Defining the impact of interpersonal gut microbiota variation on oral cholera vaccine responsiveness

PROJECT SUMMARY The human pathogen Vibrio cholerae causes cholera, a severe human diarrheal disease that affects millions of people annually. A number of oral cholera vaccines (OVC) have been developed but show varying efficacy among populations in distinct geographical regions, with poor OCV response being common in cholera endemic areas. However, the underlying causes of this variation are poorly defined. There is therefore an unmet global health need to develop strategies that boost the effectiveness of these lifesaving OCVs. The resident microbial community of the gastrointestinal tract, the gut microbiome, varies significantly among individuals, and this variation has been linked to variation in host phenotypes and responses to therapeutics. Our central hypothesis is that inter-individual variation in the microbial populations of the gut contributes to the high level of geographical variation in OCV efficacy through effects on the intestinal immune system. Our preliminary data shows that the gut microbiome represents a personalized contributor to OCV outcome; (i) specific gut bacterial taxa correlate with high and low responsiveness to OCV, inter-individual microbiota variation in cholera endemic areas (ii) directly impact infection outcome and immune responses to V. cholerae and (iii) recapitulates human donor OCV outcomes in a germfree mouse transplantation model, and (iv) gut microbiome modulation of host CD4+ T cells critically regulates immune responses to V. cholerae. Precision editing of the gut microbiome therefore represents an attractive strategy to boost OCV responsiveness, but implementation of such approaches requires detailed understanding of the specific microbes responsible, and the nature of their interactions with the host immune system. We will leverage our team’s expertise in OCV clinical studies, metagenomics, anaerobic microbiology, intestinal immunology, and gnotobiotic mouse models to make causal and mechanistic links between structural variation in the gut microbiome and human vaccine responsiveness, and to identify specific microbes able to drive strong OCV outcomes. Our ultimate goal is to identify specific microbial taxa that drive divergent immune responses to V. cholerae, which may then inform microbiome-targeted probiotic and prebiotic strategies for cholera prophylaxis. We will address this problem through the following Specific Aims: Aim 1- Determine the effect of inter-individual microbiota variation on OCV responsiveness; Aim 2- Define the microbiota targets that enhance responsiveness to oral cholera vaccines; Aim 3- Define the immune cell populations that mediate microbiota-driven effects on OCV.