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

Morbidity and mortality rates from seasonal and pandemic influenza occur disproportionately in high-risk groups, including Indigenous 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 vaccinated 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 activation profiles of circulating T follicular helper type-1 cells at the early stage correlated strongly with the total change in antibody titers induced by vaccination. Formation of influenza-specific hemagglutinin-binding memory B cells was significantly higher in seroconverters compared with nonseroconverters. In-depth antibody characterization revealed a reduction in immunoglobulin G3 before and after vaccination 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 immunization with seasonal inactivated influenza vaccines. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and their subsequent complications.

Influenza is a significant respiratory viral infection that causes a serious burden of disease. High morbidity and mortality rates from seasonal and pandemic influenza occur disproportionately in specific high-risk population groups, including children, the elderly, pregnant women, Indigenous people globally, and individuals with underlying comorbidities such as diabetes, immunosuppression, and lung and heart disease (1–3). Currently, antibody-based influenza vaccines targeting highly variable hemagglutinin (HA) and neuraminidase (NA) surface glycoproteins are the most effective way to combat seasonal infections. The inactivated influenza vaccine contains glycoproteins corresponding to the circulating A/H3N2 and A/H1N1 strains and one B strain from either the Victoria or Yamagata lineage (in trivalent/TIV vaccines) or both B lineage strains (in quadrivalent/QIV vaccines). Antigenic drift necessitates annual updates of the vaccine components to warrant protection, and despite this the overall vaccine effectiveness can vary vastly from −7 to 75% (4). Vaccine effectiveness not only differs between seasons but also between vaccine components, with H3N2 showing the lowest overall vaccine effectiveness and H1N1pdm09 (pH1N1) the highest (5). Several factors such as preexisting immunity, immunosenescence, and vaccine strain mismatch can influence vaccine effectiveness (6). Genetic factors such as HLA polymorphisms contributing to differences in HLA-II expression are associated with stronger or weaker vaccine responses (7). For example, individuals expressing HLA-DRB1*11:04 showed high titers postvaccination whereas HLA-DRB1*13:01 showed reduced antibody titers postvaccination (7).Our understanding of why some individuals fail to establish a protective immune response after influenza vaccination is still very limited. To determine which factors shape the immune response postvaccination, we and others have identified cellular and humoral responses that correlate with robust immune responses to influenza vaccination (8, 9). Importantly, 7 d postvaccination an increase in ICOS⁺CXCR3⁺CXCR5⁺CD4⁺ circulating T follicular helper 1 (cT_FH1) cells was observed that correlated with antibody-secreting cells (ASCs) and rises in antibody titers (9, 10).Indigenous populations experience higher rates of infections with a range of pathogens including tuberculosis (11) and influenza (12). Notification and hospitalization rates of seasonal influenza virus infections are 1.5 to 8.6 times and 1.2 to 4.3 times, respectively, higher in Indigenous compared with non-Indigenous Australians (12). With social determinants of health and comorbidities contributing to a higher disease burden (13), one key strategy proposed to improve health outcomes for Indigenous populations is immunization (14). However, only a few studies to date have examined viral immunity in Indigenous populations and most of our knowledge is based on studies in non-Indigenous populations. We have revealed host variations in HLA profiles in Indigenous populations (15, 16), suggesting that differences in HLA or other genetic factors might impact influenza vaccine responses in Indigenous Australians. Despite national funding, vaccination rates still remain low in Indigenous communities (17). A recent study from Menzies et al. revealed that more than 50% of unvaccinated Indigenous Australians stated that the “flu” vaccine would not be effective (18). To date, there are no published data to define immune responses to influenza vaccines in Indigenous Australians, while globally only one study assessed antibody responses following adjuvanted pH1N1 influenza immunization in Indigenous Canadians and showed comparable antibody levels pre- and postvaccination (19). Determining the immunological response to influenza vaccination in high-risk Indigenous populations can therefore provide a stronger scientific basis for influenza recommendations, which if appropriately communicated may increase vaccine uptake.In this study, we recruited Indigenous and non-Indigenous Australians vaccinated with the QIV between 2016 and 2018 and assessed their immunity pre- and postvaccination. We performed in-depth analyses of T and B cell activation, memory B cell formation, and antibody profiles as well as investigating host factors that could contribute to vaccine responses. Our study clearly demonstrates that Indigenous Australians mount effective and prototypical immune responses to the inactivated influenza vaccine and thus provides an immunological basis to support current vaccine recommendations in Indigenous populations.