Robust and prototypical immune responses toward influenza vaccines in the high-risk group of Indigenous Australians

Morbidity and mortality rates from seasonal and pandemic influ-enza occur disproportionately in high-risk groups, including Indig-enous people globally. Although vaccination against influenza is recommended for those most at risk, studies on immune responses elicited by seasonal vaccines in Indigenous populations are largely missing, with no data available for Indigenous Australians and only one report published on antibody responses in Indigenous Canadians. We recruited 78 Indigenous and 84 non-Indigenous Australians vacci-nated with the quadrivalent influenza vaccine into the Looking into InFluenza T cell immunity -Vaccination cohort study and collected blood to define baseline, early (day 7), and memory (day 28) immune responses. We performed in-depth analyses of T and B cell activation, formation of memory B cells, and antibody profiles and investigated host factors that could contribute to vaccine responses. We found ac-tivation profiles of circulating T follicular helper type-1 cells at the early stage correlated strongly with the total change in antibody titers in-duced by vaccination. Formation of influenza-specific hemagglutinin-binding memory B cells was significantly higher in seroconverters com-pared with nonseroconverters. In-depth antibody characterization revealed a reduction in immunoglobulin G3 before and after vaccina-tion in the Indigenous Australian population, potentially linked to the increased frequency of the G3m21* allotype. Overall, our data provide evidence that Indigenous populations elicit robust, broad, and prototypical immune responses following immuniza-ti on with seasonal inactivated influenza vaccines. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influ-enza virus infections and their subsequent complications.