Seroprevalence of influenza A H1N1 and seroconversion of mothers and infants induced by a single dose of monovalent vaccine.

PubMed

Chao, Anne; Huang, Yhu-Chering; Chang, Yao-Lung; Wang, Tzu-Hao; Chang, Shuenn-Dyh; Wu, Ting-Shu; Wu, Tsu-Lan; Chao, An-Shine

2013-09-01

To determine the prevalence of preexisting antibodies against the pandemic 2009 Influenza A (H1N1) virus in pregnant women and to evaluate the seroprotection of the mothers and infants by a single injection of monovalent vaccine during the pandemic. Seropositivity rate of H1N1 among the nonvaccinated were compared with the vaccinated women. A single dose of vaccine, either nonadjuvanted AdimFlu-S or MF59-adjuvanted vaccine, was injected to the voluntarily vaccinated group. Maternal and cord blood sera were collected to evaluate the antibody response of the H1N1 virus. Seropositivity was defined as a hemagglutination inhibition titer to H1N1 (A/Taiwan/126/09) ≥ 1:40. A total of 210 healthy, singleton, pregnant women were enrolled between January 2010 and May 2010. Seropositivity (≥ 1:40) of maternal hemagglutination inhibition was significantly higher in the vaccinated group (78%) than the nonvaccinated group (9.5%); 41.6% (20/48) of seropositive titers were >1:80. In nine vaccinated cases resulting in negative serum titers (<1:40), the prevalence of negative titer in the women received AdimFlu-S (14.8%, 4/31) was lower (p = 0.025) than those received MF59-adjuvanted vaccine (50%, 5/10). Subclinical infection against H1N1 was low in Taiwanese pregnant women in the pandemic 2009. Seropositivity >75% could be achieved in the paired maternal and cord serum samples by a single injection of monovalent H1N1 vaccine. Copyright © 2013. Published by Elsevier B.V.

Impact and Effectiveness of Monovalent Rotavirus Vaccine Against Severe Rotavirus Diarrhea in Ghana.

PubMed

Armah, George; Pringle, Kimberly; Enweronu-Laryea, Christabel C; Ansong, Daniel; Mwenda, Jason M; Diamenu, Stanley K; Narh, Clement; Lartey, Belinda; Binka, Fred; Grytdal, Scott; Patel, Manish; Parashar, Umesh; Lopman, Ben

2016-05-01

Ghana was among the first African nations to introduce monovalent rotavirus vaccine (RV1) into its childhood immunization schedule in April 2012. We aimed to assess the impact of vaccine introduction on rotavirus and acute gastroenteritis (AGE) hospitalizations and to estimate vaccine effectiveness (VE). Using data from 2 teaching hospitals, monthly AGE and rotavirus admissions by age were examined 40 months before and 31 months after RV1 introduction using interrupted time-series analyses. From January 2013, we enrolled children <2 years of age who were eligible for RV1 from a total of 7 sentinel sites across the country. To estimate VE, we fit unconditional logistic regression models to calculate odds ratios of vaccination by rotavirus case-patient status, controlling for potential confounders. Vaccine coverage ranged from 95% to 100% for dose 1 and 93% to 100% for dose 2. In the first 3 years after vaccine introduction, the percentage of hospital admissions positive for rotavirus fell from 48% in the prevaccine period to 28% (49% adjusted rate reduction; 95% confidence interval [CI], 32%-63%) postvaccination among <5-year-olds. With high vaccine coverage, it was not possible to arrive at robust VE estimates; any-dose VE against rotavirus hospitalization was estimated at 60% (95% CI, -2% to 84%;P= .056). Results from the first 3 years following RV1 introduction suggest substantial reductions of pediatric diarrheal disease as a result of vaccination. Our VE estimate is consistent with the observed rotavirus decrease and with efficacy estimates from elsewhere in sub-Saharan Africa. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Intussusception and Monovalent Rotavirus Vaccination in Singapore: Self-Controlled Case Series and Risk-Benefit Study.

PubMed

Yung, Chee-Fu; Chan, Siew Pang; Soh, Sally; Tan, Adriana; Thoon, Koh Cheng

2015-07-01

To investigate the association between monovalent human rotavirus vaccine (RV1) and intussusception among Asian infants and the impact of older age of vaccination. To perform risk-benefit analysis of RV1 vaccination programs in Singapore. We performed a self-controlled case series by extracting intussusception cases in infants aged <12 months from hospital databases (2005-2012) and with vaccination histories from a national immunization registry. Relative incidences were calculated by comparing incidence during defined risk periods after vaccination with times outside these periods. In the risk benefit analysis, we estimated excess intussusception hospitalization in relation to the number of infants vaccinated for hypothetical vaccination coverage scenarios. There were 86 infants hospitalized with intussusception; 20 cases had received at least 1 dose of RV1. Nearly all (19) had received their first dose at age >12 weeks old. The age-adjusted relative incidence of intussusception in the 1- to 7-day period post dose one was 8.36 (95% CI 2.42-28.96). Of all childhood hospitalizations because of rotavirus, 71% (570 cases) could be prevented with 90% vaccination coverage. There would be approximately 1 excess intussusception case per 65,000 infants vaccinated. Risk of intussusception increases about 8-fold during 1-7 days after receipt of first dose RV1 in infants of Chinese, Malay, and Indian ethnicity in Singapore, Asia. High vaccine coverage program in Singapore would be beneficial with only a low risk of excess intussusception. The relative risk of intussusception post-RV1 vaccination is not higher in Asia despite differences in background intussusception incidence compared with US and Australia, or older age of vaccination. Copyright © 2015 Elsevier Inc. All rights reserved.

A critical review on a globally-licensed, live, orally-administrable, monovalent human rotavirus vaccine: Rotarix.

PubMed

Nakagomi, Toyoko; Nakagomi, Osamu

2009-08-01

Rotavirus is the major cause of severe gastroenteritis in children worldwide, and two, live, orally-administrable vaccines are licensed globally. They are Rotarix, a monovalent, human rotavirus-based vaccine (GlaxoSmithKline), and RotaTeq, a pentavalent, bovine-human reassortant vaccine (Merck). The RIX4414 strain, a G1P[8] virus, is contained in the Rotarix vaccine. It grows efficiently in the human intestine, as evidenced by vaccine virus shedding into faeces. Efficient multiplication of RIX4414 in the intestines may play a role in stimulating immune effectors other than neutralizing antibodies that may explain the protective immunity against fully heterotypic G2P[4] strains. The protective efficacy against severe rotavirus gastroenteritis afforded by Rotarix is consistently better against strains that share with RIX4414 both G and P serotypes (i.e., G1P[8]), or only P serotype (i.e., G3P[8], G4P[8] and G9P[8]). The Rotarix vaccine is safe regarding intussusception if its first dose is administered between 6 and 12 weeks of age and the last dose by 24 weeks of age with a minimum interval of 4 weeks between the two doses. The expansion by Advisory Committee on Immunization Practices, USA, of the age limit for the first dose to age <15 weeks, and the last dose by 8 months requires close monitoring.

Effectiveness of monovalent 2009 pandemic influenza A virus subtype H1N1 and 2010-2011 trivalent inactivated influenza vaccines in Wisconsin during the 2010-2011 influenza season.

PubMed

Bateman, Allen C; Kieke, Burney A; Irving, Stephanie A; Meece, Jennifer K; Shay, David K; Belongia, Edward A

2013-04-15

The 2009 influenza A virus subtype H1N1 (A[H1N1]pdm09) did not exhibit antigenic drift during the 2010-2011 influenza season, providing an opportunity to investigate the duration of protection after vaccination. We estimated the independent effects of 2010-2011 seasonal trivalent inactivated influenza vaccine (TIV) and A(H1N1)pdm09 vaccine for preventing medically attended influenza A virus infection during the 2010-2011 season. Individuals were tested for influenza A virus by real-time reverse transcription polymerase chain reaction (rRT-PCR) after a clinical encounter for acute respiratory illness. Case-control analyses compared participants with rRT-PCR-confirmed influenza A virus infection and test-negative controls. Vaccine effectiveness was estimated separately for monovalent pandemic vaccine and TIV and was calculated as 100 × [1 - adjusted odds ratio], where the odds ratio was adjusted for potential confounders. The effectiveness of TIV against influenza A virus infection was 63% (95% confidence interval [CI], 37%-78%). The effectiveness of TIV against A(H1N1)pdm09 infection was 77% (95% CI, 44%-90%). Monovalent vaccine administered between October 2009 and April 2010 was not protective during the 2010-2011 season, with an effectiveness of -1% (95% CI, -146% to 59%) against A(H1N1)pdm09 infection.  Monovalent vaccine provided no sustained protection against A(H1N1)pdm09 infection during the 2010-2011 season. This waning effectiveness supports the need for annual revaccination, even in the absence of antigenic drift in A(H1N1)pdm09.

Profiling of humoral response to influenza A(H1N1)pdm09 infection and vaccination measured by a protein microarray in persons with and without history of seasonal vaccination.

PubMed

Huijskens, Elisabeth G W; Reimerink, Johan; Mulder, Paul G H; van Beek, Janko; Meijer, Adam; de Bruin, Erwin; Friesema, Ingrid; de Jong, Menno D; Rimmelzwaan, Guus F; Peeters, Marcel F; Rossen, John W A; Koopmans, Marion

2013-01-01

The influence of prior seasonal influenza vaccination on the antibody response produced by natural infection or vaccination is not well understood. We compared the profiles of antibody responses of 32 naturally infected subjects and 98 subjects vaccinated with a 2009 influenza A(H1N1) monovalent MF59-adjuvanted vaccine (Focetria, Novartis), with and without a history of seasonal influenza vaccination. Antibodies were measured by hemagglutination inhibition (HI) assay for influenza A(H1N1)pdm09 and by protein microarray (PA) using the HA1 subunit for seven recent and historic H1, H2 and H3 influenza viruses, and three avian influenza viruses. Serum samples for the infection group were taken at the moment of collection of the diagnostic sample, 10 days and 30 days after onset of influenza symptoms. For the vaccination group, samples were drawn at baseline, 3 weeks after the first vaccination and 5 weeks after the second vaccination. We showed that subjects with a history of seasonal vaccination generally exhibited higher baseline titers for the various HA1 antigens than subjects without a seasonal vaccination history. Infection and pandemic influenza vaccination responses in persons with a history of seasonal vaccination were skewed towards historic antigens. Seasonal vaccination is of significant influence on the antibody response to subsequent infection and vaccination, and further research is needed to understand the effect of annual vaccination on protective immunity.

Detection of rotavirus before and after monovalent rotavirus vaccine introduction and vaccine effectiveness among children in mainland Tanzania.

PubMed

Jani, Bhavin; Hokororo, Adolfine; Mchomvu, Jackson; Cortese, Margaret M; Kamugisha, Christopher; Mujuni, Delphinius; Kallovya, Dotto; Parashar, Umesh D; Mwenda, Jason M; Lyimo, DaFrossa; Materu, Antonia; Omari, Kakuri Frank; Waziri, Mark; Laswai, Theresia; Juma, Hamisi; Mlay, Josephine; Dogani, Juliana; Stephen, Eugenia; Seugendo, Mwanisha; Nkumbi, Uyanjo; Lyakurwa, Anna; Matojo, Anivera; Bendera, Elice; Senyota, Jonathan; Msingwa, Veronica; Fungo, Yohana; Michael, Fausta; Mpamba, Amina; Chambo, Alfred; Cholobi, Happy; Lyamuya, Faraja; Chami, Inviollatha; Mchome, Esther; Mshana, Amina Mohamed; Mushi, Edward; Mariki, Uforo; Chard, Ronica; Tuju, Deborah; Ambokile, Nuswe; Lukwale, Fatuma; Kyessi, Furaha; Khamis, Asha; Michael, Innocent; Macha, Doreen; Saguti, Angelina

2018-04-11

Monovalent rotavirus vaccine (RV1) was introduced in Tanzania in January 2013 under the Reach Every Child initiative, to be given at ages 6 and 10 weeks. We used the sentinel hospital rotavirus surveillance system to examine the rotavirus detection rate before and after vaccine introduction and estimate vaccine effectiveness. Before vaccine introduction, rotavirus surveillance was established at two mainland hospitals; children admitted for acute diarrhea were eligible for enrollment and stools were tested for rotavirus antigen. We compared the rotavirus positivity rate in the pre-vaccine period (Tanga Hospital, 2009 and 2011; Bugando Medical Centre, 2012) to that from post-introduction years, 2014-2015. In 2013, surveillance was established at 9 additional hospitals. We examined rotavirus positivity among infants at these sites for 2014-2015. We obtained vaccine records and calculated vaccine effectiveness at 3 sites using case-test-negative control design. At Tanga Hospital, the rotavirus positivity rate among infants was 41% (102/251) pre-vaccine and 14% (28/197) in post-vaccine years (rate ratio: 0.35 [95% CI 0.22-0.54]). At Bugando, the positivity rate was 58% (83/143) pre-vaccine, and 18% (49/277) post-introduction (rate ratio 0.30 [95% CI 0.210.44]). Results were similar among children <5 years. At the new sites, the median site rotavirus positivity rate among infants was 26% in 2014 (range 19-44%) and 18% in 2015 (range 16-33%). The effectiveness of ≥1 RV1 dose against rotavirus hospitalization among children 5-23 months was 53% (95% CI: -14, 81), and 66% (95% CI: 9-87) against hospitalization with intravenous rehydration. Following introduction, peak rotavirus activity occurred later in the year and appeared more concentrated in time. Rotavirus surveillance data from Tanzania indicate that the rotavirus positivity rate among children hospitalized with diarrhea that were enrolled was substantially reduced after vaccine introduction. Low positivity

Paralytic poliomyelitis associated with Sabin monovalent and bivalent oral polio vaccines in Hungary.

PubMed

Estívariz, Concepción F; Molnár, Zsuzsanna; Venczel, Linda; Kapusinszky, Beatrix; Zingeser, James A; Lipskaya, Galina Y; Kew, Olen M; Berencsi, György; Csohán, Agnes

2011-08-01

Historical records of patients with vaccine-associated paralytic poliomyelitis (VAPP) in Hungary during 1961-1981 were reviewed to assess the risk of VAPP after oral polio vaccine (OPV) administration. A confirmed VAPP case was defined as a diagnosis of paralytic poliomyelitis and residual paralysis at 60 days in a patient with an epidemiologic link to the vaccine. Archived poliovirus isolates were retested using polymerase chain reaction and sequencing of the viral protein 1 capsid region. This review confirmed 46 of 47 cases previously reported as VAPP. Three cases originally linked to monovalent OPV (mOPV) 3 and one case linked to mOPV1 presented after administration of bivalent OPV 1 + 3 (bOPV). The adjusted VAPP risk per million doses administered was 0.18 for mOPV1 (2 cases/11.13 million doses), 2.96 for mOPV3 (32 cases/10.81 million doses), and 12.82 for bOPV (5 cases/390,000 doses). Absence of protection from immunization with inactivated poliovirus vaccine or exposure to OPV virus from routine immunization and recent injections could explain the higher relative risk of VAPP in Hungarian children. In polio-endemic areas in which mOPV3 and bOPV are needed to achieve eradication, the higher risk of VAPP would be offset by the high risk of paralysis due to wild poliovirus and higher per-dose efficacy of mOPV3 and bOPV compared with trivalent OPV.

Efficacy and safety of the H1N1 monovalent vaccine in renal-transplant recipients and dialysis patients.

PubMed

Beaudreuil, Séverine; Krivine, Anne; Hebibi, Hadia; Ducot, Béatrice; Mazet, Anne-Aurélie; Taouffik, Yacine; Seidowsky, Alexandre; Jacquet, Antoine; Lorenzo, Hans Kristian; Charpentier, Bernard; Francois, Hélène; Durrbach, Antoine

2011-08-01

The (H1N)1v influenza virus infection emerged in 2009 as a serious disease in targeted populations. Herein, we report on the tolerability and efficacy of (anti-H1N1)v vaccination in dialysis and transplant patients. 18 renal-transplant recipients (RTR) and 19 dialysis patients (DP) [12 patients treated with peritoneal dialysis (PDP), 7 patients treated with haemodialysis (HDP)] were enrolled. DPs received one monovalent H1N1 adjuvanted-vaccine injection, and RTRs received two unadjuvanted vaccine injections within a 21-day period. Serologic response was defined as a haemagglutination inhibition titre of > 40 (seroprotection) and/or at least a four-fold increase in antibody titre from baseline (seroconversion). Seroprotection rate after vaccination was greater in DPs than RTRs (p = 0.007), as was seroconversion (p = 0.001). Serologic response was similar in PDPs and HDPs. Serologic response was satisfactory in DPs, whichever dialysis mode (DPD or HDP). It was low in RTRs as compared to DPs.

Qualitative Effects of Monovalent Vaccination Against Rotavirus: A Comparison of North America and South America.

PubMed

Young, Glenn; Shim, Eunha; Ermentrout, G Bard

2015-10-01

Rotavirus is the most common cause of severe gastroenteritis in young children worldwide. The introduction of vaccination programs has led to a significant reduction in number of hospitalizations due to rotavirus in North and South American countries. Little work has been done, however, to examine the differential impact of vaccination as a function of strain distribution and strain-specific vaccine efficacy. We developed a two-strain epidemiological model of rotavirus transmission, and used it to examine the effects of a monovalent vaccine (Rotarix) on the qualitative behaviors of infection levels in a population. For contrast, we parameterized our model with strain distribution data from North America and from South America. In all cases, the introduction of the vaccine led to significant decreases in the prevalence of primary infection due to both strains for a decade or more, after which the overall prevalence recovers to near pre-vaccination levels. The prevalence of G1P[8] is significantly higher in North America (73 % of all rotavirus infections) compared to that in South America (34 %). Our model predicts that the introduction of Rotarix might result in major strain replacement in regions such as North America where the prevalence of G1P[8] is relatively high, due to higher efficacy of Rotarix against infection caused by G1P[8], while regions with lower prevalence of G1P[8], such as South America, are not susceptible to major strain replacement.

Assessment of efficacy and safety of pandemic A/H1N1/2009 influenza vaccine in a group of health care workers.

PubMed

Mascagni, P; Vicenzi, Elisa; Kajaste-Rudnitski, Anna; Pellicciotta, G; Monti, A; Cervi, Carla; Vitalucci, Roberta; Toffoletto, F

2012-01-01

The development in an extremely short time of an efficacious and safe vaccine against the pandemi A/H1N1 virus was a challenge that involved the entire scientific community. To assess the immunological and clinical efficacy of the new H1N1v monovalent influenza vaccine (Focetria Novartis Vaccines, Siena, Italy) in a group of health care workers (HCWs). A total of 148 volunteer HCWs were enrolled between Mid-Novembre 2009 and December 2009. After measuring antibody titers, a single intramuscular dose of 7.5 microg of Focetria monovalent vaccine against A/H1N1/2009 influenza virus with MF59C.1 adjuvant was administered. Antibody titers (median value) before and after a single dose of vaccine, measured by means of standard beam-agglutination inhibition test (HAI), increased from 32 to 256 (p < 0.001). After vaccination, 79.7% of the subjects showed antibody seroconversion, and in 97.3% seroprotection was achieved. The ratio between the geometric means of antibody titers (GMTR) was 6.69. For the 3 subjects who reported symptoms of ILI (Influenza-like illness), a regular nasal-pharyngeal swab sample was taken to identify the virus type by RT-PCR, the laboratory results of tests performed on these samples were negative for pandemic A/H1N1/2009 virus. During the entire follow-up period of 6 months no severe adverse events occurred. The vaccine against pandemic A/H1N1/2009 virus provided protection against the virus and not only contributed to a significant immunization (according to EMEA criteria), but kept all 148 subjects under study free from A/H1N1/2009 influenza illness.

Lasting immune memory against hepatitis B following challenge 10-11 years after primary vaccination with either three doses of hexavalent DTPa-HBV-IPV/Hib or monovalent hepatitis B vaccine at 3, 5 and 11-12 months of age.

PubMed

Avdicova, Mária; Crasta, Priya D; Hardt, Karin; Kovac, Martina

2015-05-28

The combined hexavalent diphtheria-tetanus-pertussis-hepatitis B-inactivated poliomyelitis - Haemophilus influenzae type b conjugate vaccine (Infanrix hexa™; DTPa-HBV-IPV/Hib: GlaxoSmithKline Vaccines) induces robust responses to the HBV component when administered at 3, 5 and 11-12 months of age. We assessed long term HBV antibody persistence 10-11 years after primary vaccination in infancy. Antibody persistence and immune memory were assessed post-primary vaccination at 3, 5, 11-12 months with DTPa-HBV-IPV/Hib, or monovalent HBV vaccine (Engerix™ B, GlaxoSmithKline Vaccines) co-administered with DTPa-IPV/Hib (Infanrix™-IPV/Hib, GlaxoSmithKline Vaccines) in 185 children aged 11-12 years. Blood samples were collected before and 1 month after a challenge dose of Engerix™ B (10μg dose). 10-11 years after primary vaccination the percentage of subjects with persisting anti-HBs antibody concentrations ≥10mIU/ml was 48.4% in the DTPa-HBV-IPV/Hib group and 58.4% in the DTPa-IPV/Hib+HBV group. After the HBV challenge dose, the percentage with anti-HBs ≥100mIU/ml increased from 14.7% to 93.6% in the DTPa-HBV-IPV/Hib group and 19.1% to 94.4% in the DTPa-IPV/Hib+HBV group. Anti-HBs GMCs increased by at least 187-fold in each group. An anamnestic response (≥4-fold increase in initially seropositive or anti-HBs concentration ≥10mIU/ml in initially seronegative subjects) was observed in 96.8% and 96.6% of subjects in the DTPa-HBV-IPV/Hib and DTPa-IPV/Hib+HBV groups, respectively. No serious adverse events occurred that were considered related to challenge vaccination. Administration of HBV as part of a combination vaccine or as a monovalent vaccine induced long lasting immune memory against HBV in children primed at 3, 5 and 11 months of age. Antibody persistence and immune memory were similar, suggesting that protection afforded by DTPa-HBV-IPV/Hib and monovalent HBV vaccines, is likely to be of similar duration. The administration of HBV challenge dose 10

A systematic review and meta-analysis for the adverse effects, immunogenicity and efficacy of Lyme disease vaccines: Guiding novel vaccine development.

PubMed

Badawi, Alaa; Shering, Maria; Rahman, Shusmita; Lindsay, L Robbin

2017-04-20

Lyme borreliosis (LB) is the most prevalent arthropod-borne infectious disease in North America. Currently, no vaccine is available to prevent LB in humans, although monovalent and multivalent vaccines have been developed in the past. The aim of the current study is to conduct a systematic review and meta-analysis to evaluate and compare the findings from these two classes of vaccines for their reactogenicity, immunogenicity and efficacy, in the hope this may assist in the development of future vaccines. A search strategy was developed for online databases (PubMed, Ovid MEDLINE, and Embase). Search terms used were "vaccine/vaccination", "Lyme disease/Borreliosis", "clinical trial(s)" and "efficacy". Only seven clinical trials were included to compare the results of the monovalent vaccines to those of the multivalent one. Meta-analyses were conducted to evaluate the reactogenicity and immunogenicity of the two vaccine classes. Odds ratio (OR) for LB (and 95% confidence intervals; 95% CI) were calculated for the efficacy of the monovalent vaccine from three different clinical trials at different dose schedules. Incidence of redness (local adverse effect) and fever (systemic side effect) were, respectively, 6.8- and 2.9-fold significantly lower (p < 0.05) in individuals who received multivalent vaccines compared to those receiving the monovalent one. Incidences of all other local and systemic adverse effects were non-significantly lower in the multivalent vaccine compared to the monovalent vaccines. Seroprotection was comparable among individuals who received the two vaccine classes at the 30 μg dose level. Efficacy in the prevention of LB was only evaluated for the monovalent vaccines. OR of LB ranged from 0.49 (95% CI: 0.14-0.70; p < 0.005, vs. placebo) to 0.31 (95% CI: 0.26-0.63; p < 0.005) for the initial and final doses respectively, with an overall OR of 0.4 (95% CI: 0.26-0.63, p < 0.001). The current study further validates that the monovalent and

Recombinant LipL32 stimulates interferon-gamma production in cattle vaccinated with a monovalent Leptospira borgpetersenii serovar Hardjo subtype Hardjobovis vaccine.

PubMed

Deveson Lucas, Deanna S; Lo, Miranda; Bulach, Dieter M; Quinsey, Noelene S; Murray, Gerald L; Allen, Andy; Adler, Ben

2014-03-14

Leptospira borgpetersenii serovar Hardjo subtype Hardjobovis (Hardjobovis) is the main causative agent of bovine leptospirosis in Australia, New Zealand, North America and elsewhere. Bovine leptospirosis can result in spontaneous abortion, stillbirth and reduced milk output. The organism is shed in the urine of infected animals and contact with contaminated materials can result in zoonotic infections in humans. Protective immunity in cattle against Hardjobovis involves stimulation of a Th1 cell mediated immune response, which can be characterized by the production of IFN-γ when blood from vaccinated animals is exposed to Hardjobovis antigens. However, the leptospiral components involved in stimulating this response have yet to be identified. In this study, 238 recombinant leptospiral proteins were evaluated for their ability to stimulate IFN-γ production in blood of cattle vaccinated with a commercial monovalent Hardjobovis vaccine. The conserved lipoprotein LipL32 is the major outer membrane protein of pathogenic Leptospira spp. A pool of soluble recombinant proteins which included LipL32, as well as LipL32 alone, stimulated significant IFN-γ production in blood of vaccinated cattle. A number of recombinant LipL32 fragments was generated, which identified the amino acids between 20 and 200 as containing the bovine T-cell reactive regions of LipL32. However, whether LipL32 plays a role in stimulating protective immunity in mammals has yet to be conclusively determined. Copyright © 2014 Elsevier B.V. All rights reserved.

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Changing molecular epidemiology of rotavirus infection after introduction of monovalent rotavirus vaccination in Scotland.

PubMed

Mukhopadhya, Indrani; Murdoch, Heather; Berry, Susan; Hunt, Alison; Iturriza-Gomara, Miren; Smith-Palmer, Alison; Cameron, J Claire; Hold, Georgina L

2017-01-03

Rotaviruses (RV) are the leading cause of gastroenteritis in children less than five years of age worldwide. Rotarix®, a live attenuated monovalent vaccine containing a RV strain of G1P[8] specificity has been included in the childhood immunisation schedule from June 2013 in Scotland. This study aimed to characterise the prevalent RV strains in Scotland before and after the introduction of the RV vaccine. RV positive faecal samples from Scottish virology laboratories covering the years 2012-2015 were genotyped. Viral RNA was extracted from faecal suspensions. VP7 and VP4 gene specific primers were used for multiplex hemi-nested PCRs and sequencing. Mann-Whitney U test and Chi-square test were used for statistical comparison. There was a decrease in RV positive samples from the Scottish virology laboratories from 7409 samples in the pre-vaccination years (2009-2013) to 760 in 2014-2015, with an annual reduction of RV infections by 74.4% (RR-3.95; 95%-CI, 3.53-4.42, p<0.001). 362 samples from the pre-vaccination period and 278 samples from the post-vaccination were genotyped. There was a drop in prevalence of G1P[8] strains (72.1%, 95%-CI, 67.42-76.33 to 15%, 95%-CI, 11.38-19.79) after introduction of the vaccine. In the post-vaccination period G2P[4] was the dominant strain in Scotland (21.9%, 95%-CI, 17.48-27.17) with increase in G9P[8] (12.9%, 95%-CI, 9.50-7.41), G12P[8] (12.2%, 95%-CI, 8.89-16.60) and G3P[8] (11.9%, 95%-CI, 8.58-16.20) infections. Phylogenetic analysis of the VP7 and VP4 genes showed no major differences between the pre and post-vaccination G1P[8] strains. This laboratory based surveillance study shows significant reduction in reported RV cases and a shift in proportion from G1P[8] to G2P[4] strains after introduction of RV vaccination in Scotland. The genotyping data from a subset of the total reported RV cases will be used to ascertain cross protection against strains and identify vaccine induced RV strain shifts in the years to come

Active surveillance for intussusception in a phase III efficacy trial of an oral monovalent rotavirus vaccine in India.

PubMed

John, Jacob; Kawade, Anand; Rongsen-Chandola, Temsunaro; Bavdekar, Ashish; Bhandari, Nita; Taneja, Sunita; Antony, Kalpana; Bhatnagar, Veereshwar; Gupta, Arun; Kabra, Madhulika; Kang, Gagandeep

2014-08-11

Post licensure studies have identified an increased risk of intussusception following vaccination with currently licensed rotavirus vaccines, raising safety concerns generic to all rotavirus vaccines. We describe the surveillance for intussusception in a phase III clinical trial with an oral monovalent rotavirus vaccine developed from the neonatal 116E strain. Using broad screening criteria and active surveillance, the incidence of intussusception between 6 weeks and 2 years of age was measured in 4532 children who received three doses of vaccine and 2267 children who received a placebo in the clinical trial. Possible intussusceptions were evaluated with a screening ultrasonogram. An independent intussusception case adjudication committee reviewed all intussusceptions and graded them on Brighton Collaboration criteria for diagnostic certainty. We identified twenty-three intussusceptions on ultrasound from 1361 evaluated sentinel events. Eleven were of level 1 diagnostic certainty as determined by the independent intussusception case adjudication committee. None required surgical intervention, and the earliest identified intussusception was at 36 days following the third dose in a placebo recipient. Among vaccine recipients the first event of intussusception occurred 112 days after the third dose. The incidence of ultrasound-diagnosed intussusception was 200/100,000 child-years (95% CI, 120, 320) among those receiving the vaccine and 141/100,000 child-years (95% CI, 50, 310) among those receiving the placebo. The incidence rate of confirmed intussusception among vaccine recipients was 94/100,000 child-years (95% CI, 41, 185) and 71/100,000 child-years (95% CI, 15, 206) among those receiving the placebo. In this licensure study, 23 cases of intussusception were identified through an active surveillance system, but there was no temporal association with rotavirus vaccination. The use of active surveillance with broad criteria intended for ensuring safety of children

Impact of high coverage of monovalent human rotavirus vaccine on Emergency Department presentations for rotavirus gastroenteritis.

PubMed

Davey, Heather M; Muscatello, David J; Wood, James G; Snelling, Thomas L; Ferson, Mark J; Macartney, Kristine K

2015-03-30

Australia was one of the first countries to introduce nationally funded rotavirus vaccination. The program has had a substantial impact on both rotavirus and all-cause acute gastroenteritis (AGE) hospitalisations and rotavirus laboratory tests. Evidence for an impact on Emergency Department (ED) presentations is limited. This study assessed changes in ED presentations for rotavirus in children aged <5 years in New South Wales, Australia, following introduction of monovalent human rotavirus vaccine (RV1, Rotarix(®), GlaxoSmithKline Australia Pty Ltd., Victoria, Australia). A time series analysis to examine trends in total non-admitted ED presentations for all-cause AGE and in the rotavirus-attributable fraction using data on rotavirus positive laboratory tests. A decline in the rate of non-admitted ED presentations for all-cause AGE was observed for all ages, being most notable in 1 year old children. Compared with the pre-vaccination period, we estimated the average weekly rate was lower across the first 4.5 years of the program for both all-cause AGE (18.3%; 70.5 versus 57.5 per 100,000 population) and rotavirus attributable (55.4%; 17.3 versus 7.7 per 100,000 population) presentations. In the fourth year of the program, estimated annual rotavirus attributable presentations were 77% lower than the pre-vaccination annual mean (996 versus 4300 per year). The program was associated with a substantial decline in rotavirus attributable non-admitted AGE presentations to ED among children aged <5 years. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Antibody response to influenza A(H1N1)pdm09 among healthcare personnel receiving trivalent inactivated vaccine: effect of prior monovalent inactivated vaccine.

PubMed

Gaglani, Manjusha; Spencer, Sarah; Ball, Sarah; Song, Juhee; Naleway, Allison; Henkle, Emily; Bozeman, Sam; Reynolds, Sue; Sessions, Wendy; Hancock, Kathy; Thompson, Mark

2014-06-01

Few data are available on the immunogenicity of repeated annual doses of influenza A(H1N1)pdm09-containing vaccines. We enrolled healthcare personnel (HCP) in direct patient care during the autumn of 2010 at 2 centers with voluntary immunization. We verified the receipt of A(H1N1)pdm09-containing monovalent inactivated influenza vaccine (MIIV) and 2010-2011 trivalent inactivated vaccine (TIV). We performed hemagglutination inhibition antibody (HI) assays on preseason, post-TIV, and end-of-season serum samples. We compared the proportion of HCPs with HI titer ≥ 40 against A(H1N1)pdm09 per receipt of prior-season MIIV, current-season TIV, both, or neither. At preseason (n = 1417), HI ≥ 40 was significantly higher among those who received MIIV (34%) vs those who did not (14%) (adjusted relative risk [ARR], 3.26; 95% confidence interval [CI], 2.72-3.81). At post-TIV (n = 865), HI ≥ 40 was lower among HCP who received MIIV and TIV (66%) than among those receiving only TIV (85%) (ARR, 0.93 [95% CI, .84-.997]). At end-of-season (n = 1254), HI ≥ 40 was 40% among those who received both MIIV and TIV and 67% among those receiving only TIV (ARR, 0.76 [95% CI, .65-.88]), 52% among those who received MIIV only, and 12% among those receiving neither. HCP immunization programs should consider effects of host immune response and vaccine antigenic distance on immunogenicity of repeated annual doses of influenza vaccines.

Effect of age on the incidence of aseptic meningitis following immunization with monovalent mumps vaccine.

PubMed

Muta, Hiromi; Nagai, Takao; Ito, Yuhei; Ihara, Toshiaki; Nakayama, Tetsuo

2015-11-09

The purpose of this study was to determine the risk of aseptic meningitis after mumps vaccination in younger children compared with older children. This prospective cohort study included a total of 21,465 children under 18 years of age who had received the first dose of three of the Japanese mumps monovalent vaccine. We compared the cumulative incidence of aseptic meningitis for 30 days after vaccination among the following age groups: ≤ 1, 2, 3-4, and ≥ 5 years old. We also investigated the cumulative incidence of salivary gland swelling, a fever (≥ 38°C) lasting at least 3 days during the 10 to 25 days following immunization, vomiting of 3 times or more, headache, and seizure. A total of 10 aseptic meningitis, 551 salivary gland swelling, 844 fevers, 669 vomiting, 757 headaches, and 29 seizure cases were identified. The cumulative incidence of aseptic meningitis increased with age (0.016%, 0.021%, 0.066%, and 0.096%, respectively). Statistical significance was observed between children ≥ 3 years old and those < 3 years of age [0.078% vs. 0.018%, RR 4.35 (95% CI 1.05-18.2), p=0.04]. The cumulative incidence of salivary gland swelling also increased with age (1.8%, 3.0%, 3.5%, and 4.5%, respectively). For non-specific adverse events, the cumulative incidence of fever or seizure decreased with age. In contrast, the cumulative incidence of headache increased with age. The cumulative incidence of vomiting was similar among children ≤ 4 years of age; however, that in those children ≥ 5 years old was significantly lower. The first dose of mumps vaccine that is currently available for use in Japan may be administered in children less than 3 years of age in order to complicate a less aseptic meningitis after immunization. Copyright © 2015 Elsevier Ltd. All rights reserved.

Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial.

PubMed

Bhandari, Nita; Rongsen-Chandola, Temsunaro; Bavdekar, Ashish; John, Jacob; Antony, Kalpana; Taneja, Sunita; Goyal, Nidhi; Kawade, Anand; Kang, Gagandeep; Rathore, Sudeep Singh; Juvekar, Sanjay; Muliyil, Jayaprakash; Arya, Alok; Shaikh, Hanif; Abraham, Vinod; Vrati, Sudhanshu; Proschan, Michael; Kohberger, Robert; Thiry, Georges; Glass, Roger; Greenberg, Harry B; Curlin, George; Mohan, Krishna; Harshavardhan, G V J A; Prasad, Sai; Rao, T S; Boslego, John; Bhan, Maharaj Kishan

2014-06-21

Rotavirus is the most common cause of severe dehydrating gastroenteritis in developing countries. Safe, effective, and affordable rotavirus vaccines are needed in these countries. We aimed to assess the efficacy and tolerability of a monovalent human-bovine rotavirus vaccine for severe rotavirus gastroenteritis in low-resource urban and rural settings in India. We did a randomised double-blind, placebo-controlled, multicentre trial at three sites in Delhi (urban), Pune (rural), and Vellore (urban and rural) between March 11, 2011, and Nov 5, 2012. Infants aged 6-7 weeks were randomly assigned (2:1), via a central interactive voice or web response system with a block size of 12, to receive either three doses of oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6-7 weeks, 10 weeks, and 14 weeks. Infants' families, study investigators, paediatricians in referral hospitals, laboratory staff, and committee members were all masked to treatment allocation. The primary outcome was incidence of severe rotavirus gastroenteritis (≥11 on the Vesikari scale). Efficacy outcomes and adverse events were ascertained through active surveillance. Analysis was by intention to treat and per protocol. The trial is registered with Clinical Trial Registry-India (CTRI/2010/091/000102) and ClinicalTrials.gov (NCT01305109). 4532 infants were assigned to receive the 116E vaccine and 2267 to receive placebo, of whom 4354 (96%) and 2187 (96%) infants, respectively, were included in the primary per-protocol efficacy analysis. 71 events of severe rotavirus gastroenteritis were reported in 4752 person-years in infants in the vaccine group compared with 76 events in 2360 person-years in those in the placebo group; vaccine efficacy against severe rotavirus gastroenteritis was 53·6% (95% CI 35·0-66·9; p=0·0013) and 56·4% (36·6-70·1; p<0·0001) in the first year of life. The number of infants needed to be immunised to prevent one severe rotavirus gastroenteritis episode

Immunogenicity and safety results from a randomized multicenter trial comparing a Tdap-IPV vaccine (REPEVAX®) and a tetanus monovalent vaccine in healthy adults

PubMed Central

Laurichesse, Henri; Zimmermann, Ulrich; Galtier, Florence; Launay, Odile; Duval, Xavier; Richard, Patrick; Sadorge, Christine; Soubeyrand, Benoit

2012-01-01

In adults with a tetanus-prone injury, combined vaccines such as Tdap-IPV (REPEVAX®) can boost immunity against several diseases simultaneously. This Phase IIIb, parallel-group, open-label trial compared antibody responses to Tdap-IPV and tetanus monovalent vaccine (TMV; Vaccin Tétanique Pasteur® or Tetavax®) against tetanus toxoid 10 and 28 d post-vaccination. Between July and December 2009, four centers in France and five in Germany recruited healthy adults who had received a tetanus-containing vaccine 5−10 y previously. Participants were randomized 1:1 to receive at the first visit a single dose (0.5 mL) of Tdap-IPV or TMV, with follow-up visits at Day 10 and Day 28. Outcomes: per protocol (PP) population immunogenicity at Day 10 (primary) and at Day 28 (secondary); safety throughout the study. Of 456 adults randomized, 223 received Tdap-IPV and 233 received TMV (PP population: 183 and 199 participants, respectively). All participants receiving Tdap-IPV and 99.0% receiving TMV had an anti-tetanus antibody concentration ≥ 0.1 IU/mL, confirming non-inferiority of Tdap-IPV to TMV (95% confidence interval of the difference: –1.2, 3.6). Number of adverse events reported was comparable in each group. Injection-site reactions were reported by 76.6% participants receiving Tdap-IPV and 74.6% receiving TMV. Systemic events (e.g., malaise, myalgia and headache) were reported in 47.7% and 39.7% of the Tdap-IPV and the TMV groups, respectively. Tdap-IPV is effective and well-tolerated for use in the management of tetanus-prone injuries in emergency settings in persons for whom a booster against diphtheria, pertussis and poliomyelitis is also needed. ClinicalTrials.gov identifier: NCT00928785. Research sponsored by Sanofi Pasteur MSD. PMID:23032160

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The risk of intussusception following monovalent rotavirus vaccination in England: A self-controlled case-series evaluation.

PubMed

Stowe, Julia; Andrews, Nick; Ladhani, Shamez; Miller, Elizabeth

2016-07-12

To investigate the risk of intussusception after monovalent rotavirus vaccine (RV1) given to infants aged 2 and 3 months in England. Hospital Episode Statistics (HES) were used to identify infants aged 48-183 days admitted between 11/03/2013 and 31/10/2014 with intussusception. Diagnosis was confirmed from medical records and HES procedure codes. Vaccination status was obtained from general practitioners. The risk of admission within 1-7 and 8-21 days of vaccination was analysed using the self-controlled case-series (SCCS) method with age effect adjustment by including historical data before RVI introduction in July 2013. A total of 119 cases were identified during the study period and intussusception confirmed in 95 of whom 39 were vaccinated 1-21 days before onset. An increased relative incidence (RI) in this period was found, 4.53 (95% confidence interval 2.34-8.58) and 2.60 (1.43-4.81) respectively after the 1st and 2nd doses with an attributable risk of 1.91 and 1.49 per 100,000 doses respectively. The peak risk was 1-7 days after the first dose, RI 13.81 (6.44-28.32), with an estimated 93% of the 15 cases being vaccine-attributable. Mean interval between onset and admission, and clinical features were similar between vaccine-associated and background cases. Despite intussusception being a contraindication to rotavirus vaccination, 10 infants received a further dose; none had a recurrence. The RIs in a meta-analysis combing our results with Australia, Mexico, Brazil and Singapore using RV1, a 2, 4 month schedule and SCCS gave pooled RI estimates of 2.35 (1.45-3.8) and 1.77 (1.29-2.43) in the 21 day period after the 1st and 2nd doses, respectively. The earlier age at the 2nd dose in England did not affect the risk. We estimate that the RVI programme causes around 21 intussusception admissions annually in England but, since it prevents around 25,000 gastro-intestinal infection admissions, its benefit/risk profile remains strongly positive. Crown Copyright �

International collaboration to assess the risk of Guillain Barré Syndrome following Influenza A (H1N1) 2009 monovalent vaccines.

PubMed

Dodd, Caitlin N; Romio, Silvana A; Black, Steven; Vellozzi, Claudia; Andrews, Nick; Sturkenboom, Miriam; Zuber, Patrick; Hua, Wei; Bonhoeffer, Jan; Buttery, Jim; Crawford, Nigel; Deceuninck, Genevieve; de Vries, Corinne; De Wals, Philippe; Gutierrez-Gimeno, M Victoria; Heijbel, Harald; Hughes, Hayley; Hur, Kwan; Hviid, Anders; Kelman, Jeffrey; Kilpi, Tehri; Chuang, S K; Macartney, Kristine; Rett, Melisa; Lopez-Callada, Vesta Richardson; Salmon, Daniel; Gimenez-Sanchez, Francisco; Sanz, Nuria; Silverman, Barbara; Storsaeter, Jann; Thirugnanam, Umapathi; van der Maas, Nicoline; Yih, Katherine; Zhang, Tao; Izurieta, Hector

2013-09-13

The global spread of the 2009 novel pandemic influenza A (H1N1) virus led to the accelerated production and distribution of monovalent 2009 Influenza A (H1N1) vaccines (pH1N1). This pandemic provided the opportunity to evaluate the risk of Guillain-Barré syndrome (GBS), which has been an influenza vaccine safety concern since the swine flu pandemic of 1976, using a common protocol among high and middle-income countries. The primary objective of this project was to demonstrate the feasibility and utility of global collaboration in the assessment of vaccine safety, including countries both with and without an established infrastructure for vaccine active safety surveillance. A second objective, included a priori, was to assess the risk of GBS following pH1N1 vaccination. The primary analysis used the self-controlled case series (SCCS) design to estimate the relative incidence (RI) of GBS in the 42 days following vaccination with pH1N1 vaccine in a pooled analysis across databases and in analysis using a meta-analytic approach. We found a relative incidence of GBS of 2.42 (95% CI 1.58-3.72) in the 42 days following exposure to pH1N1 vaccine in analysis of pooled data and 2.09 (95% CI 1.28-3.42) using the meta-analytic approach. This study demonstrates that international collaboration to evaluate serious outcomes using a common protocol is feasible. The significance and consistency of our findings support a conclusion of an association between 2009 H1N1 vaccination and GBS. Given the rarity of the event the relative incidence found does not provide evidence in contradiction to international recommendations for the continued use of influenza vaccines. Copyright © 2013 Elsevier Ltd. All rights reserved.

77 FR 71167 - Foreign-Trade Zone 59-Lincoln, Nebraska, Authorization of Production Activity, Novartis Consumer...

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2012-11-29

... DEPARTMENT OF COMMERCE Foreign-Trade Zones Board [B-64-2012] Foreign-Trade Zone 59--Lincoln, Nebraska, Authorization of Production Activity, Novartis Consumer Health, Inc. (Pharmaceutical and Related Preparations Production), Lincoln, Nebraska Novartis Consumer Health, Inc. submitted a notification of proposed...

Cost-Effectiveness of Monovalent Rotavirus Vaccination of Infants in Malawi: A Postintroduction Analysis Using Individual Patient–Level Costing Data

PubMed Central

Bar-Zeev, Naor; Tate, Jacqueline E.; Pecenka, Clint; Chikafa, Jean; Mvula, Hazzie; Wachepa, Richard; Mwansambo, Charles; Mhango, Themba; Chirwa, Geoffrey; Crampin, Amelia C.; Parashar, Umesh D.; Costello, Anthony; Heyderman, Robert S.; French, Neil; Atherly, Deborah; Cunliffe, Nigel A.

2016-01-01

Background. Rotavirus vaccination reduces childhood hospitalization in Africa, but cost-effectiveness has not been determined using real-world effectiveness and costing data. We sought to determine monovalent rotavirus vaccine cost-effectiveness in Malawi, one of Africa's poorest countries and the first Gavi-eligible country to report disease reduction following introduction in 2012. Methods. This was a prospective cohort study of children with acute gastroenteritis at a rural primary health center, a rural first referral–level hospital and an urban regional referral hospital in Malawi. For each participant we itemized household costs of illness and direct medical expenditures incurred. We also collected Ministry of Health vaccine implementation costs. Using a standard tool (TRIVAC), we derived cost-effectiveness. Results. Between 1 January 2013 and 21 November 2014, we recruited 530 children aged <5 years with gastroenteritis. Costs did not differ by rotavirus test result, but were significantly higher for admitted children and those with increased severity on Vesikari scale. Adding rotavirus vaccine to the national schedule costs Malawi $0.42 per dose in system costs. Vaccine copayment is an additional $0.20. Over 20 years, the vaccine program will avert 1 026 000 cases of rotavirus gastroenteritis, 78 000 inpatient admissions, 4300 deaths, and 136 000 disability-adjusted-life-years (DALYs). For this year's birth cohort, it will avert 54 000 cases of rotavirus and 281 deaths in children aged <5 years. The program will cost $10.5 million and save $8.0 million in averted healthcare costs. Societal cost per DALY averted was $10, and the cost per rotavirus case averted was $1. Conclusions. Gastroenteritis causes substantial economic burden to Malawi. The rotavirus vaccine program is highly cost-effective. Together with the demonstrated impact of rotavirus vaccine in reducing population hospitalization burden, its cost-effectiveness makes a strong argument

Cost-Effectiveness of Monovalent Rotavirus Vaccination of Infants in Malawi: A Postintroduction Analysis Using Individual Patient-Level Costing Data.

PubMed

Bar-Zeev, Naor; Tate, Jacqueline E; Pecenka, Clint; Chikafa, Jean; Mvula, Hazzie; Wachepa, Richard; Mwansambo, Charles; Mhango, Themba; Chirwa, Geoffrey; Crampin, Amelia C; Parashar, Umesh D; Costello, Anthony; Heyderman, Robert S; French, Neil; Atherly, Deborah; Cunliffe, Nigel A

2016-05-01

Rotavirus vaccination reduces childhood hospitalization in Africa, but cost-effectiveness has not been determined using real-world effectiveness and costing data. We sought to determine monovalent rotavirus vaccine cost-effectiveness in Malawi, one of Africa's poorest countries and the first Gavi-eligible country to report disease reduction following introduction in 2012. This was a prospective cohort study of children with acute gastroenteritis at a rural primary health center, a rural first referral-level hospital and an urban regional referral hospital in Malawi. For each participant we itemized household costs of illness and direct medical expenditures incurred. We also collected Ministry of Health vaccine implementation costs. Using a standard tool (TRIVAC), we derived cost-effectiveness. Between 1 January 2013 and 21 November 2014, we recruited 530 children aged <5 years with gastroenteritis. Costs did not differ by rotavirus test result, but were significantly higher for admitted children and those with increased severity on Vesikari scale. Adding rotavirus vaccine to the national schedule costs Malawi $0.42 per dose in system costs. Vaccine copayment is an additional $0.20. Over 20 years, the vaccine program will avert 1 026 000 cases of rotavirus gastroenteritis, 78 000 inpatient admissions, 4300 deaths, and 136 000 disability-adjusted-life-years (DALYs). For this year's birth cohort, it will avert 54 000 cases of rotavirus and 281 deaths in children aged <5 years. The program will cost $10.5 million and save $8.0 million in averted healthcare costs. Societal cost per DALY averted was $10, and the cost per rotavirus case averted was $1. Gastroenteritis causes substantial economic burden to Malawi. The rotavirus vaccine program is highly cost-effective. Together with the demonstrated impact of rotavirus vaccine in reducing population hospitalization burden, its cost-effectiveness makes a strong argument for widespread utilization in other low-income, high

Experience with live rubella virus vaccine combined with live vaccines against measles and mumps*

PubMed Central

Smorodintsev, A. A.; Nasibov, M. N.; Jakovleva, N. V.

1970-01-01

Vaccination of pre-school children in the 1-7-years age-group for the specific prophylaxis of mumps and rubella is often difficult to arrange because of the already large number of inoculations given to these children. Combined vaccines to protect against measles, mumps and rubella should therefore be a valuable development. The existence of effective live vaccines for each of these 3 diseases makes possible the production of a single preparation suitable for subcutaneous inoculation. Tests on vaccine strains of measles (Leningrad-16), mumps (Leningrad-3) and rubella (Leningrad-8) viruses in various combinations have established that divalent or trivalent vaccines remain clinically harmless, highly immunogenic and epidemiologically effective. Single subcutaneous administrations of live measles vaccine combined with mumps or rubella vaccines or both, when given to children aged 1-8 years, brough about a high percentage of serological conversions and an increase in antibodies to a level comparable with that achieved with the corresponding monovalent vaccines. Morbidity from the 3 diseases was reduced among those vaccinated with the trivalent vaccine by 10 or more times, i.e., by about the same factor as when monovalent or divalent vaccines were used. PMID:5310140

Guillain-Barré syndrome following receipt of influenza A (H1N1) 2009 monovalent vaccine in Korea with an emphasis on Brighton Collaboration case definition.

PubMed

Choe, Young June; Cho, Heeyeon; Bae, Geun-Ryang; Lee, Jong-Koo

2011-03-03

In 2009-2010 season, with ongoing of influenza A (H1N1), employment of mass vaccination has generated concerns in issue of adverse events following immunization (AEFI). This study investigates the clinical and laboratory data of reported cases of Guillain-Barré syndrome (GBS) and Fisher syndrome (FS) following receipt of influenza A (H1N1) 2009 monovalent vaccine to the National Vaccine Injury Compensation Program (NVICP) in Korea, with all cases reviewed under case definition developed by Brighton Collaboration GBS Working Group. Retrospective review of medical records for all suspected cases of GBS ad FS following receipt of influenza A (H1N1) monovalent vaccine reported to NVICP from December 1, 2009, through April 28, 2010 was conducted. Additional analyses were performed for identification of levels of diagnostic certainty according to Brighton Collaboration case definition. Of 29 reported cases, 22 were confirmed to meet Brighton criteria level 1, 2, or 3 for GBS (21) or FS (1). Of those, 2 (9.1%) met level 1, 9 (40.9%) met level 2, and 11 (50.0%) met level 3. The male to female ratio was 2:0 in cases with level 1, 8:1 in cases with level 2, and 3:8 in cases with level 3. The mean age was older in cases with level 1 (54.0 ± 26.9) than that of cases with level 2 (25.6 ± 22.8), and level 3 (13.6 ± 2.4, P=0.005). The median onset interval was longer in cases with level 1 (16 days) than that of cases that met level 2 (12.44 days), and 3 (1.09 days, P=0.019). The Brighton case definition was used to improve the quality of AEFI data in Korea, and was applicable in retrospective review of medical records in cases with GBS and FS after influenza A (H1N1) vaccination. These findings suggest that standardized case definition was feasible in clarifying the AEFI data, and to further increase the understanding of possible relationship of influenza vaccine and GBS. Copyright © 2011 Elsevier Ltd. All rights reserved.

Heterogeneity of T Cell Responses to Pandemic pH1N1 Monovalent Vaccine in HIV-Infected Pregnant Women.

PubMed

Weinberg, Adriana; Muresan, Petronella; Richardson, Kelly; Fenton, Terence; Dominguez, Teresa; Bloom, Anthony; Watts, D Heather; Abzug, Mark J; Nachman, Sharon A; Levin, Myron J

2015-11-01

We investigated the Th1 protective and regulatory T and B cell (Treg and Breg) responses to pH1N1 monovalent influenza vaccine (IIV1) in HIV-infected pregnant women on combination antiretroviral therapy (cART). Peripheral blood mononuclear cells (PBMCs) from 52 study participants were cryopreserved before and after vaccination and analyzed by flow cytometry. pH1N1-specific Th1, Treg, and Breg responses were measured in PBMCs after in vitro stimulation with pH1N1 and control antigen. The cohort analysis did not detect changes in pH1N1-Th1, Treg, or Breg subsets postvaccination. However, individual analyses distinguished subjects who mounted vigorous Th1 responses postvaccination from others who did not. Postvaccination, high pH1N1-Th1 correlated with high pH1N1-Treg and Breg responses, suggesting that low influenza effector responses did not result from excessive vaccine-induced immune regulation. High postvaccination pH1N1-Th1 responses correlated with baseline high PHA- and pH1N1-IFN-γ ELISpot and circulating CD4(+)CD39(+)% and CD8(+)CD39(+)% Treg, with low CD8(+) cell numbers and CD19(+)FOXP3(+)% Breg, but not with CD4(+) cell numbers or HIV viral load. These data highlight the heterogeneity of T cell responses to vaccines in HIV-infected individuals on cART. Predictors of robust Th1 responses to IIV include CD8(+) cell numbers, T cell functionality, and circulating Breg and Treg.

Cost-effectiveness of alternate strategies for childhood immunization against meningococcal disease with monovalent and quadrivalent conjugate vaccines in Canada.

PubMed

Delea, Thomas E; Weycker, Derek; Atwood, Mark; Neame, Dion; Alvarez, Fabián P; Forget, Evelyn; Langley, Joanne M; Chit, Ayman

2017-01-01

Public health programs to prevent invasive meningococcal disease (IMD) with monovalent serogroup C meningococcal conjugate vaccine (MCV-C) and quadrivalent meningococcal conjugate vaccines (MCV-4) in infancy and adolescence vary across Canadian provinces. This study evaluated the cost-effectiveness of various vaccination strategies against IMD using current and anticipated future pricing and recent epidemiology. A cohort model was developed to estimate the clinical burden and costs (CAN$2014) of IMD in the Canadian population over a 100-year time horizon for three strategies: (1) MCV-C in infants and adolescents (MCV-C/C); (2) MCV-C in infants and MCV-4 in adolescents (MCV-C/4); and (3) MCV-4 in infants (2 doses) and adolescents (MCV-4/4). The source for IMD incidence was Canadian surveillance data. The effectiveness of MCV-C was based on published literature. The effectiveness of MCV-4 against all vaccination regimens was assumed to be the same as for MCV-C regimens against serogroup C. Herd effects were estimated by calibration to estimates reported in prior analyses. Costs were from published sources. Vaccines prices were projected to decline over time reflecting historical procurement trends. Over the modeling horizon there are a projected 11,438 IMD cases and 1,195 IMD deaths with MCV-C/C; expected total costs are $597.5 million. MCV-C/4 is projected to reduce cases of IMD by 1,826 (16%) and IMD deaths by 161 (13%). Vaccination costs are increased by $32 million but direct and indirect IMD costs are projected to be reduced by $46 million. MCV-C/4 is therefore dominant vs. MCV-C/C in the base case. Cost-effectiveness of MCV-4/4 was $111,286 per QALY gained versus MCV-C/4 (2575/206 IMD cases/deaths prevented; incremental costs $68 million). If historical trends in Canadian vaccines prices continue, use of MCV-4 instead of MCV-C in adolescents may be cost-effective. From an economic perspective, switching to MCV-4 as the adolescent booster should be considered.

Novartis School Lab: bringing young people closer to the world of research and discovering the excitement of science.

PubMed

Michel, Christiane Röckl; Standke, Gesche; Naef, Reto

2012-01-01

The Novartis School Lab (http://www.novartis.ch/schullabor) is an institution with an old tradition. The School Lab reaches about 5000 students through internal courses and an additional 5000 children at public science events where they can enjoy hands-on science in disciplines of biomedical research. The subjects range from chemistry, physics, molecular biology and genetics to toxicology and medical topics. The Novartis School Lab offers a variety of activities for youngsters aged 10-20 ranging from lab courses for school classes, continuing education for teachers and development of teaching kits, support for individual research projects to outreach for public science events. Innovation and adaptation to changes of current needs are essential aspects for the Novartis School Lab. Ongoing activities to shape the Novartis Biomedical Learning Lab include design of new teaching experiments, exploration into additional disciplines of biomedical science and the creation of a fascinating School Lab of the future.

Immunogenicity and safety of a novel monovalent high-dose inactivated poliovirus type 2 vaccine in infants: a comparative, observer-blind, randomised, controlled trial.

PubMed

Sáez-Llorens, Xavier; Clemens, Ralf; Leroux-Roels, Geert; Jimeno, José; Clemens, Sue Ann Costa; Weldon, William C; Oberste, M Steven; Molina, Natanael; Bandyopadhyay, Ananda S

2016-03-01

Following the proposed worldwide switch from trivalent oral poliovirus vaccine (tOPV) to bivalent types 1 and 3 OPV (bOPV) in 2016, inactivated poliovirus vaccine (IPV) will be the only source of protection against poliovirus type 2. With most countries opting for one dose of IPV in routine immunisation schedules during this transition because of cost and manufacturing constraints, optimisation of protection against all poliovirus types will be a priority of the global eradication programme. We assessed the immunogenicity and safety of a novel monovalent high-dose inactivated poliovirus type 2 vaccine (mIPV2HD) in infants. This observer-blind, comparative, randomised controlled trial was done in a single centre in Panama. We enrolled healthy infants who had not received any previous vaccination against poliovirus. Infants were randomly assigned (1:1) by computer-generated randomisation sequence to receive a single dose of either mIPV2HD or standard trivalent IPV given concurrently with a third dose of bOPV at 14 weeks of age. At 18 weeks, all infants were challenged with one dose of monovalent type 2 OPV (mOPV2). Primary endpoints were seroconversion and median antibody titres to type 2 poliovirus 4 weeks after vaccination with mIPV2HD or IPV; and safety (as determined by the proportion and nature of serious adverse events and important medical events for 8 weeks after vaccination). The primary immunogenicity analyses included all participants for whom a post-vaccination blood sample was available. All randomised participants were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02111135. Between April 14 and May 9, 2014, 233 children were enrolled and randomly assigned to receive mIPV2HD (117 infants) or IPV (116 infants). 4 weeks after vaccination with mIPV2HD or IPV, seroconversion to poliovirus type 2 was recorded in 107 (93·0%, 95% CI 86·8-96·9) of 115 infants in the mIPV2HD group compared with 86 (74·8%, 65·8

Molecular characterization of poliovirus isolates from children who contracted vaccine-associated paralytic poliomyelitis (VAPP) following administration of monovalent type 3 oral poliovirus vaccine in the 1960s in Hungary.

PubMed

Kapusinszky, Beatrix; Molnár, Zsuzsanna; Szomor, Katalin N; Berencsi, György

2010-03-01

Hungarian children were immunized with monovalent oral poliovaccine (mOPV) delivered at 6-week intervals in the order Sabin 1, Sabin 3, Sabin 2, from 1959 until 1992. During that period, 90 cases of vaccine-associated paralytic poliomyelitis (VAPP) were reported, 52 of which were associated with Sabin 3-related virus (76% of VAPP cases with virologic data). Because of renewed interest in type 3 mOPV (mOPV3), molecular methods were used to reanalyze 18 of the Sabin 3-related isolates from 15 VAPP patients, confirming the original identification. All isolates had the U472C 5'-untranslated region (5'-UTR) substitution associated with reversion to neurovirulence, and from zero to seven nucleotide substitutions in the virus protein 1 (VP1) region. No evidence was found for prolonged mOPV3 replication in the VAPP patients or for spread of Sabin 3-related viruses beyond close vaccinee contacts. The VAPP diseases were prevented by a single dose of inactivated poliovirus vaccine from 1992 to 2006 in Hungary, as proved by continuous surveillance of acute flaccid paralysis.

Priming effect of dengue and yellow fever vaccination on the immunogenicity, infectivity, and safety of a tetravalent dengue vaccine in humans.

PubMed

Qiao, Ming; Shaw, David; Forrat, Remi; Wartel-Tram, Anh; Lang, Jean

2011-10-01

A dengue vaccine effective against all four serotypes is urgently needed. However, safety and immunogenicity could be affected by prior exposure to flaviviruses. This open, controlled, phase IIa study was conducted in 35 healthy adults who had received monovalent, live attenuated Vero cell-derived dengue vaccine against dengue virus 1 (VDV1) or 2 (VDV2) or yellow fever (YF) vaccine 1 year before or who were flavivirus-naïve. All participants received one subcutaneous injection of tetravalent dengue vaccine (TDV) and were followed for 180 days. Previous vaccination did not increase reactogenicity, laboratory abnormalities, or incidence of vaccine viremia, but it did increase the neutralizing antibody response to dengue virus that persisted at day 180. There was no increase in YF antibodies in participants previously immunized with YF vaccine. Prior exposure to YF or monovalent dengue vaccines had no adverse effects on the safety or incidence of viremia associated with this TDV, but it increased immunogenicity.

Hazardous Waste Cleanup: Novartis Pharmaceuticals Corporation in Hanover, New Jersey

EPA Pesticide Factsheets

Novartis Pharmaceuticals Corporation is a 180-acre site, located at 59 Route 10, in an industrial, commercial and residential area of East Hanover, Morris County, New Jersey. The facility consists of a chemical manufacturing plant, a pharmaceutical

Hepatitis A, B, and A/B vaccination series completion among US adults: a claims-based analysis.

PubMed

Ghaswalla, Parinaz K; Patterson, Brandon J; Cheng, Wendy Y; Duchesneau, Emilie; Macheca, Monica; Duh, Mei Sheng

2018-06-20

Hepatitis A and B disease burden persists in the US. We assessed hepatitis A and hepatitis B vaccination series completion rates among 350,240 commercial/Medicare and 12,599 Medicaid enrollees aged ≥19 years. A vaccination series was considered as completed provided that the minimum interval between doses, as defined by the CDC, and the minimum number of doses were reached. We stratified completion rates by vaccine type (i.e. monovalent or bivalent) at initial vaccination for each cohort. In the commercial/Medicare cohort, the series completion rate was 32.0% for hepatitis A and 39.6% for hepatitis B among those who initiated with a monovalent vaccine, and it was 36.2% for hepatitis A and 48.9% for hepatitis B among those who initiated with a bivalent vaccine. In the Medicaid cohort, the series completion rate was 21.0% for hepatitis A and 24.0% for hepatitis B among those who initiated with a monovalent vaccine, and it was 19.0% for hepatitis A and 24.6% for hepatitis B among those who initiated with a bivalent vaccine. In conclusion, hepatitis A and B vaccination series completion rates were low, and appeared to be lower among Medicaid than among commercial/Medicare enrollees. Commercial/Medicare enrollees who initiated with a bivalent vaccine had higher series completion rates than those who initiated with monovalent vaccines - an observation that was not made among Medicaid enrollees.

Oral Modeling of an Adenovirus-Based Quadrivalent Influenza Vaccine in Ferrets and Mice.

PubMed

Scallan, Ciaran D; Lindbloom, Jonathan D; Tucker, Sean N

2016-06-01

Oral vaccines delivered as tablets offer a number of advantages over traditional parenteral-based vaccines including the ease of delivery, lack of needles, no need for trained medical personnel, and the ability to formulate into temperature-stable tablets. We have been evaluating an oral vaccine platform based on recombinant adenoviral vectors for the purpose of creating a prophylactic vaccine to prevent influenza, and have demonstrated vaccine efficacy in animal models and substantial immunogenicity in humans. These studies have evaluated monovalent vaccines to date. To protect against the major circulating A and B influenza strains, a multivalent influenza vaccine will be required. In this study, the immunogenicity of orally delivered monovalent, bivalent, trivalent, and quadrivalent vaccines was tested in ferrets and mice. The various vaccine combinations were tested by blending monovalent recombinant adenovirus vaccines, each expressing hemagglutinin from a single strain. Human tablet delivery was modeled in animals by oral gavage in mice and by endoscopic delivery in ferrets. We demonstrated minimal interference between the various vaccine vectors when used in combination and that the oral quadrivalent vaccine compared favorably to an approved trivalent inactivated vaccine. The quadrivalent vaccine presented here produced immune responses that we predict should be capable of providing protection against multiple influenza strains, and the platform should have applications to other multivalent vaccines. Vaxart, Inc.

Immersion vaccination of sockeye salmon (Oncorhynchus nerka) with two pathogenic strains of Vibrio anguillarum

USGS Publications Warehouse

Gould, R.W.; Antipa, R.; Amend, D.F.

1979-01-01

Sockeye salmon (Oncorhynchus nerka) were immersion-vaccinated in suspensions containing 5 × 107, 5 × 106, 5 × 105, or 5 × 104 bacteria/mL of bivalent or monovalent, formalin-killedVibrio anguillarum, Types I and II. The fish were split into two lots and held for 54 d. At that time one lot was challenged with living, virulent V. anguillarum, Type I, and one with living, virulent V.anguillarum, Type II. Immunization with bivalent bacterin effectively protected the fish from vibriosis, but monovalent vaccine was effective only against the homologous challenge. Immunization with the highest concentration of Type I monovalent bacterin resulted in 0% Type I and 58% Type II challenge mortality. Immunization with the highest concentration of Type II monovalent bacterin resulted in 41% Type I and 0% Type II challenge mortality. Immunization with the highest concentration of bivalent Type I/Type II bacterin resulted in 2% mortality in both challenges. Protective bacterins were effective at concentrations down to 5 × 105 bacteria/mL.Key words: immersion vaccination, bivalent vaccines, Vibrio anguillarum, vibriosis.

Immersion vaccination of sockeye salmon (Oncorhynchus kisutch) with two pathogenic strains of Vibrio anguillarum

USGS Publications Warehouse

Gould, R.W.; Antipa, R.; Amend, D.F.

1979-01-01

Sockeye salmon (Oncorhynchus nerka) were immersion-vaccinated in suspensions containing 5 × 107, 5 × 106, 5 × 105, or 5 × 104 bacteria/mL of bivalent or monovalent, formalin-killed Vibrio anguillarum, Types I and II. The fish were split into two lots and held for 54 d. At that time one lot was challenged with living, virulent V. anguillarum, Type I, and one with living, virulent V. anguillarum, Type II. Immunization with bivalent bacterin effectively protected the fish from vibriosis, but monovalent vaccine was effective only against the homologous challenge. Immunization with the highest concentration of Type I monovalent bacterin resulted in 0% Type I and 58% Type II challenge mortality. Immunization with the highest concentration of Type II monovalent bacterin resulted in 41% Type I and 0% Type II challenge mortality. Immunization with the highest concentration of bivalent Type I/Type II bacterin resulted in 2% mortality in both challenges. Protective bacterins were effective at concentrations down to 5 × 105 bacteria/mL. Key words: immersion vaccination, bivalent vaccines, Vibrio anguillarum, vibriosis.

Influence of oral polio vaccines on performance of the monovalent and pentavalent rotavirus vaccines.

PubMed

Patel, Manish; Steele, A Duncan; Parashar, Umesh D

2012-04-27

In recent years, two live, oral rotavirus vaccines have been successfully tested in developing and industrialized countries, and both vaccines are now recommended by the World Health Organization for all children worldwide. Both immunogenicity and efficacy of these rotavirus vaccines has been lower in developing compared to industrialized settings. We reviewed the data on the effect of trivalent OPV on the immunogenicity and efficacy of two rotavirus vaccines currently recommended by the WHO. While rotavirus vaccines have not affected immune responses to OPV, in general, the immune responses (i.e., antibody levels) to rotavirus vaccination were lower when rotavirus vaccines were co-administered with OPV. Limited data suggests that the interference is greater after the first dose of OPV, presumably because the first dose is associated with greatest intestinal replication of vaccine polio virus strains, and this interference is largely overcome with subsequent rotavirus vaccine doses. Despite the lower immunogenicity, one large efficacy study in middle income Latin American countries showed no decrease in protective efficacy of rotavirus vaccine in infants receiving concurrent OPV. While these data are encouraging and support simultaneous administration of rotavirus vaccines and OPV, additional evidence should be gathered as rotavirus vaccines are used more widely in developing country settings, where OPV is routinely used, rather than inactivated polio vaccine. Published by Elsevier Ltd.

Recombinant human adenovirus-5 expressing capsid proteins of Indian vaccine strains of foot-and-mouth disease virus elicits effective antibody response in cattle.

PubMed

Sreenivasa, B P; Mohapatra, J K; Pauszek, S J; Koster, M; Dhanya, V C; Tamil Selvan, R P; Hosamani, M; Saravanan, P; Basagoudanavar, Suresh H; de Los Santos, T; Venkataramanan, R; Rodriguez, L L; Grubman, M J

2017-05-01

Recombinant adenovirus-5 vectored foot-and-mouth disease constructs (Ad5- FMD) were made for three Indian vaccine virus serotypes O, A and Asia 1. Constructs co-expressing foot-and- mouth disease virus (FMDV) capsid and viral 3C protease sequences, were evaluated for their ability to induce a neutralizing antibody response in indigenous cattle (Bos indicus). Purified Ad5-FMD viruses were inoculated in cattle as monovalent (5×10 9 pfu/animal) or trivalent (5×10 9 pfu/animal per serotype) vaccines. Animals vaccinated with monovalent Ad5-FMD vaccines were boosted 63days later with the same dose. After primary immunization, virus neutralization tests (VNT) showed seroconversion in 83, 67 and 33% of animals vaccinated with Ad5-FMD O, A and Asia 1, respectively. Booster immunization elicited seroconversion in all of the animals (100%) in the monovalent groups. When used in a trivalent form, the Ad5-FMD vaccine induced neutralizing antibodies in only 33, 50 and 16% of animals against serotypes O, A and Asia 1, respectively on primo-vaccination, and titers were significantly lower than when the same vectors were used in monovalent form. Neutralizing antibody titers differed by serotype for both Ad5-FMD monovalent and trivalent vaccines, with Asia 1 serotype inducing the lowest titers. Antibody response to Ad5 vector in immunized cattle was also assessed by VNT. It appeared that the vector immunity did not impact the recall responses to expressed FMDV antigens on booster immunization. In summary, the study suggested that the recombinant Ad5-FMD vaccine has a potential use in monovalent form, while its application in multivalent form is not currently encouraging. Copyright © 2017 Elsevier B.V. All rights reserved.

Demonstration of 1-year duration of immunity for attenuated Bordetella bronchiseptica vaccines in dogs.

PubMed

Lehar, Craig; Jayappa, Huchappa; Erskine, Jason; Brown, Alicia; Sweeney, Diane; Wassmoen, Terri

2008-01-01

Three groups of healthy dogs with low antibody titers to Bordetella bronchiseptica (Bb), canine parainfluenza virus (CPI), and canine adenovirus type 2 (CAV-2) were used in this study. One group was vaccinated with a single dose of monovalent attenuated Bb vaccine and one group with a trivalent vaccine containing attenuated Bb, CPI, and CAV-2; dogs were vaccinated intranasally with a single dose of the respective vaccines. The third group served as unvaccinated controls. All vaccinated dogs subsequently developed serum antibody titers to Bb that persisted for at least 1 year. Following Bb challenge 1 year after vaccination, all vaccinated dogs, regardless of group, showed significantly fewer clinical signs and shed significantly fewer challenge organisms than unvaccinated controls. These results demonstrate that intranasal administration of a single dose of monovalent attenuated Bb vaccine or trivalent vaccine containing attenuated Bb, CPI, and CAV-2 provides 1 year of protection against Bb.

Efficacy of a Monovalent Human-Bovine (116E) Rotavirus Vaccine in Indian Infants: A Randomised Double Blind Placebo Controlled Trial

PubMed Central

Bhandari, Nita; Rongsen-Chandola, Temsunaro; Bavdekar, Ashish; John, Jacob; Antony, Kalpana; Taneja, Sunita; Goyal, Nidhi; Kawade, Anand; Kang, Gagandeep; Rathore, Sudeep Singh; Juvekar, Sanjay; Muliyil, Jayaprakash; Arya, Alok; Shaikh, Hanif; Abraham, Vinod; Vrati, Sudhanshu; Proschan, Michael; Kohberger, Robert; Thiry, Georges; Glass, Roger; Greenberg, Harry B; Curlin, George; Mohan, Krishna; Harshavardhan, GVJA; Prasad, Sai; Rao, TS; Boslego, John; Bhan, Maharaj Kishan

2015-01-01

and two amongst 2267 placebo recipients (P=0·73). All intussusception cases occurred after the third dose. Among vaccine and placebo recipients, the minimum interval between dosing and intussusception was 112 and 36 days, respectively. Interpretation The monovalent human-bovine (116E) rotavirus vaccine is effective and well-tolerated in Indian infants. PMID:24629994

"To patent or not to patent? the case of Novartis' cancer drug Glivec in India".

PubMed

Gabble, Ravinder; Kohler, Jillian Clare

2014-01-06

Glivec (imatinib mesylate), produced by the pharmaceutical company Novartis, is prescribed in the case of chronic myeloid leukemia, one of the most common blood cancers in eastern countries. After more than a decade of legal battles surrounding its patentability, the Supreme Court of India gave its final decision on April 1st of 2013, rejecting the appeal of the Swiss giant drug manufacturer. In 2006, the Indian Patent Office first refused Glivec's patent under Section 3(d) of the Indian Patent Act arguing that it was only a modified version of an existing drug, Imatinib, and therefore that the drug was not innovative. Novartis replied filing legal challenges against the Indian government but the final verdict in April of 2013 ends the battle. Indeed, the Supreme Court stated that even if the bioavailability of the drug was improved, it did not demonstrate enhanced efficacy and that Glivec was not patentable. The research primarily focused on journal, newspaper and magazine articles relevant to the time frame of the lawsuit (from 1994 to 2013) as well as news searches through Google, Factiva, ProQuest, PubMed, and YouTube where press articles from court verdicts were obtained by using the following keywords: "India", "Novartis", "Glivec", "Patent", "Novartis Case", and "Supreme Court of India". The data sources were interpreted and analyzed according to the authors' own prior knowledge and understanding of the exigencies of the TRIPS Agreement. This case illuminates how India is interpreting international law to fit domestic public health needs. The Novartis case arguably sets an important precedent for the global pharmaceutical industry and ideally will help improve access to lifesaving medicines in the developing world by demanding that patient health needs supersede commercial interests. The Supreme Court of India's decision may affect the interpretation of the article of the TRIPS Agreement, which states members shall be free to determine the appropriate method

Pre-travel advice, attitudes and hepatitis A and B vaccination rates among travellers from seven countries†

PubMed Central

Heywood, Anita E.; Nothdurft, Hans; Tessier, Dominique; Moodley, Melissa; Rombo, Lars; Marano, Cinzia; De Moerlooze, Laurence

2017-01-01

Background: Knowledge about the travel-associated risks of hepatitis A and B, and the extent of pre-travel health-advice being sought may vary between countries. Methods: An online survey was undertaken to assess the awareness, advice-seeking behaviour, rates of vaccination against hepatitis A and B and adherence rates in Australia, Finland, Germany, Norway, Sweden, the UK and Canada between August and October 2014. Individuals aged 18–65 years were screened for eligibility based on: travel to hepatitis A and B endemic countries within the past 3 years, awareness of hepatitis A, and/or combined hepatitis A&B vaccines; awareness of their self-reported vaccination status and if vaccinated, vaccination within the last 3 years. Awareness and receipt of the vaccines, sources of advice, reasons for non-vaccination, adherence to recommended doses and the value of immunization reminders were analysed. Results: Of 27 386 screened travellers, 19 817 (72%) were aware of monovalent hepatitis A or combined A&B vaccines. Of these 13 857 (70%) had sought advice from a healthcare provider (HCP) regarding combined hepatitis A&B or monovalent hepatitis A vaccination, and 9328 (67%) were vaccinated. Of 5225 individuals eligible for the main survey (recently vaccinated = 3576; unvaccinated = 1649), 27% (841/3111) and 37% (174/465) of vaccinated travellers had adhered to the 3-dose combined hepatitis A&B or 2-dose monovalent hepatitis A vaccination schedules, respectively. Of travellers partially vaccinated against combined hepatitis A&B or hepatitis A, 84% and 61%, respectively, believed that they had received the recommended number of doses. Conclusions: HCPs remain the main source of pre-travel health advice. The majority of travellers who received monovalent hepatitis A or combined hepatitis A&B vaccines did not complete the recommended course. These findings highlight the need for further training of HCPs and the provision of reminder services to improve traveller

Pre-travel advice, attitudes and hepatitis A and B vaccination rates among travellers from seven countries†.

PubMed

Heywood, Anita E; Nothdurft, Hans; Tessier, Dominique; Moodley, Melissa; Rombo, Lars; Marano, Cinzia; De Moerlooze, Laurence

2016-07-01

Knowledge about the travel-associated risks of hepatitis A and B, and the extent of pre-travel health-advice being sought may vary between countries. An online survey was undertaken to assess the awareness, advice-seeking behaviour, rates of vaccination against hepatitis A and B and adherence rates in Australia, Finland, Germany, Norway, Sweden, the UK and Canada between August and October 2014. Individuals aged 18-65 years were screened for eligibility based on: travel to hepatitis A and B endemic countries within the past 3 years, awareness of hepatitis A, and/or combined hepatitis A&B vaccines; awareness of their self-reported vaccination status and if vaccinated, vaccination within the last 3 years. Awareness and receipt of the vaccines, sources of advice, reasons for non-vaccination, adherence to recommended doses and the value of immunization reminders were analysed. Of 27 386 screened travellers, 19 817 (72%) were aware of monovalent hepatitis A or combined A&B vaccines. Of these 13 857 (70%) had sought advice from a healthcare provider (HCP) regarding combined hepatitis A&B or monovalent hepatitis A vaccination, and 9328 (67%) were vaccinated. Of 5225 individuals eligible for the main survey (recently vaccinated = 3576; unvaccinated = 1649), 27% (841/3111) and 37% (174/465) of vaccinated travellers had adhered to the 3-dose combined hepatitis A&B or 2-dose monovalent hepatitis A vaccination schedules, respectively. Of travellers partially vaccinated against combined hepatitis A&B or hepatitis A, 84% and 61%, respectively, believed that they had received the recommended number of doses. HCPs remain the main source of pre-travel health advice. The majority of travellers who received monovalent hepatitis A or combined hepatitis A&B vaccines did not complete the recommended course. These findings highlight the need for further training of HCPs and the provision of reminder services to improve traveller awareness and adherence to vaccination

Pricing strategies for combination pediatric vaccines based on the lowest overall cost formulary.

PubMed

Behzad, Banafsheh; Jacobson, Sheldon H; Sewell, Edward C

2012-10-01

This paper analyzes pricing strategies for US pediatric combination vaccines by comparing the lowest overall cost formularies (i.e., formularies that have the lowest overall cost). Three pharmaceutical companies compete pairwise over the sale of monovalent and combination vaccines. Particular emphasis is placed on examining the price of Sanofi Pasteur's DTaP-IPV/HIb under different conditions. The main contribution of the paper is to provide the lowest overall cost formularies for different prices of DTaP-IPV/HIb and other Sanofi Pasteur vaccines. The resulting analysis shows that DTaP-IPV/HIb could have been more competitively priced compared with the combination vaccine DTaP-HepB-IPV, for federal contract prices in 2009, 2010 and 2011. This study also proposes the lowest overall cost formularies when shortages of monovalent vaccines occur.

Atypical antibody responses in dengue vaccine recipients.

PubMed

Kanesa-Thasan, N; Sun, W; Ludwig, G V; Rossi, C; Putnak, J R; Mangiafico, J A; Innis, B L; Edelman, R

2003-12-01

Eight of 69 (12%) healthy adult volunteers vaccinated with monovalent live-attenuated dengue virus (DENV) vaccine candidates had atypical antibody responses, with depressed IgM:IgG antibody ratios and induction of high-titer hemagglutination-inhibiting and neutralizing (NT) antibodies to all four DENV serotypes. These features suggested flavivirus exposure prior to DENV vaccination, yet no volunteer had a history of previous flavivirus infection, flavivirus vaccination, or antibody to flaviviruses evident before DENV vaccination. Moreover, production of antibody to DENV by atypical responders (AR) was not accelerated compared with antibody responses in the 61 flavivirus-naive responders (NR). Further evaluation revealed no differences in sex, age, race, DENV vaccine candidate received, or clinical signs and symptoms following vaccination between AR and NR. However, viremia was delayed at the onset in AR compared with NR. A comparative panel of all AR and five randomly selected NR found flavivirus cross-reactive antibody after vaccination only in AR. Unexpectedly, six of eight AR had NT antibodies to yellow fever virus (YFV) > 1:10 before vaccination while NR had none (P = 0.04). The AR also universally demonstrated YFV NT antibody titers > or = 1:160 after DENV vaccination, whereas four of five NR failed to seroconvert (P = 0.02). Yellow fever virus priming broadens the antibody response to monovalent DENV vaccination. The effect of flavivirus priming on the clinical and immunologic response to tetravalent DENV vaccine remains to be determined.

Costs of vaccine delivery in the Gambia before and after, pentavalent and pneumococcal conjugate vaccine introductions.

PubMed

Usuf, E; Mackenzie, G; Lowe-Jallow, Y; Boye, B; Atherly, D; Suraratdecha, C; Griffiths, U K

2014-04-07

The Gambia introduced seven-valent pneumococcal conjugate vaccine (PCV) in August 2009 and switched to 13-valent PCV in April 2011. In April 2009 monovalent hepatitis B and combined Diphtheria-Tetanus-Pertussis and Haemophilus influenzae type b vaccines were transitioned to a combined pentavalent vaccine. The current schedule offers three doses of PCV and pentavalent, and continues to give children monovalent hepatitis B vaccine at birth. We estimated the overall costs of the Gambian immunisation programme and the incremental costs of introducing pentavalent and the seven-valent PCV. Twenty health facilities out of a total of 56 were surveyed. Data collected included number of vaccine doses delivered, staff time spent on vaccine delivery, distance travelled to collect vaccines, and cold chain expansion due to new vaccine introduction. National level data were collected from key informant interviews. Annualised costs were calculated in 2009 US$. With a PCV price of US$7 per dose, the incremental costs of introducing PCV was US$1.6 million, equivalent to US$25 per fully immunised child, with systems costs accounting for US$1.90. The switch to pentavalent vaccine resulted in cost savings of US$0.45 per fully immunised child. Total annual costs increased by 45% after the introduction of the new vaccines, amounting to US$ 3.0 million, or US$45 per fully immunised child. Vaccine prices were the most important determinant of total incremental costs and cold chain expansion the biggest cost component of systems costs. Copyright © 2014 Elsevier Ltd. All rights reserved.

Comparison of monovalent glycoprotein B with bivalent gB/pp65 (GP83) vaccine for congenital cytomegalovirus infection in a guinea pig model: Inclusion of GP83 reduces gB antibody response but both vaccine approaches provide equivalent protection against pup mortality.

PubMed

Swanson, Elizabeth C; Gillis, Pete; Hernandez-Alvarado, Nelmary; Fernández-Alarcón, Claudia; Schmit, Megan; Zabeli, Jason C; Wussow, Felix; Diamond, Don J; Schleiss, Mark R

2015-07-31

Cytomegalovirus (CMV) subunit vaccine candidates include glycoprotein B (gB), and phosphoprotein ppUL83 (pp65). Using a guinea pig cytomegalovirus (GPCMV) model, this study compared immunogenicity, pregnancy outcome, and congenital viral infection following pre-pregnancy immunization with a three-dose series of modified vaccinia virus Ankara (MVA)-vectored vaccines consisting either of gB administered alone, or simultaneously with a pp65 homolog (GP83)-expressing vaccine. Vaccinated and control dams were challenged at midgestation with salivary gland-adapted GPCMV. Comparisons included ELISA and neutralizing antibody responses, maternal viral load, pup mortality, and congenital infection rates. Strikingly, ELISA and neutralization titers were significantly lower in the gB/GP83 combined vaccine group than in the gB group. However, both vaccines protected against pup mortality (63.2% in controls vs. 11.4% and 13.9% in gB and gB/GP83 combination groups, respectively; p<0.0001). Reductions in pup viral load were noted for both vaccine groups compared to control, but preconception vaccination resulted in a significant reduction in GPCMV transmission only in the monovalent gB group (26/44, 59% v. 27/34, 79% in controls; p<0.05). We conclude that, using the MVA platform, the addition of GP83 to a gB subunit vaccine interferes with antibody responses and diminishes protection against congenital GPCMV infection, but does not decrease protection against pup mortality. Copyright © 2015 Elsevier Ltd. All rights reserved.

Immunogenicity and sustainability of the immune response in Brazilian HIV-1-infected individuals vaccinated with inactivated triple influenza vaccine.

PubMed

Souza, Thiago Moreno L; Santini-Oliveira, Marilia; Martorelli, Andressa; Luz, Paula M; Vasconcellos, Mauricio T L; Giacoia-Gripp, Carmem B W; Morgado, Mariza; Nunes, Estevão P; Lemos, Alberto S; Ferreira, Ana C G; Moreira, Ronaldo I; Veloso, Valdiléa G; Siqueira, Marilda; Grinsztejn, Beatriz; Camacho, Luiz A B

2016-03-01

HIV-infected individuals have a higher risk of serious illnesses following infection by infection with influenza. Although anti-influenza vaccination is recommended, immunosuppression may limit their response to active immunization. We followed-up a cohort of HIV-infected individuals vaccinated against influenza to assess the immunogenicity and sustainability of the immune response to vaccination. Individuals were vaccinated 2011 with inactivated triple influenza vaccine (TIV), and they had received in 2010 the monovalent anti-A(H1N1)pdm09 vaccine. The sustainability of the immune response to A(H1N1)pdm09 at 12 months after monovalent vaccination fell, both in individuals given two single or two double doses. For these individuals, A(H1N1)pdm09 component from TIV acted as a booster, raising around 40% the number of seroprotected individuals. Almost 70% of the HIV-infected individuals were already seroprotected to A/H3N2 at baseline. Again, TIV boosted over 90% the seroprotection to A/H3N2. Anti-A/H3N2 titers dropped by 20% at 6 months after vaccination. Pre-vaccination seroprotection rate to influenza B (victoria lineage) was the lowest among those tested, seroconversion rates were higher after vaccination. Seroconversion/protection after TIV vaccination did not differ significantly across categories of clinical and demographic variables. Anti-influenza responses in Brazilian HIV-infected individuals reflected both the previous history of virus circulation in Brazil and vaccination. © 2015 Wiley Periodicals, Inc.

Evidence of pestivirus RNA in human virus vaccines.

PubMed Central

Harasawa, R; Tomiyama, T

1994-01-01

We examined live virus vaccines against measles, mumps, and rubella for the presence of pestivirus RNA or of pestiviruses by reverse transcription PCR. Pestivirus RNA was detected in two measles-mumps-rubella combined vaccines and in two monovalent vaccines against mumps and rubella. Nucleotide sequence analysis of the PCR products indicated that a modified live vaccine strain used for immunization of cattle against bovine viral diarrhea is not responsible for the contamination of the vaccines. Images PMID:8077414

Polyvalent Envelope Glycoprotein Vaccine Elicits a Broader Neutralizing Antibody Response but Is Unable To Provide Sterilizing Protection against Heterologous Simian/Human Immunodeficiency Virus Infection in Pigtailed Macaques

PubMed Central

Cho, Michael W.; Kim, Young B.; Lee, Myung K.; Gupta, Kailash C.; Ross, Will; Plishka, Ron; Buckler-White, Alicia; Igarashi, Tatsuhiko; Theodore, Ted; Byrum, Russ; Kemp, Chris; Montefiori, David C.; Martin, Malcolm A.

2001-01-01

The great difficulty in eliciting broadly cross-reactive neutralizing antibodies (NAbs) against human immunodeficiency virus type 1 (HIV-1) isolates has been attributed to several intrinsic properties of their viral envelope glycoprotein, including its complex quaternary structure, extensive glycosylation, and marked genetic variability. Most previously evaluated vaccine candidates have utilized envelope glycoprotein from a single virus isolate. Here we compare the breadth of NAb and protective immune response following vaccination of pigtailed macaques with envelope protein(s) derived from either single or multiple viral isolates. Animals were challenged with Simian/human immunodeficiency virus strain DH12 (SHIVDH12) following priming with recombinant vaccinia virus(es) expressing gp160(s) and boosting with gp120 protein(s) from (i) LAI, RF, 89.6, AD8, and Bal (Polyvalent); (ii) LAI, RF, 89.6, AD8, Bal, and DH12 (Polyvalent-DH12); (iii) 89.6 (Monovalent-89.6); and (iv) DH12 (Monovalent-DH12). Animals in the two polyvalent vaccine groups developed NAbs against more HIV-1 isolates than those in the two monovalent vaccine groups (P = 0.0054). However, the increased breadth of response was directed almost entirely against the vaccine strains. Resistance to SHIVDH12 strongly correlated with the level of NAbs directed against the virus on the day of challenge (P = 0.0008). Accordingly, the animals in the Monovalent-DH12 and Polyvalent-DH12 vaccine groups were more resistant to the SHIVDH12 challenge than the macaques immunized with preparations lacking a DH12 component (viz. Polyvalent and Monovalent-89.6) (P = 0.039). Despite the absence of any detectable NAb, animals in the Polyvalent vaccine group, but not those immunized with Monovalent-89.6, exhibited markedly lower levels of plasma virus than those in the control group, suggesting a superior cell-mediated immune response induced by the polyvalent vaccine. PMID:11160726

Effectiveness of monovalent human rotavirus vaccine against admission to hospital for acute rotavirus diarrhoea in South African children: a case-control study.

PubMed

Groome, Michelle J; Page, Nicola; Cortese, Margaret M; Moyes, Jocelyn; Zar, Heather J; Kapongo, Constant N; Mulligan, Christine; Diedericks, Ralph; Cohen, Cheryl; Fleming, Jessica A; Seheri, Mapaseka; Mphahlele, Jeffrey; Walaza, Sibongile; Kahn, Kathleen; Chhagan, Meera; Steele, A Duncan; Parashar, Umesh D; Zell, Elizabeth R; Madhi, Shabir A

2014-11-01

The effectiveness of the rotavirus vaccine under conditions of routine use in an African setting with a high prevalence of HIV infection needs to be established. We assessed the vaccine effectiveness of monovalent human rotavirus vaccine in preventing admission to hospital for acute rotavirus diarrhoea, after its introduction at age 6 and 14 weeks into South Africa's national immunisation programme. This case-control study was done at seven hospitals in South Africa between April 19, 2010, and Oct 31, 2012. The hospitals were located in a range of urban, peri-urban, and rural settings, with varying rates of population HIV infection. Cases were children aged from 18 weeks to 23 months who were age-eligible to have received at least one dose of the human rotavirus vaccine (ie, those born after June 14, 2009) admitted to hospital with laboratory-confirmed acute rotavirus diarrhoea, and the primary control group was children admitted to hospital with diarrhoea testing negative for rotavirus. A second control group comprised children admitted to a subset of three of the seven hospitals with respiratory illness. The primary endpoint was adjusted vaccine effectiveness (1 - adjusted odds ratio × 100%) in children aged from 18 weeks to 23 months and was calculated by unconditional logistic regression. This study is registered on the South African National Clinical Trial Register, number DOH-27-0512-3247. Of 540 rotavirus-positive cases, 278 children (52%) received two doses, 126 (23%) one dose, and 136 (25%) no doses of human rotavirus vaccine, compared with 1434 rotavirus-negative controls of whom 856 (60%) received two doses, 334 (23%) one dose, and 244 (17%) no doses. Adjusted vaccine effectiveness using rotavirus-negative controls was 57% (95% CI 40-68) for two doses and 40% (16-57) for one dose; estimates were similar when respiratory controls were used as the control group. Adjusted vaccine effectiveness for two doses was similar between age groups 18 weeks

Antibody persistence and immune memory 4 years post-vaccination with combined hepatitis A and B vaccine in adults aged over 40 years.

PubMed

Chlibek, Roman; von Sonnenburg, Frank; Van Damme, Pierre; Smetana, Jan; Tichy, Petr; Gunapalaiah, Bhavyashree; Leyssen, Maarten; Jacquet, Jeanne-Marie

2011-01-01

Persistence of immune response was assessed in adults aged >40 years (N = 596) following primary vaccination with combined hepatitis A/B vaccine or concomitant monovalent hepatitis A and B vaccines. Anti-hepatitis A virus antibody responses persisted for at least 4 years regardless of the vaccine used, with anti-hepatitis B surface antibody responses higher and more sustained in subjects who received the combined hepatitis A/B vaccine. Response rates to an additional dose of the same vaccine(s) used for priming were high. © 2011 International Society of Travel Medicine.

Combined hepatitis A and B vaccines: a review of their immunogenicity and tolerability.

PubMed

Murdoch, David L; Goa, Karen; Figgitt, David P

2003-01-01

Three combined hepatitis A and B vaccine preparations are commercially available in various countries: a two-dose paediatric formulation (Ambirix) [administered at months 0 and 6-12]; and a three-dose adult (Twinrix Adult) or paediatric (Twinrix Paediatric) formulation (administered at months 0, 1 and 6). The adult vaccine provides consistent, marked immunogenicity which is at least similar to that of its constituent vaccines used together and with a tolerability profile that is possibly improved. An accelerated, day-0, -7 and -21 regimen has also shown immunogenicity similar to that of the monovalent vaccines given concurrently, and now has an emerging role in adults likely to travel to hepatitis A virus (HAV) and/or hepatitis B virus (HBV) endemic regions within 1 month. The adult vaccine appears effective and generally well tolerated when given concurrently with monovalent typhoid vaccine (Typherix). Immunogenicity of the two-dose paediatric vaccine is high and appears to be similar whether administered as a month-0, -6 or month-0, -12 schedule and when compared to that of the three-dose paediatric vaccine (months 0, 1, 6), both of which provide a similar degree of protection to the adult vaccine. Although both preparations also provide high end-of-schedule seroprotection against hepatitis B surface antigen, protection between the first and second doses of the two-dose regimen appears lower than with the three-dose schedule. Therefore, the three-dose paediatric vaccine is a practical option in individuals at risk of immediate exposure to HBV, while the two-dose regimen may have an important function in immunisation programmes in regions where such risk is low. Combined hepatitis A and B vaccines are generally well tolerated. The most frequently reported adverse events in clinical trials were injection-site pain and redness, and general fatigue and headache; most events were mild and transient. Pharmacoeconomic models suggest the combined vaccine is cost

Oral administration of live Shigella vaccine candidates in rhesus monkeys show no evidence of competition for colonization and immunogenicity between different serotypes.

PubMed

Ranallo, R T; Kaminski, R; Baqar, S; Dutta, M; Lugo-Roman, L A; Boren, T; Barnoy, S; Venkatesan, M M

2014-03-26

Live oral monovalent Shigella flexneri 2a vaccine candidates as well as bivalent formulations with Shigella sonnei were evaluated in a rhesus monkey model for colonization and immunogenicity. Freshly harvested suspensions of S. flexneri 2a vaccine candidates WRSf2G12 and WRSf2G15 as well as S. sonnei vaccine candidate WRSs3 were nasogastrically administered to groups of rhesus monkeys, Macaca mulatta, either in a monovalent form or when combined with each other. The animals were monitored daily for physical well-being, stools were subjected to quantitative colony immunoblot assays for bacterial excretion and blood and stools were evaluated for humoral and mucosal immune responses. No clinical symptoms were noted in any group of animals and the vaccine candidates were excreted robustly for 48-72h without significant changes in either the magnitude or duration of excretion when given as a monovalent or as bivalent mixtures. Similarly, immunological interferences were not apparent in the magnitude of humoral and mucosal immune responses observed toward Shigella-specific antigens when monkeys were fed monovalent or bivalent formulations. These results predict that a multivalent live oral vaccine of more than one serotype can have a favorable outcome for protection against shigellosis. Published by Elsevier Ltd.

Evaluation of long-acting oxytetracycline and a commercial monovalent vaccine for the control of Campylobacter fetus subsp. venerealis infection in beef bulls.

PubMed

Erickson, Nathan E N; Lanigan, Emily; Waugh, Taryn; Gesy, Karen; Waldner, Cheryl

2017-10-01

A blinded randomized controlled trial was used to evaluate a multi-modal therapeutic regime for treatment of beef bulls infected with Campylobacter fetus subsp. venerealis (Cfv) . Treatment included 2 doses of a commercially available monovalent vaccine and long-acting oxytetracycline applied twice at a 2-week interval with treatment completed 2 weeks before post-treatment observation. Fifteen confirmed Cfv infected bulls were randomly allocated to control ( n = 8) or treatment groups ( n = 7). Preputial scrapings were collected each week from before infection to 11 weeks following the last treatment. When the polymerase chain reaction (PCR) results for both culture and preputial scrapings were interpreted in parallel, there were no significant differences between treated and untreated bulls. Regardless of the type of diagnostic testing considered, treatment with 2 label doses of this regime did not stop shedding of Cfv in all treated bulls and is, therefore, not recommended as an effective management strategy.

Evaluation of long-acting oxytetracycline and a commercial monovalent vaccine for the control of Campylobacter fetus subsp. venerealis infection in beef bulls

PubMed Central

Erickson, Nathan E.N.; Lanigan, Emily; Waugh, Taryn; Gesy, Karen; Waldner, Cheryl

2017-01-01

A blinded randomized controlled trial was used to evaluate a multi-modal therapeutic regime for treatment of beef bulls infected with Campylobacter fetus subsp. venerealis (Cfv). Treatment included 2 doses of a commercially available monovalent vaccine and long-acting oxytetracycline applied twice at a 2-week interval with treatment completed 2 weeks before post-treatment observation. Fifteen confirmed Cfv infected bulls were randomly allocated to control (n = 8) or treatment groups (n = 7). Preputial scrapings were collected each week from before infection to 11 weeks following the last treatment. When the polymerase chain reaction (PCR) results for both culture and preputial scrapings were interpreted in parallel, there were no significant differences between treated and untreated bulls. Regardless of the type of diagnostic testing considered, treatment with 2 label doses of this regime did not stop shedding of Cfv in all treated bulls and is, therefore, not recommended as an effective management strategy. PMID:28966354

Adverse events following pandemic influenza A (H1N1) 2009 monovalent and seasonal influenza vaccinations during the 2009-2010 season in the active component U.S. military and civilians aged 17-44years reported to the Vaccine Adverse Event Reporting System.

PubMed

Bardenheier, Barbara H; Duderstadt, Susan K; Engler, Renata J M; McNeil, Michael M

2016-08-17

No comparative review of Vaccine Adverse Event Reporting System (VAERS) submissions following pandemic influenza A (H1N1) 2009 and seasonal influenza vaccinations during the pandemic season among U.S. military personnel has been published. We compared military vs. civilian adverse event reporting rates. Adverse events (AEs) following vaccination were identified from VAERS for adults aged 17-44years after pandemic (monovalent influenza [MIV], and seasonal (trivalent inactivated influenza [IIV3], live attenuated influenza [LAIV3]) vaccines. Military vaccination coverage was provided by the Department of Defense's Defense Medical Surveillance System. Civilian vaccination coverage was estimated using data from the National 2009 H1N1 Flu Survey and the Behavioral Risk Factor Surveillance System survey. Vaccination coverage was more than four times higher for MIV and more than twenty times higher for LAIV3 in the military than in the civilian population. The reporting rate of serious AE reports following MIV in service personnel (1.19 per 100,000) was about half that reported by the civilian population (2.45 per 100,000). Conversely, the rate of serious AE reports following LAIV3 among service personnel (1.32 per 100,000) was more than twice that of the civilian population. Although fewer military AEs following MIV were reported overall, the rate of Guillain-Barré Syndrome (GBS) (4.01 per million) was four times greater than that in the civilian population. (1.04 per million). Despite higher vaccination coverage in service personnel, the rate of serious AEs following MIV was about half that in civilians. The rate of GBS reported following MIV was higher in the military. Published by Elsevier Ltd.

A novel approach to make homogeneous protease-stable monovalent streptavidin

DOE PAGES

Zhang, M.; Shao, J; Xiao, J.; ...

2015-06-11

The interaction between the tetramer streptavidin and biotin is recognized as one of the strongest non-covalent associations. Owing to the tight and specific binding, the streptavidin-biotin system has been used widely for bimolecular labeling, purification, immobilization, and even for targeted delivery of therapeutics drugs. Here, we report a novel approach to make homogeneous monovalent tetramer streptavidin. The purified monovalent protein showed both thermal stability and protease stability. Unexpectedly, we found that two proteases, Proteinase K (PK) and Subtilisin (SU), can efficiently remove the His8-tag from the wild-type subunit without affecting the tetramer architecture of monovalent streptavidin, thus making it moremore » homogeneous. In addition, crystallization was performed to assure the homogeneity of the monovalent protein prepared. Overall, monovalent streptavidin shows increased homogeneity and will likely be valuable for many future applications in a wide range of research areas.« less

Tegaserod (Novartis).

PubMed

Norman, Peter

2002-02-01

Novartis has developed and launched tegaserod, an aminoguanidine indole 5-HT(4) receptor partial agonist, for the potential treatment of constipation-predominant irritable bowel syndrome (IBS) [286804], [311514] and other functional GI disorders, such as gastroesophageal reflux disease (GERD), chronic constipation and functional dyspepsia [342937], [362853]. It was launched in Mexico for IBS in July 2001 [416879] and in the Czech Republic, Venezuela and Colombia by October 2001. By this time, the product had also been approved in Switzerland [427419]. In September 2001, launch of the product for GERD, chronic constipation and functional dyspepsia was expected after 2003 [422828]; later in October 2001, the launch dates for the latter two indications were anticipated for 2004 [427419], [431614]. In December 2000, Merrill Lynch predicted sales of SFr 150 million in 2001, rising to SFr 612 million in 2004, larger than the September 2000 predictions of SFr 120 million in 2001 rising to SFr 378 million in 2004 [394812], [383742]. Later in February 2001, Merrill Lynch predicted sales of SFr 150 million in 2001 rising to SFr 785 million per annum in 2005, assuming a US launch during the third quarter of 2001 [411704]. Following the withdrawal of the MAA and then the rejection of tegaserod's NDA by the FDA, in June 2001, Merrill Lynch progressively revised its 2005 sales forecasts from SFr 1.1 billion to SFr 950 million and then to SFr 375 million [422783]. In June 2001, Merrill Lynch also suggested that there was a significant possibility that tegaserod would never reach the market. In August 2001, Deutsche Bank estimated sales of SFr 200 million in 2004 and SFr 550 million in 2005 [422674]. Analysts at Credit Suisse predicted in October 2001, that there was only a three in ten chance that tegaserod would ever reach a major market following the issuance of a 'non-approvable' letter by the FDA in June 2001. They predicted sales of SFr 5 million in 2001, rising to SFr 325

Immunogenicity, effectiveness and safety of combined hepatitis A and B vaccine: a systematic literature review.

PubMed

Bakker, Marina; Bunge, Eveline M; Marano, Cinzia; de Ridder, Marc; De Moerlooze, Laurence

2016-07-01

Hepatitis A and B are two of the most common vaccine-preventable diseases and vaccination for Hepatitis A virus (HAV) and hepatitis B virus (HBV) is recommended for those at risk of contracting HAV and/or HBV through their occupation, travel or lifestyle. To describe the vaccine efficacy, immunogenicity, effectiveness and safety of the combined vaccine against hepatitis A and hepatitis B. A systematic review of the literature published between 1990 and 2015. Anti-HAV seropositivity rates ranged from 96.2% to 100% and anti-HBs seroprotection rates from 82% to 100%. Antibodies persisted up to 15 years and geometric mean concentration (GMC) remained above the seropositivity cut-off value for both. Anti-HAV and anti-HBs immune responses were lower in less immunocompetent individuals one month after completion of the immunization schedule. The safety profiles of Twinrix(TM) and monovalent hepatitis A and B vaccines were similar. The vaccine offers satisfactory long-term immunogenicity rates, expected duration of protection and safety profile similar to the monovalent hepatitis A or B vaccines.

Pandemic influenza A (H1N1) 2009 vaccination in children: a UK perspective.

PubMed

de Whalley, Philip C S; Pollard, Andrew J

2013-03-01

Pandemic H1N1 influenza infection was common in the UK in 2009 and children were particularly vulnerable. Most cases were mild or subclinical, but there was significant mortality, predominantly in those with pre-existing disease. Despite the rapid development of monovalent pandemic vaccines, and the fast-tracked approval process, these products were not available for large-scale use until the end of the second wave of infection. Vaccine uptake was relatively low, both among children and health-care workers. The monovalent pandemic vaccines and the 2010/2011 trivalent seasonal influenza vaccines were immunogenic and effective, and they probably reduced the impact of the third wave of infection. Vaccines containing novel adjuvants enabled antigen sparing, but safety concerns could limit the future use of these adjuvanted influenza vaccines in children. Public perceptions that the threat of the pandemic was exaggerated by the authorities, and concerns about vaccine safety, might prompt an inadequate response to the next influenza pandemic, potentially compromising public health. © 2012 The Authors. Journal of Paediatrics and Child Health © 2012 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

Meningococcal serogroup C immunogenicity, antibody persistence and memory B-cells induced by the monovalent meningococcal serogroup C versus quadrivalent meningococcal serogroup ACWY conjugate booster vaccine: A randomized controlled trial.

PubMed

van Ravenhorst, Mariëtte B; van der Klis, Fiona R M; van Rooijen, Debbie M; Knol, Mirjam J; Stoof, Susanne P; Sanders, Elisabeth A M; Berbers, Guy A M

2017-08-24

Adolescents are considered the key transmitters of meningococci in the population. Meningococcal serogroup C (MenC) antibody levels wane rapidly after MenC conjugate vaccination in young children, leaving adolescents with low antibody levels. In this study, we compared MenC immune responses after booster vaccination in adolescence with either tetanus toxoid conjugated MenC (MenC-TT) or MenACWY (MenACWY-TT) vaccine, and aimed to establish an optimal age for this booster. Healthy 10-, 12-, and 15-year-olds, who received a single dose of MenC-TT vaccine in early childhood, were randomized to receive MenC-TT or MenACWY-TT vaccine. MenC serum bactericidal antibody (rSBA) titers, MenC polysaccharide (PS) specific IgG, IgG1 and IgG2 and MenC-specific IgG and IgA memory B-cells were determined before, one month and one year after the booster. Non-inferiority was tested by comparing geometric mean titers (GMTs) between vaccinees at one year. Of 501 participants, 464 (92.6%) were included in the 'according to protocol' cohort analysis. At one month, all participants developed high MenC rSBA titers (>24,000 in all groups) and MenC-PS-specific IgG levels. Non-inferiority was not demonstrated one year after the booster with higher MenC GMTs after the monovalent vaccine, but 462/464 (99.6%) participants maintained protective MenC rSBA titers. IgG levels mainly consisted of IgG1, but similar levels of increase were observed for IgG1 and IgG2. Both vaccines induced a clear increase in the number of circulating MenC-PS specific IgG and IgA memory B-cells. Between one month and one year, the highest antibody decay rate was observed in the 10-year-olds. Both MenC-TT and MenACWY-TT vaccines induced robust protective MenC immune responses after the booster vaccination, although non-inferiority could not be demonstrated for the MenACWY-TT vaccine after one year. Our results underline the importance of optimal timing of a meningococcal booster vaccination to protect against MenC disease

77 FR 23222 - Foreign-Trade Zone 59, Temporary/Interim Manufacturing Authority, Novartis Consumer Health, Inc...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-18

... DEPARTMENT OF COMMERCE Foreign-Trade Zones Board [Docket T-2-2012] Foreign-Trade Zone 59, Temporary/Interim Manufacturing Authority, Novartis Consumer Health, Inc., (Pharmaceutical Product... manufacture pharmaceutical products under FTZ procedures within FTZ 59--Sites 3 and 4, in Lincoln, Nebraska...

Response of normal children to influenza A/New Jersey/76 virus vaccine administered by jet injector.

PubMed

McIntosh, K; Orr, I; Andersen, M; Arthur, J H; Blakeman, G J

1977-12-01

Ninety-seven children six to 10 years old received monovalent influenza A/New Jersey/76 virus vaccine by jet injector. Comparison with groups receiving vaccine intramuscularly revealed that local reactions (tenderness and erythema) were more frequent and more severe in the group vaccinated by jet injector. Antibody response, however, was similar for all groups.

Intussusception after monovalent rotavirus vaccine-United States, Vaccine Adverse Event Reporting System (VAERS), 2008-2014.

PubMed

Haber, Penina; Parashar, Umesh D; Haber, Michael; DeStefano, Frank

2015-09-11

In 2006 and 2008, two new rotavirus vaccines (RotaTeq [RV5] and Rotarix [RV1]) were introduced in the United States. US data on intussusception have been mostly related to RV5, with limited data on RV1. We assessed intussusception events following RV1 reported to the Vaccine Adverse Event Reporting System (VAERS), a US national passive surveillance system, during February 2008-December 2014. We conducted a self-controlled risk interval analysis using Poisson regression to estimate the daily reporting ratio (DRR) of intussusception after the first 2 doses of RV1 comparing average daily reports 3-6 versus 0-2 days after vaccination. We calculated the excess risk of intussusception per 100,000 vaccinations based on DRRs and background rates of intussusception. Sensitivity analyses were conducted to assess effects of differential reporting completeness and inaccuracy of baseline rates. VAERS received 108 confirmed insusceptible reports after RV1. A significant clustering was observed on days 3-8 after does1 (p=0.001) and days 2-7 after dose 2 (p=0.001). The DRR comparing the 3-6 day and the 0-2 day periods after RV1 dose 1 was 7.5 (95% CI=2.3, 24.6), translating to an excess risk of 1.6 (95% CI=0.3, 5.8) per 100,000 vaccinations. The DRR was elevated but not significant after dose 2 (2.4 [95% CI=0.8,7.5]). The excess risk ranged from 1.2 to 2.8 per 100,000 in sensitivity analysis. We observed a significant increased risk of intussusception 3-6 days after dose 1 of RV1. The estimated small number of intussusception cases attributable to RV1 is outweighed by the benefits of rotavirus vaccination. Published by Elsevier Ltd.

Persistence of antibodies 20 y after vaccination with a combined hepatitis A and B vaccine

PubMed Central

Van Damme, Pierre; Leroux-Roels, Geert; Suryakiran, P.; Folschweiller, Nicolas; Van Der Meeren, Olivier

2017-01-01

ABSTRACT Vaccination is the most effective and well-tolerated method of conferring long-term protection against hepatitis A and B viruses (HAV; HBV). Long-term studies are required to characterize the duration of protection and need for boosters. Following primary immunization of 150 and 157 healthy adults with 3-doses of combined hepatitis A/hepatitis B vaccine (HAB; Twinrix™, GSK Vaccines, Belgium) at 0-1-6 months in 2 separate studies, we measured vaccine-induced antibody persistence against HAV and HBV annually for 20 y (Study A: NCT01000324; Study B: NCT01037114). Subjects with circulating anti-HAV antibodies < 15 mIU/mL or with anti-hepatitis B surface antigen < 10 mIU/mL were offered an additional monovalent hepatitis A and/or B vaccine dose (Havrix™/Engerix™-B, GSK Vaccines, Belgium). Applying the immunogenicity results from these studies, mathematical modeling predicted long-term persistence. After 20 y, 18 and 25 subjects in studies A and B, respectively, comprised the long-term according-to-protocol cohort for immunogenicity; 100% and 96.0% retained anti-HAV antibodies ≥ 15 mIU/mL, respectively; 94.4% and 92.0% had anti-HBs antibodies ≥ 10 mIU/mL, respectively. Between Years 16–20, 4 subjects who received a challenge dose of monovalent hepatitis A vaccine (N = 2) or hepatitis B vaccine (N = 2), all mounted a strong anamnestic response suggestive of immune memory despite low antibody levels. Mathematical modeling predicts that 40 y after vaccination ≥ 97% vaccinees will maintain anti-HAV ≥ 15 mIU/mL and ≥ 50% vaccinees will retain anti-HBs ≥ 10 mIU/mL. Immunogenicity data confirm that primary immunization with 3-doses of HAB induces persisting anti-HAV and anti-HBs specific antibodies in most adults for up to 20 y; mathematical modeling predicts even longer-term protection. PMID:28281907

Persistence of antibodies 20 y after vaccination with a combined hepatitis A and B vaccine.

PubMed

Van Damme, Pierre; Leroux-Roels, Geert; Suryakiran, P; Folschweiller, Nicolas; Van Der Meeren, Olivier

2017-05-04

Vaccination is the most effective and well-tolerated method of conferring long-term protection against hepatitis A and B viruses (HAV; HBV). Long-term studies are required to characterize the duration of protection and need for boosters. Following primary immunization of 150 and 157 healthy adults with 3-doses of combined hepatitis A/hepatitis B vaccine (HAB; Twinrix™, GSK Vaccines, Belgium) at 0-1-6 months in 2 separate studies, we measured vaccine-induced antibody persistence against HAV and HBV annually for 20 y (Study A: NCT01000324; Study B: NCT01037114). Subjects with circulating anti-HAV antibodies < 15 mIU/mL or with anti-hepatitis B surface antigen < 10 mIU/mL were offered an additional monovalent hepatitis A and/or B vaccine dose (Havrix™/Engerix™-B, GSK Vaccines, Belgium). Applying the immunogenicity results from these studies, mathematical modeling predicted long-term persistence. After 20 y, 18 and 25 subjects in studies A and B, respectively, comprised the long-term according-to-protocol cohort for immunogenicity; 100% and 96.0% retained anti-HAV antibodies ≥ 15 mIU/mL, respectively; 94.4% and 92.0% had anti-HBs antibodies ≥ 10 mIU/mL, respectively. Between Years 16-20, 4 subjects who received a challenge dose of monovalent hepatitis A vaccine (N = 2) or hepatitis B vaccine (N = 2), all mounted a strong anamnestic response suggestive of immune memory despite low antibody levels. Mathematical modeling predicts that 40 y after vaccination ≥ 97% vaccinees will maintain anti-HAV ≥ 15 mIU/mL and ≥ 50% vaccinees will retain anti-HBs ≥ 10 mIU/mL. Immunogenicity data confirm that primary immunization with 3-doses of HAB induces persisting anti-HAV and anti-HBs specific antibodies in most adults for up to 20 y; mathematical modeling predicts even longer-term protection.

Rotavirus Vaccines: an Overview

PubMed Central

Dennehy, Penelope H.

2008-01-01

Rotavirus infection is the most common cause of severe diarrhea disease in infants and young children worldwide and continues to have a major global impact on childhood morbidity and mortality. Vaccination is the only control measure likely to have a significant impact on the incidence of severe dehydrating rotavirus disease. In 1999, a highly efficacious rotavirus vaccine licensed in the United States, RotaShield, was withdrawn from the market after 14 months because of its association with intussusception. Two new live, oral, attenuated rotavirus vaccines were licensed in 2006: the pentavalent bovine-human reassortant vaccine (RotaTeq) and the monovalent human rotavirus vaccine (Rotarix). Both vaccines have demonstrated very good safety and efficacy profiles in large clinical trials in western industrialized countries and in Latin America. Careful surveillance has not revealed any increased risk of intussusception in the vaccinated groups with either vaccine. The new rotavirus vaccines are now introduced for routine use in a number of industrialized and developing countries. These new safe and effective rotavirus vaccines offer the best hope of reducing the toll of acute rotavirus gastroenteritis in both developed and developing countries. PMID:18202442

Possible global strategies for stopping polio vaccination and how they could be harmonized.

PubMed

Cochi, S L; Sutter, R W; Aylward, R B

2001-01-01

One of the challenges of the polio eradication initiative over the next few years will be the formulation of an optimal strategy for stopping poliovirus vaccination after global certification of polio eradication has been accomplished. This strategy must maximize the benefits and minimize the risks. A number of strategies are currently under consideration, including: (i) synchronized global discontinuation of use of oral poliovirus vaccine (OPV); (ii) regional or subregional coordinated OPV discontinuation; and (iii) moving from trivalent to bivalent or monovalent OPV. Other options include moving from OPV to global use of IPV for an interim period before cessation of IPV use (to eliminate circulation of vaccine-derived poliovirus, if necessary) or development of new OPV strains that are not transmissible. Each of these strategies is associated with specific advantages (financial benefits for OPV discontinuation) and disadvantages (cost of switch to IPV) and inherent uncertainties (risk of continued poliovirus circulation in certain populations or prolonged virus replication in immunodeficient persons). An ambitious research agenda addresses the remaining questions and issues. Nevertheless, several generalities are already clear. Unprecedented collaboration between countries, regions, and indeed the entire world will be required to implement a global OPV discontinuation strategy Regulatory approval will be needed for an interim bivalent OPV or for monovalent OPV in many countries. Manufacturers will need sufficient lead time to produce sufficient quantities of IPV Finally, the financial implications for any of these strategies need to be considered. Whatever strategy is followed it will be necessary to stockpile supplies of a poliovirus-containing vaccine (most probably all three types of monovalent OPV), and to develop contingency plans to respond should an outbreak of polio occur after stopping vaccination.

Investigation of repeated vaccination as a possible cause of glomerular disease in mink.

PubMed

Newman, Shelley Joy; Johnson, Roger; Sears, William; Wilcock, Brian

2002-07-01

The search for antigens capable of causing immune-complex-mediated glomerulonephritis continues. Modified live-virus vaccines commercially available for veterinary use are a possible source. In this study, repeated vaccination of mink with live-virus vaccines was investigated as a model for vaccine-induced glomerular injury. Three groups of 10-wk-old mink, 15 per group, were vaccinated once with 4-way vaccine against distemper, Pseudomonas aeruginosa infection, botulism and mink viral enteritis. Subsequently, all mink in each group each were vaccinated either with the 4-way vaccine, a monovalent canine distemper vaccine, or saline. Glomerular function was assessed at 2-wk intervals by determining the urinary protein:creatinine (P:C) ratio. Kidney sections taken at necropsy, 20 wk after the 1st vaccination, were examined by light and immunofluorescent microscopy for deposition of immunoglobulin and complement. There was no statistically significant difference between the treated and control groups based on average urinary P:C ratio medians. Light microscopic changes were detected in glomeruli, but Fisher's exact test showed no significant differences between any of the treatment groups. Deposition of immunoglobulin but not complement was significantly more frequent (P < 0.05) in the glomeruli of animals that received multiple injections of the 4-way vaccine than in the glomeruli of those given only the monovalent canine distemper vaccine or saline. These findings suggest that repeated vaccination may increase the glomerular deposition of immunoglobulin. Further studies are required to determine if the increased deposition of immunoglobulin contributes to the development of glomerular damage and to identify the antigens driving production of the deposited immunoglobulin.

Comparison of the immunogenicity and safety of the conventional subunit, MF59-adjuvanted, and intradermal influenza vaccines in the elderly.

PubMed

Seo, Yu Bin; Choi, Won Suk; Lee, Jacob; Song, Joon Young; Cheong, Hee Jin; Kim, Woo Joo

2014-07-01

The influenza vaccination is known as the most effective method for preventing influenza infection and its complications in the elderly. Conventional subunit (Agrippal S1; Novartis), MF59-adjuvanted (Fluad; Novartis), and intradermal (IDflu15; Sanofi Pasteur) influenza vaccines are widely used throughout South Korea. However, few comparative studies evaluating the safety and immunogenicity of these vaccines are available. Prior to the beginning of the 2011-2012 influenza season, 335 healthy elderly volunteers randomly received one of three seasonal trivalent influenza vaccines, the conventional subunit, MF59-adjuvanted, or intradermal influenza vaccine. Serum hemagglutination-inhibiting antibody levels were measured at the time of vaccination and at 1 and 6 months after vaccination. Adverse events were recorded prospectively. A total of 113 conventional subunit, 111 MF59-adjuvanted, and 111 intradermal influenza vaccine volunteers were followed up during a 6-month postvaccination period. One month after vaccination, all three vaccines satisfied Committee for Medical Products for Human Use (CHMP) immunogenicity criteria for the A/H1N1 and A/H3N2 strains but not for the B strain. Compared with the subunit vaccine, the intradermal vaccine exhibited noninferiority, while the MF59-adjuvanted vaccine exhibited superiority. Furthermore, the MF59-adjuvanted vaccine was more immunogenic against the A/H3N2 strain than was the subunit vaccine up to 6 months postvaccination. The most common local and systemic reactions to the conventional subunit, MF59-adjuvanted, and intradermal influenza vaccines were pain at the injection site (7.1%, 10.8%, and 6.3%, respectively) and generalized myalgia (0.9%, 8.1%, and 5.4%, respectively). Local and systemic reactions were similar among the three vaccine groups. MF59-adjuvanted vaccine exhibited superior immunogenicity compared with a conventional subunit vaccine and had a comparable safety profile. For older adults, the MF59-adjuvanted

Design of different strategies of multivalent DNA-based vaccination against rabies and canine distemper in mice and dogs.

PubMed

Touihri, Leila; Ahmed, Sami Belhaj; Chtourou, Yacine; Daoud, Rahma; Bahloul, Chokri

2012-12-27

During the vaccination campaigns, puppies younger than 3 months old are not targeted and remain unvaccinated for at least the first year of their lives. Almost half of the reported rabid dogs are 6 months or younger. Hence, we should recommend the vaccination against rabies of young puppies. Unfortunately, owing to the exposure of puppies to infections with either canine parvovirus (CPV) or distemper virus (CDV) after the intervention of the vaccinators, owners are reluctant to vaccinate puppies against rabies. Therefore, it is necessary to include the CPV and CDV valences in the vaccine against rabies. Multivalent DNA-based vaccination in dogs, including rabies and distemper valences, could help in raising vaccine coverage. We have designed monovalent and multivalent DNA-based vaccine candidates for in vitro and in vivo assays. These plasmids encode to the rabies virus glycoprotein and/or the canine distemper virus hemagglutinin. The first strategy of multivalent DNA-based vaccination is by mixing plasmids encoding to a single antigen each. The second is by simply fusing the genes of the antigens together. The third is by adding the foot and mouth disease virus (FMDV) 2A oligopeptide gene into the antigen genes. The last strategy is by the design and use of a bicistronic plasmid with an "Internal Ribosome Entry Site" (IRES) domain. The monovalent construct against canine distemper was efficiently validated by inducing higher humoral immune responses compared to cell-culture-derived vaccine both in mice and dogs. All multivalent plasmids efficiently expressed both valences after in vitro transfection of BHK-21 cells. In BALB/c mice, the bicistronic IRES-dependant construct was the most efficient inducer of virus-neutralizing antibodies against both valences. It was able to induce better humoral immune responses compared to the administration of either cell-culture-derived vaccines or monovalent plasmids. The FMDV 2A was also efficient in the design of multivalent

Burden of rotavirus in India--is rotavirus vaccine an answer to it?

PubMed

Taneja, Davendra K; Malik, Akash

2012-01-01

Rotavirus is currently by far the most common cause of severe diarrhea in infants and young children worldwide and of diarrheal deaths in developing countries. Worldwide Rotavirus is responsible for 611,000 childhood deaths out of which more than 80% occur in low-income countries. The resistance of rotavirus to commonly used disinfectants and ineffectiveness of oral rehydration therapy due to severe vomiting indicates that if an effective vaccine is the preferred option. WHO has recommended inclusion of rotavirus vaccine in the National Schedules where under 5 mortality due to diarrheal diseases is ≥ 10%. Currently two vaccines are available against rotavirus. Rotarix (GlaxoSmithKline) is a monovalent vaccine recommended to be orally administered in two doses at 6-12 weeks. Rota Teq (Merck) is a pentavalent vaccine recommended to be orally administered in three doses starting at 6-12 weeks of age. Serodiversity of rotavirus in India and its regional variation favor either a monovalent vaccine that can induce heterotypic immunity or a polyvalent vaccine incorporating majority of serotypes prevalent in the country. However, the efficacy of available rotavirus vaccines is less in low-income countries. Both the candidate vaccines when coadministered with OPV, immune response to first dose of these vaccines is reduced. However, immune responses to subsequent rotavirus vaccine doses are not affected. In view of this, WHO recommends three doses of either vaccine to be given to children in developing countries to produce the optimum response. Indigenous vaccine, 116E (Bharat Biotech) based on human rotavirus of serotype G9P [11] is still under Phase 2 trials. Another multivalent vaccine is being developed by Shantha Biotechnics in India. The cost effectiveness of the three dose schedule of the available and the rsults of the field trials of the indigenous vaccines should be assessed before inclusion of rotavirus vaccine in the National Immunization Schedule.

Footrot vaccines and vaccination.

PubMed

Dhungyel, Om; Hunter, James; Whittington, Richard

2014-05-30

Research on footrot in small ruminants, which is caused by Dichelobacter nodosus, has led to development of vaccines and their application for control, treatment and eradication of the disease in sheep. Footrot vaccines have evolved over decades to contain monovalent whole cell, multivalent recombinant fimbrial, and finally mono or bivalent recombinant fimbrial antigens. Initially whole cell vaccines made against the few known serogroups of D. nodosus were found to be inefficient in control of the disease in the field, which was attributed to the presence of other unidentified serogroups and also the use of inefficient adjuvants. Fimbriae or pili, which are the basis for antigenic variation, were found to be the major protective and also curative antigens but they are not cross protective between the different serogroups. Multivalent vaccines incorporating all the known serogroups have been proven to be of limited efficacy due to the phenomenon of antigenic competition. Recent studies in Nepal, Bhutan and Australia have shown that outbreak-specific vaccination which involves targeting identified serogroups with mono- or bivalent recombinant fimbrial vaccines, can be very effective in sheep and goats. Where multiple serogroups are present in a flock, antigenic competition can be overcome by sequentially targeting the serogroups with different bivalent vaccines every 3 months. A common antigen which would confer immunity to all serogroups would be the ideal immunogen but the initial studies were not successful in this area. Until universal antigen/s are available, flock specific mono or bivalent fimbrial vaccines are likely to be the most effective tool for control and eradication of footrot in sheep and goats. Future research in footrot vaccines should be focused on improving the duration of prophylaxis by incorporating new and emerging immunomodulators or adjuvants with modified delivery vehicles, discovering a common antigen and understanding the mechanisms of

Evaluation of storing hepatitis B vaccine outside the cold chain in the Solomon Islands: Identifying opportunities and barriers to implementation.

PubMed

Breakwell, Lucy; Anga, Jenniffer; Dadari, Ibrahim; Sadr-Azodi, Nahad; Ogaoga, Divinal; Patel, Minal

2017-05-15

Monovalent Hepatitis B vaccine (HepB) is heat stable, making it suitable for storage outside cold chain (OCC) at 37°C for 1month. We conducted an OCC project in the Solomon Islands to determine the feasibility of and barriers to national implementation and to evaluate impact on coverage. Healthcare workers at 13 facilities maintained monovalent HepB birth dose (HepB-BD) OCC for up to 28days over 7months. Vaccination data were recorded for children born during the project and those born during 7months before the project. Timely HepB-BD coverage among facility and home births increased from 30% to 68% and from 4% to 24%, respectively. Temperature excursions above 37°C were rare, but vaccine wastage was high and shortages common. Storing HepB OCC can increase HepB-BD coverage in countries with insufficient cold chain capacity or numerous home births. High vaccine wastage and unreliable vaccine supply must be addressed for successful implementation. Published by Elsevier Ltd.

Impact and Effectiveness of Monovalent Rotavirus Vaccine in Armenian Children.

PubMed

Sahakyan, Gayane; Grigoryan, Svetlana; Wasley, Annemarie; Mosina, Liudmila; Sargsyan, Shushan; Asoyan, Ara; Gevorgyan, Zaruhi; Kocharyan, Karine; Avagyan, Tigran; Lopman, Benjamin; Vanyan, Artavazd; Khactatryan, Sergey; Parashar, Umesh D; Cortese, Margaret M

2016-05-01

The Republic of Armenia was 1 of the 2 earliest countries in the Newly Independent States to introduce rotavirus vaccine into its national immunization program to reduce the burden of rotavirus disease (documented to cause 38% of acute gastroenteritis hospitalizations [AGE] among children aged <5 years). In November 2012, RV1 (Rotarix) was introduced for Armenian infants at ages 6 and 12 weeks. The established active surveillance system at 2 hospitals in the capital, Yerevan, whereby children aged <5 years hospitalized for AGE have stool sample tested for rotavirus antigen, was used to assess trends in rotavirus hospitalizations. Immunization records on children enrolled after vaccine introduction were obtained from clinics, and vaccine effectiveness (VE) was estimated using children with AGE who test negative for rotavirus as controls for the rotavirus-positive cases. Among infants, rotavirus hospitalizations were reduced by 48% within the first year after introduction, and by ≥75% in years 2 and 3 following introduction. Reductions of ≥30% in other young children too old to have been vaccinated suggest additional benefit through indirect protection; overall in year 3, rotavirus hospitalizations were reduced by 69% among children aged <5 years. The overall VE of 2 RV1 doses in protecting against rotavirus hospitalization (any severity) was 62% (95% confidence interval [CI], 36%-77%) among children aged 6-23 months; 68% (95% CI, 24%-86%) among those aged 6-11 months, and 60% (95% CI, 20%-80%) in children aged 12-23 months. Against more severe rotavirus disease, VE was 79% (95% CI, 55%-90%) and similarly high in both age groups. RV1 is effective in young Armenian children and substantially reduced rotavirus hospitalizations shortly after introduction. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

75 FR 51460 - Novartis AG; Analysis of Proposed Agreement Containing Consent Orders to Aid Public Comment

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-20

... of a controlling interest in Alcon, Inc. (``Alcon'') from Nestle, S.A. The proposed Consent Agreement..., Novartis proposes to acquire all of the outstanding shares of Alcon held by Nestle in a transaction valued... pharmaceuticals headquartered in Basel, Switzerland. Nestle is the world's largest food company, and is...

Phase 2 Assessment of the Safety and Immunogenicity of Two Inactivated Pandemic Monovalent H1N1 Vaccines in Adults as a Component of the U.S. Pandemic Preparedness Plan in 2009

PubMed Central

Chen, Wilbur H.; Winokur, Patricia L.; Edwards, Kathryn M.; Jackson, Lisa A.; Wald, Anna; Walter, Emmanuel B.; Noah, Diana L.; Wolff, Mark; Kotloff, Karen L.

2012-01-01

Background The influenza A/H1N1 pandemic in 2009 created an urgent need to develop vaccines for mass immunization. To guide decisions regarding the optimal immunization dosage and schedule for adults, we evaluated two monovalent, inactivated, unadjuvanted H1N1 influenza vaccines in independent, but simultaneously conducted, multi-center Phase 2 trials of identical design. Methods Healthy adults, stratified by age (18 to 64 years and ≥65 years), were randomized (1:1 allocation), in a double-blind, parallel-group design, to receive two intramuscular doses (21 days apart) of vaccine containing approximately 15 μg or 30 μg of hemagglutinin (HA). Primary endpoints were safety (reactogenicity for 8 days after each vaccination and vaccine-associated serious adverse events during the 7 month study) and immunogenicity (proportion of subjects, stratified by age, achieving a serum hemagglutination inhibition [HI] antibody titer ≥1:40 or a ≥4-fold rise in titer after a single injection of either dosage). Results Both vaccines were well-tolerated. A single 15 μg dose induced HI titers ≥1:40 in 90% of younger adults (95% confidence interval [CI] 82%-95%) and 81% of elderly (95% CI 71%–88%) who received Sanofi-Pasteur vaccine (subsequently found to contain 24 μg HA in the standard potency assay), and in 80% of younger adults (95% CI 71%–88%) and 60% of elderly (95% CI 50%–70%) who received CSL vaccine. Both vaccines were significantly more immunogenic in younger compared with elderly adults by at least one endpoint measure. Increasing the dose to 30 μg raised the frequency of HI titers ≥1:40 in the elderly by approximately 10%. Higher dosage did not significantly enhance immunogenicity in younger adults and a second dose provided little additional benefit to either age group. Conclusion These trials provided evidence for policymakers that a single 15 μg dose of 2009 A/H1N1 vaccine would likely protect most U.S. adults and suggest a potential benefit of a 30

Phase 2 assessment of the safety and immunogenicity of two inactivated pandemic monovalent H1N1 vaccines in adults as a component of the U.S. pandemic preparedness plan in 2009.

PubMed

Chen, Wilbur H; Winokur, Patricia L; Edwards, Kathryn M; Jackson, Lisa A; Wald, Anna; Walter, Emmanuel B; Noah, Diana L; Wolff, Mark; Kotloff, Karen L

2012-06-13

The influenza A/H1N1 pandemic in 2009 created an urgent need to develop vaccines for mass immunization. To guide decisions regarding the optimal immunization dosage and schedule for adults, we evaluated two monovalent, inactivated, unadjuvanted H1N1 influenza vaccines in independent, but simultaneously conducted, multi-center Phase 2 trials of identical design. Healthy adults, stratified by age (18-64 years and ≥65 years), were randomized (1:1 allocation), in a double-blind, parallel-group design, to receive two intramuscular doses (21 days apart) of vaccine containing approximately 15 μg or 30 μg of hemagglutinin (HA). Primary endpoints were safety (reactogenicity for 8 days after each vaccination and vaccine-associated serious adverse events during the 7 month study) and immunogenicity (proportion of subjects, stratified by age, achieving a serum hemagglutination inhibition [HI] antibody titer ≥1:40 or a ≥4-fold rise in titer after a single injection of either dosage). Both vaccines were well-tolerated. A single 15 μg dose induced HI titers ≥1:40 in 90% of younger adults (95% confidence interval [CI] 82-95%) and 81% of elderly (95% CI 71-88%) who received Sanofi-Pasteur vaccine (subsequently found to contain 24 μg HA in the standard potency assay), and in 80% of younger adults (95% CI 71-88%) and 60% of elderly (95% CI 50-70%) who received CSL vaccine. Both vaccines were significantly more immunogenic in younger compared with elderly adults by at least one endpoint measure. Increasing the dose to 30 μg raised the frequency of HI titers ≥1:40 in the elderly by approximately 10%. Higher dosage did not significantly enhance immunogenicity in younger adults and a second dose provided little additional benefit to either age group. These trials provided evidence for policymakers that a single 15 μg dose of 2009 A/H1N1 vaccine would likely protect most U.S. adults and suggest a potential benefit of a 30 μg dose for the elderly. Copyright © 2012

Induction of a melanoma-specific antibody response by a monovalent, but not a divalent, synthetic GM2 neoglycopeptide.

PubMed

Bay, S; Fort, S; Birikaki, L; Ganneau, C; Samain, E; Coïc, Y-M; Bonhomme, F; Dériaud, E; Leclerc, C; Lo-Man, R

2009-04-01

The GM2 ganglioside represents an important target for specific anticancer immunotherapy. We designed and synthesized a neoglycopeptide immunogen displaying one or two copies of the GM2 tetrasaccharidic moiety. These glycopeptides were prepared using the Huisgen cycloaddition, which enables the efficient ligation of the alkyne-functionalized biosynthesized GM2 with an azido CD4(+) T cell epitope peptide. It is worth noting that the GM2 can be produced on a gram scale in bacteria, which can be advantageous for a scale-up of the process. We show here for the first time that a fully synthetic glycopeptide, which is based on a ganglioside carbohydrate moiety, can induce human tumor cell-specific antibodies after immunization in mice. Interestingly, the monovalent, but not the divalent, form of GM2 peptide construct induced antimelanoma antibodies. Unlike traditional vaccines, this vaccine is a pure chemically-defined entity, a key quality for consistent studies and safe clinical evaluation. Therefore, such carbohydrate-peptide conjugate represents a promising cancer vaccine strategy for active immunotherapy targeting gangliosides.

The evolving history of influenza viruses and influenza vaccines.

PubMed

Hannoun, Claude

2013-09-01

The isolation of influenza virus 80 years ago in 1933 very quickly led to the development of the first generation of live-attenuated vaccines. The first inactivated influenza vaccine was monovalent (influenza A). In 1942, a bivalent vaccine was produced after the discovery of influenza B. It was later discovered that influenza viruses mutated leading to antigenic changes. Since 1973, the WHO has issued annual recommendations for the composition of the influenza vaccine based on results from surveillance systems that identify currently circulating strains. In 1978, the first trivalent vaccine included two influenza A strains and one influenza B strain. Currently, there are two influenza B lineages circulating; in the latest WHO recommendations, it is suggested that a second B strain could be added to give a quadrivalent vaccine. The history of influenza vaccine and the associated technology shows how the vaccine has evolved to match the evolution of influenza viruses.

Immunogenicity of sanofi pasteur tetravalent dengue vaccine.

PubMed

Guy, Bruno

2009-10-01

A candidate tetravalent (TV) dengue vaccine based on the yellow fever (YF) 17D vaccine has been developed by sanofi pasteur. This dengue TV vaccine induced a controlled dendritic cell stimulation in vitro. In clinical trials, Th1 and CD8 responses were induced with an IFN-gamma/TNF-alpha ratio favouring IFN-gamma in both cases, regardless of whether the vaccine recipients were flavivirus naive or not. There was an absence of Th2 response in all cases. The Th1 response was dominated by the D4 serotype in flavivirus naive individuals after initial vaccination but broadened to include all serotypes after second vaccination. This broadened response was also observed after primary dengue TV vaccination in subjects previously administered monovalent live-attenuated dengue 1 and dengue 2 vaccines. Notably, virtually no cross-reactivity between YF 17D and dengue NS3 antigens at the CD8 level was observed. Clinical and pre-clinical results support the favourable immunogenicity and short-term safety of the dengue TV. Future studies will establish the longevity of the vaccine-induced immunity and requirements for boosters.

Monovalent Strep-Tactin for strong and site-specific tethering in nanospectroscopy.

PubMed

Baumann, Fabian; Bauer, Magnus S; Milles, Lukas F; Alexandrovich, Alexander; Gaub, Hermann E; Pippig, Diana A

2016-01-01

Strep-Tactin, an engineered form of streptavidin, binds avidly to the genetically encoded peptide Strep-tag II in a manner comparable to streptavidin binding to biotin. These interactions have been used in protein purification and detection applications. However, in single-molecule studies, for example using atomic force microscopy-based single-molecule force spectroscopy (AFM-SMFS), the tetravalency of these systems impedes the measurement of monodispersed data. Here, we introduce a monovalent form of Strep-Tactin that harbours a unique binding site for Strep-tag II and a single cysteine that allows Strep-Tactin to specifically attach to the atomic force microscope cantilever and form a consistent pulling geometry to obtain homogeneous rupture data. Using AFM-SMFS, the mechanical properties of the interaction between Strep-tag II and monovalent Strep-Tactin were characterized. Rupture forces comparable to biotin:streptavidin unbinding were observed. Using titin kinase and green fluorescent protein, we show that monovalent Strep-Tactin is generally applicable to protein unfolding experiments. We expect monovalent Strep-Tactin to be a reliable anchoring tool for a range of single-molecule studies.

Monovalent Strep-Tactin for strong and site-specific tethering in nanospectroscopy

NASA Astrophysics Data System (ADS)

Baumann, Fabian; Bauer, Magnus S.; Milles, Lukas F.; Alexandrovich, Alexander; Gaub, Hermann E.; Pippig, Diana A.

2016-01-01

Strep-Tactin, an engineered form of streptavidin, binds avidly to the genetically encoded peptide Strep-tag II in a manner comparable to streptavidin binding to biotin. These interactions have been used in protein purification and detection applications. However, in single-molecule studies, for example using atomic force microscopy-based single-molecule force spectroscopy (AFM-SMFS), the tetravalency of these systems impedes the measurement of monodispersed data. Here, we introduce a monovalent form of Strep-Tactin that harbours a unique binding site for Strep-tag II and a single cysteine that allows Strep-Tactin to specifically attach to the atomic force microscope cantilever and form a consistent pulling geometry to obtain homogeneous rupture data. Using AFM-SMFS, the mechanical properties of the interaction between Strep-tag II and monovalent Strep-Tactin were characterized. Rupture forces comparable to biotin:streptavidin unbinding were observed. Using titin kinase and green fluorescent protein, we show that monovalent Strep-Tactin is generally applicable to protein unfolding experiments. We expect monovalent Strep-Tactin to be a reliable anchoring tool for a range of single-molecule studies.

AS03- and MF59-Adjuvanted Influenza Vaccines in Children

PubMed Central

Wilkins, Amanda L.; Kazmin, Dmitri; Napolitani, Giorgio; Clutterbuck, Elizabeth A.; Pulendran, Bali; Siegrist, Claire-Anne; Pollard, Andrew J.

2017-01-01

Influenza is a major cause of respiratory disease leading to hospitalization in young children. However, seasonal trivalent influenza vaccines (TIVs) have been shown to be ineffective and poorly immunogenic in this population. The development of live-attenuated influenza vaccines and adjuvanted vaccines are important advances in the prevention of influenza in young children. The oil-in-water emulsions MF59 and adjuvant systems 03 (AS03) have been used as adjuvants in both seasonal adjuvanted trivalent influenza vaccines (ATIVs) and pandemic monovalent influenza vaccines. Compared with non-adjuvanted vaccine responses, these vaccines induce a more robust and persistent antibody response for both homologous and heterologous influenza strains in infants and young children. Evidence of a significant improvement in vaccine efficacy with these adjuvanted vaccines resulted in the use of the monovalent (A/H1N1) AS03-adjuvanted vaccine in children in the 2009 influenza pandemic and the licensure of the seasonal MF59 ATIV for children aged 6 months to 2 years in Canada. The mechanism of action of MF59 and AS03 remains unclear. Adjuvants such as MF59 induce proinflammatory cytokines and chemokines, including CXCL10, but independently of type-1 interferon. This proinflammatory response is associated with improved recruitment, activation and maturation of antigen presenting cells at the injection site. In young children MF59 ATIV produced more homogenous and robust transcriptional responses, more similar to adult-like patterns, than did TIV. Early gene signatures characteristic of the innate immune response, which correlated with antibody titers were also identified. Differences were detected when comparing child and adult responses including opposite trends in gene set enrichment at day 3 postvaccination and, unlike adult data, a lack of correlation between magnitude of plasmablast response at day 7 and antibody titers at day 28 in children. These insights show the utility

AS03- and MF59-Adjuvanted Influenza Vaccines in Children.

PubMed

Wilkins, Amanda L; Kazmin, Dmitri; Napolitani, Giorgio; Clutterbuck, Elizabeth A; Pulendran, Bali; Siegrist, Claire-Anne; Pollard, Andrew J

2017-01-01

Influenza is a major cause of respiratory disease leading to hospitalization in young children. However, seasonal trivalent influenza vaccines (TIVs) have been shown to be ineffective and poorly immunogenic in this population. The development of live-attenuated influenza vaccines and adjuvanted vaccines are important advances in the prevention of influenza in young children. The oil-in-water emulsions MF59 and adjuvant systems 03 (AS03) have been used as adjuvants in both seasonal adjuvanted trivalent influenza vaccines (ATIVs) and pandemic monovalent influenza vaccines. Compared with non-adjuvanted vaccine responses, these vaccines induce a more robust and persistent antibody response for both homologous and heterologous influenza strains in infants and young children. Evidence of a significant improvement in vaccine efficacy with these adjuvanted vaccines resulted in the use of the monovalent (A/H1N1) AS03-adjuvanted vaccine in children in the 2009 influenza pandemic and the licensure of the seasonal MF59 ATIV for children aged 6 months to 2 years in Canada. The mechanism of action of MF59 and AS03 remains unclear. Adjuvants such as MF59 induce proinflammatory cytokines and chemokines, including CXCL10, but independently of type-1 interferon. This proinflammatory response is associated with improved recruitment, activation and maturation of antigen presenting cells at the injection site. In young children MF59 ATIV produced more homogenous and robust transcriptional responses, more similar to adult-like patterns, than did TIV. Early gene signatures characteristic of the innate immune response, which correlated with antibody titers were also identified. Differences were detected when comparing child and adult responses including opposite trends in gene set enrichment at day 3 postvaccination and, unlike adult data, a lack of correlation between magnitude of plasmablast response at day 7 and antibody titers at day 28 in children. These insights show the utility

Inactivated poliovirus type 2 vaccine delivered to rat skin via high density microprojection array elicits potent neutralising antibody responses.

PubMed

Muller, David A; Pearson, Frances E; Fernando, Germain J P; Agyei-Yeboah, Christiana; Owens, Nick S; Corrie, Simon R; Crichton, Michael L; Wei, Jonathan C J; Weldon, William C; Oberste, M Steven; Young, Paul R; Kendall, Mark A F

2016-02-25

Polio eradication is progressing rapidly, and the live attenuated Sabin strains in the oral poliovirus vaccine (OPV) are being removed sequentially, starting with type 2 in April 2016. For risk mitigation, countries are introducing inactivated poliovirus vaccine (IPV) into routine vaccination programs. After April 2016, monovalent type 2 OPV will be available for type 2 outbreak control. Because the current IPV is not suitable for house-to-house vaccination campaigns (the intramuscular injections require health professionals), we developed a high-density microprojection array, the Nanopatch, delivered monovalent type 2 IPV (IPV2) vaccine to the skin. To assess the immunogenicity of the Nanopatch, we performed a dose-matched study in rats, comparing the immunogenicity of IPV2 delivered by intramuscular injection or Nanopatch immunisation. A single dose of 0.2 D-antigen units of IPV2 elicited protective levels of poliovirus antibodies in 100% of animals. However, animals receiving IPV2 by IM required at least 3 immunisations to reach the same neutralising antibody titres. This level of dose reduction (1/40th of a full dose) is unprecedented for poliovirus vaccine delivery. The ease of administration coupled with the dose reduction observed in this study points to the Nanopatch as a potential tool for facilitating inexpensive IPV for mass vaccination campaigns.

Inactivated poliovirus type 2 vaccine delivered to rat skin via high density microprojection array elicits potent neutralising antibody responses

PubMed Central

Muller, David A.; Pearson, Frances E.; Fernando, Germain J.P.; Agyei-Yeboah, Christiana; Owens, Nick S.; Corrie, Simon R.; Crichton, Michael L.; Wei, Jonathan C.J.; Weldon, William C.; Oberste, M. Steven; Young, Paul R.; Kendall, Mark A. F.

2016-01-01

Polio eradication is progressing rapidly, and the live attenuated Sabin strains in the oral poliovirus vaccine (OPV) are being removed sequentially, starting with type 2 in April 2016. For risk mitigation, countries are introducing inactivated poliovirus vaccine (IPV) into routine vaccination programs. After April 2016, monovalent type 2 OPV will be available for type 2 outbreak control. Because the current IPV is not suitable for house-to-house vaccination campaigns (the intramuscular injections require health professionals), we developed a high-density microprojection array, the Nanopatch, delivered monovalent type 2 IPV (IPV2) vaccine to the skin. To assess the immunogenicity of the Nanopatch, we performed a dose-matched study in rats, comparing the immunogenicity of IPV2 delivered by intramuscular injection or Nanopatch immunisation. A single dose of 0.2 D-antigen units of IPV2 elicited protective levels of poliovirus antibodies in 100% of animals. However, animals receiving IPV2 by IM required at least 3 immunisations to reach the same neutralising antibody titres. This level of dose reduction (1/40th of a full dose) is unprecedented for poliovirus vaccine delivery. The ease of administration coupled with the dose reduction observed in this study points to the Nanopatch as a potential tool for facilitating inexpensive IPV for mass vaccination campaigns. PMID:26911254

Delivering vaccines to the people who need them most

PubMed Central

Barocchi, Michèle Anne; Rappuoli, Rino

2015-01-01

Thanks to the Global Alliance for Vaccines and Immunization (GAVI), the Vaccine Fund and the Bill & Melinda Gates Foundation, the global health community has made enormous progress in providing already existing vaccines to developing countries. However, there still exists a gap to develop vaccines for which there is no market in the Western world, owing to low economic incentives for the private sector to justify the investments necessary for vaccine development. In many cases, industry has the technologies, but lacks the impetus to direct resources to develop these vaccine products. The present emergency with the Ebola vaccine provides us an excellent example where a vaccine was feasible several years ago, but the global health community waited for a humanitarian disaster to direct efforts and resources to develop this vaccine. In the beginning of 2015, the first large-scale trials of two experimental vaccines against Ebola virus disease have begun in West Africa. During the past few years, several institutions have dedicated efforts to the development of vaccines against diseases present only in low-income countries. These include the International Vaccine Institute, the Novartis Vaccines Institute for Global Health, the Hilleman Institute, the Sabin Vaccine Institute and the Infectious Disease Research Institute. Nevertheless, solving this problem requires a more significant global effort than that currently invested. These efforts include a clear policy, global coordination of funds dedicated to the development of neglected disease and an agreement on regulatory strategies and incentives for the private sector. PMID:25964460

Live attenuated tetravalent dengue vaccine.

PubMed

Bhamarapravati, N; Sutee, Y

2000-05-26

The development of a live attenuated tetravalent dengue vaccine is currently the best strategy to obtain a vaccine against dengue viruses. The Mahidol University group developed candidate live attenuated vaccines by attenuation through serial passages in certified primary cell cultures. Dengue serotype 1, 2 and 4 viruses were developed in primary dog kidney cells, whereas dengue serotype 3 was serially passaged in primary African green monkey kidney cells. Tissue culture passaged strain viruses were subjected to biological marker studies. Candidate vaccines have been tested as monovalent (single virus), bivalent (two viruses), trivalent (three viruses) and tetravalent (all four serotype viruses) vaccines in Thai volunteers. They were found to be safe and immunogenic in both adults and children. The Mahidol live attenuated dengue 2 virus was also tested in American volunteers and resulted in good immune response indistinguishable from those induced in Thai volunteers. The master seeds from the four live attenuated virus strains developed were provided to Pasteur Merieux Connaught of France for production on an industrial scale following good manufacturing practice guidelines.

Bluetongue control using vaccines: the experience of Emilia Romagna, Italy.

PubMed

Santi, A; Piccolomini, L Loli; Viappiani, P; Tamba, M; Calabrese, R; Massirio, I

2004-01-01

In 2003, thirty municipalities of the provinces of Parma, Reggio Emilia and Modena in the Emilia Romagna region of Italy, bordering the region of Tuscany, were included in the national bluetongue (BT) vaccination programme, using monovalent live-attenuated type 2 vaccine. The purpose of the study was to evaluate the organisation of a vaccination programme designed by the Regional Veterinary Service and the relative cost of the campaign, as a large number of animals were involved. To better evaluate the real cost of the campaign, costs sustained by the Reggio Emilia Local Sanitary Unit were specifically analysed. BT vaccination of all domestic ruminants is a very expensive operation (euro9.20 per vaccinated animal). Consequently, to evaluate the need for a vaccination campaign in a new area, the risk of disease spread, as well as the cost of the operation, should be considered.

Compliance with birth dose of Hepatitis B vaccine in high endemic and hard to reach areas in the Colombian amazon: results from a vaccination survey.

PubMed

Choconta-Piraquive, Luz Angela; De la Hoz-Restrepo, Fernando; Sarmiento-Limas, Carlos Arturo

2016-07-21

Hepatitis B vaccination was introduced into the Expanded Program of Immunization in Colombia in 1992, in response to WHO recommendations on hepatitis B immunization. Colombia is a low endemic country for Hepatitis B virus infection (HBV) but it has several high endemic areas like the Amazon basin where more than 70 % of adults had been infected. A cross- sectional study was carried out in three rural areas of the Colombian Amazon to evaluate compliance with the recommended schedule for hepatitis B vaccine in Colombian children (one monovalent dose given in the first 24 h after birth + 3 doses of a pentavalent containing Hepatitis B. (DPT + Hib + Hep B). A household survey was conducted in order to collect vaccination data from children aged from 6 months to <8 years. Vaccination status was related to sociodemographic data obtained from children caretakers. Among 938 children above 6 months and < 8 years old studied, 79 % received a monovalent dose of hepatitis B vaccine, but only 30.7 % were vaccinated in the first 24 h after birth. This proportion did not increase by age or subsequent birth cohorts. Coverage with three doses of a DTP-Hib-HepB vaccine was 98 %, but most children did not receive them according to the recommended schedule. Being born in a health facility was the strongest predictor of receiving a timely birth dose. This study suggests that more focused strategies on improving compliance with hepatitis B birth dose should be implemented in rural areas of the Amazon, if elimination of perinatal transmission of HBV is to be achieved. Increasing the proportion of newborns delivered at health facilities should be one of the priorities to reach that goal.

75 FR 42455 - Novartis Pharmaceuticals Corp. et al.; Withdrawal of Approval of 27 New Drug Applications and 58...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-21

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-N-0318... NDA 6-008 Mesantoin (mephenytoin) Tablets Novartis Pharmaceuticals Corp., One Health Plaza, East... Endo Pharmaceuticals NDA 17-255 MPI DTPA Chelate multidose (kit for Medi-Physics, Inc., d/b/a GE...

[A seroconversion study of the measles component of the MMR vaccine in adolescents of the town of Sabrosa].

PubMed

Gonçalves, G; Tavares, F; de Andrade, H R

1998-12-01

The Portuguese national programme of vaccination has instituted a two-dose MMR vaccine schedule. The second dose of MMR (measles-mumps-rubella combined vaccine) is given at 11-13 years of age, for both sexes. This study was conducted to evaluate the duration of immunity of the monovalent measles vaccine, and the efficacy of a second dose given as MMR. MMR (Triviraten Berna with the strain Edmonston-Zagreb) was given to the 38 participants. Blood samples were collected before and after vaccination. Thirty-six participants had been vaccinated with measles monovalent vaccine during childhood. To measure anti-measles IgG (mIgG), an enzyme immunoassay was used. Participants were classified as "susceptible" or "immune", using 200 mIU/ml (milli international units per millilitre) as the threshold for "immune". Geometric mean concentration (GMC) of mIgG was 1401 mIU/ml in prevaccination sera (n = 38). Thirty-five (92%) of the adolescents were "immune". Only the two unvaccinated had a positive measles history. GMC in the sera of the 36 vaccinated participants was 1301 mIU/ml. Neither the time since measles vaccination nor age at vaccination were correlated with the levels of mIgG. After receiving MMR, all adolescents became "immune". GMC of mIgG was 2879 mIU/ml in postvaccination sera (n = 38). In 28 (74%) participants, mIgG levels increased after receiving MMR. Mean concentration increase was 1082 mIU/ml. For measles, results support the use of a two-dose MMR vaccine schedule in Portugal.

Delivering vaccines to the people who need them most.

PubMed

Barocchi, Michèle Anne; Rappuoli, Rino

2015-06-19

Thanks to the Global Alliance for Vaccines and Immunization (GAVI), the Vaccine Fund and the Bill & Melinda Gates Foundation, the global health community has made enormous progress in providing already existing vaccines to developing countries. However, there still exists a gap to develop vaccines for which there is no market in the Western world, owing to low economic incentives for the private sector to justify the investments necessary for vaccine development. In many cases, industry has the technologies, but lacks the impetus to direct resources to develop these vaccine products. The present emergency with the Ebola vaccine provides us an excellent example where a vaccine was feasible several years ago, but the global health community waited for a humanitarian disaster to direct efforts and resources to develop this vaccine. In the beginning of 2015, the first large-scale trials of two experimental vaccines against Ebola virus disease have begun in West Africa. During the past few years, several institutions have dedicated efforts to the development of vaccines against diseases present only in low-income countries. These include the International Vaccine Institute, the Novartis Vaccines Institute for Global Health, the Hilleman Institute, the Sabin Vaccine Institute and the Infectious Disease Research Institute. Nevertheless, solving this problem requires a more significant global effort than that currently invested. These efforts include a clear policy, global coordination of funds dedicated to the development of neglected disease and an agreement on regulatory strategies and incentives for the private sector. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Reduction by monovalent zinc, cadmium, and nickel cations

NASA Technical Reports Server (NTRS)

Meyerstein, D.; Mulac, W. A.

1969-01-01

Understanding of chemical properties of monovalent transition metal cations in aqueous solutions was obtained by a study of kinetics of reduction of different inorganic substrates by zinc, cadmium, and nickel.

Molecular-level analysis of the serum antibody repertoire in young adults before and after seasonal influenza vaccination.

PubMed

Lee, Jiwon; Boutz, Daniel R; Chromikova, Veronika; Joyce, M Gordon; Vollmers, Christopher; Leung, Kwanyee; Horton, Andrew P; DeKosky, Brandon J; Lee, Chang-Han; Lavinder, Jason J; Murrin, Ellen M; Chrysostomou, Constantine; Hoi, Kam Hon; Tsybovsky, Yaroslav; Thomas, Paul V; Druz, Aliaksandr; Zhang, Baoshan; Zhang, Yi; Wang, Lingshu; Kong, Wing-Pui; Park, Daechan; Popova, Lyubov I; Dekker, Cornelia L; Davis, Mark M; Carter, Chalise E; Ross, Ted M; Ellington, Andrew D; Wilson, Patrick C; Marcotte, Edward M; Mascola, John R; Ippolito, Gregory C; Krammer, Florian; Quake, Stephen R; Kwong, Peter D; Georgiou, George

2016-12-01

Molecular understanding of serological immunity to influenza has been confounded by the complexity of the polyclonal antibody response in humans. Here we used high-resolution proteomics analysis of immunoglobulin (referred to as Ig-seq) coupled with high-throughput sequencing of transcripts encoding B cell receptors (BCR-seq) to quantitatively determine the antibody repertoire at the individual clonotype level in the sera of young adults before and after vaccination with trivalent seasonal influenza vaccine. The serum repertoire comprised between 40 and 147 clonotypes that were specific to each of the three monovalent components of the trivalent influenza vaccine, with boosted pre-existing clonotypes accounting for ∼60% of the response. An unexpectedly high fraction of serum antibodies recognized both the H1 and H3 monovalent vaccines. Recombinant versions of these H1 + H3 cross-reactive antibodies showed broad binding to hemagglutinins (HAs) from previously circulating virus strains; several of these antibodies, which were prevalent in the serum of multiple donors, recognized the same conserved epitope in the HA head domain. Although the HA-head-specific H1 + H3 antibodies did not show neutralization activity in vitro, they protected mice against infection with the H1N1 and H3N2 virus strains when administered before or after challenge. Collectively, our data reveal unanticipated insights regarding the serological response to influenza vaccination and raise questions about the added benefits of using a quadrivalent vaccine instead of a trivalent vaccine.

An international technology platform for influenza vaccines.

PubMed

Hendriks, Jan; Holleman, Marit; de Boer, Otto; de Jong, Patrick; Luytjes, Willem

2011-07-01

Since 2008, the World Health Organization has provided seed grants to 11 manufacturers in low- and middle-income countries to establish or improve their pandemic influenza vaccine production capacity. To facilitate this ambitious project, an influenza vaccine technology platform (or "hub") was established at the Netherlands Vaccine Institute for training and technology transfer to developing countries. During its first two years of operation, a robust and transferable monovalent pilot process for egg-based inactivated whole virus influenza A vaccine production was established under international Good Manufacturing Practice standards, as well as in-process and release assays. A course curriculum was designed, including a two-volume practical handbook on production and quality control. Four generic hands-on training courses were successfully realized for over 40 employees from 15 developing country manufacturers. Planned extensions to the curriculum include cell-culture based technology for viral vaccine production, split virion influenza production, and generic adjuvant formulation. We conclude that technology transfer through the hub model works well, significantly builds vaccine manufacturing capacity in developing countries, and thereby increases global and equitable access to vaccines of high public health relevance. Copyright © 2011 Elsevier Ltd. All rights reserved.

Multicenter Safety and Immunogenicity Trial of an Attenuated Measles Vaccine for NHP

PubMed Central

Yee, JoAnn L; McChesney, Michael B; Christe, Kari L

2015-01-01

Measles is a highly contagious viral disease in NHP. The infection can range from asymptomatic to rapidly fatal, resulting in significant morbidity and mortality in captive populations. In addition to appropriate quarantine practices, restricted access, the immunization of all personnel in contact with NHP, and the wearing of protective clothing including face masks, measles immunization further reduces the infection risk. Commercially available measles vaccines are effective for use in NHP, but interruptions in their availability have prevented the implementation of ongoing, consistent vaccination programs. This need for a readily available vaccine led us to perform a broad, multicenter safety and immunogenicity study of another candidate vaccine, MVac (Serum Institute of India), a monovalent measles vaccine derived from live Edmonston–Zagreb strain virus that had been attenuated after 22 passages on human diploid cells. PMID:26473350

Key aspects of the Novartis compound collection enhancement project for the compilation of a comprehensive chemogenomics drug discovery screening collection.

PubMed

Jacoby, Edgar; Schuffenhauer, Ansgar; Popov, Maxim; Azzaoui, Kamal; Havill, Benjamin; Schopfer, Ulrich; Engeloch, Caroline; Stanek, Jaroslav; Acklin, Pierre; Rigollier, Pascal; Stoll, Friederike; Koch, Guido; Meier, Peter; Orain, David; Giger, Rudolph; Hinrichs, Jürgen; Malagu, Karine; Zimmermann, Jürg; Roth, Hans-Joerg

2005-01-01

The NIBR (Novartis Institutes for BioMedical Research) compound collection enrichment and enhancement project integrates corporate internal combinatorial compound synthesis and external compound acquisition activities in order to build up a comprehensive screening collection for a modern drug discovery organization. The main purpose of the screening collection is to supply the Novartis drug discovery pipeline with hit-to-lead compounds for today's and the future's portfolio of drug discovery programs, and to provide tool compounds for the chemogenomics investigation of novel biological pathways and circuits. As such, it integrates designed focused and diversity-based compound sets from the synthetic and natural paradigms able to cope with druggable and currently deemed undruggable targets and molecular interaction modes. Herein, we will summarize together with new trends published in the literature, scientific challenges faced and key approaches taken at NIBR to match the chemical and biological spaces.

Influenza Virus Vaccines: Lessons from the 2009 H1N1 pandemic

PubMed Central

Broadbent, Andrew J.; Subbarao, Kanta

2011-01-01

Reflecting on the 2009 H1N1 pandemic, we summarize lessons regarding influenza vaccines that can be applied in the future. The two major challenges to vaccination during the 2009 H1N1 pandemic were timing and availability of vaccine. Vaccines were, however, well-tolerated and immunogenic, with inactivated vaccines containing 15μg of HA generally inducing antibody titers ≥1:40 in adults within 2 weeks of the administration of a single dose. Moreover, the use of oil-in-water adjuvants in Europe permitted dose- reduction, with vaccines containing as little as 3.75 or 7.5μg HA being immunogenic. Case-control studies demonstrated that monovalent 2009 H1N1 vaccines were effective in preventing infection with the 2009 H1N1 virus, but preliminary data suggests that it is important for individuals to be re-immunized annually. PMID:22125588

Developing an Inactivated Rotavirus Vaccine and Evaluating the Immunogenicity Against a Commercially Available Attenuated Rotavirus Vaccine Using a Mice Animal Model.

PubMed

Hashim, Ayaa S M; Aboshanab, Khaled M A; El-Sayed, Aly F M

2016-12-01

There is a high demand for public immunization against Rotavirus (RV), especially in Africa. In Africa, the attenuated RV vaccination is contraindicated in patients with immune diseases and nutrition deficiency. Therefore, the inactivated RV vaccine (IRVV) could be an alternative. In this study, we aimed to develop a pentavalent-IRVV using the most circulating RV strains in Egypt and evaluate it against the commercially available Rotarix ® vaccine. Trial-IRVV was developed with 5% sucrose, 2% polysorbate-80, and adsorbed on Alum to potentiate the vaccine immune response. Then, it was injected subcutaneously into mice groups at 0-, 21-, and 35-time intervals. In parallel, Rotarix was administered twice on 0 and 28 th day. The success of the pentavalent-IRVV/monovalent-Rotarix vaccine immunity rested on achieving immunoglobulin G (IgG) exceeding 1:6,400 that implies less susceptibility to RV infection (RVI). IRVV stimulating IgG >1:6,400 could be an alternative vaccination approach to reach a reasonable protective immunization level against RVI. In addition, Alum adjuvant incorporation effectively provoked a triple elevation of the immunization pattern.

Monovalent IgG4 molecules

PubMed Central

Wilkinson, Ian C.; Fowler, Susan B.; Machiesky, LeeAnn; Miller, Kenneth; Hayes, David B.; Adib, Morshed; Her, Cheng; Borrok, M. Jack; Tsui, Ping; Burrell, Matthew; Corkill, Dominic J.; Witt, Susanne; Lowe, David C.; Webster, Carl I.

2013-01-01

Antibodies have become the fastest growing class of biological therapeutics, in part due to their exquisite specificity and ability to modulate protein-protein interactions with a high biological potency. The relatively large size and bivalency of antibodies, however, limits their use as therapeutics in certain circumstances. Antibody fragments, such as single-chain variable fragments and antigen binding-fragments, have emerged as viable alternatives, but without further modifications these monovalent formats have reduced terminal serum half-lives because of their small size and lack of an Fc domain, which is required for FcRn-mediated recycling. Using rational engineering of the IgG4 Fc domain to disrupt key interactions at the CH3-CH3 interface, we identified a number of point mutations that abolish Fc dimerization and created half-antibodies, a novel monovalent antibody format that retains a monomeric Fc domain. Introduction of these mutations into an IgG1 framework also led to the creation of half-antibodies. These half-antibodies were shown to be soluble, thermodynamically stable and monomeric, characteristics that are favorable for use as therapeutic proteins. Despite significantly reduced FcRn binding in vitro, which suggests that avidity gains in a dimeric Fc are critical to optimal FcRn binding, this format demonstrated an increased terminal serum half-life compared with that expected for most alternative antibody fragments. PMID:23567207

Monovalent Streptavidin that Senses Oligonucleotides**

PubMed Central

Wang, Jingxian; Kostic, Natasa; Stojanovic, Milan N.

2013-01-01

We report a straightforward chemical route to monovalent streptavidin, a valuable reagent for imaging. The one-step process is based on a (tris)biotinylated-oligonucleotide blocking three of streptavidin’s four biotin binding sites. Further, the complex is highly sensitive to single-base differences - whereby perfectly matched oligonucleotides trigger dissociation of the biotin-streptavidin interaction at higher rates than single-base mismatches. Unique properties and ease of synthesis open wide opportunities for practical applications in imaging and biosensing. PMID:23606329

Vaccines for preventing influenza in healthy adults.

PubMed

Jefferson, T O; Rivetti, D; Di Pietrantonj, C; Rivetti, A; Demicheli, V

2007-04-18

influenza when the vaccine matched the circulating strain and circulation was high, but decreased to 50% (95% CI 27% to 65%) when it did not. Excluding the studies of the 1968 to 1969 pandemic, effectiveness was 15% (95% CI 9% to 22%) and efficacy was 73% (95% CI 53% to 84%). Vaccination had a modest effect on time off work, but there was insufficient evidence to draw conclusions on hospital admissions or complication rates. Inactivated vaccines caused local tenderness and soreness and erythema. Spray vaccines had more modest performance. Monovalent whole-virion vaccines matching circulating viruses had high efficacy (VE 93%, 95% CI 69% to 98%) and effectiveness (VE 66%, 95% CI 51% to 77%) against the 1968 to 1969 pandemic. Influenza vaccines are effective in reducing cases of influenza, especially when the content predicts accurately circulating types and circulation is high. However, they are less effective in reducing cases of influenza-like illness and have a modest impact on working days lost. There is insufficient evidence to assess their impact on complications. Whole-virion monovalent vaccines may perform best in a pandemic.

Combination vaccines against diarrheal diseases

PubMed Central

Venkatesan, Malabi M; Van de Verg, Lillian L

2015-01-01

Abstract Diarrheal diseases remain a leading cause of global childhood mortality and morbidity. Several recent epidemiological studies highlight the rate of diarrheal diseases in different parts of the world and draw attention to the impact on childhood growth and survival. Despite the well-documented global burden of diarrheal diseases, currently there are no combination diarrheal vaccines, only licensed vaccines for rotavirus and cholera, and Salmonella typhi-based vaccines for typhoid fever. The recognition of the impact of diarrheal episodes on infant growth, as seen in resource-poor countries, has spurred action from governmental and non-governmental agencies to accelerate research toward affordable and effective vaccines against diarrheal diseases. Both travelers and children in endemic countries will benefit from a combination diarrheal vaccine, but it can be argued that the greater proportion of any positive impact will be on the public health status of the latter. The history of combination pediatric vaccines indicate that monovalent or single disease vaccines are typically licensed first prior to formulation in a combination vaccine, and that the combinations themselves undergo periodic revision in response to need for improvement in safety or potential for wider coverage of important pediatric pathogens. Nevertheless combination pediatric vaccines have proven to be an effective tool in limiting or eradicating communicable childhood diseases worldwide. The landscape of diarrheal vaccine candidates indicates that there now several in active development that offer options for potential testing of combinations to combat those bacterial and viral pathogens responsible for the heaviest disease burden—rotavirus, ETEC, Shigella, Campylobacter, V. cholera and Salmonella. PMID:25891647

Selective removal of arsenic and monovalent ions from brackish water reverse osmosis concentrate.

PubMed

Xu, Pei; Capito, Marissa; Cath, Tzahi Y

2013-09-15

Concentrate disposal and management is a considerable challenge for the implementation of desalination technologies, especially for inland applications where concentrate disposal options are limited. This study has focused on selective removal of arsenic and monovalent ions from brackish groundwater reverse osmosis (RO) concentrate for beneficial use and safe environmental disposal using in situ and pre-formed hydrous ferric oxides/hydroxides adsorption, and electrodialysis (ED) with monovalent permselective membranes. Coagulation with ferric salts is highly efficient at removing arsenic from RO concentrate to meet a drinking water standard of 10 μg/L. The chemical demand for ferric chloride however is much lower than ferric sulfate as coagulant. An alternative method using ferric sludge from surface water treatment plant is demonstrated as an efficient adsorbent to remove arsenic from RO concentrate, providing a promising low cost, "waste treat waste" approach. The monovalent permselective anion exchange membranes exhibit high selectivity in removing monovalent anions over di- and multi-valent anions. The transport of sulfate and phosphate through the anion exchange membranes was negligible over a broad range of electrical current density. However, the transport of divalent cations such as calcium and magnesium increases through monovalent permselective cation exchange membranes with increasing current density. Higher overall salt concentration reduction is achieved around limiting current density while higher normalized salt removal rate in terms of mass of salt per membrane area and applied energy is attained at lower current density because the energy unitization efficiency decreases at higher current density. Copyright © 2013 Elsevier B.V. All rights reserved.

Safety and immunogenicity of one dose of MenACWY-CRM, an investigational quadrivalent meningococcal glycoconjugate vaccine, when administered to adolescents concomitantly or sequentially with Tdap and HPV vaccines.

PubMed

Arguedas, A; Soley, C; Loaiza, C; Rincon, G; Guevara, S; Perez, A; Porras, W; Alvarado, O; Aguilar, L; Abdelnour, A; Grunwald, U; Bedell, L; Anemona, A; Dull, P M

2010-04-19

This Phase III study evaluates an investigational quadrivalent meningococcal CRM(197) conjugate vaccine, MenACWY-CRM (Novartis Vaccines), when administered concomitantly or sequentially with two other recommended adolescent vaccines; combined tetanus, reduced diphtheria and acellular pertussis (Tdap), and human papillomavirus (HPV) vaccine. In this single-centre study, 1620 subjects 11-18 years of age, were randomized to three groups (1:1:1) to receive MenACWY-CRM concomitantly or sequentially with Tdap and HPV. Meningococcal serogroup-specific serum bactericidal assay using human complement (hSBA), and antibodies to Tdap antigens and HPV virus-like particles were determined before and 1 month after study vaccinations. Proportions of subjects with hSBA titres > or =1:8 for all four meningococcal serogroups (A, C, W-135, Y) were non-inferior for both concomitant and sequential administration. Immune responses to Tdap and HPV antigens were comparable when these vaccines were given alone or concomitantly with MenACWY-CRM. All vaccines were well tolerated; concomitant or sequential administration did not increase reactogenicity. MenACWY-CRM was well tolerated and immunogenic in subjects 11-18 years of age, with comparable immune responses to the four serogroups when given alone or concomitantly with Tdap or HPV antigens. This is the first demonstration that these currently recommended adolescent vaccines could be administered concomitantly without causing increased reactogenicity. Copyright 2010 Elsevier Ltd. All rights reserved.

Serologic responses after vaccination of fennec foxes (Vulpes zerda) and meerkats (Suricata suricatta) with a live, canarypox-vectored canine distemper virus vaccine.

PubMed

Coke, Rob L; Backues, Kay A; Hoover, John P; Saliki, Jeremiah T; Ritchey, Jerry W; West, Gary D

2005-06-01

Fennec foxes (Vulpes zerda) and meerkats (Suricata suricatta) are considered to be susceptible to canine distemper virus (CDV) infection. Although no definitive clinical cases of natural CDV infections have been reported, mortalities due to CDV have been suspected and are reported in other closely related species. A commercially available monovalent, live, canarypox-vectored CDV vaccine induced neutralizing antibody titers that were maintained for at least a year in both fennec foxes and meerkats.

Predicting stability of DNA duplexes in solutions containing magnesium and monovalent cations.

PubMed

Owczarzy, Richard; Moreira, Bernardo G; You, Yong; Behlke, Mark A; Walder, Joseph A

2008-05-13

Accurate predictions of DNA stability in physiological and enzyme buffers are important for the design of many biological and biochemical assays. We therefore investigated the effects of magnesium, potassium, sodium, Tris ions, and deoxynucleoside triphosphates on melting profiles of duplex DNA oligomers and collected large melting data sets. An empirical correction function was developed that predicts melting temperatures, transition enthalpies, entropies, and free energies in buffers containing magnesium and monovalent cations. The new correction function significantly improves the accuracy of predictions and accounts for ion concentration, G-C base pair content, and length of the oligonucleotides. The competitive effects of potassium and magnesium ions were characterized. If the concentration ratio of [Mg (2+)] (0.5)/[Mon (+)] is less than 0.22 M (-1/2), monovalent ions (K (+), Na (+)) are dominant. Effects of magnesium ions dominate and determine duplex stability at higher ratios. Typical reaction conditions for PCR and DNA sequencing (1.5-5 mM magnesium and 20-100 mM monovalent cations) fall within this range. Conditions were identified where monovalent and divalent cations compete and their stability effects are more complex. When duplexes denature, some of the Mg (2+) ions associated with the DNA are released. The number of released magnesium ions per phosphate charge is sequence dependent and decreases surprisingly with increasing oligonucleotide length.

Monovalent type-1 oral poliovirus vaccine given at short intervals in Pakistan: a randomised controlled, four-arm, open-label, non-inferiority trial.

PubMed

Mir, Fatima; Quadri, Farheen; Mach, Ondrej; Ahmed, Imran; Bhatti, Zaid; Khan, Asia; Rehman, Najeeb Ur; Durry, Elias; Salama, Maha; Oberste, Steven M; Weldon, William C; Sutter, Roland W; Zaidi, Anita K M

2015-08-01

Supplementary immunisation activities with oral poliovirus vaccines (OPVs) are usually separated by 4 week intervals; however, shorter intervals have been used in security-compromised areas and for rapid outbreak responses. We assessed the immunogenicity of monovalent type-1 oral poliovirus vaccine (mOPV1) given at shorter than usual intervals in Karachi, Pakistan. This was a multicentre, randomised, controlled, four-arm, open-label, non-inferiority trial done at five primary health-care centres in low-income communities in and around Karachi, Pakistan. Eligible participants were healthy newborn babies with a birthweight of at least 2·5 kg, for whom informed consent was provided by their parent or guardian, and lived less than 30 km from the study clinic. After receiving a birth dose of trivalent OPV, we enrolled and randomly assigned newborn babies (1:1:1:1) to receive two doses of mOPV1 with an interval of 1 week (mOPV1-1 week), 2 weeks (mOPV1-2 weeks), or 4 weeks (mOPV1-4 weeks) between doses, or two doses of bivalent OPV (bOPV) with an interval of 4 weeks between doses (bOPV-4 weeks). We gave the first study dose of OPV at age 6 weeks. We did the randomisation with a centrally generated, computerised allocation sequence with blocks of 16; participants' families and study physicians could not feasibly be masked to the allocations. Trial participants were excluded from local supplementary immunisation activities during the study period. The primary outcome was non-inferiority (within a 20% margin) between groups in seroconversion to type-1 poliovirus. The primary and safety analyses were done in the per-protocol population of infants who received all three doses of vaccine. This trial is registered with ClinicalTrials.gov, number NCT01586572, and is closed to new participants. Between March 1, 2012, and May 31, 2013, we enrolled 1009 newborn babies, and randomly assigned 829 (82%) to treatment. 554 (67%) of the 829 babies were included in the per

Comparative study and evaluation of further attenuated, live measles vaccines alone and in combination with mumps and rubella vaccines.

PubMed

Wegmann, A; Glück, R; Just, M; Mischler, R; Paroz, P; Germanier, R

1986-01-01

The further attenuated Enders (FAE) measles vaccine strain and the Edmonston B-Zagreb (EZ) measles vaccine strain were compared. In VERO-cells plaque sizes of FAE varied between 0.5 and 1 mm, those of EZ between 1 and 2 mm in diameter. The lots available in Switzerland during a 2 year period showed virus titers of 10(3.1) to 10(4.0) TCID50 per dose in the one vaccine (FAE) and of 10(3.1) to 10(4.5) TCID50 per dose in the other (EZ). Clinical investigations were performed with FAE and EZ monovalent and trivalent (measles + mumps + rubella) vaccine preparations. The virus titers of the vaccine lots used were 10(3.1) to 10(4.0) TCID50 per dose. The overall seroconversion rates of 96% to 100% indicate that both types of vaccine have comparable immunization properties. Stability tests demonstrated good stability of both the FAE and the EZ vaccines. Thus conservation at 37 degrees C was possible for 2 and 4 weeks, respectively, and at 41 degrees C for 6 and 6 days, respectively, without undue loss of live virus content (less than 1 log 10). Since the EZ vaccine is derived from human diploid cells, it is particularly suitable for the vaccination of persons with a history of allergy to avian proteins.

Condensation of monovalent and divalent metal ions on a Langmuir monolayer

NASA Astrophysics Data System (ADS)

Bloch, J. Mati; Yun, Wenbing

1990-01-01

A system that consists of a monolayer spread on a solution containing a monovalent and a divalent ion is investigated. The solution of the Poisson-Boltzmann-Stern equation for this system indicates that the metal ions segregating to the surface can be found in two distinct states. Divalent ions are chemically condensed on the monolayer, while monovalent ions are electrically attracted to it. We derive simple expressions for the charge left on the surfactant monolayer and the amount of metal ions condensed on the monolayer. These formulas reproduce very accurately (to within pro milles) the values obtained using the nonlinear Grahame equation and eliminate the need to solve that equation. That permits a simple identification of the state of the surfactant monolayer and we propose a universal condensation chart that characterizes the state of the surfactant. We further derive a chemical equilibrium equation for the surface components that has considerable range of validity. This equation requires a knowledge of the bulk concentrations only, and thus allows in many cases the identification of the state of the monolayer, avoiding the need to solve the full nonlinear Poisson-Boltzmann equation. All existing experimental results on Langmuir systems are in good agreement with the one-dimensional Poisson-Boltzmann-Stern model with no adjustable parameters. Several of these fits are presented in this work and are also mapped on the condensation chart. Our calculations point to some characteristic differences between the monovalent and the divalent ions that explain why it is possible to build Langmuir-Blodgett multilayers from divalent compensated surfactants but not from monovalent ones.

Chaotropic Monovalent Anion-Induced Rectification Inversion at Nanopipettes Modified by Polyimidazolium Brushes.

PubMed

He, Xiulan; Zhang, Kailin; Liu, Yang; Wu, Fei; Yu, Ping; Mao, Lanqun

2018-04-16

A nonintuitive observation of monovalent anion-induced ion current rectification inversion at polyimidazolium brush (PimB)-modified nanopipettes is presented. The rectification inversion degree is strongly dependent on the concentration and species of monovalent anions. For chaotropic anions (for example, ClO 4 - ), the rectification inversion is easily observed at a low concentration (5 mm), while there is no rectification inversion observed for kosmotropic anions (Cl - ) even at a high concentration (1 m). Moreover, at the specific concentration (for example, 10 mm), the variation of rectification ratio on the type of anions is ranged by Hofmeister series (Cl - ≥NO 3 - >BF 4 - >ClO 4 - >PF 6 - >Tf 2 N - ). Estimation of the electrokinetic charge density (σ ek ) demonstrates that rectification inversion originates from the charge inversion owing to the over-adsorption of chaotropic monovalent anion. To qualitatively understand this phenomenon, a concentration-dependent adsorption mechanism is proposed. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

A cohort study to evaluate persistence of hepatitis B immunogenicity after administration of hexavalent vaccines

PubMed Central

Giambi, Cristina; Bella, Antonino; Barale, Antonella; Montù, Domenico; Marchisio, Maria; Oddone, Maurizio; Zito, Salvatore; Rapicetta, Maria; Chionne, Paola; Madonna, Elisabetta; Atti, Marta L Ciofi degli

2008-01-01

Background In 2001, two hexavalent vaccines were licensed in Italy (Hexavac®, Infanrix Hexa®), and since 2002 were extensively used for primary immunization in the first year of life (at 3, 5, 11/12 months of age). In 2005, the market authorization of Hexavac® was precautionary suspended by EMEA, because of doubts on long-term protection against hepatitis B virus. The objectives of this study were to evaluate the persistence of antibodies to anti-HBs, in children in the third year of life, and to investigate the response to a booster dose of hepatitis B vaccine. Methods Participant children were enrolled concomitantly with the offering of anti-polio booster dose, in the third year of life. Anti-HBs titers were determined on capillary blood samples. A booster dose of hepatitis B vaccine was administered to children with anti-HBs titers < 10 mIU/ml, with the monovalent precursor product of the previously received hexavalent vaccine. HBsAb titers were tested again one month after the booster. Results Sera from 113 children previously vaccinated with Hexavac®, and from 124 vaccinated with Infanrix Hexa® were tested for anti-HBs. Titers were ≥ 10 mIU/ml in 69% and 96% (p < 0,0001) respectively. The proportion of children with titers ≥ 100 mIU/ml did also significantly differ among groups (27% and 78%; p < 0,0001). Post-booster, 93% of children achieved titers ≥ 10 mIU/ml, with no significant difference by vaccine group. Discussion Fifteen months after third dose administration, a significant difference in anti-HBs titers was noted in the two vaccine groups considered. Monovalent hepatitis B vaccine administration in 3-year old children induced a proper booster response, confirming that immunologic memory persists in children with anti-HBs titers < 10 mIU/ml. However, long-term persistence of HBV protection after hexavalent vaccines administration should be further evaluated over time. PMID:18662386

Population Impact and Effectiveness of Monovalent Rotavirus Vaccination in Urban Malawian Children 3 Years After Vaccine Introduction: Ecological and Case-Control Analyses

PubMed Central

Bar-Zeev, Naor; Jere, Khuzwayo C.; Bennett, Aisleen; Pollock, Louisa; Tate, Jacqueline E.; Nakagomi, Osamu; Iturriza-Gomara, Miren; Costello, Anthony; Mwansambo, Charles; Parashar, Umesh D.; Heyderman, Robert S.; French, Neil; Cunliffe, Nigel A.

2016-01-01

Background. Rotavirus vaccines have been introduced in many low-income African countries including Malawi in 2012. Despite early evidence of vaccine impact, determining persistence of protection beyond infancy, the utility of the vaccine against specific rotavirus genotypes, and effectiveness in vulnerable subgroups is important. Methods. We compared rotavirus prevalence in diarrheal stool and hospitalization incidence before and following rotavirus vaccine introduction in Malawi. Using case-control analysis, we derived vaccine effectiveness (VE) in the second year of life and for human immunodeficiency virus (HIV)–exposed and stunted children. Results. Rotavirus prevalence declined concurrent with increasing vaccine coverage, and in 2015 was 24% compared with prevaccine mean baseline in 1997–2011 of 32%. Since vaccine introduction, population rotavirus hospitalization incidence declined in infants by 54.2% (95% confidence interval [CI], 32.8–68.8), but did not fall in older children. Comparing 241 rotavirus cases with 692 test-negative controls, VE was 70.6% (95% CI, 33.6%–87.0%) and 31.7% (95% CI, −140.6% to 80.6%) in the first and second year of life, respectively, whereas mean age of rotavirus cases increased from 9.3 to 11.8 months. Despite higher VE against G1P[8] than against other genotypes, no resurgence of nonvaccine genotypes has occurred. VE did not differ significantly by nutritional status (78.1% [95% CI, 5.6%–94.9%] in 257 well-nourished and 27.8% [95% CI, −99.5% to 73.9%] in 205 stunted children; P = .12), or by HIV exposure (60.5% [95% CI, 13.3%–82.0%] in 745 HIV-unexposed and 42.2% [95% CI, −106.9% to 83.8%] in 174 exposed children; P = .91). Conclusions. Rotavirus vaccination in Malawi has resulted in reductions in disease burden in infants <12 months, but not in older children. Despite differences in genotype-specific VE, no genotype has emerged to suggest vaccine escape. VE was not demonstrably affected by HIV exposure

Population Impact and Effectiveness of Monovalent Rotavirus Vaccination in Urban Malawian Children 3 Years After Vaccine Introduction: Ecological and Case-Control Analyses.

PubMed

Bar-Zeev, Naor; Jere, Khuzwayo C; Bennett, Aisleen; Pollock, Louisa; Tate, Jacqueline E; Nakagomi, Osamu; Iturriza-Gomara, Miren; Costello, Anthony; Mwansambo, Charles; Parashar, Umesh D; Heyderman, Robert S; French, Neil; Cunliffe, Nigel A

2016-05-01

Rotavirus vaccines have been introduced in many low-income African countries including Malawi in 2012. Despite early evidence of vaccine impact, determining persistence of protection beyond infancy, the utility of the vaccine against specific rotavirus genotypes, and effectiveness in vulnerable subgroups is important. We compared rotavirus prevalence in diarrheal stool and hospitalization incidence before and following rotavirus vaccine introduction in Malawi. Using case-control analysis, we derived vaccine effectiveness (VE) in the second year of life and for human immunodeficiency virus (HIV)-exposed and stunted children. Rotavirus prevalence declined concurrent with increasing vaccine coverage, and in 2015 was 24% compared with prevaccine mean baseline in 1997-2011 of 32%. Since vaccine introduction, population rotavirus hospitalization incidence declined in infants by 54.2% (95% confidence interval [CI], 32.8-68.8), but did not fall in older children. Comparing 241 rotavirus cases with 692 test-negative controls, VE was 70.6% (95% CI, 33.6%-87.0%) and 31.7% (95% CI, -140.6% to 80.6%) in the first and second year of life, respectively, whereas mean age of rotavirus cases increased from 9.3 to 11.8 months. Despite higher VE against G1P[8] than against other genotypes, no resurgence of nonvaccine genotypes has occurred. VE did not differ significantly by nutritional status (78.1% [95% CI, 5.6%-94.9%] in 257 well-nourished and 27.8% [95% CI, -99.5% to 73.9%] in 205 stunted children;P= .12), or by HIV exposure (60.5% [95% CI, 13.3%-82.0%] in 745 HIV-unexposed and 42.2% [95% CI, -106.9% to 83.8%] in 174 exposed children;P= .91). Rotavirus vaccination in Malawi has resulted in reductions in disease burden in infants <12 months, but not in older children. Despite differences in genotype-specific VE, no genotype has emerged to suggest vaccine escape. VE was not demonstrably affected by HIV exposure or stunting. © The Author 2016. Published by Oxford University Press

A polyvalent inactivated rhinovirus vaccine is broadly immunogenic in rhesus macaques

PubMed Central

Lee, Sujin; Nguyen, Minh Trang; Currier, Michael G.; Jenkins, Joe B.; Strobert, Elizabeth A.; Kajon, Adriana E.; Madan-Lala, Ranjna; Bochkov, Yury A.; Gern, James E.; Roy, Krishnendu; Lu, Xiaoyan; Erdman, Dean D.; Spearman, Paul; Moore, Martin L.

2016-01-01

As the predominant aetiological agent of the common cold, human rhinovirus (HRV) is the leading cause of human infectious disease. Early studies showed that a monovalent formalin-inactivated HRV vaccine can be protective, and virus-neutralizing antibodies (nAb) correlated with protection. However, co-circulation of many HRV types discouraged further vaccine efforts. Here, we test the hypothesis that increasing virus input titres in polyvalent inactivated HRV vaccine may result in broad nAb responses. We show that serum nAb against many rhinovirus types can be induced by polyvalent, inactivated HRVs plus alhydrogel (alum) adjuvant. Using formulations up to 25-valent in mice and 50-valent in rhesus macaques, HRV vaccine immunogenicity was related to sufficient quantity of input antigens, and valency was not a major factor for potency or breadth of the response. Thus, we have generated a vaccine capable of inducing nAb responses to numerous and diverse HRV types. PMID:27653379

Quadrivalent meningococcal vaccination of adults: phase III comparison of an investigational conjugate vaccine, MenACWY-CRM, with the licensed vaccine, Menactra.

PubMed

Reisinger, Keith S; Baxter, Roger; Block, Stanley L; Shah, Jina; Bedell, Lisa; Dull, Peter M

2009-12-01

Neisseria meningitidis is a leading cause of bacterial meningitis in the United States, with the highest case fatality rates reported for individuals > or = 15 years of age. This study compares the safety and immunogenicity of the Novartis Vaccines investigational quadrivalent meningococcal CRM(197) conjugate vaccine, MenACWY-CRM, to those of the licensed meningococcal conjugate vaccine, Menactra, when administered to healthy adults. In this phase III multicenter study, 1,359 adults 19 to 55 years of age were randomly assigned to one of four groups (1:1:1:1 ratio) to receive a single dose of one of three lots of MenACWY-CRM or a single dose of Menactra. Serum samples obtained at baseline and 1 month postvaccination were tested for serogroup-specific serum bactericidal activity using human complement (hSBA). The hSBA titers following vaccination with MenACWY-CRM and Menactra were compared in noninferiority and prespecified superiority analyses. Reactogenicity was similar in the MenACWY-CRM and Menactra groups, and neither vaccine was associated with a serious adverse event. When compared with Menactra, MenACWY-CRM met the superiority criteria for the proportions of recipients achieving a seroresponse against serogroups C, W-135, and Y and the proportion of subjects achieving postvaccination titers of > or = 1:8 for serogroups C and Y. MenACWY-CRM's immunogenicity was statistically noninferior (the lower limit of the two-sided 95% confidence interval was more than -10%) to that of Menactra for all four serogroups, with the postvaccination hSBA geometric mean titers being consistently higher for MenACWY-CRM than for Menactra. MenACWY-CRM is well tolerated in adults 19 to 55 years of age, with immune responses to each of the serogroups noninferior and, in some cases, statistically superior to those to Menactra.

Intestinal Immune Responses to Type 2 Oral Polio Vaccine (OPV) Challenge in Infants Previously Immunized With Bivalent OPV and Either High-Dose or Standard Inactivated Polio Vaccine.

PubMed

Brickley, Elizabeth B; Strauch, Carolyn B; Wieland-Alter, Wendy F; Connor, Ruth I; Lin, Shu; Weiner, Joshua A; Ackerman, Margaret E; Arita, Minetaro; Oberste, M Steven; Weldon, William C; Sáez-Llorens, Xavier; Bandyopadhyay, Ananda S; Wright, Peter F

2018-01-17

The impact of inactivated polio vaccines (IPVs) on intestinal mucosal immune responses to live poliovirus is poorly understood. In a 2014 phase 2 clinical trial, Panamanian infants were immunized at 6, 10, and 14 weeks of age with bivalent oral polio vaccine (bOPV) and randomized to receive either a novel monovalent high-dose type 2-specific IPV (mIPV2HD) or a standard trivalent IPV at 14 weeks. Infants were challenged at 18 weeks with a monovalent type 2 oral polio vaccine (mOPV2). Infants' intestinal immune responses during the 3 weeks following challenge were investigated by measuring poliovirus type-specific neutralization and immunoglobulin (Ig) A, IgA1, IgA2, IgD, IgG, and IgM antibodies in stool samples. Despite mIPV2HD's 4-fold higher type 2 polio D-antigen content and heightened serum neutralization profile, mIPV2HD-immunized infants' intestinal immune responses to mOPV2 challenge were largely indistinguishable from those receiving standard IPV. Mucosal responses were tightly linked to evidence of active infection and, in the 79% of participants who shed virus, robust type 2-specific IgA responses and stool neutralization were observed by 2 weeks after challenge. Enhancing IPV-induced serum neutralization does not substantively improve intestinal mucosal immune responses or limit viral shedding on mOPV2 challenge. NCT02111135. © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.

Intestinal Immune Responses to Type 2 Oral Polio Vaccine (OPV) Challenge in Infants Previously Immunized With Bivalent OPV and Either High-Dose or Standard Inactivated Polio Vaccine

PubMed Central

Brickley, Elizabeth B; Strauch, Carolyn B; Wieland-Alter, Wendy F; Connor, Ruth I; Lin, Shu; Weiner, Joshua A; Ackerman, Margaret E; Arita, Minetaro; Oberste, M Steven; Weldon, William C; Sáez-Llorens, Xavier; Bandyopadhyay, Ananda S; Wright, Peter F

2018-01-01

Abstract Background The impact of inactivated polio vaccines (IPVs) on intestinal mucosal immune responses to live poliovirus is poorly understood. Methods In a 2014 phase 2 clinical trial, Panamanian infants were immunized at 6, 10, and 14 weeks of age with bivalent oral polio vaccine (bOPV) and randomized to receive either a novel monovalent high-dose type 2–specific IPV (mIPV2HD) or a standard trivalent IPV at 14 weeks. Infants were challenged at 18 weeks with a monovalent type 2 oral polio vaccine (mOPV2). Infants’ intestinal immune responses during the 3 weeks following challenge were investigated by measuring poliovirus type-specific neutralization and immunoglobulin (Ig) A, IgA1, IgA2, IgD, IgG, and IgM antibodies in stool samples. Results Despite mIPV2HD’s 4-fold higher type 2 polio D–antigen content and heightened serum neutralization profile, mIPV2HD-immunized infants’ intestinal immune responses to mOPV2 challenge were largely indistinguishable from those receiving standard IPV. Mucosal responses were tightly linked to evidence of active infection and, in the 79% of participants who shed virus, robust type 2–specific IgA responses and stool neutralization were observed by 2 weeks after challenge. Conclusions Enhancing IPV-induced serum neutralization does not substantively improve intestinal mucosal immune responses or limit viral shedding on mOPV2 challenge. Clinical Trials Registration NCT02111135. PMID:29304199

Safety and Immunogenicity of Sequential Rotavirus Vaccine Schedules

PubMed Central

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

2016-01-01

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

Epidemiology of hand, foot and mouth disease in China, 2008 to 2015 prior to the introduction of EV-A71 vaccine.

PubMed

Yang, Bingyi; Liu, Fengfeng; Liao, Qiaohong; Wu, Peng; Chang, Zhaorui; Huang, Jiao; Long, Lu; Luo, Li; Li, Yu; Leung, Gabriel M; Cowling, Benjamin J; Yu, Hongjie

2017-12-01

Hand, foot and mouth disease (HFMD) is usually caused by several serotypes from human enterovirus A species, including enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16). Two inactivated monovalent EV-A71 vaccines have been recently licensed in China and monovalent CV-A16 vaccine and bivalent EV-A71 and CV-A16 vaccine are under development. Using notifications from the national surveillance system, we describe the epidemiology and dynamics of HFMD in the country, before the introduction of EV-A71 vaccination, from 2008 through 2015. Laboratory-identified serotype categories, i.e. CV-A16, EV-A71 and other enteroviruses, circulated annually. EV-A71 remained the most virulent serotype and was the major serotype for fatal cases (range: 88.5-95.4%) and severe cases (range: 50.7-82.3%) across years. Except for 2013 and 2015, when other enteroviruses were more frequently found in mild HFMD (48.8% and 52.5%), EV-A71 was more frequently detected from mild cases in the rest of the years covered by the study (range: 39.4-52.6%). The incidence rates and severity risks of HFMD associated with all serotype categories were the highest for children aged 1 year and younger, and decreased with increasing age. This study provides baseline epidemiology for evaluation of vaccine impact and potential serotype replacement.

Cost-utility of universal hepatitis A vaccination in Canada.

PubMed

Bauch, C T; Anonychuk, A M; Pham, B Z; Gilca, V; Duval, B; Krahn, M D

2007-12-12

Hepatitis A (HA) vaccination in Canada is currently targeted toward high-risk groups. The cost-effectiveness and expected health outcomes of universal vaccination relative to targeted vaccination in low-incidence countries such as Canada are currently unknown. Here, we conducted a cost-utility analysis for this situation, with Canada as the study population. We included vaccine costs, time costs, infection costs, and public health costs. We assessed a range of possible universal vaccination strategies over an 80-year time horizon using multiple cost perspectives. A dynamic model was used to account for herd immunity. Aggregate health gains from switching to universal vaccination are modest (10-30 QALYs per year). However, a "9+9" strategy that replaces two doses of monovalent hepatitis B (HB) vaccine at 9/10 years (universally administered in most provinces) with two doses of bivalent HA/HB vaccine is cost-saving from the societal perspective. At a willingness to pay threshold of $50,000/QALY, mean net benefit is +49.4 QALYs (S.D. 12.6) from the societal perspective and +3.8 QALYS (S.D. 3.0) from the payer perspective for the "9+9" strategy. Net benefit from the payer perspective is sensitive to the marginal cost of HA/HB vaccine relative to HB vaccine. Similar conclusions may apply in other countries with low incidence and a targeted vaccination policy.

Near Real-Time Surveillance for Influenza Vaccine Safety: Proof-of-Concept in the Vaccine Safety Datalink Project

PubMed Central

Greene, Sharon K.; Kulldorff, Martin; Lewis, Edwin M.; Li, Rong; Yin, Ruihua; Weintraub, Eric S.; Fireman, Bruce H.; Lieu, Tracy A.; Nordin, James D.; Glanz, Jason M.; Baxter, Roger; Jacobsen, Steven J.; Broder, Karen R.; Lee, Grace M.

2010-01-01

The emergence of pandemic H1N1 influenza in 2009 has prompted public health responses, including production and licensure of new influenza A (H1N1) 2009 monovalent vaccines. Safety monitoring is a critical component of vaccination programs. As proof-of-concept, the authors mimicked near real-time prospective surveillance for prespecified neurologic and allergic adverse events among enrollees in 8 medical care organizations (the Vaccine Safety Datalink Project) who received seasonal trivalent inactivated influenza vaccine during the 2005/06–2007/08 influenza seasons. In self-controlled case series analysis, the risk of adverse events in a prespecified exposure period following vaccination was compared with the risk in 1 control period for the same individual either before or after vaccination. In difference-in-difference analysis, the relative risk in exposed versus control periods each season was compared with the relative risk in previous seasons since 2000/01. The authors used Poisson-based analysis to compare the risk of Guillian-Barré syndrome following vaccination in each season with that in previous seasons. Maximized sequential probability ratio tests were used to adjust for repeated analyses on weekly data. With administration of 1,195,552 doses to children under age 18 years and 4,773,956 doses to adults, no elevated risk of adverse events was identified. Near real-time surveillance for selected adverse events can be implemented prospectively to rapidly assess seasonal and pandemic influenza vaccine safety. PMID:19965887

School-Based Influenza Vaccination: Health and Economic Impact of Maine's 2009 Influenza Vaccination Program.

PubMed

Basurto-Dávila, Ricardo; Meltzer, Martin I; Mills, Dora A; Beeler Asay, Garrett R; Cho, Bo-Hyun; Graitcer, Samuel B; Dube, Nancy L; Thompson, Mark G; Patel, Suchita A; Peasah, Samuel K; Ferdinands, Jill M; Gargiullo, Paul; Messonnier, Mark; Shay, David K

2017-12-01

To estimate the societal economic and health impacts of Maine's school-based influenza vaccination (SIV) program during the 2009 A(H1N1) influenza pandemic. Primary and secondary data covering the 2008-09 and 2009-10 influenza seasons. We estimated weekly monovalent influenza vaccine uptake in Maine and 15 other states, using difference-in-difference-in-differences analysis to assess the program's impact on immunization among six age groups. We also developed a health and economic Markov microsimulation model and conducted Monte Carlo sensitivity analysis. We used national survey data to estimate the impact of the SIV program on vaccine coverage. We used primary data and published studies to develop the microsimulation model. The program was associated with higher immunization among children and lower immunization among adults aged 18-49 years and 65 and older. The program prevented 4,600 influenza infections and generated $4.9 million in net economic benefits. Cost savings from lower adult vaccination accounted for 54 percent of the economic gain. Economic benefits were positive in 98 percent of Monte Carlo simulations. SIV may be a cost-beneficial approach to increase immunization during pandemics, but programs should be designed to prevent lower immunization among nontargeted groups. © Health Research and Educational Trust.

Clinical Severity and Rotavirus Vaccination among Children Hospitalized for Acute Gastroenteritis in Belém, Northern Brazil.

PubMed

Justino, Maria Cleonice A; Brasil, Patrícia; Abreu, Erika; Miranda, Yllen; Mascarenhas, Joana D'Arc P; Guerra, Sylvia F S; Linhares, Alexandre C

2016-08-01

In March 2006, Brazil introduced the monovalent rotavirus (RV) vaccine (Rotarix™) into the public sector. This study assessed the severity of rotavirus gastroenteritis (RVGE) according to the vaccination status among hospitalized children. We identified 1023 RVGE episodes among not vaccinated (n = 252), partially vaccinated (n = 156) and fully vaccinated (n = 615) children. Very severe gastroenteritis (scored ≥ 15) was reported in 16.7, 17.9 and 13.5% of not vaccinated, partially vaccinated and fully vaccinated children, respectively. There was a trend for a shorter duration of RV diarrhoea among vaccinated children than in not vaccinated children (p = 0.07). A protective effect of vaccination was noted when mean duration of symptoms and hospital stay are analysed, comparing unvaccinated, partially vaccinated and fully vaccinated children (p < 0.05). We showed a vaccination dose effect trend, with fully vaccinated children having less-severe RVGE than not vaccinated and partially vaccinated children. © The Author [2016]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

[Current events in vaccination].

PubMed

Aubert, M; Aumaître, H; Beytout, J; Bloch, K; Bouhour, D; Callamand, P; Chave, C; Cheymol, J; Combadière, B; Dahlab, A; Denis, F; De Pontual, L; Dodet, B; Dommergues, M-A; Dufour, V; Gagneur, A; Gaillat, J; Gaudelus, J; Gavazzi, G; Gillet, Y; Gras-le-Guen, C; Haas, H; Hanslik, T; Hau-Rainsard, I; Larnaudie, S; Launay, O; Lorrot, M; Loulergue, P; Malvy, D; Marchand, S; Picherot, G; Pinquier, D; Pulcini, C; Rabaud, C; Regnier, F; Reinert, P; Sana, C; Savagner, C; Soubeyrand, B; Stephan, J-L; Strady, C

2011-11-01

The annual meeting of the Infectious Disease Society of America (IDSA) ; which brought together nearly 5000 participants from over 80 countries in Vancouver, Canada, October 21 to 24, 2010 ; provided a review of the influenza (H1N1) 2009 pandemic, evaluated vaccination programmes and presented new vaccines under development. With 12,500 deaths in the United States in 2009-2010, the influenza (H1N1) 2009 pandemic was actually less deadly than the seasonal flu. But it essentially hit the young, and the toll calculated in years of life lost is high. The monovalent vaccines, whether live attenuated or inactivated with or without adjuvants, were well tolerated in toddlers, children, adults and pregnant women. In order to protect infants against pertussis, family members are urged to get their booster shots. The introduction of the 13-valent Pneumococcal conjugated vaccine in the beginning of 2010 may solve - but for how long ? - the problem of serotype replacement, responsible for the re-increasing incidence of invasive Pneumococcal infections observed in countries that had introduced the 7-valent vaccine. The efficacy of a rotavirus vaccine has been confirmed, with a reduction in hospitalization in the United States and a reduction in gastroenteritis-related deaths in Mexico. In the United States, vaccination of pre-adolescents against human papillomavirus (HPV) has not resulted in any specific undesirable effects. Routine vaccination against chicken pox, recommended since 1995, has not had an impact on the evolution of the incidence of shingles. Vaccination against shingles, recommended in the United States for subjects 60 years and over, shows an effectiveness of 55 %, according to a cohort study (Kaiser Permanente, Southern California). Although some propose the development of personalized vaccines according to individual genetic characteristics, the priority remains with increasing vaccine coverage, not only in infants but also in adults and the elderly. Vaccine

[Current events in vaccination].

PubMed

Aubert, M; Aumaître, H; Beytout, J; Bloch, K; Bouhour, D; Callamand, P; Chave, C; Cheymol, J; Combadière, B; Dahlab, A; Denis, F; De Pontual, L; Dodet, B; Dommergues, M A; Dufour, V; Gagneur, A; Gaillat, J; Gaudelus, J; Gavazzi, G; Gillet, Y; Gras-le-Guen, C; Haas, H; Hanslik, T; Hau-Rainsard, I; Larnaudie, S; Launay, O; Lorrot, M; Loulergue, P; Malvy, D; Marchand, S; Picherot, G; Pinquier, D; Pulcini, C; Rabaud, C; Regnier, F; Reinert, P; Sana, C; Savagner, C; Soubeyrand, B; Stephan, J L; Strady, C

2011-05-01

The annual meeting of the Infectious Disease Society of America (IDSA); which brought together nearly 5000 participants from over 80 countries in Vancouver, Canada, October 21 to 24, 2010; provided a review of the influenza (H1N1) 2009 pandemic, evaluated vaccination programmes and presented new vaccines under development. With 12,500 deaths in the United States in 2009-2010, the influenza (H1N1) 2009 pandemic was actually less deadly than the seasonal flu. But it essentially hit the young, and the toll calculated in years of life lost is high. The monovalent vaccines, whether live attenuated or inactivated with or without adjuvants, were well tolerated in toddlers, children, adults and pregnant women. In order to protect infants against pertussis, family members are urged to get their booster shots. The introduction of the 13-valent Pneumococcal conjugated vaccine in the beginning of 2010 may solve--but for how long?--the problem of serotype replacement, responsible for the re-increasing incidence of invasive Pneumococcal infections observed in countries that had introduced the 7-valent vaccine. The efficacy of a rotavirus vaccine has been confirmed, with a reduction in hospitalization in the United States and a reduction in gastroenteritis-related deaths in Mexico. In the United States, vaccination of pre-adolescents against human papillomavirus (HPV) has not resulted in any specific undesirable effects. Routine vaccination against chicken pox, recommended since 1995, has not had an impact on the evolution of the incidence of shingles. Vaccination against shingles, recommended in the United States for subjects 60 years and over, shows an effectiveness of 55%, according to a cohort study (Kaiser Permanente, Southern California). Although some propose the development of personalized vaccines according to individual genetic characteristics, the priority remains with increasing vaccine coverage, not only in infants but also in adults and the elderly. Vaccine

A Replication-Defective Human Type 5 Adenovirus-Based Trivalent Vaccine Confers Complete Protection against Plague in Mice and Nonhuman Primates

PubMed Central

Kirtley, Michelle L.; Klages, Curtis; Erova, Tatiana E.; Telepnev, Maxim; Ponnusamy, Duraisamy; Fitts, Eric C.; Baze, Wallace B.; Sivasubramani, Satheesh K.; Lawrence, William S.; Patrikeev, Igor; Peel, Jennifer E.; Andersson, Jourdan A.; Kozlova, Elena V.; Tiner, Bethany L.; Peterson, Johnny W.; McWilliams, David; Patel, Snehal; Rothe, Eric; Motin, Vladimir L.

2016-01-01

Currently, no plague vaccine exists in the United States for human use. The capsular antigen (Caf1 or F1) and two type 3 secretion system (T3SS) components, the low-calcium-response V antigen (LcrV) and the needle protein YscF, represent protective antigens of Yersinia pestis. We used a replication-defective human type 5 adenovirus (Ad5) vector and constructed recombinant monovalent and trivalent vaccines (rAd5-LcrV and rAd5-YFV) that expressed either the codon-optimized lcrV or the fusion gene designated YFV (consisting of ycsF, caf1, and lcrV). Immunization of mice with the trivalent rAd5-YFV vaccine by either the intramuscular (i.m.) or the intranasal (i.n.) route provided protection superior to that with the monovalent rAd5-LcrV vaccine against bubonic and pneumonic plague when animals were challenged with Y. pestis CO92. Preexisting adenoviral immunity did not diminish the protective response, and the protection was always higher when mice were administered one i.n. dose of the trivalent vaccine (priming) followed by a single i.m. booster dose of the purified YFV antigen. Immunization of cynomolgus macaques with the trivalent rAd5-YFV vaccine by the prime-boost strategy provided 100% protection against a stringent aerosol challenge dose of CO92 to animals that had preexisting adenoviral immunity. The vaccinated and challenged macaques had no signs of disease, and the invading pathogen rapidly cleared with no histopathological lesions. This is the first report showing the efficacy of an adenovirus-vectored trivalent vaccine against pneumonic plague in mouse and nonhuman primate (NHP) models. PMID:27170642

Induction of protective immunity against Eimeria tenella, Eimeria necatrix, Eimeria maxima and Eimeria acervulina infections using multivalent epitope DNA vaccines.

PubMed

Song, Xiaokai; Ren, Zhe; Yan, Ruofeng; Xu, Lixin; Li, Xiangrui

2015-06-04

Avian coccidiosis is mostly caused by mixed infection of several Eimeria species under natural conditions and immunity to avian coccidiosis is largely dependent on T-cell immune response. In this study, 14 T-cell epitope fragments from eight antigens of Eimeria tenella (E. tenella), Eimeria necatrix (E. necatrix), Eimeria maxima (E. maxima) and Eimeria acervulina (E. acervulina) were ligated with pVAX1 producing 14 monovalent DNA vaccines, respectively. Protective immunity of the monovalent DNA vaccines was assessed by in vivo challenge experiments and then four most protective fragments of each species were chosen to construct multivalent epitope DNA vaccines with or without chicken IL-2 as genetic adjuvant. Protective efficacies of the epitope DNA vaccines on chickens against E. tenella, E. necatrix, E. maxima and E. acervulina were evaluated. The results showed that the constructed multivalent epitope DNA vaccines significantly increased body weight gain, alleviated enteric lesions and reduced oocyst output of the infected birds. Especially, the multivalent epitope DNA vaccines of pVAX1-NA4-1-TA4-1-LDH-2-EMCDPK-1 and pVAX1-NA4-1-TA4-1-LDH-2-EMCDPK-1-IL-2 not only significantly increased body weight gain, alleviated enteric lesions and reduced oocyst output of the infected birds, but also resulted in anti-coccidial index (ACI) more than 170 against E. tenella, E. necatrix, E. maxima and E. acervulina, which indicated they could induce protective immunity against E. tenella, E. necatrix, E. maxima and E. acervulina. Our findings suggest the constructed multivalent epitope DNA vaccines are the potential candidate multivalent vaccines against mixed infection of Eimeria. Copyright © 2015 Elsevier Ltd. All rights reserved.

Rational design of HIV vaccines and microbicides: report of the EUROPRISE network annual conference 2010

PubMed Central

2011-01-01

Novel, exciting intervention strategies to prevent infection with HIV have been tested in the past year, and the field is rapidly evolving. EUROPRISE is a network of excellence sponsored by the European Commission and concerned with a wide range of activities including integrated developmental research on HIV vaccines and microbicides from discovery to early clinical trials. A central and timely theme of the network is the development of the unique concept of co-usage of vaccines and microbicides. This review, prepared by the PhD students of the network captures much of the research ongoing between the partners. The network is in its 5th year and involves over 50 institutions from 13 European countries together with 3 industrial partners; GSK, Novartis and Sanofi-Pasteur. EUROPRISE is involved in 31 separate world-wide trials of Vaccines and Microbicides including 6 in African countries (Tanzania, Mozambique, South Africa, Kenya, Malawi, Rwanda), and is directly supporting clinical trials including MABGEL, a gp140-hsp70 conjugate trial and HIVIS, vaccine trials in Europe and Africa. PMID:21486446

Rational design of HIV vaccines and microbicides: report of the EUROPRISE network annual conference 2010.

PubMed

Brinckmann, Sarah; da Costa, Kelly; van Gils, Marit J; Hallengärd, David; Klein, Katja; Madeira, Luisa; Mainetti, Lara; Palma, Paolo; Raue, Katharina; Reinhart, David; Reudelsterz, Marc; Ruffin, Nicolas; Seifried, Janna; Schäfer, Katrein; Sheik-Khalil, Enas; Sköld, Annette; Uchtenhagen, Hannes; Vabret, Nicolas; Ziglio, Serena; Scarlatti, Gabriella; Shattock, Robin; Wahren, Britta; Gotch, Frances

2011-04-12

Novel, exciting intervention strategies to prevent infection with HIV have been tested in the past year, and the field is rapidly evolving. EUROPRISE is a network of excellence sponsored by the European Commission and concerned with a wide range of activities including integrated developmental research on HIV vaccines and microbicides from discovery to early clinical trials. A central and timely theme of the network is the development of the unique concept of co-usage of vaccines and microbicides. This review, prepared by the PhD students of the network captures much of the research ongoing between the partners. The network is in its 5th year and involves over 50 institutions from 13 European countries together with 3 industrial partners; GSK, Novartis and Sanofi-Pasteur. EUROPRISE is involved in 31 separate world-wide trials of Vaccines and Microbicides including 6 in African countries (Tanzania, Mozambique, South Africa, Kenya, Malawi, Rwanda), and is directly supporting clinical trials including MABGEL, a gp140-hsp70 conjugate trial and HIVIS, vaccine trials in Europe and Africa.

Is hepatitis B birth dose vaccine needed in Africa?

PubMed

Tamandjou, Cynthia Raissa; Maponga, Tongai Gibson; Chotun, Nafiisah; Preiser, Wolfgang; Andersson, Monique Ingrid

2017-01-01

This commentary describes the need for a birth dose monovalent hepatitis B virus (HBV) vaccine and an effective programme for the prevention of mother-to-child-transmission (MTCT) of HBV in Africa. Current World Health Organization guidelines recommend routine maternal screening for HBV followed by treatment of highly infectious HBV-infected mothers, and HBV birth dose vaccination and the administration of hepatitis B immunoglobulin for HBV-exposed infants as an effective strategy for the prevention of HBV MTCT. None of these practices are currently in place in most parts of Africa. To date, fewer than 10 African countries vaccinate children at birth against HBV. Despite the hurdles associated with implementing this practice, its expansion to the rest of Africa is feasible and crucial to reducing the global number of new HBV infections by 90% by 2030, as targeted by the current Global Health Strategy for the elimination of viral hepatitis.

Preclinical immunogenicity and functional activity studies of an A+W meningococcal outer membrane vesicle (OMV) vaccine and comparisons with existing meningococcal conjugate- and polysaccharide vaccines.

PubMed

Tunheim, G; Arnemo, M; Næss, L M; Fjeldheim, Å K; Nome, L; Bolstad, K; Aase, A; Mandiarote, A; González, H; González, D; García, L; Cardoso, D; Norheim, G; Rosenqvist, E

2013-12-09

Meningococci of serogroups A and W (MenA and MenW) are the main causes of epidemic bacterial meningitis outbreaks in sub-Saharan Africa. In this study we prepared a detergent extracted outer membrane vesicle (dOMV) vaccine from representative African MenA and MenW strains, and compared the immunogenicity of this vaccine with existing meningococcal conjugate and polysaccharide (PS) vaccines in mice. NMRI mice were immunized with preclinical batches of the A+W dOMV vaccine, or with commercially available vaccines; a MenA conjugate vaccine (MenAfriVac(®), Serum Institute of India), ACYW conjugate vaccine (Menveo(®), Novartis) or ACYW PS vaccine (Mencevax(®), GlaxoSmithKline). The mice received 2 doses of 1/10 or 1/50 of a human dose with a three week interval. Immune responses were tested in ELISA, serum bactericidal activity (SBA) and opsonophagocytic activity (OPA) assays. High levels of IgG antibodies against both A and W dOMV were detected in mice receiving the A+W dOMV vaccine. High SBA titers against both MenA and MenW vaccine strains were detected after only one dose of the A+W dOMV vaccine, and the titers were further increased after the second dose. The SBA and OPA titers in mice immunized with dOMV vaccine were significantly higher than in mice immunized with the ACYW-conjugate vaccine or the PS vaccine. Furthermore, the A+W dOMV vaccine was shown to induce SBA and OPA titers against MenA of the same magnitude as the titers induced by the A-conjugate vaccine. In conclusion, the A+W dOMV vaccine induced high levels of functional antibodies to both MenA and MenW strains, levels that were shown to be higher or equal to the levels induced by licensed meningococcal vaccines. Thus, an A+W dOMV vaccine could potentially serve as an alternative or a supplement to existing conjugate and PS vaccines in the African meningitis belt. Copyright © 2013 Elsevier Ltd. All rights reserved.

Oral vaccination with a live Salmonella Enteritidis/Typhimurium bivalent vaccine in layers induces cross-protection against caecal and internal organ colonization by a Salmonella Infantis strain.

PubMed

Eeckhaut, Venessa; Haesebrouck, Freddy; Ducatelle, Richard; Van Immerseel, Filip

2018-05-01

Salmonella is an important zoonotic agent, and poultry products remain one of the main sources of infection for humans. Salmonella Infantis is an emerging serotype in poultry worldwide, reflected by an increased prevalence in poultry flocks, on broiler meat and in human foodborne illness cases. In the current study, the efficacy of oral administration of a live monovalent Salmonella Enteritidis and a live bivalent Salmonella Enteritidis/Typhimurium vaccine, against a Salmonella Enteritidis and Infantis infection, was determined. Oral administration of the live vaccines to day-old chickens caused a decrease in caecal colonization by Salmonella Enteritidis, but not Infantis, at day 7, when challenged at day 2. Vaccination with the bivalent vaccine at day 1 resulted in a decreased spleen colonization by both Salmonella Infantis and Enteritidis. Twice (at day 1 and week 6) and thrice vaccination (at day 1, week 6 and 16) of laying hens with the bivalent vaccine resulted in a decreased caecal colonization by Salmonella Enteritidis and Infantis, and significantly lower oviduct colonization levels by Salmonella Enteritidis. These data show cross-protection against Salmonella Infantis by oral administration of live vaccine strains belonging to other serogroups. Copyright © 2018 Elsevier B.V. All rights reserved.

Poliovirus vaccination during the endgame: insights from integrated modeling.

PubMed

Duintjer Tebbens, Radboud J; Thompson, Kimberly M

2017-06-01

Managing the polio endgame requires access to sufficient quantities of poliovirus vaccines. After oral poliovirus vaccine (OPV) cessation, outbreaks may occur that require outbreak response using monovalent OPV (mOPV) and/or inactivated poliovirus vaccine. Areas covered: We review the experience and challenges with managing vaccine supplies in the context of the polio endgame. Building on models that explored polio endgame risks and the potential mOPV needs to stop outbreaks from live poliovirus reintroductions, we conceptually explore the potential demands for finished and bulk mOPV doses from a stockpile in the context of limited shelf-life of finished vaccine and time delays to convert bulk to finished vaccine. Our analysis suggests that the required size of the mOPV stockpile varies by serotype, with the highest expected needs for serotype 1 mOPV. Based on realizations of poliovirus risks after OPV cessation, the stockpile required to eliminate the chance of a stock-out appears considerably larger than the currently planned mOPV stockpiles. Expert commentary: The total required stockpile size depends on the acceptable probability of a stock-out, and increases with longer times to finish bulk doses and shorter shelf-lives of finished doses. Successful polio endgame management will require careful attention to poliovirus vaccine supplies.

Immunogenicity and thermal stability of a combined vaccine against Haemophilus influenzae type b and Neisseria meningitidis serogroup C diseases.

PubMed

Saydam, Manolya; Burkin, Karena; Care, Rory; Rigsby, Peter; Bolgiano, Barbara; Mawas, Fatme

2010-08-31

The immunogenicity, structure and stability of a combined conjugate vaccine against Haemophilus influenzae type b and meningococcal serogroup C (Hib/MenC) were investigated. A rat model for immunogenicity showed that antibody responses to Hib and MenC in the combined vaccine were similar to or higher than those of individual conjugates given alone, or concomitantly at separate sites. At elevated temperatures, the combination vaccine was slightly more stable than a monovalent Hib-TT vaccine, with respect to molecular size, which could be attributed to differences in the formulations. Following 5 weeks incubation at 56 degrees C, there was some dissociation of high molecular weight conjugate without significant loss of saccharide integrity; however, this did not significantly affect the vaccine immunogenicity, demonstrating the stability of this lyophilized vaccine. (c) 2010 Elsevier Ltd. All rights reserved.

Monovalent virus-like particle vaccine protects guinea pigs and nonhuman primates against infection with multiple Marburg viruses.

PubMed

Swenson, Dana L; Warfield, Kelly L; Larsen, Tom; Alves, D Anthony; Coberley, Sadie S; Bavari, Sina

2008-05-01

Virus-like particle (VLP)-based vaccines have the advantage of being morphologically and antigenically similar to the live virus from which they are derived. Expression of the glycoprotein and VP40 matrix protein from Lake Victoria marburgvirus (MARV) results in spontaneous production of VLPs in mammalian cells. Guinea pigs vaccinated with Marburg virus VLPs (mVLPs) or inactivated MARV (iMARV) develop homologous humoral and T-cell responses and are completely protected from a lethal homologous MARV challenge. To determine whether mVLPs based on the Musoke (aka Lake Victoria) isolate of MARV could broadly protect against diverse isolates of MARV, guinea pigs were vaccinated with mVLPs or iMARV-Musoke and challenged with MARV-Musoke, -Ravn or -Ci67. Prior to challenge, the mVLP- and iMARV-vaccinated guinea pigs had high levels of homologous MARV-Musoke and heterologous MARV-Ravn and -Ci67 antibodies. The Musoke-based mVLPs and iMARV vaccines provided complete protection in guinea pigs against viremia, viral replication and pathological changes in tissues, and lethal disease following challenge with MARV-Musoke, -Ravn or -Ci67. Guinea pigs vaccinated with RIBI adjuvant alone and infected with guinea pig-adapted MARV-Musoke, -Ravn or -Ci67 had histopathologic findings similar to those seen in the nonhuman primate model for MARV infection. Based on the strong protection observed in guinea pigs, we next vaccinated cynomolgus macaques with Musoke-based mVLPs and showed the VLP-vaccinated monkeys were broadly protected against three isolates of MARV (Musoke, Ravn and Ci67). Musoke mVLPs are effective at inducing broad heterologous immunity and protection against multiple MARV isolates.

Detection of influenza A virus in aerosols of vaccinated and non-vaccinated pigs in a warm environment.

PubMed

Neira, Victor; Allerson, Matt; Corzo, Cesar; Culhane, Marie; Rendahl, Aaron; Torremorell, Montserrat

2018-01-01

The 2009 influenza pandemic, the variant H3N2v viruses in agricultural fairs and the zoonotic poultry H5N9 infections in China have highlighted the constant threat that influenza A viruses (IAV) present to people and animals. In this study we evaluated the effect of IAV vaccination on aerosol shedding in pigs housed in warm environmental conditions. Thirty-six, three-week old weaned pigs were obtained from an IAV negative herd and were randomly allocated to one of 4 groups: 1) a homologous vaccine group, 2) a heterologous multivalent vaccine group, 3) a heterologous monovalent group and, 4) a non-vaccinated group. After vaccination pigs were challenged with the triple reassortant A/Sw/IA/00239/04 H1N1 virus. Environmental temperature and relative humidity were recorded throughout the study. Nasal swabs, oral fluids and air samples were collected daily. All samples were tested by RRT-PCR and virus isolation was attempted on positive samples. Average temperature and relative humidity throughout the study were 27°C (80°F) and 53%, respectively. A significantly higher proportion of infected pigs was detected in the non-vaccinated than in the vaccinated group. Lower levels of nasal virus shedding were found in vaccinated groups compared to non-vaccinated group and IAV was not detected in air samples of any of the vaccinated groups. In contrast, positive air samples were detected in the non-vaccinated group at 1, 2 and 3 days post infection although the overall levels were considered low most likely due to the elevated environmental temperature. In conclusion, both the decrease in shedding and the increase in environmental temperature may have contributed to the inability to detect airborne IAV in vaccinated pigs.

Effect of Age at Vaccination on Rotavirus Vaccine Effectiveness in Bolivian Infants.

PubMed

Burke, Rachel M; Tate, Jacqueline E; Pringle, Kimberly D; Patel, Manish; De Oliveira, Lucia H; Parashar, Umesh D

2018-01-16

Rotavirus vaccines are less effective in developing countries versus developed countries. One hypothesis for this difference in performance is that higher levels of maternal antibodies in developing countries may interfere with vaccine response, suggesting that delayed dosing could be beneficial. The present analysis aims to assess whether rotavirus vaccine effectiveness (VE) varies by age at vaccination during routine use in Bolivia. Data were merged from two post-licensure evaluations of monovalent rotavirus vaccine (RV1) in Bolivia, where two doses of RV1 are recommended at two and four months of age. For each dose, children were classified as receiving each dose "early," "on-time," or "late." Stratified unconditional logistic regression models were used to estimate VE, using unvaccinated children as the referent. VE was calculated as (1 - odds ratio) x 100%. Models were adjusted for hospital, age, and time since RV1 introduction (via including terms for month and year of birth). VE for two doses of RV1 tended to be higher in infants receiving the first dose early (VE 92%; 95% confidence interval [CI] [70%, 98%]), when compared to infants receiving their first dose on time (72% [62%, 81%]) or late (68% [51%, 79%]). Estimates of VE were not substantially different when comparing children by age at second dose (early: VE 76% [50%, 89%]; on time: VE 70% [50%, 89%]; late: VE 75% [60%, 84%]), including all children. Our results indicate that early administration may improve VE and support the current WHO recommendations for the RV1 schedule.

A Replication-Defective Human Type 5 Adenovirus-Based Trivalent Vaccine Confers Complete Protection against Plague in Mice and Nonhuman Primates.

PubMed

Sha, Jian; Kirtley, Michelle L; Klages, Curtis; Erova, Tatiana E; Telepnev, Maxim; Ponnusamy, Duraisamy; Fitts, Eric C; Baze, Wallace B; Sivasubramani, Satheesh K; Lawrence, William S; Patrikeev, Igor; Peel, Jennifer E; Andersson, Jourdan A; Kozlova, Elena V; Tiner, Bethany L; Peterson, Johnny W; McWilliams, David; Patel, Snehal; Rothe, Eric; Motin, Vladimir L; Chopra, Ashok K

2016-07-01

Currently, no plague vaccine exists in the United States for human use. The capsular antigen (Caf1 or F1) and two type 3 secretion system (T3SS) components, the low-calcium-response V antigen (LcrV) and the needle protein YscF, represent protective antigens of Yersinia pestis We used a replication-defective human type 5 adenovirus (Ad5) vector and constructed recombinant monovalent and trivalent vaccines (rAd5-LcrV and rAd5-YFV) that expressed either the codon-optimized lcrV or the fusion gene designated YFV (consisting of ycsF, caf1, and lcrV). Immunization of mice with the trivalent rAd5-YFV vaccine by either the intramuscular (i.m.) or the intranasal (i.n.) route provided protection superior to that with the monovalent rAd5-LcrV vaccine against bubonic and pneumonic plague when animals were challenged with Y. pestis CO92. Preexisting adenoviral immunity did not diminish the protective response, and the protection was always higher when mice were administered one i.n. dose of the trivalent vaccine (priming) followed by a single i.m. booster dose of the purified YFV antigen. Immunization of cynomolgus macaques with the trivalent rAd5-YFV vaccine by the prime-boost strategy provided 100% protection against a stringent aerosol challenge dose of CO92 to animals that had preexisting adenoviral immunity. The vaccinated and challenged macaques had no signs of disease, and the invading pathogen rapidly cleared with no histopathological lesions. This is the first report showing the efficacy of an adenovirus-vectored trivalent vaccine against pneumonic plague in mouse and nonhuman primate (NHP) models. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

A new application of value-stream mapping in new drug development: a case study within Novartis.

PubMed

Heinzen, Mareike; Mettler, Samuel; Coradi, Annina; Boutellier, Roman

2015-03-01

In this case study, we evaluated the effect of colocation on the drug development process using value-stream mapping (VSM) on the Novartis Campus in Basel, Switzerland. We compared a colocated team with a control group that was not colocated. The data showed that colocation was not associated with increased process speed in terms of lead lines. However, the colocated team communicated more and reported beneficial experiences, such as faster working processes or improved mutual understanding. VSM workshops revealed not only performance indicators about colocation, but also enhanced communication and cooperation through the evolving discussion. Copyright © 2014 Elsevier Ltd. All rights reserved.

Characterization of Protection Afforded by a Bivalent Virus-Like Particle Vaccine against Bluetongue Virus Serotypes 1 and 4 in Sheep

PubMed Central

Pérez de Diego, Ana Cristina; Athmaram, Thimmasandra N.; Stewart, Meredith; Rodríguez-Sánchez, Belén; Sánchez-Vizcaíno, José Manuel; Noad, Robert; Roy, Polly

2011-01-01

Background Bluetongue virus (BTV) is an economically important, arthropod borne, emerging pathogen in Europe, causing disease mainly in sheep and cattle. Routine vaccination for bluetongue would require the ability to distinguish between vaccinated and infected individuals (DIVA). Current vaccines are effective but are not DIVA. Virus-like particles (VLPs) are highly immunogenic structural mimics of virus particles, that only contain a subset of the proteins present in a natural infection. VLPs therefore offer the potential for the development of DIVA compatible bluetongue vaccines. Methodology/Principal Findings Merino sheep were vaccinated with either monovalent BTV-1 VLPs or a bivalent mixture of BTV-1 VLPs and BTV-4 VLPs, and challenged with virulent BTV-1 or BTV-4. Animals were monitored for clinical signs, antibody responses, and viral RNA. 19/20 animals vaccinated with BTV-1 VLPs either alone or in combination with BTV-4 VLPs developed neutralizing antibodies to BTV-1, and group specific antibodies to BTV VP7. The one animal that showed no detectable neutralizing antibodies, or group specific antibodies, had detectable viral RNA following challenge but did not display any clinical signs on challenge with virulent BTV-1. In contrast, all control animals' demonstrated classical clinical signs for bluetongue on challenge with the same virus. Six animals were vaccinated with bivalent vaccine and challenged with virulent BTV-4, two of these animals had detectable viral levels of viral RNA, and one of these showed clinical signs consistent with BTV infection and died. Conclusions There is good evidence that BTV-1 VLPs delivered as monovalent or bivalent immunogen protect from bluetongue disease on challenge with virulent BTV-1. However, it is possible that there is some interference in protective response for BTV-4 in the bivalent BTV-1 and BTV-4 VLP vaccine. This raises the question of whether all combinations of bivalent BTV vaccines are possible, or if

A clinical analysis of gelatin allergy and determination of its causal relationship to the previous administration of gelatin-containing acellular pertussis vaccine combined with diphtheria and tetanus toxoids.

PubMed

Nakayama, T; Aizawa, C; Kuno-Sakai, H

1999-02-01

The number of patients with allergic reactions after administration of gelatin-containing live vaccines is increasingly reported in Japan. These allergic reactions appear to be caused by gelatin allergy. It is still unknown how the patients were sensitized to gelatin. To determine the incidence of gelatin allergy and to identify contributing factors to gelatin allergy, we investigated the following clinical aspects: the development of IgE antibodies to gelatin and the relationship of the patients' past history of acellular pertussis vaccine combined with diphtheria and tetanus toxoid (DTaP) to the development of gelatin allergy. We evaluated 366 patient reports, submitted from 1994 to 1997, of adverse reactions after immunization with monovalent measles, mumps, and rubella vaccines containing 0.2% gelatin as stabilizer. On the basis of physician reports, the patients were categorized as to the nature of the adverse reaction. We determined the presence of IgE antibodies to gelatin and obtained past immunization history. The 366 reported patients were categorized as follows: 34 with anaphylaxis, 76 with urticaria, 215 with nonurticarial generalized eruption, and 41 with local reactions only. In 206 patients from whom serum was available, IgE antibodies to gelatin were detected in 25 of 27 (93%) with anaphylaxis, 27 of 48 (56%) with urticaria, and 8 of 90 (9%) with a generalized eruption. None of a group of 41 patients with only local reactions at the injected site and none of a control group of 29 subjects with no adverse reaction had such antibodies. Among 202 patients for whom prior vaccine information was available, all had received DTaP vaccines. Among those for whom the prior DTaP vaccine could be determined to contain gelatin or be free of gelatin, 155 of 158 (98%) subjects had received gelatin-containing DTaP vaccines. This rate is higher than would be expected on the basis of the market share of gelatin-containing (vs gelatin-free) DTaP vaccines (75

A quantitative risk assessment of exposure to adventitious agents in a cell culture-derived subunit influenza vaccine.

PubMed

Gregersen, Jens-Peter

2008-06-19

A risk-assessment model has demonstrated the ability of a new cell culture-based vaccine manufacturing process to reduce the level of any adventitious agent to a million-fold below infectious levels. The cell culture-derived subunit influenza vaccine (OPTAFLU), Novartis Vaccines and Diagnostics) is produced using Madin-Darby canine kidney (MDCK) cells to propagate seasonal viral strains, as an alternative to embryonated chicken-eggs. As only a limited range of mammalian viruses can grow in MDCK cells, similar to embryonated eggs, MDCK cells can act as an effective filter for a wide range of adventitious agents that might be introduced during vaccine production. However, the introduction of an alternative cell substrate (for example, MDCK cells) into a vaccine manufacturing process requires thorough investigations to assess the potential for adventitious agent risk in the final product, in the unlikely event that contamination should occur. The risk assessment takes into account the entire manufacturing process, from initial influenza virus isolation, through to blending of the trivalent subunit vaccine and worst-case residual titres for the final vaccine formulation have been calculated for >20 viruses or virus families. Maximum residual titres for all viruses tested were in the range of 10(-6) to 10(-16) infectious units per vaccine dose. Thus, the new cell culture-based vaccine manufacturing process can reduce any adventitious agent to a level that is unable to cause infection.

Vaccination against Lyme disease: Are we ready for it?

PubMed

Kaaijk, Patricia; Luytjes, Willem

2016-03-03

Lyme disease is the most common tick-borne illness in the Northern hemisphere and is caused by spirochetes of the Borrelia burgdorferi sensu lato complex. A first sign of Borrelia infection is a circular skin rash, erythema migrans, but it can develop to more serious manifestations affecting skin, nervous system, joints, and/or heart. The marked increase in Lyme disease incidence over the past decades, the severity of the disease, and the associated high medical costs of, in particular, the persistent forms of Lyme disease requires adequate measures for control. Vaccination would be the most effective intervention for prevention, but at present no vaccine is available. In the 1990s, 2 vaccines against Lyme disease based on the OspA protein from the predominant Borrelia species of the US showed to be safe and effective in clinical phase III studies. However, failed public acceptance led to the demise of these monovalent OspA-based vaccines. Nowadays, public seem to be more aware of the serious health problems that Lyme disease can cause and seem more ready for the use of a broadly protective vaccine. This article discusses several aspects that should be considered to enable the development and implementation of a vaccine to prevent Lyme disease successfully.

Vaccination against Lyme disease: Are we ready for it?

PubMed Central

Kaaijk, Patricia; Luytjes, Willem

2016-01-01

Abstract Lyme disease is the most common tick-borne illness in the Northern hemisphere and is caused by spirochetes of the Borrelia burgdorferi sensu lato complex. A first sign of Borrelia infection is a circular skin rash, erythema migrans, but it can develop to more serious manifestations affecting skin, nervous system, joints, and/or heart. The marked increase in Lyme disease incidence over the past decades, the severity of the disease, and the associated high medical costs of, in particular, the persistent forms of Lyme disease requires adequate measures for control. Vaccination would be the most effective intervention for prevention, but at present no vaccine is available. In the 1990s, 2 vaccines against Lyme disease based on the OspA protein from the predominant Borrelia species of the US showed to be safe and effective in clinical phase III studies. However, failed public acceptance led to the demise of these monovalent OspA-based vaccines. Nowadays, public seem to be more aware of the serious health problems that Lyme disease can cause and seem more ready for the use of a broadly protective vaccine. This article discusses several aspects that should be considered to enable the development and implementation of a vaccine to prevent Lyme disease successfully. PMID:26337648

Statistical and Ontological Analysis of Adverse Events Associated with Monovalent and Combination Vaccines against Hepatitis A and B Diseases

PubMed Central

Xie, Jiangan; Zhao, Lili; Zhou, Shangbo; He, Yongqun

2016-01-01

Vaccinations often induce various adverse events (AEs), and sometimes serious AEs (SAEs). While many vaccines are used in combination, the effects of vaccine-vaccine interactions (VVIs) on vaccine AEs are rarely studied. In this study, AE profiles induced by hepatitis A vaccine (Havrix), hepatitis B vaccine (Engerix-B), and hepatitis A and B combination vaccine (Twinrix) were studied using the VAERS data. From May 2001 to January 2015, VAERS recorded 941, 3,885, and 1,624 AE case reports where patients aged at least 18 years old were vaccinated with only Havrix, Engerix-B, and Twinrix, respectively. Using these data, our statistical analysis identified 46, 69, and 82 AEs significantly associated with Havrix, Engerix-B, and Twinrix, respectively. Based on the Ontology of Adverse Events (OAE) hierarchical classification, these AEs were enriched in the AEs related to behavioral and neurological conditions, immune system, and investigation results. Twenty-nine AEs were classified as SAEs and mainly related to immune conditions. Using a logistic regression model accompanied with MCMC sampling, 13 AEs (e.g., hepatosplenomegaly) were identified to result from VVI synergistic effects. Classifications of these 13 AEs using OAE and MedDRA hierarchies confirmed the advantages of the OAE-based method over MedDRA in AE term hierarchical analysis. PMID:27694888

H1N1 vaccination in pediatric renal transplant patients.

PubMed

Kelen, K; Ferenczi, D; Jankovics, I; Varga, M; Molnar, M Z; Sallay, P; Reusz, G; Langer, R M; Pasti, K; Gerlei, Z; Szabo, A J

2011-05-01

Solid organ transplant recipients undergoing immunosuppressive therapy are considered to be at high risk of serious infectious complications. In 2009, a new influenza pandemic caused serious infections and deaths, especially among children and immunocompromised patients. Herein we have reported the safety and efficacy of a single-shot monovalent whole-virus vaccine against H1N1 infection in the pediatric renal transplant population. In November and December 2009, we vaccinated 37 renal transplant children and adolescents and measured their antibody responses. Seroprotection, seroconversion, and seroconversion factors were analyzed at 21 days after vaccination. None of the vaccinated patients experienced vaccine-related side effects. None of the patients had an H1N1 influenza infection after vaccination. All of the patients showed elevations in antibody titer at 21 days after vaccination. In contrast, only 29.72% of the patients achieved a safe seroprotection level and only 18.75% a safe seroconversion rate. More intense immunosuppressive treatment displayed negative effect on seroprotection and seroconversion, and antibody production significantly increased with age. No other factor was observed to influence seroprotection. We recommend vaccination of children and adolescent renal transplant recipients against H1N1 virus. However, a single shot of vaccine may not be sufficient; to achieve seroprotection, a booster vaccination and measurement of the antibody response are needed to assure protection of our patients. Copyright © 2011 Elsevier Inc. All rights reserved.

Rotavirus vaccine effectiveness in low-income settings: An evaluation of the test-negative design.

PubMed

Schwartz, Lauren M; Halloran, M Elizabeth; Rowhani-Rahbar, Ali; Neuzil, Kathleen M; Victor, John C

2017-01-03

The test-negative design (TND), an epidemiologic method currently used to measure rotavirus vaccine (RV) effectiveness, compares the vaccination status of rotavirus-positive cases and rotavirus-negative controls meeting a pre-defined case definition for acute gastroenteritis. Despite the use of this study design in low-income settings, the TND has not been evaluated to measure rotavirus vaccine effectiveness. This study builds upon prior methods to evaluate the use of the TND for influenza vaccine using a randomized controlled clinical trial database. Test-negative vaccine effectiveness (VE-TND) estimates were derived from three large randomized placebo-controlled trials (RCTs) of monovalent (RV1) and pentavalent (RV5) rotavirus vaccines in sub-Saharan Africa and Asia. Derived VE-TND estimates were compared to the original RCT vaccine efficacy estimates (VE-RCTs). The core assumption of the TND (i.e., rotavirus vaccine has no effect on rotavirus-negative diarrhea) was also assessed. TND vaccine effectiveness estimates were nearly equivalent to original RCT vaccine efficacy estimates. Neither RV had a substantial effect on rotavirus-negative diarrhea. This study supports the TND as an appropriate epidemiologic study design to measure rotavirus vaccine effectiveness in low-income settings. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

[Antirabies vaccine from the brain of the suckling rat: antigen composition and immunogenic capacity].

PubMed

Díaz, A M; Dellepiane, N; Palomo, L F

1989-09-01

Suckling mouse brain (SMB) rabies vaccine is the preparation most widely used in the countries of Latin American and the Caribbean. This vaccine, prepared according to the Fuenzalida and Palacios method, consists of three fixed rabies virus strains (CVS, 51, and 91). However, the World Health Organization recommends that rabies vaccines for human use be prepared using only a single strain of this virus. In order to determine whether any one of the antigens of the SMB vaccine could be eliminated from the preparation, the immunogenic capacity of the standard trivalent SMB vaccine was compared with that of experimental bivalent (CVS-51, CVS-91, and 51-91) and monovalent (CVS, 51, and 91) SMB vaccines. The study was conducted using adult and suckling albino mice provided by the laboratory at the Pan American Zoonoses Center, Buenos Aires, Argentina, and different strains of fixed and street rabies virus. The experimental vaccines were prepared using the Fuenzalida-Palacios method. Potency and cross-immunity tests were conducted. The results showed that the trivalent vaccine was the most effective in protecting the mice against both fixed and street rabies virus infections and also in inducing rapid development of neutralizing antibody at high titers.

The effect of mass immunisation campaigns and new oral poliovirus vaccines on the incidence of poliomyelitis in Pakistan and Afghanistan, 2001-11: a retrospective analysis.

PubMed

O'Reilly, Kathleen M; Durry, Elias; ul Islam, Obaid; Quddus, Arshad; Abid, Ni'ma; Mir, Tahir P; Tangermann, Rudi H; Aylward, R Bruce; Grassly, Nicholas C

2012-08-04

Pakistan and Afghanistan are two of the three remaining countries yet to interrupt wild-type poliovirus transmission. The increasing incidence of poliomyelitis in these countries during 2010-11 led the Executive Board of WHO in January, 2012, to declare polio eradication a "programmatic emergency for global public health". We aimed to establish why incidence is rising in these countries despite programme innovations including the introduction of new vaccines. We did a matched case-control analysis based on a database of 46,977 children aged 0-14 years with onset of acute flaccid paralysis between Jan 1, 2001, and Dec 31, 2011. The vaccination history of children with poliomyelitis was compared with that of children with acute flaccid paralysis due to other causes to estimate the clinical effectiveness of oral poliovirus vaccines (OPVs) in Afghanistan and Pakistan by conditional logistic regression. We estimated vaccine coverage and serotype-specific vaccine-induced population immunity in children aged 0-2 years and assessed their association with the incidence of poliomyelitis over time in seven regions of Afghanistan and Pakistan. Between Jan 1, 2001, and Dec 31, 2011, there were 883 cases of serotype 1 poliomyelitis (710 in Pakistan and 173 in Afghanistan) and 272 cases of poliomyelitis serotype 3 (216 in Pakistan and 56 in Afghanistan). The estimated clinical effectiveness of a dose of trivalent OPV against serotype 1 poliomyelitis was 12·5% (95% CI 5·6-18·8) compared with 34·5% (16·1-48·9) for monovalent OPV (p=0·007) and 23·4% (10·4-34·6) for bivalent OPV (p=0·067). Bivalent OPV was non-inferior compared with monovalent OPV (p=0·21). Vaccination coverage decreased during 2006-11 in the Federally Administered Tribal Areas (FATA), Balochistan, and Khyber Pakhtunkhwa in Pakistan and in southern Afghanistan. Although partially mitigated by the use of more effective vaccines, these decreases in coverage resulted in lower vaccine-induced population

Rational design of HIV vaccine and microbicides: report of the EUROPRISE annual conference.

PubMed

Wahren, Britta; Biswas, Priscilla; Borggren, Marie; Coleman, Adam; Da Costa, Kelly; De Haes, Winni; Dieltjens, Tessa; Dispinseri, Stefania; Grupping, Katrijn; Hallengärd, David; Hornig, Julia; Klein, Katja; Mainetti, Lara; Palma, Paolo; Reudelsterz, Marc; Seifried, Janna; Selhorst, Philippe; Sköld, Annette; Uchtenhagen, Hannes; van Gils, Marit J; Weber, Caroline; Shattock, Robin; Scarlatti, Gabriella

2010-07-26

EUROPRISE is a Network of Excellence sponsored from 2007 to 2011 by the European Commission within the 6th Framework Program. The Network encompasses a wide portfolio of activities ranging from an integrated research program in the field of HIV vaccines and microbicides to training, dissemination and advocacy. The research program covers the whole pipeline of vaccine and microbicide development from discovery to early clinical trials. The Network is composed of 58 partners representing more than 65 institutions from 13 European countries; it also includes three major pharmaceutical companies (GlaxoSmithKline, Novartis and Sanofi-Pasteur) involved in HIV microbicide and vaccine research. The Network displays a dedicated and informative web page: http://www.europrise.org. Finally, a distinguishing trait of EUROPRISE is its PhD School of students from across Europe, a unique example in the world of science aimed at spreading excellence through training. EUROPRISE held its second annual conference in Budapest in November, 2009. The conference had 143 participants and their presentations covered aspects of vaccine and microbicide research, development and discovery. Since training is a major task of the Network, the students of the EUROPRISE PhD program summarized certain presentations and their view of the conference in this paper.

Rational design of HIV vaccine and microbicides: report of the EUROPRISE annual conference

PubMed Central

2010-01-01

EUROPRISE is a Network of Excellence sponsored from 2007 to 2011 by the European Commission within the 6th Framework Program. The Network encompasses a wide portfolio of activities ranging from an integrated research program in the field of HIV vaccines and microbicides to training, dissemination and advocacy. The research program covers the whole pipeline of vaccine and microbicide development from discovery to early clinical trials. The Network is composed of 58 partners representing more than 65 institutions from 13 European countries; it also includes three major pharmaceutical companies (GlaxoSmithKline, Novartis and Sanofi-Pasteur) involved in HIV microbicide and vaccine research. The Network displays a dedicated and informative web page: http://www.europrise.org. Finally, a distinguishing trait of EUROPRISE is its PhD School of students from across Europe, a unique example in the world of science aimed at spreading excellence through training. EUROPRISE held its second annual conference in Budapest in November, 2009. The conference had 143 participants and their presentations covered aspects of vaccine and microbicide research, development and discovery. Since training is a major task of the Network, the students of the EUROPRISE PhD program summarized certain presentations and their view of the conference in this paper. PMID:20659333

Sustained Effectiveness of Rotavirus Vaccine Against Very Severe Rotavirus Disease Through the Second Year of Life, Bolivia 2013-2014.

PubMed

Pringle, Kimberly D; Patzi, Maritza; Tate, Jacqueline E; Iniguez Rojas, Volga; Patel, Manish; Inchauste Jordan, Lucia; Montesano, Raul; Zarate, Adolfo; De Oliveira, Lucia; Parashar, Umesh

2016-05-01

In Bolivia, monovalent rotavirus vaccine was introduced in 2008 and a previous evaluation reported a vaccine effectiveness (VE) of 77% with 2 doses of vaccine in children aged <3 years. This evaluation sought to determine if rotavirus vaccine provided protection through the second year of life against circulating genotypes. A case-control study was performed in 5 hospitals from April 2013 to March 2014. Among enrolled participants who met study criteria and had rotavirus stool testing performed and vaccine status confirmed, we calculated VE using a logistic regression model. Subgroup analyses were performed among children aged <1 year and those aged ≥1 year, among children with severe diarrhea (Vesikari score ≥11) and very severe diarrhea (Vesikari score ≥15), and among G and P strains with at least 40 specimens. A total of 776 children were enrolled. For children <1 year and ≥1 year of age with severe diarrhea, VE for 2 doses was 75% (95% confidence interval [CI], 46%-88%) and 53% (95% CI, 9%-76%), respectively. For children <1 year and ≥1 year of age with very severe diarrhea, VE for 2 doses was 80% (95% CI, 44%-93%) and 74% (95% CI, 35%-90%), respectively. Genotype-specific analysis demonstrated similar VE for the 4 most common G and P types (G3, G9, P[6] and P[8]). A monovalent rotavirus vaccine remains effective against a broad range of circulating strains as part of a routine immunization program >5 years after its introduction in Bolivia. Although VE appears to wane in children aged ≥1 year, it still provides significant protection, and does not wane against severe disease. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Lot-to-lot consistency study of the fully liquid pentavalent DTwP-HepB-Hib vaccine Quinvaxem® demonstrating clinical equivalence, suitability of the vaccine as a booster and concomitant administration with measles vaccine

PubMed Central

Aspinall, Sanet; Traynor, Deirdre; Bedford, Philip; Hartmann, Katharina

2012-01-01

This double-blind, randomized study evaluated the immunogenicity and safety of three production lots of the fully liquid combination DTwP-Hep-Hib vaccine, Quinvaxem® (Crucell, The Netherlands) in 360 healthy infants aged 42–64 d old given at 6, 10 and 14 weeks of age (Core Study). The Core Study was followed by an open-label Booster Phase evaluating immunogenicity and safety of a booster dose of Quinvaxem® given with either concomitant or deferred measles vaccine in 227 infants who completed the Core Study. One month after the third dose of Quinvaxem® immune responses reflecting seroprotection or seroconversion were observed in more than 90% of infants for all three vaccine lots. Quinvaxem® elicited a strong booster response as demonstrated by a large increase in antibodies against all antigens, which appeared to be unaffected by concomitant administration of the measles vaccine. Safety results were in line with previous reports for Quinvaxem® with no unexpected adverse events (AEs) being reported. In the Core Study and Booster Phase, Quinvaxem® was well tolerated. No study vaccine-related serious AEs were reported. Thus, Quinvaxem® was immunogenic and well-tolerated when administered to infants according to a 6–10–14 week vaccination schedule. The three production lots had consistent reactogenicity and immunogenicity profiles. The booster dose of Quinvaxem® was also immunogenic and safe, regardless of whether a monovalent measles vaccine was administered concomitantly or one month later. PMID:22854660

Implementation of Rotavirus Surveillance and Vaccine Introduction - World Health Organization African Region, 2007-2016.

PubMed

Mwenda, Jason M; Burke, Rachel M; Shaba, Keith; Mihigo, Richard; Tevi-Benissan, Mable Carole; Mumba, Mutale; Biey, Joseph Nsiari-Muzeyi; Cheikh, Dah; Poy MSc, Alain; Zawaira, Felicitas R; Aliabadi, Negar; Tate, Jacqueline E; Hyde, Terri; Cohen, Adam L; Parashar, Umesh D

2017-11-03

Rotavirus is a leading cause of severe pediatric diarrhea globally, estimated to have caused 120,000 deaths among children aged <5 years in sub-Saharan Africa in 2013 (1). In 2009, the World Health Organization (WHO) recommended rotavirus vaccination for all infants worldwide (2). Two rotavirus vaccines are currently licensed globally: the monovalent Rotarix vaccine (RV1, GlaxoSmithKline; 2-dose series) and the pentavalent RotaTeq vaccine (RV5, Merck; 3-dose series). This report describes progress of rotavirus vaccine introduction (3), coverage (using estimates from WHO and the United Nations Children's Fund [UNICEF]) (4), and impact on pediatric diarrhea hospitalizations in the WHO African Region. By December 2016, 31 (66%) of 47 countries in the WHO African Region had introduced rotavirus vaccine, including 26 that introduced RV1 and five that introduced RV5. Among these countries, rotavirus vaccination coverage (completed series) was 77%, according to WHO/UNICEF population-weighted estimates. In 12 countries with surveillance data available before and after vaccine introduction, the proportion of pediatric diarrhea hospitalizations that were rotavirus-positive declined 33%, from 39% preintroduction to 26% following rotavirus vaccine introduction. These results support introduction of rotavirus vaccine in the remaining countries in the region and continuation of rotavirus surveillance to monitor impact.

The effect of mass immunisation campaigns and new oral poliovirus vaccines on the incidence of poliomyelitis in Pakistan and Afghanistan, 2001–11: a retrospective analysis

PubMed Central

O'Reilly, Kathleen M; Durry, Elias; ul Islam, Obaid; Quddus, Arshad; Abid, Ni'ma; Mir, Tahir P; Tangermann, Rudi H; Aylward, R Bruce; Grassly, Nicholas C

2012-01-01

Summary Background Pakistan and Afghanistan are two of the three remaining countries yet to interrupt wild-type poliovirus transmission. The increasing incidence of poliomyelitis in these countries during 2010–11 led the Executive Board of WHO in January, 2012, to declare polio eradication a “programmatic emergency for global public health”. We aimed to establish why incidence is rising in these countries despite programme innovations including the introduction of new vaccines. Methods We did a matched case-control analysis based on a database of 46 977 children aged 0–14 years with onset of acute flaccid paralysis between Jan 1, 2001, and Dec 31, 2011. The vaccination history of children with poliomyelitis was compared with that of children with acute flaccid paralysis due to other causes to estimate the clinical effectiveness of oral poliovirus vaccines (OPVs) in Afghanistan and Pakistan by conditional logistic regression. We estimated vaccine coverage and serotype-specific vaccine-induced population immunity in children aged 0–2 years and assessed their association with the incidence of poliomyelitis over time in seven regions of Afghanistan and Pakistan. Findings Between Jan 1, 2001, and Dec 31, 2011, there were 883 cases of serotype 1 poliomyelitis (710 in Pakistan and 173 in Afghanistan) and 272 cases of poliomyelitis serotype 3 (216 in Pakistan and 56 in Afghanistan). The estimated clinical effectiveness of a dose of trivalent OPV against serotype 1 poliomyelitis was 12·5% (95% CI 5·6–18·8) compared with 34·5% (16·1–48·9) for monovalent OPV (p=0·007) and 23·4% (10·4–34·6) for bivalent OPV (p=0·067). Bivalent OPV was non-inferior compared with monovalent OPV (p=0·21). Vaccination coverage decreased during 2006–11 in the Federally Administered Tribal Areas (FATA), Balochistan, and Khyber Pakhtunkhwa in Pakistan and in southern Afghanistan. Although partially mitigated by the use of more effective vaccines, these decreases in

Immunogenicity, Safety and Antibody Persistence of a Booster Dose of Quadrivalent Meningococcal ACWY-tetanus Toxoid Conjugate Vaccine Compared with Monovalent Meningococcal Serogroup C Vaccine Administered Four Years After Primary Vaccination Using the Same Vaccines.

PubMed

Vesikari, Timo; Forsten, Aino; Bianco, Veronique; Van der Wielen, Marie; Miller, Jacqueline M

2015-12-01

We evaluated safety, immunogenicity and antibody persistence of meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT) booster vaccination 4 years after priming of toddlers. This phase III, open-label, controlled study in Finland (NCT00955682) enrolled children previously randomized (3:1) at 12-23 months (NCT00474266) to receive 1 dose of MenACWY-TT or MenC conjugate vaccine (MenC-CRM197). Serum bactericidal antibody titers using rabbit (rSBA, cut-off 1:8) and human complement (hSBA, cut-off 1:8) were assessed at year 3 and 4 after priming and 1 month and 1 year after administration of a booster dose of the same vaccine given for primary vaccination. Reactogenicity and safety were assessed, and vaccination-related serious adverse events were recorded from the time of primary vaccination. Before booster (year 4), 74.1%, 40.4%, 49.3% and 58.2% of MenACWY-TT-recipients retained rSBA titers ≥1:8 for serogroups A, C, W and Y, respectively; 28.8%, 73.2%, 80.6% and 65.4% retained hSBA ≥1:8. Percentages for the MenC-CRM group were 35.6% (rSBA-MenC) and 46.9% (hSBA-MenC). After MenACWY-TT booster, ≥99.5% had rSBA ≥1:8 and hSBA ≥1:8 for each serogroup. After MenC-CRM197 booster, all children had rSBA-MenC ≥1:8 and hSBA-MenC ≥1:8. At year 5, percentages above the cut-off were ≥97.4% (rSBA) and ≥95.5% (hSBA) in MenACWY-TT-vaccinees for each serogroup. The MenACWY-TT booster dose had a clinically acceptable safety profile. No vaccine-related serious adverse events were reported. There was evidence of antibody persistence 4 years after toddlers were primed with MenACWY-TT. Booster vaccination induced robust immune responses for all serogroups with an acceptable safety profile.

Conformationally selective biophysical assay for influenza vaccine potency determination.

PubMed

Wen, Yingxia; Han, Liqun; Palladino, Giuseppe; Ferrari, Annette; Xie, Yuhong; Carfi, Andrea; Dormitzer, Philip R; Settembre, Ethan C

2015-10-05

Influenza vaccines are the primary intervention for reducing the substantial health burden from pandemic and seasonal influenza. Hemagglutinin (HA) is the most important influenza vaccine antigen. Subunit and split influenza vaccines are formulated, released for clinical use, and tested for stability based on an in vitro potency assay, single-radial immunodiffusion (SRID), which selectively detects HA that is immunologically active (capable of eliciting neutralizing or hemagglutination inhibiting antibodies in an immunized subject). The time consuming generation of strain-specific sheep antisera and calibrated antigen standards for SRID can delay vaccine release. The limitation in generating SRID reagents was evident during the early days of the 2009 pandemic, prompting efforts to develop more practical, alternative, quantitative assays for immunologically active HA. Here we demonstrate that, under native conditions, trypsin selectively digests HA produced from egg or mammalian cell in monovalent vaccines that is altered by stress conditions such as reduced pH, elevated temperature, or deamidation, leaving native, pre-fusion HA, intact. Subsequent reverse-phase high pressure liquid chromatography (RP-HPLC) can separate trypsin-resistant HA from the digested HA. Integration of the resulting RP-HPLC peak yields HA quantities that match well the values obtained by SRID. Therefore, trypsin digestion, to pre-select immunologically active HA, followed by quantification by RP-HPLC is a promising alternative in vitro potency assay for influenza vaccines. Copyright © 2015 Elsevier Ltd. All rights reserved.

Technology transfer of oil-in-water emulsion adjuvant manufacturing for pandemic influenza vaccine production in Romania.

PubMed

Fox, Christopher B; Huynh, Chuong; O'Hara, Michael K; Onu, Adrian

2013-03-15

Many developing countries lack or have inadequate pandemic influenza vaccine manufacturing capacity. In the 2009 H1N1 pandemic, this led to delayed and inadequate vaccine coverage in the developing world. Thus, bolstering developing country influenza vaccine manufacturing capacity is urgently needed. The Cantacuzino Institute in Bucharest, Romania has been producing seasonal influenza vaccine since the 1970s, and has the capacity to produce ∼5 million doses of monovalent vaccine in the event of an influenza pandemic. Inclusion of an adjuvant in the vaccine could enable antigen dose sparing, expanding vaccine coverage and potentially allowing universal vaccination of the Romanian population and possibly neighboring countries. However, adjuvant formulation and manufacturing know-how are difficult to access. This manuscript describes the successful transfer of oil-in-water emulsion adjuvant manufacturing and quality control technologies from the Infectious Disease Research Institute in Seattle, USA to the Cantacuzino Institute. By describing the challenges and accomplishments of the project, it is hoped that the knowledge and experience gained will benefit other institutes involved in similar technology transfer projects designed to facilitate increased vaccine manufacturing capacity in developing countries. Copyright © 2012 Elsevier Ltd. All rights reserved.

Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? There Is Only One True Winner.

PubMed

Halstead, Scott B

2018-06-01

The scientific community now possesses information obtained directly from human beings that makes it possible to understand why breakthrough-enhanced dengue virus (DENV) infections occurred in children receiving Sanofi Pasteur's Dengvaxia tetravalent live attenuated vaccine and to predict the possibility of breakthrough-enhanced DENV infections following immunization with two other tetravalent live attenuated vaccines now in phase III testing. Based upon recent research, Dengvaxia, lacking DENV nonstructural protein antigens, did not protect seronegatives because it failed to raise a competent T-cell response and/or antibodies to NS1. It is also possible that chimeric structure does not present the correct virion conformation permitting the development of protective neutralizing antibodies. A premonitory signal shared by the Sanofi Pasteur and the Takeda vaccines was the failure of fully immunized subhuman primates to prevent low-level viremia and/or anamnestic antibody responses to live DENV challenge. The vaccine developed by the National Institute of Allergy and Infectious Diseases (National Institutes of Health [NIH]) has met virtually all of the goals needed to demonstrate preclinical efficacy and safety for humans. Each monovalent vaccine was comprehensively studied for reactogenicity and immunogenicity in human volunteers. Protective immunity in subjects receiving tetravalent candidate vaccines was evidenced by the fact that when vaccinated subjects were given further doses of vaccine or different strains of DENV the result was "solid immunity," a nonviremic and nonanamnestic immune response. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Protective effects of high-potency FMDV O1 Manisa monovalent vaccine in cattle challenged with FMDV O/SKR/2010 at 7 or 4 days post vaccination.

PubMed

Horsington, Jacquelyn; Perez, Claudia Beascoechea; Maradei, Eduardo; Novo, Sabrina Galdo; Gonzales, Jose L; Singanallur, Nagendrakumar B; Bonastre, Paula; Vosloo, Wilna

2017-09-12

Serotype O foot-and-mouth disease (FMD) virus belonging to the SEA topotype continues to be a significant problem in the Eastern Asia region, with outbreaks in Japan and South Korea resulting in the culling of over 3.5 million cattle and pigs in recent years. High-potency O1 Manisa vaccine was previously shown to provide protection in cattle 21days post vaccination (dpv) following challenge with a representative virus, O/SKR/2010. This study tested the ability of the O1 Manisa vaccine to protect cattle from infection and disease with the O/SKR/2010 virus within just 4 or 7days post vaccination. The vaccine protected 50% of cattle from clinical disease when administered 7days prior to challenge, but was not protective with just 4days between vaccination and challenge. Viraemia was significantly reduced in animals challenged 7 dpv but not 4 dpv, compared to unvaccinated controls, however, there were no effects on the level of virus detected in nasal and oral secretions regardless of vaccination time. The level of neutralising antibodies detected in cattle challenged 7 dpv correlated with protection from clinical disease. All animals seroconverted to FMDV non-structural proteins, suggesting no sterile protection. An equal number of animals became persistently infected in both vaccine groups. The results indicated that high-potency O1 Manisa vaccine administered just 7days prior to challenge should provide partial protection of cattle if an outbreak of O/SKR/2010, or related viruses, occurs, and would be useful to limit spread of FMDV when used in conjunction with other control measures. Copyright © 2017 Elsevier Ltd. All rights reserved.

Monovalent Cation Permeation through the Connexin40 Gap Junction Channel

PubMed Central

Beblo, Dolores A.; Veenstra, Richard D.

1997-01-01

The unitary conductances and permeability sequences of the rat connexin40 (rCx40) gap junction channels to seven monovalent cations and anions were studied in rCx40-transfected neuroblastoma 2A (N2A) cell pairs using the dual whole cell recording technique. Chloride salt cation substitutions (115 mM principal salt) resulted in the following junctional maximal single channel current-voltage relationship slope conductances (γj in pS): CsCl (153), RbCl (148), KCl (142), NaCl (115), LiCl (86), TMACl (71), TEACl (63). Reversible block of the rCx40 channel was observed with TBA. Potassium anion salt γj are: Kglutamate (160), Kacetate (160), Kaspartate (158), KNO3 (157), KF (148), KCl (142), and KBr (132). Ion selectivity was verified by measuring reversal potentials for current in rCx40 gap junction channels with asymmetric salt solutions in the two electrodes and using the Goldman-Hodgkin-Katz equation to calculate relative permeabilities. The permeabilities relative to Li+ are: Cs+ (1.38), Rb+ (1.32), K+ (1.31), Na+ (1.16), TMA+ (0.53), TEA+ (0.45), TBA+ (0.03), Cl− (0.19), glutamate− (0.04), and NO3− (0.14), assuming that the monovalent anions permeate the channel by forming ion pairs with permeant monovalent cations within the pore thereby causing proportionate decreases in the channel conductance. This hypothesis can account for why the predicted increasing conductances with increasing ion mobilities in an essentially aqueous channel were not observed for anions in the rCx40 channel. The rCx40 effective channel radius is estimated to be 6.6 Å from a theoretical fit of the relationship of relative permeability and cation radius. PMID:9101408

Immunogenicity of type 2 monovalent oral and inactivated poliovirus vaccines for type 2 poliovirus outbreak response: an open-label, randomised controlled trial.

PubMed

Zaman, Khalequ; Estívariz, Concepción F; Morales, Michelle; Yunus, Mohammad; Snider, Cynthia J; Gary, Howard E; Weldon, William C; Oberste, M Steven; Wassilak, Steven G; Pallansch, Mark A; Anand, Abhijeet

2018-06-01

Monovalent type 2 oral poliovirus vaccine (mOPV2) and inactivated poliovirus vaccine (IPV) are used to respond to type 2 poliovirus outbreaks. We aimed to assess the effect of two mOPV2 doses on the type 2 immune response by varying the time interval between mOPV2 doses and IPV co-administration with mOPV2. We did a randomised, controlled, parallel, open-label, non-inferiority, inequality trial at two study clinics in Dhaka, Bangladesh. Healthy infants aged 6 weeks (42-48 days) at enrolment were randomly assigned (1:1:1:1) to receive two mOPV2 doses (each dose consisting of two drops [0·1 mL in total] of about 10 5 50% cell culture infectious dose of type 2 Sabin strain) at intervals of 1 week, 2 weeks, 4 weeks (standard or control group), or 4 weeks with IPV (0·5 mL of type 1 [Mahoney, 40 D-antigen units], type 2 [MEF-1, 8 D-antigen units], and type 3 [Saukett, 32 D-antigen units]) administered intramuscularly with the first mOPV2 dose. We used block randomisation, randomly selecting blocks of sizes four, eight, 12, or 16 stratified by study sites. We concealed randomisation assignment from staff managing participants in opaque, sequentially numbered, sealed envelopes. Parents and clinic staff were unmasked to assignment after the randomisation envelope was opened. Laboratory staff analysing sera were masked to assignment, but investigators analysing data and assessing outcomes were not. The primary outcome was type 2 immune response measured 4 weeks after mOPV2 administration. The primary modified intention-to-treat analysis included participants with testable serum samples before and after vaccination. A non-inferiority margin of 10% and p=0·05 (one-tailed) was used. This trial is registered at ClinicalTrials.gov, number NCT02643368, and is closed to accrual. Between Dec 7, 2015, and Jan 5, 2016, we randomly assigned 760 infants to receive two mOPV2 doses at intervals of 1 week (n=191), 2 weeks (n=191), 4 weeks (n=188), or 4 weeks plus IPV (n=190). Immune

Neurological and autoimmune disorders after vaccination against pandemic influenza A (H1N1) with a monovalent adjuvanted vaccine: population based cohort study in Stockholm, Sweden

PubMed Central

Persson, Ingemar; Örtqvist, Åke; Bergman, Ulf; Ludvigsson, Jonas F; Granath, Fredrik

2011-01-01

Objective To examine the risk of neurological and autoimmune disorders of special interest in people vaccinated against pandemic influenza A (H1N1) with Pandemrix (GlaxoSmithKline, Middlesex, UK) compared with unvaccinated people over 8-10 months. Design Retrospective cohort study linking individualised data on pandemic vaccinations to an inpatient and specialist database on healthcare utilisation in Stockholm county for follow-up during and after the pandemic period. Setting Stockholm county, Sweden. Population All people registered in Stockholm county on 1 October 2009 and who had lived in this region since 1 January 1998; 1 024 019 were vaccinated against H1N1 and 921 005 remained unvaccinated. Main outcome measures Neurological and autoimmune diagnoses according to the European Medicines Agency strategy for monitoring of adverse events of special interest defined using ICD-10 codes for Guillain-Barré syndrome, Bell’s palsy, multiple sclerosis, polyneuropathy, anaesthesia or hypoaesthesia, paraesthesia, narcolepsy (added), and autoimmune conditions such as rheumatoid arthritis, inflammatory bowel disease, and type 1 diabetes; and short term mortality according to vaccination status. Results Excess risks among vaccinated compared with unvaccinated people were of low magnitude for Bell’s palsy (hazard ratio 1.25, 95% confidence interval 1.06 to 1.48) and paraesthesia (1.11, 1.00 to 1.23) after adjustment for age, sex, socioeconomic status, and healthcare utilisation. Risks for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis remained unchanged. The risks of paraesthesia and inflammatory bowel disease among those vaccinated in the early phase (within 45 days from 1 October 2009) of the vaccination campaign were significantly increased; the risk being increased within the first six weeks after vaccination. Those vaccinated in the early phase were at a slightly reduced risk of death than those who were unvaccinated (0

Strain diversity plays no major role in the varying efficacy of rotavirus vaccines: an overview.

PubMed

Velasquez, Daniel E; Parashar, Umesh D; Jiang, Baoming

2014-12-01

While a monovalent Rotarix® [RV1] and a pentavalent RotaTeq® [RV5] have been extensively tested and found generally safe and equally efficacious in clinical trials, the question still lingers about the evolving diversity of circulating rotavirus strains over time and their relationship with protective immunity induced by rotavirus vaccines. We reviewed data from clinical trials and observational studies that assessed the efficacy or field effectiveness of rotavirus vaccines against different rotavirus strains worldwide. RV1 provided broad clinical efficacy and field effectiveness against severe diarrhea due to all major circulating strains, including the homotypic G1P[8] and the fully heterotypic G2P[4] strains. Similarly, RV5 provided broad efficacy and effectiveness against RV5 and non-RV5 strains throughout different locations. Rotavirus vaccination provides broad heterotypic protection; however continuing surveillance is needed to track the change of circulating strains and monitor the effectiveness and safety of vaccines. Published by Elsevier B.V.

Titration of individual strains in trivalent live-attenuated influenza vaccine without neutralization.

PubMed

Sirinonthanawech, Naraporn; Surichan, Somchaiya; Namsai, Aphinya; Puthavathana, Pilaipan; Auewarakul, Prasert; Kongchanagul, Alita

2016-11-01

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. Copyright © 2016 Elsevier B.V. All rights reserved.

Vaccine-Derived NSP2 Segment in Rotaviruses from Vaccinated Children with Gastroenteritis in Nicaragua

PubMed Central

Bucardo, Filemón; Rippinger, Christine M.; Svensson, Lennart; Patton, John T.

2012-01-01

Rotavirus (RV) vaccination programs have been established in several countries using the human-attenuated G1P[8] monovalent vaccine Rotarix™ (GlaxoSmithKline) and/or the human-bovine reassortant G1, G2, G3, G4, P[8] 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[8], 1 G3P[8]) 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[8] viruses and the single G3P[8] virus had genome constellations typical of human G1P[8] and G3P[8] RVs: G1/3-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. However, two of the G1P[8] viruses had atypical constellations, G1-P[8]-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[8] 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

Risk of anaphylaxis after vaccination in children and adults

PubMed Central

McNeil, Michael M.; Weintraub, Eric S.; Duffy, Jonathan; Sukumaran, Lakshmi; Jacobsen, Steven J.; Klein, Nicola P.; Hambidge, Simon J.; Lee, Grace M.; Jackson, Lisa A.; Irving, Stephanie A.; King, Jennifer P.; Kharbanda, Elyse O.; Bednarczyk, Robert A.; DeStefano, Frank

2015-01-01

Background Anaphylaxis is a potentially life-threatening allergic reaction. The risk of anaphylaxis after vaccination has not been well described in adults or with newer vaccines in children. Objective We sought to estimate the incidence of anaphylaxis after vaccines and describe the demographic and clinical characteristics of confirmed cases of anaphylaxis. Methods Using health care data from the Vaccine Safety Datalink, we determined rates of anaphylaxis after vaccination in children and adults. We first identified all patients with a vaccination record from January 2009 through December 2011 and used diagnostic and procedure codes to identify potential anaphylaxis cases. Medical records of potential cases were reviewed. Confirmed cases met the Brighton Collaboration definition for anaphylaxis and had to be determined to be vaccine triggered. We calculated the incidence of anaphylaxis after all vaccines combined and for selected individual vaccines. Results We identified 33 confirmed vaccine-triggered anaphylaxis cases that occurred after 25,173,965 vaccine doses. The rate of anaphylaxis was 1.31 (95% CI, 0.90-1.84) per million vaccine doses. The incidence did not vary significantly by age, and there was a nonsignificant female predominance. Vaccine-specific rates included 1.35 (95% CI, 0.65-2.47) per million doses for inactivated trivalent influenza vaccine (10 cases, 7,434,628 doses given alone) and 1.83 (95% CI, 0.22-6.63) per million doses for inactivated monovalent influenza vaccine (2 cases, 1,090,279 doses given alone). The onset of symptoms among cases was within 30 minutes (8 cases), 30 to less than 120 minutes (8 cases), 2 to less than 4 hours (10 cases), 4 to 8 hours (2 cases), the next day (1 case), and not documented (4 cases). Conclusion Anaphylaxis after vaccination is rare in all age groups. Despite its rarity, anaphylaxis is a potentially life-threatening medical emergency that vaccine providers need to be prepared to treat. PMID:26452420

Cost-effectiveness of rotavirus vaccination in Albania.

PubMed

Ahmeti, Albana; Preza, Iria; Simaku, Artan; Nelaj, Erida; Clark, Andrew David; Felix Garcia, Ana Gabriela; Lara, Carlos; Hoestlandt, Céline; Blau, Julia; Bino, Silvia

2015-05-07

Rotavirus vaccines have been introduced in several European countries but can represent a considerable cost, particularly for countries that do not qualify for any external financial support. This study aimed to evaluate the cost-effectiveness of introducing rotavirus vaccination into Albania's national immunization program and to inform national decision-making by improving national capacity to conduct economic evaluations of new vaccines. The TRIVAC model was used to assess vaccine impact and cost-effectiveness. The model estimated health and economic outcomes attributed to 10 successive vaccinated birth cohorts (2013-2022) from a government and societal perspective. Epidemiological and economic data used in the model were based on national cost studies, and surveillance data, as well as estimates from the scientific literature. Cost-effectiveness was estimated for both the monovalent (RV1) and pentavalent vaccines (RV5). A multivariate scenario analysis (SA) was performed to evaluate the uncertainty around the incremental cost-effectiveness ratios (ICERs). With 3% discounting of costs and health benefits over the period 2013-2022, rotavirus vaccination in Albania could avert 51,172 outpatient visits, 14,200 hospitalizations, 27 deaths, 950 disability-adjusted life-years (DALYs), and gain 801 life-years. When both vaccines were compared to no vaccination, the discounted cost per DALY averted was US$ 2008 for RV1 and US$ 5047 for RV5 from a government perspective. From the societal perspective the values were US$ 517 and US$ 3556, respectively. From both the perspectives, the introduction of rotavirus vaccine to the Albanian immunization schedule is either cost-effective or highly cost-effective for a range of plausible scenarios. In most scenarios, including the base-case scenario, the discounted cost per DALY averted was less than three times the gross domestic product (GDP) per capita. However, rotavirus vaccination was not cost-effective when rotavirus cases

High resolution identity testing of inactivated poliovirus vaccines

PubMed Central

Mee, Edward T.; Minor, Philip D.; Martin, Javier

2015-01-01

Background Definitive identification of poliovirus strains in vaccines is essential for quality control, particularly where multiple wild-type and Sabin strains are produced in the same facility. Sequence-based identification provides the ultimate in identity testing and would offer several advantages over serological methods. Methods We employed random RT-PCR and high throughput sequencing to recover full-length genome sequences from monovalent and trivalent poliovirus vaccine products at various stages of the manufacturing process. Results All expected strains were detected in previously characterised products and the method permitted identification of strains comprising as little as 0.1% of sequence reads. Highly similar Mahoney and Sabin 1 strains were readily discriminated on the basis of specific variant positions. Analysis of a product known to contain incorrect strains demonstrated that the method correctly identified the contaminants. Conclusion Random RT-PCR and shotgun sequencing provided high resolution identification of vaccine components. In addition to the recovery of full-length genome sequences, the method could also be easily adapted to the characterisation of minor variant frequencies and distinction of closely related products on the basis of distinguishing consensus and low frequency polymorphisms. PMID:26049003

High resolution identity testing of inactivated poliovirus vaccines.

PubMed

Mee, Edward T; Minor, Philip D; Martin, Javier

2015-07-09

Definitive identification of poliovirus strains in vaccines is essential for quality control, particularly where multiple wild-type and Sabin strains are produced in the same facility. Sequence-based identification provides the ultimate in identity testing and would offer several advantages over serological methods. We employed random RT-PCR and high throughput sequencing to recover full-length genome sequences from monovalent and trivalent poliovirus vaccine products at various stages of the manufacturing process. All expected strains were detected in previously characterised products and the method permitted identification of strains comprising as little as 0.1% of sequence reads. Highly similar Mahoney and Sabin 1 strains were readily discriminated on the basis of specific variant positions. Analysis of a product known to contain incorrect strains demonstrated that the method correctly identified the contaminants. Random RT-PCR and shotgun sequencing provided high resolution identification of vaccine components. In addition to the recovery of full-length genome sequences, the method could also be easily adapted to the characterisation of minor variant frequencies and distinction of closely related products on the basis of distinguishing consensus and low frequency polymorphisms. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Selective monovalent cation association and exchange around Keplerate polyoxometalate macroanions in dilute aqueous solutions.

PubMed

Pigga, Joseph M; Teprovich, Joseph A; Flowers, Robert A; Antonio, Mark R; Liu, Tianbo

2010-06-15

The interaction between water-soluble Keplerate polyoxometalate {Mo(72)Fe(30)} macroions and small countercations is explored by laser light scattering, anomalous small-angle X-ray scattering (ASAXS), and isothermal titration calorimetry (ITC) techniques. The macroions are found to be able to select the type of associated counterions based upon the counterions' valence state and hydrated size, when multiple types of additional cations are present in solution (even among different monovalent cations). The preference goes to the cations with higher valences or smaller hydrated sizes if the valences are identical. This counterion exchange process changes the magnitude of the macroion-counterion interaction and, thus, is reflected in the dimension of the self-assembled {Mo(72)Fe(30)} blackberry supramolecular structures. The hydrophilic macroions exhibit a competitive recognition of various monovalent counterions in dilute solutions. A critical salt concentration (CSC) for each type of cation exists for the blackberry formation of {Mo(72)Fe(30)} macroions, above which the blackberry size increases significantly with the increasing total ionic strength in solution. The CSC values are much smaller for cations with higher valences and also decrease with the cations' hydrated size for various monovalent cations. The change of blackberry size corresponding to the change of ionic strength in solution is reversible.

Trivalent Human Papillomavirus (HPV) VLP vaccine covering HPV type 58 can elicit high level of humoral immunity but also induce immune interference among component types.

PubMed

Zhang, Ting; Xu, Yufei; Qiao, Liang; Wang, Youchun; Wu, Xueling; Fan, Dongsheng; Peng, Qinglin; Xu, Xuemei

2010-04-26

Both Human Papillomavirus (HPV) type 16/18 bivalent vaccine and type 16/18/6/11 quadrivalent vaccine have been proved to be safe and effective, and licensed for public use. However, these two vaccines do not quite match the distribution of HPV types in China, Southeast Asia and Latin America, where HPV 58 is highly prevalent. Here we produced three types of virus-like particles (VLPs) in baculovirus expression system, formulated a trivalent vaccine containing HPV 16, 18, and 58 L1 VLPs and examined its in vitro neutralizing titers. This vaccine could induce high level and long-term humoral immunity against the component types. But immune interference was observed when comparing type specific neutralizing antibody levels induced by trivalent vaccine to those by corresponding monovalent vaccines. This kind of interference would become more obvious when formulating more types of VLPs into multivalent vaccines, but could be greatly overcome by decreasing the antigen dosage and adding a proper adjuvant. Copyright 2010 Elsevier Ltd. All rights reserved.

Thermodynamic Origins of Monovalent Facilitated RNA Folding

PubMed Central

Holmstrom, Erik D.; Fiore, Julie L.; Nesbitt, David J.

2012-01-01

Cations have long been associated with formation of native RNA structure and are commonly thought to stabilize the formation of tertiary contacts by favorably interacting with the electrostatic potential of the RNA, giving rise to an “ion atmosphere”. A significant amount of information regarding the thermodynamics of structural transitions in the presence of an ion atmosphere has accumulated and suggests stabilization is dominated by entropic terms. This work provides an analysis of how RNA–cation interactions affect the entropy and enthalpy associated with an RNA tertiary transition. Specifically, temperature-dependent single-molecule fluorescence resonance energy transfer studies have been exploited to determine the free energy (ΔG°), enthalpy (ΔH°), and entropy (ΔS°) of folding for an isolated tetraloop–receptor tertiary interaction as a function of Na+ concentration. Somewhat unexpectedly, increasing the Na+ concentration changes the folding enthalpy from a strongly exothermic process [e.g., ΔH° = −26(2) kcal/mol at 180 mM] to a weakly exothermic process [e.g., ΔH° = −4(1) kcal/mol at 630 mM]. As a direct corollary, it is the strong increase in folding entropy [Δ(ΔS°) > 0] that compensates for this loss of exothermicity for the achievement of more favorable folding [Δ(ΔG°) < 0] at higher Na+ concentrations. In conjunction with corresponding measurements of the thermodynamics of the transition state barrier, these data provide a detailed description of the folding pathway associated with the GAAA tetraloop–receptor interaction as a function of Na+ concentration. The results support a potentially universal mechanism for monovalent facilitated RNA folding, whereby an increasing monovalent concentration stabilizes tertiary structure by reducing the entropic penalty for folding. PMID:22448852

Absorption Spectroscopy Analysis of Calcium-Phosphate Glasses Highly Doped with Monovalent Copper.

PubMed

Jiménez, José A

2016-06-03

CaO-P2 O5 glasses with high concentrations of monovalent copper ions were prepared by a simple melt-quench method through CuO and SnO co-doping. Spectroscopic characterization was carried out by optical absorption with the aim of analyzing the effects of Cu(+) ions on the optical band-gap energies, which were estimated on the basis of indirect-allowed transitions. The copper(I) content is estimated in the CuO/SnO-containing glasses after the assessment of the concentration dependence of Cu(2+) absorption in the visible region for CuO singly doped glasses. An exponential dependence of the change in optical band gaps (relative to the host) with Cu(+) concentration is inferred up to about 10 mol %. However, the entire range is divided into two distinct linear regions that are characterized by different rates of change with respect to concentration: 1) below 5 mol %, where the linear dependence presents a relatively high magnitude of the slope; and 2) from 5-10 mol %, where a lower magnitude of the slope is manifested. With increasing concentration, the mean Cu(+) -Cu(+) interionic distance decreases, thereby decreasing the sensitivity of monovalent copper for light absorption. The decrease in optical band-gap energies is ultimately shown to follow a linear dependence with the interionic distance, suggesting the potential of the approach to gauge the concentration of monovalent copper straightforwardly in amorphous hosts. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The 2009 Influenza Pandemic: An Overview

DTIC Science & Technology

2009-10-15

to receive the pandemic vaccine nonetheless. 42 See, for example, the figure by Sanofi Pasteur (a flu vaccine manufacturer), “A(H1N1) Vaccine ...made by four companies: Sanofi Pasteur Inc., CSL Limited, Novartis Vaccines and Diagnostics Limited, and MedImmune LLC.46 The first three products...officials have procured millions of doses of pandemic flu vaccine , and have begun a voluntary nationwide vaccination program. It is being coordinated

Cost-effectiveness analysis of rotavirus vaccination in Argentina.

PubMed

Urueña, Analía; Pippo, Tomás; Betelu, María Sol; Virgilio, Federico; Hernández, Laura; Giglio, Norberto; Gentile, Ángela; Diosque, Máximo; Vizzotti, Carla

2015-05-07

Rotavirus is a leading cause of severe diarrhea in children under 5. In Argentina, the most affected regions are the Northeast and Northwest, where hospitalizations and deaths are more frequent. This study estimated the cost-effectiveness of adding either of the two licensed rotavirus vaccines to the routine immunization schedule. The integrated TRIVAC vaccine cost-effectiveness model from the Pan American Health Organization's ProVac Initiative (Version 2.0) was used to assess health benefits, costs savings, life-years gained (LYGs), DALYs averted, and cost/DALY averted of vaccinating 10 successive cohorts, from the health care system and societal perspectives. Two doses of monovalent (RV1) rotavirus vaccine and three doses of pentavalent (RV5) rotavirus vaccine were each compared to a scenario assuming no vaccination. The price/dose was US$ 7.50 and US$ 5.15 for RV1 and RV5, respectively. We ran both a national and sub-national analysis, discounting all costs and benefits 3% annually. Our base case results were compared to a range of alternative univariate and multivariate scenarios. The number of LYGs was 5962 and 6440 for RV1 and RV5, respectively. The cost/DALY averted when compared to no vaccination from the health care system and societal perspective was: US$ 3870 and US$ 1802 for RV1, and US$ 2414 and US$ 358 for RV5, respectively. Equivalent figures for the Northeast were US$ 1470 and US$ 636 for RV1, and US$ 913 and US$ 80 for RV5. Therefore, rotavirus vaccination was more cost-effective in the Northeast compared to the whole country; and, in the Northwest, health service's costs saved outweighed the cost of introducing the vaccine. Vaccination with either vaccine compared to no vaccination was highly cost-effective based on WHO guidelines and Argentina's 2011 per capita GDP of US$ 9090. Key variables influencing results were vaccine efficacy, annual loss of efficacy, relative coverage of deaths, vaccine price, and discount rate. Compared to no

Rapid Generation of Replication-Deficient Monovalent and Multivalent Vaccines for Bluetongue Virus: Protection against Virulent Virus Challenge in Cattle and Sheep

PubMed Central

Celma, Cristina C. P.; Boyce, Mark; van Rijn, Piet A.; Eschbaumer, Michael; Wernike, Kerstin; Hoffmann, Bernd; Beer, Martin; Haegeman, Andy; De Clercq, Kris

2013-01-01

Since 1998, 9 of the 26 serotypes of bluetongue virus (BTV) have spread throughout Europe, and serotype 8 has suddenly emerged in northern Europe, causing considerable economic losses, direct (mortality and morbidity) but also indirect, due to restriction in animal movements. Therefore, many new types of vaccines, particularly subunit vaccines, with improved safety and efficacy for a broad range of BTV serotypes are currently being developed by different laboratories. Here we exploited a reverse genetics-based replication-deficient BTV serotype 1 (BTV-1) (disabled infectious single cycle [DISC]) strain to generate a series of DISC vaccine strains. Cattle and sheep were vaccinated with these viruses either singly or in cocktail form as a multivalent vaccine candidate. All vaccinated animals were seroconverted and developed neutralizing antibody responses to their respective serotypes. After challenge with the virulent strains at 21 days postvaccination, vaccinated animals showed neither any clinical reaction nor viremia. Further, there was no interference with protection with a multivalent preparation of six distinct DISC viruses. These data indicate that a very-rapid-response vaccine could be developed based on which serotypes are circulating in the population at the time of an outbreak. PMID:23824810

Rapid generation of replication-deficient monovalent and multivalent vaccines for bluetongue virus: protection against virulent virus challenge in cattle and sheep.

PubMed

Celma, Cristina C P; Boyce, Mark; van Rijn, Piet A; Eschbaumer, Michael; Wernike, Kerstin; Hoffmann, Bernd; Beer, Martin; Haegeman, Andy; De Clercq, Kris; Roy, Polly

2013-09-01

Since 1998, 9 of the 26 serotypes of bluetongue virus (BTV) have spread throughout Europe, and serotype 8 has suddenly emerged in northern Europe, causing considerable economic losses, direct (mortality and morbidity) but also indirect, due to restriction in animal movements. Therefore, many new types of vaccines, particularly subunit vaccines, with improved safety and efficacy for a broad range of BTV serotypes are currently being developed by different laboratories. Here we exploited a reverse genetics-based replication-deficient BTV serotype 1 (BTV-1) (disabled infectious single cycle [DISC]) strain to generate a series of DISC vaccine strains. Cattle and sheep were vaccinated with these viruses either singly or in cocktail form as a multivalent vaccine candidate. All vaccinated animals were seroconverted and developed neutralizing antibody responses to their respective serotypes. After challenge with the virulent strains at 21 days postvaccination, vaccinated animals showed neither any clinical reaction nor viremia. Further, there was no interference with protection with a multivalent preparation of six distinct DISC viruses. These data indicate that a very-rapid-response vaccine could be developed based on which serotypes are circulating in the population at the time of an outbreak.

Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian children in the second year of life.

PubMed

Bhandari, Nita; Rongsen-Chandola, Temsunaro; Bavdekar, Ashish; John, Jacob; Antony, Kalpana; Taneja, Sunita; Goyal, Nidhi; Kawade, Anand; Kang, Gagandeep; Rathore, Sudeep Singh; Juvekar, Sanjay; Muliyil, Jayaprakash; Arya, Alok; Shaikh, Hanif; Abraham, Vinod; Vrati, Sudhanshu; Proschan, Michael; Kohberger, Robert; Thiry, Georges; Glass, Roger; Greenberg, Harry B; Curlin, George; Mohan, Krishna; Harshavardhan, G V J A; Prasad, Sai; Rao, T S; Boslego, John; Bhan, Maharaj Kishan

2014-08-11

Rotavirus gastroenteritis is one of the leading causes of diarrhea in Indian children less than 2 years of age. The 116E rotavirus strain was developed as part of the Indo-US Vaccine Action Program and has undergone efficacy trials. This paper reports the efficacy and additional safety data in children up to 2 years of age. In a double-blind placebo controlled multicenter trial, 6799 infants aged 6-7 weeks were randomized to receive three doses of an oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6, 10, and 14 weeks. The primary outcome was severe (≥11 on the Vesikari scale) rotavirus gastroenteritis. Efficacy outcomes and adverse events were ascertained through active surveillance. We randomly assigned 4532 and 2267 subjects to receive vaccine and placebo, respectively, with over 96% subjects receiving all three doses of the vaccine or placebo. The per protocol analyses included 4354 subjects in the vaccine and 2187 subjects in the placebo group. The overall incidence of severe RVGE per 100 person years was 1.3 in the vaccine group and 2.9 in the placebo recipients. Vaccine efficacy against severe rotavirus gastroenteritis in children up to 2 years of age was 55.1% (95% CI 39.9 to 66.4; p<0.0001); vaccine efficacy in the second year of life of 48.9% (95% CI 17.4 to 68.4; p=0.0056) was only marginally less than in the first year of life [56.3% (95% CI 36.7 to 69.9; p<0.0001)]. The number of infants needed to be immunized to prevent one episode of severe RVGE in the first 2 years of life was 40 (95% CI 28.0 to 63.0) and for RVGE of any severity, it was 21 (95% CI 16.0 to 32.0). Serious adverse events were observed at the same rates in the two groups. None of the eight intussusception events occurred within 30 days of a vaccine dose and all were reported only after the third dose. The sustained efficacy of the 116E in the second year of life is reassuring. The trial is registered with Clinical Trial Registry-India (# CTRI/2010

Vaccine manufacturing and technology: from biotechnological platforms to syntethic epitopes, current viepoint.

PubMed

Ignateva, G A

2016-01-01

The Purposes: the review take into account short history of vaccination practice and development of vaccine technology. In the review we include data from several monographs about manufacturing of vaccines published by authors from such companies as Merck & Co; Sanofi Pasteur; Dynavax Europe/Rhein Biotech GmbH; Latham Biopharm Group; Aridis Pharmaceuticals LLC; Genentech; Amgen; Shamir Biologics LLC; Biopharm Services US; Novartis Pharma AG, аnd several research centers: Laboratory of Bacterial Polysaccharides, Center for Biologics Evaluation and Research; Purdue University, West Lafayette, IN, US; Department of Pharmaceutical Chemistry, Univ. Of Kansas; Max Planck Institute for dynamics of Complex Technical Systems; Fraunhofer USA Center for Molecular Biotechnology; US Dep. of Agriculture Animal and Plant Health Inspection Service, etc. In historic literature there are data about inoculation practices in antique China, Persia, India, Byzantium, native Americans, some African population. In modern immunology since the end of XIX century the vaccines were produced at the in vivo platforms - in animals (rabbits, mice, cows). Since 1931 due to E. Goodpasture' elaboration most virus vaccines were and are produced at the in ovo platform. In 1949 J.F. Enders elaborated large-scale polio virus production in the primary culture of monkey kidney cells in vitro. Up to day primary culture of chiken embrio fibroblasts are used to large-scale production of vaccine viruses of measles, mumps, rabies. Since 2000-th in Western countries most part of virus vaccines were began to produced via a cultivation in continuous tumor cell lines. The last technology is the most low cost for large-scale production of vaccines. We review several new biotechnological platforms for the production of the recombinant protein or virus-like particles as subunit vaccines: plant system, algae, mushrooms, insect cells, etc. Beside of good purpose of vaccination - prophylactic of several infectious

Lasting immune memory against hepatitis B in 12-13-year-old adolescents previously vaccinated with 4 doses of hexavalent DTPa-HBV-IPV/Hib vaccine in infancy.

PubMed

Behre, Ulrich; Van Der Meeren, Olivier; Crasta, Priya; Hanssens, Linda; Mesaros, Narcisa

2016-11-01

Vaccinating infants against hepatitis B virus (HBV) is the most effective way of preventing the disease. However, since HBV exposure can increase during adolescence, it is essential that antibody persistence is maintained. We evaluated the antibody persistence and immune memory against hepatitis B, in 12-13 y olds who had received complete primary + booster vaccination with diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenza type b (DTPa-HBV-IPV/Hib) vaccine in infancy. Open phase-IV study conducted at 12 centers in Germany [NCT02052661]. Adolescents aged 12-13 y, vaccinated with 4 doses of DTPa-HBV-IPV/Hib (Infanrix hexa™, GSK Vaccines) in infancy, received a single challenge dose of monovalent pediatric hepatitis B vaccine (Engerix™-B Kinder; GSK Vaccines). Blood samples were taken before and 1-month post-challenge to measure anti-hepatitis B (anti-HBs) antibodies using a chemiluminescence immunoassay (seroprotection cut-off: ≥10 mIU/ml). Post-challenge adverse events (AEs) were monitored. 300 subjects were vaccinated; of 293 subjects in the ATP immunogenicity cohort, 60.5% had pre-challenge anti-HBs antibodies ≥10 mIU/ml, which rose to 97.6% post-challenge (≥100 mIU/ml in 94.1%). An anamnestic response was seen in 96.5% subjects. A 150-fold increase in antibody geometric mean concentrations was observed (22.4 to 3502.6 mIU/ml). Pain (44%) and fatigue (24.3%) were the most frequent solicited local and general AEs, respectively; 14.7% subjects reported unsolicited symptoms during the 31-day post-vaccination period. Two vaccine-unrelated serious AEs occurred. Vaccination with DTPa-HBV-IPV/Hib in infancy induces sustained seroprotection and immune memory against HBV, as shown by the strong anamnestic response to the hepatitis B vaccine challenge in 12-13 year-old adolescents.

Lot-to-lot consistency, safety and immunogenicity of 3 lots of Haemophilus influenzae type b conjugate vaccine: results from a phase III randomized, multicenter study in infants.

PubMed

Klein, Nicola P; Abu-Elyazeed, Remon; Cornish, Matthew; Leonardi, Michael L; Weiner, Leonard B; Silas, Peter E; Grogg, Stanley E; Varman, Meera; Frenck, Robert W; Cheuvart, Brigitte; Baine, Yaela; Miller, Jacqueline M; Leyssen, Maarten; Mesaros, Narcisa; Roy-Ghanta, Sumita

2017-06-16

Vaccination against Haemophilus influenzae type b (Hib) is included in routine pediatric immunization schedule in the United States. Previous vaccine shortages have created the need for additional options for Hib vaccination. This phase III, randomized, multi-centered study (NCT01000974) evaluated the safety and immunogenicity of a monovalent tetanus toxoid-conjugate Hib vaccine (Hib-TT) compared to a monovalent (Hib-TT control) and a combination Hib-TT vaccine. We hierarchically assessed lot-to-lot consistency of 3 Hib-TT lots and non-inferiority of Hib-TT to Hib-TT control. We co-administered routine pediatric vaccines with Hib-TT vaccines at 2, 4, 6months (primary vaccination) and 15-18months of age (booster vaccination). We recorded adverse events (AEs) for 4 (solicited) and 31days (unsolicited) post-vaccination and serious AEs (SAEs) throughout the study. Of 4009 enrolled children, 3086 completed booster phase. Lot-to-lot consistency was not demonstrated. The study met statistical criteria for non-inferiority of Hib-TT to Hib-TT control in terms of immune responses to Hib and co-administered vaccines' antigens, but not in terms of participants achieving post-primary vaccination anti-PRP levels ≥1µg/mL. Because of the hierarchical nature of the objectives, non-inferiority could not be established. In all groups, 92.5-96.7% and 99.6-100% of participants achieved anti-PRP levels ≥0.15µg/mL, while 78.3-89.8% and 97.9-99.1% had anti-PRP levels ≥1µg/mL, post-primary and post-booster vaccination, respectively. Immune responses to co-administered vaccines and reported incidence of AEs were comparable among groups. We recorded SAEs for 107/2963 (3.6%), 24/520 (4.6%), and 21/520 (4.0%) children post-primary vaccination, and 29/2337 (1.2%), 4/435 (0.9%), and 2/400 (0.5%) children post-booster vaccination with Hib-TT, Hib-TT control and combination Hib-TT vaccine, respectively; 6/5330 (0.1%) SAEs in the Hib-TT groups were considered vaccine-related. Hib

T-cell-mediated immune response to pneumococcal conjugate vaccine (PCV-13) and tetanus toxoid vaccine in patients with moderate-to-severe psoriasis during tofacitinib treatment.

PubMed

Winthrop, Kevin L; Korman, Neil; Abramovits, William; Rottinghaus, Scott T; Tan, Huaming; Gardner, Annie; Mukwaya, Geoffrey; Kaur, Mandeep; Valdez, Hernan

2018-06-01

Psoriasis is often treated with immunomodulatory therapies that can affect the immune response to common antigens. Tofacitinib is an oral Janus kinase inhibitor. To characterize the effect of long-term exposure to tofacitinib 10 mg twice daily on T-cell function in psoriasis patients. Patients completing at least 3 months' continuous treatment with tofacitinib 10 mg twice daily were vaccinated with T-cell-dependent vaccines (monovalent tetanus toxoid and 13-valent pneumococcal conjugate [PCV-13]). Patients were assessed at baseline (before vaccination) and then again 4 weeks after vaccination. For PCV-13, we evaluated serotype-specific, opsonophagocytic antibody responses, and for tetanus toxoid, we evaluated humoral responses. Among 60 patients who completed the study, the geometric mean fold rise from baseline for the 13 PCV serotypes at 4 weeks postvaccination varied from 8.3 (serotype 3) to 101.9 (serotype 6A). Similar results were observed for patients with and without lymphopenia at baseline. For tetanus toxoid, 51 (88%) patients had ≥2-fold and 35 (60%) patients had ≥4-fold rise in antibody concentration. There was no placebo control. Most psoriasis patients who receive tofacitinib can mount satisfactory T-cell-dependent responses to PCV-13 and tetanus vaccines. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

A genetically inactivated two-component acellular pertussis vaccine, alone or combined with tetanus and reduced-dose diphtheria vaccines, in adolescents: a phase 2/3, randomised controlled non-inferiority trial.

PubMed

Sricharoenchai, Sirintip; Sirivichayakul, Chukiat; Chokephaibulkit, Kulkanya; Pitisuttithum, Punnee; Dhitavat, Jittima; Pitisuthitham, Arom; Phongsamart, Wanatpreeya; Boonnak, Kobporn; Lapphra, Keswadee; Sabmee, Yupa; Wittawatmongkol, Orasri; Chinwangso, Pailinrut; Poredi, Indrajeet Kumar; Petre, Jean; Thai, Pham Hong; Viviani, Simonetta

2018-01-01

Increasing evidence shows that protection induced by acellular pertussis vaccines is short-lived, requiring repeated booster vaccination to control pertussis disease. We aimed to assess the safety and immunogenicity of a recombinant acellular pertussis vaccine containing genetically inactivated pertussis toxin and filamentous haemagglutinin, as either a monovalent vaccine (aP [PTgen/FHA] ) or in combination with tetanus and reduced-dose diphtheria vaccines (TdaP [PTgen/FHA] ), versus a licensed tetanus and reduced-dose diphtheria and acellular pertussis combination vaccine (Tdap). We did this phase 2/3, randomised controlled non-inferiority trial at two sites in Bangkok, Thailand. Healthy adolescents (aged 12-17 years) were randomly assigned (1:1:1), via a computer-generated randomisation list with block sizes of three, to receive one dose (0·5 mL) of aP (PTgen/FHA) , TdaP (PTgen/FHA) , or Tdap (comparator). Clinical research staff responsible for participant randomisation, vaccine preparation and administration, and accountability were aware of group allocation. However, allocation was concealed from all other site study staff, data management personnel, statisticians, laboratory staff, and study participants. The primary outcome was non-inferior immunogenicity of TdaP (PTgen/FHA) to Tdap based on seroconversion rates (a four-fold increase or more) for pertussis toxin and filamentous haemagglutinin IgG antibodies 28 days after vaccination, with a predefined 10% margin of equivalence. We did analysis by per protocol. This study is registered with the Thai Clinical Trial Registry, number TCTR20150703002. Between July 6 and Aug 20, 2015, we allocated 450 participants to receive one dose of TdaP (PTgen/FHA) (n=150), aP (PTgen/FHA) (n=150), or comparator Tdap (n=150). 28 days after vaccination, seroconversion rates for anti-pertussis toxin IgG were 96·6% (95% CI 93·8-99·5; n=144) in the TdaP (PTgen/FHA) group and 55·0% (47·1-63·0; n=82) in the comparator Tdap

Entropic effects in the electric double layer of model colloids with size-asymmetric monovalent ions

NASA Astrophysics Data System (ADS)

Guerrero-García, Guillermo Iván; González-Tovar, Enrique; Olvera de la Cruz, Mónica

2011-08-01

The structure of the electric double layer of charged nanoparticles and colloids in monovalent salts is crucial to determine their thermodynamics, solubility, and polyion adsorption. In this work, we explore the double layer structure and the possibility of charge reversal in relation to the size of both counterions and coions. We examine systems with various size-ratios between counterions and coions (ion size asymmetries) as well as different total ion volume fractions. Using Monte Carlo simulations and integral equations of a primitive-model electric double layer, we determine the highest charge neutralization and electrostatic screening near the electrified surface. Specifically, for two binary monovalent electrolytes with the same counterion properties but differing only in the coion's size surrounding a charged nanoparticle, the one with largest coion size is found to have the largest charge neutralization and screening. That is, in size-asymmetric double layers with a given counterion's size the excluded volume of the coions dictates the adsorption of the ionic charge close to the colloidal surface for monovalent salts. Furthermore, we demonstrate that charge reversal can occur at low surface charge densities, given a large enough total ion concentration, for systems of monovalent salts in a wide range of ion size asymmetries. In addition, we find a non-monotonic behavior for the corresponding maximum charge reversal, as a function of the colloidal bare charge. We also find that the reversal effect disappears for binary salts with large-size counterions and small-size coions at high surface charge densities. Lastly, we observe a good agreement between results from both Monte Carlo simulations and the integral equation theory across different colloidal charge densities and 1:1-elec-trolytes with different ion sizes.

Delayed Dosing of Oral Rotavirus Vaccine Demonstrates Decreased Risk of Rotavirus Gastroenteritis Associated With Serum Zinc: A Randomized Controlled Trial.

PubMed

Colgate, E Ross; Haque, Rashidul; Dickson, Dorothy M; Carmolli, Marya P; Mychaleckyj, Josyf C; Nayak, Uma; Qadri, Firdausi; Alam, Masud; Walsh, Mary Claire; Diehl, Sean A; Zaman, K; Petri, William A; Kirkpatrick, Beth D

2016-09-01

Rotavirus is the world's leading cause of childhood diarrheal death. Despite successes, oral rotavirus vaccines are less effective in developing countries. In an urban slum of Dhaka, we performed active diarrhea surveillance to evaluate monovalent G1P[8] rotavirus vaccine (RV1) efficacy and understand variables contributing to risk of rotavirus diarrhea (RVD). We performed a randomized controlled trial of monovalent oral rotavirus vaccine (RV1). Seven hundred healthy infants received RV1 or no RV1 (1:1) using delayed dosing (10 and 17 weeks) and were followed for 1 year. Intensive diarrhea surveillance was performed. The primary outcome was ≥1 episode of RVD. Nutritional, socioeconomic, and immunologic factors were assessed by logistic regression best-subsets analysis for association with risk of RVD and interactions with vaccine arm. Incidence of all RVD was 38.3 cases per 100 person-years. Per-protocol RV1 efficacy was 73.5% (95% confidence interval [CI], 45.8%-87.0%) against severe RVD and 51% (95% CI, 33.8%-63.7%) against all RVD. Serum zinc level (odds ratio [OR], 0.77; P = .002) and lack of rotavirus immunoglobulin A (IgA) seroconversion (OR, 1.95; P = .018) were associated with risk of RVD, independent of vaccination status. Water treatment and exclusive breastfeeding were of borderline significance. Factors not associated with RVD included height for age at 10 weeks, vitamin D, retinol binding protein, maternal education, household income, and sex. In an urban slum with high incidence of RVD, the efficacy of RV1 against severe RVD was higher than anticipated in the setting of delayed dosing. Lower serum zinc level and lack of IgA seroconversion were associated with increased risk of RVD independent of vaccination. NCT01375647. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

A dose-range study assessing immunogenicity and safety of one dose of a new candidate meningococcal serogroups A, C, W-135, Y tetanus toxoid conjugate (MenACWY-TT) vaccine administered in the second year of life and in young children.

PubMed

Knuf, M; Kieninger-Baum, D; Habermehl, P; Muttonen, P; Maurer, H; Vink, P; Poolman, J; Boutriau, D

2010-01-08

Meningococcal disease incidence is highest in young children, yet a tetravalent conjugate vaccine is currently not available for this age group. This study evaluated a single dose of four different ACWY-TT conjugate vaccine formulations in 240 toddlers (12-14 months) and 268 children (3-5 years) compared to licensed age-appropriate control vaccines. In toddlers, rSBA-MenC GMTs for the selected formulation were statistically higher than after monovalent-MenC-conjugate vaccine. In children, rSBA-GMTs against each serogroup were statistically higher than after tetravalent polysaccharide vaccine. The safety profile was comparable to licensed controls. The new ACWY-TT conjugate vaccine promises high seroprotection levels against meningococcal disease from 1 year of age.

A Single Serine Residue Determines Selectivity to Monovalent Metal Ions in Metalloregulators of the MerR Family

PubMed Central

Ibáñez, María M.

2015-01-01

ABSTRACT MerR metalloregulators alleviate toxicity caused by an excess of metal ions, such as copper, zinc, mercury, lead, cadmium, silver, or gold, by triggering the expression of specific efflux or detoxification systems upon metal detection. The sensor protein binds the inducer metal ion by using two conserved cysteine residues at the C-terminal metal-binding loop (MBL). Divalent metal ion sensors, such as MerR and ZntR, require a third cysteine residue, located at the beginning of the dimerization (α5) helix, for metal coordination, while monovalent metal ion sensors, such as CueR and GolS, have a serine residue at this position. This serine residue was proposed to provide hydrophobic and steric restrictions to privilege the binding of monovalent metal ions. Here we show that the presence of alanine at this position does not modify the activation pattern of monovalent metal sensors. In contrast, GolS or CueR mutant sensors with a substitution of cysteine for the serine residue respond to monovalent metal ions or Hg(II) with high sensitivities. Furthermore, in a mutant deleted of the Zn(II) exporter ZntA, they also trigger the expression of their target genes in response to either Zn(II), Cd(II), Pb(II), or Co(II). IMPORTANCE Specificity in a stressor's recognition is essential for mounting an appropriate response. MerR metalloregulators trigger the expression of specific resistance systems upon detection of heavy metal ions. Two groups of these metalloregulators can be distinguished, recognizing either +1 or +2 metal ions, depending on the presence of a conserved serine in the former or a cysteine in the latter. Here we demonstrate that the serine residue in monovalent metal ion sensors excludes divalent metal ion detection, as its replacement by cysteine renders a pan-metal ion sensor. Our results indicate that the spectrum of signals detected by these sensors is determined not only by the metal-binding ligand availability but also by the metal-binding cavity

Use of oral polio vaccine for polio eradication.

PubMed

Bhatnagar, Pankaj; Bahl, Sunil; Biswal, P

2005-12-01

The experience in three of the world's six WHO Regions (the Americas, the European and the Western Pacific Regions) shows that OPV is the right choice for stopping wild poliovirus transmission. Polio can be eradicated by carrying out SIAs to supplement routine vaccination and by placing added emphasis on reaching every child during every polio round. Monovalent OPV will be key tool in helping us to achieve the goal of polio eradication. The task of global eradication of poliomyelitis is uphill but well within our reach. A strong will and political commitment by the Government of India and effective contributions by each one of us will make our nation polio-free world in the near future.

Cellular and humoral immunity after vaccination or natural mumps infection.

PubMed

Terada, Kihei; Hagihara, Kimiko; Oishi, Tomohiro; Miyata, Ippei; Akaike, Hiroto; Ogita, Satoko; Ohno, Naoki; Ouchi, Kazunobu

2017-08-01

This study measured cell-mediated immunity (CMI) and serum antibody to clarify the basis of breakthrough after vaccination and reinfection after mumps. From a pool of 54 college students, 17 seronegative subjects and 14 subjects with intermediate level of antibodies against mumps were vaccinated with a monovalent mumps vaccine, and CMI was assessed using interferon-γ release assay. CMI positivity according to pre-existing antibody level, defined as titer <2.0 index units, negative; 2.0-3.9 index units, intermediate; and ≥4.0 index units, positive, was 8/17 (47.1%), 9/14 (64.3%) and 19/23 (82.6%) before vaccination, respectively. Of the 17 seronegative subjects, seven (41.2%) had a history of vaccination and/or natural infection, four (57.1%) of whom were CMI positive or intermediate. Ten (71%) of 14 subjects with intermediate antibody level had a history of vaccination or natural infection, eight (80%) of whom were CMI positive or intermediate. After vaccination the interferon (IFN)-γ and antibody titers increased significantly, but seven (41.2%) of the 17 seronegative subjects and 13 (92.9%) of the 14 intermediate-level subjects tested positive for both antibody and CMI. In a comparison of the natural infection group (confirmed as IgG seropositive and/or CMI positive without vaccination) versus the vaccination group, IgG antibody titer (mean ± SD) was 14.4 ± 8.0 versus 3.6 ± 2.4 index units (P < 0.01) and IFN-γ was 122.7 ± 90.0 pg/mL versus 59.5 ± 37.8 pg/mL (P > 0.05), respectively. Vaccination or even natural mumps infection did not always induce both cellular and humoral immunity. © 2017 Japan Pediatric Society.

Evaluation of T and B memory cell responses elicited by the pandemic H1N1 vaccine in HIV-infected and HIV-uninfected individuals.

PubMed

Sun, Peifang; Crum-Cianflone, Nancy F; Defang, Gabriel; Williams, Maya; Ganesan, Anuradha; Agan, Brian K; Lalani, Tahaniyat; Whitman, Timothy; Brandt, Carolyn; Burgess, Timothy H

2017-10-27

This study was to compare B and T memory cells elicited by a single dose monovalent 2009 influenza A (H1N1) vaccine (strain A/California/7/2009 H1N1) in HIV + and HIV - groups, and to analyze the impact of the prior seasonal vaccines to the immunogenicity of this vaccine. Blood samples were collected before vaccination (day 0) and at days 28 and 180. Participants were categorized into HIV - /LAIV, HIV - /TIV and HIV + /TIV subgroups according to the trivalent live-attenuated or inactivated (LAIV or TIV) seasonal influenza vaccines they received previously. The IgG + memory B cells (B Mem ) and IFNγ + T cells were measured against antigens including the H1N1 vaccine, the hemagglutinin (HA) and neuraminidase (NA) proteins or peptide pools of the pandemic and the seasonal H1N1 strains, respectively. Overall B Mem responses increased significantly at day 28 but returned to baseline by day 180 in all three subgroups. The average frequency of the H1N1-specific B Mem at day 28 for the HIV - /LAIV, HIV - /TIV and HIV + /TIV groups was 2.14%, 1.26% and 1.67%, respectively, and the average fold change was 14.39, 3.81 and 3.93, respectively. The differences of B Mem between HIV - /LAIV and the two TIV subgroups were significant. For the IFNγ response, the overall spot counts ranged widely between 0 and 958/10 6 PBMCs. The group average spot counts to H1N1 vaccine was 89, 102, and 30 at day 28 for HIV - /LAIV, HIV - /TIV and HIV + /TIV subgroups, respectively. The average increase of IFNγ response at day 28 vs day 0 in all three subgroups did not reach 2-fold. Participants with a prior LAIV seasonal vaccine, as compared to a TIV seasonal vaccine, responded significantly better to the monovalent H1N1 vaccine. Excluding LAIV participants, no difference was seen between the HIV + and HIV - subject groups in terms of B Mem . The B Mem response declined at 6months. Copyright © 2017. Published by Elsevier Ltd.

Predicting 3D structure and stability of RNA pseudoknots in monovalent and divalent ion solutions.

PubMed

Shi, Ya-Zhou; Jin, Lei; Feng, Chen-Jie; Tan, Ya-Lan; Tan, Zhi-Jie

2018-06-01

RNA pseudoknots are a kind of minimal RNA tertiary structural motifs, and their three-dimensional (3D) structures and stability play essential roles in a variety of biological functions. Therefore, to predict 3D structures and stability of RNA pseudoknots is essential for understanding their functions. In the work, we employed our previously developed coarse-grained model with implicit salt to make extensive predictions and comprehensive analyses on the 3D structures and stability for RNA pseudoknots in monovalent/divalent ion solutions. The comparisons with available experimental data show that our model can successfully predict the 3D structures of RNA pseudoknots from their sequences, and can also make reliable predictions for the stability of RNA pseudoknots with different lengths and sequences over a wide range of monovalent/divalent ion concentrations. Furthermore, we made comprehensive analyses on the unfolding pathway for various RNA pseudoknots in ion solutions. Our analyses for extensive pseudokonts and the wide range of monovalent/divalent ion concentrations verify that the unfolding pathway of RNA pseudoknots is mainly dependent on the relative stability of unfolded intermediate states, and show that the unfolding pathway of RNA pseudoknots can be significantly modulated by their sequences and solution ion conditions.

The protective capacity of high payload FMDV A22 IRQ vaccine in sheep against direct-contact challenge with a heterologous, contemporary FMDV A strain from South East Asia.

PubMed

Horsington, Jacquelyn; Nfon, Charles; Bittner, Hilary; Durr, Peter A; Singanallur, Nagendrakumar; Alexandersen, Soren; Vosloo, Wilna

2018-01-01

Foot-and-mouth disease (FMD) is an acute, highly contagious viral disease of domestic and wild cloven-hoofed animals, caused by FMD virus (FMDV). An FMD outbreak can cause major production losses and have significant implications for trade. Vaccination can assist in controlling the disease, and emergency vaccination using high antigen payload vaccines (>6 PD50/dose) is considered an important control approach in the event of an outbreak. In recent years there has been a divergence of serotype A viruses in South East Asia (SEA) into several distinct genetic and antigenic clusters. Numerous variants were found to poorly match serotype A vaccines commonly included in international antigen banks. This study examined the ability of single vaccination with high-potency monovalent A22 IRQ vaccine to protect sheep following challenge with the A/VIT/15/2012 strain, just four days following vaccination. The vaccine proved effective at limiting clinical disease but did not prevent infection.

Effective Protection Induced by a Monovalent DNA Vaccine against Dengue Virus (DV) Serotype 1 and a Bivalent DNA Vaccine against DV1 and DV2 in Mice.

PubMed

Zheng, Xiaoyan; Chen, Hui; Wang, Ran; Fan, Dongying; Feng, Kaihao; Gao, Na; An, Jing

2017-01-01

Dengue virus (DV) is the causal pathogen of dengue fever, which is one of the most rapidly spread mosquito-borne disease worldwide and has become a severe public health problem. Currently, there is no specific treatment for dengue; thus, a vaccine would be an effective countermeasure to reduce the morbidity and mortality. Although, the chimeric Yellow fever dengue tetravalent vaccine has been approved in some countries, it is still necessary to develop safer, more effective, and less costly vaccines. In this study, a DNA vaccine candidate pVAX1-D1ME expressing the prME protein of DV1 was inoculated in BALB/c mice via intramuscular injection or electroporation, and the immunogenicity and protection were evaluated. Compared with traditional intramuscular injection, administration with 50 μg pVAX1-D1ME via electroporation with three immunizations induced persistent humoral and cellular immune responses and effectively protected mice against lethal DV1 challenge. In addition, immunization with a bivalent vaccine consisting of pVAX1-D1ME and pVAX1-D2ME via electroporation generated a balanced IgG response and neutralizing antibodies against DV1 and DV2 and could protect mice from lethal challenge with DV1 and DV2. This study sheds new light on developing a dengue tetravalent DNA vaccine.

Superconducting state parameters of monovalent and polyvalent amorphous

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

Sonvane, Y. A., E-mail: yas@ashd.svnit.ac.in; Patel, H. P., E-mail: patel.harshal2@gmail.com; Thakor, P. B., E-mail: pbthakor@rediffmail.com

2015-08-28

In the present study deals, we have calculated superconducting state parameter (SSP) like electron-phonon coupling strength λ, coulomb pseudo potential, μ*, transition temperature Tc, isotope effect exponent α and effective interaction strength N{sub 0}V of monovalent (Li), divalent (Zn), trivalent (In) and tetravalent (Pb) amorphous. To carry out this work we have used our newly constructed model pseudo potential to describe electron ion interaction along with three different local field correction functions like Hartree, Taylor and Sarkar et al. The present results are found in good agreement with other available theoretical as well as experimental data.

Superconducting state parameters of monovalent and polyvalent amorphous

NASA Astrophysics Data System (ADS)

Sonvane, Y. A.; Patel, H. P.; Thakor, P. B.

2015-08-01

In the present study deals, we have calculated superconducting state parameter (SSP) like electron-phonon coupling strength λ, coulomb pseudo potential, μ*, transition temperature Tc, isotope effect exponent α and effective interaction strength N0V of monovalent (Li), divalent (Zn), trivalent (In) and tetravalent (Pb) amorphous. To carry out this work we have used our newly constructed model pseudo potential to describe electron ion interaction along with three different local field correction functions like Hartree, Taylor and Sarkar et al. The present results are found in good agreement with other available theoretical as well as experimental data.

Cross-neutralisation of Australian brown snake, taipan and death adder venoms by monovalent antibodies.

PubMed

Isbister, Geoffrey K; O'Leary, Margaret A; Hagan, Jessica; Nichols, Kearney; Jacoby, Tammy; Davern, Kathleen; Hodgson, Wayne C; Schneider, Jennifer J

2010-01-08

An understanding of the cross-neutralisation of snake venoms by antibodies is important for snake antivenom development. We investigated the cross-neutralisation of brown snake (Pseudonaja textilis) venom, taipan (Oxyuranus scutellatus) venom and death adder (Acanthophis antarcticus) with commercial antivenoms and monovalent anti-snake IgG, using enzyme immunoassays, in vitro clotting and neurotoxicity assays. Each commercial antivenom bound all three venoms, and neutralised clotting activity of brown snake and taipan venoms and neurotoxicity of death adder venom. The 'in-house' monovalent anti-snake venom IgG raised against procoagulant brown snake and taipan venoms, did not neutralise the neurotoxic effects of death adder venom. However, they did cross-neutralise the procoagulant effects of both procoagulant venoms. This supports the idea of developing antivenoms against groups of snake toxins rather than individual snake venoms.

Lipid domains in zwitterionic-anionic lipid mixtures induced by combined effect of monovalent and divalent ions

NASA Astrophysics Data System (ADS)

Xu, Hongcheng; Ganesan, Sai; Matysiak, Silvina

Lipid domain formation is an important process for many cellular processes. In experiment, the effects of Ba2+, Sr2+, Ca2+ and Mg2+ in inducing lateral phase separation in the binary phosphatidylcholine-phosphatidylserine (PC-PS) bilayer are quite different, of which the molecular mechanism remains to be understood. We have explored the effect of monovalent (MI) and divalent (MII) cationic radii on lipid domain formation in mixed zwitterionic-anionic lipid bilayers. We propose a mechanism for the formation of divalent-cation-induced lipid domains based on MD simulations with our Water-Explicit Polarizable MEMbrane (WEPMEM) coarse-grained model, which uses PC as the model for zwitterionic and PS for anionic lipids. Lipid aggregation only occurs with limited range of monovalent and divalent ion sizes in agreement with experimental observations. More ordering and closer packing of the lipids are noted within the domains, which correlate with bilayer thickness, curvature and lipid asymmetry. The results of the simulations reveal that the lipid domain consists of MII-mediated anionic lipid dimer/trimer complexes bridged by monovalent ions MI and provide a stereochemical insight in understanding the experimentally observed calcium-induced phase separation.

Development of a new live attenuated mumps virus vaccine in human diploid cells.

PubMed

Sassani, A; Mirchamsy, H; Shafyi, A; Ahourai, P; Razavi, J; Gholami, M R; Mohammadi, A; Ezzi, A; Rahmani, M; Fateh, G

1991-07-01

A new live attenuated mumps vaccine was developed in human diploid cells. The S-12 virus was isolated from a 10-year-old girl showing typical symptoms of mumps infection, the diagnosis was confirmed by a pediatrician. The virus was isolated in green monkey kidney cells, without passage in chick embryo cavity or chick embryo fibroblasts. Attenuation of the wild virus was performed by serial passages in human diploid cells (MRC-5). The attenuated virus was characterized by identity tests, as well as by a reduction in plaque size, as marker tests. The virus was free from adventitious agents and safe for laboratory animals as well as for monkeys. The reactogenicity and immunogenicity of the S-12 virus for man was investigated by administration of a monovalent vaccine to 20 seronegative adult male volunteers and 30 children aged 1 to 5 years without history of mumps infection or vaccination. Seroconversion was obtained in 95% of the vaccinees. The new vaccine has the advantage of not requiring specific pathogen-free eggs, and being free from avian proteins and therefore can be used in sensitized patients.

Safety, immunogenicity and dose ranging of a new Vi-CRM₁₉₇ conjugate vaccine against typhoid fever: randomized clinical testing in healthy adults.

PubMed

van Damme, Pierre; Kafeja, Froukje; Anemona, Alessandra; Basile, Venere; Hilbert, Anne Katrin; De Coster, Ilse; Rondini, Simona; Micoli, Francesca; Qasim Khan, Rana M; Marchetti, Elisa; Di Cioccio, Vito; Saul, Allan; Martin, Laura B; Podda, Audino

2011-01-01

Typhoid fever causes more than 21 million cases of disease and 200,000 deaths yearly worldwide, with more than 90% of the disease burden being reported from Asia. Epidemiological data show high disease incidence in young children and suggest that immunization programs should target children below two years of age: this is not possible with available vaccines. The Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM₁₉₇) for infant vaccination concomitantly with EPI vaccines, either starting at 6 weeks with DTP or at 9 months with measles vaccine. We report the results from a Phase 1 and a Phase 2 dose ranging trial with Vi-CRM₁₉₇ in European adults. Following randomized blinded comparison of single vaccination with either Vi-CRM₁₉₇ or licensed polysaccharide vaccines (both containing 25·0 µg of Vi antigen), a randomised observer blinded dose ranging trial was performed in the same center to compare three concentrations of Vi-CRM₁₉₇ (1·25 µg, 5·0 µg and 12·5 µg of Vi antigen) with the polysaccharide vaccine. All vaccines were well tolerated. Compared to the polysaccharide vaccine, Vi-CRM₁₉₇ induced a higher incidence of mild to moderate short lasting local pain. All Vi-CRM₁₉₇ formulations induced higher Vi antibody levels compared to licensed control, with clear dose response relationship. Vi-CRM₁₉₇ did not elicit safety concerns, was highly immunogenic and is therefore suitable for further clinical testing in endemic populations of South Asia. ClinicalTrials.gov NCT01123941 NCT01193907.

[Vaccines: producers in countries of the Southern hemisphere].

PubMed

Bertrand, J J

2007-08-01

Vaccine producers in southern hemisphere countries now contribute significantly to global output. In 2006 southern hemisphere countries accounted for more than 10% of the total worldwide production with a progression approximately 70% greater than all producers combined in the two-year period between 2004 and 2006. Though difficult to measure, production in volume is higher due to lower prices practiced in most of these countries. For many years before the 1980s, production was scattered among numerous limited-scale companies. Most were founded at the initiative of governments striving to cover the needs of the population for essential vaccines. A number of institutions and private structures such as Institut Pasteur Production, Connaught Laboratories, and Institut Merieux have also set up production facilities. Today's producers can be divided into two categories, i.e., local producers that produce mainly monovalent vaccines and worldwide producers with strong R&D investment programs. Local producers are located mainly in large southern hemisphere countries such as China, India, Brazil, and Indonesia as well as in eastern countries. For the most dynamic companies, international development is focused on southern hemisphere countries excluding North America and Europe. With the support international organization such as WHO, UNICEF and GAVI, alliances are now being formed and networks are being organized in an effort to ensure reliable supplies of high quality vaccines at affordable prices in developing countries. The contribution of these producers will increase for the greater benefit of the people living in the southern hemisphere.

Towards ambient temperature-stable vaccines: the identification of thermally stabilizing liquid formulations for measles virus using an innovative high-throughput infectivity assay.

PubMed

Schlehuber, Lisa D; McFadyen, Iain J; Shu, Yu; Carignan, James; Duprex, W Paul; Forsyth, William R; Ho, Jason H; Kitsos, Christine M; Lee, George Y; Levinson, Douglas A; Lucier, Sarah C; Moore, Christopher B; Nguyen, Niem T; Ramos, Josephine; Weinstock, B André; Zhang, Junhong; Monagle, Julie A; Gardner, Colin R; Alvarez, Juan C

2011-07-12

As a result of thermal instability, some live attenuated viral (LAV) vaccines lose substantial potency from the time of manufacture to the point of administration. Developing regions lacking extensive, reliable refrigeration ("cold-chain") infrastructure are particularly vulnerable to vaccine failure, which in turn increases the burden of disease. Development of a robust, infectivity-based high throughput screening process for identifying thermostable vaccine formulations offers significant promise for vaccine development across a wide variety of LAV products. Here we describe a system that incorporates thermal stability screening into formulation design using heat labile measles virus as a prototype. The screening of >11,000 unique formulations resulted in the identification of liquid formulations with marked improvement over those used in commercial monovalent measles vaccines, with <1.0 log loss of activity after incubation for 8h at 40°C. The approach was shown to be transferable to a second unrelated virus, and therefore offers significant promise towards the optimization of formulation for LAV vaccine products. Copyright © 2011 Elsevier Ltd. All rights reserved.

Effectiveness of rotavirus vaccines against hospitalisations in Japan.

PubMed

Fujii, Yoshiyuki; Noguchi, Atsuko; Miura, Shinobu; Ishii, Haruka; Nakagomi, Toyoko; Nakagomi, Osamu; Takahashi, Tsutomu

2017-07-11

In Japan, rotavirus hospitalisation occurs at a rate from 2.8 to 13.7 per 1000 child-years among children age less than 5 years, and it imposes a substantial burden to the healthcare system in the country. While both monovalent (RV1) and pentavalent (RV5) rotavirus vaccines are licensed in Japan, neither has been incorporated in the national infant immunization programme. In this study, we estimated vaccine effectiveness (VE) in Japan. This study was conducted in Yuri-Kumiai General Hospital located in a city in the north-western part of Japan. Age-eligible children for rotavirus vaccination were enrolled if they were hospitalized for rotavirus gastroenteritis between September 2013 and August 2016. Rotavirus gastroenteritis was defined by the detection of rotavirus antigen by immunochromatography. "Vaccinated" was defined as infant inoculated with at least one dose of either RV1 or RV5. A conditional logistic regression analysis was performed by modelling the year of birth, year of admission, residence of the children and vaccination status, and by matching the age of cases with that of test-negative controls. The adjusted odds ratio of the vaccinated over unvaccinated was then used to calculate VE in the formula of (1 - adjusted odds ratio) × 100. Out of the 244 patients enrolled, rotavirus antigen was detected in 55 (22.5%) of whom 10 (18.2%) were vaccinated, whereas 94 (49.7%) of 189 test-negative controls were vaccinated. During the study period, the vaccine uptake rate in the controls increased from 36.2% to 61.8%. On the other hand, the vaccination coverage over the three years was 64.2% in Yuri-Honjo city (three quarters of the catchment), and 91.4% in Nikaho city (one quarter of the catchment). The VE was calculated to be 70.4% (95% confidence interval: 36.0-86.4%, P = 0.002). The point estimate of the VE was lower but its 95% confidence interval overlaps those of the efficacies obtained from clinical trials in Japan. The rotavirus vaccine was

Impact of genetic changes, pathogenicity and antigenicity on Enterovirus- A71 vaccine development.

PubMed

Yee, Pinn Tsin Isabel; Laa Poh, Chit

2017-06-01

Enterovirus-A71 (EV-A71) is an etiological agent of the hand, foot and mouth disease (HFMD). EV-A71 infection produces high fever and ulcers in children. Some EV-A71 strains produce severe infections leading to pulmonary edema and death. Although the protective efficacy of the inactivated vaccine (IV) was ≥90% against mild HFMD, there was approximately 80% protection against severe HFMD. The monovalent EV-A71 IV elicits humoral immunity but lacks long-term immunogenicity. Spontaneous mutations of the EV-A71 genome could lead to antigenicity changes and the virus may not be neutralized by antibodies elicited by the IV. A better alternative would be the live attenuated vaccine (LAV) that elicits cellular and humoral immunity. The LAV induces excellent antigenicity and chances of reversion is reduced by presence of multiple mutations which could reduce pathogenicity. Besides CV-A16, outbreaks have been caused by CV-A6 and CV-A10, hence the development of bivalent and trivalent vaccines is required. Copyright © 2017 Elsevier Inc. All rights reserved.

Monovalent Cation Activation of the Radical SAM Enzyme Pyruvate Formate-Lyase Activating Enzyme.

PubMed

Shisler, Krista A; Hutcheson, Rachel U; Horitani, Masaki; Duschene, Kaitlin S; Crain, Adam V; Byer, Amanda S; Shepard, Eric M; Rasmussen, Ashley; Yang, Jian; Broderick, William E; Vey, Jessica L; Drennan, Catherine L; Hoffman, Brian M; Broderick, Joan B

2017-08-30

Pyruvate formate-lyase activating enzyme (PFL-AE) is a radical S-adenosyl-l-methionine (SAM) enzyme that installs a catalytically essential glycyl radical on pyruvate formate-lyase. We show that PFL-AE binds a catalytically essential monovalent cation at its active site, yet another parallel with B 12 enzymes, and we characterize this cation site by a combination of structural, biochemical, and spectroscopic approaches. Refinement of the PFL-AE crystal structure reveals Na + as the most likely ion present in the solved structures, and pulsed electron nuclear double resonance (ENDOR) demonstrates that the same cation site is occupied by 23 Na in the solution state of the as-isolated enzyme. A SAM carboxylate-oxygen is an M + ligand, and EPR and circular dichroism spectroscopies reveal that both the site occupancy and the identity of the cation perturb the electronic properties of the SAM-chelated iron-sulfur cluster. ENDOR studies of the PFL-AE/[ 13 C-methyl]-SAM complex show that the target sulfonium positioning varies with the cation, while the observation of an isotropic hyperfine coupling to the cation by ENDOR measurements establishes its intimate, SAM-mediated interaction with the cluster. This monovalent cation site controls enzyme activity: (i) PFL-AE in the absence of any simple monovalent cations has little-no activity; and (ii) among monocations, going down Group 1 of the periodic table from Li + to Cs + , PFL-AE activity sharply maximizes at K + , with NH 4 + closely matching the efficacy of K + . PFL-AE is thus a type I M + -activated enzyme whose M + controls reactivity by interactions with the cosubstrate, SAM, which is bound to the catalytic iron-sulfur cluster.

3D cell culture systems--towards primary drug discovery platforms: an interview with Heinz Ruffner (Novartis) and Jan Lichtenberg (InSphero).

PubMed

Ruffner, Heinz; Lichtenberg, Jan

2012-07-01

Advanced cell culture systems for regenerative medicine, drug efficacy and toxicity testing, enabling technologies to create and analyze 3D cell culture systems were the topics of the 3D cell culture meeting taking place in March 14-16, 2012 at the Technopark in Zurich, Switzerland. At this meeting Biotechnology Journal had the pleasure to talk to Dr. Heinz Ruffner, Novartis AG, and Dr. Jan Lichtenberg, co-founder and CEO of InSphero AG, about challenges and perspectives in using 3D cell culture systems as primary drug discovery platforms. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Knowledge, attitudes, beliefs and practices of construction workers towards tetanus vaccine in Northern Italy.

PubMed

Riccò, Matteo; Cattani, Silvia; Veronesi, Licia; Colucci, Maria Eugenia

2016-12-07

Construction workers (CWs) are both more exposed to tetanus and at higher risk to be inadequately immunized. Our aim was to evaluate tetanus immunization status and knowledge/attitudes towards tetanus vaccination in CWs in Italy. In this field report, the immunization status of 554 unskilled CWs (i.e. labourers). Immunization status was assessed recalling immunization booklets/certificates. Attitudes and knowledge were collected through a standardized questionnaire. In 240/554 CWs, immunization status was inadequate/not documented: in 184 subjects (33.2%), the last vaccination shot was older than 10 years, whereas basal immunization was incomplete in 20 cases, more frequently in foreign-born people (FBP) than in Italian born (IBP) (OR=7.116). In 198 cases (35.7%), an Occupational Physician (OPh) performed last booster, usually with monovalent (T, n=173) vaccine. The main reason for inadequate immunization was having forgotten the periodic booster (148/554; 26.7%), whereas 42 subjects (7.6%) deliberately avoided tetanus vaccine because of personal/religious beliefs, more frequently in FBP than in IBP (OR=3.182). In summary, the prevalence of inadequate immunization status was relatively high (43.4%): the high prevalence of "forgotten boosters" enlightens the key role of OPh in recalling and promoting vaccination policies. Moreover, the inappropriate use of Td vaccine points out the opportunity for educational campaigns in OPh.

Use of MenACWY-CRM vaccine in children aged 2 through 23 months at increased risk for meningococcal disease: recommendations of the Advisory Committee on Immunization Practices, 2013.

PubMed

MacNeil, Jessica R; Rubin, Lorry; McNamara, Lucy; Briere, Elizabeth C; Clark, Thomas A; Cohn, Amanda C

2014-06-20

During its October 2013 meeting, the Advisory Committee on Immunization Practices (ACIP) recommended use of a third meningococcal conjugate vaccine, MenACWY-CRM (Menveo, Novartis), as an additional option for vaccinating infants aged 2 through 23 months at increased risk for meningococcal disease. MenACWY-CRM is the first quadrivalent meningococcal conjugate vaccine licensed for use in children aged 2 through 8 months. MenACWY-D (Menactra, Sanofi Pasteur) is recommended for use in children aged 9 through 23 months who are at increased risk for meningococcal disease, and Hib-MenCY-TT (MenHibrix, GlaxoSmithKline) is recommended for use in children aged 6 weeks through 18 months at increased risk. This report summarizes information on MenACWY-CRM administration in infants and provides recommendations for vaccine use in infants aged 2 through 23 months who are at increased risk for meningococcal disease. Because the burden of meningococcal disease in infants is low in the United States and the majority of cases that do occur are caused by serogroup B, which is not included in any vaccine licensed in the United States, only those infants who are at increased risk for meningococcal disease are recommended to receive a meningococcal vaccine.

Impact of a vaccination programme in children vaccinated with ProQuad, and ProQuad-specific effectiveness against varicella in the Veneto region of Italy.

PubMed

Giaquinto, Carlo; Gabutti, Giovanni; Baldo, Vincenzo; Villa, Marco; Tramontan, Lara; Raccanello, Nadia; Russo, Francesca; Poma, Chiara; Scamarcia, Antonio; Cantarutti, Luigi; Lundin, Rebecca; Perinetti, Emilia; Cornen, Xavier; Thomas, Stéphane; Ballandras, Céline; Souverain, Audrey; Hartwig, Susanne

2018-03-05

Monovalent varicella vaccines have been available in the Veneto Region of Italy since 2004. In 2006, a single vaccine dose was added to the immunisation calendar for children aged 14 months. ProQuad®, a quadrivalent measles-mumps-rubella-varicella vaccine, was introduced in May 2007 and used, among other varicella vaccines, until October 2008. This study aimed to evaluate the effectiveness of a single dose of ProQuad, and the population impact of a vaccination program (VP) against varicella of any severity in children who received a first dose of ProQuad at 14 months of age in the Veneto Region, METHODS: All children born in 2006/2007, i.e., eligible for varicella vaccination after ProQuad was introduced, were retrospectively followed through individual-level data linkage between the Pedianet database (varicella cases) and the Regional Immunization Database (vaccination status). The direct effectiveness of ProQuad was estimated as the incidence rate of varicella in ProQuad-vaccinated children aged < 6 years compared to children with no varicella vaccination from the same birth cohort. The impact of the VP on varicella was measured by comparing children eligible for the VP to an unvaccinated historical cohort from 1997/1998. The vaccine impact measures were: total effect (the combined effect of ProQuad vaccination and being covered by the Veneto VP); indirect effect (the effect of the VP on unvaccinated individuals); and overall effect (the effect of the VP on varicella in the entire population of the Veneto Region, regardless of their vaccination status). The adjusted direct effectiveness of ProQuad was 94%. The vaccine impact measures total, indirect, and overall effect were 97%, 43%, and 90%, respectively. These are the first results on the effectiveness and impact of ProQuad against varicella; data confirmed its high effectiveness, based on immunological correlates for protection. Direct effectiveness is our only ProQuad-specific measure; all impact

Pharmacoeconomic spotlight on rotavirus vaccine RIX4414 (Rotarix™) in developed countries.

PubMed

Plosker, Greg L

2012-12-01

The most common cause of severe diarrhea in infants and young children is rotavirus gastroenteritis (RVGE), which is associated with significant morbidity, healthcare resource use, and direct and indirect costs in industrialized nations. The monovalent rotavirus vaccine RIX4414 (Rotarix™) is administered as a two-dose oral series in infants and has demonstrated protective efficacy against RVGE in clinical trials conducted in developed countries. In addition, various naturalistic studies have demonstrated 'real-world' effectiveness after the introduction of widespread rotavirus vaccination programs in the community setting. Numerous cost-effectiveness analyses have been conducted in developed countries in which a universal rotavirus vaccination program using RIX4414 was compared with no universal rotavirus vaccination program. There was a high degree of variability in base-case results across studies even when the studies were conducted in the same country, often reflecting differences in the selection of data sources or assumptions used to populate the models. In addition, results were sensitive to plausible changes in a number of key input parameters. As such, it is not possible to definitively state whether a universal rotavirus vaccination program with RIX4414 is cost effective in developed countries, although results of some analyses in some countries suggest this is the case. In addition, international guidelines advocate universal vaccination of infants and children against rotavirus. It is also difficult to draw conclusions regarding the cost effectiveness of rotavirus vaccine RIX4414 relative to that of the pentavalent rotavirus vaccine, which is administered as a three-dose oral series. Although indirect comparisons in cost-effectiveness analyses indicate that RIX4414 provided more favorable incremental cost-effectiveness ratios when each vaccine was compared with no universal rotavirus vaccination program, results were generally sensitive to vaccine

Safety and immune response to a challenge dose of hepatitis B vaccine in healthy children primed 10years earlier with hexavalent vaccines in a 3, 5, 11-month schedule: An open-label, controlled, multicentre trial in Italy.

PubMed

Zanetti, Alessandro; Desole, Maria Giuseppina; Romanò, Luisa; d'Alessandro, Antonio; Conversano, Michele; Ferrera, Giuseppe; Panico, Maria Grazia; Tomasi, Alberto; Zoppi, Giorgio; Zuliani, Massimo; Thomas, Stéphane; Soubeyrand, Benoît; Eymin, Cécile; Lockhart, Stephen

2017-07-13

The strategy of vaccinating infants to prevent hepatitis B virus infection in adolescence or adulthood requires durable immunity. This study investigated responses to a challenge dose of monovalent hepatitis B vaccine in children primed with three doses of either Hexavac® or Infanrix hexa® 10years earlier during infancy. This open-label, controlled, multicentre study conducted in Italy, enrolled 751 healthy pre-adolescents (aged 11-13years) who were given either Hexavac (n=409) or Infanrix hexa (n=342) at 3, 5 and 11months of life. All participants received a challenge dose of a monovalent hepatitis B vaccine (HBVaxPro® 5µg). The concentrations of antibodies to hepatitis B surface antigen (anti-HBs) were measured before and 1month after the challenge dose. The analysis was descriptive and no formal hypothesis was tested. One month post-challenge, 331 participants in the Hexavac cohort [83.6%, 95% CI: 79.6; 87.1] and 324 in the Infanrix hexa cohort [96.4%, 95% CI: 93.8; 98.1] had anti-HBs concentrations ≥10mIU/mL. Before the challenge dose, an anti-HBs concentration of ≥10mIU/mL was found in 94 children in the Hexavac cohort [23.9%, 95% CI: 19.7; 28.4] and in 232 children in the Infanrix hexa cohort [69%, 95% CI: 63.8; 74.0]. Among children with a pre-challenge anti-HBs concentration of <10mIU/mL, 236 [78.7%, 95% CI: 73.6; 83.2] in the Hexavac cohort and 92 [88.5%, 95% CI: 80.7; 93.9] in the Infanrix hexa cohort achieved protective anti-HBs antibody concentrations. No evidence of active hepatitis B disease was observed in either group, and the HBVaxPro challenge dose was well tolerated. These data confirm that immune memory persists in a high percentage of children (>80%) at least 10years after a two-dose primary and booster vaccination schedule with a hexavalent vaccine (Hexavac or Infanrix hexa). EudraCT Number: 2013-001602-28; clinicaltrials.gov: NCT02012998. Copyright © 2017 Elsevier Ltd. All rights reserved.

Safety of a Trivalent Inactivated Influenza Vaccine in Health Care Workers in Kurdistan Province, Western Iran; A Longitudinal Follow-up Study.

PubMed

Soltani, Jafar; Jamil Amjadi, Mohamad

2014-03-01

We studied the safety of a trivalent inactivated surface antigen (split virion, inactivated) influenza vaccine, Begrivac® (Novartis Company), widely used in health care workers in Kurdistan. A longitudinal follow-up study was performed in Sanandaj city, west of Iran, recruiting 936 people. A questionnaire was completed for each participant, and all symptoms or abnormal physical findings were recorded. In part 1 of the study, the post-vaccination complaints were headache (5.3%), fever (7.9%), weakness (9.6%), chills (10.1%), sweating (10.5%), arthralgia (20.2%), and malaise (21.5%). Swelling of the injection site was seen in 267 (30.3%) participants, and pruritus of the injection site was seen in 290 (32.9%) participants. Redness and induration were also reported in 42.5% of the participants. Local reactions were mainly mild and lasted for 1-2 days. No systemic reactions were reported in the second part of the study. None of the participants experienced any inconvenience. We concluded that local adverse reactions after the trivalent inactivated split influenza vaccine, Begrivac®, in health care workers were far more common than expected. Continuous surveillance is needed to assess the potential risks and benefits of newly produced influenza vaccines.

Safety of a Trivalent Inactivated Influenza Vaccine in Health Care Workers in Kurdistan Province, Western Iran; A Longitudinal Follow-up Study

PubMed Central

Soltani, Jafar; Jamil Amjadi, Mohamad

2014-01-01

We studied the safety of a trivalent inactivated surface antigen (split virion, inactivated) influenza vaccine, Begrivac® (Novartis Company), widely used in health care workers in Kurdistan. A longitudinal follow-up study was performed in Sanandaj city, west of Iran, recruiting 936 people. A questionnaire was completed for each participant, and all symptoms or abnormal physical findings were recorded. In part 1 of the study, the post-vaccination complaints were headache (5.3%), fever (7.9%), weakness (9.6%), chills (10.1%), sweating (10.5%), arthralgia (20.2%), and malaise (21.5%). Swelling of the injection site was seen in 267 (30.3%) participants, and pruritus of the injection site was seen in 290 (32.9%) participants. Redness and induration were also reported in 42.5% of the participants. Local reactions were mainly mild and lasted for 1-2 days. No systemic reactions were reported in the second part of the study. None of the participants experienced any inconvenience. We concluded that local adverse reactions after the trivalent inactivated split influenza vaccine, Begrivac®, in health care workers were far more common than expected. Continuous surveillance is needed to assess the potential risks and benefits of newly produced influenza vaccines. PMID:24753646

Challenge with a hepatitis B vaccine in two cohorts of 4-7-year-old children primed with hexavalent vaccines: an open-label, randomised trial in Italy.

PubMed

Zanetti, Alessandro; Parlato, Antonino; Romanò, Luisa; Desole, Maria Giuseppina; Ferrera, Giuseppe; Giurdanella, Filippo; Zuliani, Massimo; Richard, Patrick; Thomas, Stéphane; Fiquet, Anne

2012-08-24

The anamnestic response to a challenge dose of vaccine can assess immune memory and protection against hepatitis B infection. This study investigated responses to a challenge dose of monovalent hepatitis B vaccine in children immunised with three doses of either Hexavac or Infanrix-Hexa during infancy. This open-label, randomised, controlled, four-arm study enrolled 410 healthy children aged 4-7 years who had received either Hexavac (n=201) or Infanrix-Hexa (n=209) at 3, 5 and 11 months of life. Children received a single intramuscular challenge dose of either hepatitis B vaccine, HBVaxPro (Hexavac, n=34; Infanrix-Hexa, n=28) or Engerix-B (Hexavac, n=167; Infanrix-Hexa, n=181). Hepatitis B surface antibody (anti-HBs) concentrations were measured before and 1 month after the challenge vaccine dose. The analysis was descriptive and no formal hypothesis was tested. One month post-challenge, 91.2% of children in the Hexavac group (95% confidence interval [CI] 86.3, 94.8) and 98.0% (95% CI 94.9, 99.4) in the Infanrix-Hexa group had anti-HBs concentrations ≥10 mIU/ml (primary endpoint). In a post hoc analysis, most children with pre-challenge anti-HBs concentration <10 mIU/ml achieved anti-HBs concentrations ≥10 mIU/ml (Hexavac group, 85.3% [95% CI 77.6, 91.2]; Infanrix-Hexa group, 91.9% [95% CI 78.1, 98.3]). Both challenge vaccines were well tolerated. These data suggest that immune memory persists for long-term (5 years) after a primary vaccination in infancy with a hexavalent vaccine (Hexavac or Infanrix-Hexa). Copyright © 2012 Elsevier Ltd. All rights reserved.

Evaluation of immune response and protective effect of four vaccines against the tick-borne encephalitis virus.

PubMed

Morozova, O V; Bakhvalova, V N; Potapova, O F; Grishechkin, A E; Isaeva, E I; Aldarov, K V; Klinov, D V; Vorovich, M F

2014-05-23

Among three main subtypes of the tick-borne encephalitis virus (TBEV), the Siberian subtype is currently dominant in a majority of the endemic regions of Russia. However, inactivated vaccines are based on TBEV strains of the heterologous Far Eastern or the European subtypes isolated 40-77 years ago. To analyze the efficacy of the available vaccines against currently prevailing TBEV isolates of the Siberian subtype, mice were immunized subcutaneously three times (one group per each vaccine). The expression of seven cytokine genes was determined using RT-PCR. Sera were studied using homologous and heterologous ELISA, hemagglutination inhibition (HI) and neutralization tests with TBEV strains of the Far Eastern, Siberian and European subtypes. Cross-protective efficacy of the vaccines was evaluated with the TBEV strain 2689 of Siberian subtype isolated from an ixodid tick from the Novosibirsk, South-Western Siberia, Russia in 2010. The cytokine gene expression profile indicates a predominantly Th2 response due to exogenous antigen presentation. Titers for homologous combinations of vaccine strain and strain in ELISA, HI and neutralization tests exceeded those for heterologous antigen-antibody pairs. Despite antibody detection by means of ELISA, HI and neutralization tests, the mouse protection afforded by the vaccines differed significantly. Complete protection of mice challenged with 100 LD50 virus of the Siberian subtype was induced by the vaccine "Encevir" ("Microgen", Tomsk, Russia). The minimal immunization doze (MID50) of "Encevir" protecting 50% of the mice was less than 0.0016 ml. Partial protective effect of vaccines produced in Moscow, Russia and Austria revealed MID50 within recommended intervals (0.001-0.017 ml). However, the MID50 for the vaccine "Encepur" (Novartis, Germany) 0.04 ml exceeded acceptable limits with total loss of mice immunized with vaccine diluted 32, 100 and 320 fold. These results suggest regular evaluation of TBEV vaccines in regions

[Dynamics of cytokine production in adults after administration of influenza vaccine from A/California/7/2009 (H1N1) strain].

PubMed

Terkacheva, O A; Kostinov, M P; Zhirova, S N; Cherdantsev, A P

2012-01-01

Study dynamics of IFNalpha, IFNgamma, TNFalpha cytokines in healthy adults after administration of inactivated subunit monovalent influenza vaccine, A/California/7/2009 (H1N1) strain. Levels of IFNalpha, IFNgamma, TNFalpha cytokines were studied in blood sera of 58 mostly healthy adults aged 18 - 60 years. Kits for enzyme immunoassay determination of cytokine levels (Vector-Best, Novosibirsk) were used in the study. Antibody titers to A/California/7/2009 (H1N1) strain were determined at analogous time by using microneutralization reaction (MNR). Changes in the level of IFNalpha, IFNgamma, TNFalpha in healthy volunteers immunized by pandemic influenza vaccine were evaluated. Vaccine was safe. Two immunizations did not result in an increase of TNFalpha level that is an additional evidence of vaccine safety. IFNalpha level had a tendency to increase in vaccinated volunteers. IFNgamma levels in volunteers with normal level of this cytokine (below 10 pg/ml) were increased significantly after the second immunization (from 2.66 +/- 2.48 to 5.21 +/- 2.56). Correlation analysis showed that there is a strong negative association between IFNalpha, IFNgamma and seroconversion.

A comparative study of the incidence of aseptic meningitis in symptomatic natural mumps patients and monovalent mumps vaccine recipients in Japan.

PubMed

Nagai, Takao; Okafuji, Teruo; Miyazaki, Chiaki; Ito, Yuhei; Kamada, Makoto; Kumagai, Takuji; Yuri, Kenji; Sakiyama, Hiroshi; Miyata, Akiko; Ihara, Toshiaki; Ochiai, Hitoshi; Shimomura, Kunihisa; Suzuki, Eitaro; Torigoe, Sadayoshi; Igarashi, Masahiro; Kase, Tetsuo; Okuno, Yoshinobu; Nakayama, Tetsuo

2007-03-30

To compare the incidence of aseptic meningitis associated with symptomatic natural mumps infection and in mumps vaccine recipients, we conducted a prospective comparative study. Consecutive samples of 1051 children with mumps were enrolled by 10 pediatricians and 21,465 vaccine recipients by 143 pediatric primary care practitioners, from January 1, 2000 to January 1, 2003. Parents used a daily diary to record symptoms during the period of illness (15 days) or 30-day period following immunization. Mumps infection was confirmed by virus isolation and/or detection of mumps virus genome in salivary and CSF samples. The incidence of aseptic meningitis was 13/1051 (1.24%) in patients with symptomatic natural mumps infection and was estimated to be 0.7-1.1% of overall infection in considering asymptomatic infection, and 10/21,465 (0.05%) in vaccine recipients. Although aseptic meningitis is a clear side effect of the mumps vaccine, the incidence is considerably lower than among those with symptomatic natural infection. Our results provide an informative data for consideration to resume mumps vaccine as a part of routine immunization schedule for Japanese children.

Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y tetanus toxoid conjugate vaccine for infants and toddlers.

PubMed

Bryant, Kristina A; Marshall, Gary S

2011-07-01

The highest rates of invasive meningococcal disease occur in children under 2 years of age, yet as of early 2011 no vaccine was licensed for the youngest infants. However, a novel vaccine consisting of capsular polysaccharides from Haemophilus influenzae type b (Hib) and Neisseria meningitidis serogroups C and Y conjugated to tetanus toxoid (HibMenCY-TT; MenHibrix, GlaxoSmithKline) is in the late stages of development. In clinical trials involving more than 7800 children, HibMenCY-TT was shown to be safe and immunogenic when administered at 2, 4, 6 and 12-15 months of age. Anti-polyribosylribitol phosphate antibody responses were noninferior to those elicited by licensed monovalent Hib vaccines, and most vaccinees developed bactericidal antibodies against N. meningitidis serogroups C and Y. The majority of subjects retained antibody responses as far as 3 years after vaccination. If licensed, HibMenCY-TT not only represents an incremental option for protection against invasive Hib, but also has the potential to prevent invasive meningococcal disease without increasing the number of injections.

Mixed polyvalent-monovalent metal coating for carbon-graphite fibers

NASA Technical Reports Server (NTRS)

Harper-Tervet, J.; Tervet, F. W.; Humphrey, M. F. (Inventor)

1982-01-01

An improved coating of gasification catalyst for carbon-graphite fibers is provided comprising a mixture of a polyvalent metal such as calcium and a monovalent metal such as lithium. The addition of lithium provides a lighter coating and a more flexible coating when applied to a coating of a carboxyl containing resin such as polyacrylic acid since it reduces the crosslink density. Furthermore, the presence of lithium provides a glass-like substance during combustion which holds the fiber together resulting in slow, even combustion with much reduced evolution of conductive fragments. The coated fibers are utilized as fiber reinforcement for composites.

Concentration-dependent and configuration-dependent interactions of monovalent ions with an RNA tetraloop

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

Miner, Jacob Carlson; Garcia, Angel Enrique

Monovalent salt solutions have strongly coupled interactions with biopolymers, from large polyelectrolytes to small RNA oligomers. High salt concentrations have been known to induce transitions in the structure of RNA, producing non-canonical configurations and even driving RNA to precipitate out of solution. Using all-atom molecular dynamics simulations, we model a monovalent salt species (KCL) at high concentrations (0.1–3m) and calculate the equilibrium distributions of water and ions around a small tetraloop-forming RNA oligomer in a variety of structural arrangements: folded A-RNA (canonical) and Z-RNA (non-canonical) tetraloops and unfolded configurations. From these data, we calculate the ion preferential binding coefficients andmore » Donnan coefficients for the RNA oligomer as a function of concentration and structure. We find that cation accumulation is highest around non-canonical Z-RNA configurations at concentrations below 0.5m, while unfolded configurations accumulate the most co-ions in all concentrations. By contrast, canonical A-RNA structures consistently show the lowest accumulations for all ion species. Water distributions vary markedly with RNA configuration but show little dependency on KCL concentration. Based on Donnan coefficient calculations, the net charge of the solution at the surface of the RNA decreases linearly as a function of salt concentration and becomes net-neutral near 2.5–3m KCL for folded configurations, while unfolded configurations still show a positive solution charge. Our findings show that all-atom molecular dynamics can describe the equilibrium distributions of monovalent salt in the presence of small RNA oligomers at KCL concentrations where ion correlation effects become important. Furthermore, these results provide valuable insights into the distributions of water and ions near the RNA oligomer surface as a function of structural configuration.« less

Concentration-dependent and configuration-dependent interactions of monovalent ions with an RNA tetraloop

DOE PAGES

Miner, Jacob Carlson; Garcia, Angel Enrique

2018-05-29

Monovalent salt solutions have strongly coupled interactions with biopolymers, from large polyelectrolytes to small RNA oligomers. High salt concentrations have been known to induce transitions in the structure of RNA, producing non-canonical configurations and even driving RNA to precipitate out of solution. Using all-atom molecular dynamics simulations, we model a monovalent salt species (KCL) at high concentrations (0.1–3m) and calculate the equilibrium distributions of water and ions around a small tetraloop-forming RNA oligomer in a variety of structural arrangements: folded A-RNA (canonical) and Z-RNA (non-canonical) tetraloops and unfolded configurations. From these data, we calculate the ion preferential binding coefficients andmore » Donnan coefficients for the RNA oligomer as a function of concentration and structure. We find that cation accumulation is highest around non-canonical Z-RNA configurations at concentrations below 0.5m, while unfolded configurations accumulate the most co-ions in all concentrations. By contrast, canonical A-RNA structures consistently show the lowest accumulations for all ion species. Water distributions vary markedly with RNA configuration but show little dependency on KCL concentration. Based on Donnan coefficient calculations, the net charge of the solution at the surface of the RNA decreases linearly as a function of salt concentration and becomes net-neutral near 2.5–3m KCL for folded configurations, while unfolded configurations still show a positive solution charge. Our findings show that all-atom molecular dynamics can describe the equilibrium distributions of monovalent salt in the presence of small RNA oligomers at KCL concentrations where ion correlation effects become important. Furthermore, these results provide valuable insights into the distributions of water and ions near the RNA oligomer surface as a function of structural configuration.« less

Concentration-dependent and configuration-dependent interactions of monovalent ions with an RNA tetraloop

NASA Astrophysics Data System (ADS)

Miner, Jacob Carlson; García, Angel Enrique

2018-06-01

Monovalent salt solutions have strongly coupled interactions with biopolymers, from large polyelectrolytes to small RNA oligomers. High salt concentrations have been known to induce transitions in the structure of RNA, producing non-canonical configurations and even driving RNA to precipitate out of solution. Using all-atom molecular dynamics simulations, we model a monovalent salt species (KCL) at high concentrations (0.1-3m) and calculate the equilibrium distributions of water and ions around a small tetraloop-forming RNA oligomer in a variety of structural arrangements: folded A-RNA (canonical) and Z-RNA (non-canonical) tetraloops and unfolded configurations. From these data, we calculate the ion preferential binding coefficients and Donnan coefficients for the RNA oligomer as a function of concentration and structure. We find that cation accumulation is highest around non-canonical Z-RNA configurations at concentrations below 0.5m, while unfolded configurations accumulate the most co-ions in all concentrations. By contrast, canonical A-RNA structures consistently show the lowest accumulations for all ion species. Water distributions vary markedly with RNA configuration but show little dependency on KCL concentration. Based on Donnan coefficient calculations, the net charge of the solution at the surface of the RNA decreases linearly as a function of salt concentration and becomes net-neutral near 2.5-3m KCL for folded configurations, while unfolded configurations still show a positive solution charge. Our findings show that all-atom molecular dynamics can describe the equilibrium distributions of monovalent salt in the presence of small RNA oligomers at KCL concentrations where ion correlation effects become important. Furthermore, these results provide valuable insights into the distributions of water and ions near the RNA oligomer surface as a function of structural configuration.

Concentration-dependent and configuration-dependent interactions of monovalent ions with an RNA tetraloop.

PubMed

Miner, Jacob Carlson; García, Angel Enrique

2018-06-14

Monovalent salt solutions have strongly coupled interactions with biopolymers, from large polyelectrolytes to small RNA oligomers. High salt concentrations have been known to induce transitions in the structure of RNA, producing non-canonical configurations and even driving RNA to precipitate out of solution. Using all-atom molecular dynamics simulations, we model a monovalent salt species (KCL) at high concentrations (0.1-3m) and calculate the equilibrium distributions of water and ions around a small tetraloop-forming RNA oligomer in a variety of structural arrangements: folded A-RNA (canonical) and Z-RNA (non-canonical) tetraloops and unfolded configurations. From these data, we calculate the ion preferential binding coefficients and Donnan coefficients for the RNA oligomer as a function of concentration and structure. We find that cation accumulation is highest around non-canonical Z-RNA configurations at concentrations below 0.5m, while unfolded configurations accumulate the most co-ions in all concentrations. By contrast, canonical A-RNA structures consistently show the lowest accumulations for all ion species. Water distributions vary markedly with RNA configuration but show little dependency on KCL concentration. Based on Donnan coefficient calculations, the net charge of the solution at the surface of the RNA decreases linearly as a function of salt concentration and becomes net-neutral near 2.5-3m KCL for folded configurations, while unfolded configurations still show a positive solution charge. Our findings show that all-atom molecular dynamics can describe the equilibrium distributions of monovalent salt in the presence of small RNA oligomers at KCL concentrations where ion correlation effects become important. Furthermore, these results provide valuable insights into the distributions of water and ions near the RNA oligomer surface as a function of structural configuration.

Cumulative Risk of Guillain–Barré Syndrome Among Vaccinated and Unvaccinated Populations During the 2009 H1N1 Influenza Pandemic

PubMed Central

Iqbal, Shahed; Stewart, Brock; Tokars, Jerome; DeStefano, Frank

2014-01-01

Objectives. We sought to assess risk of Guillain–Barré syndrome (GBS) among influenza A (H1N1) 2009 monovalent (pH1N1) vaccinated and unvaccinated populations at the end of the 2009 pandemic. Methods. We applied GBS surveillance data from a US population catchment area of 45 million from October 15, 2009, through May 31, 2010. GBS cases meeting Brighton Collaboration criteria were included. We calculated the incidence density ratio (IDR) among pH1N1 vaccinated and unvaccinated populations. We also estimated cumulative GBS risk using life table analysis. Additionally, we used vaccine coverage data and census population estimates to calculate denominators. Results. There were 392 GBS cases; 64 (16%) occurred after pH1N1vaccination. The vaccinated population had lower average risk (IDR = 0.83, 95% confidence interval = 0.63, 1.08) and lower cumulative risk (6.6 vs 9.2 cases per million persons, P = .012) of GBS. Conclusions. Our findings suggest that at the end of the influenza season cumulative GBS risk was less among the pH1N1vaccinated than the unvaccinated population, suggesting the benefit of vaccination as it relates to GBS. The observed potential protective effect on GBS attributed to vaccination warrants further study. PMID:24524517

Cost effectiveness evaluation of a rotavirus vaccination program in Argentina.

PubMed

Martí, Sebastián García; Alcaraz, Andrea; Valanzasca, Pilar; McMullen, Mercedes; Standaert, Baudouin; Garay, Ulises; Lepetic, Alejandro; Gomez, Jorge

2015-10-13

Rotavirus diarrhea is one of the most important vaccine-preventable causes of severe diarrhea in children worldwide. There are two live-attenuated virus vaccines licensed, Rotarix (RV1) a monovalent vaccine by GlaxoSmithKline and a pentavalent vaccine, RotaTeq(RV5), by Merck & Co., with similar results. This study aim was to evaluate the cost-effectiveness of the utilization of RV1 compared with RV5 in Argentina. A deterministic Markov model based on the lifetime follow up of a static cohort was used. Quality Adjusted Life Years (QALYs) as a measure of results, the perspective of the health care system and a 5% discount rate for health benefits and costs has been used. A review of the literature to obtain epidemiologic and resources utilization of rotavirus diarrhea was performed. The sources used to estimate epidemiologic parameters were the National Health Surveillance System, the national mortality statistics and national database of hospital discharges records. Costs were obtained from different health subsectors and are expressed in local currency. Both vaccination alternatives were less costly and more effective than the strategy without vaccination (total costs $ 69,700,645 and 2575 total QALYs lost). When comparing RV1 vs. RV5, RV1 was less expensive ($ 60,174,508 vs. $ 67,545,991 total costs) and more effective (1105 vs. 1213 total QALYs lost) than RV5, RV1 being therefore a dominating strategy. Probabilistic sensitivity analysis showed results to be robust with a 100% probability of being cost-effective at a WTP threshold of 1 GDP per capita when comparing the RV1 vs. no vaccination. Both RV1 and RV5 schedules dominate the no vaccination strategy and RV5 was dominated by RV1. This information is a valuable input regarding the incorporation of this kind of vaccines into the national vaccination programs. Copyright © 2015 Elsevier Ltd. All rights reserved.

Safety and immunogenicity of an investigational meningococcal ACWY conjugate vaccine (MenACWY-CRM) in healthy Indian subjects aged 2 to 75 years.

PubMed

Lalwani, Sanjay; Agarkhedkar, Sharad; Gogtay, Nithya; Palkar, Sonali; Agarkhedkar, Shalaka; Thatte, Urmila; Vakil, Hoshang; Jonnalagedda, Rekha; Pedotti, Paola; Hoyle, Margaret; Bhusal, Chiranjiwi; Arora, Ashwani

2015-09-01

This phase 3, multi-center, open-label study evaluated the immunogenicity and safety of a quadrivalent meningococcal conjugate vaccine (MenACWY-CRM, Menveo(®); Novartis Vaccines and Diagnostics S.r.l., Siena, Italy) in healthy Indian subjects aged 2-75 years, to provide data for licensure in India. A total of 180 subjects were enrolled (60 subjects 2-10 years, 60 subjects 11-18 years, and 60 subjects 19-75 years) and received one dose of MenACWY-CRM. Serum bactericidal activity with human complement (hSBA) was measured before and 1 month after vaccination. Adverse events were collected throughout the 29-day study period. Percentages of subjects with post-vaccination hSBA ≥8 were 72%, 95%, 94%, and 90% for serogroups A, C, W, and Y, respectively. Geometric mean titers rose 7-fold to 42-fold against the four serogroups. Similar immune responses were observed for the age subgroups 2-10 years, 11-18 years, and 19-75 years. Seroresponse rates at 1 month following vaccination were 72%, 88%, 55%, and 71% for serogroups A, C, W, and Y, respectively. The vaccine was well tolerated with no safety concerns. A single dose of MenACWY-CRM induced a robust immune response against all four meningococcal serogroups and was well tolerated in an Indian population 2-75 years of age. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Levels of diphtheria and tetanus specific IgG of Portuguese adult women, before and after vaccination with adult type Td. Duration of immunity following vaccination

PubMed Central

Gonçalves, Guilherme; Santos, Maria Augusta; Frade, João Graça; Cunha, José Saraiva

2007-01-01

Background The need for tetanus toxoid decennial booster doses has been questioned by some experts. Several counter arguments have been presented, supporting the maintenance of decennial adult booster doses with tetanus and diphtheria toxoids (adult formulation of the vaccine: Td). This study aimed to evaluate the use of Td in Portuguese adult women under routine conditions. For that purpose we selected a group of women 30+ years of age to which vaccination was recommended. We intended to know if pre-vaccination antibody concentrations were associated with factors as age at first and last vaccination, number of doses and time since last revaccination. We also intended to assess the serological efficacy of Td booster. Methods Following the Portuguese guidelines 100 women were vaccinated with Td. Antitetanus toxin IgG (ATT IgG) and antidiphtheria toxin IgG (ADT IgG) levels were measured (mIU/ml) in 100 pre-vaccination and 91 post-vaccination sera. Detailed vaccination records were available from 88 participants. Results Twenty-two women (Group A) began vaccination with DPT/DT in their early childhood and their pre-vaccination ATT IgG levels increased with the number of doses received (p = 0.022) and decreased with time since last vaccination (p = 0.016). Among the 66 women who began vaccination in adolescence and adulthood (Group B), with monovalent TT, ATT IgG levels decreased with age at first dose (p < 0.001) and with time since last vaccination (p = 0.041). In Group A, antidiphtheria toxin IgG kinetics was very similar to that observed for ATT IgG. Among women not vaccinated with diphtheria toxoid, ADT IgG levels decreased with age. Serological response to both components of Td was good but more pronounced for ATT IgG. Conclusion Our study suggests that, to protect against tetanus, there is no need to administer decennial boosters to the Portuguese adults who have complied with the childhood/adolescent schedule (6 doses of tetanus toxoid). The adult booster

Validation of current procedural terminology codes for rotavirus vaccination among infants in two commercially insured US populations.

PubMed

Hoffman, Veena; Everage, Nicholas J; Quinlan, Scott C; Skerry, Kathleen; Esposito, Daina; Praet, Nicolas; Rosillon, Dominique; Holick, Crystal N; Dore, David D

2016-12-01

We validated procedure codes used in health insurance claims for reimbursement of rotavirus vaccination by comparing claims for monovalent live-attenuated human rotavirus vaccine (RV1) and live, oral pentavalent rotavirus vaccine (RV5) to medical records. Using administrative data from two commercially insured United States populations, we randomly sampled vaccination claims for RV1 and RV5 from a cohort of infants aged less than 1 year from an ongoing post-licensure safety study of rotavirus vaccines. The codes for RV1 and RV5 found in claims were confirmed through medical record review. The positive predictive value (PPV) of the Current Procedural Terminology codes for RV1 and RV5 was calculated as the number of medical record-confirmed vaccinations divided by the number of medical records obtained. Medical record review confirmed 92 of 104 RV1 vaccination claims (PPV: 88.5%; 95% CI: 80.7-93.9%) and 98 of 113 RV5 vaccination claims (PPV: 86.7%; 95% CI: 79.1-92.4%). Among the 217 medical records abstracted, only three (1.4%) of vaccinations were misclassified in claims-all were RV5 misclassified as RV1. The medical records corresponding to 9 RV1 and 15 RV5 claims contained insufficient information to classify the type of rotavirus vaccine. Misclassification of rotavirus vaccines is infrequent within claims. The PPVs reported here are conservative estimates as those with insufficient information in the medical records were assumed to be incorrectly coded in the claims. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

A novel enzyme-linked immuno-sorbent assay (ELISA) for the quantification of total and free polysaccharide in Haemophilus influenzae b-Tetanus toxoid conjugate vaccines in monovalent and combined vaccine formulations.

PubMed

Saydam, Manolya; Rigsby, Peter; Mawas, Fatme

2014-01-01

Current Haemophilus influenzae b conjugate vaccines (Hib), which are made of purified capsular polysaccharide (poly-ribosyl-ribitol-phosphate; PRP) conjugated to a carrier protein, are almost completely evaluated by physico-chemical methods to ensure the integrity and stability of the vaccine and consistency of manufacture of batches. The absence of a potency assay makes the quantification of total PRP content (in SI units) and of % free polysaccharide in final fills or bulk components of Hib vaccines critical release tests for both manufacturers and national control authorities. Here we describe a simple and sensitive Enzyme-Linked Immuno-sorbent Assay (ELISA) which has been developed to quantify total and free PRP content in Hib-TT vaccine alone or when in combination with other vaccines. The assay is robust, specific and highly sensitive. Copyright © 2013 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Evaluation of the new control methods for oral poliomyelitis vaccine.

PubMed

Grachev, V P; Karganova, G G; Rumyantsev, A A; Ivanova, O E; Eremeeva, T P; Drozdov, S G

2001-01-01

In the draft recommendations for production and control of OPV the WHO proposed new control methods: (i) mutant analysis with PCR and restriction enzyme cleavage (MAPREC) assay that allows evaluation of poliovirus population heterogeneity at the molecular level; (ii) neurovirulence (NV) test using transgenic mice susceptible to polioviruses and (iii) control of the seed lots for the presence of the simian virus 40 (SV40) DNA sequence. This paper is focused on our experience in the practical implementation of the new methods at the Institute of Poliomyelitis and Viral Encephalitides (IPVE). Using methods based on PCR we have demonstrated that working seed viruses used by IPVE for OPV production are free from SV40 DNA sequences. Our experience on the conduction of the OPV type 3 control using TgPVR21 mice NV test (seven vaccine lots) and the MAPREC assay (more than 150 samples of single harvests and monovalent bulks) showed that these methods may be used instead of the monkey NV test, because they could not pass the vaccine failed monkey NV test. The necessity for single harvests control is discussed.

Foot-and-mouth disease vaccination induces cross-reactive IFN-γ responses in cattle that are dependent on the integrity of the 140S particles.

PubMed

Bucafusco, Danilo; Di Giacomo, Sebastián; Pega, Juan; Schammas, Juan Manuel; Cardoso, Nancy; Capozzo, Alejandra Victoria; Perez-Filgueira, Mariano

2015-02-01

Interferon-γ (IFN-γ) recall responses against foot-and-mouth disease virus (FMDV) in FMD vaccinated cattle are utilized to study T-lymphocyte immunity against this virus. Here, a recall IFN-γ assay based on a commercial ELISA was set up using 308 samples from naïve and vaccinated cattle. The assay was used to study cross-reactive responses between different FMDV vaccine strains. Blood samples from cattle immunized with monovalent vaccines containing A24/Cruzeiro/Brazil/55, A/Argentina/2001 or O1/Campos/Brazil/58 strains were tested using purified-inactivated FMDV from homologous and heterologous strains. A24/Cruzeiro was the most efficient IFN-γ inducer in all vaccinated animals, both when included in the vaccine or as stimulating antigen. We demonstrate that this was mainly due to the structural stability of the whole viral particle. These results show that IFN-γ production relies on the presence of 140S particles that can maintain their integrity along the incubation process in vitro, and throughout the vaccine's shelf-life, when used in vivo. Copyright © 2014 Elsevier Inc. All rights reserved.

Sustained impact of rotavirus vaccine introduction on rotavirus gastroenteritis hospitalizations in children <5 years of age, Ghana, 2009-2016.

PubMed

Enweronu-Laryea, Christabel C; Armah, George; Sagoe, Kwamena W; Ansong, Daniel; Addo-Yobo, Emmanuel; Diamenu, Stanley K; Mwenda, Jason M; Parashar, Umesh D; Tate, Jacqueline E

2018-05-08

Ghana introduced monovalent rotavirus vaccine in April 2012. We sought to determine the long-term impact of routine rotavirus vaccination on rotavirus gastroenteritis hospitalizations in Ghana during the first 4 years following rotavirus vaccine introduction. Active sentinel surveillance for acute gastroenteritis hospitalizations among children <5 years of age was conducted at two sites from July 2009 through June 2016. Stool specimens were collected from enrolled children and tested by enzyme immunoassay. Changes in the proportion of all-cause gastroenteritis hospitalizations due to rotavirus pre- (July 2009-June 2012) and post-vaccine introduction (July 2012-June 2016) were compared using chi-square test. The proportion of acute gastroenteritis hospitalizations due to rotavirus among children <5 years of age significantly declined by 42% from a pre-vaccine median of 50% (343/684) to a post-vaccine median of 29% (118/396) (p < 0.001). The age distribution of rotavirus hospitalizations shifted toward older ages with 64% (759/1197) of rotavirus hospitalizations occurring in children <12 months of age pre-vaccine introduction to 47% (212/453) occurring in children <12 months of age post-vaccine introduction (p < 0.001). The decline in rotavirus hospitalizations following rotavirus vaccine introduction have been sustained over the first 4 years of the vaccination program in Ghana. Continued vaccination against rotavirus will ensure that this burden remains low. Copyright © 2018. Published by Elsevier Ltd.

Rotavirus vaccine RIX4414 (Rotarix): a review of its use in the prevention of rotavirus gastroenteritis.

PubMed

McCormack, Paul L; Keam, Susan J

2009-01-01

Rotavirus vaccine RIX4414 is an oral vaccine composed of a monovalent, live, attenuated, human rotavirus strain of G1P[8] type. RIX4414 vaccination in infants aged 6-17 weeks at enrolment provided protection against rotavirus gastroenteritis (RVGE) of any severity and high-level protection against severe RVGE requiring hospitalization in large, randomized clinical trials conducted in a wide range of geographic regions. Protective efficacy was evident over the period (2 months) between the first and second doses of vaccine, and the protection afforded by the full two-dose course was sustained for at least 2 years, the limit to which efficacy was assessed. RIX4414 displayed protective efficacy against the common rotavirus G, P[8] types (G1P[8], G3P[8], G4P[8], and G9P[8]) and the fully heterotypic G2P[4] type. RIX4414 did not interfere with other common childhood injectable immunizations when administered concomitantly, suggesting that it should be possible to integrate the vaccine into most routine childhood vaccination schedules, including those still using oral poliovirus vaccine. RIX4414 was generally well tolerated and there was no evidence of an increased risk of intussusception. Although dependent on many factors, including prevalent infecting strains, efficacy rates, and vaccine costs, pharmacoeconomic analyses suggest that mass immunization with RIX4414 would be cost effective in many countries, especially when assessed from the societal perspective. Therefore, rotavirus vaccine RIX4414 offers a highly effective control strategy for reducing the burden of RVGE in infants.

The history of MF59(®) adjuvant: a phoenix that arose from the ashes.

PubMed

O'Hagan, Derek T; Ott, Gary S; Nest, Gary Van; Rappuoli, Rino; Giudice, Giuseppe Del

2013-01-01

The first clinical trial of an MF59(®)-adjuvanted influenza vaccine (Novartis) was conducted 20 years ago in 1992. The product that emerged (Fluad(®), Novartis) was licensed first in Italy in 1997 and is now licensed worldwide in 30 countries. US licensure is expected in the coming years. By contrast, many alternative adjuvanted vaccines have failed to progress. The key decisions that allowed MF59 to succeed in such a challenging environment are highlighted here and the lessons that were learned along the way are discussed. MF59 was connected to vaccines that did not succeed and was perceived as a 'failure' before it was a success. Importantly, it never failed for safety reasons and was always well tolerated. Even when safety issues have emerged for alternative adjuvants, careful analysis of the substantial safety database for MF59 have shown that there are no significant concerns with widespread use, even in more 'sensitive' populations.

Safety and Immune Responses in Children After Concurrent or Sequential 2009 H1N1 and 2009–2010 Seasonal Trivalent Influenza Vaccinations

PubMed Central

Frey, Sharon E.; Bernstein, David I.; Gerber, Michael A.; Keyserling, Harry L.; Munoz, Flor M.; Winokur, Patricia L.; Turley, Christine B.; Rupp, Richard E.; Hill, Heather; Wolff, Mark; Noah, Diana L.; Ross, Allison C.; Cress, Gretchen; Belshe, Robert B.

2012-01-01

Background. Administering 2 separate vaccines for seasonal and pandemic influenza was necessary in 2009. Therefore, we conducted a randomized trial of monovalent 2009 H1N1 influenza vaccine (2009 H1N1 vaccine) and seasonal trivalent inactivated influenza vaccine (TIV; split virion) given sequentially or concurrently in previously vaccinated children. Methods. Children randomized to 4 study groups and stratified by age received 1 dose of seasonal TIV and 2 doses of 2009 H1N1 vaccine in 1 of 4 combinations. Injections were given at 21-day intervals and serum samples for hemagglutination inhibition antibody responses were obtained prior to and 21 days after each vaccination. Reactogenicity and adverse events were monitored. Results. All combinations of vaccines were safe in the 531 children enrolled. Generally, 1 dose of 2009 H1N1 vaccine and 1 dose of TIV, regardless of sequence or concurrency of administration, was immunogenic in children ≥10 years of age; children <10 years of age required 2 doses of 2009 H1N1 vaccine. Conclusions. Vaccines were generally well tolerated. The immune responses to 2009 H1N1 vaccine were adequate regardless of the sequence of vaccination in all age groups but the sequence affected titers to TIV antigens. Two doses of 2009 H1N1 vaccine were required to achieve a protective immune response in children <10 years of age. Clinical Trials Registration. NCT00943202. PMID:22802432

Neutralising antibody titration in 25,000 sera of dogs and cats vaccinated against rabies in France, in the framework of the new regulations that offer an alternative to quarantine.

PubMed

Cliquet, F; Verdier, Y; Sagné, L; Aubert, M; Schereffer, J L; Selve, M; Wasniewski, M; Servat, A

2003-12-01

Regulations governing international movements of domestic carnivores from rabies-infected to rabies-free countries have recently been loosened, with the adoption of a system that combines vaccination against rabies and serological surveillance (neutralising antibody titration test with a threshold of 0.5 UI/ml). Since 1993, the Research Laboratory for Rabies and Wild Animal Pathology in Nancy, France, has analysed over 25,000 sera from dogs and cats using a viral seroneutralisation technique. The statistical analyses performed during this time show that cats respond better than dogs. Although no significant difference in titres was observed between primovaccinated and repeat-vaccinated cats, repeat-vaccinated dogs had titres above 0.5 IU/ml more frequently. In primovaccinated dogs, monovalent vaccines offered a better serological conversion rate than multivalent ones. Finally, the results of these analyses showed a strong correlation between antibody counts and the time that elapsed between the last vaccination and the blood sampling.

A phase 1, open-label, randomized study to compare the immunogenicity and safety of different administration routes and doses of virosomal influenza vaccine in elderly.

PubMed

Levin, Yotam; Kochba, Efrat; Shukarev, Georgi; Rusch, Sarah; Herrera-Taracena, Guillermo; van Damme, Pierre

2016-10-17

Influenza remains a significant problem in elderly despite widespread vaccination coverage. This randomized, phase-I study in elderly compared different strategies of improving vaccine immunogenicity. A total of 370 healthy participants (⩾65years) were randomized equally 1:1:1:1:1:1 to six influenza vaccine treatments (approximately 60-63 participants per treatment arm) at day 1 that consisted of three investigational virosomal vaccine formulations at doses of 7.5, 15, and 45μg HA antigen/strain administered intradermally (ID) by MicronJet600™ microneedle device (NanoPass Technologies) or intramuscularly (IM), and three comparator registered seasonal vaccines; Inflexal V™ (Janssen) and MF59 adjuvanted Fluad™ (Novartis) administered IM and Intanza™ (Sanofi Pasteur) administered ID via Soluvia™ prefilled microinjection system (BD). Serological evaluations were performed at days 22 and 90 and safety followed-up for 6months. Intradermal delivery of virosomal vaccine using MicronJet600™ resulted in significantly higher immunogenicity than the equivalent dose of virosomal Inflexal V™ administered intramuscularly across most of the parameters and strains, as well as in some of the readouts and strains as compared with the 45μg dose of virosomal vaccine formulation. Of 370 participants, 300 (81.1%) reported ⩾1 adverse event (AE); more participants reported solicited local AEs (72.2%) than solicited systemic AEs (12.2%). Intradermal delivery significantly improved influenza vaccine immunogenicity compared with intramuscular delivery. Triple dose (45μg) virosomal vaccine did not demonstrate any benefit on vaccine's immunogenicity over 15μg commercial presentation. All treatments were generally safe and well-tolerated. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Risk of Preterm or Small-for-Gestational-Age Birth After Influenza Vaccination During Pregnancy: Caveats When Conducting Retrospective Observational Studies

PubMed Central

Vazquez-Benitez, Gabriela; Kharbanda, Elyse O.; Naleway, Allison L.; Lipkind, Heather; Sukumaran, Lakshmi; McCarthy, Natalie L.; Omer, Saad B.; Qian, Lei; Xu, Stanley; Jackson, Michael L.; Vijayadev, Vinutha; Klein, Nicola P.; Nordin, James D.

2016-01-01

Vaccines are increasingly targeted toward women of reproductive age, and vaccines to prevent influenza and pertussis are recommended during pregnancy. Prelicensure clinical trials typically have not included pregnant women, and when they are included, trials cannot detect rare events. Thus, postmarketing vaccine safety assessments are necessary. However, analysis of observational data requires detailed assessment of potential biases. Using data from 8 Vaccine Safety Datalink sites in the United States, we analyzed the association of monovalent H1N1 influenza vaccine (MIV) during pregnancy with preterm birth (<37 weeks) and small-for-gestational-age birth (birth weight < 10th percentile). The cohort included 46,549 pregnancies during 2009–2010 (40% of participants received the MIV). We found potential biases in the vaccine–birth outcome association that might occur due to variable access to vaccines, the time-dependent nature of exposure to vaccination within pregnancy (immortal time bias), and confounding from baseline differences between vaccinated and unvaccinated women. We found a strong protective effect of vaccination on preterm birth (relative risk = 0.79, 95% confidence interval: 0.74, 0.85) when we ignored potential biases and no effect when accounted for them (relative risk = 0.91; 95% confidence interval: 0.83, 1.0). In contrast, we found no important biases in the association of MIV with small-for-gestational-age birth. Investigators conducting studies to evaluate birth outcomes after maternal vaccination should use statistical approaches to minimize potential biases. PMID:27449414

Characterization of Functional Antibody and Memory B-Cell Responses to pH1N1 Monovalent Vaccine in HIV-Infected Children and Youth

PubMed Central

Curtis, Donna J.; Muresan, Petronella; Nachman, Sharon; Fenton, Terence; Richardson, Kelly M.; Dominguez, Teresa; Flynn, Patricia M.; Spector, Stephen A.; Cunningham, Coleen K.; Bloom, Anthony; Weinberg, Adriana

2015-01-01

Objectives We investigated immune determinants of antibody responses and B-cell memory to pH1N1 vaccine in HIV-infected children. Methods Ninety subjects 4 to <25 years of age received two double doses of pH1N1 vaccine. Serum and cells were frozen at baseline, after each vaccination, and at 28 weeks post-immunization. Hemagglutination inhibition (HAI) titers, avidity indices (AI), B-cell subsets, and pH1N1 IgG and IgA antigen secreting cells (ASC) were measured at baseline and after each vaccination. Neutralizing antibodies and pH1N1-specific Th1, Th2 and Tfh cytokines were measured at baseline and post-dose 1. Results At entry, 26 (29%) subjects had pH1N1 protective HAI titers (≥1:40). pH1N1-specific HAI, neutralizing titers, AI, IgG ASC, IL-2 and IL-4 increased in response to vaccination (p<0.05), but IgA ASC, IL-5, IL-13, IL-21, IFNγ and B-cell subsets did not change. Subjects with baseline HAI ≥1:40 had significantly greater increases in IgG ASC and AI after immunization compared with those with HAI <1:40. Neutralizing titers and AI after vaccination increased with older age. High pH1N1 HAI responses were associated with increased IgG ASC, IFNγ, IL-2, microneutralizion titers, and AI. Microneutralization titers after vaccination increased with high IgG ASC and IL-2 responses. IgG ASC also increased with high IFNγ responses. CD4% and viral load did not predict the immune responses post-vaccination, but the B-cell distribution did. Notably, vaccine immunogenicity increased with high CD19+CD21+CD27+% resting memory, high CD19+CD10+CD27+% immature activated, low CD19+CD21-CD27-CD20-% tissue-like, low CD19+CD21-CD27-CD20-% transitional and low CD19+CD38+HLADR+% activated B-cell subsets. Conclusions HIV-infected children on HAART mount a broad B-cell memory response to pH1N1 vaccine, which was higher for subjects with baseline HAI≥1:40 and increased with age, presumably due to prior exposure to pH1N1 or to other influenza vaccination/infection. The response

DNA vaccination elicits protective immune responses against pandemic and classic swine influenza viruses in pigs.

PubMed

Gorres, J Patrick; Lager, Kelly M; Kong, Wing-Pui; Royals, Michael; Todd, John-Paul; Vincent, Amy L; Wei, Chih-Jen; Loving, Crystal L; Zanella, Eraldo L; Janke, Bruce; Kehrli, Marcus E; Nabel, Gary J; Rao, Srinivas S

2011-11-01

Swine influenza is a highly contagious viral infection in pigs that significantly impacts the pork industry due to weight loss and secondary infections. There is also the potential of a significant threat to public health, as was seen in 2009 when the pandemic H1N1 influenza virus strain emerged from reassortment events among avian, swine, and human influenza viruses within pigs. As classic and pandemic H1N1 strains now circulate in swine, an effective vaccine may be the best strategy to protect the pork industry and public health. Current inactivated-virus vaccines available for swine influenza protect only against viral strains closely related to the vaccine strain, and egg-based production of these vaccines is insufficient to respond to large outbreaks. DNA vaccines are a promising alternative since they can potentially induce broad-based protection with more efficient production methods. In this study we evaluated the potentials of monovalent and trivalent DNA vaccine constructs to (i) elicit both humoral and gamma interferon (IFN-γ) responses and (ii) protect pigs against viral shedding and lung disease after challenge with pandemic H1N1 or classic swine H1N1 influenza virus. We also compared the efficiency of a needle-free vaccine delivery method to that of a conventional needle/syringe injection. We report that DNA vaccination elicits robust serum antibody and cellular responses after three immunizations and confers significant protection against influenza virus challenge. Needle-free delivery elicited improved antibody responses with the same efficiency as conventional injection and should be considered for development as a practical alternative for vaccine administration.

Selective Precipitation and Purification of Monovalent Proteins Using Oligovalent Ligands and Ammonium Sulfate

PubMed Central

Mirica, Katherine A.; Lockett, Matthew R.; Snyder, Phillip W.; Shapiro, Nathan D.; Mack, Eric T.; Nam, Sarah; Whitesides, George M.

2012-01-01

This paper describes a method for the selective precipitation and purification of a monovalent protein (carbonic anhydrase is used as a demonstration) from cellular lysate using ammonium sulfate and oligovalent ligands. The oligovalent ligands induce the formation of protein-ligand aggregates, and at an appropriate concentration of dissolved ammonium sulfate, these complexes precipitate. The purification involves three steps: i) the removal of high-molecular weight impurities through the addition of ammonium sulfate to the crude cell lysate; ii) the introduction of an oligovalent ligand and the selective precipitation of the target protein-ligand aggregates from solution; and iii) the removal of the oligovalent ligand from the precipitate by dialysis to release the target protein. The increase of mass and volume of the proteins upon aggregate formation reduces their solubility, and results in the selective precipitation of these aggregates. We recovered human carbonic anhydrase, from crude cellular lysate, in 82% yield and 95% purity with a trivalent benzene sulfonamide ligand. This method provides a chromatography-free strategy of purifying monovalent proteins—for which appropriate oligovalent ligands can be synthesized—and combines the selectivity of affinity-based purification with the convenience of salt-induced precipitation. PMID:22188202

Selective precipitation and purification of monovalent proteins using oligovalent ligands and ammonium sulfate.

PubMed

Mirica, Katherine A; Lockett, Matthew R; Snyder, Phillip W; Shapiro, Nathan D; Mack, Eric T; Nam, Sarah; Whitesides, George M

2012-02-15

This paper describes a method for the selective precipitation and purification of a monovalent protein (carbonic anhydrase is used as a demonstration) from cellular lysate using ammonium sulfate and oligovalent ligands. The oligovalent ligands induce the formation of protein-ligand aggregates, and at an appropriate concentration of dissolved ammonium sulfate, these complexes precipitate. The purification involves three steps: (i) the removal of high-molecular-weight impurities through the addition of ammonium sulfate to the crude cell lysate; (ii) the introduction of an oligovalent ligand and the selective precipitation of the target protein-ligand aggregates from solution; and (iii) the removal of the oligovalent ligand from the precipitate by dialysis to release the target protein. The increase of mass and volume of the proteins upon aggregate formation reduces their solubility, and results in the selective precipitation of these aggregates. We recovered human carbonic anhydrase, from crude cellular lysate, in 82% yield and 95% purity with a trivalent benzene sulfonamide ligand. This method provides a chromatography-free strategy of purifying monovalent proteins--for which appropriate oligovalent ligands can be synthesized--and combines the selectivity of affinity-based purification with the convenience of salt-induced precipitation.

Vaccine adverse events reported in post-marketing study of the Kitasato Institute from 1994 to 2004.

PubMed

Nakayama, Tetsuo; Onoda, Kazumasa

2007-01-05

General physicians, pediatricians and parents realize that serious adverse events occur with an extremely rare incidence, but have no information on the incidences of vaccine-associated adverse events. A proper understanding of vaccine adverse events would be helpful in promoting an immunization strategy. Causal association can rarely be determined in adverse events through laboratory examinations. We examined the cases reported in the post-marketing surveillance of the Kitasato Institute, categorizing them into two groups: allergic reactions and severe systemic illnesses. Anaphylactic patients with gelatin allergy after immunization with live measles, rubella and mumps monovalent vaccines have been reported since 1993, but the number of reported cases with anaphylaxis dramatically decreased after 1999 when gelatin was removed from all brands of DPT. The incidence of anaphylactic reaction was estimated to be 0.63 per million for Japanese encephalitis virus (JEV) vaccine, 0.95 for DPT and 0.68 for Influenza vaccine, but the causative component has not yet been specified. Among 67.2 million immunization practices, 6 cases with encephalitis or encephalopathy, 7 with acute disseminated encephalomyelitis (ADEM), 10 with Guillain-Barré syndrome and 12 with idiopathic thrombocytopenic purpura (ITP) were reported. The wild-type measles virus genome was detected in a patient with encephalitis and in two of four bone marrow aspirates obtained from ITP after measles vaccination. Enterovirus infection was identified in two patients after mumps vaccination (one each with encephalitis and ADEM), one patient with encephalitis after immunization with JEV vaccine, and one with aseptic meningitis after immunization with influenza vaccine. The total estimated incidence of serious neurological illness after vaccination was 0.1-0.2 per million immunization practices. We found that enterovirus or wild-type measles virus infection was coincidentally associated with vaccination in

Immunogenicity, reactogenicity, and safety of a P1.7b,4 strain-specific serogroup B meningococcal vaccine given to preteens.

PubMed

Hosking, Jamie; Rasanathan, Kumanan; Mow, Florina Chan; Jackson, Catherine; Martin, Diana; O'Hallahan, Jane; Oster, Philipp; Ypma, Ellen; Reid, Stewart; Aaberge, Ingeborg; Crengle, Sue; Stewart, Joanna; Lennon, Diana

2007-11-01

New Zealand (NZ) has experienced a Neisseria meningitidis serogroup B epidemic since 1991. MeNZB, a strain-specific outer membrane vesicle vaccine made using an NZ epidemic strain isolate, NZ98/254 (B:4:P1.7b,4), from two manufacturing sites, the Norwegian Institute of Public Health (NIPH) and Chiron Vaccines (CV; now Novartis), was evaluated for safety, immunogenicity, and reactogenicity in this observer-blind trial with 8- to 12-year-old children. In year 1, cohort A (n = 302) was randomized 4:1 for receipt of NIPH-MeNZB or MenBvac (Norwegian parent vaccine strain 44/76; B:15:P1.7,16). In year 2, cohort B (n = 313) was randomized 4:1 for receipt of CV-MeNZB or NIPH-MeNZB. Participants all received three vaccinations 6 weeks apart. Local and systemic reactions were monitored for 7 days. Seroresponse was defined as a fourfold or greater rise in the serum bactericidal antibody titer from the baseline titer as measured by a serum bactericidal assay. Those with baseline titers of <1:4 required titers of >/=1:8 to serorespond. Intention-to-treat (ITT) and per protocol (PP) analyses are presented. In cohort A, 74% (ITT) and 73% (PP) of NIPH-MeNZB recipients demonstrated seroresponses against NZ98/254 after three doses, versus 32% (ITT and PP) of MenBvac recipients. In cohort B, seroresponses against NZ98/254 after three doses occurred in 79% (ITT and PP) of CV-MeNZB versus 75% (ITT) and 76% (PP) of NIPH-MeNZB recipients. Vaccines were tolerable, with no vaccine-related serious adverse events. In conclusion, the NZ strain meningococcal B vaccine (MeNZB) from either manufacturing site was immunogenic against New Zealand epidemic vaccine strain meningococci with no safety concerns when given in three doses to these 8- to 12-year-old children.

Epidemiology of group A rotavirus infection after the introduction of monovalent vaccine in the National Immunization Program of Saudi Arabia.

PubMed

Al-Ayed, Mohammed Saeed Zayed; Asaad, Ahmed Morad; Qureshi, Mohamed Ansar; Hawan, Ali Abdullah

2017-03-01

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[8] (69.2%) followed by P[4] (25.6%). The decrease in the prevalence of G1P[8] from 51% to 37.1% was associated with an increase in the prevalence of G2P[4] 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[6]. The parallel rise and spread of G2P[4] 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. © 2016 Wiley Periodicals, Inc.

H1N1 antibody persistence 1 year after immunization with an adjuvanted or whole-virion pandemic vaccine and immunogenicity and reactogenicity of subsequent seasonal influenza vaccine: a multicenter follow-on study.

PubMed

Walker, Woolf T; de Whalley, Philip; Andrews, Nick; Oeser, Clarissa; Casey, Michelle; Michaelis, Louise; Hoschler, Katja; Harrill, Caroline; Moulsdale, Phoebe; Thompson, Ben; Jones, Claire; Chalk, Jem; Kerridge, Simon; John, Tessa M; Okike, Ifeanyichukwu; Ladhani, Shamez; Tomlinson, Richard; Heath, Paul T; Miller, Elizabeth; Faust, Saul N; Snape, Matthew D; Finn, Adam; Pollard, Andrew J

2012-03-01

We investigated antibody persistence in children 1 year after 2 doses of either an AS03(B)-adjuvanted split-virion or nonadjuvanted whole-virion monovalent pandemic influenza vaccine and assessed the immunogenicity and reactogenicity of a subsequent dose of trivalent influenza vaccine (TIV). Children previously immunized at age 6 months to 12 years in the original study were invited to participate. After a blood sample was obtained to assess persistence of antibody against swine influenza A/H1N1(2009) pandemic influenza, children received 1 dose of 2010/2011 TIV, reactogenicity data were collected for 7 days, and another blood sample was obtained 21 days after vaccination. Of 323 children recruited, 302 received TIV. Antibody persistence (defined as microneutralization [MN] titer ≥1:40) 1 year after initial vaccination was significantly higher in the AS03(B)-adjuvanted compared with the whole-virion vaccine group, 100% (95% confidence interval [CI], 94.1%-100%) vs 32.4% (95% CI, 21.5%-44.8%) in children immunized <3 years old and 96.9% (95% CI, 91.3%-99.4%) vs 65.9% (95% CI, 55.3%-75.5%) in those 3-12 years old at immunization, respectively (P < .001 for both groups). All children receiving TIV had post-vaccination MN titers ≥1:40. Although TIV was well tolerated in all groups, reactogenicity in children <5 years old was slightly greater in those who originally received AS03(B)-adjuvanted vaccine. This study provides serological evidence that 2 doses of AS03(B)-adjuvanted pandemic influenza vaccine may be sufficient to maintain protection across 2 influenza seasons. Administration of TIV to children who previously received 2 doses of either pandemic influenza vaccine is safe and is immunogenic for the H1N1 strain.

H1N1 Antibody Persistence 1 Year After Immunization With an Adjuvanted or Whole-Virion Pandemic Vaccine and Immunogenicity and Reactogenicity of Subsequent Seasonal Influenza Vaccine: A Multicenter Follow-on Study

PubMed Central

Walker, Woolf T.; de Whalley, Philip; Andrews, Nick; Oeser, Clarissa; Casey, Michelle; Michaelis, Louise; Hoschler, Katja; Harrill, Caroline; Moulsdale, Phoebe; Thompson, Ben; Jones, Claire; Chalk, Jem; Kerridge, Simon; John, Tessa M.; Okike, Ifeanyichukwu; Ladhani, Shamez; Tomlinson, Richard; Heath, Paul T.; Miller, Elizabeth; Snape, Matthew D.; Finn, Adam; Pollard, Andrew J.

2012-01-01

Background. We investigated antibody persistence in children 1 year after 2 doses of either an AS03B-adjuvanted split-virion or nonadjuvanted whole-virion monovalent pandemic influenza vaccine and assessed the immunogenicity and reactogenicity of a subsequent dose of trivalent influenza vaccine (TIV). Methods. Children previously immunized at age 6 months to 12 years in the original study were invited to participate. After a blood sample was obtained to assess persistence of antibody against swine influenza A/H1N1(2009) pandemic influenza, children received 1 dose of 2010/2011 TIV, reactogenicity data were collected for 7 days, and another blood sample was obtained 21 days after vaccination. Results. Of 323 children recruited, 302 received TIV. Antibody persistence (defined as microneutralization [MN] titer ≥1:40) 1 year after initial vaccination was significantly higher in the AS03B-adjuvanted compared with the whole-virion vaccine group, 100% (95% confidence interval [CI], 94.1%–100%) vs 32.4% (95% CI, 21.5%–44.8%) in children immunized <3 years old and 96.9% (95% CI, 91.3%–99.4%) vs 65.9% (95% CI, 55.3%–75.5%) in those 3–12 years old at immunization, respectively (P < .001 for both groups). All children receiving TIV had post-vaccination MN titers ≥1:40. Although TIV was well tolerated in all groups, reactogenicity in children <5 years old was slightly greater in those who originally received AS03B-adjuvanted vaccine. Conclusions. This study provides serological evidence that 2 doses of AS03B-adjuvanted pandemic influenza vaccine may be sufficient to maintain protection across 2 influenza seasons. Administration of TIV to children who previously received 2 doses of either pandemic influenza vaccine is safe and is immunogenic for the H1N1 strain. PMID:22267719

Immunogenicity study to investigate the interchangeability among three different types of polio vaccine: A cohort study in Japan.

PubMed

Ohfuji, Satoko; Ito, Kazuya; Ishibashi, Motoki; Shindo, Shizuo; Takasaki, Yoshio; Yokoyama, Takashi; Yokoyama, Takato; Yamashita, Yuji; Shibao, Keigo; Nakano, Takashi; Tsuru, Tomomi; Irie, Shin; Hirota, Yoshio

2017-06-01

In Japan, the routine immunization program with oral polio vaccine (OPV) has been suspended since September 2012, when a program with 4 doses of inactivated monovalent polio vaccine (IPV) or quadrivalent vaccine against diphtheria, pertussis, and tetanus with IPV (DTaP-IPV) was introduced. The aim of this study was to examine the interchangeability among these 3 types of polio vaccines.We conducted a prospective cohort study at 5 pediatric clinics in Japan. A total of 153 infants were assigned to 1 of the 4 groups by considering the vaccination history of OPV and trivalent vaccine against DTaP. Eleven infants with a history of OPV received 3 doses of DTaP-IPV; 49 infants with a history of OPV and DTaP received 3 doses of IPV; 50 polio vaccine-naïve infants received 2 doses of IPV followed by 2 doses of DTaP-IPV; and 43 polio vaccine-naive infants received 2 doses of DTaP-IPV followed by IPV. The immunogenicity after polio vaccination was evaluated among these 4 groups.After 2 doses of polio vaccination, more than 80% of the infants exhibited a neutralization antibody titer ≥1:8 for all Sabin strains and wild strains in all groups. After the third dose, the seroprotection proportion (i.e., a neutralization antibody titer ≥1:8) reached about 100%. After the fourth dose, a neutralization antibody titer exceeded the required protective levels (i.e., a neutralization antibody titer ≥1:8) considerably in all groups.Four doses of polio vaccines induced a sufficient level of immunity in Japanese infants, irrespective of vaccine combinations or order.

Nanoparticle-based B-cell targeting vaccines: Tailoring of humoral immune responses by functionalization with different TLR-ligands.

PubMed

Zilker, Claudia; Kozlova, Diana; Sokolova, Viktoriya; Yan, Huimin; Epple, Matthias; Überla, Klaus; Temchura, Vladimir

2017-01-01

Induction of an appropriate type of humoral immune response during vaccination is essential for protection against viral and bacterial infections. We recently observed that biodegradable calcium phosphate (CaP) nanoparticles coated with proteins efficiently targeted and activated naïve antigen-specific B-cells in vitro. We now compared different administration routes for CaP-nanoparticles and demonstrated that intramuscular immunization with such CaP-nanoparticles induced stronger immune responses than immunization with monovalent antigen. Additional functionalization of the CaP-nanoparticles with TRL-ligands allowed modulating the IgG subtype response and the level of mucosal IgA antibodies. CpG-containing CaP-nanoparticles were as immunogenic as a virus-like particle vaccine. Functionalization of CaP-nanoparticles with T-helper cell epitopes or CpG also allowed overcoming lack of T-cell help. Thus, our results indicate that CaP-nanoparticle-based B-cell targeting vaccines functionalized with TLR-ligands can serve as a versatile platform for efficient induction and modulation of humoral immune responses in vivo. Copyright © 2016 Elsevier Inc. All rights reserved.

Monovalent Virus-Like Particle Vaccine Protects Guinea Pigs and Nonhuman Primates Against Infection with Multiple Marburg Viruses

DTIC Science & Technology

2008-05-01

illness and death. Guinea pig necropsy, histology & immunohistochemistry Two animals randomly selected from each group were eutha- nized on 6–7 days... Gastritis , neutrophilic - - - - - - +/++ +/++ - Intestine Cellular lysis - - - - - - + + + Enteritis, neutrophilic...isolates in both guinea pigs and NHPs. Clinical, histological and immunohisto- logical findings, restricted to six animals in the three RIBI-vaccinated

Comparison of a novel microcrystalline tyrosine adjuvant with aluminium hydroxide for enhancing vaccination against seasonal influenza.

PubMed

Heath, M D; Swan, N J; Marriott, A C; Silman, N J; Hallis, B; Prevosto, C; Gooch, K E; Skinner, M A

2017-03-27

Vaccination against seasonal influenza strains is recommended for "high risk" patient groups such as infants, elderly and those with respiratory or circulatory diseases. However, efficacy of the trivalent influenza vaccine (TIV) is poor in many cases and in the event of an influenza pandemic, mono-valent vaccines have been rapidly developed and deployed. One of the main issues with use of vaccine in pandemic situations is the lack of a suitable quantity of vaccine early enough during the pandemic to exert a major influence on the transmission of virus and disease outcome. One approach is to use a dose-sparing regimen which inevitably involves enhancing the efficacy using adjuvants. In this study we compare the use of a novel microcrystalline tyrosine (MCT) adjuvant, which is currently used in a niche area of allergy immunotherapy, for its ability to enhance the efficacy of a seasonal TIV preparation. The efficacy of the MCT adjuvant formulation was compared to alum adjuvanted TIV and to TIV administered without adjuvant using a ferret challenge model to determine vaccine efficacy. The MCT was found to possess high protein-binding capacity. In the two groups where TIV was formulated with adjuvant, the immune response was found to be higher (as determined by HAI titre) than vaccine administered without adjuvant and especially so after challenge with a live influenza virus. Vaccinated animals exhibited lower viral loads (as determined using RT-PCR) than control animals where no vaccine was administered. The attributes of each adjuvant in stimulating single-dose protection against a poorly immunogenic vaccine was demonstrated. The properties of MCT that lead to the reported effectiveness warrants further exploration in this and other vaccine targets - particularly where appropriate immunogenic, biodegradable and stable alternative adjuvants are sought.

A tetravalent alphavirus-vector based Dengue vaccine provides effective immunity in an early life mouse model

PubMed Central

Khalil, Syed Muaz; Tonkin, Daniel R.; Mattocks, Melissa D.; Snead, Andrew T.; Johnston, Robert E.; White, Laura J.

2014-01-01

Dengue viruses (DENV1-4) cause 390 million clinical infections every year, several hundred thousand of which progress to severe hemorrhagic and shock syndromes. Preexisting immunity resulting from a previous DENV infection is the major risk factor for severe dengue during secondary heterologous infections. During primary infections in infants, maternal antibodies pose an analogous risk. At the same time, maternal antibodies are likely to prevent induction of endogenous anti-DENV antibodies in response to current live, attenuated virus (LAV) vaccine candidates. Any effective early life dengue vaccine has to overcome maternal antibody interference (leading to ineffective vaccination) and poor induction of antibody responses (increasing the risk of severe dengue disease upon primary infection). In a previous study, we demonstrated that a non-propagating Venezuelan equine encephalitis virus replicon expression vector (VRP), expressing the ectodomain of DENV E protein (E85), overcomes maternal interference in a BALB/c mouse model. We report here that a single immunization with a tetravalent VRP vaccine induced NAb and T-cell responses to each serotype at a level equivalent to the monovalent vaccine components, suggesting that this vaccine modality can overcome serotype interference. Furthermore, neonatal immunization was durable and could be boosted later in life to further increase NAb and T-cell responses. Although the neonatal immune response was lower in magnitude than responses in adult BALB/c mice, we demonstrate that VRP vaccines generated protective immunity from a lethal challenge after a single neonatal immunization. In summary, VRP vaccines expressing DENV antigens were immunogenic and protective in neonates, and hence are promising candidates for safe and effective vaccination in early life. PMID:24882043

DNA vaccines targeting heavy chain C-terminal fragments of Clostridium botulinum neurotoxin serotypes A, B, and E induce potent humoral and cellular immunity and provide protection from lethal toxin challenge.

PubMed

Scott, Veronica L; Villarreal, Daniel O; Hutnick, Natalie A; Walters, Jewell N; Ragwan, Edwin; Bdeir, Khalil; Yan, Jian; Sardesai, Niranjan Y; Finnefrock, Adam C; Casimiro, Danilo R; Weiner, David B

2015-01-01

Botulinum neurotoxins (BoNTs) are deadly, toxic proteins produced by the bacterium Clostridium botulinum that can cause significant diseases in humans. The use of the toxic substances as potential bioweapons has raised concerns by the Centers for Disease Control and Prevention and the United States Military. Currently, there is no licensed vaccine to prevent botulinum intoxication. Here we present an immunogenicity study to evaluate the efficacy of novel monovalent vaccines and a trivalent cocktail DNA vaccine targeting the heavy chain C-terminal fragments of Clostridium botulinum neurotoxin serotypes A, B, and E. These synthetic DNA vaccines induced robust humoral and polyfunctional CD4(+) T-cell responses which fully protected animals against lethal challenge after just 2 immunizations. In addition, naïve animals administered immunized sera mixed with the lethal neurotoxin were 100% protected against intoxication. The data demonstrate the protective efficacy induced by a combinative synthetic DNA vaccine approach. This study has importance for the development of vaccines that provide protective immunity against C. botulinum neurotoxins and other toxins.

Changes in Rotavirus Genotypes before and after Vaccine Introduction: a Multicenter, Prospective Observational Study in Three Areas of Japan.

PubMed

Tanaka, Takaaki; Kamiya, Hajime; Asada, Kazutoyo; Suga, Shigeru; Ido, Masaru; Umemoto, Masakazu; Ouchi, Kazunobu; Ito, Hiroaki; Kuroki, Haruo; Nakano, Takashi; Taniguchi, Koki

2017-07-24

In Japan, monovalent and pentavalent rotavirus (RV) vaccines were approved in 2011 and 2012, respectively. To monitor changes in the RV genotypes before and after vaccine introduction, we performed a prospective observational study among children (＜ 5 years) with gastroenteritis who tested RV-positive on antigen rapid tests. Stool samples were collected from 3 different sites in Japan: Tsu City, Mie Prefecture; Kurashiki City, Okayama Prefecture; and Isumi City, Chiba Prefecture. RV genotypes were determined using reverse transcription-polymerase chain reaction. In Tsu City, G3P[8] was dominant (61.0-77.1%) before vaccine introduction, but decreased after introduction. Meanwhile, in an inverse proportion to the decrease in G3P[8], G1P[8] increased until the 2013/14 season, when a sudden predominance of G2P[4] (100%) occurred. A similar trend was observed in Kurashiki City in terms of the extent of reduction in G3P[8] and the emergence of G2P[4]. In Isumi City, G1P[8] was dominant (70.3%) before vaccine introduction, and G9P[8] became predominant (83.3%) in the 2013/14 season. To determine whether the genotype changes are attributable to vaccines or natural epidemiological changes, ongoing continuous monitoring of the RV genotypes is required.

An early (3-6 weeks) active surveillance study to assess the safety of pandemic influenza vaccine Focetria in a province of Emilia-Romagna region, Italy - part one.

PubMed

Candela, Silvia; Pergolizzi, Sara; Ragni, Pietro; Cavuto, Silvio; Nobilio, Lucia; Di Mario, Simona; Dragosevic, Valentina; Groth, Nicola; Magrini, Nicola

2013-02-27

An observational, non-comparative, prospective, surveillance study of individuals vaccinated with the MF59-adjuvanted A/H1N1 influenza vaccine, Focetria, (Novartis Vaccines & Diagnostics, Siena, Italy), was performed in Italy during the 2009 A/H1N1 influenza pandemic. This study assessed the short-term (six-week) safety profile of the investigational vaccine in real time. After vaccination (N=7943), adverse events (AE) were assessed using both active (telephone) and passive (healthcare database) follow-up in enrolled vaccinated subjects, including infants (6-23 months), pregnant women, and the immunosuppressed. The treating physicians of all subjects experiencing AEs post-vaccination were consulted for clinical information on the conditions reported. All AEs were coded according to ICD-10. A total of 1583 AEs occurred during the study, 67 (4.2%) of which were serious adverse events (SAEs). One SAE was considered to be possibly related to vaccination (transitory and ill-defined neurologic disorder experienced by a 16-year-old asthmatic male). Three adverse events of special interest (AESI) were identified (convulsions experienced by two epileptic subjects), none of which were considered to be vaccine-related. Six individuals died during the study period, in each case the cause of death was not related to vaccination (four cases of severe underlying co-morbidity, one case of psychoactive drug misuse, and one case of acute myocardial infarction). No cases of clinically relevant AEs, SAEs, or AESI were observed within a six-week period of vaccine administration. In accordance with existing clinical and post-marketing safety data, the results of this active surveillance study demonstrate a good safety profile for the MF59-adjuvanted A/H1N1 vaccine, Focetria, within the general population. Copyright © 2012 Elsevier Ltd. All rights reserved.

Effects of Monovalent Cations on the Sodium-Alanine Interaction in Rabbit Ileum

PubMed Central

Frizzell, Raymond A.; Schultz, Stanley G.

1970-01-01

H, K, Rb, and Li inhibit Na-dependent alanine influx across the brush border of rabbit ileum. Kinetic analysis indicates that H and K behave as competitive inhibitors of influx so that increasing the concentration of H or K in the mucosal solution is kinetically indistinguishable from decreasing the Na concentration. In addition the coupling between alanine and Na influxes is markedly reduced at pH 2.5. With the exception of H and Li, none of these monovalent cations significantly affects carrier-mediated alanine influx in the absence of Na indicating that their inhibitory effects are largely restricted to the Na-dependent fraction of influx. Increasing H concentration from 0.03 to 3 mM does not affect influx in the absence of Na but markedly inhibits influx in the presence of Na. Li significantly enhances alanine influx in the absence of Na. Ag, UO2, and La also inhibit the Na-dependent fraction of alanine influx. These findings suggest that anionic groups having a pKa of approximately 4 are involved in the interaction between Na and the alanine-carrier complex; present evidence implicates carboxylate groups however, phosphoryl residues cannot be ruled out. The previously proposed kinetic model for the Na-alanine interaction has been extended to accommodate these effects of H and other monovalent cations. The mechanistic and physiological implications of these findings are discussed. PMID:5507092

Bell’s palsy and influenza(H1N1)pdm09 containing vaccines: A self-controlled case series

PubMed Central

Wijnans, Leonoor; Weibel, Daniel; Sturkenboom, Miriam

2017-01-01

Background An association between AS03 adjuvanted pandemic influenza vaccine and the occurrence of Bell’s palsy was found in a population based cohort study in Stockholm, Sweden. To evaluate this association in a different population, we conducted a self-controlled case series in a primary health care database, THIN, in the United Kingdom. The aim of this study was to determine whether there was an increased risk of Bell’s palsy following vaccination with any influenza vaccine containing A/California/7/2009 (H1N1)-like viral strains. Secondly, we investigated whether risks were different following pandemic influenza A(H1N1)pdm09 vaccines and seasonal influenza vaccines containing the influenza A(H1N1)pdm09 strain. Methods The study population comprised all incident Bell’s palsy cases between 1 June 2009 and 30 June 2013 identified in THIN. We determined the relative incidence (RI) of Bell’s palsy during the 6 weeks following vaccination with either pandemic or seasonal influenza vaccine. All analyses were adjusted for seasonality and confounding variables. Results We found an incidence rate of Bell’s palsy of 38.7 per 100,000 person years. Both acute respiratory infection (ARI) consultations and pregnancy were found to be confounders. When adjusted for seasonality, ARI consultations and pregnancies, the RI during the 42 days after vaccination with an influenza vaccine was 0.85 (95% CI: 0.72–1.01). The RI was similar during the 42 days following seasonal vaccine (0.96, 95%CI: 0.82–1.13) or pandemic vaccine (0.73, 95%CI: 0.47–1.12). Conclusion We found no evidence for an increased incidence of Bell’s palsy following seasonal influenza vaccination overall, nor for monovalent pandemic influenza vaccine in 2009. PMID:28467420

Quantifying the Impact of Natural Immunity on Rotavirus Vaccine Efficacy Estimates: A Clinical Trial in Dhaka, Bangladesh (PROVIDE) and a Simulation Study.

PubMed

Rogawski, Elizabeth T; Platts-Mills, James A; Colgate, E Ross; Haque, Rashidul; Zaman, K; Petri, William A; Kirkpatrick, Beth D

2018-03-05

The low efficacy of rotavirus vaccines in clinical trials performed in low-resource settings may be partially explained by acquired immunity from natural exposure, especially in settings with high disease incidence. In a clinical trial of monovalent rotavirus vaccine in Bangladesh, we compared the original per-protocol efficacy estimate to efficacy derived from a recurrent events survival model in which children were considered naturally exposed and potentially immune after their first rotavirus diarrhea (RVD) episode. We then simulated trial cohorts to estimate the expected impact of prior exposure on efficacy estimates for varying rotavirus incidence rates and vaccine efficacies. Accounting for natural immunity increased the per-protocol vaccine efficacy estimate against severe RVD from 63.1% (95% confidence interval [CI], 33.0%-79.7%) to 70.2% (95% CI, 44.5%-84.0%) in the postvaccination period, and original year 2 efficacy was underestimated by 14%. The simulations demonstrated that this expected impact increases linearly with RVD incidence, will be greatest for vaccine efficacies near 50%, and can reach 20% in settings with high incidence and low efficacy. High rotavirus incidence leads to predictably lower vaccine efficacy estimates due to the acquisition of natural immunity in unvaccinated children, and this phenomenon should be considered when comparing efficacy estimates across settings. NCT01375647.

Exploring monovalent copper compounds with oxygen and hydrogen

PubMed Central

Korzhavyi, Pavel A.; Soroka, Inna L.; Isaev, Eyvaz I.; Lilja, Christina; Johansson, Börje

2012-01-01

New important applications of copper metal, e.g., in the areas of hydrogen production, fuel cell operation, and spent nuclear fuel disposal, require accurate knowledge of the physical and chemical properties of stable and metastable copper compounds. Among the copper(I) compounds with oxygen and hydrogen, cuprous oxide Cu2O is the only one stable and the best studied. Other such compounds are less known (CuH) or totally unknown (CuOH) due to their instability relative to the oxide. Here we combine quantum-mechanical calculations with experimental studies to search for possible compounds of monovalent copper. Cuprous hydride (CuH) and cuprous hydroxide (CuOH) are proved to exist in solid form. We establish the chemical and physical properties of these compounds, thereby filling the existing gaps in our understanding of hydrogen- and oxygen-related phenomena in Cu metal. PMID:22219370

Sero-prevalence of virus neutralizing antibodies for rabies in different groups of dogs following vaccination.

PubMed

Pimburage, R M S; Gunatilake, M; Wimalaratne, O; Balasuriya, A; Perera, K A D N

2017-05-18

Mass vaccination of dogs is considered fundamental for national rabies control programmes in Sri Lanka, as dog is the main reservoir and transmitter of the disease. Dogs were followed to determine the sero-prevalence of antibodies to the rabies virus. Altogether 510 previously vaccinated and unvaccinated dogs with owners (domestic dogs) and dogs without owners (stray dogs) of the local guard dog breed in different age groups recruited from Kalutara District, Sri Lanka. The dogs were vaccinated with a monovalent inactivated vaccine intramuscularly and serum antibody titres on days 0, 30, 180 and 360 were determined by the Rapid Fluorescent Focus Inhibition Test (RFFIT). The results indicated, a single dose of anti-rabies vaccination fails to generate a protective level of immunity (0.5 IU/ml) which lasts until 1 year in 40.42% of dogs without owners and 57.14% of previously unvaccinated juvenile (age: 3 months to 1 year) dogs with owners. More than one vaccination would help to maintain antibody titres above the protective level in the majority of dogs. The pattern of antibody titre development in annually vaccinated and irregularly vaccinated (not annual) adult dogs with owners is closely similar irrespective of regularity in vaccination. Previously vaccinated animals have higher (2 IU/ml) antibody titres to begin with and have a higher antibody titre on day 360 too. They show a very good antibody titre by day 180. Unvaccinated animals start with low antibody titre and return to low titres by day 360, but have a satisfactory antibody titre by day 180. A single dose of anti-rabies vaccination is not sufficient for the maintenance of antibody titres for a period of 1 year in puppies, juvenile dogs with owners and in dogs without owners. Maternal antibodies do not provide adequate protection to puppies of previously vaccinated dams and puppies of previously unvaccinated dams. Immunity development after vaccination seems to be closely similar in both the groups

Protective efficacy of a virus-vectored multi-component vaccine against porcine reproductive and respiratory syndrome virus, porcine circovirus type 2 and swine influenza virus.

PubMed

Tian, Debin; Sooryanarain, Harini; Matzinger, Shannon R; Gauger, Phil C; Karuppannan, Anbu K; Elankumaran, Subbiah; Opriessnig, Tanja; Meng, Xiang-Jin

2017-12-01

Porcine reproductive and respiratory syndrome virus (PRRSV), porcine circovirus type 2 (PCV2) and swine influenza virus (SIV) are three of the most economically important swine pathogens, causing immense economic losses to the global swine industry. Monovalent commercial vaccines against each of the three viruses are routinely used in pig farms worldwide. A trivalent vaccine against all three pathogens would greatly simplify the vaccination programme and reduce the financial burden to the swine industry. In this study, by using an attenuated strain of PRRSV (strain DS722) as a live virus vector, we generated a multi-component vaccine virus, DS722-SIV-PCV2, which expresses the protective antigens from SIV and PCV2. The DS722-SIV-PCV2 trivalent vaccine virus replicates well, and expresses PCV2 capsid and SIV HA proteins in vitro. A subsequent vaccination and challenge study in 48 pigs revealed that the DS722-SIV-PCV2-vaccinated pigs had significantly reduced lung lesions and viral RNA loads when challenged with PRRSV. Upon challenge with PCV2, the vaccinated pigs had partially reduced lymphoid lesions and viral DNA loads, and when challenged with SIV the vaccinated pigs had significantly reduced acute respiratory sign scores. The results from this study demonstrate the potential of DS722-SIV-PCV2 as a candidate trivalent vaccine, and also shed light on exploring PRRSV as a potential live virus vaccine vector.

Determination of influenza B identity and potency in quadrivalent inactivated influenza vaccines using lineage-specific monoclonal antibodies

PubMed Central

Verma, Swati; Soto, Jackeline; Vasudevan, Anupama; Schmeisser, Falko; Alvarado-Facundo, Esmeralda; Wang, Wei; Weiss, Carol D.

2017-01-01

Co-circulation of two antigenically and genetically distinct lineages of influenza B virus, represented by prototype viruses B/Victoria/2/1987 and B/Yamagata/16/1988, has led to the development of quadrivalent influenza vaccines that contain two influenza B antigens. The inclusion of two influenza B antigens presents challenges for the production and regulation of inactivated quadrivalent vaccines, including the potential for cross-reactivity of the reagents used in identity and potency assays because of the relative close relatedness of the hemagglutinin (HA) from the two virus lineages. Monoclonal antibodies (mAbs) specific for the two lineages of influenza B HA were generated and characterized and used to set-up simple identity tests that distinguish the influenza B antigens in inactivated trivalent and quadrivalent vaccines. The lineage-specific mAbs bound well to the HA of influenza B strains included in influenza vaccines over a period of more than 10 years, suggesting that identity tests using such lineage-specific mAbs would not necessarily have to be updated with every influenza B vaccine strain change. These lineage-specific mAbs were also used in an antibody capture ELISA format to quantify HA in vaccine samples, including monovalent, trivalent, and quadrivalent vaccine samples from various manufacturers. The results demonstrated correlation with HA values determined by the traditional single radial immunodiffusion (SRID) assay. Further, the antibody-capture ELISA was able to distinguish heat-stressed vaccine from unstressed vaccine, and was similar to the SRID in quantifying the resultant loss of potency. These mAb reagents should be useful for further development of antibody-based alternative influenza B identity and potency assays. PMID:28423025

Determination of influenza B identity and potency in quadrivalent inactivated influenza vaccines using lineage-specific monoclonal antibodies.

PubMed

Verma, Swati; Soto, Jackeline; Vasudevan, Anupama; Schmeisser, Falko; Alvarado-Facundo, Esmeralda; Wang, Wei; Weiss, Carol D; Weir, Jerry P

2017-01-01

Co-circulation of two antigenically and genetically distinct lineages of influenza B virus, represented by prototype viruses B/Victoria/2/1987 and B/Yamagata/16/1988, has led to the development of quadrivalent influenza vaccines that contain two influenza B antigens. The inclusion of two influenza B antigens presents challenges for the production and regulation of inactivated quadrivalent vaccines, including the potential for cross-reactivity of the reagents used in identity and potency assays because of the relative close relatedness of the hemagglutinin (HA) from the two virus lineages. Monoclonal antibodies (mAbs) specific for the two lineages of influenza B HA were generated and characterized and used to set-up simple identity tests that distinguish the influenza B antigens in inactivated trivalent and quadrivalent vaccines. The lineage-specific mAbs bound well to the HA of influenza B strains included in influenza vaccines over a period of more than 10 years, suggesting that identity tests using such lineage-specific mAbs would not necessarily have to be updated with every influenza B vaccine strain change. These lineage-specific mAbs were also used in an antibody capture ELISA format to quantify HA in vaccine samples, including monovalent, trivalent, and quadrivalent vaccine samples from various manufacturers. The results demonstrated correlation with HA values determined by the traditional single radial immunodiffusion (SRID) assay. Further, the antibody-capture ELISA was able to distinguish heat-stressed vaccine from unstressed vaccine, and was similar to the SRID in quantifying the resultant loss of potency. These mAb reagents should be useful for further development of antibody-based alternative influenza B identity and potency assays.

Differential Impact of the Monovalent Ions Li+, Na+, K+, and Rb+ on DNA Conformational Properties

PubMed Central

2015-01-01

The present report demonstrates that the conformational properties of DNA in solution are sensitive to the type of monovalent ion. Results are based on the ability of a polarizable force field using the classical Drude oscillator to reproduce experimental solution X-ray scattering data more accurately than two nonpolarizable DNA models, AMBER Parmbsc0 and CHARMM36. The polarizable model is then used to calculate scattering profiles of DNA in the presence of four different monovalent salts, LiCl, NaCl, KCl, and RbCl, showing the conformational properties of DNA to vary as a function of ion type, with that effect being sequence-dependent. The primary conformational mode associated with the variations is contraction of the DNA minor groove width with decreasing cation size. These results indicate that the Drude polarizable model provides a more realistic representation of ion–DNA interactions than additive models that may lead to a new level of understanding of the physical mechanisms driving salt-mediated biological processes involving nucleic acids. PMID:25580188

Monovalent Rotavirus Vaccine Effectiveness and Impact on Rotavirus Hospitalizations in Zanzibar, Tanzania: Data From the First 3 Years After Introduction.

PubMed

Abeid, Khamis Ali; Jani, Bhavin; Cortese, Margaret M; Kamugisha, Christopher; Mwenda, Jason M; Pandu, Aziza Salim; Msaada, Kazija Ali; Mohamed, Abdallah Said; Khamis, Asha Ussi; Parashar, Umesh D; Saleh, Abdulhamid A

2017-01-15

Low-income settings challenge the level of protection provided by live attenuated oral rotavirus vaccines. Rotarix (RV1) was introduced in the United Republic of Tanzania in early 2013, with 2 doses given at the World Health Organization-recommended schedule of ages 6 and 10 weeks, along with oral poliovirus vaccine. We performed active surveillance for rotavirus hospitalizations at the largest hospital in Zanzibar, Tanzania, from 2010 through 2015. Using a case-test-negative control design, we estimated the vaccine effectiveness (VE) of 2 RV1 doses in preventing rotavirus hospitalizations. Based on 204 rotavirus case patients and 601 test-negative controls aged 5-23 months, the VE of 2 RV1 doses against hospitalization for rotavirus diarrhea was 57% (95% confidence interval, 14%-78%). VE tended to increase against hospitalizations with higher severity, reaching 69% (95% confidence interval, 15%-88%) against the severity score for the top quarter of case patients. Compared with the prevaccine period, there were estimated reductions of 40%, 46%, and 69% in the number of rotavirus hospitalizations among infants in 2013, 2014, and 2015, respectively, and reductions of 36%, 26%, and 64%, respectively, among children aged <5 years. With data encompassing 3 years before and 3 years after vaccine introduction, our results indicate that successful delivery of RV1 on the current World Health Organization schedule can provide substantial health benefits in a resource-limited setting. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US

Interaction of monovalent cations with acetonitrile

NASA Astrophysics Data System (ADS)

Černušák, Ivan; Aranyosiová, Monika; Vollárová, Ol'ga; Velič, Dušan; Kirdajová, Ol'ga; Benko, Ján

Solvation of monovalent cations (Me+) of alkali metals=Na+, K+, Rb+, and Cs+, coinage metals=Cu+, Ag+, Au+, and p-block elements Ga+, In+, and Tl+ with acetonitrile was studied by means of ab initio calculations and time-of-flight secondary ion mass spectrometry (TOF-SIMS). The intermolecular interactions in the complexes Me+···CH3CN were investigated using the coupled clusters theory including single, double, and noniterative triple substitutions (CCSD(T)) in conjunction with the Pol and Pol-dk basis sets. The binding energies of these donor-acceptor complexes were estimated; taking into account the basis set superposition error, zero-point vibrations, correlation contribution, and scalar relativistic corrections. The theoretical ΔG0298 K values based on CCSD(T)/Pol and/or CCSD(T)/Pol-dk binding energies correlated well with experimental transfer Gibbs energies (from water to acetonitrile) for the series of cations. In the case of Au monocation, relativistic correction turned out to be extremely important. Composition of the complex of Ag+ and Na+ with acetonitrile was determined by using SIMS supporting both theoretical and experimental transfer Gibbs energies.

A novel inactivated enterovirus 71 vaccine can elicit cross-protective immunity against coxsackievirus A16 in mice.

PubMed

Yang, Lisheng; Liu, Yajing; Li, Shuxuan; Zhao, Huan; Lin, Qiaona; Yu, Hai; Huang, Xiumin; Zheng, Qingbing; Cheng, Tong; Xia, Ningshao

2016-11-21

Hand, foot, and mouth disease (HFMD) is a highly contagious disease that mainly affects infants and children. Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the major pathogens of HFMD. Two EV71 vaccines were recently licensed in China and the administration of the EV71 vaccines is believed to significantly reduce the number of HFMD-related severe or fatal cases. However, a monovalent EV71 vaccine cannot cross-protect against CA16 infection, this may result in that it cannot effectively control the overall HFMD epidemic. In this study, a chimeric EV71, whose VP1/210-225 epitope was replaced by that of CA16, was constructed using a reverse genetics technique to produce a candidate EV71/CA16 bivalent vaccine strain. The chimeric EV71 was infectious and showed similar growth characteristics as its parental strain. The replacement of the VP1/210-225 epitope did not significantly affect the antigenicity and immunogenicity of EV71. More importantly, the chimeric EV71 could induce protective immunity against both EV71 and CA16, and protect neonatal mice against either EV71 or CA16 lethal infections, the chimeric EV71 constructed in this study was shown to be a feasible and promising candidate bivalent vaccine against both EV71 and CA16. The construction of a chimeric enterovirus also provides an alternative platform for broad-spectrum HFMD vaccines development. Copyright © 2016 Elsevier Ltd. All rights reserved.

A physico-chemical assessment of the thermal stability of pneumococcal conjugate vaccine components

PubMed Central

Gao, Fang; Lockyer, Kay; Burkin, Karena; Crane, Dennis T; Bolgiano, Barbara

2014-01-01

Physico-chemical analysis of pneumococcal polysaccharide (PS)-protein conjugate vaccine components used for two commercially licensed vaccines was performed to compare the serotype- and carrier protein-specific stabilities of these vaccines. Nineteen different monovalent pneumococcal conjugates from commercial vaccines utilizing CRM197, diphtheria toxoid (DT), Protein D (PD) or tetanus toxoid (TT) as carrier proteins were incubated at temperatures up to 56°C for up to eight weeks or were subjected to freeze-thawing (F/T). Structural stability was evaluated by monitoring their size, integrity and carrier protein conformation. The molecular size of the vaccine components was well maintained for Protein D, TT and DT conjugates at -20°C, 4°C and F/T, and for CRM197 conjugates at 4°C and F/T. It was observed that four of the eight serotypes of Protein D conjugates tended to form high molecular weight complexes at 37°C or above. The other conjugated carrier proteins also appeared to form oligomers or ‘aggregates’ at elevated temperatures, but rarely when frozen and thawed. There was evidence of degradation in some of the conjugates as evidenced by the formation of lower molecular weight materials which correlated with measured free saccharide. In conclusion, pneumococcal-Protein D/TT/DT and most CRM197 bulk conjugate vaccines were stable when stored at 2–8°C, the recommended temperature. In common between the conjugates produced by the two manufacturers, serotypes 1, 5, and 19F were relatively less stable and 6B was the most stable, with types 7F and 23F also showing good stability. PMID:25483488

Methodological challenges in measuring vaccine effectiveness using population cohorts in low resource settings

PubMed Central

King, C.; Beard, J.; Crampin, A.C.; Costello, A.; Mwansambo, C.; Cunliffe, N.A.; Heyderman, R.S.; French, N.; Bar-Zeev, N.

2015-01-01

Post-licensure real world evaluation of vaccine implementation is important for establishing evidence of vaccine effectiveness (VE) and programme impact, including indirect effects. Large cohort studies offer an important epidemiological approach for evaluating VE, but have inherent methodological challenges. Since March 2012, we have conducted an open prospective cohort study in two sites in rural Malawi to evaluate the post-introduction effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) against all-cause post-neonatal infant mortality and monovalent rotavirus vaccine (RV1) against diarrhoea-related post-neonatal infant mortality. Our study sites cover a population of 500,000, with a baseline post-neonatal infant mortality of 25 per 1000 live births. We conducted a methodological review of cohort studies for vaccine effectiveness in a developing country setting, applied to our study context. Based on published literature, we outline key considerations when defining the denominator (study population), exposure (vaccination status) and outcome ascertainment (mortality and cause of death) of such studies. We assess various definitions in these three domains, in terms of their impact on power, effect size and potential biases and their direction, using our cohort study for illustration. Based on this iterative process, we discuss the pros and cons of our final per-protocol analysis plan. Since no single set of definitions or analytical approach accounts for all possible biases, we propose sensitivity analyses to interrogate our assumptions and methodological decisions. In the poorest regions of the world where routine vital birth and death surveillance are frequently unavailable and the burden of disease and death is greatest We conclude that provided the balance between definitions and their overall assumed impact on estimated VE are acknowledged, such large scale real-world cohort studies can provide crucial information to policymakers by providing

Quality, immunogenicity and stability of meningococcal serogroup ACWY-CRM197, DT and TT glycoconjugate vaccines.

PubMed

Beresford, Nicola J; Martino, Angela; Feavers, Ian M; Corbel, Michael J; Bai, Xilian; Borrow, Ray; Bolgiano, Barbara

2017-06-16

A physicochemical and immunological study of the stability of three different meningococcal (Men) ACWY conjugate vaccines was performed to evaluate any patterns of serogroup oligo- or polysaccharide-specific or carrier protein-specific stability that would affect immunogenicity. Critical quality and stability-indicating characteristics were measured, with the study supporting the suitability of both HPLC-SEC and HPAEC-PAD methods to detect changes following inappropriate vaccine storage. All three final products, ACWY-CRM 197 , -DT and -TT conjugate vaccines had expected quality indicator values and similar immunogenicity in a mouse model (anti-PS IgG and rSBA) when stored at +2-8°C. When stored at ≥+37°C, all conjugated carrier proteins and serogroup saccharides were affected. Direct correlations were observed between the depolymerization of the MenA saccharide as evidenced by a size-reduction in the MenA conjugates (CRM 197 , DT and TT) and their immunogenicity. MenA was the most labile serogroup, followed by MenC; then MenW and Y, which were similar. At high temperatures, the conjugated carrier proteins were prone to unfolding and/or aggregation. The anti-MenC IgG responses of the multivalent conjugate vaccines in mice were equivalent to those observed in monovalent MenC conjugate vaccines, and were independent of the carrier protein. For any newly developing MenACWY saccharide-protein conjugate vaccines, a key recommendation would be to consider the lyophilization of final product to prevent deleterious degradation that would affect immunogenicity. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

The permeability of endplate channels to monovalent and divalent metal cations

PubMed Central

1980-01-01

The relative permeability of endplate channels to monovalent and divalent metal ions was determined from reversal potentials. Thallium is the most permeant ion with a permeability ratio relative to Na+ of 2.5. The selectivity among alkali metals is weak with a sequence, Cs+ greater than Rb+ greater than K+ greater than Na+ greater than Li+, and permeability ratios of 1.4, 1.3, 1.1, 1.0, and 0.9. The selectivity among divalent ions is also weak, with a sequence for alkaline earths of Mg++ greater than Ca++ greater than Ba++ greater than Sr++. The transition metal ions Mn++, Co++, Ni++, Zn++, and Cd++ are also permeant. Permeability ratios for divalent ions decreased as the concentration of divalent ion was increased in a manner consistent with the negative surface potential theory of Lewis (1979 J. Physiol. (Lond.). 286: 417--445). With 20 mM XCl2 and 85.5 mM glucosamine.HCl in the external solution, the apparent permeability ratios for the alkaline earth cations (X++) are in the range 0.18--0.25. Alkali metal ions see the endplate channel as a water-filled, neutral pore without high-field-strength sites inside. Their permeability sequence is the same as their aqueous mobility sequence. Divalent ions, however, have a permeability sequence almost opposite from their mobility sequence and must experience some interaction with groups in the channel. In addition, the concentrations of monovalent and divalent ions are increased near the channel mouth by a weak negative surface potential. PMID:6247423

Ontology-Based Combinatorial Comparative Analysis of Adverse Events Associated with Killed and Live Influenza Vaccines

PubMed Central

Sarntivijai, Sirarat; Xiang, Zuoshuang; Shedden, Kerby A.; Markel, Howard; Omenn, Gilbert S.; Athey, Brian D.; He, Yongqun

2012-01-01

severe adverse events than TIV. In addition, our meta-analysis found that all previously reported positive correlation between GBS and influenza vaccine immunization were based on trivalent influenza vaccines instead of monovalent influenza vaccines. PMID:23209624

Guillain-Barré Syndrome During the 2009–2010 H1N1 Influenza Vaccination Campaign: Population-based Surveillance Among 45 Million Americans

PubMed Central

Wise, Matthew E.; Viray, Melissa; Sejvar, James J.; Lewis, Paige; Baughman, Andrew L.; Connor, Walter; Danila, Richard; Giambrone, Greg P.; Hale, Christa; Hogan, Brenna C.; Meek, James I.; Murphree, Rendi; Oh, John Y.; Reingold, Arthur; Tellman, Norisse; Conner, Susan M.; Singleton, James A.; Lu, Peng-Jun; DeStefano, Frank; Fridkin, Scott K.; Vellozzi, Claudia; Morgan, Oliver W.

2012-01-01

Because of widespread distribution of the influenza A (H1N1) 2009 monovalent vaccine (pH1N1 vaccine) and the prior association between Guillain-Barré syndrome (GBS) and the 1976 H1N1 influenza vaccine, enhanced surveillance was implemented to estimate the magnitude of any increased GBS risk following administration of pH1N1 vaccine. The authors conducted active, population-based surveillance for incident cases of GBS among 45 million persons residing at 10 Emerging Infections Program sites during October 2009–May 2010; GBS was defined according to published criteria. The authors determined medical and vaccine history for GBS cases through medical record review and patient interviews. The authors used vaccine coverage data to estimate person-time exposed and unexposed to pH1N1 vaccine and calculated age- and sex-adjusted rate ratios comparing GBS incidence in these groups, as well as age- and sex-adjusted numbers of excess GBS cases. The authors received 411 reports of confirmed or probable GBS. The rate of GBS immediately following pH1N1 vaccination was 57% higher than in person-time unexposed to vaccine (adjusted rate ratio = 1.57, 95% confidence interval: 1.02, 2.21), corresponding to 0.74 excess GBS cases per million pH1N1 vaccine doses (95% confidence interval: 0.04, 1.56). This excess risk was much smaller than that observed during the 1976 vaccine campaign and was comparable to some previous seasonal influenza vaccine risk assessments. PMID:22582209

Effectiveness of rotavirus vaccine in preventing severe gastroenteritis in young children according to socioeconomic status

PubMed Central

Gosselin, Virginie; Généreux, Mélissa; Gagneur, Arnaud; Petit, Geneviève

2016-01-01

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

EmrE, a multidrug transporter from Escherichia coli, transports monovalent and divalent substrates with the same stoichiometry.

PubMed

Rotem, Dvir; Schuldiner, Shimon

2004-11-19

Multidrug transporters recognize and transport substrates with apparently little common structural features. At times these substrates are neutral, negatively, or positively charged, and only limited information is available as to how these proteins deal with the energetic consequences of transport of substrates with different charges. Multidrug transporters and drug-specific efflux systems are responsible for clinically significant resistance to chemotherapeutic agents in pathogenic bacteria, fungi, parasites, and human cancer cells. Understanding how these efflux systems handle different substrates may also have practical implications in the development of strategies to overcome the resistance mechanisms mediated by these proteins. Here, we compare transport of monovalent and divalent substrates by EmrE, a multidrug transporter from Escherichia coli, in intact cells and in proteoliposomes reconstituted with the purified protein. The results demonstrated that whereas the transport of monovalent substrates involves charge movement (i.e. electrogenic), the transport of divalent substrate does not (i.e. electroneutral). Together with previous results, these findings suggest that an EmrE dimer exchanges two protons per substrate molecule during each transport cycle. In intact cells, under conditions where the only driving force is the electrical potential, EmrE confers resistance to monovalent substrates but not to divalent ones. In the presence of proton gradients, resistance to both types of substrates is detected. The finding that under some conditions EmrE does not remove certain types of drugs points out the importance of an in-depth understanding of mechanisms of action of multidrug transporters to devise strategies for coping with the problem of multidrug resistance.

Immunogenicity and Safety of a Combination of Two Serogroup B Meningococcal Outer Membrane Vesicle Vaccines▿

PubMed Central

Sandbu, Synne; Feiring, Berit; Oster, Philipp; Helland, Oddveig S.; Bakke, Hilde S. W.; Næss, Lisbeth M.; Aase, Audun; Aaberge, Ingeborg S.; Kristoffersen, Anne-Cathrine; Rydland, Kjersti M.; Tilman, Sandrine; Nøkleby, Hanne; Rosenqvist, Einar

2007-01-01

MenBvac and MeNZB are safe and efficacious vaccines against serogroup B meningococcal disease. MenBvac is prepared from a B:15:P1.7,16 meningococcal strain (strain 44/76), and MeNZB is prepared from a B:4:P1.7-2,4 strain (strain NZ98/254). At 6-week intervals, healthy adults received three doses of MenBvac (25 μg), MeNZB (25 μg), or the MenBvac and MeNZB (doses of 12.5 μg of each vaccine) vaccines combined, followed by a booster 1 year later. Two-thirds of the subjects who received a monovalent vaccine in the primary schedule received the other monovalent vaccine as a booster dose. The immune responses to the combined vaccine were of the same magnitude as the homologous responses to each individual vaccine observed. At 6 weeks after the third dose, 77% and 87% of the subjects in the combined vaccine group achieved serum bactericidal titers of ≥4 against strains 44/76 and NZ98/254, respectively, and 97% and 93% of the subjects achieved a fourfold or greater increase in opsonophagocytic activity against strains 44/76 and NZ98/254, respectively. For both strains, a trend of higher responses after the booster dose was observed in all groups receiving at least one dose of the respective strain-specific vaccine. Local and systemic reactions were common in all vaccine groups. Most reactions were mild or moderate in intensity, and there were no vaccine-related serious adverse events. The safety profile of the combined vaccine was not different from those of the separate monovalent vaccines. In conclusion, use of either of the single vaccines or the combination of MenBvac and MeNZB may have a considerable impact on the serogroup B meningococcal disease situation in many countries. PMID:17634513

Whole-cell and single channel monovalent cation currents through the novel rabbit epithelial Ca2+ channel ECaC

PubMed Central

Nilius, Bernd; Vennekens, Rudi; Prenen, Jean; Hoenderop, Joost G J; Bindels, René J M; Droogmans, Guy

2000-01-01

This study describes properties of monovalent cation currents through ECaC, a recently cloned epithelial Ca2+-permeable channel from rabbit. The kinetics of currents through ECaC was strongly modulated by divalent cations. Currents were inhibited in the presence of extracellular Ca2+. They showed an initial voltage-dependent decay in the presence of 1 mm Mg2+ at hyperpolarizing steps in Ca2+-free solutions, which represents a voltage-dependent Mg2+ block through binding of Mg2+ to a site localized in the electrical field of the membrane (δ = 0.31) and a voltage-dependent binding constant (at 0 mV 3.1 mm Ca2+, obtained from a Woodhull type analysis). Currents were only stable in the absence of divalent cations and showed under these conditions a small time- and voltage-dependent component of activation. Single channel currents in cell-attached and inside-out patches had a conductance of 77.5 ± 4.9 pS (n = 11) and reversed at +14.8 ± 1.6 mV (n = 9) in the absence of divalent cations. The permeation sequence for monovalent cations through ECaC was Na+ > Li+ > K+ > Cs+ > NMDG+ which is identical to the Eisenmann sequence X for a strong field-strength binding site. It is concluded that the permeation profile of ECaC for monovalent cations suggests a strong field-strength binding site that may be involved in Ca2+ permeation and Mg2+ block. PMID:10970426

Impact of rotavirus vaccination on rotavirus and all-cause gastroenteritis in peri-urban Kenyan children.

PubMed

Wandera, Ernest Apondi; Mohammad, Shah; Bundi, Martin; Komoto, Satoshi; Nyangao, James; Kathiiko, Cyrus; Odoyo, Erick; Miring'u, Gabriel; Taniguchi, Koki; Ichinose, Yoshio

2017-09-12

A monovalent rotavirus vaccine (RV1) was introduced into the National Immunization Program in Kenya in July 2014. We examined the impact of the vaccine on hospitalization for all-cause acute gastroenteritis (AGE) and rotavirus-specific AGE and strain distribution at a large referral hospital which serves a predominantly peri-urban population in Central Kenya. Data on rotavirus AGE and strain distribution were derived from ongoing hospital-based AGE surveillance. Hospital administrative data were used to compare trends in all-cause AGE. Pre-vaccine (July 2009-June 2014) and post-vaccine (July 2014-June 2016) periods were compared for changes in hospitalization for all-cause AGE and rotavirus AGE and strain distribution. Following the vaccine introduction, the proportion of children aged <5years hospitalized for rotavirus declined by 30% (95% CI: 19-45%) in the first year and 64% (95% CI: 49-77%) in the second year. Reductions in rotavirus positivity were most pronounced among the vaccine-eligible group (<12months) in the first year post-vaccination at 42% (95% CI: 28-56%). Greater reductions of 67% (95% CI: 51-79%) were seen in the second year in the 12-23months age group. Similarly, hospitalizations for all-cause AGE among children <5years of age decreased by 31% (95% CI: 24-40%) in the first year and 58% (95% CI: 49-67%) in the second year of vaccine introduction. Seasonal peaks of rotavirus and all-cause AGE were reduced substantially. There was an increased detection of G2P[4], G3P[6] and G3P[8], which coincided temporally with the timing of the vaccine introduction. Thus, introducing the rotavirus vaccine into the routine immunization program in Kenya has resulted in a notable decline in rotavirus and all-cause AGE hospitalizations in Central Kenya. This provides early evidence for public health policy makers in Kenya to support the sustained use of the rotavirus vaccine in routine immunizations. Copyright © 2017 Elsevier Ltd. All rights reserved.

Estimates of Pandemic Influenza Vaccine Effectiveness in Europe, 2009–2010: Results of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) Multicentre Case-Control Study

PubMed Central

Valenciano, Marta; Kissling, Esther; Cohen, Jean-Marie; Oroszi, Beatrix; Barret, Anne-Sophie; Rizzo, Caterina; Nunes, Baltazar; Pitigoi, Daniela; Larrauri Cámara, Amparro; Mosnier, Anne; Horvath, Judith K.; O'Donnell, Joan; Bella, Antonino; Guiomar, Raquel; Lupulescu, Emilia; Savulescu, Camelia; Ciancio, Bruno C.; Kramarz, Piotr; Moren, Alain

2011-01-01

Background A multicentre case-control study based on sentinel practitioner surveillance networks from seven European countries was undertaken to estimate the effectiveness of 2009–2010 pandemic and seasonal influenza vaccines against medically attended influenza-like illness (ILI) laboratory-confirmed as pandemic influenza A (H1N1) (pH1N1). Methods and Findings Sentinel practitioners swabbed ILI patients using systematic sampling. We included in the study patients meeting the European ILI case definition with onset of symptoms >14 days after the start of national pandemic vaccination campaigns. We compared pH1N1 cases to influenza laboratory-negative controls. A valid vaccination corresponded to >14 days between receiving a dose of vaccine and symptom onset. We estimated pooled vaccine effectiveness (VE) as 1 minus the odds ratio with the study site as a fixed effect. Using logistic regression, we adjusted VE for potential confounding factors (age group, sex, month of onset, chronic diseases and related hospitalizations, smoking history, seasonal influenza vaccinations, practitioner visits in previous year). We conducted a complete case analysis excluding individuals with missing values and a multiple multivariate imputation to estimate missing values. The multivariate imputation (n = 2902) adjusted pandemic VE (PIVE) estimates were 71.9% (95% confidence interval [CI] 45.6–85.5) overall; 78.4% (95% CI 54.4–89.8) in patients <65 years; and 72.9% (95% CI 39.8–87.8) in individuals without chronic disease. The complete case (n = 1,502) adjusted PIVE were 66.0% (95% CI 23.9–84.8), 71.3% (95% CI 29.1–88.4), and 70.2% (95% CI 19.4–89.0), respectively. The adjusted PIVE was 66.0% (95% CI −69.9 to 93.2) if vaccinated 8–14 days before ILI onset. The adjusted 2009–2010 seasonal influenza VE was 9.9% (95% CI −65.2 to 50.9). Conclusions Our results suggest good protection of the pandemic monovalent vaccine against medically attended pH1N1 and no

Improvement of the Dengue Virus (DENV) Nonhuman Primate Model via a Reverse Translational Approach Based on Dengue Vaccine Clinical Efficacy Data against DENV-2 and -4

PubMed Central

Mantel, Nathalie; De Montfort, Aymeric; Pagnon, Anke; Pradezynski, Fabrine; Lang, Jean; Boudet, Florence

2018-01-01

ABSTRACT Recent data obtained with the live-attenuated tetravalent dengue CYD-TDV vaccine showed higher protective efficacy against dengue virus type 4 (DENV-4) than against DENV-2. In contrast, results from previous studies in nonhuman primates predicted comparable high levels of protection against each serotype. Maximum viral loads achieved in macaques by subcutaneous inoculation of DENV are generally much lower than those observed in naturally dengue virus-infected humans. This may contribute to an overestimation of vaccine efficacy. Using more-stringent DENV infection conditions consisting of the intravenous inoculation of 107 50% cell culture infectious doses (CCID50) in CYD-TDV-vaccinated macaques, complete protection (i.e., undetectable viral RNA) was achieved in all 6 monkeys challenged with DENV-4 and in 6/18 of those challenged with DENV-2, including transiently positive animals. All other infected macaques (12/18) developed sustained DENV-2 RNAemia (defined as detection of viral RNA in serum samples) although 1 to 3 log10 units below the levels achieved in control animals. Similar results were obtained with macaques immunized with either CYD-TDV or monovalent (MV) CYD-2. This suggests that partial protection against DENV-2 was mediated mainly by CYD-2 and not by the other CYDs. Postchallenge induction of strong anamnestic responses, suggesting efficient vaccine priming, likely contributed to the reduction of DENV-2 RNAemia. Finally, an inverse correlation between DENV RNA titers postchallenge and vaccine-induced homotypic neutralizing antibody titers prechallenge was found, emphasizing the key role of these antibodies in controlling DENV infection. Collectively, these data show better agreement with reported data on CYD-TDV clinical vaccine efficacy against DENV-2 and DENV-4. Despite inherent limitations of the nonhuman primate model, these results reinforce its value in assessing the efficacy of dengue vaccines. IMPORTANCE The nonhuman primate (NHP

Improvement of the Dengue Virus (DENV) Nonhuman Primate Model via a Reverse Translational Approach Based on Dengue Vaccine Clinical Efficacy Data against DENV-2 and -4.

PubMed

Barban, Veronique; Mantel, Nathalie; De Montfort, Aymeric; Pagnon, Anke; Pradezynski, Fabrine; Lang, Jean; Boudet, Florence

2018-06-15

Recent data obtained with the live-attenuated tetravalent dengue CYD-TDV vaccine showed higher protective efficacy against dengue virus type 4 (DENV-4) than against DENV-2. In contrast, results from previous studies in nonhuman primates predicted comparable high levels of protection against each serotype. Maximum viral loads achieved in macaques by subcutaneous inoculation of DENV are generally much lower than those observed in naturally dengue virus-infected humans. This may contribute to an overestimation of vaccine efficacy. Using more-stringent DENV infection conditions consisting of the intravenous inoculation of 10 7 50% cell culture infectious doses (CCID 50 ) in CYD-TDV-vaccinated macaques, complete protection (i.e., undetectable viral RNA) was achieved in all 6 monkeys challenged with DENV-4 and in 6/18 of those challenged with DENV-2, including transiently positive animals. All other infected macaques (12/18) developed sustained DENV-2 RNAemia (defined as detection of viral RNA in serum samples) although 1 to 3 log 10 units below the levels achieved in control animals. Similar results were obtained with macaques immunized with either CYD-TDV or monovalent (MV) CYD-2. This suggests that partial protection against DENV-2 was mediated mainly by CYD-2 and not by the other CYDs. Postchallenge induction of strong anamnestic responses, suggesting efficient vaccine priming, likely contributed to the reduction of DENV-2 RNAemia. Finally, an inverse correlation between DENV RNA titers postchallenge and vaccine-induced homotypic neutralizing antibody titers prechallenge was found, emphasizing the key role of these antibodies in controlling DENV infection. Collectively, these data show better agreement with reported data on CYD-TDV clinical vaccine efficacy against DENV-2 and DENV-4. Despite inherent limitations of the nonhuman primate model, these results reinforce its value in assessing the efficacy of dengue vaccines. IMPORTANCE The nonhuman primate (NHP) model is

Efficacy of a high potency O1 Manisa monovalent vaccine against heterologous challenge with foot-and-mouth disease virus of O/SEA/Mya-98 lineage in sheep.

PubMed

Singanallur, N B; Pacheco, J M; Arzt, J; Stenfeldt, C; Fosgate, G T; Rodriguez, L; Vosloo, W

2017-09-01

Potency tests for commercial oil-adjuvanted foot-and-mouth disease (FMD) vaccines are usually carried out in cattle, using a full dose (2 ml) of vaccine and homologous virus challenge. However, in sheep the recommended vaccine dose is half of the cattle dose (1 ml) and most vaccines have not been potency tested for this species, especially with heterologous viruses. To determine the efficacy of a high potency (>6PD 50 ) FMD virus (FMDV) O1Manisa vaccine in sheep, we carried out a study using a heterologous FMDV (FMDV O/SKR/2010 - Mya-98 strain) challenge. Groups of seven animals each were vaccinated with 2×, 1×, 1/2× or 1/4× dose (2 ml, 1 ml, 0.5 ml or 0.25 ml respectively) and challenged at 7 days post vaccination (dpv). Only 3 of the 7 sheep in the group vaccinated with 2 ml were protected. With 2 additional groups, receiving double or single doses and challenged at 14 dpv, 4 of 7 sheep were protected in each group. None of the sheep had measurable neutralising antibodies against the vaccine or challenge virus at 7 dpv. However, all vaccinated animals challenged at 14 dpv had a homologous neutralising response against FMDV O1 Manisa on the day of challenge and all but one animal also had a heterologous response to FMDV O/SKR/2010. Infectious FMDV and viral RNA could be found in nasal swabs between 1 and 6 days post challenge (dpc) in most vaccinated sheep, but those vaccinated with higher doses or challenged at 14 dpv showed significant decreases in the level of FMDV detection. Intermittent virus shedding was noticed between 1 and 35 dpc in all vaccinated groups, but persistent infection could be demonstrated only in 4 sheep (20%). This study showed that at the recommended dose, a high potency (>6 PD 50 ) FMDV O1Manisa vaccine does not protect sheep against a heterologous challenge at 7 dpv. However, partial protection was observed when a double dose was used at 7 dpv or when double or single dose vaccinated sheep were challenged at 14 dpv. Copyright �

Quantifying low-frequency revertants in oral poliovirus vaccine using next generation sequencing.

PubMed

Sarcey, Eric; Serres, Aurélie; Tindy, Fabrice; Chareyre, Audrey; Ng, Siemon; Nicolas, Marine; Vetter, Emmanuelle; Bonnevay, Thierry; Abachin, Eric; Mallet, Laurent

2017-08-01

Spontaneous reversion to neurovirulence of live attenuated oral poliovirus vaccine (OPV) serotype 3 (chiefly involving the n.472U>C mutation), must be monitored during production to ensure vaccine safety and consistency. Mutant analysis by polymerase chain reaction and restriction enzyme cleavage (MAPREC) has long been endorsed by the World Health Organization as the preferred in vitro test for this purpose; however, it requires radiolabeling, which is no longer supported by many laboratories. We evaluated the performance and suitability of next generation sequencing (NGS) as an alternative to MAPREC. The linearity of NGS was demonstrated at revertant concentrations equivalent to the study range of 0.25%-1.5%. NGS repeatability and intermediate precision were comparable across all tested samples, and NGS was highly reproducible, irrespective of sequencing platform or analysis software used. NGS was performed on OPV serotype 3 working seed lots and monovalent bulks (n=21) that were previously tested using MAPREC, and which covered the representative range of vaccine production. Percentages of 472-C revertants identified by NGS and MAPREC were comparable and highly correlated (r≥0.80), with a Pearson correlation coefficient of 0.95585 (p<0.0001). NGS demonstrated statistically equivalent performance to that of MAPREC for quantifying low-frequency OPV serotype 3 revertants, and offers a valid alternative to MAPREC. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Changes in Phosphatidylcholine Headgroup Tilt and Water Order Induced by Monovalent Salts: Molecular Dynamics Simulations

PubMed Central

Sachs, Jonathan N.; Nanda, Hirsh; Petrache, Horia I.; Woolf, Thomas B.

2004-01-01

The association between monovalent salts and neutral lipid bilayers is known to influence global bilayer structural properties such as headgroup conformational fluctuations and the dipole potential. The local influence of the ions, however, has been unknown due to limited structural resolution of experimental methods. Molecular dynamics simulations are used here to elucidate local structural rearrangements upon association of a series of monovalent Na+ salts to a palmitoyl-oleoyl-phosphatidylcholine bilayer. We observe association of all ion types in the interfacial region. Larger anions, which are meant to rationalize data regarding a Hofmeister series of anions, bind more deeply within the bilayer than either Cl− or Na+. Although the simulations are able to reproduce experimentally measured quantities, the analysis is focused on local properties currently invisible to experiments, which may be critical to biological systems. As such, for all ion types, including Cl−, we show local ion-induced perturbations to headgroup tilt, the extent and direction of which is sensitive to ion charge and size. Additionally, we report salt-induced ordering of the water well beyond the interfacial region, which may be significant in terms of hydration repulsion between stacked bilayers. PMID:15189873

Positioning, labelling, and medical information control of co-artemether tablets (CPG 56697): a fixed novel combination of artemether and benflumetol. Novartis Co-Artemether International Development Team.

PubMed

Skelton-Stroud, P; Mull, R

1998-01-01

Coartemether is a fixed 1:6 ratio of artemether and lumefantrine (benflumetol), a joint development between Novartis Pharma and the Academy of Military Medical Sciences (Beijing, China). It is well tolerated and has a high efficacy against uncomplicated and drug resistant falciparum malaria by oral administration. The preclinical profile of coartemether revealed no prohibitive toxicological, teratogenic or mutagenic findings. No evidence of neurotoxicity was seen in oral preclinical studies. It shows a negative response to the induction of resistance and prevents recrudescence. Clinically, coartemether shows a rapid onset of antiparasitic action, resolution of symptoms, no clinical neurotoxicity and excellent parasite clearance.

Immunogenicity, Reactogenicity, and Safety of a P1.7b,4 Strain-Specific Serogroup B Meningococcal Vaccine Given to Preteens▿

PubMed Central

Hosking, Jamie; Rasanathan, Kumanan; Mow, Florina Chan; Jackson, Catherine; Martin, Diana; O'Hallahan, Jane; Oster, Philipp; Ypma, Ellen; Reid, Stewart; Aaberge, Ingeborg; Crengle, Sue; Stewart, Joanna; Lennon, Diana

2007-01-01

New Zealand (NZ) has experienced a Neisseria meningitidis serogroup B epidemic since 1991. MeNZB, a strain-specific outer membrane vesicle vaccine made using an NZ epidemic strain isolate, NZ98/254 (B:4:P1.7b,4), from two manufacturing sites, the Norwegian Institute of Public Health (NIPH) and Chiron Vaccines (CV; now Novartis), was evaluated for safety, immunogenicity, and reactogenicity in this observer-blind trial with 8- to 12-year-old children. In year 1, cohort A (n = 302) was randomized 4:1 for receipt of NIPH-MeNZB or MenBvac (Norwegian parent vaccine strain 44/76; B:15:P1.7,16). In year 2, cohort B (n = 313) was randomized 4:1 for receipt of CV-MeNZB or NIPH-MeNZB. Participants all received three vaccinations 6 weeks apart. Local and systemic reactions were monitored for 7 days. Seroresponse was defined as a fourfold or greater rise in the serum bactericidal antibody titer from the baseline titer as measured by a serum bactericidal assay. Those with baseline titers of <1:4 required titers of ≥1:8 to serorespond. Intention-to-treat (ITT) and per protocol (PP) analyses are presented. In cohort A, 74% (ITT) and 73% (PP) of NIPH-MeNZB recipients demonstrated seroresponses against NZ98/254 after three doses, versus 32% (ITT and PP) of MenBvac recipients. In cohort B, seroresponses against NZ98/254 after three doses occurred in 79% (ITT and PP) of CV-MeNZB versus 75% (ITT) and 76% (PP) of NIPH-MeNZB recipients. Vaccines were tolerable, with no vaccine-related serious adverse events. In conclusion, the NZ strain meningococcal B vaccine (MeNZB) from either manufacturing site was immunogenic against New Zealand epidemic vaccine strain meningococci with no safety concerns when given in three doses to these 8- to 12-year-old children. PMID:17898183

Antibody persistence and booster response 68 months after vaccination at 2-10 years of age with one dose of MenACWY-TT conjugate vaccine.

PubMed

Knuf, Markus; Helm, Klaus; Kolhe, Devayani; Van Der Wielen, Marie; Baine, Yaela

2018-05-31

We evaluated antibody persistence up to 68 months (M) post-vaccination with a quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT) or a licensed monovalent MenC conjugate vaccine (MenC-CRM 197 ) and subsequent booster responses to MenACWY-TT in healthy European children. In the initial study (NCT00674583), healthy children, 2-10 years of age, were randomized to receive a single dose of either MenACWY-TT or MenC-CRM 197 . In the follow-up study, we present the persistence at 32, 44, 56, and 68 M post-vaccination, overall and stratified by age (2-5 and 6-10 years), and the immunogenicity and safety of MenACWY-TT administered to all study participants at M68 post-primary vaccination. At M68, 33.3% (age group 2-5 years) and 47.1% (age group 6-10 years) of the children vaccinated with MenACWY-TT, and 50.0% (age group 2-5 years) and 75.9% (age group 6-10 years) vaccinated with MenC-CRM 197 retained titers ≥1:8 for MenC, as assessed by a serum bactericidal assay using rabbit complement (rSBA). In the MenACWY-TT recipients, the percentages of children retaining rSBA titers ≥1:8 for MenA, MenW, and MenY were 81.7%, 47.3% and 66.7% in age group 2-5 years and 91.8%, 58,8% and 76.5% in age group 6-10 years, respectively. The booster dose induced robust responses (100% for all serogroups) and was well-tolerated. Antibody persistence (rSBA titers ≥ 1:8) for serogroups A, W and Y was observed in more than 50.0% of the children 68 M after receiving one dose of MenACWY-TT; for MenC, antibody persistence was observed in more than one third of MenACWY-TT and more than half of MenC-CRM 197 recipients. Vaccination with a booster dose of MenACWY-TT induced robust immune responses for all serogroups. Copyright © 2018. Published by Elsevier Ltd.

Live attenuated influenza vaccine use and safety in children and adults with asthma.

PubMed

Duffy, Jonathan; Lewis, Melissa; Harrington, Theresa; Baxter, Roger; Belongia, Edward A; Jackson, Lisa A; Jacobsen, Steven J; Lee, Grace M; Naleway, Allison L; Nordin, James; Daley, Matthew F

2017-04-01

Live attenuated influenza vaccine (LAIV) might increase the risk of wheezing in persons with asthma or children younger than 5 years with a history of recurrent wheezing. To describe the use and assess the safety of LAIV in persons with asthma in the Vaccine Safety Datalink population. We identified persons with asthma using diagnosis codes and medication records in 7 health care organizations over 3 influenza seasons (2008-2009 through 2010-2011) and determined their influenza vaccination rates. Using the self-controlled risk interval method, we calculated the incidence rate ratio of medically attended respiratory events in the 14 days after LAIV compared with 29 to 42 days after vaccination in persons 2 through 49 years old. In our population of 6.3 million, asthma prevalence was 5.9%. Of persons with asthma, approximately 50% received any influenza vaccine but less than 1% received LAIV. The safety study included 12,354 LAIV doses (75% in children; 93% in those with intermittent or mild persistent asthma). The incidence rate ratio for inpatient and emergency department visits for lower respiratory events (including asthma exacerbation and wheezing) was 0.98 (95% confidence interval 0.63-1.51) and the incidence rate ratio for upper respiratory events was 0.94 (95% confidence interval 0.48-1.86). The risk of lower respiratory events was similar for intermittent and mild persistent asthma, across age groups, and for seasonal trivalent LAIV and 2009 H1N1 pandemic monovalent LAIV. LAIV use in asthma was mostly in persons with intermittent or mild persistent asthma. LAIV was not associated with an increased risk of medically attended respiratory adverse events. Published by Elsevier Inc.

Safety and immunogenicity of meningococcal ACWY CRM197-conjugate vaccine in children, adolescents and adults in Russia.

PubMed

Ilyina, Natalia; Kharit, Susanna; Namazova-Baranova, Leila; Asatryan, Asmik; Benashvili, Mayya; Tkhostova, Elmira; Bhusal, Chiranjiwi; Arora, Ashwani Kumar

2014-01-01

Neisseria meningitidis is the leading cause of bacterial invasive infections in people aged <15 years in the Russian Federation. The aim of this phase III, multicenter, open-label study was to assess the immunogenicity and safety of the quadrivalent meningococcal CRM197-conjugate vaccine MenACWY when administered to healthy Russian subjects aged 2 years and above. A total of 197 subjects were immunized with a single dose of the vaccine, and serogroup-specific serum bactericidal activity was measured pre and 1-month post-vaccination with human complement (hSBA) serum titers. Regardless of baseline serostatus, 1 month after a single dose of MenACWY-CRM197 85% (95%CI, 79-90%) of subjects showed serologic response against serogroup A, 74% (67-80%) against serogroup C, 60% (53-67%) against serogroup W, and 83% (77-88%) against serogroup Y. The percentage of subjects with hSBA titers ≥ 1:8 1 month after vaccination was 89% (83-93%) against serogroup A, 84% (78-89%) against serogroup C, 97% (93-99%) against serogroup W, and 88% (82-92%) against serogroup Y. Comparable results were obtained across all subjects: children (2 to 10 years), adolescents (11 to 17 years), and adults (≥18 years). The MenACWY-CRM197 vaccine showed an acceptable safety profile and was well tolerated across all age groups, with no serious adverse events or deaths reported during the study. In conclusion, a single dose of meningococcal MenACWY-CRM197 vaccine is immunogenic and has an acceptable safety profile, provides a broad protection against the most frequent epidemic serogroups, and is a suitable alternative to currently available unconjugated monovalent or bivalent polysaccharide vaccines in Russia.

Heterovariant Cross-Reactive B-Cell Responses Induced by the 2009 Pandemic Influenza Virus A Subtype H1N1 Vaccine

PubMed Central

He, Xiao-Song; Sasaki, Sanae; Baer, Jane; Khurana, Surender; Golding, Hana; Treanor, John J.; Topham, David J.; Sangster, Mark Y.; Jin, Hong; Dekker, Cornelia L.; Subbarao, Kanta; Greenberg, Harry B.

2013-01-01

Background. The generation of heterovariant immunity is a highly desirable feature of influenza vaccines. The goal of this study was to compare the heterovariant B-cell response induced by the monovalent inactivated 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) vaccine with that induced by the 2009 seasonal trivalent influenza vaccine (sTIV) containing a seasonal influenza A virus subtype H1N1 (A[H1N1]) component in young and elderly adults. Methods. Plasmablast-derived polyclonal antibodies (PPAb) from young and elderly recipients of A(H1N1)pdm09 vaccine or sTIV were tested for binding activity to various influenza antigens. Results. In A(H1N1)pdm09 recipients, the PPAb titers against homotypic A(H1N1)pdm09 vaccine were similar to those against the heterovariant seasonal A(H1N1) vaccine and were similar between young and elderly subjects. The PPAb avidity was higher among elderly individuals, compared with young individuals. In contrast, the young sTIV recipients had 10-fold lower heterovariant PPAb titers against the A(H1N1)pdm09 vaccine than against the homotypic seasonal A(H1N1) vaccine. In binding assays with recombinant head and stalk domains of hemagglutinin, PPAb from the A(H1N1)pdm09 recipients but not PPAb from the sTIV recipients bound to the conserved stalk domain. Conclusion. The A(H1N1)pdm09 vaccine induced production of PPAb with heterovariant reactivity, including antibodies targeting the conserved hemagglutinin stalk domain. PMID:23107783

Effect of Monovalent Ion Parameters on Molecular Dynamics Simulations of G-Quadruplexes.

PubMed

Havrila, Marek; Stadlbauer, Petr; Islam, Barira; Otyepka, Michal; Šponer, Jiří

2017-08-08

G-quadruplexes (GQs) are key noncanonical DNA and RNA architectures stabilized by desolvated monovalent cations present in their central channels. We analyze extended atomistic molecular dynamics simulations (∼580 μs in total) of GQs with 11 monovalent cation parametrizations, assessing GQ overall structural stability, dynamics of internal cations, and distortions of the G-tetrad geometries. Majority of simulations were executed with the SPC/E water model; however, test simulations with TIP3P and OPC water models are also reported. The identity and parametrization of ions strongly affect behavior of a tetramolecular d[GGG] 4 GQ, which is unstable with several ion parametrizations. The remaining studied RNA and DNA GQs are structurally stable, though the G-tetrad geometries are always deformed by bifurcated H-bonding in a parametrization-specific manner. Thus, basic 10-μs-scale simulations of fully folded GQs can be safely done with a number of cation parametrizations. However, there are parametrization-specific differences and basic force-field errors affecting the quantitative description of ion-tetrad interactions, which may significantly affect studies of the ion-binding processes and description of the GQ folding landscape. Our d[GGG] 4 simulations indirectly suggest that such studies will also be sensitive to the water models. During exchanges with bulk water, the Na + ions move inside the GQs in a concerted manner, while larger relocations of the K + ions are typically separated. We suggest that the Joung-Cheatham SPC/E K + parameters represent a safe choice in simulation studies of GQs, though variation of ion parameters can be used for specific simulation goals.

Guillain-Barré Syndrome, Influenza Vaccination, and Antecedent Respiratory and Gastrointestinal Infections: A Case-Centered Analysis in the Vaccine Safety Datalink, 2009–2011

PubMed Central

Greene, Sharon K.; Rett, Melisa D.; Vellozzi, Claudia; Li, Lingling; Kulldorff, Martin; Marcy, S. Michael; Daley, Matthew F.; Belongia, Edward A.; Baxter, Roger; Fireman, Bruce H.; Jackson, Michael L.; Omer, Saad B.; Nordin, James D.; Jin, Robert; Weintraub, Eric S.; Vijayadeva, Vinutha; Lee, Grace M.

2013-01-01

Background Guillain-Barré Syndrome (GBS) can be triggered by gastrointestinal or respiratory infections, including influenza. During the 2009 influenza A (H1N1) pandemic in the United States, monovalent inactivated influenza vaccine (MIV) availability coincided with high rates of wildtype influenza infections. Several prior studies suggested an elevated GBS risk following MIV, but adjustment for antecedent infection was limited. Methods We identified patients enrolled in health plans participating in the Vaccine Safety Datalink and diagnosed with GBS from July 2009 through June 2011. Medical records of GBS cases with 2009–10 MIV, 2010–11 trivalent inactivated influenza vaccine (TIV), and/or a medically-attended respiratory or gastrointestinal infection in the 1 through 141 days prior to GBS diagnosis were reviewed and classified according to Brighton Collaboration criteria for diagnostic certainty. Using a case-centered design, logistic regression models adjusted for patient-level time-varying sources of confounding, including seasonal vaccinations and infections in GBS cases and population-level controls. Results Eighteen confirmed GBS cases received vaccination in the 6 weeks preceding onset, among 1.27 million 2009–10 MIV recipients and 2.80 million 2010–11 TIV recipients. Forty-four confirmed GBS cases had infection in the 6 weeks preceding onset, among 3.77 million patients diagnosed with medically-attended infection. The observed-versus-expected odds that 2009–10 MIV/2010–11 TIV was received in the 6 weeks preceding GBS onset was odds ratio = 1.54, 95% confidence interval (CI), 0.59–3.99; risk difference = 0.93 per million doses, 95% CI, −0.71–5.16. The association between GBS and medically-attended infection was: odds ratio = 7.73, 95% CI, 3.60–16.61; risk difference = 11.62 per million infected patients, 95% CI, 4.49–26.94. These findings were consistent in sensitivity analyses using alternative infection definitions

Safety and Immunogenicity of Cell Culture-Derived A/H3N2 Variant Influenza Vaccines: A Phase I Randomized, Observer-Blind, Dose-Ranging Study.

PubMed

Johnson, Casey; Hohenboken, Matthew; Poling, Terry; Jaehnig, Peter; Kanesa-Thasan, Niranjan

2015-07-01

A/H3N2 variant (H3N2v) influenza may sustain human-to-human transmission, and an available candidate vaccine would be important. In this phase I, randomized, observer-blind, dose-ranging study, 627 healthy subjects ≥ 3 years of age were randomized to receive 2 vaccinations with H3N2c cell-culture-derived vaccine doses containing 3.75 µg, 7.5 µg, or 15 µg hemagglutinin antigen of H3N2v with or without MF59 (registered trademark of Novartis AG) adjuvant (an oil-in-water emulsion). This paper reports Day 43 planned interim data. Single MF59-adjuvanted H3N2c doses elicited immune responses in almost all subjects regardless of antigen and adjuvant dose; the Center for Biologics Evaluation Research and Review (CBER) licensure criteria were met for all groups. Subjects with prevaccination hemagglutination inhibition titers <10 and children 3-<9 years achieve CBER criteria only after receiving 2 doses of nonadjuvanted H3N2c vaccine. Highest antibody titers were observed in the 7.5 µg + 0.25 mL MF59 groups in all age cohorts. MF59-adjuvanted H3N2c vaccines showed the highest rates of solicited local and systemic events, predominately mild or moderate. A single dose of H3N2c vaccine may be immunogenic and supports further development of MF59-adjuvanted H3N2c vaccines, especially for pediatric populations. ClinicalTrials.gov identifier NCT01855945 (http://clinicaltrials.gov/ct2/show/NCT01855945). © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Effect of withholding breastfeeding on the immune response to a live oral rotavirus vaccine in North Indian infants.

PubMed

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

2014-08-11

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. Copyright © 2014. Published by Elsevier Ltd.

Influenza A (H1N1) 2009 monovalent and seasonal influenza vaccination among adults 25 to 64 years of age with high-risk conditions—United States, 2010

PubMed Central

Lu, Peng-jun; Gonzalez-Feliciano, Amparo; Ding, Helen; Bryan, Leah N.; Yankey, David; Monsell, Elizabeth A.; Greby, Stacie M.; Euler, Gary L.

2018-01-01

Background Seasonal influenza vaccination has been routinely recommended for adults with high-risk conditions. The Advisory Committee on Immunization Practices recommended that persons 25 to 64 years of age with high-risk conditions be one of the initial target groups to receive H1N1 vaccination during the 2009-2010 season. Methods We used data from the 2009-2010 Behavioral Risk Factor Surveillance System survey. Vaccination levels of H1N1 and seasonal influenza vaccination among respondents 25 to 64 years with high-risk conditions were assessed. Multivariable logistic regression models were performed to identify factors independently associated with vaccination. Results Overall, 24.8% of adults 25 to 64 years of age were identified to have high-risk conditions. Among adults 25 to 64 years of age with high-risk conditions, H1N1 and seasonal vaccination coverage were 26.3% and 47.6%, respectively. Characteristics independently associated with an increased likelihood of H1N1 vaccination were as follows: higher age; Hispanic race/ethnicity; medical insurance; ability to see a doctor if needed; having a primary doctor; a routine checkup in the previous year; not being a current smoker; and having high-risk conditions other than asthma, diabetes, and heart disease. Characteristics independently associated with seasonal influenza vaccination were similar compared with factors associated with H1N1 vaccination. Conclusion Immunization programs should work with provider organizations to review efforts made to reach adults with high-risk conditions during the recent pandemic and assess how and where they can increase vaccination coverage during future pandemics. PMID:23419613

Susceptibility of Meningococcal Strains Responsible for Two Serogroup B Outbreaks on U.S. University Campuses to Serum Bactericidal Activity Elicited by the MenB-4C Vaccine.

PubMed

Rossi, Raffaella; Beernink, Peter T; Giuntini, Serena; Granoff, Dan M

2015-12-01

In 2013 and 2014, two U.S. universities had meningococcal serogroup B outbreaks (a total of 14 cases) caused by strains from two different clonal complexes. To control the outbreaks, students were immunized with a serogroup B meningococcal vaccine (Novartis) that was not yet licensed in the United States. The vaccine (referred to as MenB-4C) contains four components capable of eliciting bactericidal activity. Both outbreak strains had high expression levels of two of the vaccine antigens (subfamily B factor H binding protein [FHbp] and neisserial heparin binding antigen [NHba]); the university B outbreak strain also had moderate expression of a third antigen, NadA. We investigated the bactericidal activity of sera from mice immunized with FHbp, NHba, or NadA and sera from MenB-4C-immunized infant macaques and an adult human. The postimmunization bactericidal activity of the macaque or human serum against isolates from university B with FHbp identification (ID) 1 that exactly matched the vaccine FHbp sequence variant was 8- to 21-fold higher than that against isolates from university A with FHbp ID 276 (96% identity to the vaccine antigen). Based on the bactericidal activity of mouse antisera to FHbp, NadA, or NHba and macaque or human postimmunization serum that had been depleted of anti-FHbp antibody, the bactericidal activity against both outbreak strains largely or entirely resulted from antibodies to FHbp. Thus, despite the high level of strain expression of FHbp from a subfamily that matched the vaccine antigen, there can be large differences in anti-FHbp bactericidal activity induced by MenB-4C vaccination. Further, strains with moderate to high NadA and/or NHba expression can be resistant to anti-NadA or anti-NHba bactericidal activity elicited by MenB-4C vaccination. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

A Novel Virus-Like Particle Based Vaccine Platform Displaying the Placental Malaria Antigen VAR2CSA.

PubMed

Thrane, Susan; Janitzek, Christoph M; Agerbæk, Mette Ø; Ditlev, Sisse B; Resende, Mafalda; Nielsen, Morten A; Theander, Thor G; Salanti, Ali; Sander, Adam F

2015-01-01

Placental malaria caused by Plasmodium falciparum is a major cause of mortality and severe morbidity. Clinical testing of a soluble protein-based vaccine containing the parasite ligand, VAR2CSA, has been initiated. VAR2CSA binds to the human receptor chondroitin sulphate A (CSA) and is responsible for sequestration of Plasmodium falciparum infected erythrocytes in the placenta. It is imperative that a vaccine against malaria in pregnancy, if administered to women before they become pregnant, can induce a strong and long lasting immune response. While most soluble protein-based vaccines have failed during clinical testing, virus-like particle (VLP) based vaccines (e.g., the licensed human papillomavirus vaccines) have demonstrated high efficacy, suggesting that the spatial assembly of the vaccine antigen is a critical parameter for inducing an optimal long-lasting protective immune response. We have developed a VLP vaccine display platform by identifying regions of the HPV16 L1 coat protein where a biotin acceptor site (AviTagTM) can be inserted without compromising VLP-assembly. Subsequent biotinylation of Avi-L1 VLPs allow us to anchor monovalent streptavidin (mSA)-fused proteins to the biotin, thereby obtaining a dense and repetitive VLP-display of the vaccine antigen. The mSA-VAR2CSA antigen was delivered on the Avi-L1 VLP platform and tested in C57BL/6 mice in comparison to two soluble protein-based vaccines consisting of naked VAR2CSA and mSA-VAR2CSA. The mSA-VAR2CSA Avi-L1 VLP and soluble mSA-VAR2CSA vaccines induced higher antibody titers than the soluble naked VAR2CSA vaccine after three immunizations. The VAR2CSA Avi-L1 VLP vaccine induced statistically significantly higher endpoint titres compared to the soluble mSA-VAR2CSA vaccine, after 1st and 2nd immunization; however, this difference was not statistically significant after 3rd immunization. Importantly, the VLP-VAR2CSA induced antibodies were functional in inhibiting the binding of parasites to CSA

Immune response to pandemic H1N1 2009 influenza a vaccination in pediatric liver transplant recipients.

PubMed

Haller, Wolfram; Buttery, Jim; Laurie, Karen; Beyerle, Kathe; Hardikar, Winita; Alex, George

2011-08-01

After the announcement of a worldwide pandemic in June 2009, a single dose of a monovalent pandemic H1N1 2009 influenza A (pH1N1/09) vaccine was advocated for all Australians who were 10 years and older because of excellent immunogenicity trial results for healthy children and adults. Immunocompromised patients have previously been shown to have lower seroconversion rates after routine vaccinations. There is a lack of data concerning the immune response of this patient group after pH1N1/09 vaccination. The aim of this study was to assess the immunogenicity of a pH1N1/09 vaccine in pediatric liver transplant recipients 10 years of age or older. Liver transplant recipients ≥ 10 years were prospectively recruited. All participants were administered a single intramuscular injection of the pH1N1/09 vaccine (15 μg). Serum antibody levels were determined by hemagglutination immediately before and ≥ 6 weeks after vaccination. Clinical and laboratory data (age, time since transplantation, immunosuppression, and lymphocyte counts) were analyzed comparing seroconverters and nonconverters with the Student's t test. A second dose of the vaccine was offered to all those who displayed no seroprotective titers after the first vaccination. Antibody levels were again determined 6 weeks later. Twenty-one of 28 liver transplant patients completed the study. The seroconversion rate was 62% after the first dose and 89.5% after the second dose. At baseline, 7 of 21 patients (33.4%) were already seropositive. Increasing time since transplantation positively correlated with successful seroconversion. In conclusion, a single dose of a pandemic influenza A vaccine does not elicit a reliable immune response in adolescent pediatric liver transplant patients. A second dose of the vaccine is warranted in this group of patients, at least in a pandemic scenario. There is an urgent need to further assess vaccine strategies in this high-risk group. Copyright © 2011 American Association for the

An inactivated vaccine made from a U.S. field isolate of porcine epidemic disease virus is immunogenic in pigs as demonstrated by a dose-titration.

PubMed

Collin, Emily A; Anbalagan, Srivishnupriya; Okda, Faten; Batman, Ron; Nelson, Eric; Hause, Ben M

2015-03-15

Porcine epidemic diarrhea virus (PEDV), a highly pathogenic and transmissible virus in swine, was first detected in the U.S. in May, 2013, and has caused tremendous losses to the swine industry. Due to the difficulty in isolating and growing this virus in cell culture, few vaccine studies using cell culture propagated PEDV have been performed on U.S. strains in pigs. Therefore, the objective of this study was to evaluate the humoral immune response to the selected inactivated PEDV vaccine candidate in a dose-titration manner. PEDV was isolated from a pig with diarrhea and complete genome sequencing found >99% nucleotide identity to other U.S. PEDV. Inactivated adjuvanted monovalent vaccines were administered intramuscularly to five week old pigs in a dose titration experimental design, ranging from 6.0-8.0 log10 tissue culture infective dose (TCID50/mL), to evaluate immunogenicity using a fluorescent foci neutralization assay (FFN), fluorescent microsphere immunoassay (FMIA), and enzyme-linked immunosorbent assay (ELISA) on sera. Pigs vaccinated with 8.0 log10 TCID50/mL inactivated virus showed significantly higher FFN titers as well as FMIA and ELISA values than 6.0 log10 TCID50/mL vaccinates and the negative controls. These results demonstrate the immunogenicity of a PEDV inactivated viral vaccine with a U.S. strain via dose-titration. A future vaccination-challenge study would illustrate the efficacy of an inactivated vaccine and help evaluate protective FFN titers and ELISA and FMIA responses.

The safety profile of Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y tetanus toxoid conjugate vaccine (HibMenCY).

PubMed

Rinderknecht, Stephen; Bryant, Kristina; Nolan, Terry; Pavia-Ruz, Noris; Doniz, Carlos Aranza; Weber, Miguel Angel Rodriguez; Cohen, Christopher; Aris, Emmanuel; Mesaros, Narcisa; Miller, Jacqueline M

2012-03-01

The safety profile of HibMenCY was compared with licensed Hib conjugate vaccines in a pooled analysis that included more than 8,500 subjects who were administered a four-dose series of HibMenCY or commercially available Hib vaccines at 2, 4, 6 and 12-15 mo of age in two primary vaccination and two fourth dose phase 3 studies. In all studies, HibMenCY or Hib vaccine was co-administered with age-appropriate, routinely recommended vaccines. In one primary and one fourth dose study (n = 4180), local and general symptoms were solicited using diary cards for 4 d after each dose. Serious adverse events (SAEs) and the occurrence of adverse events (AEs) indicating new onset of chronic disease (NOCD), rash, and conditions prompting Emergency Room (ER) visits were reported from dose 1 until 6 mo after dose 4. The incidences of solicited local and general symptoms were similar following HibMenCY and commercially available Hib vaccines. For some solicited symptoms (pain at the injection site and irritability), rates were lower in the HibMenCY group compared with the Hib control group (p value < 0.05). There were no statistically significant differences between groups in the incidences of SAEs, NOCDs, rash, or AEs leading to ER visits, with the exceptions of anemia and viral gastroenteritis, which occurred significantly less frequently in those receiving HibMenCY than those receiving commercially available Hib vaccines. In this pooled safety analysis, the safety profile of HibMenCY was similar to the safety profile of licensed monovalent Hib vaccines, despite the addition of meningococcal antigens. These studies are registered at www.clinicaltrials.gov NCT00345579 (primary vaccination study), NCT00345683 (fourth dose vaccination study) and NCT00289783 (primary and fourth dose vaccination studies).

Causality Assessment of Serious Neurologic Adverse Events Following 2009 H1N1 Vaccination

PubMed Central

Williams, S Elizabeth; Pahud, Barbara A; Vellozzi, Claudia; Donofrio, Peter D; Dekker, Cornelia L; Halsey, Neal; Klein, Nicola P; Baxter, Roger P; Marchant, Colin D; LaRussa, Philip S; Barnett, Elizabeth D; Tokars, Jerome I; McGeeney, Brian E; Sparks, Robert C; Aukes, Laurie L.; Jakob, Kathleen; Coronel, Silvia; Sejvar, James J; Slade, Barbara A; Edwards, Kathryn M

2016-01-01

Background Adverse events occurring after vaccination are routinely reported to the Vaccine Adverse Event Reporting System (VAERS). We studied serious adverse events (SAEs) of a neurologic nature reported after receipt of influenza A (H1N1) 2009 monovalent vaccine during the 2009–10 influenza season. Investigators in the Clinical Immunization Safety Assessment (CISA) Network sought to characterize these SAEs and to assess their possible causal relationship to vaccination. Methods Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA) physicians reviewed all SAE reports (as defined by the Code of Federal Regulations, 21CFR§314.80) after receipt of H1N1 vaccine reported to VAERS between October 1st 2009 and March 31st 2010. Non-fatal SAE reports with neurologic presentation were referred to CISA investigators, who requested and reviewed additional medical records and clinical information as available. CISA investigators assessed the causal relationship between vaccination and the event using modified WHO criteria as defined. Results 212 VAERS reports of non-fatal serious neurological events were referred for CISA review. Case reports were equally distributed by gender (50.9% female) with an age range of 6 months to 83 years (median 38 years). The most frequent diagnoses reviewed were: Guillain-Barré Syndrome (37.3%), seizures (10.8%), cranial neuropathy (5.7%), and acute disseminated encephalomyelitis (3.8%). Causality assessment resulted in classification of 72 events as “possibly” related (33%), 108 as “unlikely” related (51%), and 20 as “unrelated” (9%) to H1N1 vaccination; none were classified as “probable” or “definite” and 12 were unclassifiable (6%). Conclusion The absence of a specific test to indicate whether a vaccine component contributes to the pathogenesis of an event occurring within a biologically plausible time period makes assessing causality difficult. The development of standardized protocols

The influence of monovalent cations on trimeric G protein G(i)1α activity in HEK293 cells stably expressing DOR-G(i)1α (Cys(351)-Ile(351)) fusion protein.

PubMed

Vošahlíková, M; Svoboda, P

2011-01-01

The effect of monovalent cations on trimeric G protein G(i)1α was measured at equimolar concentration of chloride anion in pertussis-toxin (PTX)-treated HEK293 cells stably expressing PTX-insensitive DOR- G(i)1α (Cys(351)-Ile(351)) fusion protein by high-affinity [(35)S]GTPgammaS binding assay. The high basal level of binding was detected in absence of DOR agonist and monovalent ions and this high level was inhibited with the order of: Na(+) > K(+) > Li(+). The first significant inhibition was detected at 1 mM NaCl. The inhibition by monovalent ions was reversed by increasing concentrations of DOR agonist DADLE. The maximum DADLE response was also highest for sodium and decreased in the order of: Na(+) > K(+) ~ Li(+). Our data indicate i) an inherently high activity of trimeric G protein G(i)1α when expressed within DOR- G(i)1α fusion protein and determined in the absence of monovalent cations, ii) preferential sensitivity of DOR- G(i)1alpha to sodium as far as maximum of agonist response is involved.

Comparison of serum hemagglutinin and neuraminidase inhibition antibodies after 2010-2011 trivalent inactivated influenza vaccination in healthcare personnel.

PubMed

Laguio-Vila, Maryrose R; Thompson, Mark G; Reynolds, Sue; Spencer, Sarah M; Gaglani, Manjusha; Naleway, Allison; Ball, Sarah; Bozeman, Sam; Baker, Steven; Martínez-Sobrido, Luis; Levine, Min; Katz, Jackie; Fry, Alicia M; Treanor, John J

2015-01-01

Background.  Most inactivated influenza vaccines contain purified and standardized hemagglutinin (HA) and residual neuraminidase (NA) antigens. Vaccine-associated HA antibody responses (hemagglutination inhibition [HAI]) are well described, but less is known about the immune response to the NA. Methods.  Serum of 1349 healthcare personnel (HCP) electing or declining the 2010-2011 trivalent-inactivated influenza vaccine ([IIV3], containing A/California/7/2009 p(H1N1), A/Perth/16/2009 [H3N2], B/Brisbane/60/2008 strains) were tested for NA-inhibiting (NAI) antibody by a modified lectin-based assay using pseudotyped N1 and N2 influenza A viruses with an irrelevant (H5) HA. Neuraminidase-inhibiting and HAI antibody titers were evaluated approximately 30 days after vaccination and end-of-season for those with polymerase chain reaction (PCR)-confirmed influenza infection. Results.  In 916 HCP (68%) receiving IIV3, a 2-fold increase in N1 and N2 NAI antibody occurred in 63.7% and 47.3%, respectively. Smaller responses occurred in HCP age >50 years and those without prior 2009-2010 IIV3 nor monovalent A(H1N1)pdm09 influenza vaccinations. Forty-four PCR-confirmed influenza infections were observed, primarily affecting those with lower pre-exposure HAI and NAI antibodies. Higher pre-NAI titers correlated with shorter duration of illness for A(H1N1)pdm09 virus infections. Conclusions.  Trivalent-inactivated influenza vaccine is modestly immunogenic for N1 and N2 antigens in HCP. Vaccines eliciting robust NA immune responses may improve efficacy and reduce influenza-associated morbidity.

Methodological challenges in measuring vaccine effectiveness using population cohorts in low resource settings.

PubMed

King, C; Beard, J; Crampin, A C; Costello, A; Mwansambo, C; Cunliffe, N A; Heyderman, R S; French, N; Bar-Zeev, N

2015-09-11

Post-licensure real world evaluation of vaccine implementation is important for establishing evidence of vaccine effectiveness (VE) and programme impact, including indirect effects. Large cohort studies offer an important epidemiological approach for evaluating VE, but have inherent methodological challenges. Since March 2012, we have conducted an open prospective cohort study in two sites in rural Malawi to evaluate the post-introduction effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) against all-cause post-neonatal infant mortality and monovalent rotavirus vaccine (RV1) against diarrhoea-related post-neonatal infant mortality. Our study sites cover a population of 500,000, with a baseline post-neonatal infant mortality of 25 per 1000 live births. We conducted a methodological review of cohort studies for vaccine effectiveness in a developing country setting, applied to our study context. Based on published literature, we outline key considerations when defining the denominator (study population), exposure (vaccination status) and outcome ascertainment (mortality and cause of death) of such studies. We assess various definitions in these three domains, in terms of their impact on power, effect size and potential biases and their direction, using our cohort study for illustration. Based on this iterative process, we discuss the pros and cons of our final per-protocol analysis plan. Since no single set of definitions or analytical approach accounts for all possible biases, we propose sensitivity analyses to interrogate our assumptions and methodological decisions. In the poorest regions of the world where routine vital birth and death surveillance are frequently unavailable and the burden of disease and death is greatest We conclude that provided the balance between definitions and their overall assumed impact on estimated VE are acknowledged, such large scale real-world cohort studies can provide crucial information to policymakers by providing

Effectiveness of Rubella vaccine in a rubella outbreak in Guangzhou city, China, 2014.

PubMed

Chang, Caiyun; Mo, Xianghuan; Hu, Pei; Liang, Wenjia; Ma, Huilai; An, Zhijie; Liu, Jun; Zheng, Huizhen

2015-06-22

-97). VE of a single dose of domestic monovalent rubella vaccine that used BRD-II strain vaccine was 93% (95%CI: 73-98). VE for those who received the vaccine between 1 and 2 years of age was 95% (95% CI: 67-99) while the VE was 100% for those vaccinated after 2 years of age. VE among those who received RCV <12 years ago was 100% while VE among those who received RCV ≥12 years ago was 92% (95%CI: 70-98). The rubella vaccines used in China that are based on the BRD-II rubella vaccine strain have VE of 94%, which is similar to the more commonly used RA27/3-based RCVs. Low vaccination coverage contributed to this outbreak; early reporting of an outbreak is necessary for effective outbreak response immunization. Copyright © 2015 Elsevier Ltd. All rights reserved.

Bicistronic DNA vaccines simultaneously encoding HIV, HSV and HPV antigens promote CD8⁺ T cell responses and protective immunity.

PubMed

Santana, Vinicius C; Diniz, Mariana O; Cariri, Francisco A M O; Ventura, Armando M; Cunha-Neto, Edécio; Almeida, Rafael R; Campos, Marco A; Lima, Graciela K; Ferreira, Luís C S

2013-01-01

Millions of people worldwide are currently infected with human papillomavirus (HPV), herpes simplex virus (HSV) or human immunodeficiency virus (HIV). For this enormous contingent of people, the search for preventive and therapeutic immunological approaches represents a hope for the eradication of latent infection and/or virus-associated cancer. To date, attempts to develop vaccines against these viruses have been mainly based on a monovalent concept, in which one or more antigens of a virus are incorporated into a vaccine formulation. In the present report, we designed and tested an immunization strategy based on DNA vaccines that simultaneously encode antigens for HIV, HSV and HPV. With this purpose in mind, we tested two bicistronic DNA vaccines (pIRES I and pIRES II) that encode the HPV-16 oncoprotein E7 and the HIV protein p24 both genetically fused to the HSV-1 gD envelope protein. Mice i.m. immunized with the DNA vaccines mounted antigen-specific CD8⁺ T cell responses, including in vivo cytotoxic responses, against the three antigens. Under experimental conditions, the vaccines conferred protective immunity against challenges with a vaccinia virus expressing the HIV-derived protein Gag, an HSV-1 virus strain and implantation of tumor cells expressing the HPV-16 oncoproteins. Altogether, our results show that the concept of a trivalent HIV, HSV, and HPV vaccine capable to induce CD8⁺ T cell-dependent responses is feasible and may aid in the development of preventive and/or therapeutic approaches for the control of diseases associated with these viruses.

Impact of rotavirus vaccine introduction and post-introduction etiology of diarrhea requiring hospital admission in Haydom, Tanzania, a rural African setting.

PubMed

Platts-Mills, James A; Amour, Caroline; Gratz, Jean; Nshama, Rosemary; Walongo, Thomas; Mujaga, Buliga; Maro, Athanasia; McMurry, Timothy L; Liu, Jie; Mduma, Estomih; Houpt, Eric R

2017-05-29

No data are available on the etiology of diarrhea requiring hospitalization after rotavirus vaccine introduction in Africa. The monovalent rotavirus vaccine was introduced in Tanzania on January 1, 2013. We performed a vaccine impact and effectiveness study as well as a qPCR-based etiology study at a rural Tanzanian hospital. We obtained data on admissions among children under 5 years to Haydom Lutheran Hospital between January 1, 2010 and December 31, 2015, and estimated the impact of vaccine introduction on all-cause diarrhea admissions. We then performed a vaccine effectiveness study using the test-negative design. Finally, we tested diarrheal specimens during 2015 by qPCR for a broad range of enteropathogens and calculated pathogen-specific attributable fractions. Vaccine introduction was associated with a 44.9% (95% CI 17.6 - 97.4) reduction in diarrhea admissions in 2015, as well as delay of the rotavirus season. The effectiveness of two doses of vaccine was 74.8% (-8.2 - 94.1) using an enzyme immunoassay-based case definition and 85.1% (26.5 - 97.0) using a qPCR-based case definition. Among 146 children enrolled in 2015, rotavirus remained the leading etiology of diarrhea requiring hospitalization (AF 25.8%, 95% CI: 24.4 - 26.7), followed by heat-stabile enterotoxin-producing E. coli (18.4%, 12.9 - 21.9), Shigella/enteroinvasive E. coli (14.5%, 10.2 - 22.8), and Cryptosporidium (7.9%, 6.2 - 9.3). Despite the clear impact of vaccine introduction in this setting, rotavirus remained the leading etiology of diarrhea requiring hospitalization. Further efforts to maximize vaccine coverage and improve vaccine performance in these settings are warranted. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Differential Cationization of Fatty Acids with Monovalent Cations Studied by ESI-MS/MS and Computational Approach.

PubMed

Sudarshana Reddy, B; Pavankumar, P; Sridhar, L; Saha, Soumen; Narahari Sastry, G; Prabhakar, S

2018-04-24

The intercellular and intracellular transport of charged species (Na + /K + ) entail interaction of the ions with neutral organic molecules and formation of adduct ions. The rate of transport of the ions across the cell membrane(s) may depend on the stability of the adduct ions, which in turn rely on structural aspects of the organic molecules that interact with the ions. Positive ion ESI mass spectra were recorded for the solutions containing fatty acids (FAs) and monovalent cations (X=Li + , Na + , K + , Rb + and Cs + ). Product ion spectra of the [FA+X] + ions were recorded at different collision energies. Theoretical studies were exploited under both gas phase and solvent phase to investigate the structural effects of the fatty acids during cationization. Stability of [FA+X] + adduct ions were further estimated by means of AIM topological analyses and interaction energy (IE) values. Positive ion ESI-MS analyses of the solution of FAs and X + ions showed preferential binding of the K + ions to FAs. The K + ion binding increased with the increase in number of double bonds of FAs, while decreased with increase in the number of carbons of FAs. Dissociation curves of [FA+X] + ions indicated the relative stability order of the [FA+X] + ions and it was in line with the observed trends in ESI-MS. The solvent phase computational studies divulged the mode of binding and the binding efficiencies of different FAs with monovalent cations. Among the studied monovalent cations, the cationization of FAs follow the order K + >Na + >Li + >Rb + >Cs + . The docosahexaenoic acid showed high efficiency in binding with K + ion. The K + ion binding efficiency of FAs depends on the number of double bonds in unsaturated FAs and the carbon chain length in saturated FAs. The cationization trends of FAs obtained from the ESI-MS, ESI-MS/MS analyses were in good agreement with solvent phase computational studies. This article is protected by copyright. All rights reserved.

Paresthesia and sensory disturbances associated with 2009 pandemic vaccine receipt: Clinical features and risk factors.

PubMed

De Serres, Gaston; Rouleau, Isabelle; Skowronski, Danuta M; Ouakki, Manale; Lacroix, Kevin; Bédard, Fernand; Toth, Eveline; Landry, Monique; Dupré, Nicolas

2015-08-26

Paresthesia was the third-most-common adverse event following immunization (AEFI) with 2009 monovalent AS03-adjuvanted A(H1N1)pdm09 vaccine in Quebec, Canada and was also frequently reported in Europe. This study assessed clinical features and risk factors associated with this unexpected AEFI. Reports to the passive surveillance system were summarized. A case-control study was conducted to assess risk factors and additional investigations were undertaken among cases with symptoms persisting ≥12 months. There were 328 reports of paresthesia affecting the vaccinated arm (58%), but also face (45%), lower limbs (40%) and back/thorax (23%) with numbness but also muscle weakness (61%), motor impairment (61%), generalized myalgia (37%), visual (14%) and/or speech effects (15%). Reporting rate was highest in women of reproductive age, peaking at 30-39 years-old (28/100,000 doses administered) and exceeding that of men of the same age (7/100,000 doses) by 4-fold. Median time to onset was 2h. Symptoms subsided within one week in 37% but lasted ≥6 months in 26%. No consistent or objective neurological findings were identified. Risk was increased with allergy history, respiratory illness the day of vaccination, depressive symptoms and family history of pulmonary disease, but decreased with physical activity the day of vaccination, and regular weekly alcohol consumption. Paresthesia following 2009 pandemic vaccine receipt lasted several weeks and included other motor-sensory disturbances in an important subset of patients. Although it does not correspond with known neurological disease, and causality remains uncertain, further investigation is warranted to understand the nature and frequency of paresthesia as a possible AEFI with influenza vaccines. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Comparison of Serum Hemagglutinin and Neuraminidase Inhibition Antibodies After 2010–2011 Trivalent Inactivated Influenza Vaccination in Healthcare Personnel

PubMed Central

Laguio-Vila, Maryrose R.; Thompson, Mark G.; Reynolds, Sue; Spencer, Sarah M.; Gaglani, Manjusha; Naleway, Allison; Ball, Sarah; Bozeman, Sam; Baker, Steven; Martínez-Sobrido, Luis; Levine, Min; Katz, Jackie; Fry, Alicia M.; Treanor, John J.

2015-01-01

Background. Most inactivated influenza vaccines contain purified and standardized hemagglutinin (HA) and residual neuraminidase (NA) antigens. Vaccine-associated HA antibody responses (hemagglutination inhibition [HAI]) are well described, but less is known about the immune response to the NA. Methods. Serum of 1349 healthcare personnel (HCP) electing or declining the 2010–2011 trivalent-inactivated influenza vaccine ([IIV3], containing A/California/7/2009 p(H1N1), A/Perth/16/2009 [H3N2], B/Brisbane/60/2008 strains) were tested for NA-inhibiting (NAI) antibody by a modified lectin-based assay using pseudotyped N1 and N2 influenza A viruses with an irrelevant (H5) HA. Neuraminidase-inhibiting and HAI antibody titers were evaluated approximately 30 days after vaccination and end-of-season for those with polymerase chain reaction (PCR)-confirmed influenza infection. Results. In 916 HCP (68%) receiving IIV3, a 2-fold increase in N1 and N2 NAI antibody occurred in 63.7% and 47.3%, respectively. Smaller responses occurred in HCP age >50 years and those without prior 2009–2010 IIV3 nor monovalent A(H1N1)pdm09 influenza vaccinations. Forty-four PCR-confirmed influenza infections were observed, primarily affecting those with lower pre-exposure HAI and NAI antibodies. Higher pre-NAI titers correlated with shorter duration of illness for A(H1N1)pdm09 virus infections. Conclusions. Trivalent-inactivated influenza vaccine is modestly immunogenic for N1 and N2 antigens in HCP. Vaccines eliciting robust NA immune responses may improve efficacy and reduce influenza-associated morbidity. PMID:25884004

An evaluation of emerging vaccines for childhood meningococcal disease

PubMed Central

2011-01-01

Background Meningococcal meningitis is a major cause of disease worldwide, with frequent epidemics particularly affecting an area of sub-Saharan Africa known as the “meningitis belt”. Neisseria meningitidis group A (MenA) is responsible for major epidemics in Africa. Recently W-135 has emerged as an important pathogen. Currently, the strategy for control of such outbreaks is emergency use of meningococcal (MC) polysaccharide vaccines, but these have a limited ability to induce herd immunity and elicit an adequate immune response in infant and young children. In recent times initiatives have been taken to introduce meningococcal conjugate vaccine in these African countries. Currently there are two different types of MC conjugate vaccines at late stages of development covering serogroup A and W-135: a multivalent MC conjugate vaccine against serogroup A,C,Y and W-135; and a monovalent conjugate vaccine against serogroup A. We aimed to perform a structured assessment of these emerging meningococcal vaccines as a means of reducing global meningococal disease burden among children under 5 years of age. Methods We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In the first stage we systematically reviewed the literature related to emerging MC vaccines relevant to 12 criteria of interest. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). They answered questions from CHNRI framework and their “collective optimism” towards each criterion was documented on a scale from 0 to 100%. Results For MenA conjugate vaccine the experts showed very high level of optimism (~ 90% or more) for 7 out of the 12 criteria. The experts felt that the likelihood of efficacy on meningitis was very high (~ 90%). Deliverability, acceptability to health

A Novel Dynamic Model for Health Economic Analysis of Influenza Vaccination in the Elderly.

PubMed

Mullikin, Mark; Tan, Litjen; Jansen, Jeroen P; Van Ranst, Marc; Farkas, Norbert; Petri, Eckhardt

2015-12-01

population ranged from $27 million (low intensity, low match) to $934 million (high intensity, high match). Univariate sensitivity analysis of relative vaccine prices in the average intensity, average match scenario indicated that aTIV could be marginally cost saving relative to QIV at the currently published Medicare price for influenza vaccines offering enhanced efficacy in the elderly. Elderly vaccination with aTIV was associated with a higher overall cost compared with TIV in only two scenarios (low intensity with average or high match); the incremental cost/QALY relative to TIV was $9980 in the average match scenario and $28,800 in the high match scenario. Vaccination of persons aged ≥65 years with aTIV has the potential to provide clinical and economic benefit relative to QIV and TIV. The new model allows the assessment of various alternative strategies for available influenza vaccines. Novartis Vaccines.

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

PubMed

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

2015-11-17

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

Outbreak of Type 2 Vaccine-Derived Poliovirus in Nigeria: Emergence and Widespread Circulation in an Underimmunized Population

PubMed Central

Pate, Muhammad Ali; Wannemuehler, Kathleen; Jenks, Julie; Burns, Cara; Chenoweth, Paul; Abanida, Emmanuel Ade; Adu, Festus; Baba, Marycelin; Gasasira, Alex; Iber, Jane; Mkanda, Pascal; Williams, A. J.; Shaw, Jing; Pallansch, Mark; Kew, Olen

2011-01-01

Wild poliovirus has remained endemic in northern Nigeria because of low coverage achieved in the routine immunization program and in supplementary immunization activities (SIAs). An outbreak of infection involving 315 cases of type 2 circulating vaccine-derived poliovirus (cVDPV2; >1% divergent from Sabin 2) occurred during July 2005–June 2010, a period when 23 of 34 SIAs used monovalent or bivalent oral poliovirus vaccine (OPV) lacking Sabin 2. In addition, 21 “pre-VDPV2” (0.5%–1.0% divergent) cases occurred during this period. Both cVDPV and pre-VDPV cases were clinically indistinguishable from cases due to wild poliovirus. The monthly incidence of cases increased sharply in early 2009, as more children aged without trivalent OPV SIAs. Cumulative state incidence of pre-VDPV2/cVDPV2 was correlated with low childhood immunization against poliovirus type 2 assessed by various means. Strengthened routine immunization programs in countries with suboptimal coverage and balanced use of OPV formulations in SIAs are necessary to minimize risks of VDPV emergence and circulation. PMID:21402542

Attractive non-DLVO forces induced by adsorption of monovalent organic ions.

PubMed

Smith, Alexander M; Maroni, Plinio; Borkovec, Michal

2017-12-20

Direct force measurements between negatively charged colloidal particles were carried out using an atomic force microscope (AFM) in aqueous solutions containing monovalent organic cations, namely tetraphenylarsonium (Ph 4 As + ), 1-hexyl-3-methylimidazolium (HMIM + ), and 1-octyl-3-methylimidazolium (OMIM + ). These ions adsorb to the particle surface, and induce a charge reversal. The forces become attractive at the charge neutralization point, but they are stronger than van der Waals forces. This additional and unexpected attraction decays exponentially with a decay length of a few nanometers, and is strikingly similar to the one previously observed in the presence of multivalent ions. This attractive force probably originates from coupled spontaneous charge fluctuations on the respective surfaces as initially suggested by Kirkwood and Shumaker.

Impact of rotavirus vaccine on diarrheal hospitalization and outpatient consultations in the Philippines: First evidence from a middle-income Asian country.

PubMed

Lopez, Anna Lena; Raguindin, Peter Francis; Esparagoza, Joel; Fox, Kimberley; Batmunkh, Nyambat; Bonifacio, Joseph; Parashar, Umesh D; Tate, Jacqueline E; Ducusin, Maria Joyce

2018-05-31

Monovalent rotavirus (RV) vaccine was introduced in the Philippines in a phased manner beginning in 2012. To assess the impact of RV vaccine, we conducted a retrospective review of diarrheal admissions in two hospitals. Records of physician-diagnosed diarrheal admissions were reviewed in D.O. Plaza Hospital (DOPH) from 2009 to 2016 in Agusan del Sur where RV vaccine was introduced in the immunization program; and in Cotabato Regional Medical Center (CRMC) from 2011 to 2016 in a region where the vaccine was not introduced. Reports from consultations in public health clinics in Agusan Del Sur and RV vaccine coverage were obtained. All-cause diarrheal admissions among children <5 years old in DOPH declined from 2013 to 2016 following RV vaccine introduction in 2012. Using the 2009-2011 mean number of hospitalizations as baseline (X‾ = 1,141), the reductions were 28% (n = 821), 56% (n = 507), 63% (n = 417) and 59% (n = 466) in 2013, 2014, 2015 and 2016, respectively. In comparison, no substantial declines in diarrheal hospitalizations were seen in CRMC from 2011 to 2016. A declining trend was also seen in outpatient consultations in Agusan del Sur following RV vaccine introduction with declines of 27% (n = 2,333), 33% (n = 2,143), 45% (n = 1,764) and 67% (n = 1,059) in 2013, 2014, 2015 and 2016. From September 2012 to December 2016, the 1 and 2-dose RV vaccine coverage gradually increased from 5% and 4% in 2012 to 92% and 88% in 2015, but decreased in 2016 to 53% and 52%, respectively. RV vaccine introduction was associated with a substantial decline in diarrheal hospitalizations and outpatient consultations for diarrhea in Agusan del Sur, Philippines. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Lessons From Globally Coordinated Cessation of Serotype 2 Oral Poliovirus Vaccine for the Remaining Serotypes

PubMed Central

Duintjer Tebbens, Radboud J.

2017-01-01

Abstract Background. Comparing model expectations with the experience of oral poliovirus vaccine (OPV) containing serotype 2 (OPV2) cessation can inform risk management for the expected cessation of OPV containing serotypes 1 and 3 (OPV13). Methods. We compare the expected post-OPV2-cessation OPV2-related viruses from models with the evidence available approximately 6 months after OPV2 cessation. We also model the trade-offs of use vs nonuse of monovalent OPV (mOPV) for outbreak response considering all 3 serotypes. Results. Although too early to tell definitively, the observed die-out of OPV2-related viruses in populations that attained sufficiently intense trivalent OPV (tOPV) use prior to OPV2 cessation appears consistent with model expectations. As expected, populations that did not intensify tOPV use prior to OPV2 cessation show continued circulation of serotype 2 vaccine-derived polioviruses (VDPVs). Failure to aggressively use mOPV to respond to circulating VDPVs results in a high risk of uncontrolled outbreaks that would require restarting OPV. Conclusions. Ensuring a successful endgame requires more aggressive OPV cessation risk management than has occurred to date for OPV2 cessation. This includes maintaining high population immunity to transmission up until OPV13 cessation, meeting all prerequisites for OPV cessation, and ensuring sufficient vaccine supply to prevent and respond to outbreaks. PMID:28838198

Self-Amplifying mRNA Vaccines Expressing Multiple Conserved Influenza Antigens Confer Protection against Homologous and Heterosubtypic Viral Challenge

PubMed Central

Magini, Diletta; Giovani, Cinzia; Mangiavacchi, Simona; Maccari, Silvia; Cecchi, Raffaella; Ulmer, Jeffrey B.; De Gregorio, Ennio; Geall, Andrew J.; Brazzoli, Michela; Bertholet, Sylvie

2016-01-01

Current hemagglutinin (HA)-based seasonal influenza vaccines induce vaccine strain-specific neutralizing antibodies that usually fail to provide protection against mismatched circulating viruses. Inclusion in the vaccine of highly conserved internal proteins such as the nucleoprotein (NP) and the matrix protein 1 (M1) was shown previously to increase vaccine efficacy by eliciting cross-reactive T-cells. However, appropriate delivery systems are required for efficient priming of T-cell responses. In this study, we demonstrated that administration of novel self-amplifying mRNA (SAM®) vectors expressing influenza NP (SAM(NP)), M1 (SAM(M1)), and NP and M1 (SAM(M1-NP)) delivered with lipid nanoparticles (LNP) induced robust polyfunctional CD4 T helper 1 cells, while NP-containing SAM also induced cytotoxic CD8 T cells. Robust expansions of central memory (TCM) and effector memory (TEM) CD4 and CD8 T cells were also measured. An enhanced recruitment of NP-specific cytotoxic CD8 T cells was observed in the lungs of SAM(NP)-immunized mice after influenza infection that paralleled with reduced lung viral titers and pathology, and increased survival after homologous and heterosubtypic influenza challenge. Finally, we demonstrated for the first time that the co-administration of RNA (SAM(M1-NP)) and protein (monovalent inactivated influenza vaccine (MIIV)) was feasible, induced simultaneously NP-, M1- and HA-specific T cells and HA-specific neutralizing antibodies, and enhanced MIIV efficacy against a heterologous challenge. In conclusion, systemic administration of SAM vectors expressing conserved internal influenza antigens induced protective immune responses in mice, supporting the SAM® platform as another promising strategy for the development of broad-spectrum universal influenza vaccines. PMID:27525409

Active-site monovalent cations revealed in a 1.55-Å-resolution hammerhead ribozyme structure.

PubMed

Anderson, Michael; Schultz, Eric P; Martick, Monika; Scott, William G

2013-10-23

We have obtained a 1.55-Å crystal structure of a hammerhead ribozyme derived from Schistosoma mansoni under conditions that permit detailed observations of Na(+) ion binding in the ribozyme's active site. At least two such Na(+) ions are observed. The first Na(+) ion binds to the N7 of G10.1 and the adjacent A9 phosphate in a manner identical with that previously observed for divalent cations. A second Na(+) ion binds to the Hoogsteen face of G12, the general base in the hammerhead cleavage reaction, thereby potentially dissipating the negative charge of the catalytically active enolate form of the nucleotide base. A potential but more ambiguous third site bridges the A9 and scissile phosphates in a manner consistent with that of previous predictions. Hammerhead ribozymes have been observed to be active in the presence of high concentrations of monovalent cations, including Na(+), but the mechanism by which monovalent cations substitute for divalent cations in hammerhead catalysis remains unclear. Our results enable us to suggest that Na(+) directly and specifically substitutes for divalent cations in the hammerhead active site. The detailed geometry of the pre-catalytic active-site complex is also revealed with a new level of precision, thanks to the quality of the electron density maps obtained from what is currently the highest-resolution ribozyme structure in the Protein Data Bank. Copyright © 2013 Elsevier Ltd. All rights reserved.

Competition among Li+, Na+, K+ and Rb+ Monovalent Ions for DNA in Molecular Dynamics Simulations using the Additive CHARMM36 and Drude Polarizable Force Fields

PubMed Central

Savelyev, Alexey; MacKerell, Alexander D.

2015-01-01

In the present study we report on interactions of and competition between monovalent ions for two DNA sequences in MD simulations. Efforts included the development and validation of parameters for interactions among the first-group monovalent cations, Li+, Na+, K+ and Rb+, and DNA in the Drude polarizable and additive CHARMM36 force fields (FF). The optimization process targeted gas-phase QM interaction energies of various model compounds with ions and osmotic pressures of bulk electrolyte solutions of chemically relevant ions. The optimized ionic parameters are validated against counterion condensation theory and buffer exchange-atomic emission spectroscopy measurements providing quantitative data on the competitive association of different monovalent ions with DNA. Comparison between experimental and MD simulation results demonstrates that, compared to the additive CHARMM36 model, the Drude FF provides an improved description of the general features of the ionic atmosphere around DNA and leads to closer agreement with experiment on the ionic competition within the ion atmosphere. Results indicate the importance of extended simulation systems on the order of 25 Å beyond the DNA surface to obtain proper convergence of ion distributions. PMID:25751286

Effectiveness of Pentavalent and Monovalent Rotavirus Vaccines in Concurrent Use Among US Children <5 Years of Age, 2009–2011

PubMed Central

Payne, Daniel C.; Boom, Julie A.; Staat, Mary Allen; Edwards, Kathryn M.; Szilagyi, Peter G.; Klein, Eileen J.; Selvarangan, Rangaraj; Azimi, Parvin H.; Harrison, Christopher; Moffatt, Mary; Johnston, Samantha H.; Sahni, Leila C.; Baker, Carol J.; Rench, Marcia A.; Donauer, Stephanie; McNeal, Monica; Chappell, James; Weinberg, Geoffrey A.; Tasslimi, Azadeh; Tate, Jacqueline E.; Wikswo, Mary; Curns, Aaron T.; Sulemana, Iddrisu; Mijatovic-Rustempasic, Slavica; Esona, Mathew D.; Bowen, Michael D.; Gentsch, Jon R.; Parashar, Umesh D.

2015-01-01

Background We assessed vaccine effectiveness (VE) for RotaTeq (RV5; 3 doses) and Rotarix (RV1; 2 doses) at reducing rotavirus acute gastroenteritis (AGE) inpatient and emergency department (ED) visits in US children. Methods We enrolled children <5 years of age hospitalized or visiting the ED with AGE symptoms from November 2009–June 2010 and from November 2010–June 2011 at 7 medical institutions. Fecal specimens were tested for rotavirus by enzyme immunoassay and genotyped. Vaccination among laboratory-confirmed rotavirus cases was compared with rotavirus-negative AGE controls. Regression models calculated VE estimates for each vaccine, age, ethnicity, genotype, and clinical setting. Results RV5-specific analyses included 359 rotavirus cases and 1811 rotavirus-negative AGE controls. RV1-specific analyses included 60 rotavirus cases and 155 rotavirus-negative AGE controls. RV5 and RV1 were 84% (95% confidence interval [CI], 78%–88%) and 70% (95% CI, 39%–86%) effective, respectively, against rotavirus-associated ED visits and hospitalizations combined. By clinical setting, RV5 VE against ED and inpatient rotavirus-associated visits was 81% (95% CI, 70%–84%) and 86% (95% CI, 74%–91%), respectively. RV1 was 78% (95% CI, 46%–91%) effective against ED rotavirus disease; study power was insufficient to evaluate inpatient RV1 VE. No waning of immunity was evident during the first 4 years of life for RV5, nor during the first 2 years of life for RV1. RV5 provided genotype-specific protection against each of the predominant strains (G1P[8], G2P[4], G3P[8], G12P[8]), while RV1 VE was statistically significant for the most common genotype, G3P[8]. Conclusions Both RV5 and RV1 significantly protected against medically attended rotavirus gastroenteritis in this real-world assessment. PMID:23487388

In-vitro neurotoxicity of two Malaysian krait species (Bungarus candidus and Bungarus fasciatus) venoms: neutralization by monovalent and polyvalent antivenoms from Thailand.

PubMed

Rusmili, Muhamad Rusdi Ahmad; Yee, Tee Ting; Mustafa, Mohd Rais; Othman, Iekhsan; Hodgson, Wayne C

2014-03-12

Bungarus candidus and Bungarus fasciatus are two species of krait found in Southeast Asia. Envenoming by these snakes is often characterized by neurotoxicity and, without treatment, causes considerable morbidity and mortality. In this study, the in vitro neurotoxicity of each species, and the effectiveness of two monovalent antivenoms and a polyvalent antivenom, against the neurotoxic effects of the venoms, were examined in a skeletal muscle preparation. Both venoms caused concentration-dependent inhibition of indirect twitches, and attenuated responses to exogenous nicotinic receptor agonists, in the chick biventer preparation, with B. candidus venom being more potent than B. fasciatus venom. SDS-PAGE and western blot analysis indicated different profiles between the venoms. Despite these differences, most proteins bands were recognized by all three antivenoms. Antivenom, added prior to the venoms, attenuated the neurotoxic effect of the venoms. Interestingly, the respective monovalent antivenoms did not neutralize the effects of the venom from the other Bungarus species indicating a relative absence of cross-neutralization. Addition of a high concentration of polyvalent antivenom, at the t90 time point after addition of venom, partially reversed the neurotoxicity of B. fasciatus venom but not B. candidus venom. The monovalent antivenoms had no significant effect when added at the t90 time point. This study showed that B. candidus and B. fasciatus venoms display marked in vitro neurotoxicity in the chick biventer preparation and administration of antivenoms at high dose is necessary to prevent or reverse neurotoxicity.

The impact of rotavirus vaccination on emergency department visits and hospital admissions for acute diarrhea in children under 5 years.

PubMed

Paulo, Rodrigo Locatelli Pedro; Rodrigues, André Broggin Dutra; Machado, Beatriz Marcondes; Gilio, Alfredo Elias

2016-09-01

Acute diarrheal disease is the second cause of death in children under 5 years. In Brazil, from 2003 to 2009, acute diarrhea was responsible for nearly 100,000 hospital admissions per year and 4% of the deaths in children under 5 years. Rotavirus is the leading cause of severe acute diarrhea worldwide. In 2006, the rotavirus monovalent vaccine (RV1) was added to the Brazilian National Immunization Program. To analyze the impact of the RV1 on emergency department (ED) visits and hospital admissions for acute diarrhea. A retrospective ecologic study at the University Hospital, University of São Paulo. The study analyzed the pre-vaccine (2003-2005) and the post-vaccine (2007-2009) periods. We screened the main diagnosis of all ED attendances and hospital admissions of children under 5 years in an electronic registry system database and calculated the rates of ED visits and hospital admissions. The reduction rate was analyzed according to the following formula: reduction (%) = (1 - odds ratio) x 100. The rates of ED visits for acute diarrhea was 85.8 and 80.9 per 1,000 total ED visits in the pre and post vaccination periods, respectively, resulting in 6% reduction (95CI 4 to 9%, p<0.001). The rates of hospital admissions for acute diarrhea was 40.8 per 1,000 in the pre-vaccine period and dropped to 24.9 per 1,000 hospitalizations, resulting in 40% reduction (95CI 22 to 54%, p<0.001). The introduction of the RV1 vaccine resulted in 6% reduction in the ED visits and 40% reduction in hospital admissions for acute diarrhea.

A Single-Vector, Single-Injection Trivalent Filovirus Vaccine: Proof of Concept Study in Outbred Guinea Pigs.

PubMed

Mire, Chad E; Geisbert, Joan B; Versteeg, Krista M; Mamaeva, Natalia; Agans, Krystle N; Geisbert, Thomas W; Connor, John H

2015-10-01

The filoviruses, Marburg marburgvirus (MARV), Zaire ebolavirus (ZEBOV), and Sudan ebolavirus (SEBOV), cause severe and often fatal hemorrhagic fever in humans and nonhuman primates (NHPs). Monovalent recombinant vesicular stomatitis virus (rVSV)-based vaccine vectors, which encode a filovirus glycoprotein (GP) in place of the VSV glycoprotein, have shown 100% efficacy against homologous filovirus challenge in rodent and NHP studies. Here, we examined the utility of a single-vector, single-injection trivalent rVSV vector expressing MARV, ZEBOV, and SEBOV GPs to protect against MARV-, ZEBOV-, and SEBOV-induced disease in outbred Hartley guinea pigs where we observed protection from effects of all 3 filoviruses. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Febrile seizures after 2009 influenza A (H1N1) vaccination and infection: a nationwide registry-based study.

PubMed

Bakken, Inger Johanne; Aaberg, Kari Modalsli; Ghaderi, Sara; Gunnes, Nina; Trogstad, Lill; Magnus, Per; Håberg, Siri Eldevik

2015-11-09

During the 2009 influenza A (H1N1) pandemic, a monovalent pandemic strain vaccine containing the oil-in-water adjuvant AS03 (Pandemrix®) was offered to the Norwegian population. The coverage among children reached 54%. Our aim was to estimate the risk of febrile seizure in children after exposure to pandemic influenza vaccination or infection. The study population comprised 226,889 children born 2006-2009 resident in Norway per October 1st, 2009. Febrile seizure episodes were defined by emergency hospital admissions / emergency outpatient hospital care with International Classification of Diseases, Version 10, codes R56.0 or R56.8. The self-controlled case series method was applied to estimate incidence rate ratios (IRRs) in pre-defined risk periods compared to the background period. The total observation window was ± 180 days from exposure day. Among 113,068 vaccinated children, 656 (0.6%) had at least one febrile seizure episode. The IRR of febrile seizures 1-3 days after vaccination was 2.00 (95% confidence interval [CI]: 1.15-3.51). In the period 4-7 days after vaccination, no increased risk was observed. Among the 8172 children diagnosed with pandemic influenza, 84 (1.0%) had at least one febrile seizure episode. The IRR of febrile seizures on the same day as a diagnosis of influenza was 116.70 (95% CI: 62.81-216.90). In the period 1-3 days after a diagnosis of influenza, a tenfold increased risk was observed (IRR 10.12, 95% CI: 3.82 - 26.82). In this large population-based study with precise timing of exposures and outcomes, we found a twofold increased risk of febrile seizures 1-3 days after pandemic influenza vaccination. However, we found that pandemic influenza infection was associated with a much stronger increase in risk of febrile seizures.

A/H1N1 influenza vaccination in patients with systemic lupus erythematosus: safety and immunity.

PubMed

Lu, Chun-Chi; Wang, Yeau-Ching; Lai, Jenn-Haung; Lee, Tony Szu-Hsien; Lin, Hui-Tsu; Chang, Deh-Ming

2011-01-10

To determine the safety of and immunogenicity induced by A/H1N1 influenza vaccination in patients with systemic lupus erythematosus (SLE). The study population comprised 21 SLE patients and 15 healthy control subjects who underwent split-virion, inactivated monovalent A/H1N1 vaccination between December 2009 and January 2010. Sera were obtained before, three weeks after, and six months after vaccination. SLE disease activity index (SLEDAI) scores and autoantibodies were measured at every visit in SLE patients. Haemagglutination inhibition and the serum immunoglobulin G (IgG) level were calculated using the World Health Organization (WHO) procedure to evaluate the antibody responses. We also recorded current medications and past seasonal influenza vaccinations to analyse the interactions between vaccinations and the autoimmunity of SLE patients. The mean age of the enrolled population was 34.3 years for SLE patients and 39.4 years for control subjects. The average SLEDAI score for SLE patients was 4.1 at vaccination, 4.5 at three weeks, and 4.3 at six months. The seroprotection rate at three weeks was 76.2% in SLE patients and 80.0% in healthy control subjects; by six months, the seroprotection rate was 66.7% in SLE patients and 60% in healthy control subjects. The seroconversion rate was 76.2% in SLE patients and 80% in healthy controls at three weeks; by six months, the seroconversion rate was 52.4% in SLE patients and 53.3% in healthy controls. The response in SLE patients met the criteria of the European Committee for Proprietary Medicinal Products guidelines at three weeks, while the percentage of seroprotection did not at six months. The clinical disease activity and SLEDAI scores did not differ significantly from before to after vaccination in SLE patients, although the level of anticardiolipin IgG increased at three weeks after vaccination, but with no apparent clinical manifestations. The A/H1N1 influenza vaccine is safe and effective in SLE patients and

Monovalent Cation Doping of CH3NH3PbI3 for Efficient Perovskite Solar Cells.

PubMed

Abdi-Jalebi, Mojtaba; Dar, M Ibrahim; Sadhanala, Aditya; Senanayak, Satyaprasad P; Grätzel, Michael; Friend, Richard H

2017-03-19

Here, we demonstrate the incorporation of monovalent cation additives into CH3NH3PbI3 perovskite in order to adjust the optical, excitonic, and electrical properties. The possibility of doping was investigated by adding monovalent cation halides with similar ionic radii to Pb 2+ , including Cu + , Na + , and Ag + . A shift in the Fermi level and a remarkable decrease of sub-bandgap optical absorption, along with a lower energetic disorder in the perovskite, was achieved. An order-of-magnitude enhancement in the bulk hole mobility and a significant reduction of transport activation energy within an additive-based perovskite device was attained. The confluence of the aforementioned improved properties in the presence of these cations led to an enhancement in the photovoltaic parameters of the perovskite solar cell. An increase of 70 mV in open circuit voltage for AgI and a 2 mA/cm 2 improvement in photocurrent density for NaI- and CuBr-based solar cells were achieved compared to the pristine device. Our work paves the way for further improvements in the optoelectronic quality of CH3NH3PbI3 perovskite and subsequent devices. It highlights a new avenue for investigations on the role of dopant impurities in crystallization and controls the electronic defect density in perovskite structures.

Monovalent Cation Doping of CH3NH3PbI3 for Efficient Perovskite Solar Cells

PubMed Central

Abdi-Jalebi, Mojtaba; Dar, M. Ibrahim; Sadhanala, Aditya; Senanayak, Satyaprasad P.; Grätzel, Michael; Friend, Richard H.

2017-01-01

Here, we demonstrate the incorporation of monovalent cation additives into CH3NH3PbI3 perovskite in order to adjust the optical, excitonic, and electrical properties. The possibility of doping was investigated by adding monovalent cation halides with similar ionic radii to Pb2+, including Cu+, Na+, and Ag+. A shift in the Fermi level and a remarkable decrease of sub-bandgap optical absorption, along with a lower energetic disorder in the perovskite, was achieved. An order-of-magnitude enhancement in the bulk hole mobility and a significant reduction of transport activation energy within an additive-based perovskite device was attained. The confluence of the aforementioned improved properties in the presence of these cations led to an enhancement in the photovoltaic parameters of the perovskite solar cell. An increase of 70 mV in open circuit voltage for AgI and a 2 mA/cm2 improvement in photocurrent density for NaI- and CuBr-based solar cells were achieved compared to the pristine device. Our work paves the way for further improvements in the optoelectronic quality of CH3NH3PbI3 perovskite and subsequent devices. It highlights a new avenue for investigations on the role of dopant impurities in crystallization and controls the electronic defect density in perovskite structures. PMID:28362369

The Effect of Formulation on Spray Dried Sabin Inactivated Polio Vaccine.

PubMed

Kanojia, Gaurav; Ten Have, Rimko; Brugmans, Debbie; Soema, Peter C; Frijlink, Henderik W; Amorij, Jean-Pierre; Kersten, Gideon

2018-05-19

The objective of this study was to develop a stable spray dried formulation, containing the three serotypes of Sabin inactivated polio vaccine (sIPV), aiming for minimal loss of native conformation (D-antigen) during drying and subsequent storage. The influence of atomization and drying stress during spray drying on trivalent sIPV was investigated. This was followed by excipient screening, in which monovalent sIPV was formulated and spray dried. Excipient combinations and concentrations were tailored to maximize both the antigen recovery of respective sIPV serotypes after spray drying and storage (T= 40°C and t= 7 days). Furthermore, a fractional factorial design was developed around the most promising formulations to elucidate the contribution of each excipient in stabilizing D-antigen during drying. Serotype 1 and 2 could be dried with 98 % and 97 % recovery, respectively. When subsequently stored at 40°C for 7 days, the D-antigenicity of serotype 1 was fully retained. For serotype 2 the D-antigenicity dropped to 71 %. Serotype 3 was more challenging to stabilize and a recovery of 56 % was attained after drying, followed by a further loss of 37 % after storage at 40°C for 7 days. Further studies using a design of experiments approach demonstrated that trehalose/monosodium glutamate and maltodextrin/arginine combinations were crucial for stabilizing serotype 1 and 2, respectively. For sIPV serotype 3, the best formulation contained Medium199, glutathione and maltodextrin. For the trivalent vaccine it is therefore probably necessary to spray dry the different serotypes separately and mix the dry powders afterwards to obtain the trivalent vaccine. Copyright © 2018. Published by Elsevier B.V.

Lessons From Globally Coordinated Cessation of Serotype 2 Oral Poliovirus Vaccine for the Remaining Serotypes.

PubMed

Thompson, Kimberly M; Duintjer Tebbens, Radboud J

2017-07-01

Comparing model expectations with the experience of oral poliovirus vaccine (OPV) containing serotype 2 (OPV2) cessation can inform risk management for the expected cessation of OPV containing serotypes 1 and 3 (OPV13). We compare the expected post-OPV2-cessation OPV2-related viruses from models with the evidence available approximately 6 months after OPV2 cessation. We also model the trade-offs of use vs nonuse of monovalent OPV (mOPV) for outbreak response considering all 3 serotypes. Although too early to tell definitively, the observed die-out of OPV2-related viruses in populations that attained sufficiently intense trivalent OPV (tOPV) use prior to OPV2 cessation appears consistent with model expectations. As expected, populations that did not intensify tOPV use prior to OPV2 cessation show continued circulation of serotype 2 vaccine-derived polioviruses (VDPVs). Failure to aggressively use mOPV to respond to circulating VDPVs results in a high risk of uncontrolled outbreaks that would require restarting OPV. Ensuring a successful endgame requires more aggressive OPV cessation risk management than has occurred to date for OPV2 cessation. This includes maintaining high population immunity to transmission up until OPV13 cessation, meeting all prerequisites for OPV cessation, and ensuring sufficient vaccine supply to prevent and respond to outbreaks. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Molecular simulation of the swelling of polyelectrolyte gels by monovalent and divalent counterions

PubMed Central

Yin, De-Wei; Horkay, Ferenc; Douglas, Jack F.; de Pablo, Juan J.

2008-01-01

Permanently crosslinked polyelectrolyte gels are known to undergo discontinuous first-order volume phase transitions, the onset of which may be caused by a number of factors. In this study we examine the volumetric properties of such polyelectrolyte gels in relation to the progressive substitution of monovalent counterions by divalent counterions as the gels are equilibrated in solvents of different dielectric qualities. We compare the results of coarse-grained molecular dynamics simulations of polyelectrolyte gels with previous experimental measurements by others on polyacrylate gels. The simulations show that under equilibrium conditions there is an approximate cancellation between the electrostatic contribution and the counterion excluded-volume contribution to the osmotic pressure in the gel-solvent system; these two contributions to the osmotic pressure have, respectively, energetic and entropic origins. The finding of such a cancellation between the two contributions to the osmotic pressure of the gel-solvent system is consistent with experimental observations that the swelling behavior of polyelectrolyte gels can be described by equations of state for neutral gels. Based on these results, we show and explain that a modified form of the Flory–Huggins model for nonionic polymer solutions, which accounts for neither electrostatic effects nor counterion excluded-volume effects, fits both experimental and simulated data for polyelectrolyte gels. The Flory–Huggins interaction parameters obtained from regression to the simulation data are characteristic of ideal polymer solutions, whereas the experimentally obtained interaction parameters, particularly that associated with the third virial coefficient, exhibit a significant departure from ideality, leading us to conclude that further enhancements to the simulation model, such as the inclusion of excess salt, the allowance for size asymmetric electrolytes, or the use of a distance-dependent solvent dielectricity

Molecular simulation of the swelling of polyelectrolyte gels by monovalent and divalent counterions.

PubMed

Yin, De-Wei; Horkay, Ferenc; Douglas, Jack F; de Pablo, Juan J

2008-10-21

Permanently crosslinked polyelectrolyte gels are known to undergo discontinuous first-order volume phase transitions, the onset of which may be caused by a number of factors. In this study we examine the volumetric properties of such polyelectrolyte gels in relation to the progressive substitution of monovalent counterions by divalent counterions as the gels are equilibrated in solvents of different dielectric qualities. We compare the results of coarse-grained molecular dynamics simulations of polyelectrolyte gels with previous experimental measurements by others on polyacrylate gels. The simulations show that under equilibrium conditions there is an approximate cancellation between the electrostatic contribution and the counterion excluded-volume contribution to the osmotic pressure in the gel-solvent system; these two contributions to the osmotic pressure have, respectively, energetic and entropic origins. The finding of such a cancellation between the two contributions to the osmotic pressure of the gel-solvent system is consistent with experimental observations that the swelling behavior of polyelectrolyte gels can be described by equations of state for neutral gels. Based on these results, we show and explain that a modified form of the Flory-Huggins model for nonionic polymer solutions, which accounts for neither electrostatic effects nor counterion excluded-volume effects, fits both experimental and simulated data for polyelectrolyte gels. The Flory-Huggins interaction parameters obtained from regression to the simulation data are characteristic of ideal polymer solutions, whereas the experimentally obtained interaction parameters, particularly that associated with the third virial coefficient, exhibit a significant departure from ideality, leading us to conclude that further enhancements to the simulation model, such as the inclusion of excess salt, the allowance for size asymmetric electrolytes, or the use of a distance-dependent solvent dielectricity

Tandem truncated rotavirus VP8* subunit protein with T cell epitope as non-replicating parenteral vaccine is highly immunogenic.

PubMed

Wen, Xiaobo; Cao, Dianjun; Jones, Ronald W; Hoshino, Yasutaka; Yuan, Lijuan

2015-01-01

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[8] 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[8] ΔVP8*-P[8] ΔVP8* and P2-P[8] ΔVP8*-P[6] ΔVP8* based on Escherichia coli expression system. The two resulting recombinant tandem proteins were highly soluble and P2-P[8] ΔVP8*-P[8] ΔVP8* was generated with high yield. Moreover, guinea pigs immunized intramuscularly by 3 doses of the P2-P[8] ΔVP8*-P[8] ΔVP8* or P2-P[8] ΔVP8*-P[6] 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[8], P[4] or P[6] 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.

Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials.

PubMed

Vesikari, Timo; Esposito, Susanna; Prymula, Roman; Ypma, Ellen; Kohl, Igor; Toneatto, Daniela; Dull, Peter; Kimura, Alan

2013-03-09

who contributed safety data after at least one dose of study vaccine. These trials are registered with ClinicalTrials.gov, numbers NCT00657709 and NCT00847145. We enrolled 2627 infants in the open-label phase, 1003 in the observer-blind phase, and 1555 in the booster study. Lot-to-lot consistency was shown for the three 4CMenB lots, with the lowest 95% lower confidence limit being 0·74 and the highest upper limit being 1·33. Of 1181–1184 infants tested 1 month after three 4CMenB doses (all lots pooled), 100% (95% CI 99–100) had hSBA titres of 5 or more against strains selective for factor H binding protein and neisserial adhesin A, and 84% (82–86) for New Zealand outer-membrane vesicle. In a subset (n=100), 84% (75–91) of infants had hSBA titres of 5 or more against neisseria heparin binding antigen. At 12 months of age, waning titres were boosted by a fourth dose, such that 95–100% of children had hSBA titres of 5 or more for all antigens, with or without concomitant MMRV. Immune responses to routine vaccines were much the same with or without concomitant 4CMenB, but concomitant vaccination was associated with increased reactogenicity. 77% (1912 of 2478) of infants had fever of 38·5°C or higher after any 4CMenB dose, compared with 45% (295 of 659) after routine vaccines alone and 47% (228 of 490) with MenC, but only two febrile seizures were deemed probably related to 4CMenB. 4CMenB is immunogenic in infants and children aged 12 months with no clinically relevant interference with routine vaccines, but increases reactogenicity when administered concomitantly with routine vaccines. This breakthrough vaccine offers an innovative solution to the major remaining cause of bacterial meningitis in infant and toddlers. Novartis Vaccines and Diagnostics.

Attraction between like-charged monovalent ions.

PubMed

Zangi, Ronen

2012-05-14

Ions with like-charges repel each other with a magnitude given by the Coulomb law. The repulsion is also known to persist in aqueous solutions albeit factored by the medium's dielectric constant. In this paper, we report results from molecular dynamics simulations of alkali halides salt solutions indicating an effective attraction between some of the like-charged monovalent ions. The attraction is observed between anions, as well as between cations, leading to the formation of dimers with lifetimes on the order of few picoseconds. Two mechanisms have been identified to drive this counterintuitive attraction. The first is exhibited by high-charge density ions, such as fluoride, at low salt concentrations, yielding effective attractions with magnitude up to the order of 1-2 kT. In this case, the stronger local electric field generated when the two ions are in contact augments the alignment of neighboring waters toward the ions. This results in a gain of substantial favorable ion-water interaction energy. For fluorides, this interaction constitutes the major change among the different energy components compensating for the anion-anion repulsion, and therefore, rendering like-charge association possible. The second mechanism involves mediation by counterions, the attractions increase with salt concentration and are characterized by small magnitudes. In particular, clusters of ion triplets, in which a counterion is either bridging the two like-charged ions or is paired to only one of them, are formed. Although these two mechanisms may not yield net attractions in many cases, they might still be operational and significant, explaining effective repulsions between like-charged ions with magnitudes much smaller than expected based on continuum electrostatics.

The role of monovalent cations in the ATPase reaction of DNA gyrase.

PubMed

Hearnshaw, Stephen James; Chung, Terence Tsz-Hong; Stevenson, Clare Elizabeth Mary; Maxwell, Anthony; Lawson, David Mark

2015-04-01

Four new crystal structures of the ATPase domain of the GyrB subunit of Escherichia coli DNA gyrase have been determined. One of these, solved in the presence of K(+), is the highest resolution structure reported so far for this domain and, in conjunction with the three other structures, reveals new insights into the function of this domain. Evidence is provided for the existence of two monovalent cation-binding sites: site 1, which preferentially binds a K(+) ion that interacts directly with the α-phosphate of ATP, and site 2, which preferentially binds an Na(+) ion and the functional significance of which is not clear. The crystallographic data are corroborated by ATPase data, and the structures are compared with those of homologues to investigate the broader conservation of these sites.

The role of monovalent cations in the ATPase reaction of DNA gyrase

PubMed Central

Hearnshaw, Stephen James; Chung, Terence Tsz-Hong; Stevenson, Clare Elizabeth Mary; Maxwell, Anthony; Lawson, David Mark

2015-01-01

Four new crystal structures of the ATPase domain of the GyrB subunit of Escherichia coli DNA gyrase have been determined. One of these, solved in the presence of K+, is the highest resolution structure reported so far for this domain and, in conjunction with the three other structures, reveals new insights into the function of this domain. Evidence is provided for the existence of two monovalent cation-binding sites: site 1, which preferentially binds a K+ ion that interacts directly with the α-phosphate of ATP, and site 2, which preferentially binds an Na+ ion and the functional significance of which is not clear. The crystallographic data are corroborated by ATPase data, and the structures are compared with those of homologues to investigate the broader conservation of these sites. PMID:25849408

Early and long term anamnestic response to HBV booster dose among fully vaccinated Egyptian children during infancy.

PubMed

Salama, Iman I; Sami, Samia M; Said, Zeinab N; Salama, Somaia I; Rabah, Thanaa M; Abdel-Latif, Ghada A; Elmosalami, Dalia M; Saleh, Rehan M; Abdel Mohsin, Aida M; Metwally, Ammal M; Hassanin, Amal I; Emam, Hanaa M; Hemida, Samia A; Elserougy, Safaa M; Shaaban, Fatma A; Fouad, Walaa A; Mohsen, Amira; El-Sayed, Manal H

2018-04-05

To evaluate early and long term anamnestic response to a booster dose of HBV vaccine among non-seroprotected children. A national community based project was carried out on 3600 children aged 9 months to 16 years, fully vaccinated during infancy. They were recruited from 6 governorates representing Egypt. It revealed that 1535 children (42.8%) had non sero-protective anti-HBs (<10 IU/L) and were HBsAg or anti-HBc negative. A challenging dose of 10 μg of mono-valent Euvax HBV vaccine was given to 1121/1535 children. Quantitative assessment of anti-HBs was performed to detect early (2-4 weeks) and long term (one year) anamnestic responses. Early anamnestic response developed among 967/1070 children (90.3%).Children having detectable anti-HBs (1-9 IU/L) significantly developed early anamnestic response (90%) compared to 85% with undetectable anti-HBs (<1 IU/L), P < 0.001. Multiple logistic analysis revealed that undetectable anti-HBs, living in rural residence and children aged 15-16 years were the most significant predicting risk factors for the absence of early anamnestic response (<10 IU/L), with AOR 2.7, 2.7 & 4.7 respectively. After one year, long term anamnestic response was absent among 15% of children who previously showed early response. Poor early anamnestic response and undetectable pre-booster anti-HBs were the significant predicting risk factors for absent long term anamnestic response, with AOR 18.7 & 2.7 respectively. Immunological memory for HBV vaccine outlasts the presence of anti- HBs and HBV vaccination program provides effective long term protection even in children showing waning or undetectable concentrations of anti-HBs. This signifies no need for a booster dose especially to healthy children. Copyright © 2018 Elsevier Ltd. All rights reserved.

Vaccine-induced mucosal immunity to poliovirus: analysis of cohorts from an open-label, randomised controlled trial in Latin American infants.

PubMed

Wright, Peter F; Connor, Ruth I; Wieland-Alter, Wendy F; Hoen, Anne G; Boesch, Austin W; Ackerman, Margaret E; Oberste, M Steven; Gast, Chris; Brickley, Elizabeth B; Asturias, Edwin J; Rüttimann, Ricardo; Bandyopadhyay, Ananda S

2016-12-01

Identification of mechanisms that limit poliovirus replication is crucial for informing decisions aimed at global polio eradication. Studies of mucosal immunity induced by oral poliovirus (OPV) or inactivated poliovirus (IPV) vaccines and mixed schedules thereof will determine the effectiveness of different vaccine strategies to block virus shedding. We used samples from a clinical trial of different vaccination schedules to measure intestinal immunity as judged by neutralisation of virus and virus-specific IgA in stools. In the FIDEC trial, Latin American infants were randomly assigned to nine groups to assess the efficacy of two schedules of bivalent OPV (bOPV) and IPV and challenge with monovalent type 2 OPV, and stools samples were collected. We selected three groups of particular interest-the bOPV control group (serotypes 1 and 3 at 6, 10, and 14 weeks), the trivalent attenuated OPV (tOPV) control group (tOPV at 6, 10, and 14 weeks), and the bOPV-IPV group (bOPV at 6, 10, and 14 weeks plus IPV at 14 weeks). Neutralising activity and poliovirus type-specific IgA were measured in stool after a monovalent OPV type 2 challenge at 18 weeks of age. Mucosal immunity was measured by in-vitro neutralisation of a type 2 polio pseudovirus (PV2). Neutralisation titres and total and poliovirus-type-specific IgG and IgA concentrations in stools were assessed in samples collected before challenge and 2 weeks after challenge from all participants. 210 infants from Guatemala and Dominican Republic were included in this analysis. Of 38 infants tested for mucosal antibody in the tOPV group, two were shedding virus 1 week after challenge, compared with 59 of 85 infants receiving bOPV (p<0·0001) and 53 of 87 infants receiving bOPV-IPV (p<0·0001). Mucosal type 2 neutralisation and type-specific IgA were noted primarily in response to tOPV. An inverse correlation was noted between virus shedding and both serum type 2 neutralisation at challenge (p<0·0001) and mucosal type 2

A vaccine formulation combining rhoptry proteins NcROP40 and NcROP2 improves pup survival in a pregnant mouse model of neosporosis.

PubMed

Pastor-Fernández, Iván; Arranz-Solís, David; Regidor-Cerrillo, Javier; Álvarez-García, Gema; Hemphill, Andrew; García-Culebras, Alicia; Cuevas-Martín, Carmen; Ortega-Mora, Luis M

2015-01-30

Currently there are no effective vaccines for the control of bovine neosporosis. During the last years several subunit vaccines based on immunodominant antigens and other proteins involved in adhesion, invasion and intracellular proliferation of Neospora caninum have been evaluated as targets for vaccine development in experimental mouse infection models. Among them, the rhoptry antigen NcROP2 and the immunodominant NcGRA7 protein have been assessed with varying results. Recent studies have shown that another rhoptry component, NcROP40, and NcNTPase, a putative dense granule antigen, exhibit higher expression levels in tachyzoites of virulent N. caninum isolates, suggesting that these could be potential vaccine candidates to limit the effects of infection. In the present work, the safety and efficacy of these recombinant antigens formulated in Quil-A adjuvant as monovalent vaccines or pair-wise combinations (rNcROP40+rNcROP2 and rNcGRA7+rNcNTPase) were evaluated in a pregnant mouse model of neosporosis. All the vaccine formulations elicited a specific immune response against their respective native proteins after immunization. Mice vaccinated with rNcROP40 and rNcROP2 alone or in combination produced the highest levels of IFN-γ and exhibited low parasite burdens and low IgG antibody levels after the challenge. In addition, most of the vaccine formulations were able to increase the median survival time in the offspring. However, pup survival only ensued in the groups vaccinated with rNcROP40+rNcROP2 (16.2%) and rNcROP2 (6.3%). Interestingly, vertical transmission was not observed in those survivor pups immunized with rNcROP40+rNcROP2, as shown by PCR analyses. These results show a partial protection against N. caninum infection after vaccination with rNcROP40+rNcROP2, suggesting a synergistic effect of the two recombinant rhoptry antigens. Copyright © 2014 Elsevier B.V. All rights reserved.

Clinical Features of Post-Vaccination Guillain-Barré Syndrome (GBS) in Korea

PubMed Central

2017-01-01

Guillain-Barré syndrome (GBS) is the most common immune-mediated polyradiculoneuropathy and it is also the most commonly reported severe adverse event following immunization in adults. To evaluate the results of clinical and laboratory features of GBS after vaccination in Korea, we analyzed the claims-based data from 2002 to 2014 using materials collected for the Advisory Committee Vaccination Injury Compensation (ACVIC) meeting including, clinical features, nerve conduction studies (NCSs), cerebrospinal fluid (CSF) profiles, treatment, and outcomes. Forty-eight compensated GBS cases (median age, 15 years; interquartile range [IQR], 13–51; male:female ratio, 1:1) of 68 suspected GBS were found following immunization and all of them with influenza immunizations with either monovalent (n = 35) or trivalent (n = 13). Among them, 30 cases fulfilled the Brighton criteria level 1–3 (62.5%). The median duration between the onset of symptoms to nadir, duration of the nadir, and total admission period were 3 (IQR, 2–7 days), 2 (IQR, 1–5 days), and 14 (IQR, 6–33 days) days, respectively. The most frequently reported symptom was quadriparesis which was present in 36 cases (75%) at nadir. CSF examination revealed albuminocytologic dissociation in 25.0% and NCS was abnormal in 61.8%. After treatment, most of them showed improvement. Clinical features were similar to typical post-infectious GBS and there were both demyelinating and axonal forms suggesting heterogeneous pathogenic mechanism. In order to improve the diagnostic certainty of post-vaccination GBS, careful documentation of clinical features and timely diagnostic work-up with follow-up studies are needed. PMID:28581273

A prophylactic multivalent vaccine against different filovirus species is immunogenic and provides protection from lethal infections with Ebolavirus and Marburgvirus species in non-human primates.

PubMed

Callendret, Benoit; Vellinga, Jort; Wunderlich, Kerstin; Rodriguez, Ariane; Steigerwald, Robin; Dirmeier, Ulrike; Cheminay, Cedric; Volkmann, Ariane; Brasel, Trevor; Carrion, Ricardo; Giavedoni, Luis D; Patterson, Jean L; Mire, Chad E; Geisbert, Thomas W; Hooper, Jay W; Weijtens, Mo; Hartkoorn-Pasma, Jutta; Custers, Jerome; Grazia Pau, Maria; Schuitemaker, Hanneke; Zahn, Roland

2018-01-01

The search for a universal filovirus vaccine that provides protection against multiple filovirus species has been prompted by sporadic but highly lethal outbreaks of Ebolavirus and Marburgvirus infections. A good prophylactic vaccine should be able to provide protection to all known filovirus species and as an upside potentially protect from newly emerging virus strains. We investigated the immunogenicity and protection elicited by multivalent vaccines expressing glycoproteins (GP) from Ebola virus (EBOV), Sudan virus (SUDV), Taï Forest virus (TAFV) and Marburg virus (MARV). Immune responses against filovirus GP have been associated with protection from disease. The GP antigens were expressed by adenovirus serotypes 26 and 35 (Ad26 and Ad35) and modified Vaccinia virus Ankara (MVA) vectors, all selected for their strong immunogenicity and good safety profile. Using fully lethal NHP intramuscular challenge models, we assessed different vaccination regimens for immunogenicity and protection from filovirus disease. Heterologous multivalent Ad26-Ad35 prime-boost vaccination regimens could give full protection against MARV (range 75%-100% protection) and EBOV (range 50% to 100%) challenge, and partial protection (75%) against SUDV challenge. Heterologous multivalent Ad26-MVA prime-boost immunization gave full protection against EBOV challenge in a small cohort study. The use of such multivalent vaccines did not show overt immune interference in comparison with monovalent vaccines. Multivalent vaccines induced GP-specific antibody responses and cellular IFNγ responses to each GP expressed by the vaccine, and cross-reactivity to TAFV GP was detected in a trivalent vaccine expressing GP from EBOV, SUDV and MARV. In the EBOV challenge studies, higher humoral EBOV GP-specific immune responses (p = 0.0004) were associated with survival from EBOV challenge and less so for cellular immune responses (p = 0.0320). These results demonstrate that it is feasible to generate a

A prophylactic multivalent vaccine against different filovirus species is immunogenic and provides protection from lethal infections with Ebolavirus and Marburgvirus species in non-human primates

PubMed Central

Callendret, Benoit; Vellinga, Jort; Wunderlich, Kerstin; Steigerwald, Robin; Dirmeier, Ulrike; Cheminay, Cedric; Volkmann, Ariane; Brasel, Trevor; Carrion, Ricardo; Giavedoni, Luis D.; Patterson, Jean L.; Mire, Chad E.; Geisbert, Thomas W.; Hooper, Jay W.; Weijtens, Mo; Hartkoorn-Pasma, Jutta; Custers, Jerome; Grazia Pau, Maria; Schuitemaker, Hanneke

2018-01-01

The search for a universal filovirus vaccine that provides protection against multiple filovirus species has been prompted by sporadic but highly lethal outbreaks of Ebolavirus and Marburgvirus infections. A good prophylactic vaccine should be able to provide protection to all known filovirus species and as an upside potentially protect from newly emerging virus strains. We investigated the immunogenicity and protection elicited by multivalent vaccines expressing glycoproteins (GP) from Ebola virus (EBOV), Sudan virus (SUDV), Taï Forest virus (TAFV) and Marburg virus (MARV). Immune responses against filovirus GP have been associated with protection from disease. The GP antigens were expressed by adenovirus serotypes 26 and 35 (Ad26 and Ad35) and modified Vaccinia virus Ankara (MVA) vectors, all selected for their strong immunogenicity and good safety profile. Using fully lethal NHP intramuscular challenge models, we assessed different vaccination regimens for immunogenicity and protection from filovirus disease. Heterologous multivalent Ad26-Ad35 prime-boost vaccination regimens could give full protection against MARV (range 75%-100% protection) and EBOV (range 50% to 100%) challenge, and partial protection (75%) against SUDV challenge. Heterologous multivalent Ad26-MVA prime-boost immunization gave full protection against EBOV challenge in a small cohort study. The use of such multivalent vaccines did not show overt immune interference in comparison with monovalent vaccines. Multivalent vaccines induced GP-specific antibody responses and cellular IFNγ responses to each GP expressed by the vaccine, and cross-reactivity to TAFV GP was detected in a trivalent vaccine expressing GP from EBOV, SUDV and MARV. In the EBOV challenge studies, higher humoral EBOV GP-specific immune responses (p = 0.0004) were associated with survival from EBOV challenge and less so for cellular immune responses (p = 0.0320). These results demonstrate that it is feasible to generate a

Vaccine Efficacy Against a New Avian Influenza (H9N2) Field Isolate from the Middle East (Serology and Challenge Studies).

PubMed

Gharaibeh, Saad; Amareen, Shadi

2016-05-01

Avian influenza subtype H9N2 is endemic in many countries in the Middle East. The reported prevalence of infection was variable between countries and ranged from 28.7% in Tunisia to 71% in Jordan. Several commercial killed whole-virus vaccine products are used as monovalent or bivalent mixed with Newcastle disease virus. Recently, we have noticed that many of the vaccinated broiler flocks did not show a production advantage over nonvaccinated flocks in the field. A new avian influenza field virus (H9N2) was isolated from these vaccinated and infected broiler flocks in 2013. This virus had 89.1% similarity of its hemagglutinin (HA) gene to the classical virus used for manufacturing the classical vaccine. Inactivated autogenous vaccine was manufactured from this new field isolate to investigate its serological response and protection in specific-pathogen-free (SPF) and breeder-male chickens compared to the classical vaccine. Oropharyngeal virus shedding of vaccinated breeder-male chickens was evaluated at 3, 9, 10, and 14 days postchallenge (DPC). Percentage of chickens shedding the virus at 3 DPC was 64%, 50%, and 64% in the classical vaccine group, autogenous vaccine group, and the control challenged group, respectively. At 7 DPC percentage of virus shedding was 42%, 7%, and 64% in the classical vaccine group, autogenous vaccine group, and the control challenged group, respectively. At 10 DPC only 9% of classical vaccine group was shedding the virus and there was no virus shedding in any of the groups at 14 DPC. There was statistical significance difference (P < 0.05) in shedding only at 7 DPC between the autogenous vaccine group and the other two groups. At 42 days of age (14 DPC), average body weight was 2.720, 2.745, 2.290, and 2.760 kg for the classical vaccine group, autogenous vaccine group, control challenged group, and control unchallenged group, respectively. Only the control challenged group had significantly (P < 0.05) lower average body weight. In

[Vaccination against viral hepatitis A and B in adults aged over 40 years--antibody persistence and immune memory].

PubMed

Chlibek, R; Smetana, J; Bostíková, V; Splino, M

2011-09-01

Primary vaccination with combined vaccine against viral hepatitis A (VHA) and viral hepatitis B (VHB) induces higher anti-hepatitis B surface (anti-HBs) antibody responses and similar anti-hepatitis A virus (anti-HAV) antibody responses in adults aged over 40 years in comparison with concomitant monovalent vaccines against VHA and VHB. Th e objectives were to assess, in a clinical study, persistence of anti-HAV and anti-HBs antibodies in adults aged over 40 years four years after primary VHA/VHB vaccination and antibody response following a booster dose of the vaccine. Five hundred and ninety-six subjects aged > 40 years were vaccinated with three doses of the combined VHA/VHB vaccine at Months 0, 1, 6 (HAB group) or with concomitant VHA and VHB vaccines at Months 0, 6 and 0, 1, 6 (ENG+HAV and HBVX+VAQ, respectively). Blood samples were collected one month following primary vaccination (Month 7) and then at one-year intervals for four years after the booster dose with the same vaccine as used for the primary vaccination. The anti-HBs and anti-HAV antibody levels were determined prior to the booster dose and at days 14 and 30 after the booster dose. At Month 7, > 97% of study subjects were seropositive for anti-HAV antibodies in all groups analyzed. Four years after primary vaccination, anti-HAV antibody seropositivity persisted in > 93% of study subjects, increasing to > 99% after the booster dose. At Month 7, the highest proportion of study subjects with anti-HBs antibody levels > or = 10 mIU/ml was found in the HAB group (91.7% versus 79.7% in the ENG+HAV group versus 71.0% in the HBVX+VAQ group). Four years after vaccination, anti-HBs antibody levels of 10 mIU/ml persisted in 57.1% of the HAB study subjects in comparison with 40.1% and 26.6% of the study subjects in the ENG+HAV and HBVX+VAQ groups, respectively. One month after the booster dose, anti-HBs antibody levels increased and antibody levels > or = 10 mIU/ml was achived in 95.2% of study subjects in the

Diphtheria toxin-induced channels in Vero cells selective for monovalent cations

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

Sandvig, K.; Olsnes, S.

1988-09-05

Ion fluxes associated with translocation of diphtheria toxin across the surface membrane of Vero cells were studied. When cells with surface-bound toxin were exposed to low pH to induce toxin entry, the cells became permeable to Na+, K+, H+, choline+, and glucosamine+. There was no increased permeability to Cl-, SO4(-2), glucose, or sucrose, whereas the uptake of /sup 45/Ca2+ was slightly increased. The influx of Ca2+, which appears to be different from that of monovalent cations, was reduced by several inhibitors of anion transport and by verapamil, Mn2+, Co2+, and Ca2+, but not by Mg2+. The toxin-induced fluxes of N+,more » K+, and protons were inhibited by Cd2+. Cd2+ also protected the cells against intoxication by diphtheria toxin, suggesting that the open cation-selective channel is required for toxin translocation. The involvement of the toxin receptor is discussed.« less

Simultaneous Analysis of Monovalent Anions and Cations with a Sub-Microliter Dead-Volume Flow-Through Potentiometric Detector for Ion Chromatography

PubMed Central

Dumanli, Rukiye; Attar, Azade; Erci, Vildan; Isildak, Ibrahim

2016-01-01

A microliter dead-volume flow-through cell as a potentiometric detector is described in this article for sensitive, selective and simultaneous detection of common monovalent anions and cations in single column ion chromatography for the first time. The detection cell consisted of less selective anion- and cation-selective composite membrane electrodes together with a solid-state composite matrix reference electrode. The simultaneous separation and sensitive detection of sodium (Na+), potassium (K+), ammonium (NH4+), chloride (Cl−) and nitrate (NO3−) in a single run was achieved by using 98% 1.5 mM MgSO4 and 2% acetonitrile eluent with a mixed-bed ion-exchange separation column without suppressor column system. The separation and simultaneous detection of the anions and cations were completed in 6 min at the eluent flow-rate of 0.8 mL/min. Detection limits, at S/N = 3, were ranged from 0.2 to 1.0 µM for the anions and 0.3 to 3.0 µM for the cations, respectively. The developed method was successfully applied to the simultaneous determination of monovalent anions and cations in several environmental and biological samples. PMID:26786906

A randomized study to evaluate the immunogenicity and safety of a heptavalent diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, haemophilus influenzae b, and meningococcal serogroup C combination vaccine administered to infants at 2, 4 and 12 months of age.

PubMed

Thollot, Franck; Scheifele, David; Pankow-Culot, Heidemarie; Cheuvart, Brigitte; Leyssen, Maarten; Ulianov, Liliana; Miller, Jacqueline M

2014-12-01

The immunogenicity and safety of the investigational diphtheria, tetanus, acellular pertussis, hepatitis B, poliomyelitis, Haemophilus influenzae type b (Hib) and meningococcal serogroup C (MenC) heptavalent combination vaccine were compared with those of licensed control vaccines. In this open, phase II, randomized study (NCT01090453), 480 infants from Germany, France and Canada received the heptavalent vaccine (Hepta group) or hexavalent and monovalent MenC control vaccines (HexaMenC group) co-administered with a 13-valent pneumococcal conjugate vaccine at 2, 4 and 12 months of age. Immunogenicity was measured 1 month after the second primary dose, and before and 1 month after the booster dose. Safety and reactogenicity were also evaluated. Non-inferiority of immune responses to MenC and Hib induced by 2-dose primary vaccination with the heptavalent vaccine versus control vaccines was demonstrated. In exploratory analyses, postprimary and postbooster functional antibody geometric mean titers against MenC tended to be lower (1119.5 vs. 3200.5; 2653.8 vs. 6028.4) and antibody geometric mean concentrations against Hib higher (1.594 vs. 0.671 μg/mL; 17.678 vs. 13.737 μg/mL) in the Hepta versus the HexaMenC group. The heptavalent and control vaccines were immunogenic to all other antigens, although immune responses to poliovirus were lower than expected in both groups. No differences in safety and reactogenicity profiles were detected between groups. The heptavalent vaccine induced non-inferior MenC and Hib responses compared with control vaccines. Both vaccination regimens, when administered at 2, 4 and 12 months of age, had comparable safety profiles and were immunogenic to all antigens, with lower-than-expected responses to poliomyelitis.

Immunogenicity and safety of a tetravalent E. coli O-antigen bioconjugate vaccine in animal models.

PubMed

van den Dobbelsteen, Germie P J M; Faé, Kellen C; Serroyen, Jan; van den Nieuwenhof, Ingrid M; Braun, Martin; Haeuptle, Micha A; Sirena, Dominique; Schneider, Joerg; Alaimo, Cristina; Lipowsky, Gerd; Gambillara-Fonck, Veronica; Wacker, Michael; Poolman, Jan T

2016-07-29

Extra-intestinal pathogenic Escherichia coli (ExPEC) are major human pathogens; however, no protective vaccine is currently available. We assessed in animal models the immunogenicity and safety of a 4-valent E. coli conjugate vaccine (ExPEC-4V, serotypes O1, O2, O6 and O25 conjugated to Exotoxin A from Pseudomonas aeruginosa (EPA)) produced using a novel in vivo bioconjugation method. Three doses of ExPEC-4V (with or without aluminum hydroxide) were administered to rabbits (2μg or 20μg per O-antigen, subcutaneously), mice (0.2μg or 2μg per O-antigen, subcutaneously) and rats (0.4μg or 4μg per O-antigen, intramuscularly). Antibody persistence and boostability were evaluated in rats using O6-EPA monovalent conjugate (0.4μg O-antigen/dose, intramuscularly). Toxicity was assessed in rats (16μg total polysaccharide, intramuscularly). Serum IgG and IgM antibodies were measured by ELISA. Robust antigen-specific IgG responses were observed in all animal models, with increased responses in rabbits when administered with adjuvant. O antigen-specific antibody responses persisted up to 168days post-priming. Booster immunization induced a rapid recall response. Toxicity of ExPEC-4V when administered to rats was considered to be at the no observed adverse effect level. ExPEC-4V conjugate vaccine showed good immunogenicity and tolerability in animal models supporting progression to clinical evaluation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Immunogenicity and safety of a single dose of a CRM-conjugated meningococcal ACWY vaccine in children and adolescents aged 2-18 years in Taiwan: results of an open label study.

PubMed

Huang, Li-Min; Chiu, Nan-Chang; Yeh, Shu-Jen; Bhusal, Chiranjiwi; Arora, Ashwani Kumar

2014-09-08

MenACWY-CRM (Menveo®, Novartis Vaccines, Siena, Italy) is a quadrivalent meningococcal conjugate vaccine developed to help prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W, and Y. It is approved within the European Union in persons >2 years of age and in persons from 2 months to 55 years of age in the United States, among other countries. Little is known about the immunogenicity and safety of this vaccine in Taiwanese children >2 years and adolescents. This study assessed the immunogenicity and safety of a single injection of MenACWY-CRM vaccine in Taiwanese subjects aged 2-18 years old. In this phase III, multicentre, open-label study 341 subjects received one dose of MenACWY-CRM. Immunogenicity measures were rates of seroresponse (defined as the proportion of subjects with a postvaccination hSBA ≥1:8 if the prevaccination (baseline) titre was <1:4, or at least a fourfold higher hSBA titre than baseline if the prevaccination titre was ≥1:4), percentages of subjects with serum bactericidal activity (hSBA) ≥1:8 for serogroups A, C, W and Y and hSBA geometric mean titres (GMTs). Local and systemic reactions and all adverse events (AEs) were recorded for 7 days, and medically attended AEs for 1 month post-vaccination. Seroresponse rates after MenACWY-CRM vaccination at Day 29 for the serogroups A, C, W, and Y were 83%, 93%, 50%, and 65%, respectively. At Day 29 the percentages of subjects with hSBA ≥1:8 against all four serogroups A, C, W and Y were: 83%, 96%, 96% and 82%, respectively. GMTs against all serogroups rose by ≥7-fold from baseline to Day 29. The vaccine was well tolerated. A single dose of MenACWY-CRM demonstrated a robust immune response, and an acceptable safety profile in Taiwanese children and adolescents. Copyright © 2014 Elsevier Ltd. All rights reserved.

A randomized study to assess the immunogenicity, antibody persistence and safety of a tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine in children aged 2–10 years

PubMed Central

Vesikari, Timo; Forstén, Aino; Boutriau, Dominique; Bianco, Véronique; Van der Wielen, Marie; Miller, Jacqueline M.

2012-01-01

Incidence of meningococcal diseases is high in children, and effective vaccines are needed for this age group. In this phase II, open, controlled study, 309 children aged 2–10 y from Finland were randomized (3:1) into two parallel groups to receive one dose of meningococcal ACWY-tetanus toxoid conjugate vaccine (ACWY-TT group; n = 231) or a licensed meningococcal ACWY polysaccharide vaccine (Men-PS group; n = 78). Serum bactericidal activity using rabbit complement (rSBA) was evaluated up to three years post-vaccination. Exploratory comparisons suggested that rSBA vaccine response rates and geometric mean titers (GMTs) for each serogroup at one month post-vaccination and rSBA GMTs for serogroups A, W-135 and Y up to three years post-vaccination were higher in the ACWY-TT compared with Men-PS group, but did not detect any difference between groups in terms of rSBA-MenC GMTs at three years post-vaccination; this is explained by the higher proportion of children from the Men-PS group who were excluded because they were re-vaccinated with a monovalent meningococcal serogroup C vaccine due to loss of protective antibody levels against this serogroup. Although there was a higher incidence of local reactogenicity in the ACWY-TT group, general and unsolicited symptoms reporting rates were comparable in both groups. This study showed that MenACWY-TT was immunogenic with a clinically acceptable safety profile in children aged 2–10 y. MenACWY-TT induced higher functional antibody titers for all serogroups, which persisted longer for serogroups A, W-135 and Y, than the MenACWY polysaccharide vaccine. This study has been registered at www.clinicaltrials.gov NCT00427908. PMID:23032168

Mimicking the cell membrane: bio-inspired simultaneous functions with monovalent anion selectivity and antifouling properties of anion exchange membrane

PubMed Central

Zhao, Yan; Liu, Huimin; Tang, Kaini; Jin, Yali; Pan, Jiefeng; der Bruggen, Bart Van; Shen, Jiangnan; Gao, Congjie

2016-01-01

A new bio-inspired method was applied in this study to simultaneously improve the monovalent anion selectivity and antifouling properties of anion exchange membranes (AEMs). Three-layer architecture was developed by deposition of polydopamine (PDA) and electro-deposition of N-O-sulfonic acid benzyl chitosan (NSBC). The innermost and outermost layers were PDA with different deposition time. The middle layer was prepared by NSBC. Fourier transform infrared spectroscopy and scanning electron microscopy confirmed that PDA and NSBC were successfully modified on the surfaces of AEMs. The contact angle of the membranes indicated an improved hydrophilicity of the modified membranes. A series of electrodialysis experiments in which Cl−/SO42− separation was studied, demonstrating the monovalent anion selectivity of the samples. The Cl−/SO42− permselectivity of the modified membranes can reach up to 2.20, higher than that of the commercial membrane (only 0.78) during 90 minutes in electrodialysis (ED). The increase value of the resistance of the membranes was also measured to evaluate the antifouling properties. Sodium dodecyl benzene sulfonate (SDBS) was used as the fouling material in the ED process and the membrane area resistance of modified membrane increase value of was only 0.08 Ωcm2 30 minutes later. PMID:27853255

Mimicking the cell membrane: bio-inspired simultaneous functions with monovalent anion selectivity and antifouling properties of anion exchange membrane.

PubMed

Zhao, Yan; Liu, Huimin; Tang, Kaini; Jin, Yali; Pan, Jiefeng; der Bruggen, Bart Van; Shen, Jiangnan; Gao, Congjie

2016-11-17

A new bio-inspired method was applied in this study to simultaneously improve the monovalent anion selectivity and antifouling properties of anion exchange membranes (AEMs). Three-layer architecture was developed by deposition of polydopamine (PDA) and electro-deposition of N-O-sulfonic acid benzyl chitosan (NSBC). The innermost and outermost layers were PDA with different deposition time. The middle layer was prepared by NSBC. Fourier transform infrared spectroscopy and scanning electron microscopy confirmed that PDA and NSBC were successfully modified on the surfaces of AEMs. The contact angle of the membranes indicated an improved hydrophilicity of the modified membranes. A series of electrodialysis experiments in which Cl - /SO 4 2- separation was studied, demonstrating the monovalent anion selectivity of the samples. The Cl - /SO 4 2- permselectivity of the modified membranes can reach up to 2.20, higher than that of the commercial membrane (only 0.78) during 90 minutes in electrodialysis (ED). The increase value of the resistance of the membranes was also measured to evaluate the antifouling properties. Sodium dodecyl benzene sulfonate (SDBS) was used as the fouling material in the ED process and the membrane area resistance of modified membrane increase value of was only 0.08 Ωcm 2 30 minutes later.

Mimicking the cell membrane: bio-inspired simultaneous functions with monovalent anion selectivity and antifouling properties of anion exchange membrane

NASA Astrophysics Data System (ADS)

Zhao, Yan; Liu, Huimin; Tang, Kaini; Jin, Yali; Pan, Jiefeng; der Bruggen, Bart Van; Shen, Jiangnan; Gao, Congjie

2016-11-01

A new bio-inspired method was applied in this study to simultaneously improve the monovalent anion selectivity and antifouling properties of anion exchange membranes (AEMs). Three-layer architecture was developed by deposition of polydopamine (PDA) and electro-deposition of N-O-sulfonic acid benzyl chitosan (NSBC). The innermost and outermost layers were PDA with different deposition time. The middle layer was prepared by NSBC. Fourier transform infrared spectroscopy and scanning electron microscopy confirmed that PDA and NSBC were successfully modified on the surfaces of AEMs. The contact angle of the membranes indicated an improved hydrophilicity of the modified membranes. A series of electrodialysis experiments in which Cl-/SO42- separation was studied, demonstrating the monovalent anion selectivity of the samples. The Cl-/SO42- permselectivity of the modified membranes can reach up to 2.20, higher than that of the commercial membrane (only 0.78) during 90 minutes in electrodialysis (ED). The increase value of the resistance of the membranes was also measured to evaluate the antifouling properties. Sodium dodecyl benzene sulfonate (SDBS) was used as the fouling material in the ED process and the membrane area resistance of modified membrane increase value of was only 0.08 Ωcm2 30 minutes later.

A preclinical study comparing approaches for augmenting the immunogenicity of a heptavalent KLH-conjugate vaccine against epithelial cancers.

PubMed

Ragupathi, Govind; Koide, Fusataka; Sathyan, Natarajan; Kagan, Ella; Spassova, Maria; Bornmann, William; Gregor, Polly; Reis, Celso A; Clausen, Henrik; Danishefsky, Samuel J; Livingston, Philip O

2003-10-01

Previously using a series of monovalent vaccines, we demonstrated that the optimal method for inducing an antibody response against cancer cell-surface antigens is covalent conjugation of the antigens to keyhole limpet hemocyanin (KLH) and the use of a saponin adjuvant. We have prepared a heptavalent-KLH conjugate vaccine containing the seven epithelial cancer antigens GM2, Globo H, Lewis(y), TF(c), Tn(c), STn(c), and glycosylated MUC1. In preparation for testing this vaccine in the clinic, we tested the impact on antibody induction of administering the individual conjugates plus adjuvant compared with a mixture of the seven conjugates plus adjuvant, and of several variables thought to augment immunogenicity. These include approaches for decreasing suppressor cell activity or increasing helper T-lymphocyte activity (low dose cyclophosphamide or anti-CTLA-4 MAb), different saponin adjuvants at various doses (QS-21 and GPI-0100), and different methods of formulation (lyophilization and use of polysorbate 80). We find that: (1). Immunization with the heptavalent-KLH conjugate plus GPI-0100 vaccine induces antibodies against the seven antigens of comparable titer to those induced by the individual-KLH conjugate vaccines, high titers of antibodies against Tn (median ELISA titer IgM/IgG 320/10240), STn (640/5120), TF (320/10240), MUC1 (80/20480), and globo H (640/40); while lower titers of antibodies against Lewis(y)()(160/0) and only occasional antibodies against GM2 are induced. (2). These antibodies reacted with the purified synthetic antigens by ELISA, and with naturally expressed antigens on the cancer cell surface by FACS. (3). None of the approaches for further altering the suppressor cell/helper T-cell balance nor changes to the standard formulation by lyophilization or use of polysorbate 80 had any impact on antibody titers. (4). An optimal dose of saponin adjuvant, QS-21 (50 microg) or GPI-0100 (1000 microg), is required for optimal antibody titers. This

Factors influencing the efficacy of two injections of a pandemic 2009 influenza A (H1N1) nonadjuvanted vaccine in systemic lupus erythematosus.

PubMed

Mathian, A; Devilliers, H; Krivine, A; Costedoat-Chalumeau, N; Haroche, J; Huong, D Boutin-Le Thi; Wechsler, B; Hervier, B; Miyara, M; Morel, N; Le Corre, N; Arnaud, L; Piette, J C; Musset, L; Autran, B; Rozenberg, F; Amoura, Z

2011-11-01

To assess the factors influencing the efficacy of 2 injections of a pandemic 2009 influenza A (H1N1) vaccine in patients with systemic lupus erythematosus (SLE). We conducted a single-center, observational prospective study of 111 patients who were vaccinated with a monovalent, inactivated, nonadjuvanted, split-virus vaccine during December 2009 and January 2010 and received a second dose of vaccine 3 weeks later. The antibody response was evaluated using the hemagglutination inhibition assay according to the guidelines recommended for the pandemic vaccine, consisting of 3 immunogenicity criteria (i.e., a seroprotection rate of 70%, a seroconversion rate of 40%, and a geometric mean ratio [GMR] of 2.5). The 3 immunogenicity criteria were met on day 42 (seroprotection rate 80.0% [95% confidence interval (95% CI) 72.5-87.5%], seroconversion rate 71.8% [95% CI 63.4-80.2%], and GMR 10.3 [95% CI 2.9-14.2]), while only 2 criteria were met on day 21 (seroprotection rate 66.7% [95% CI 57.9-75.4%], seroconversion rate 60.4% [95% CI 51.3-69.5%], and GMR 8.5 [95% CI 3.2-12.0]). The vaccine was well tolerated. Disease activity, assessed by the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index, the British Isles Lupus Assessment Group score, and the Systemic Lupus Activity Questionnaire, did not increase. In the multivariate analysis, vaccination failure was significantly associated with immunosuppressive treatment or a lymphocyte count of ≤ 1.0 × 10⁹/liter. The second injection significantly increased the immunogenicity in these subgroups, but not high enough to fulfill the seroprotection criterion in patients receiving immunosuppressive treatment. Our findings indicate that the efficacy of the vaccine was impaired in patients who were receiving immunosuppressive drugs or who had lymphopenia. A second injection increased vaccine immunogenicity without reaching all efficacy criteria for a pandemic vaccine in patients

Overcoming Antigenic Diversity by Enhancing the Immunogenicity of Conserved Epitopes on the Malaria Vaccine Candidate Apical Membrane Antigen-1

PubMed Central

Dutta, Sheetij; Dlugosz, Lisa S.; Drew, Damien R.; Ge, Xiopeng; Ababacar, Diouf; Rovira, Yazmin I.; Moch, J. Kathleen; Shi, Meng; Long, Carole A.; Foley, Michael; Beeson, James G.; Anders, Robin F.; Miura, Kazutoyo; Haynes, J. David; Batchelor, Adrian H.

2013-01-01

Malaria vaccine candidate Apical Membrane Antigen-1 (AMA1) induces protection, but only against parasite strains that are closely related to the vaccine. Overcoming the AMA1 diversity problem will require an understanding of the structural basis of cross-strain invasion inhibition. A vaccine containing four diverse allelic proteins 3D7, FVO, HB3 and W2mef (AMA1 Quadvax or QV) elicited polyclonal rabbit antibodies that similarly inhibited the invasion of four vaccine and 22 non-vaccine strains of P. falciparum. Comparing polyclonal anti-QV with antibodies against a strain-specific, monovalent, 3D7 AMA1 vaccine revealed that QV induced higher levels of broadly inhibitory antibodies which were associated with increased conserved face and domain-3 responses and reduced domain-2 response. Inhibitory monoclonal antibodies (mAb) raised against the QV reacted with a novel cross-reactive epitope at the rim of the hydrophobic trough on domain-1; this epitope mapped to the conserved face of AMA1 and it encompassed the 1e-loop. MAbs binding to the 1e-loop region (1B10, 4E8 and 4E11) were ∼10-fold more potent than previously characterized AMA1-inhibitory mAbs and a mode of action of these 1e-loop mAbs was the inhibition of AMA1 binding to its ligand RON2. Unlike the epitope of a previously characterized 3D7-specific mAb, 1F9, the 1e-loop inhibitory epitope was partially conserved across strains. Another novel mAb, 1E10, which bound to domain-3, was broadly inhibitory and it blocked the proteolytic processing of AMA1. By itself mAb 1E10 was weakly inhibitory but it synergized with a previously characterized, strain-transcending mAb, 4G2, which binds close to the hydrophobic trough on the conserved face and inhibits RON2 binding to AMA1. Novel inhibition susceptible regions and epitopes, identified here, can form the basis for improving the antigenic breadth and inhibitory response of AMA1 vaccines. Vaccination with a few diverse antigenic proteins could provide universal

Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya.

PubMed

Ogutu, Bernhards R; Apollo, Odika J; McKinney, Denise; Okoth, Willis; Siangla, Joram; Dubovsky, Filip; Tucker, Kathryn; Waitumbi, John N; Diggs, Carter; Wittes, Janet; Malkin, Elissa; Leach, Amanda; Soisson, Lorraine A; Milman, Jessica B; Otieno, Lucas; Holland, Carolyn A; Polhemus, Mark; Remich, Shon A; Ockenhouse, Christian F; Cohen, Joe; Ballou, W Ripley; Martin, Samuel K; Angov, Evelina; Stewart, V Ann; Lyon, Jeffrey A; Heppner, D Gray; Withers, Mark R

2009-01-01

The antigen, falciparum malaria protein 1 (FMP1), represents the 42-kDa C-terminal fragment of merozoite surface protein-1 (MSP-1) of the 3D7 clone of P. falciparum. Formulated with AS02 (a proprietary Adjuvant System), it constitutes the FMP1/AS02 candidate malaria vaccine. We evaluated this vaccine's safety, immunogenicity, and efficacy in African children. A randomised, double-blind, Phase IIb, comparator-controlled trial.The trial was conducted in 13 field stations of one mile radii within Kombewa Division, Nyanza Province, Western Kenya, an area of holoendemic transmission of P. falciparum. We enrolled 400 children aged 12-47 months in general good health.Children were randomised in a 1ratio1 fashion to receive either FMP1/AS02 (50 microg) or Rabipur(R) rabies vaccine. Vaccinations were administered on a 0, 1, and 2 month schedule. The primary study endpoint was time to first clinical episode of P. falciparum malaria (temperature >/=37.5 degrees C with asexual parasitaemia of >/=50,000 parasites/microL of blood) occurring between 14 days and six months after a third dose. Case detection was both active and passive. Safety and immunogenicity were evaluated for eight months after first immunisations; vaccine efficacy (VE) was measured over a six-month period following third vaccinations. 374 of 400 children received all three doses and completed six months of follow-up. FMP1/AS02 had a good safety profile and was well-tolerated but more reactogenic than the comparator. Geometric mean anti-MSP-1(42) antibody concentrations increased from1.3 microg/mL to 27.3 microg/mL in the FMP1/AS02 recipients, but were unchanged in controls. 97 children in the FMP1/AS02 group and 98 controls had a primary endpoint episode. Overall VE was 5.1% (95% CI: -26% to +28%; p-value = 0.7). FMP1/AS02 is not a promising candidate for further development as a monovalent malaria vaccine. Future MSP-1(42) vaccine development should focus on other formulations and antigen constructs

Blood Stage Malaria Vaccine Eliciting High Antigen-Specific Antibody Concentrations Confers No Protection to Young Children in Western Kenya

PubMed Central

Ogutu, Bernhards R.; Apollo, Odika J.; McKinney, Denise; Okoth, Willis; Siangla, Joram; Dubovsky, Filip; Tucker, Kathryn; Waitumbi, John N.; Diggs, Carter; Wittes, Janet; Malkin, Elissa; Leach, Amanda; Soisson, Lorraine A.; Milman, Jessica B.; Otieno, Lucas; Holland, Carolyn A.; Polhemus, Mark; Remich, Shon A.; Ockenhouse, Christian F.; Cohen, Joe; Ballou, W. Ripley; Martin, Samuel K.; Angov, Evelina; Stewart, V. Ann; Lyon, Jeffrey A.; Heppner, D. Gray; Withers, Mark R.

2009-01-01

Objective The antigen, falciparum malaria protein 1 (FMP1), represents the 42-kDa C-terminal fragment of merozoite surface protein-1 (MSP-1) of the 3D7 clone of P. falciparum. Formulated with AS02 (a proprietary Adjuvant System), it constitutes the FMP1/AS02 candidate malaria vaccine. We evaluated this vaccine's safety, immunogenicity, and efficacy in African children. Methods A randomised, double-blind, Phase IIb, comparator-controlled trial.The trial was conducted in 13 field stations of one mile radii within Kombewa Division, Nyanza Province, Western Kenya, an area of holoendemic transmission of P. falciparum. We enrolled 400 children aged 12–47 months in general good health.Children were randomised in a 1∶1 fashion to receive either FMP1/AS02 (50 µg) or Rabipur® rabies vaccine. Vaccinations were administered on a 0, 1, and 2 month schedule. The primary study endpoint was time to first clinical episode of P. falciparum malaria (temperature ≥37.5°C with asexual parasitaemia of ≥50,000 parasites/µL of blood) occurring between 14 days and six months after a third dose. Case detection was both active and passive. Safety and immunogenicity were evaluated for eight months after first immunisations; vaccine efficacy (VE) was measured over a six-month period following third vaccinations. Results 374 of 400 children received all three doses and completed six months of follow-up. FMP1/AS02 had a good safety profile and was well-tolerated but more reactogenic than the comparator. Geometric mean anti-MSP-142 antibody concentrations increased from1.3 µg/mL to 27.3 µg/mL in the FMP1/AS02 recipients, but were unchanged in controls. 97 children in the FMP1/AS02 group and 98 controls had a primary endpoint episode. Overall VE was 5.1% (95% CI: −26% to +28%; p-value = 0.7). Conclusions FMP1/AS02 is not a promising candidate for further development as a monovalent malaria vaccine. Future MSP-142 vaccine development should focus on other formulations and antigen

Virologic Monitoring of Poliovirus Type 2 after Oral Poliovirus Vaccine Type 2 Withdrawal in April 2016 - Worldwide, 2016-2017.

PubMed

Diop, Ousmane M; Asghar, Humayun; Gavrilin, Evgeniy; Moeletsi, Nicksy Gumede; Benito, Gloria Rey; Paladin, Fem; Pattamadilok, Sirima; Zhang, Yan; Goel, Ajay; Quddus, Arshad

2017-05-26

The Global Polio Eradication Initiative (GPEI) has made substantial progress since its launch in 1988; only 37 wild poliovirus type 1 (WPV1) cases were detected in 2016, the lowest annual count ever. Wild poliovirus type 3 has not been detected since November 2012, and wild poliovirus type 2 was officially declared eradicated in September 2015. This success is attributable to the wide use of live oral poliovirus vaccines (OPVs). Since 2001, numerous outbreaks were caused by the emergence of genetically divergent vaccine-derived polioviruses (VDPVs) whose genetic drift from the parental OPV strains indicates prolonged replication or circulation (1). In 2015, circulating VDPV type 2 (cVDPV2) outbreaks were detected in five countries worldwide (Nigeria, Pakistan, Guinea, Burma, and South Sudan), and VDPV2 single events were reported in 22 countries. These events prompted the GPEI to withdraw the type 2 component (Sabin2) of trivalent OPV (tOPV) in a globally coordinated, synchronized manner in April 2016 (2,3), at which time all OPV-using countries switched to using bivalent OPV (bOPV), containing Sabin types 1 and 3. This report details for the first time the virologic tracking of elimination of a live vaccine that has been withdrawn from routine and mass immunization systems worldwide (3). To secure elimination, further monitoring is warranted to detect any use of tOPV or monovalent OPV type 2 (mOPV2).

Robust real-time cell analysis method for determining viral infectious titers during development of a viral vaccine production process.

PubMed

Charretier, Cédric; Saulnier, Aure; Benair, Loïc; Armanet, Corinne; Bassard, Isabelle; Daulon, Sandra; Bernigaud, Bertrand; Rodrigues de Sousa, Emanuel; Gonthier, Clémence; Zorn, Edouard; Vetter, Emmanuelle; Saintpierre, Claire; Riou, Patrice; Gaillac, David

2018-02-01

The classical cell-culture methods, such as cell culture infectious dose 50% (CCID 50 ) assays, are time-consuming, end-point assays currently used during the development of a viral vaccine production process to measure viral infectious titers. However, they are not suitable for handling the large number of tests required for high-throughput and large-scale screening analyses. Impedance-based bio-sensing techniques used in real-time cell analysis (RTCA) to assess cell layer biological status in vitro, provide real-time data. In this proof-of-concept study, we assessed the correlation between the results from CCID 50 and RTCA assays and compared time and costs using monovalent and tetravalent chimeric yellow fever dengue (CYD) vaccine strains. For the RTCA assay, Vero cells were infected with the CYD sample and real-time impedance was recorded, using the dimensionless cell index (CI). The CI peaked just after infection and decreased as the viral cytopathic effect occurred in a dose-dependent manner. The time to the median CI (CIT med ) was correlated with viral titers determined by CCID 50 over a range of about 4-5log 10 CCID 50 /ml. This in-house RTCA virus-titration assay was shown to be a robust method for determining real-time viral infectious titers, and could be an alternative to the classical CCID 50 assay during the development of viral vaccine production process. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Potential of mean force between identical charged nanoparticles immersed in a size-asymmetric monovalent electrolyte

NASA Astrophysics Data System (ADS)

Guerrero-García, Guillermo Iván; González-Mozuelos, Pedro; de la Cruz, Mónica Olvera

2011-10-01

In a previous theoretical and simulation study [G. I. Guerrero-García, E. González-Tovar, and M. Olvera de la Cruz, Soft Matter 6, 2056 (2010)], it has been shown that an asymmetric charge neutralization and electrostatic screening depending on the charge polarity of a single nanoparticle occurs in the presence of a size-asymmetric monovalent electrolyte. This effect should also impact the effective potential between two macroions suspended in such a solution. Thus, in this work we study the mean force and the potential of mean force between two identical charged nanoparticles immersed in a size-asymmetric monovalent electrolyte, showing that these results go beyond the standard description provided by the well-known Derjaguin-Landau-Verwey-Overbeek theory. To include consistently the ion-size effects, molecular dynamics (MD) simulations and liquid theory calculations are performed at the McMillan-Mayer level of description in which the solvent is taken into account implicitly as a background continuum with the suitable dielectric constant. Long-range electrostatic interactions are handled properly in the simulations via the well established Ewald sums method and the pre-averaged Ewald sums approach, originally proposed for homogeneous ionic fluids. An asymmetric behavior with respect to the colloidal charge polarity is found for the effective interactions between two identical nanoparticles. In particular, short-range attractions are observed between two equally charged nanoparticles, even though our model does not include specific interactions; these attractions are greatly enhanced for anionic nanoparticles immersed in standard electrolytes where cations are smaller than anions. Practical implications of some of the presented results are also briefly discussed. A good accord between the standard Ewald method and the pre-averaged Ewald approach is attained, despite the fact that the ionic system studied here is certainly inhomogeneous. In general, good

Immunogenicity and Safety of Varying Dosages of a Monovalent 2009 H1N1 Influenza Vaccine Given With and Without AS03 Adjuvant System in Healthy Adults and Older Persons

PubMed Central

Jackson, Lisa A.; Chen, Wilbur H.; Stapleton, Jack T.; Dekker, Cornelia L.; Wald, Anna; Brady, Rebecca C.; Edupuganti, Srilatha; Winokur, Patricia; Mulligan, Mark J.; Keyserling, Harry L.; Kotloff, Karen L.; Rouphael, Nadine; Noah, Diana L.; Hill, Heather; Wolff, Mark C.

2012-01-01

Background. Adjuvanted vaccines have the potential to improve influenza pandemic response. AS03 adjuvant has been shown to enhance the immune response to inactivated influenza vaccines. Methods. This trial was designed to evaluate the immunogenicity and safety of an inactivated 2009 H1N1 influenza vaccine at varying dosages of hemagglutinin with and without extemporaneously mixed AS03 adjuvant system in adults ≥18 years of age. Adults were randomized to receive 2 doses of 1 of 5 vaccine formulations (3.75 µg, 7.5 µg, or 15 µg with AS03 or 7.5 µg or 15 µg without adjuvant). Results. The study population included 544 persons <65 years of age and 245 persons ≥65 years of age. Local adverse events tended to be more frequent in the adjuvanted vaccine groups, but severe reactions were uncommon. In both age groups, hemagglutination inhibition antibody geometric mean titers after dose one were higher in the adjuvanted groups, compared with the 15 µg unadjuvanted group, and this difference was statistically significant for the comparison of the 15 µg adjuvanted group with the 15 µg unadjuvanted group. Conclusions. AS03 adjuvant system improves the immune response to inactivated 2009 H1N1 influenza vaccine in both younger and older adults and is generally well tolerated. ClinicalTrials.gov NCT00963157 PMID:22782949

Immunity to hepatitis A and B persists for at least 15 years after immunisation of adolescents with a combined hepatitis A and B vaccine.

PubMed

Beran, Jiri; Van Der Meeren, Olivier; Leyssen, Maarten; D'silva, Priya

2016-05-23

The exact duration of antibody persistence to hepatitis A and B and the need for booster dosing following primary immunisation remains undefined. A long-term study was designed to follow antibody persistence and immune memory on an annual basis for up to 15 years following vaccination during adolescence. Subjects received a combined hepatitis A and B vaccine (Twinrix™, GSK Vaccines, Belgium) at 12-15 years of age, either as 2-dose of the adult formulation or 3-dose of the paediatric formulation. Blood samples were taken every year thereafter to assess antibody persistence and immune memory to hepatitis A and B. Antibodies to hepatitis A virus (anti-HAV) and hepatitis B surface antigen (anti-HBs) were measured at Years 11-15. At Year 15 immune memory was further assessed by measuring the anamnestic response to a challenge dose of the monovalent vaccine, which was administered to subjects whose antibody concentrations fell below the pre-defined cut-offs (anti-HAV: <15mIU/mL; anti-HBs: <10mIU/mL). 209 subjects returned for follow-up at Year 15 of whom 162 were included in the long-term according-to-protocol immunogenicity cohort. All subjects remained seropositive for anti-HAV antibodies, while 81.1% and 81.8% still had anti-HBs antibodies ≥10mIU/mL in the 2- and 3-dose groups, respectively. Following hepatitis B vaccine challenge dose administration to 19 subjects, all except one in the 3-dose group, mounted a robust anamnestic response. The safety and reactogenicity profile of the hepatitis B challenge was consistent with previous experience. Immunity to hepatitis A and B persists 15 years after adolescent vaccination with a combined hepatitis A and B vaccine. Highly effective anamnestic response indicates that a booster dose should not be required for 15 years after primary vaccination. http://www.clinicaltrials.govNCT00875485. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

A novel antibody engineering strategy for making monovalent bispecific heterodimeric IgG antibodies by electrostatic steering mechanism.

PubMed

Liu, Zhi; Leng, Esther C; Gunasekaran, Kannan; Pentony, Martin; Shen, Min; Howard, Monique; Stoops, Janelle; Manchulenko, Kathy; Razinkov, Vladimir; Liu, Hua; Fanslow, William; Hu, Zhonghua; Sun, Nancy; Hasegawa, Haruki; Clark, Rutilio; Foltz, Ian N; Yan, Wei

2015-03-20

Producing pure and well behaved bispecific antibodies (bsAbs) on a large scale for preclinical and clinical testing is a challenging task. Here, we describe a new strategy for making monovalent bispecific heterodimeric IgG antibodies in mammalian cells. We applied an electrostatic steering mechanism to engineer antibody light chain-heavy chain (LC-HC) interface residues in such a way that each LC strongly favors its cognate HC when two different HCs and two different LCs are co-expressed in the same cell to assemble a functional bispecific antibody. We produced heterodimeric IgGs from transiently and stably transfected mammalian cells. The engineered heterodimeric IgG molecules maintain the overall IgG structure with correct LC-HC pairings, bind to two different antigens with comparable affinity when compared with their parental antibodies, and retain the functionality of parental antibodies in biological assays. In addition, the bispecific heterodimeric IgG derived from anti-HER2 and anti-EGF receptor (EGFR) antibody was shown to induce a higher level of receptor internalization than the combination of two parental antibodies. Mouse xenograft BxPC-3, Panc-1, and Calu-3 human tumor models showed that the heterodimeric IgGs strongly inhibited tumor growth. The described approach can be used to generate tools from two pre-existent antibodies and explore the potential of bispecific antibodies. The asymmetrically engineered Fc variants for antibody-dependent cellular cytotoxicity enhancement could be embedded in monovalent bispecific heterodimeric IgG to make best-in-class therapeutic antibodies. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Safety and immunogenicity of an MF59-adjuvanted A/H1N1 pandemic influenza vaccine in children from three to seventeen years of age.

PubMed

Knuf, Markus; Leroux-Roels, Geert; Rümke, Hans C; Abarca, Katia; Rivera, Luis; Lattanzi, Maria; Pedotti, Paola; Arora, Ashwani; Kieninger-Baum, Dorothee; Della Cioppa, Giovanni

2015-01-01

This study was designed to identify the optimal dose of an MF59-adjuvanted, monovalent, A/H1N1 influenza vaccine in healthy paediatric subjects. Subjects aged 3-8 years (n=194) and 9-17 years (n=160) were randomized to receive two primary doses of A/H1N1 vaccine containing either 3.75 μg antigen with half a standard dose of MF59 adjuvant, 7.5 μg antigen with a full dose of MF59, or (children 3-8 years only), a non-adjuvanted 15 μg formulation. A booster dose of MF59-adjuvanted seasonal influenza vaccine including homologous A/H1N1 strain was given one year after priming. Immunogenicity was assessed by haemagglutination inhibition (HI) and microneutralization assays. Vaccine safety was assessed throughout the study (up to 18 months). A single priming dose of either MF59-adjuvanted formulation was sufficient to meet the European licensure criteria for pandemic influenza vaccines (HI titres ≥1:40>70%; seroconversion>40%; and GMR>2.5). Two non-adjuvanted vaccine doses were required to meet the same licensure criteria. After first and second doses, percentage of subjects with HI titres ≥1:40 were between 97% and 100% in the adjuvanted vaccine groups compared with 68% and 91% in the non-adjuvanted group, respectively. Postvaccination seroconversion rates ranged from 91% to 98% in adjuvanted groups and were 68% (first dose) and 98% (second dose) in the non-adjuvanted group. HI titres ≥1:330 after primary doses were achieved in 69% to 90% in adjuvanted groups compared with 41% in the non-adjuvanted group. Long-term antibody persistence after priming and a robust antibody response to booster immunization were observed in all vaccination groups. All A/H1N1 vaccine formulations were generally well tolerated. No vaccine-related serious adverse events occurred, and no subjects were withdrawn from the study due to an adverse event. An MF59-adjuvanted influenza vaccine containing 3.75 μg of A/H1N1 antigen was well tolerated and sufficiently immunogenic to meet all the

Immunogenicity and safety of a fully liquid aluminum phosphate adjuvanted Haemophilus influenzae type b PRP-CRM197-conjugate vaccine in healthy Japanese children: A phase III, randomized, observer-blind, multicenter, parallel-group study.

PubMed

Togashi, Takehiro; Mitsuya, Nodoka; Kogawara, Osamu; Sumino, Shuji; Takanami, Yohei; Sugizaki, Kayoko

2016-08-31

Broad use of monovalent Haemophilus influenzae type b (Hib) conjugate vaccines based on the capsular polysaccharide polyribosyl-ribitol phosphate (PRP), has significantly reduced invasive Hib disease burden in children worldwide, particularly in children aged <1year. In Japan, PRP conjugated to tetanus toxoid (PRP-T) vaccine has been widely used since the initiation of public funding programs followed by a routine vaccination designation in 2013. We compared the immunogenicity and safety of PRP conjugated to a non-toxic diphtheria toxin mutant (PRP-CRM197) vaccine with the PRP-T vaccine when administered subcutaneously to healthy Japanese children in a phase III study. Additionally, we evaluated the immunogenicity and safety profiles of a diphtheria-tetanus acellular pertussis (DTaP) combination vaccine when concomitantly administered with either PRP-CRM197 or PRP-T vaccines. The primary endpoint was the "long-term seroprotection rate", defined as the group proportion with anti-PRP antibody titers ⩾1.0μg/mL, after the primary series. Long-term seroprotection rates were 99.3% in the PRP-CRM197 group and 95.6% in the PRP-T group. The intergroup difference (PRP-CRM197 group - PRP-T group) was 3.7% (95% confidence interval: 0.099-7.336), demonstrating that PRP-CRM197 vaccine was non-inferior to PRP-T vaccine (p<0.0001). Furthermore, the "short-term seroprotection rate" (anti-PRP antibody titer ⩾0.15μg/mL) before booster vaccination was higher in the PRP-CRM197 group than in PRP-T. Concomitant administration of PRP-CRM197 vaccine with DTaP vaccine showed no differences in terms of immunogenicity compared with concomitant vaccination with PRP-T vaccine and DTaP vaccine. Although CRM197 vaccine had higher local reactogenicity, overall, both Hib vaccines had acceptable safety and tolerability profiles. The immunogenicity of PRP-CRM197 vaccine administered subcutaneously as a three-dose primary series in children followed by a booster vaccination 1year after the

Association Between Pandemic Influenza A(H1N1) Vaccination in Pregnancy and Early Childhood Morbidity in Offspring.

PubMed

Hviid, Anders; Svanström, Henrik; Mølgaard-Nielsen, Ditte; Lambach, Philipp