Greater Gut Microbial Diversity and Several Reduced Taxonomic Group Abundances Are Associated with Higher Humoral Responsiveness to Single-dose Oral Typhoid Ty21a Vaccination

Variability across individuals in immune responses to oral vaccines poses a challenge for achieving uniform protection against enteric pathogens, and the gut microbiome has emerged as a potential modulator of vaccine immunogenicity. The live-attenuated oral typhoid vaccine Ty21a elicits mucosal immunoglobulin A (IgA) and systemic immunoglobulin G (IgG) responses; however, microbial characteristics associated with humoral responses to Ty21a remain poorly characterized. The present study investigated the associations between gut microbial diversity, community composition, taxonomic abundance and predicted functional pathways with humoral responses following Ty21a vaccination. Immunological and microbiome data from 17 participants were obtained from a previously published dataset. Our analyses focused on vaccinated participants with available antibody response data. Individuals were classified according to post-vaccination IgA and IgG responses as co-responders (Both), single-antibody responders (IgA and IgG) or non-responders (None). Co-responders to a single dose of Ty21a exhibited significantly greater gut microbial richness and phylogenetic diversity relative to non-responders, although no significant differences in alpha diversity were observed among participants following four doses. Moreover, differential abundance analysis also identified six genus level taxonomic groups that were underrepresented in single dose co-responders compared with non-responders. In contrast, predicted functional profiles and individual MetaCyc pathways did not differ significantly between response groups. Together, these findings suggest that gut microbial diversity, and taxonomic composition correlate with humoral responsiveness to single dose Ty21a vaccination, while providing limited evidence for differences in predicted microbial functions. Larger studies are needed to further determine the biological significance of these associations.