Associations between the microbiome and immune responses to an adenovirus-based HIV-1 candidate vaccine are distinct between African and US cohorts

Optimization of prophylactic vaccine regimens to elicit strong, long-lasting immunity is an urgent need highlighted by the COVID-19 pandemic. Stronger vaccine immunogenicity is frequently reported in individuals living in high-income countries compared to individuals living in low- and middle-income countries. While numerous host genetic and immune factors may influence vaccine responses, geographic restrictions to vaccine effectiveness may also be influenced by the intestinal microbiota, which modulates host immune systems. However, the potential role of the gut microbiota on responses to HIV-1 vaccines has not yet been explored. We analyzed the bacteriome by targeted 16S sequencing and the virome by virus-like particle sequencing of 154 fecal samples collected from healthy individuals in Uganda, Rwanda, and the United States early (week 2) and late (week 26) after vaccination with multivalent adenovirus serotype 26 (Ad26)-vectored mosaic HIV-1 vaccines. Vaccination did not affect the enteric bacteriome or virome regardless of geographic location. However, geography was the major driver of microbiota differences within this cohort. Differences in overall bacterial and viral diversity and in specific microbial taxa, including <i>Bacteroidota</i> and <i>Bacillota</i>, between participants from the United States and East African countries correlated with differential immune responses, including specific antibody titers, antibody functionality, and cellular immune responses to vaccination regimens. These findings support the microbiota as a putative modifier of vaccine immunogenicity.IMPORTANCEOur research examined how gut bacteria might influence vaccine effectiveness in different parts of the world. We studied adults from the United States, Rwanda, and Uganda who received an experimental HIV vaccine. We found that participants from East Africa had more diverse gut bacteria than those from the United States, but their immune responses to the vaccine were weaker. This is the first study to directly show this relationship between higher gut bacterial diversity and reduced vaccine effectiveness in the same group of people. We also identified specific types of bacteria that were linked to either stronger or weaker immune responses. These findings are particularly relevant now as we use vaccines globally to fight diseases like COVID-19, as they suggest that regional differences in gut bacteria <i>Bacteroidota</i> and <i>Bacillota</i> might help explain why vaccines work better in some places than others. This could inform how we design and test future vaccines.