Effect of substituting IPV for tOPV on immunity to poliovirus in Bangladeshi infants: An open-label randomized controlled trial

AbstractBackgroundThe Polio Endgame strategy includes phased withdrawal of oral poliovirus vaccines (OPV) coordinated with introduction of inactivated poliovirus vaccine (IPV) to ensure population immunity. The impact of IPV introduction into a primary OPV series of immunizations in a developing country is uncertain.MethodsBetween May 2011 and November 2012, we enrolled 700 Bangladeshi infant-mother dyads from Dhaka slums into an open-label randomized controlled trial to test whether substituting an injected IPV dose for the standard Expanded Program on Immunization (EPI) fourth tOPV dose at infant age 39 weeks would reduce fecal shedding and enhance systemic immunity. The primary endpoint was mucosal immunity to poliovirus at age one year, measured by fecal excretion of any Sabin virus at five time points up to 25 days post-52 week tOPV challenge, analyzed by the intention to treat principle.FindingsWe randomized 350 families to the tOPV and IPV vaccination arms. Neither study arm resulted in superior intestinal protection at 52 weeks measured by the prevalence of infants shedding any of three poliovirus serotypes, but the IPV dose induced significantly higher seroprevalence and seroconversion rates. This result was identical for poliovirus detection by cell culture or RT-qPCR. The non-significant estimated culture-based shedding risk difference was −3% favoring IPV, and the two vaccination schedules were inferred to be equivalent within a 95% confidence margin of −10% to +4%. Results for shedding analyses stratified by poliovirus type were similar.ConclusionsNeither of the vaccination regimens is superior to the other in enhancing intestinal immunity as measured by poliovirus shedding at 52 weeks of age and the IPV regimen provides similar intestinal immunity to the four tOPV series, although the IPV regimen strongly enhances humoral immunity. The IPV-modified regimen may be considered for vaccination programs without loss of intestinal protection

Neonatal vitamin A supplementation and immune responses to oral polio vaccine in Zimbabwean infants.

Background: Micronutrient deficiencies may contribute to reduced oral vaccine immunogenicity in developing countries. We hypothesised that neonatal vitamin A supplementation (NVAS) would improve oral vaccine responses. Methods: We performed a cross-sectional study of infants recruited at birth to the Zimbabwe Vitamin A for Mothers and Babies (ZVITAMBO) trial, a randomised controlled trial of single, high-dose NVAS vs placebo conducted in Zimbabwe between 1997-2001. We measured poliovirus-specific IgA to type 1-3 polio strains by semiquantitative capture ELISA in cryopreserved plasma samples collected at 6 months of age. Results: A total of 181 infants fulfilled inclusion criteria, of whom 80 were randomised to NVAS and 101 to placebo. There were no significant differences in baseline characteristics between groups. At 6 months of age, median (IQR) vaccine titres for infants randomised to NVAS vs placebo were 932 (421-3001) vs 1774 (711-5431) for Sabin-1 (p=0.04); 1361 (705-3402) vs 2309 (1081-4283) for Sabin-2 (p=0.15); and 1584 (796-4216) vs 2260 (996-5723) for Sabin-3 (p=0.14), respectively. After adjusting for breast feeding status, birth weight, season and infant sex in a linear regression model, there was only weak evidence of difference in log mean titres between vitamin A and placebo groups for Sabin-1 (p=0.08) and no evidence of difference in log mean titres for Sabin-2 and Sabin-3. Conclusions: NVAS did not augment oral polio vaccine responses in Zimbabwean infants. Further research is required to understand the impact of NVAS on responses to other oral vaccines. The trial is registered with clinicaltrials.gov identifier: NCT00198718.The ZVITAMBO trial was supported by the Canadian International Development Agency (CIDA) (R/C Project 690/M3688), United States Agency for International Development (USAID) (cooperative agreement number HRN-A-00-97-00015-00 between Johns Hopkins University and the Office of Health and Nutrition – USAID) and a grant from the Bill and Melinda Gates Foundation, Seattle WA. Additional funding was received from the SARA Project, which is operated by the Academy for Educational Development, Washington DC and is funded by USAID’s Bureau for Africa, Office of Sustainable Development under the terms of Contract AOT-C-00-99-00237-00, the Rockefeller Foundation (NY, NY) and BASF (Ludwigshafen, Germany). This current study was supported by the Sanitation & Hygiene Applied Research for Equity (SHARE) Consortium and Barts Charity (grant number 212563 to JAC). JAC (Grant 201293/Z/16/Z) and AJP (Grant 108065/Z/15/Z) are supported by the Wellcome Trust

Immune responses to oral poliovirus vaccine in HIV-exposed uninfected Zimbabwean infants.

It remains uncertain whether HIV-exposed uninfected (HEU) infants have impaired responses to oral vaccines. We performed a cross-sectional study of 6-month-old infants recruited at birth to the ZVITAMBO trial in Zimbabwe between 1997-2001, before introduction of prevention of mother-to-child transmission interventions. We measured poliovirus-specific IgA to type 1-3 polio strains by semi-quantitative capture ELISA in cryopreserved serum samples collected from 85 HEU and 101 HIV-unexposed infants at 6 months of age, one month after their last immunisation with trivalent OPV. Almost all infants were breastfed, with the majority in both groups mixed breastfed (70.6% HEU versus 71.3% HIV-unexposed). Median (IQR) vaccine titers for HEU and HIV-unexposed infants were 1592 (618-4896) vs. 1774 (711-5431) for Sabin 1 (P = 0.46); 1895 (810-4398) vs. 2308 (1081-4283) for Sabin 2 (P = 0.52); and 1798 (774-4192) vs. 2260 (996-5723) for Sabin 3 (P = 0.18). There were no significant differences in vaccine titers between HEU and HIV-unexposed infants, suggesting that vertical HIV exposure does not impact oral poliovirus vaccine immunogenicity.ZVITAMBO trial was supported by the Canadian International Development Agency (CIDA) (R/C Project 690/M3688), United States Agency for International Development (USAID) (cooperative agreement number HRN-A-00-97-00015-00 between Johns Hopkins University and the Office of Health and Nutrition – USAID) and a grant from the Bill and Melinda Gates Foundation, Seattle WA. Additional funding was received from the SARA Project, which is operated by the Academy for Educational Development, Washington DC and is funded by USAID’s Bureau for Africa, Office of Sustainable Development under the terms of Contract AOT-C-00-99-00237-00, the Rockefeller Foundation (NY, NY) and BASF (Ludwigshafen, Germany). This current study was supported by the Sanitation & Hygiene Applied Research for Equity (SHARE) Consortium and Barts Charity (grant number 212563 to JAC). JAC (Grant 201293/Z/16/Z) and AJP (Grant 108065/Z/15/Z) are supported by the Wellcome Trust

Predictors of oral rotavirus vaccine immunogenicity in rural Zimbabwean infants.

BACKGROUND: Oral 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. METHODS: Anti-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. RESULTS: Among 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). CONCLUSIONS: Infant 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

Enteropathogens were not associated with rotavirus vaccine immunogenicity in a cluster-randomized trial of improved water, sanitation and hygiene in rural Zimbabwe

This is the accepted manuscript of an article to be published in Pediatric Infectious Disease Journal."This is a non-final version of an article published in final form in The Pediatric Infectious Disease Journal: December 2019 - Volume 38 - Issue 12 - p 1242–1248 doi: 10.1097/INF.0000000000002485.

Environmental Enteropathy, Oral Vaccine Failure and Growth Faltering in Infants in Bangladesh

Background: Environmental enteropathy (EE) is a subclinical enteric condition found in low-income countries that is characterized by intestinal inflammation, reduced intestinal absorption, and gut barrier dysfunction. We aimed to assess if EE impairs the success of oral polio and rotavirus vaccines in infants in Bangladesh. Methods: We conducted a prospective observational study of 700 infants from an urban slum of Dhaka, Bangladesh from May 2011 to November 2014. Infants were enrolled in the first week of life and followed to age one year through biweekly home visits with EPI vaccines administered and growth monitored. EE was operationally defied as enteric inflammation measured by any one of the fecal biomarkers reg1B, alpha-1-antitrypsin, MPO, calprotectin, or neopterin. Oral polio vaccine success was evaluated by immunogenicity, and rotavirus vaccine response was evaluated by immunogenicity and protection from disease. This study is registered with ClinicalTrials.gov, number NCT01375647. Findings: EE was present in greater than 80% of infants by 12 weeks of age. Oral poliovirus and rotavirus vaccines failed in 20.2% and 68.5% of the infants respectively, and 28.6% were malnourished (HAZ < −2) at one year of age. In contrast, 0%, 9.0%, 7.9% and 3.8% of infants lacked protective levels of antibody from tetanus, Haemophilus influenzae type b, diphtheria and measles vaccines respectively. EE was negatively associated with oral polio and rotavirus response but not parenteral vaccine immunogenicity. Biomarkers of systemic inflammation and measures of maternal health were additionally predictive of both oral vaccine failure and malnutrition. The selected biomarkers from multivariable analysis accounted for 46.3% variation in delta HAZ. 24% of Rotarix® IgA positive individuals can be attributed to the selected biomarkers. Interpretation: EE as well as systemic inflammation and poor maternal health were associated with oral but not parenteral vaccine underperformance and risk for future growth faltering. These results offer a potential explanation for the burden of these problems in low-income problems, allow early identification of infants at risk, and suggest pathways for intervention. Funding: The Bill and Melinda Gates Foundation (OPP1017093)

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

AbstractBackgroundOral 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

Associations between biomarkers of environmental enteric dysfunction and oral rotavirus vaccine immunogenicity in rural Zimbabwean infants

Background: Oral rotavirus vaccines (RVV) are poorly immunogenic in low-income countries. Environmental enteric dysfunction (EED) resulting from poor water, sanitation and hygiene (WASH) may contribute. We therefore tested associations between EED and RVV immunogenicity, and evaluated the effect of improved WASH on EED. Methods: We measured nine biomarkers of EED among Zimbabwean infants born to mothers enrolled in a cluster-randomised 2 × 2 factorial trial of improved WASH and improved feeding between November 2012 and March 2015 (NCT01824940). We used multivariable regression to determine associations between EED biomarkers and RVV seroconversion, seropositivity and geometric mean titer. Log-binomial regression was used to evaluate the effect of improved WASH on EED. Findings: Among 303 infants with EED biomarkers and immunogenicity data, plasma intestinal fatty-acid binding protein and stool myeloperoxidase were positively associated with RVV seroconversion; adjusted RR 1.63 (95%CI 1.04, 2.57) and 1.29 (95%CI 1.01, 1.65), respectively. There were no other associations between RVV immunogenicity and either individual biomarkers or EED domains (intestinal permeability, intestinal damage, intestinal inflammation and microbial translocation). EED biomarkers did not differ between randomised WASH and non-WASH groups. Interpretation: We found no evidence that EED was associated with poor RVV immunogenicity. Contrary to our hypothesis, there was weak evidence that EED was associated with increased seroconversion. EED biomarkers were not affected by a package of household-level WASH interventions

In a randomized trial, the live attenuated tetravalent dengue vaccine TV003 is well-tolerated and highly immunogenic in subjects with flavivirus exposure prior to vaccination - Fig 3

<p>Mean peak neutralizing antibody titers (PRNT₅₀) for DENV-1(<b>A</b>), DENV-2 (<b>B</b>), DENV-3 (<b>C</b>), and DENV-4 (<b>D)</b> up to 90 days following one dose of TV003 in flavivirus-naïve subjects (n = 58, from ref. [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005584#pntd.0005584.ref019" target="_blank">19</a>]), all flavivirus-experienced (all FV+) subjects (n = 38) and by two subgroups–those with yellow fever virus (YF+, n = 31) or dengue virus exposure (Dengue, n = 11). All data represent mean titers (GMT) ± 95% confidence interval. Statistical significance of the difference between FV-naïve group was assessed by one-way ANOVA with Sidak correction for multiple comparisons. *, <i>P</i> < 0.05, **, <i>P</i> < 0.01, *** <i>P</i>, < 0.001.</p