Atypical B cells and inflammatory profiles delineate immunity to influenza vaccination in First Nations and non-Indigenous people with chronic multimorbidity.

Indigenous people are disproportionately impacted by influenza viruses and chronic multimorbidity. Yet, the impact of comorbidities on immunity towards influenza vaccination is unknown. We recruited Australian First Nations and non-Indigenous people vaccinated with seasonal inactivated influenza vaccines and assessed their humoral and cellular responses in the context of comorbidities at baseline and after immunisation. Our study highlights prevalence of multimorbidity in First Nations people, associated with elevated baseline cellular activation, pro-inflammatory cytokines and agalactosylated IgG. Following vaccination, all groups had increased antibody titres and haemagglutinin-specific IgD- B-cell frequencies as compared to baseline. However, we reveal increased prevalence of pro-inflammatory atypical B cells within influenza haemagglutinin-specific IgD- B cells and lack of significant circulating T follicular helper type-1 cell activation in individuals with comorbidities, correlating with multimorbidity-associated baseline inflammatory features. Our findings thus reveal that vaccinees with comorbidities, both Australian First Nations and non-Indigenous participants, can mount antibody responses following influenza vaccination, although their cellular immune features, haemagglutinin-specific IgD- B cells and cTFH1 compartments, display features of perturbed humoral axis functionality linked to multimorbidity-associated inflammation and IgG glycosylation patterns at baseline. Our study supports influenza vaccination for individuals with comorbidities, especially relevant to Indigenous populations with prevalent multimorbidity.