| Summary: | Oral vaccines have consistently underperformed in the low-income countries where they are needed most. This has formed a potent obstacle to several public health initiatives that rely on such vaccines, including the polio eradication endgame. This thesis examines the hypothesis that the composition of the intestinal microbiota – including both pathogenic and commensal microbes – contributes to the impaired performance of oral vaccines in low-income countries. Based on a systematic review and meta-analysis, we observed a decrease in the likelihood of responding to oral poliovirus vaccine (OPV) among infants with concurrent enterovirus infections or diarrhoea. We subsequently tested for multiple bacterial, viral, and eukaryotic enteropathogens and sequenced the 16S rRNA gene (to characterise the total bacterial microbiota) among infants living in a semi-urban slum in south India who had received Rotarix (an oral rotavirus vaccine) and OPV at 6 and 10 weeks of age. We did not observe significant differences in bacterial microbiota composition according to seroconversion status for either vaccine. However, the presence of bacterial pathogens was positively correlated with Rotarix response and negatively correlated with OPV response, suggesting that distinct mechanisms may impact these vaccines. The same methods were applied to samples from 6–11 month-old infants who had received OPV after a 3-day course of azithromycin or placebo. Once again, the association between bacterial microbiota composition and vaccine outcome was modest, although microbiota diversity was negatively correlated with vaccine poliovirus replication. As expected, viral pathogens were associated with a decrease in OPV immunogenicity. Moreover, recently acquired viral infections appeared to inhibit OPV response to a greater extent than persistent viruses. Together, these findings have substantiated the inhibitory effect of viral pathogens on OPV response, while implicating bacterial pathogens as a potential risk factor for OPV failure in early infancy. Risk factors for rotavirus vaccine failure remain elusive.
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