated that it was caused by VP7 type 4, whereas NA results suggested it was caused by VP7 type 3. Our results confirm that EBA is a sensitive and specific method for determining VP7 type-specific immune responses after natural rotavirus infections. PMID:1374761
González-Ochoa, G; J, G de; Calleja-García, P M; Rosas-Rodríguez, J A; Virgen-Ortíz, A; Tamez-Guerra, P
Rotavirus is the most common cause of gastroenteritis in children up to five years of age worldwide. The aim of the present study was to analyze the genotypes of rotavirus strains isolated from children with gastroenteritis, after the introduction of the rotavirus vaccine in México. Rotavirus was detected in 14/100 (14%) fecal samples from children with gastroenteritis, using a commercial test kit. The viral genome was purified from these samples and used as a template in RT-PCR amplification of the VP4 and VP7 genes, followed by gene cloning and sequencing. Among the rotavirus strains, 4/14 (28.5%) were characterized as G12P, 2/14 (14.3%), as G12P (not typed), and 3/14 (21.42%) as G (not typed) P. Phylogenetic analysis of the VP7 gene showed that G12 genotypes clustered in lineage III. Phylogenetic analysis revealed that VP4 genotype P sequences clustered in lineage V, whereas other P sequences previously reported in Mexico (2005-2008) clustered in different lineages. Rotavirus genotype G12 is currently recognized as a globally emerging rotavirus. To our knowledge, this is the first report of this emerging rotavirus strain G12P in México. Ongoing surveillance is recommended to monitor the distribution of rotavirus genotypes and to continually reassess the suitability of currently available rotavirus vaccines.
Popova, P Yu; Mikshis, N I
Live genetic engineering anthrax vaccines on the platform of avirulent and probiotic micro-organisms are a safe and adequate alternative to preparations based on attenuated Bacillus anthracis strains. Mucosal application results in a direct contact of the vaccine preparations with mucous membranes in those organs arid tissues of the macro-organisms, that are exposed to the pathogen in the first place, resulting in a development of local and systemic immune response. Live recombinant anthrax vaccines could be used both separately as well as in a prime-boost immunization scheme. The review focuses on immunogenic and protective properties of experimental live genetic engineering prearations, created based on members of geni of Salmonella, Lactobacillus and adenoviruses.
Than, Van Thai; Jeong, Sunyoung; Kim, Wonyong
Rotavirus infections continue to be the leading cause of severe diarrhea in young Korean children. Rotavirus data acquired from uninterrupted surveillance studies between 1989 and 2009 in South Korea were analyzed to better understand the genetic diversity and evolution. The relationship between rotaviruses and the currently licensed rotavirus vaccine viruses was also examined. The most prevalent rotavirus strains, with genotype G1P, followed by G3P, G4P, and G2P, accounted for approximately 76.7% of the total identified strains, and more recently, rotavirus G9P has significance increased to be the fifth most common genotype. Phylogenetic analyses underscored the heterogeneity between viral populations within each genotype, with different lineages and sub-lineages. Although the currently licensed rotavirus vaccines are effective, safe, and economical, additional data from rotavirus monitoring is necessary to evaluate the efficacy of these vaccines for their sustained use in South Korea. The present study provides comprehensive and up-to-date information regarding the epidemiology, genetic diversity, and evolution of the circulating rotaviruses in South Korea.
Ohtake, Satoshi; Martin, Russell; Saxena, Atul; Pham, Binh; Chiueh, Gary; Osorio, Manuel; Kopecko, Dennis; Xu, DeQi; Lechuga-Ballesteros, David; Truong-Le, Vu
Foam drying, a modified freeze drying process, was utilized to produce a heat-stable, live attenuated Salmonella Typhi ‘Ty21a’ bacterial vaccine. Ty21a vaccine was formulated with pharmaceutically approved stabilizers, including sugars, plasticizers, amino acids, and proteins. Growth media and harvesting conditions of the bacteria were also studied to enhance resistance to desiccation stress encountered during processing as well as subsequent storage at elevated temperatures. The optimized Ty21a vaccine, formulated with trehalose, methionine, and gelatin, demonstrated stability for approximately 12 weeks at 37°C (i.e., time required for the vaccine to decrease in potency by 1log10 CFU) and no loss in titer at 4 and 25°C following storage for the same duration. Furthermore, the foam dried Ty21a elicited a similar immunogenic response in mice as well as protection in challenge studies compared to Vivotif™, the commercial Ty21a vaccine. The enhanced heat stability of the Ty21a oral vaccine, or Ty21a derivatives expressing foreign antigens (e.g. anthrax), could mitigate risks of vaccine potency loss during long term storage, shipping, delivery to geographical areas with warmer climates or during emergency distribution following a bioterrorist attack. Because the foam drying process is conducted using conventional freeze dryers and can be readily implemented at any freeze drying manufacturing facility, this technology appears ready and appropriate for large scale processing of foam dried vaccines. PMID:21300096
Chaussee, Michael S; Sandbulte, Heather R; Schuneman, Margaret J; Depaula, Frank P; Addengast, Leslie A; Schlenker, Evelyn H; Huber, Victor C
Mortality associated with influenza virus super-infections is frequently due to secondary bacterial complications. To date, super-infections with Streptococcus pyogenes have been studied less extensively than those associated with Streptococcus pneumoniae. This is significant because a vaccine for S. pyogenes is not clinically available, leaving vaccination against influenza virus as our only means for preventing these super-infections. In this study, we directly compared immunity induced by two types of influenza vaccine, either inactivated influenza virus (IIV) or live, attenuated influenza virus (LAIV), for the ability to prevent super-infections. Our data demonstrate that both IIV and LAIV vaccines induce similar levels of serum antibodies, and that LAIV alone induces IgA expression at mucosal surfaces. Upon super-infection, both vaccines have the ability to limit the induction of pro-inflammatory cytokines within the lung, including IFN-γ which has been shown to contribute to mortality in previous models of super-infection. Limiting expression of these pro-inflammatory cytokines within the lungs subsequently limits recruitment of macrophages and neutrophils to pulmonary surfaces, and ultimately protects both IIV- and LAIV-vaccinated mice from mortality. Despite their overall survival, both IIV- and LAIV-vaccinated mice demonstrated levels of bacteria within the lung tissue that are similar to those seen in unvaccinated mice. Thus, influenza virus:bacteria super-infections can be limited by vaccine-induced immunity against influenza virus, but the ability to prevent morbidity is not complete.
Posa, Molly R.; Kelly, Maria N.
Intussusception is one of the most frequent causes of intestinal obstruction in infants. Rotavirus vaccination has been associated with intussusception in the medical literature. We report a case of a 4-month-old female with intussusception requiring hemicolectomy one week following rotavirus vaccination. We review the pathophysiology, presentation, and management of intussusception with a distinct focus on the history of rotavirus vaccination and risks of intussusception associated with timing of rotavirus vaccine administration. The discussion makes a strong case for rotavirus vaccine counseling regarding signs of intestinal obstruction and the importance of early recognition. PMID:28163948
Jones, Forrest K; Ko, Albert I; Becha, Chris; Joshua, Cynthia; Musto, Jennie; Thomas, Sarah; Ronsse, Axelle; Kirkwood, Carl D; Sio, Alison; Aumua, Audrey; Nilles, Eric J
Flooding on 1 of the Solomon Islands precipitated a nationwide epidemic of diarrhea that spread to regions unaffected by flooding and caused >6,000 cases and 27 deaths. Rotavirus was identified in 38% of case-patients tested in the city with the most flooding. Outbreak potential related to weather reinforces the need for global rotavirus vaccination.
Jones, Forrest K.; Ko, Albert I.; Becha, Chris; Joshua, Cynthia; Musto, Jennie; Thomas, Sarah; Ronsse, Axelle; Kirkwood, Carl D.; Sio, Alison; Aumua, Audrey
Flooding on 1 of the Solomon Islands precipitated a nationwide epidemic of diarrhea that spread to regions unaffected by flooding and caused >6,000 cases and 27 deaths. Rotavirus was identified in 38% of case-patients tested in the city with the most flooding. Outbreak potential related to weather reinforces the need for global rotavirus vaccination. PMID:27088272
Lagos, R; Fasano, A; Wasserman, S S; Prado, V; San Martin, O; Abrego, P; Losonsky, G A; Alegria, S; Levine, M M
Several live oral vaccines (polio, bovine rotavirus, CVD 103-HgR cholera) are less immunogenic in developing than in industrialized countries. It was hypothesized that proximal small bowel bacterial overgrowth (common in children in less developed countries but rare in industrialized settings) diminishes the vibriocidal antibody response to CVD 103-HgR. In total, 202 fasting Santiago schoolchildren aged 5-9 years had lactulose breath H2 tests to detect proximal small bowel bacteria 1 day before ingesting CVD 103-HgR. Florid small bowel overgrowth was observed in 10 (5.6%) of 178 analyzable children. In children with florid overgrowth, vibriocidal seroconversion differed little from other children (60% vs. 67%), but the geometric mean titer was lower (160 vs. 368; P=.25). By logistic regression, increased peak breath H2 at small bowel time points was associated with diminished seroconversion (P=.04), as was the interaction of H2 value and weight (children >25 kg had lower seroconversion rates among subjects with heaviest overgrowth).
Department of the Army position unless so designated by other authorized documents. 7, S"|ECuRITY CLASSIFICATION Or THIS PAGE (W*PR Deem Enteewd) REPORT...properties justifying trial as oral-route vaccine in human volunteers will soon he completed. If such a strain gives satisfactory results, in respect of...biosynthetic (aro) both in biotype and in that it is virulent for calves’?. A nLn- pathway. A complete block at any .step of this pathway should reverting
Zhang, Zhilun; Zhu, Xiangjun; Hu, Yuansheng; Liang, Miao; Sun, Jin; Song, Yufei; Yang, Qi; Ji, Haiquan; Zeng, Gang; Song, Lifei; Chen, Jiangting
In China, both inactivated hepatitis A (HA) vaccine and live attenuated HA vaccine are available. We conducted a trial to evaluate 5-year immune persistence induced by one dose of inactivated or live attenuated HA vaccines in children. Subjects with no HA vaccination history had randomly received one dose of inactivated or live attenuated HA vaccine at 18-60 months of age. Anti-HAV antibody concentrations were measured before vaccination and at the first, second, and fifth year after vaccination. Suspected cases of hepatitis A were monitored during the study period. A total of 332 subjects were enrolled and 182 provided evaluable serum samples at all planned time points. seropositive rate at 5 y was 85.9% in the inactivated HA vaccine group and 90.7% in the live attenuated HA vaccine group. GMCs were 76.3% mIU/ml (95% CI: 61.7 - 94.4) and 66.8mIU/ml (95% CI: 57.8 - 77.3), respectively. No significant difference in antibody persistence between 2 groups was found. No clinical hepatitis A case was reported. A single dose of an inactivated or live attenuated HA vaccine at 18-60 months of age resulted in high HAV seropositive rate and anti-HAV antibody concentrations that lasted for at least 5 y.
Chokephaibulkit, K; Houillon, G; Feroldi, E; Bouckenooghe, A
JE-CV (IMOJEV®, Sanofi Pasteur, France) is a live attenuated virus vaccine constructed by inserting coding sequences of the prM and E structural proteins of the Japanese encephalitis SA14-14-2 virus into the genome of yellow fever 17D virus. Primary immunization with JE-CV requires a single dose of the vaccine. This article reviews clinical trials of JE-CV in children aged up to 6 years conducted in countries across South-East Asia. Strong and persistent antibody responses were observed after single primary and booster doses, with 97% of children seroprotected up to five years after booster vaccination. Models of long-term antibody persistence predict a median duration of protection of approximately 30 years after a booster dose. The safety and reactogenicity profiles of JE-CV primary and booster doses are comparable to other widely used childhood vaccines.
Si, Longlong; Xu, Huan; Zhou, Xueying; Zhang, Ziwei; Tian, Zhenyu; Wang, Yan; Wu, Yiming; Zhang, Bo; Niu, Zhenlan; Zhang, Chuanling; Fu, Ge; Xiao, Sulong; Xia, Qing; Zhang, Lihe; Zhou, Demin
The conversion of life-threatening viruses into live but avirulent vaccines represents a revolution in vaccinology. In a proof-of-principle study, we expanded the genetic code of the genome of influenza A virus via a transgenic cell line containing orthogonal translation machinery. This generated premature termination codon (PTC)-harboring viruses that exerted full infectivity but were replication-incompetent in conventional cells. Genome-wide optimization of the sites for incorporation of multiple PTCs resulted in highly reproductive and genetically stable progeny viruses in transgenic cells. In mouse, ferret, and guinea pig models, vaccination with PTC viruses elicited robust humoral, mucosal, and T cell-mediated immunity against antigenically distinct influenza viruses and even neutralized existing infecting strains. The methods presented here may become a general approach for generating live virus vaccines that can be adapted to almost any virus.
Ghosh, Pallab; Shippy, Daniel C; Talaat, Adel M
Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) causes Johne's disease, a chronic enteric infection in ruminants with severe economic impact on the dairy industry in the USA and worldwide. Currently, available vaccines have limited protective efficacy against disease progression and does not prevent spread of the infection among animals. Because of their ability to elicit wide-spectrum immune responses, we adopted a live-attenuated vaccine approach based on a sigH knock-out strain of M. paratuberculosis (ΔsigH). Earlier analysis of the ΔsigH mutant in mice indicated their inadequate ability to colonize host tissues, unlike the isogenic wild-type strain, validating the role of this sigma factor in M. paratuberculosis virulence. In the present study, we evaluated the performance of the ΔsigH mutant compared to inactivated vaccine constructs in a vaccine/challenge model of murine paratuberculosis. The presented analysis indicated that ΔsigH mutant with or without QuilA adjuvant is capable of eliciting strong immune responses (such as interferon gamma-γ, IFN-γ) suggesting their immunogenicity and ability to potentially initiate effective vaccine-induced immunity. Following a challenge with virulent strains of M. paratuberculosis, ΔsigH conferred protective immunity as indicated by the reduced bacterial burden accompanied with reduced lesions in main body organs (liver, spleen and intestine) usually infected with M. paratuberculosis. More importantly, our data indicated better ability of the ΔsigH vaccine to confer protection compared to the inactivated vaccine constructs even with the presence of oil-adjuvant. Overall, our approach provides a rational basis for using live-attenuated mutant strains to develop improved vaccines that elicit robust immunity against this chronic infection.
Li, Yang; Hu, Yan; Cui, Shuai; Fu, Jiayuan; Wang, Yixin; Cui, Zhizhong; Fang, Lichun; Chang, Shuang; Zhao, Peng
The aim of this study was to investigate possible causes of the pervasiveness of chicken infectious anemia virus ( CIAV: ) infection in chickens in recent years in China. A total of 14 batches of live-virus vaccines were examined using PCR to detect CIAV contamination, of which only 2 samples (a Newcastle disease vaccine and a fowl pox vaccine) tested positive for CIAV. These Newcastle and fowl pox vaccines were then inoculated into 1-day-old specific-pathogen-free chickens. Serum samples were collected from chickens infected with the PCR-positive vaccines, and these tested positive for CIAV-specific antibodies as tested using ELISA. In addition, DNA samples isolated from the serum samples also tested positive by PCR. The results indicated that the samples were contaminated with CIAV and identified 2 exogenous CIAV strains, designated CIAV-N22 and CIAV-F10, in the respective samples. The full genome sequences of these novel CIAV strains were sequenced and analyzed. Phylogenetic tree analysis indicated that the CIAV-F10 strain might represent a recombinant viral strain arising from the parental CIAV strains JQ690762 and KJ728816. Overall, the results suggested that vaccination with CIAV-contaminated vaccines contributed to the prevalence and spread of CIAV infection in chickens. Furthermore, the CIAV contaminant was likely subsequently transmitted to commercial chickens through congenital transmission. Our findings therefore highlight the need for more extensive screening of live-virus vaccines for poultry in China to reduce the threat of contamination with exogenous viruses.
Commercially available attenuated strains of Mycoplasma gallisepticum (MG) are commonly used within the layer industry to control MG-induced mycoplasmosis. Among these are two live MG vaccines derived from the moderately pathogenic MG “chick F” strain. In the present study, the commercially availa...
Live egg -yolk tularemia vaccine used cutaneously causes in the human organism the same special intradermal allergy reaction to tularemia as does...tularemia was distinguished by sharpness during the entire period of observations, in the following proportions: during the first month after
To develop attenuated bacteria as potential live vaccines, sparfloxacin was used in this study to modify 40 isolates of Streptococcus agalactiae. Majority of S. agalactiae used in this study were able to develop at least 80-fold resistance to sparfloxacin. When the virulence of the sparfloxacin-resi...
Bergthaler, Andreas; Gerber, Nicolas U; Merkler, Doron; Horvath, Edit; de la Torre, Juan Carlos; Pinschewer, Daniel D
Arenaviruses such as Lassa fever virus cause significant mortality in endemic areas and represent potential bioterrorist weapons. The occurrence of arenaviral hemorrhagic fevers is largely confined to Third World countries with a limited medical infrastructure, and therefore live-attenuated vaccines have long been sought as a method of choice for prevention. Yet their rational design and engineering have been thwarted by technical limitations. In addition, viral genes had not been identified that are needed to cause disease but can be deleted or substituted to generate live-attenuated vaccine strains. Lymphocytic choriomeningitis virus, the prototype arenavirus, induces cell-mediated immunity against Lassa fever virus, but its safety for humans is unclear and untested. Using this virus model, we have developed the necessary methodology to efficiently modify arenavirus genomes and have exploited these techniques to identify an arenaviral Achilles' heel suitable for targeting in vaccine design. Reverse genetic exchange of the viral glycoprotein for foreign glycoproteins created attenuated vaccine strains that remained viable although unable to cause disease in infected mice. This phenotype remained stable even after extensive propagation in immunodeficient hosts. Nevertheless, the engineered viruses induced T cell-mediated immunity protecting against overwhelming systemic infection and severe liver disease upon wild-type virus challenge. Protection was established within 3 to 7 d after immunization and lasted for approximately 300 d. The identification of an arenaviral Achilles' heel demonstrates that the reverse genetic engineering of live-attenuated arenavirus vaccines is feasible. Moreover, our findings offer lymphocytic choriomeningitis virus or other arenaviruses expressing foreign glycoproteins as promising live-attenuated arenavirus vaccine candidates.
Wang, Jin Yuan; Harley, Regina H.; Galen, James E.
Bacterial live vector vaccines represent a vaccine development strategy that offers exceptional flexibility. In this approach, genes encoding protective antigens of unrelated bacterial, viral or parasitic pathogens are expressed in an attenuated bacterial vaccine strain that delivers these foreign antigens to the immune system, thereby eliciting relevant immune responses. Rather than expressing these antigens using low copy expression plasmids, here we pursue expression of foreign proteins from the live vector chromosome. Our strategy is designed to compensate for the inherent disadvantage of loss of gene dosage (vs. plasmid-based expression) by integrating antigen-encoding gene cassettes into multiple chromosomal sites already inactivated in an attenuated Salmonella enterica serovar Typhi vaccine candidate. We tested expression of a cassette encoding the green fluorescent protein (GFPuv) integrated separately into native guaBA, htrA or clyA chromosomal loci. Using single integrations, we show that expression levels of GFPuv are significantly affected by the site of integration, regardless of the inclusion of additional strong promoters within the incoming cassette. Using cassettes integrated into both guaBA and htrA, we observe cumulative synthesis levels from two integration sites superior to single integrations. Most importantly, we observe that GFPuv expression increases in a growth phase-dependent manner, suggesting that foreign antigen synthesis may be “tuned” to the physiology of the live vaccine. We expect this novel platform expression technology to prove invaluable in the development of a wide variety of multivalent live vector vaccines, capable of expressing multiple antigens from both chromosomal and plasmid-based expression systems within a single strain. PMID:23406777
Marcus, Philip I; Ngunjiri, John M; Sekellick, Margaret J; Wang, Leyi; Lee, Chang-Won
Two effective (vac+) and two ineffective (vac-) candidate live-attenuated influenza vaccines (LAIVs) derived from naturally selected genetically stable variants of A/TK/OR/71-delNS1[1-124] (H7N3) that differed only in the length and kind of amino acid residues at the C terminus of the nonstructural NS1 protein were analyzed for their content of particle subpopulations. These subpopulations included total physical particles (measured as hemagglutinating particles [HAPs]) with their subsumed biologically active particles of infectious virus (plaque-forming particles [PFPs]) and different classes of noninfectious virus, namely, interferon-inducing particles (IFPs), noninfectious cell-killing particles (niCKPs), and defective interfering particles (DIPs). The vac+ variants were distinguished from the vac- variants on the basis of their content of viral subpopulations by (i) the capacity to induce higher quantum yields of interferon (IFN), (ii) the generation of an unusual type of IFN-induction dose-response curve, (iii) the presence of IFPs that induce IFN more efficiently, (iv) reduced sensitivity to IFN action, and (v) elevated rates of PFP replication that resulted in larger plaques and higher PFP and HAP titers. These in vitro analyses provide a benchmark for the screening of candidate LAIVs and their potential as effective vaccines. Vaccine design may be improved by enhancement of attributes that are dominant in the effective (vac+) vaccines.
Kirkwood, Carl D; Boniface, Karen; Bishop, Ruth F; Barnes, Graeme L
The Australian Rotavirus Surveillance Program together with 15 collaborating laboratories Australia-wide conducts a laboratory based rotavirus surveillance program. This report describes the genotypes of rotavirus strains responsible for the hospitalisation of children with acute gastroenteritis during the period 1 July 2009 to 30 June 2010, the 3rd year of surveillance following introduction of rotavirus vaccines into the National Immunisation Program. Seven hundred and seventy-eight faecal samples were referred to the centre for G and P genotype analysis using hemi-nested multiplex reverse transcription-polymerase chain reaction. Of the 422 confirmed as rotavirus positive, genotype G1P was the dominant type nationally, representing 49.3%, followed by genotype G2P (21.1%). Genotypes G3P, G4P and G9P each represented less than 3% of circulating strains nationally. The dominance of G1P was in part associated with a large outbreak of severe gastroenteritis in the Northern Territory in 2010. The identification of uncommon rotavirus genotype combinations has increased since vaccine introduction, with G1P, G2P and G9P identified during this survey. Single strains of G1P and G4P were identified during this study period. This survey continues to highlight the fluctuations in rotavirus genotypes, and results from this survey suggest there is limited genotype selection based on vaccine usage. However, the large G1P outbreak of gastroenteritis in the Northern Territory may have resulted from vaccine pressure on wild-type strains.
Kirkwood, Carl D; Cannan, David; Boniface, Karen; Bishop, Ruth F; Barnes, Graeme L
The National Rotavirus Reference Centre together with collaborating laboratories Australia-wide conducts a laboratory based rotavirus surveillance program. This report describes the types of rotavirus strains responsible for the hospitalisation of children with acute gastroenteritis during the period 1 July 2007 to 30 June 2008, the first complete year of surveillance following introduction of rotavirus into the National Immunisation Program. Six hundred faecal samples from across Australia were examined using a combined approach of monoclonal antibody immunoassays and reverse transcription-polymerase chain reaction. Of the 419 confirmed as rotavirus positive, serotype G1 was the dominant serotype nationally, representing 52% of specimens, followed by serotype G2 (19.8%), serotype G9 (12.2%), and serotype G3 (11%). No serotype G4 strains were identified. All G1, G3 and G9 strains assayed for P genotype contained the P genotype, while all G2 strains contained the P genotype, except one G2 strain which possessed a P. Uncommon rotavirus genotypes, G8 (n = 2) and P (n = 2) were identified during this study period. There was no evidence of unexpected changes in serotype distribution during the first 12 months of rotavirus vaccine use in the National Immunisation Program.
Choi, Won Suk; Choi, Jung-Hyun; Choi, Jun Yong; Eom, Joong Sik; Kim, Sang Il; Pai, Hyunjoo; Peck, Kyong Ran; Sohn, Jang Wook; Cheong, Hee Jin
A live attenuated zoster vaccine (ZOSTAVAX™, Merck & Co., Inc.) was approved by the Korea Ministry of Food and Drug Safety in 2009. However, the immunogenicity and safety of the vaccine has not been assessed in Korean population. This is multi-center, open-label, single-arm study performed with 180 healthy Korean adults ≥ 50 yr of age. The geometric mean titer (GMT) and geometric mean fold rise (GMFR) of varicella zoster virus (VZV) antibodies were measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) at 4 weeks post-vaccination. Subjects were followed for exposure to varicella or herpes zoster (HZ), the development of any varicella/varicella-like or HZ/HZ-like rashes, and any other clinical adverse experiences (AEs) for 42 days post-vaccination. For the 166 subjects included in the per-protocol population, the GMT at Day 1 was 66.9. At 4 weeks post-vaccination, the GMT for this population was 185.4, with a GMFR of 2.8 (95% CI, 2.5-3.1). Of the 180 subjects vaccinated, 62.8% experienced ≥ 1 AE, with 53.3% of subjects reporting injection-site AEs. The most frequently reported injection-site AEs were erythema (45.0%) with the majority being mild in intensity. Overall, 44 (24.4%) subjects experienced ≥ 1 systemic AE, 10 (5.5%) subjects experienced a systemic vaccine-related AE, and 3 (1.7%) subjects experienced ≥ 1 serious AE not related to vaccine. No subjects reported a VZV-like rash. There was no subject of death and no subject discontinued due to an adverse event. A single dose of zoster vaccine induced VZV-specific gpELISA antibody response and was generally well-tolerated in healthy Korean adults ≥50 yr of age (registry at www.clinicaltrial.gov No. NCT01556451).
Patel, Ekta H; Lubembe, Donald M; Gachanja, James; Mwaura, Stephen; Spooner, Paul; Toye, Philip
The current Infection and Treatment Method of vaccination against East Coast fever comprises an inoculation of live Theileria parva sporozoites and simultaneous administration of oxytetracycline. Immunization with a combination of parasite types has been shown to provide broader protection than inoculation of individual strains. In this study, we used a high-throughput capillary electrophoresis system to determine the genotypic composition of the Muguga Cocktail, a widely used vaccine stabilate derived from three seed stabilates-Muguga, Serengeti-transformed and Kiambu 5. Five satellite markers were used to genotype the vaccine and reference stabilates from two commercial-scale preparations of the vaccine. In addition, 224 cloned cell lines established by infection of bovine lymphocytes with T. parva parasites from the component stabilates were genotyped. The results indicate that, for the recently prepared batch, there are at least eight genotypes in each of the Muguga and the Serengeti-transformed stabilates, while parasites from the Kiambu 5 stabilate showed no diversity at the five loci. The Serengeti-transformed stabilate contained parasites of the Kiambu 5 genotype and of two genotypes present in the Muguga stabilate, whereas there were no genotypes common to the Muguga and Kiambu 5 stabilates. When stabilates from the two vaccine batches were compared, no allelic variations were identified between the Muguga and Kiambu 5 parasites, while lack of sufficient clones prevented a full comparison of the Serengeti-transformed stabilates. The findings will facilitate examination of the extent to which the vaccine strains become resident in areas under vaccination, the identification of 'breakthrough' strains and the establishment of the quality assurance protocols to detect variations in the production of the vaccine. The cloned cell lines will be useful for further understanding the antigenic diversity of parasites in the vaccine.
Using PCR-select subtractive cDNA hybridization technique, 41 expressed sequence tags (EST's) were isolated from a modified live vaccine strain (AQUAVAC-ESC formerly RD-33) vs a virulent parent strain (EILO) of Edwardsiella ictaluri. Transcriptional levels of the 41 ESTs in the vaccine strain and th...
In the United States there are currently two influenza vaccine platforms approved for use in humans - conventional inactivated virus and live-attenuated influenza virus (LAIV). One of the major challenges for influenza vaccination is designing a platform that provides cross-protection across strains...
Nandre, Rahul M; Lee, Dajeong; Lee, John Hwa
In this study, a genetically engineered live attenuated Salmonella Enteritidis (SE) vaccine was evaluated for its ability to protect against Salmonella Typhimurium (ST) infection in chickens. The birds were orally primed with the vaccine on the 1st day of life and given an oral booster at 5 wk of age. Control birds were orally inoculated with phosphate-buffered saline. Both groups of birds were orally challenged with a virulent ST strain at 9 wk of age. Compared with the control chickens, the vaccinated chickens had significantly higher levels of systemic IgG and mucosal IgA against specific ST antigens and a significantly greater lymphoproliferative response to ST antigens. The excretion of ST into the feces was significantly lower in the vaccinated group than in the control group on days 9 and 13 d after challenge. In addition, the vaccinated group had significantly fewer pronounced gross lesions in the liver and spleen and lower bacterial counts in the internal organs than the control group after challenge. These data indicate that genetically engineered live attenuated SE may induce humoral and cellular immune responses against ST antigens and may confer protection against virulent ST challenge.
Nandre, Rahul M.; Lee, Dajeong; Lee, John Hwa
In this study, a genetically engineered live attenuated Salmonella Enteritidis (SE) vaccine was evaluated for its ability to protect against Salmonella Typhimurium (ST) infection in chickens. The birds were orally primed with the vaccine on the 1st day of life and given an oral booster at 5 wk of age. Control birds were orally inoculated with phosphate-buffered saline. Both groups of birds were orally challenged with a virulent ST strain at 9 wk of age. Compared with the control chickens, the vaccinated chickens had significantly higher levels of systemic IgG and mucosal IgA against specific ST antigens and a significantly greater lymphoproliferative response to ST antigens. The excretion of ST into the feces was significantly lower in the vaccinated group than in the control group on days 9 and 13 d after challenge. In addition, the vaccinated group had significantly fewer pronounced gross lesions in the liver and spleen and lower bacterial counts in the internal organs than the control group after challenge. These data indicate that genetically engineered live attenuated SE may induce humoral and cellular immune responses against ST antigens and may confer protection against virulent ST challenge. PMID:25673904
Wang, Xijun; Feng, Na; Ge, Jinying; Shuai, Lei; Peng, Liyan; Gao, Yuwei; Yang, Songtao; Xia, Xianzhu; Bu, Zhigao
Effective, safe, and affordable rabies vaccines are still being sought. Attenuated live vaccine has been widely used to protect carnivores from canine distemper. In this study, we generated a recombinant canine distemper virus (CDV) vaccine strain, rCDV-RVG, expressing the rabies virus glycoprotein (RVG) by using reverse genetics. The recombinant virus rCDV-RVG retained growth properties similar to those of vector CDV in Vero cell culture. Animal studies demonstrated that rCDV-RVG was safe in mice and dogs. Mice inoculated intracerebrally or intramuscularly with rCDV-RVG showed no apparent signs of disease and developed a strong rabies virus (RABV) neutralizing antibody response, which completely protected mice from challenge with a lethal dose of street virus. Canine studies showed that vaccination with rCDV-RVG induced strong and long-lasting virus neutralizing antibody responses to RABV and CDV. This is the first study demonstrating that recombinant CDV has the potential to serve as bivalent live vaccine against rabies and canine distemper in animals.
Harper, Marina; John, Marietta; Edmunds, Mark; Wright, Amy; Ford, Mark; Turni, Conny; Blackall, P J; Cox, Andrew; Adler, Ben; Boyce, John D
Pasteurella multocida is a major animal pathogen that causes a range of diseases including fowl cholera. P. multocida infections result in considerable losses to layer and breeder flocks in poultry industries worldwide. Both killed whole-cell and live-attenuated vaccines are available; these vaccines vary in their protective efficacy, particularly against heterologous strains. Moreover, until recently there was no knowledge of P. multocida LPS genetics and structure to determine precisely how LPS structure affects the protective capacity of these vaccines. In this study we show that defined lipopolysaccharide (LPS) mutants presented as killed whole-cell vaccines elicited solid protective immunity only against P. multocida challenge strains expressing highly similar or identical LPS structures. This finding indicates that vaccination of commercial flocks with P. multocida killed cell formulations will not protect against strains producing an LPS structure different to that produced by strains included in the vaccine formulation. Conversely, protective immunity conferred by vaccination with live P. multocida strains was found to be largely independent of LPS structure. Birds vaccinated with a range of live mutants belonging to the L1 and L3 LPS genotypes, each expressing a specific truncated LPS structure, were protected against challenge with the parent strain. Moreover, birds vaccinated with any of the five LPS mutants belonging to the L1 LPS genotype were also protected against challenge with an unrelated strain and two of the five groups vaccinated with live LPS mutants belonging to the L3 genotype were protected against challenge with an unrelated strain. In summary, vaccination with live P. multocida aroA mutants producing full-length L1 or L3 LPS or vaccination with live strains producing shortened L1 LPS elicited strong protective immunity against both homologous and heterologous challenge.
Klug, Bettina; Robertson, James S; Condit, Richard C; Seligman, Stephen J; Laderoute, Marian P; Sheets, Rebecca; Williamson, Anna-Lise; Gurwith, Marc; Kochhar, Sonali; Chapman, Louisa; Carbery, Baevin; Mac, Lisa M; Chen, Robert T
Vaccines are one of the most effective public health medicinal products with an excellent safety record. As vaccines are produced using biological materials, there is a need to safeguard against potential contamination with adventitious agents. Adventitious agents could be inadvertently introduced into a vaccine through starting materials used for production. Therefore, extensive testing has been recommended at specific stages of vaccine manufacture to demonstrate the absence of adventitious agents. Additionally, the incorporation of viral clearance steps in the manufacturing process can aid in reducing the risk of adventitious agent contamination. However, for live viral vaccines, aside from possible purification of the virus or vector, extensive adventitious agent clearance may not be feasible. In the event that an adventitious agent is detected in a vaccine, it is important to determine its origin, evaluate its potential for human infection and pathology, and discern which batches of vaccine may have been affected in order to take risk mitigation action. To achieve this, it is necessary to have archived samples of the vaccine and ancillary components, ideally from developmental through to current batches, as well as samples of the biological materials used in the manufacture of the vaccine, since these are the most likely sources of an adventitious agent. The need for formal guidance on such vaccine sample archiving has been recognized but not fulfilled. We summarize in this paper several prior major cases of vaccine contamination with adventitious agents and provide points for consideration on sample archiving of live recombinant viral vector vaccines for use in humans.
Brenneman, Karen E.; Willingham, Crystal; Kilbourne, Jacquelyn A.; 3rd, Roy Curtiss; Roland, Kenneth L.
The low pH of the stomach serves as a barrier to ingested microbes and must be overcome or bypassed when delivering live bacteria for vaccine or probiotic applications. Typically, the impact of stomach acidity on bacterial survival is evaluated in vitro, as there are no small animal models to evaluate these effects in vivo. To better understand the effect of this low pH barrier to live attenuated Salmonella vaccines, which are often very sensitive to low pH, we investigated the value of the histamine mouse model for this application. A low pH gastric compartment was transiently induced in mice by the injection of histamine. This resulted in a gastric compartment of approximately pH 1.5 that was capable of distinguishing between acid-sensitive and acid-resistant microbes. Survival of enteric microbes during gastric transit in this model directly correlated with their in vitro acid resistance. Because many Salmonella enterica serotype Typhi vaccine strains are sensitive to acid, we have been investigating systems to enhance the acid resistance of these bacteria. Using the histamine mouse model, we demonstrate that the in vivo survival of S. Typhi vaccine strains increased approximately 10-fold when they carried a sugar-inducible arginine decarboxylase system. We conclude that this model will be a useful for evaluating live bacterial preparations prior to clinical trials. PMID:24489912
Rodríguez Camarillo, Sergio D; García Ortiz, Miguel Angel; Rojas Ramírez, Edmundo E; Cantó Alarcón, Germinal J; Preciado de la Torre, Jesús F; Rosario Cruz, Rodrigo; Ramos Aragón, Juan A; Aboytes Torres, Ramón
Anaplasma marginale Yucatan strain was found to have low virulence in cattle. We studied the virulence of this isolate by experimental inoculation of 113 susceptible cattle at increasing doses, after which only one animal required treatment for clinical disease. Subsequently, 104 cattle received a live vaccine of this strain by inoculation, which induced immunoprotection after heterologous challenged exposure with a different A. marginale isolate. In this study 14% of the immunized cattle required treatment as compared with the control nonimmunized cattle, in which 56% required treatment. The A. marginale vaccine strains used for the immunization studies had MSP1a variable regions that were different from those used for the challenge exposure.
Background The highest incidence of rotavirus gastroenteritis has generally been reported in children 6-24 months of age. Young infants are thought to be partially protected by maternal antibodies acquired transplacentally or via breast milk. The purpose of our study was to assess the age distribution of children with confirmed community-acquired rotavirus gastroenteritis presenting to an urban referral hospital. Methods Children presenting to The Children's Hospital of Philadelphia with acute gastroenteritis have been monitored for the presence of rotavirus antigen in the stool by ELISA (followed by genotyping if ELISA-positive) since the 1994-95 epidemic season. Results Over the last 12 rotavirus seasons prior to the introduction of the pentavalent rotavirus vaccine in 2006, stool specimens from 1646 patients tested positive for community-acquired rotavirus infection. Gender or age was not recorded in 6 and 5 cases, respectively. Overall, 58% of the cases occurred in boys. G1 was the predominant VP7 serotype, accounting for 72% of cases. The median (IQR) age was 11 (5-21) months. A total of 790 (48%) cases occurred in children outside the commonly quoted peak age range, with 27% in infants <6 months of age and 21% in children >24 months of age. A total of 220 (13%) cases occurred during the first 3 months of life, and the highest number of episodes per month of age [97 (6%)] was observed during the second month of life. Conclusions The incidence of community-acquired rotavirus gastroenteritis monitored over 12 seasons in the prevaccine era at a major university hospital was nearly constant for each month of age during the first year of life, revealing an unexpectedly high incidence of symptomatic rotavirus disease in infants <3 months old. A sizeable fraction of cases occurred in children too young to have been vaccinated according to current recommendations. PMID:20540748
van Loon, A A W M; Suurland, B; van der Marel, P
The efficacy of live reovirus vaccines may be determined by challenge via the foot pad route 3 to 4 weeks after vaccination. Swelling and discoloration in the foot pad and shank are scored for a period of 14 days. The major disadvantages of this challenge model are the subjective judgement of gross foot pad and/or shank lesions, that it is very difficult to induce lesions in broilers, and that it causes animal suffering. Other reovirus challenge models are based on reisolation of the virus from different tissues or on scoring microscopic lesions in the tendons. Some disadvantages of these models are that they either cannot be used after vaccination with live reovirus because they cannot discriminate between vaccine and challenge virus or that the microscopic lesions scored need not necessarily be related to the challenge virus but may have been induced by other factors. Therefore, we have attempted to develop a reovirus challenge model that was an improvement on the existing ones, using isolation of reovirus from different organs followed by specific detection of the challenge virus with a monoclonal antibody that can discriminate between challenge and vaccine virus. The reovirus challenge model was examined in specific pathogen free (SPF) White Leghorn chickens and commercial broilers. In vivo studies were conducted to examine the efficacy of an attenuated reovirus vaccine in SPF White Leghorn chickens and commercial broilers with maternal immunity against reovirus. No challenge virus could be detected in any of the organs of the vaccinated chickens 3 and 10 days after challenge. In contrast, challenge virus could be isolated from the unvaccinated control group. At an increased challenge dose all unvaccinated challenge control birds were positive, while the vaccinated chickens were protected. It was shown that 1-day-old vaccination in the presence of maternal immunity was effective. It seemed that protection induced in broilers by the attenuated reovirus vaccine
Zeller, Mark; Patton, John T; Heylen, Elisabeth; De Coster, Sarah; Ciarlet, Max; Van Ranst, Marc; Matthijnssens, Jelle
Two live-attenuated rotavirus group A (RVA) vaccines, Rotarix (G1P) and RotaTeq (G1-G4, P), have been successfully introduced in many countries worldwide, including Belgium. The parental RVA strains used to generate the vaccines were isolated more than 20 years ago in France (G4 parental strain in RotaTeq) and the United States (all other parental strains). At present, little is known about the relationship between currently circulating human RVAs and the vaccine strains. In this study, we determined sequences for the VP7 and VP4 outer capsid proteins of representative G1P, G2P, G3P, G4P, G9P, and G12P RVAs circulating in Belgium during 2007 to 2009. The analyses showed that multiple amino acid differences existed between the VP7 and VP4 antigenic epitopes of the vaccine viruses and the Belgian isolates, regardless of their G and P genotypes. However, the highest variability was observed among the circulating G1P RVA strains and the G1 and P components of both RVA vaccines. In particular, RVA strains of the P lineage 4 (OP354-like) showed a significant number of amino acid differences with the P VP4 of both vaccines. In addition, the circulating Belgian G3 RVA strains were found to possibly possess an extra N-linked glycosylation site compared to the G3 RVA vaccine strain of RotaTeq. These results indicate that the antigenic epitopes of RVA strains contained in the vaccines differ substantially from those of the currently circulating RVA strains in Belgium. Over time, these differences might result in selection for strains that escape the RVA neutralizing-antibody pressure induced by vaccines.
Fiuza, Jacqueline Araújo; Gannavaram, Sreenivas; Santiago, Helton da Costa; Selvapandiyan, Angamuthu; Souza, Daniel Menezes; Passos, Lívia Silva Araújo; de Mendonça, Ludmila Zanandreis; Lemos-Giunchetti, Denise da Silveira; Ricci, Natasha Delaqua; Bartholomeu, Daniella Castanheira; Giunchetti, Rodolfo Cordeiro; Bueno, Lilian Lacerda; Correa-Oliveira, Rodrigo; Nakhasi, Hira L; Fujiwara, Ricardo Toshio
Live attenuated Leishmania donovani parasites such as LdCen(-/-) have been shown elicit protective immunity against leishmanial infection in mice and hamster models. Previously, we have reported on the induction of strong immunogenicity in dogs upon vaccination with LdCen(-/-) including an increase in immunoglobulin isotypes, higher lymphoproliferative response, higher frequencies of activated CD4(+) and CD8(+) T cells, IFN-γ production by CD8(+) T cells, increased secretion of TNF-α and IL-12/IL-23p40 and, finally, decreased secretion of IL-4. To further explore the potential of LdCen(-/-) parasites as vaccine candidates, we performed a 24-month follow up of LdCen(-/-) immunized dogs after challenge with virulent Leishmania infantum, aiming determination of parasite burden by qPCR, antibody production (ELISA) and cellular responses (T cell activation and cytokine production) by flow cytometry and sandwich ELISA. Our data demonstrated that vaccination with a single dose of LdCen(-/-) (without any adjuvant) resulted in the reduction of up to 87.3% of parasite burden after 18 months of virulent challenge. These results are comparable to those obtained with commercially available vaccine in Brazil (Leishmune(®)). The protection was associated with antibody production and CD4(+) and CD8(+) proliferative responses, as well as T cell activation and significantly higher production of IFN-γ, IL-12/IL-23p40 and TNF-α, which was comparable to responses induced by immunization with Leishmune(®), with significant differences when compared to control animals (Placebo). Moreover, only animals immunized with LdCen(-/-) expressed lower levels of IL-4 when compared to animals vaccinated either with Leishmune(®) or PBS. Our results support further studies aiming to demonstrate the potential of genetically modified live attenuated L. donovani vaccine to control L. infantum transmission in endemic areas for CVL.
Zemke, Johanna; König, Patricia; Mischkale, Katrin; Reimann, Ilona; Beer, Martin
Protection against Bovine viral diarrhea virus (BVDV) type 2 infection of commercially available vaccines is often limited due to marked genetic and antigenic differences between BVDV types 1 (BVDV-1) and 2 (BVDV-2). Therefore, the immunogenicity of selected BVDV-1 and BVDV-2 mutants derived from infectious full-length cDNA clones and their use as modified-live vaccine candidates against challenge infection with a virulent heterologous BVDV-2 field isolate were investigated. Deletion mutants of BVDV-1 and BVDV-2 lacking a part of the N(pro) gene (BVDV-1DeltaN(pro)/BVDV-2DeltaN(pro)) were used as well as a packaged replicon with a deletion in the structural core protein encoding region (BVDV-2DeltaC-pseudovirions). The 25 calves used in this vaccination/challenge trial were allocated in five groups (n=5/group). One group received BVDV-1DeltaN(pro) (1 shot), one group BVDV-2DeltaN(pro) (1 shot), one group received both, BVDV-1DeltaN(pro) and BVDV-2DeltaN(pro) (1 shot), and one group was immunised with the BVDV-2DeltaC-pseudovirions (2 shots). The fifth group served as non-vaccinated control group. All groups were challenged intranasally with the BVDV-2 strain HI916 and monitored for signs of clinical disease, virus shedding and viremia. All tested BVDV vaccine candidates markedly reduced the outcome of the heterologous virulent BVDV-2 challenge infection showing graduated protective effects. The BVDV-2DeltaN(pro) mutant was able to induce complete protection and a "sterile immunity" upon challenge. Thus it represents a promising candidate for an efficacious future live vaccine.
Groves, Peter J; Sharpe, Sue M; Cox, Julian M
Responses to the parenteral administration of a live aroA deletion Salmonella serovar Typhimurium vaccine given to three brown egg layer strains and two broiler strains were studied. Twenty-five birds of each strain were reared together in floor pens to 6 weeks of age and then moved as individual strains to new floor pens and injected with 10(8) colony forming units (CFU) per bird of the vaccine bacteria intramuscularly or subcutaneously, 10(6) CFU per bird subcutaneously, or phosphate buffered saline (PBS) subcutaneously as a vaccination control. Three birds of one layer strain were injected intramuscularly with 0.5mg/ bird S. Typhimurium lipopolysaccharide (LPS) to evaluate whether response was similar for vaccine and endotoxin. Birds were weighed, and rectal temperatures recorded at the time of injection, then observed over 24 hours. Rectal temperatures were measured and blood samples collected for serum IL-6 assay at 3 hours post injection (PI). At 12 hours PI blood samples were drawn for analyses for plasma phosphorus (P), glucose (Glu), cholesterol (Cho), aspartate transaminase (AST), total protein (Ptn) and creatinine kinase (CK). Blood was sampled 14 days PI and tested for serum antibody to S. Typhimurium. Vaccination resulted in significant seroconversion by 14 days PI in all strains compared to the controls. The three layer strains exhibited a clinical malaise, evident within 90 minutes of injection, lasting for 12 hours, with complete recovery by 24 hours PI. Only the 10(8) CFU dose given subcutaneously produced an increase in rectal temperature 3 hours PI. Vaccination had no effect on IL-6 or Ptn. All vaccine doses increased P and the higher dose by either route decreased Cho in all bird strains. The 10(8) vaccine dose increased Glu and intramuscular injection markedly elevated CK only in the layer strains. The response was not completely congruous with that to LPS alone. The results highlight the need for consideration of differences in response of
Saxena, Kapil; Blutt, Sarah E.; Ettayebi, Khalil; Zeng, Xi-Lei; Broughman, James R.; Crawford, Sue E.; Karandikar, Umesh C.; Sastri, Narayan P.; Conner, Margaret E.; Opekun, Antone R.; Graham, David Y.; Qureshi, Waqar; Sherman, Vadim; Foulke-Abel, Jennifer; In, Julie; Kovbasnjuk, Olga; Zachos, Nicholas C.; Donowitz, Mark
gastrointestinal infections such as HRV infection. HRVs remain a major worldwide cause of diarrhea-associated morbidity and mortality in children ≤5 years of age. Current in vitro models of rotavirus infection rely primarily on the use of animal rotaviruses because HRV growth is limited in most transformed cell lines and animal models. We demonstrate that HIEs are novel, cellularly diverse, and physiologically relevant epithelial cell cultures that recapitulate in vivo properties of HRV infection. HIEs will allow the study of HRV biology, including human host-pathogen and live, attenuated vaccine interactions; host and cell type restriction; virus-induced fluid secretion; cell-cell communication within the epithelium; and the epithelial response to infection in cultures from genetically diverse individuals. Finally, drug therapies to prevent/treat diarrheal disease can be tested in these physiologically active cultures. PMID:26446608
Xue, Jianmin; Chen, Xia; Selby, Dale; Hung, Chiung-Yu; Yu, Jieh-Juen; Cole, Garry T
Coccidioidomycosis (also known as San Joaquin Valley fever) is an occupational disease. Workers exposed to outdoor dust which contains spores of the soil-inhabiting fungus have a significantly increased risk of respiratory infection. In addition, people with compromised T-cell immunity, the elderly, and certain racial groups, particularly African-Americans and Filipinos, who live in regions of endemicity in the southwestern United States have an elevated incidence of symptomatic infection caused by inhalation of spores of Coccidioides posadasii or Coccidioides immitis. Recurring epidemics and escalation of medical costs have helped to motivate production of a vaccine against valley fever. The major focus has been the development of a defined, T-cell-reactive, recombinant protein vaccine. However, none of the products described to date have provided full protection to coccidioidal disease-susceptible BALB/c mice. Here we describe the first genetically engineered, live, attenuated vaccine that protects both BALB/c and C57BL/6 mice against coccidioidomycosis. Two chitinase genes (CTS2 and CTS3) were disrupted to yield the attenuated strain, which was unable to endosporulate and was no longer infectious. Vaccinated survivors mounted an immune response characterized by production of both T-helper-1- and T-helper-2-type cytokines. Histology revealed well-formed granulomas and markedly diminished inflammation. Significantly fewer organisms were observed in the lungs of survivors than in those of nonvaccinated mice. Additional investigations are required to further define the nature of the live, attenuated vaccine-induced immunity against Coccidioides infection.
evidence “favors rejection” of the idea that either the measles- mumps-rubella vaccine or thimerosal-containing vaccines cause autism (IOM...Immunization Safety Review: Vaccines and Autism , Washington, D.C., National Academies Press, 2004). 46ACIP’s rotavirus vaccine fact sheet is at [http...that the vaccines or preservatives or packaging might cause autism and other neurodevelopmental disorders. One focus has been on thimerosal, a mercury
Gormley, Eamonn; Ní Bhuachalla, Deirdre; O'Keeffe, James; Murphy, Denise; Aldwell, Frank E; Fitzsimons, Tara; Stanley, Paul; Tratalos, Jamie A; McGrath, Guy; Fogarty, Naomi; Kenny, Kevin; More, Simon J; Messam, Locksley L McV; Corner, Leigh A L
A field trial was conducted to investigate the impact of oral vaccination of free-living badgers against natural-transmitted Mycobacterium bovis infection. For a period of three years badgers were captured over seven sweeps in three zones and assigned for oral vaccination with a lipid-encapsulated BCG vaccine (Liporale-BCG) or with placebo. Badgers enrolled in Zone A were administered placebo while all badgers enrolled in Zone C were vaccinated with BCG. Badgers enrolled in the middle area, Zone B, were randomly assigned 50:50 for treatment with vaccine or placebo. Treatment in each zone remained blinded until the end of the study period. The outcome of interest was incident cases of tuberculosis measured as time to seroconversion events using the BrockTB Stat-Pak lateral flow serology test, supplemented with post-mortem examination. Among the vaccinated badgers that seroconverted, the median time to seroconversion (413 days) was significantly longer (p = 0.04) when compared with non-vaccinated animals (230 days). Survival analysis (modelling time to seroconversion) revealed that there was a significant difference in the rate of seroconversion between vaccinated and non-vaccinated badgers in Zones A and C throughout the trial period (p = 0.015). For badgers enrolled during sweeps 1-2 the Vaccine Efficacy (VE) determined from hazard rate ratios was 36% (95% CI: -62%- 75%). For badgers enrolled in these zones during sweeps 3-6, the VE was 84% (95% CI: 29%- 97%). This indicated that VE increased with the level of vaccine coverage. Post-mortem examination of badgers at the end of the trial also revealed a significant difference in the proportion of animals presenting with M. bovis culture confirmed lesions in vaccinated Zone C (9%) compared with non-vaccinated Zone A (26%). These results demonstrate that oral BCG vaccination confers protection to badgers and could be used to reduce incident rates in tuberculosis-infected populations of badgers.
Gormley, Eamonn; Ní Bhuachalla, Deirdre; O’Keeffe, James; Murphy, Denise; Aldwell, Frank E.; Fitzsimons, Tara; Stanley, Paul; Tratalos, Jamie A.; McGrath, Guy; Fogarty, Naomi; Kenny, Kevin; More, Simon J.; Messam, Locksley L. McV.; Corner, Leigh A. L.
A field trial was conducted to investigate the impact of oral vaccination of free-living badgers against natural-transmitted Mycobacterium bovis infection. For a period of three years badgers were captured over seven sweeps in three zones and assigned for oral vaccination with a lipid-encapsulated BCG vaccine (Liporale-BCG) or with placebo. Badgers enrolled in Zone A were administered placebo while all badgers enrolled in Zone C were vaccinated with BCG. Badgers enrolled in the middle area, Zone B, were randomly assigned 50:50 for treatment with vaccine or placebo. Treatment in each zone remained blinded until the end of the study period. The outcome of interest was incident cases of tuberculosis measured as time to seroconversion events using the BrockTB Stat-Pak lateral flow serology test, supplemented with post-mortem examination. Among the vaccinated badgers that seroconverted, the median time to seroconversion (413 days) was significantly longer (p = 0.04) when compared with non-vaccinated animals (230 days). Survival analysis (modelling time to seroconversion) revealed that there was a significant difference in the rate of seroconversion between vaccinated and non-vaccinated badgers in Zones A and C throughout the trial period (p = 0.015). For badgers enrolled during sweeps 1–2 the Vaccine Efficacy (VE) determined from hazard rate ratios was 36% (95% CI: -62%– 75%). For badgers enrolled in these zones during sweeps 3–6, the VE was 84% (95% CI: 29%– 97%). This indicated that VE increased with the level of vaccine coverage. Post-mortem examination of badgers at the end of the trial also revealed a significant difference in the proportion of animals presenting with M. bovis culture confirmed lesions in vaccinated Zone C (9%) compared with non-vaccinated Zone A (26%). These results demonstrate that oral BCG vaccination confers protection to badgers and could be used to reduce incident rates in tuberculosis-infected populations of badgers. PMID:28121981
Simuyandi, M.; Kapulu, M.
Summary We have observed previously that micronutrient supplementation ameliorated suppression of α‐defensin expression during diarrhoea. However, how interactions between anti‐microbial peptide (AMP) expression and diarrhoeal disease are altered by micronutrient supplementation remain unclear. Using oral vaccination as a model of intestinal infection, we measured changes in AMP expression during multiple micronutrient supplementation. In the first part, volunteers underwent duodenal jejunal biopsy before and at 1, 2, 4 or 7 days after administration of one of three live, attenuated oral vaccines against rotavirus, typhoid and enterotoxigenic Escherichia coli. In the second part, participants were randomized to receive a multiple micronutrient supplement or placebo for 6 weeks before undergoing intestinal biopsy, vaccination against typhoid and rebiopsy after 14 days. Expression of human alpha‐defensin (HD)5, HD6, hBD1, hBD2 and LL‐37 was measured by quantitative reverse transcription–polymerase chain reaction. Taken together, the bacterial vaccines, but not rotavirus vaccine, reduced HD5 expression (P = 0·02, signed‐rank test) and reduced LL‐37 expression in seven of the eight individuals whose biopsies had expression prevaccination (P = 0·03). hBD2 was not detected. In the controlled trial, HD5 and HD6 expression after vaccination was lower [median ratio 0·5, interquartile range (IQR) = 0·07–2·2 and 0·58, IQR = 0·13–2·3, respectively] than before vaccination. There was no significant effect detected of micronutrient supplementation on expression of HD5, HD6, hBD1 or LL‐37. We conclude that live attenuated bacterial vaccines, but not rotavirus vaccine, can reduce intestinal α‐defensins, and typhoid vaccine reduced LL‐37 expression. We found no evidence that micronutrient supplementation in the short term had any impact on anti‐microbial peptide expression. PMID:27465597
Wright, Peter F.; Hoen, Anne G.; Ilyushina, Natalia A.; Brown, Eric P.; Ackerman, Margaret E.; Wieland-Alter, Wendy; Connor, Ruth I.; Jegaskanda, Sinthujan; Rosenberg-Hasson, Yael; Haynes, Brenda C.; Luke, Catherine J.; Subbarao, Kanta; Treanor, John J.
Background. The efficacy of live, attenuated live attenuated influenza vaccine(LAIV) and inactivated influenza vaccine(IIV) is poorly explained by either single or composite immune responses to vaccination. Protective biomarkers were therefore studied in response to LAIV or IIV followed by LAIV challenge in children. Methods. Serum and mucosal responses to LAIV or IIV were analyzed using immunologic assays to assess both quantitative and functional responses. Cytokines and chemokines were measured in nasal washes collected before vaccination, on days 2, 4, and 7 after initial LAIV, and again after LAIV challenge using a 63-multiplex Luminex panel. Results. Patterns of immunity induced by LAIV and IIV were significantly different. Serum responses induced by IIV, including hemagglutination inhibition, did not correlate with detection or quantitation of LAIV on subsequent challenge. Modalities that induced sterilizing immunity seen after LAIV challenge could not be defined by any measurements of mucosal or serum antibodies induced by the initial LAIV immunization. No single cytokine or chemokine was predictive of protection. Conclusions. The mechanism of protective immunity observed after LAIV could not be defined, and traditional measurements of immunity to IIV did not correlate with protection against an LAIV challenge. PMID:27419180
Kong, Huihui; Zhang, Qianyi; Gu, Chunyang; Shi, Jianzhong; Deng, Guohua; Ma, Shujie; Liu, Jinxiong; Chen, Pucheng; Guan, Yuntao; Jiang, Yongping; Chen, Hualan
The continued spread of the newly emerged H7N9 viruses among poultry in China, together with the emergence of drug-resistant variants and the possibility of human-to-human transmission, has spurred attempts to develop an effective vaccine. An MF59-adjuvant H7N9 inactivated vaccine is reported to be well-tolerated and immunogenic in humans; however a study in ferrets indicated that while a single dose of the inactivated H7N9 vaccine reduced disease severity, it did not prevent virus replication and transmission. In this study, we used reverse genetics to produce a cold-adapted, live attenuated H7N9 vaccine (H7N9/AAca) that contains wild-type HA and NA genes from AH/1, and the backbone of the cold-adapted influenza H2N2 A/Ann Arbor/6/60 virus (AAca). H7N9/AAca was attenuated in mice and ferrets, and induced robust neutralizing antibody responses in rhesus mice, ferrets, and guinea pigs immunized once or twice intranasally. The animals immunized twice were completely protected from H7N9 virus challenge. Importantly, the animals vaccinated once were fully protected from transmission when exposed to or in contact with the H7N9 virus-inoculated animals. These results demonstrate that a cold-adapted H7N9 vaccine can prevent H7N9 virus transmission; they provide a compelling argument for further testing of this vaccine in human trials. PMID:26058711
Plante, Kenneth S; Rossi, Shannan L.; Bergren, Nicholas A.; Seymour, Robert L.; Weaver, Scott C.
We recently described a new, live-attenuated vaccine candidate for chikungunya (CHIK) fever, CHIKV/IRES. This vaccine was shown to be well attenuated, immunogenic and efficacious in protecting against CHIK virus (CHIKV) challenge of mice and nonhuman primates. To further evaluate its preclinical safety, we compared CHIKV/IRES distribution and viral loads in interferon-α/β receptor-incompetent A129 mice to another CHIK vaccine candidate, 181/clone25, which proved highly immunogenic but mildly reactive in human Phase I/II clinical trials. Compared to wild-type CHIK virus, (wt-CHIKV), both vaccines generated lower viral loads in a wide variety of tissues and organs, including the brain and leg muscle, but CHIKV/IRES exhibited marked restrictions in dissemination and viral loads compared to 181/clone25, and was never found outside the blood, spleen and muscle. Unlike wt-CHIKV, which caused disrupted splenic architecture and hepatic lesions, histopathological lesions were not observed in animals infected with either vaccine strain. To examine the stability of attenuation, both vaccines were passaged 5 times intracranially in infant A129 mice, then assessed for changes in virulence by comparing parental and passaged viruses for footpad swelling, weight stability and survival after subcutaneous infection. Whereas strain 181/clone25 p5 underwent a significant increase in virulence as measured by weight loss (from <10% to >30%) and mortality (from 0 to 100%), CHIKV/IRES underwent no detectible change in any measure of virulence (no significant weight loss and no mortality). These data indicate greater nonclinical safety of the CHIKV/IRES vaccine candidate compared to 181/clone25, further supporting its eligibility for human testing. PMID:26340754
Tabynov, K; Kydyrbayev, Zh; Ryskeldinova, Sh; Assanzhanova, N; Sansyzbay, A
We previously created a live vaccine against equine influenza based the new reassortant cold-adapted (Ca) strain A/HK/Otar/6:2/2010. The live vaccine contains surface proteins (HA, NA) from the wild-type virus A/equine/Otar/764/2007 (Н3N8; American Lineage Florida Clade 2), and internal proteins (PB2, PB1, PA, NP, M, NS) from the attenuated Ca donor virus A/Hong Kong/1/68/162/35CA (H3N2). To determine the safety and duration of the protective immune responses, 90 yearlings were intranasally vaccinated in single mode, double mode at an interval of 42 days (10(7.0) EID50/animal for both vaccinations), or with PBS (control group). Ten animals from each group were challenged with the homologous wild-type virus A/equine/Otar/764/07 (Н3N8) at 1, 2, 3, 4, 5, 6, 9 and 12 months after vaccination. Similarly, 10 animals from each group were challenged with the heterologous wild-type virus A/equine/Sydney/2888-8/07 (Н3N8; American Lineage Florida Clade 1) 12 months after vaccination. The vaccine was completely safe, and single intranasal vaccination of yearlings was capable of inducing statistically significant (from P=0.03 to P<0.0001) clinical and virological protection against the homologous virus; however, only double mode vaccination generated significant (from P=0.02 to P<0.0001) protection against the heterologous virus at 12 months (observation period). Interestingly, this vaccine enables the differentiation of infected and vaccinated animals. On this basis of this study, we recommend double intranasal administration of this vaccine at an interval of 42 days in veterinary practice.
Hughes, Austin L
Analysis of patterns of nucleotide sequence diversity in wild-type rabies virus (RABV) genomes and in the SAD live attenuated oral vaccine lineage was used to test for the relaxation of purifying selection in the latter and provide evidence regarding the genomic regions where such relaxation of selection occurs. The wild-type sequences showed evidence of strong past and ongoing purifying selection both on nonsynonymous sites in coding regions and on non-coding regions, particularly the start, end and 5' UTR regions. SAD vaccine sequences showed a relaxation of purifying selection at nonsynonymous sites in coding regions, resulting a substantial number of amino acid sequence polymorphisms at sites that were invariant in the wild-type sequences. Moreover, SAD vaccine sequences showed high levels of mutation accumulation in the non-coding regions that were most conserved in the wild-type sequences. Understanding the biological effects of the unique mutations accumulated in the vaccine lineage is important because of their potential effects on antigenicity and effectiveness of the vaccine.
Mielcarek, Nathalie; Debrie, Anne-Sophie; Raze, Dominique; Bertout, Julie; Rouanet, Carine; Younes, Amena Ben; Creusy, Colette; Engle, Jacquelyn; Goldman, William E; Locht, Camille
Pertussis is still among the principal causes of death worldwide, and its incidence is increasing even in countries with high vaccine coverage. Although all age groups are susceptible, it is most severe in infants too young to be protected by currently available vaccines. To induce strong protective immunity in neonates, we have developed BPZE1, a live attenuated Bordetella pertussis strain to be given as a single-dose nasal vaccine in early life. BPZE1 was developed by the genetic inactivation or removal of three major toxins. In mice, BPZE1 was highly attenuated, yet able to colonize the respiratory tract and to induce strong protective immunity after a single nasal administration. Protection against B. pertussis was comparable to that induced by two injections of acellular vaccine (aPV) in adult mice, but was significantly better than two administrations of aPV in infant mice. Moreover, BPZE1 protected against Bordetella parapertussis infection, whereas aPV did not. BPZE1 is thus an attractive vaccine candidate to protect against whooping cough by nasal, needle-free administration early in life, possibly at birth.
Leyman, Bregje; Boyen, Filip; Van Parys, Alexander; Verbrugghe, Elin; Haesebrouck, Freddy; Pasmans, Frank
Vaccination is an important measure to control Salmonella contamination in the meat production chain. A previous study showed that both the ΔrfaJ and ΔrfaL strains are suitable markers and allow serological differentiation of infected and vaccinated animals. The aim of this study was to verify whether deletion of the lon gene in a Salmonella Typhimurium ΔrfaJ marker strain resulted in decreased environmental survival. Our results indicate that deletion of the lon gene in the ΔrfaJ strain did not affect invasiveness in IPEC-J2 cells and resulted in an increased susceptibility to UV, disinfectants (such as hydrogen peroxide and tosylchloramide sodium) and citric acid. Immunization of pigs with inactivated ΔrfaJ or ΔlonΔrfaJ vaccines allowed differentiation of infected and vaccinated pigs. Furthermore, deletion of the lon gene did not reduce the protection conferred by live wild type or ΔrfaJ vaccines against subsequent challenge with a virulent Salmonella Typhimurium strain in BALB/c mice. Based on our results in mice, we conclude that deletion of lon in ΔrfaJ contributes to environmental safety of the ΔrfaJ DIVA strain.
Bernau, Maren; Kremer, Prisca V; Kreuzer, Lena S; Emrich, Daniela; Pappenberger, Elke; Cussler, Klaus; Hoffmann, Andreas; Leipig, Miriam; Hermanns, Walter; Scholz, Armin Manfred
The safety of veterinary vaccines is assessed in clinical trials in Europe. The assessment of the local tissue reaction to vaccination by magnetic resonance imaging (MRI) could reduce the number of animals needed because repeated examinations can be performed in the same animal over time. The present study compared the evaluation of local tissue reactions to vaccination using MRI in live pigs with histopathology of porcine tissue, the current gold standard in regulatory safety testing. Eight piglets each were administered one of two commercial vaccines into marked injection sites. All animals were sedated and scanned repeatedly by MRI using a contrast agent up to day 29 after vaccination. On day 29, the animals were euthanized and underwent a pathological examination. The MRI results were compared with the pathomorphological findings at the injection site by regression analysis. The MR images and the pathological examinations yielded matching results concerning the sizes of the affected tissue volumes or areas. The use of MRI for regulatory safety testing can reduce the number of animals needed to 8 per examination group. The volume of a local reaction and its progression over time can be evaluated and documented. If persistent lesions develop a final pathomorphological examination is needed to identify the kind and local distribution of the reaction.
Mielcarek, Nathalie; Debrie, Anne-Sophie; Raze, Dominique; Bertout, Julie; Rouanet, Carine; Younes, Amena Ben; Creusy, Colette; Engle, Jacquelyn; Goldman, William E; Locht, Camille
Pertussis is still among the principal causes of death worldwide, and its incidence is increasing even in countries with high vaccine coverage. Although all age groups are susceptible, it is most severe in infants too young to be protected by currently available vaccines. To induce strong protective immunity in neonates, we have developed BPZE1, a live attenuated Bordetella pertussis strain to be given as a single-dose nasal vaccine in early life. BPZE1 was developed by the genetic inactivation or removal of three major toxins. In mice, BPZE1 was highly attenuated, yet able to colonize the respiratory tract and to induce strong protective immunity after a single nasal administration. Protection against B. pertussis was comparable to that induced by two injections of acellular vaccine (aPV) in adult mice, but was significantly better than two administrations of aPV in infant mice. Moreover, BPZE1 protected against Bordetella parapertussis infection, whereas aPV did not. BPZE1 is thus an attractive