Combined vaccination with live oral polio vaccine and the bovine rotavirus RIT 4237 strain

A clinical trial was carried out in 3-month-old infants to assess whether concomitant oral administration of live polio and rotavirus RIT 4237 vaccines would reduce their immunogenicities as a result of mutual interference. One hundred and sixty breast-fed male and female infants were randomly allocated to four study groups to receive in a blind fashion the poliovirus vaccine, the RIT 4237 vaccine, a combination of both vaccines or a placebo preparation. Antibody titres were measured in pre- and postvaccination serum samples by the ELISA test and the neutralizing antibody test (NT) for rotavirus and by the NT for polioviruses types 1 and 3. The percentage of subjects with immune responses to rotavirus in the placebo group was low, indicating the absence of wild rotavirus circulation in the population. Antibody responses against polio types 1 and 3 were found in about a quarter of the infants receiving a placebo because the study was performed during a polio vaccination campaign when vaccine viruses are known to circulate. The results showed that 73% of seroconversion was obtained when RIT 4237 was administered alone and that the responses to polioviruses types 1 and 3 were good. However, simultaneous administration of polio and RIT 4237 vaccines caused a significant reduction of the antibody response to rotavirus but not to polioviruses types 1 and 3.     

Immunogenicity of four doses of oral poliovirus vaccine when co-administered with the human neonatal rotavirus vaccine (RV3-BB)

BackgroundThe RV3-BB human neonatal rotavirus vaccine was developed to provide protection from severe rotavirus disease from birth. The aim of this study was to investigate the potential for mutual interference in the immunogenicity of oral polio vaccine (OPV) and RV3-BB.MethodsA randomized, placebo-controlled trial involving 1649 participants was conducted from January 2013 to July 2016 in Central Java and Yogyakarta, Indonesia. Participants received three doses of oral RV3-BB, with the first dose given at 0–5 days (neonatal schedule) or ~8 weeks (infant schedule), or placebo. Two sub-studies assessed the immunogenicity of RV3-BB when co-administered with either trivalent OPV (OPV group, n = 282) or inactivated polio vaccine (IPV group, n = 333). Serum samples were tested for antibodies to poliovirus strains 1, 2 and 3 by neutralization assays following doses 1 and 4 of OPV.ResultsSero-protective rates to poliovirus type 1, 2 or 3 were similar (range 0.96–1.00) after four doses of OPV co-administered with RV3-BB compared with placebo. Serum IgA responses to RV3-BB were similar when co-administered with either OPV or IPV (difference in proportions OPV vs IPV: sIgA responses; neonatal schedule 0.01, 95% CI −0.12 to 0.14; p = 0.847; infant schedule −0.10, 95% CI −0.21 to −0.001; p = 0.046: sIgA GMT ratio: neonatal schedule 1.23, 95% CI 0.71–2.14, p = 0.463 or infant schedule 1.20, 95% CI 0.74–1.96, p = 0.448).ConclusionsThe co-administration of OPV with RV3-BB rotavirus vaccine in a birth dose strategy did not reduce the immunogenicity of either vaccine. These findings support the use of a neonatal RV3-BB vaccine where either OPV or IPV is used in the routine vaccination schedule.     

Co-administration study in South African infants of a live-attenuated oral human rotavirus vaccine (RIX4414) and poliovirus vaccines

A double-blind, placebo-controlled phase II trial (e-Track 444563-014/NCT00346892) was conducted in South Africa to evaluate the co-administration of RIX4414 (live-attenuated human G1P[8] rotavirus vaccine) and oral poliovirus vaccine (OPV) administered simultaneously. Healthy infants (n=450) were randomized into three groups (RIX4414+OPV, RIX4414+IPV or Placebo+OPV) to receive two oral doses of RIX4414/placebo with OPV or IPV using two vaccination schedules (6-10 weeks and 10-14 weeks). Serum anti-rotavirus IgA antibodies (ELISA) and neutralizing antibodies (micro-neutralization assay) to poliovirus serotypes 1, 2 and 3 were measured. Co-administration of RIX4414 with OPV did not result in a decrease in the high sero-protection rates against poliovirus serotypes 1, 2 and 3 detected after the third OPV dose (98-100%). The anti-rotavirus IgA antibody sero-conversion rates were higher for the 10-14 weeks schedule (55-61%) compared to the 6-10 weeks schedule (36-43%). Solicited symptoms were reported at similar rates between RIX4414 and placebo groups and no serious adverse events related to RIX4414 were reported. This study provided evidence that RIX4414 can be co-administered with routine EPI immunizations including OPV and that two doses of RIX4414 were well tolerated and immunogenic in South African infants.     

The effect of probiotics and zinc supplementation on the immune response to oral rotavirus vaccine: A randomized,factorial design,placebo-controlled study among Indian infants

BackgroundStrategies are needed to improve oral rotavirus vaccine (RV), which provides suboptimal protection in developing countries. Probiotics and zinc supplementation could improve RV immunogenicity by altering the intestinal microbiota and immune function.MethodsInfants 5 weeks old living in urban Vellore, India were enrolled in a randomized, double-blind, placebo-controlled trial with a 4-arm factorial design to assess the effects of daily zinc (5 mg), probiotic (10¹⁰ Lactobacillus rhamnosus GG) or placebo on the immunogenicity of two doses of RV (Rotarix®, GlaxoSmithKline Biologicals) given at 6 and 10 weeks of age. Infants were eligible for participation if healthy, available for the study duration and without prior receipt of RV or oral poliovirus vaccine other than the birth dose. The primary outcome was seroconversion to rotavirus at 14 weeks of age based on detection of VP6-specific IgA at ≥20 U/ml in previously seronegative infants or a fourfold rise in concentration.ResultsThe study took place during July 2012 to February 2013. 620 infants were randomized equally between study arms and 551 (88.9%) completed per protocol. Seroconversion was recorded in 54/137 (39.4%), 42/136 (30.9%), 40/143 (28.0%), and 37/135 (27.4%) infants receiving (1) probiotic and zinc, (2) probiotic and placebo, (3) placebo and zinc, (4) two placebos. Seroconversion showed a modest improvement among infants receiving probiotic (difference between groups 1, 2 and 3, 4 was 7.5% (97.5% Confidence Interval (CI): −1.4%, 16.2%), p = 0.066) but not zinc (difference between groups 1, 3 and 2, 4 was 4.4% (97.5% CI: −4.4%, 13.2%), p = 0.272). 16 serious adverse events were recorded, none related to study interventions.ConclusionsZinc or probiotic supplementation did not significantly improve the low immunogenicity of rotavirus vaccine given to infants in a poor urban community in India. A modest effect of combined supplementation deserves further investigation.Trial registrationThe trial was registered in India (CTRI/2012/05/002677).     

Impact of rotavirus vaccine on all-cause diarrhea and rotavirus hospitalizations in Madagascar

BackgroundRotavirus vaccine was introduced into the Extended Program on Immunization in Madagascar in May 2014. We analyzed trends in prevalence of all cause diarrhea and rotavirus hospitalization in children <5 years of age before and after vaccine introduction and assessed trend of circulating rotavirus genotypes at Centre Hospitalier Universitaire Mère Enfant Tsaralalàna (CHU MET).MethodsFrom January 2010 to December 2016, we reviewed the admission logbook to observe the rate of hospitalization caused by gastroenteritis among 19619 children <5 years of age admitted at the hospital. In June 2013–December 2016, active rotavirus surveillance was also conducted at CHUMET with support from WHO. Rotavirus antigen was detected by EIA from stool specimen of children who are eligible for rotavirus gastroenteritis surveillance at sentinel site laboratory and rotavirus positive specimens were further genotyped at Regional Reference Laboratory by RT-PCR.ResultsDiarrhea hospitalizations decreased after rotavirus vaccine introduction. The median proportion of annual hospitalizations due to diarrhea was 26% (range: 31–22%) before vaccine introduction; the proportion was 25% the year of vaccine introduction, 17% in 2015 and 16% in 2016. Rotavirus positivity paralleled patterns observed in diarrhea. Before vaccine introduction, 56% of stool specimens tested positive for rotavirus; the percent positive was 13% in 2015, 12% in 2016. Diverse genotypes were detected in the pre-vaccine period; the most common were G3P[8] (n = 53; 66%), G2P[4] (n = 12; 15%), and G1P[8] (n = 11; 14%). 6 distinct genotypes were found in 2015; the most common genotype was G2P[4] (n = 10; 67%), the remaining, 5, G12[P8], G3[P8], G1G3[P4], G3G12[P4][P8] and G1G3[NT] had one positive specimen each.ConclusionsFollowing rotavirus vaccine introduction all-cause diarrhea and rotavirus-specific hospitalizations declined dramatically. The most common genotypes detected in the pre-vaccine period were G3P[8] and G2P[4] in 2015, the post vaccine period.     

Polio endgame: Lessons for the global rotavirus vaccination program

Poliovirus and rotavirus share notable similarities. Although rotavirus is not amenable to eradication because of animal reservoirs, live, attenuated oral vaccines have been the bedrock of both prevention and control programs, providing intestinal and humoral immunity. Both programs have also encountered safety concerns and suboptimal immune responses to oral vaccines in low-income settings that have been challenges, prompting the search for alternative solutions. In this paper, we review the progress made by polio prevention and eradication efforts over the past six decades. Specifically, we discuss the roles of the oral polio vaccine (OPV) and the inactivated polio vaccine (IPV) in achieving polio eradication, and explore potential application of these lessons to rotavirus. Recent scientific evidence has confirmed that a combined schedule of IPV and OPV adds synergistic value that may give the polio eradication effort the tools to end all poliovirus circulation worldwide. For rotavirus, oral vaccine is the only currently licensed and recommended vaccine for use in all children worldwide, providing heterologous protection against a broad range of strains. However, parenteral rotavirus vaccines are in the pre-clinical and clinical trial stage and insight from polio provides strong justification for accelerating the development of these vaccines. While challenges for parenteral rotavirus vaccines will need to be addressed, such as achieving protection against a broad range of strains, the principle of combined use of oral and parenteral rotavirus vaccines may provide the necessary humoral and intestinal immunity necessary to close the efficacy gaps between developing and developed countries, therefore controlling rotavirus worldwide. This strategy may also potentially reduce risk of intussusception.     

Evaluation of cost-effectiveness of live oral pentavalent reassortant rotavirus vaccine introduction in Ghana

Background

Globally, rotavirus gastroenteritis is the most common identifiable cause of severe diarrhea in children under 5. Recently introduced rotavirus vaccines from Merck &; Co. and GlaxoSmithKline have the potential to save hundreds of thousands of lives. Efficacy results in Ghana suggest Merck &; Co.’s live oral pentavalent rotavirus vaccine (RotaTeq^®) prevents 65.0% of severe gastroenteritis due to rotavirus infection in children under 5. The announcement by Merck and GSK to make their rotavirus vaccines available for developing nations at reduced prices provides Ghana with the opportunity to introduce rotavirus vaccines into the national immunization program after investigation of the medical, economic and political implications.

Methods

We estimated the average costs of treating children with diarrhea in the Ashanti region of Ghana as inpatients and outpatients. Using these results, data from rotavirus surveillance studies, and recent rotavirus vaccine efficacy evaluation, we estimated the cost-effectiveness of introducing RotaTeq in Ghana.

Results

Based on our prospective calculations, we estimated an average inpatient and outpatient costs of $233.97 and $17.09, respectively, for treating childhood diarrhea. Using the 2003 birth cohort, RotaTeq introduction could save 1554 lives and avert 93,109 disability-adjusted life-years (DALYs) annually. At a market price of $5 per dose, introducing RotaTeq would have a base-case cost of $62.26 per DALY averted, at a market price of $3.50 per dose, a base-case cost of $39.59 per DALY averted and at market cost of $1 per dose, a base-case cost of $1.81 per DALY averted. All three values are below the 2009 Ghana per capita GDP. Thus, RotaTeq introduction into Ghana will be very cost-effective. Sensitivity analyses suggest these results are robust.

Conclusions

RotaTeq vaccination for children under five in Ghana would be a highly cost-effective public health intervention. Ghanaian health officials should seek GAVI funding and evaluate how to maximize RotaTeq access.     

Predictors of oral rotavirus vaccine immunogenicity in rural Zimbabwean infants

BackgroundOral rotavirus vaccines (RVV) have poor immunogenicity in low-income countries, for reasons that remain unclear. This study identified the determinants of RVV immunogenicity among infants in rural Zimbabwe.MethodsAnti-rotavirus IgA titres were measured among a sub-group of infants enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial (NCT01824940). SHINE was a cluster-randomized trial of improved infant and young child feeding, and improved water, sanitation and hygiene (WASH) in two rural Zimbabwean districts. Infants received RVV as part of the national immunisation programme. Among HIV-unexposed infants in the non-WASH trial arms, we evaluated associations between potential risk factors (vaccine schedule and dose, maternal and infant nutritional status, infant diarrhoea, and household environment) and RVV immunogenicity (seroconversion, seropositivity and geometric mean titres) using multivariable regression.ResultsAmong 219 infants with seroconversion data, 43 (20%) successfully seroconverted and 176 (80%) failed to seroconvert to RVV. Seroconversion was positively associated with a higher length-for-age Z-score (LAZ) around the time of vaccination (adjusted RR 1.27 (95% CI 1.04, 1.55), P = 0.021), and negatively associated with concurrent OPV and RVV administration (adjusted RR 0.36 (0.19, 0.71), P = 0.003). Among 472 infants with post-vaccination titres, a higher LAZ score was associated with increased seropositivity (aRR 1.21 (95% CI 1.06, 1.38), P = 0.004), and higher birthweight was associated with increased IgA titres (0.45 (95%CI 0.18, 1.09) U/mL greater per 100 g gain in birthweight; P = 0.001).ConclusionsInfant ponderal and linear growth were positively associated with RVV immunogenicity, while concurrent administration of OPV was negatively associated with RVV immunogenicity. Together, these findings suggest that improving foetal growth and separating RVV and OPV administration are plausible approaches to increasing RVV immunogenicity.     

Uptake of oral rotavirus vaccine and timeliness of routine immunization in Brazil's National Immunization Program

Introduction

In March, 2006, oral rotavirus vaccine was added to Brazil's infant immunization schedule with recommended upper age limits for initiating (by age 14 weeks) and completing (by age 24 weeks) the two-dose series to minimize age-specific risk of intussusception following rotavirus vaccination. Several years after introduction, estimated coverage with rotavirus vaccine (83%) was lower compared to coverage for other recommended childhood immunizations (≥94%).

Methods

We analyzed data from Brazil's national immunization program on uptake of oral rotavirus vaccine by geographic region and compared administrative coverage estimates for first and second doses of oral rotavirus vaccine (Rota1 and Rota2) with first and second doses of diphtheria-tetanus-pertussis-Haemophilus influenzae type b vaccine (DTP-Hib1 and DTP-Hib2). For 27 Brazilian cities, we compared differences between estimated rotavirus and DTP-Hib coverage in 2010 with delayed receipt of DTP-Hib vaccine among a cohort of children surveyed before rotavirus introduction.

Results

In 2010, infant vaccination coverage was 99.0% for DTP-Hib1 versus 95.2% for Rota1 (3.8% difference), and 98.4% for DTP-Hib2 versus 83.0% for Rota2 (15.4% difference), with substantial regional variation. Differences between DTP-Hib and rotavirus vaccination coverage in Brazilian cities correlated with delay in DTP-Hib vaccination among children surveyed. Age restrictions for initiating and completing the rotavirus vaccination series likely contributed to lower coverage with rotavirus vaccine in Brazil.

Conclusion

To maximize benefits of rotavirus vaccination, strategies are needed to improve timeliness of routine immunizations; monitoring rotavirus vaccine uptake and intussusception risk is needed to guide further recommendations for rotavirus vaccination.     

Impact of routine rotavirus vaccination on all-cause and rotavirus hospitalizations during the first four years following vaccine introduction in Rwanda

BackgroundRwanda introduced pentavalent rotavirus vaccine into its national immunization program in 2012. To determine the long-term impact of rotavirus vaccine on disease burden in a high burden setting, we examined trends in rotavirus and all-cause diarrhea hospitalizations in the first four years following rotavirus vaccine introduction.MethodsWe used data from an active surveillance system, from a review of pediatric ward registries, and from the Health Management Information System to describe trends in rotavirus and all-cause diarrhea hospitalizations from January 2009 through December 2016. Percent reductions were calculated to compare the number of all-cause and rotavirus diarrhea hospitalizations pre- and post-rotavirus vaccine introduction.ResultsThe proportion of diarrhea hospitalizations due to rotavirus declined by 25–44% among all children <5 years of age during 2013–2015 with a shift in rotavirus hospitalizations to older age groups. The proportion of total hospitalizations due to diarrhea among children <5 years of age decreased from 19% pre-vaccine introduction to 12–13% post-vaccine introduction. In the national hospital discharge data, substantial decreases were observed in all-cause diarrhea hospitalizations among children <5 years of age in 2013 and 2014 but these gains lessened in 2015–2016.DiscussionContinued monitoring of long-term trends in all-cause diarrhea and rotavirus hospitalizations is important to ensure that the impact of the vaccination program is sustained over time and to better understand the changing age dynamics of diarrhea and rotavirus hospitalizations in the post-vaccine introduction era.     

Effects of rotavirus NSP4 protein on the immune response and protection of the SR69A-VP8* nanoparticle rotavirus vaccine

Rotavirus causes severe diarrhea and dehydration in young children. Even with the implementation of the current live vaccines, rotavirus infections still cause significant mortality and morbidity, indicating a need for new rotavirus vaccines with improved efficacy. To this end, we have developed an S_R69A-VP8*/S₆₀-VP8* nanoparticle rotavirus vaccine candidate that will be delivered parenterally with Alum adjuvant. In this study, as parts of our further development of this nanoparticle vaccine, we evaluated 1) roles of rotavirus nonstructural protein 4 (NSP4) that is the rotavirus enterotoxin, a possible vaccine target, and an immune stimulator, and 2) effects of CpG adjuvant that is a toll-like receptor 9 (TLR9) ligand and agonist on the immune response and protection of our S_R69A-VP8*/S₆₀-VP8* nanoparticle vaccine. The resulted vaccine candidates were examined for their IgG responses in mice. In addition, the resulted mouse sera were assessed for i) blocking titers against interactions of rotavirus VP8* proteins with their glycan ligands, ii) neutralization titers against rotavirus replication in cell culture, and iii) passive protection against rotavirus challenge with diarrhea in suckling mice. Our data showed that the Alum adjuvant appeared to work better with the S_R69A-VP8*/S₆₀-VP8* nanoparticles than the CpG adjuvant, while an addition of the NSP4 antigen to the S_R69A-VP8*/S₆₀-VP8* vaccine may not help to further increase the immune response and protection of the resulted vaccine.     

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

BackgroundMonovalent 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.MethodsBefore 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.ResultsAt 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.ConclusionRotavirus 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 rates among infants were detected at hospitals across the country. Overall, the data support that rotavirus vaccine has been successfully introduced and is effective in Tanzanian children.     

2015 - 2017年湖北省口服轮状病毒减毒活疫苗安全性监测分析

目的 分析湖北省2015 - 2017年口服轮状病毒减毒活疫苗（oral live attenuated rotavirus vaccine,ORV）疑似预防接种异常反应（adverse Events following Immunization, AEFI）的发生特征,评价ORV预防接种的安全性。方法 通过中国AEFI信息管理系统,收集湖北省2015 - 2017年接种ORV发生的AEFI个案数据,采用描述流行病学方法进行分析。结果 湖北省2015 - 2017年接种ORV发生AEFI 223例（33.82/10万剂）,未报告肠套叠等严重AEFI病例,其中一般反应、异常反应分别为197例（29.88/10万剂）和20例（3.03/10万剂次）。一般反应主要表现为发热（25.63/10万剂）和胃肠道反应（9.71/10万剂）,异常反应主要为过敏性皮疹（2.12/10万剂）和荨麻疹（0.91/10万剂）。发病年龄集中在2岁以下,其中51.57%发生在＜1岁,35.43%发生在1~2岁;各剂次中,首剂接种后发生186例（83.41%）、第2剂30例（13.45%）、第3剂7例(3.14%);66.37%的病例发生在接种当天;17.04%发生在接种后1 d;4.48%发生在接种后2 d,0.45%发生在接种后3 d及以上;联合接种时92.04%为一般反应;98.21%病例治愈或好转,无后遗症和死亡病例报告。结论 口服轮状病毒减毒活疫苗具有良好的安全性。     

Phase I trial of RV3-BB rotavirus vaccine: A human neonatal rotavirus vaccine

Introduction

RV3 is a human neonatal rotavirus strain (G3P[6]) that has been associated with asymptomatic neonatal infection and replicates well in the infant gut. RV3-BB rotavirus vaccine has been developed as a rotavirus vaccine candidate for administration at birth.

Methods

A single-centre, double-blind, randomised placebo-controlled Phase I study evaluated the safety and tolerability of a single oral dose of the second generation RV3-BB rotavirus vaccine (8.3 × 10⁶ FFU/mL) in 20 adults, 20 children and 20 infants (10 vaccine and 10 placebo per age cohort). Vaccine take was defined as seroconversion (a 3-fold increase in serum anti-rotavirus IgA or serum neutralising antibody (SNA) from baseline at day 28 post-dose) or evidence of RV3-BB viral replication in the faeces by RT-PCR analysis 3–6 days post-vaccination. RV3-BB presence was confirmed by sequence analysis.

Results

The RV3-BB vaccine was well tolerated in all participants, with no pattern of adverse events shown to be associated with the study vaccine. In the infant cohort, vaccine take was demonstrated in 8/9 infants following a single dose of vaccine compared with 2/7 placebo recipients. In the infant vaccine group, 5/9 infants exhibited either IgA or SNA seroconversion and 7/9 infants had evidence of RV3-BB replication on days 3–6, compared with 2/7 infants who seroconverted and 0/10 infants with evidence of replication in the placebo group. Two infants in the placebo group had serological evidence of a rotavirus infection within the 28-day study period: one demonstrated an IgA and the other an SNA response, with wild-type virus replication detected in another infant.

Conclusion

A single dose of RV3-BB rotavirus vaccine was well tolerated in adults, children and infants. Most infants (8/9) who received RV3-BB demonstrated vaccine take following a single dose. These data support progression of RV3-BB to Phase II immunogenicity and efficacy trials.     

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

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

Potential for a booster dose of rotavirus vaccine to further reduce diarrhea mortality

Concern has grown that children vaccinated against rotavirus in developing countries may be vulnerable to rotavirus diarrhea in the second year of life due to waning immunity. Adding a booster dose of rotavirus vaccine at 9 or 12 months of age with measles vaccine has been suggested as a strategy to address this. We evaluated the hypothetical potential benefits of a booster dose on reduction of rotavirus mortality. The projected number of deaths averted were calculated using national level full series vaccination coverage, estimated national rotavirus deaths by week of age, and VE at <12 months of age and ≥12 months of age derived from the published literature. We assumed three functional forms of waning based on the VE estimates: stepwise, linear, and logarithmic. We modeled three potential boosting scenarios: (a) reduced VE waning in the second year of life by 50%, (b) reestablished second year of life VE to the levels in the first year of life, and (c) boosted first year VE by 50% of the difference between VE in the first and second years. To express uncertainty resulting from the parameters, each of the nine models were run 1000 times using a random sample of input values. Across all WHO regions, with the stepwise models we estimated a median of 9800 (95%CI: 9400, 10,200), 19,600 (95%CI: 18,800, 20,400), and 29,400 (95%CI: 28,200, 30,700) additional rotavirus deaths averted in the reduced VE waning, reestablished VE, and boosted VE scenarios. These estimates were highly sensitive to the assumed functional form of waning with approximately 65–80% fewer deaths averted if immunity waned in a linear or logarithmic fashion compared to the stepwise model. While these projections will benefit from improved input data points, our results inform consideration of booster doses of rotavirus vaccine.     

Shedding of oral pentavalent bovine-human reassortant rotavirus vaccine indicates high uptake rate of vaccine and prominence of G-type G1

BackgroundLive oral pentavalent bovine-human reassortant rotavirus (RV) vaccine, RotaTeq®, contains bovine rotaviruses reassorted with human G-types G1, G2, G3 and G4, and P-type P[8]. Shedding of RotaTeq® vaccine, as studied by RT-PCR, has been shown to be more common than initially reported, and may include formation of vaccine-derived double-reassortant G1P[8] RVs. We studied the extent and duration of RotaTeq® vaccine virus shedding, genotypes shed, and clinical symptoms associated with shedding.Material and methodsWe enrolled a total of 301 infants who received RotaTeq® vaccine according to Finnish schedule at 2, 3 and 5 months of age. Stool samples were collected 5–10 days after the first and 0–7 days before the third dose of the vaccine. Additional stool samples 6 and 12 weeks later were collected if the second stool sample was positive. All stools were studied with RT-PCR for RV VP7, VP4 and VP6. Parents filled a symptom diary for a week after each vaccine dose.ResultsWe found that 93% of the vaccinees shed vaccine related viral particles in one sample taken 5–10 days after the first dose, indicating that stool shedding is very common and may be regarded as a marker of successful vaccination. Genotype G1 was the predominant genotype in shedding, often in association with P[8], and the only genotype found in long-term shedding. Also G4 was commonly detected whereas other vaccine G-types and bovine-type P[5] were not.ConclusionsShedding of RotaTeq® vaccine-derived viruses is a sign for successful vaccination. Intense shedding of G1 with or without P[8]reflects effective multiplication and may be an important factor in the induction of protective immunity. Shedding of G1 containing vaccine viruses may be prolonged up to 8 months of age. These results suggest that the pentavalent vaccine functions largely like a monovalent G1 vaccine.Eudra-CT: 2014-004252-60.     

Rapid impact of rotavirus vaccine introduction to the National Immunization Plan in Southern Israel: Comparison between 2 distinct populations

BackgroundRotavirus vaccines were licensed in Israel in 2007, and in 2011 the pentavalent-vaccine (RV5) was introduced into the Israeli National Immunization plan.AimTo determine the effect of rotavirus-vaccines on the incidence of hospital visits due to rotavirus gastroenteritis (RVGE) and all-cause diarrhea in Jewish and Bedouin children <5 year residing in southern Israel.MethodsWe conducted a population-based, prospective, observational study. Data from 2006 through 2013 were analyzed. Our hospital is the only medical center in the region, enabling age-specific incidences calculation.ResultsIn the pre-vaccine period, the overall RVGE hospital visits rates per 1000 in children <12, 12–23 and 24–59 m were 16.1, 18.6 and 1.4 in Jewish children, respectively. The respective rates in Bedouin children were 26.4, 12.5 and 0.7 (P < 0.001 for <12 m).Hospitalization rates were higher among Bedouin than among Jewish children (60.0% vs. 39.7%, P < 0.001). Vaccine uptake was faster in the Jewish vs. the Bedouin population.In the year following RV5 introduction, RVGE hospital visits rates declined by 82%, 70% (P < 0.001 both) and 36% (P = 0.092) in Jewish children <12, 12–23 and 24–59 m, respectively. In Bedouin children, the respective RVGE rates declined by 70% (P < 0.001), 21% (P = ns) and 14% (P = ns).Throughout the study, RVGE rates declined significantly in children <12, and 12–23 m by 80% and 88% in Jewish children, respectively, and by 62 and 75% in Bedouin children, respectively (P < 0.001 for all declines). In children 24–59 m, RVGE rates declined by 46% (P = 0.025) in Jewish children, but no reduction was observed in Bedouin children. The dynamics of all-cause diarrhea rates were similar to that of RVGE.ConclusionsSignificant reductions of RVGE rates were observed, following Rota-vaccine introduction in southern Israel in both Jewish and Bedouin children. However, the impact was faster and more profound in Jewish children, probably related to higher vaccine uptake and possibly to lifestyle differences.     

Immunogenicity and safety of sabin-strain based inactivated poliovirus vaccine replacing salk-strain based inactivated poliovirus vaccine: An innovative application of different strain-IPVs replacement

BackgroundA domestic Sabin strain-based inactivated poliovirus vaccine (Sabin IPV) was approved by China Food and Drug Administration in 2017 as a replacement for the Salk strain-based inactivated poliovirus vaccine (Salk IPV) that has been in use in China for over 10 years. The present post-marketing trial was implemented in China to assess the immunogenicity and safety of replacing the Salk IPV with the Sabin IPV in the last two immunizations of the standard three-dose schedule.MethodsWe conducted a randomized, controlled clinical trial with two groups that received three doses of IPVs at the age of 2, 3, and 4 months: the Salk-Sabin-Sabin group and the Salk-Salk-Salk group. Blood samples were collected before vaccination and 30–40 days after the third dose of vaccination. The seroconversion rates and antibody geometric mean titers (GMTs) were calculated and analyzed to evaluate immunogenicity. The safety of both immunization schedules was also monitored and analyzed.ResultsOf 360 recruited healthy infants, all three IPV doses were administered and blood collection was completed in 330 infants. All participants (100%) in both groups were seropositive for all three poliovirus types after the last vaccination. There were significant differences between the two groups (P < 0.001) in the GMTs for antibodies against poliovirus types 1 and 2, but no significant difference was observed for antibodies against type 3 (P = 0.009). A non-inferiority t-test showed that the post-immunization GMTs for all three types in the Salk-Sabin-Sabin group were not inferior to those in the Salk-Salk-Salk group (P < 0.001). Safety assessment indicated that there was no significant difference in the incidence of all adverse events between the two groups (P = 0.806).ConclusionsThe Salk-Sabin-Sabin IPV immunization schedule is not inferior to the Salk-Salk-Salk IPV schedule in terms of both immunogenicity and safety.Clinical trial number: NCT04051736.