Association of gut microbiota and regulatory T cells with vaccine immunogenicity in HIV-exposed uninfected and HIV-unexposed infants: a longitudinal cohort study

Background Responses to vaccines reflect the functionality of the immune system. We measured BCG, tetanus and measles vaccine responses in HIV-exposed uninfected (HEU) and HIV-unexposed (HUU) infants to identify factors associated with HEU immunologic defects. Methods We assessed cell-mediated immunity (CMI) by FluoroSpot, antibodies by ELISA, regulatory and immunologic checkpoint inhibitor-expressing T cells (Tregs/Ticis) by flow cytometry, and gut microbiota by 16S rRNA gene sequencing. CMI and antibody responses were the primary outcome measures. Associations with Tregs/Ticis and gut microbiome parameters were identified using the hurdle model, Spearman correlations and enrichment analyses. Findings Among 123 HEUs and 117 HUUs, HEUs tended to have lower BCG-CMI than HUUs without reaching statistical significance (p = 0.07) and similar tetanus-CMI, measles-CMI, and measles-antibodies. Multiple Treg and Tici subsets had significant or marginal negative effects on CMI (p = 0.003–0.10). Treg/Tici inclusion in the hurdle model decreased the statistical significance of the negative effect of HEU status on BCG-CMI suggesting that Tregs/Ticis may have contributed to the difference between HEUs and HUUs. Enrichment of the gut microbiota in Actinobacteria and Firmicutes was significantly associated with low vaccine immunogenicity (p = 0.002–0.04), and Bacteroidetes and Proteobacteria with high immunogenicity (p < 0.0001–0.10). The Firmicute Murdochiella sp. had a higher negative effect size on BCG-CMI in HEUs than HUUs (p < 0.0001). High microbiome diversity negatively correlated with CMI responses (p = 0.002–0.03), with higher effect sizes in HEUs than HUUs (p = 0.047). Interpretation The frequency of Tregs/Ticis and the composition of the gut microbiome are associated with immune responses to vaccines and may contribute to decreased responses in HEUs. The internally consistent association between the enrichment of gut microbiota in specific phyla and the immunogenicity of several vaccines suggests the possibility of designing mitigating interventions that target the gut microbiome. Funding National Institute of Allergy and Infectious Diseases and Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.