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

Vaccination with multivalent Ad26-vectored mosaic HIV-1 vaccines did not affect the enteric bacteriome or virome regardless of geographic location.

• 154 fecal samples were analyzed from healthy individuals in Uganda, Rwanda, and the United States.
• Samples were collected early (week 2) and late (week 26) after vaccination.
• Both the bacteriome (assessed by targeted 16S sequencing) and virome (assessed by virus-like particle sequencing) were unaffected by vaccination.
• This finding held regardless of geographic location of participants.

Geography was the major driver of microbiota differences within this cohort.

• Participants were from Uganda, Rwanda, and the United States.
• Geographic location distinguished both bacterial and viral community composition.
• Differences were observed in overall bacterial and viral diversity as well as in specific microbial taxa.
• The microbiota differences between US and East African participants were larger than any vaccination-associated changes.

East African participants had more diverse gut bacteria than US participants but weaker immune responses to the HIV-1 vaccine.

• Participants from Uganda and Rwanda showed higher gut bacterial diversity compared to US participants.
• Despite higher bacterial diversity, East African participants mounted weaker vaccine immune responses.
• This is described as the first study to directly show the relationship between higher gut bacterial diversity and reduced vaccine effectiveness in the same cohort.
• This pattern is consistent with previously reported lower vaccine immunogenicity in low- and middle-income countries.

Specific microbial taxa including Bacteroidota and Bacillota differed between US and East African participants and correlated with differential vaccine immune responses.

• Differences in Bacteroidota and Bacillota were identified between US and East African cohorts.
• These taxa correlated with specific antibody titers, antibody functionality, and cellular immune responses to vaccination regimens.
• The correlations suggest these bacterial phyla as putative modifiers of vaccine immunogenicity.
• Both bacteriome and virome compositional differences between geographies were associated with immune response variation.

The gut microbiota is supported as a putative modifier of vaccine immunogenicity in the context of HIV-1 vaccination.

• This is described as the first exploration of the potential role of the gut microbiota on responses to HIV-1 vaccines.
• Associations between the microbiome and immune responses were distinct between African and US cohorts.
• Immune response measures examined included specific antibody titers, antibody functionality, and cellular immune responses.
• Findings suggest that regional differences in gut bacteria may help explain geographic disparities in vaccine effectiveness.

Stronger vaccine immunogenicity is frequently reported in individuals living in high-income countries compared to individuals in low- and middle-income countries, and the intestinal microbiota may contribute to this disparity.

• The gut microbiota modulates host immune systems and may geographically restrict vaccine effectiveness.
• Numerous host genetic and immune factors may also influence vaccine responses.
• The COVID-19 pandemic highlighted the urgent need for optimization of prophylactic vaccine regimens.
• Prior to this study, the potential role of gut microbiota on HIV-1 vaccine responses had not been explored.