Poster Presentation 16th Lorne Infection and Immunity 2026

Atypical B cells, immune hyperactivation and hyperinflammation underlie immunity to influenza vaccination in First Nations and non-Indigenous people with chronic multimorbidity (132088)

Morgan J Skinner 1 , Lukasz Kedzierski 1 , Ruth A Purcell 1 , Mark Mayo 2 , Bianca F Middleton 2 , Lilith F Allen 1 , Ruth R Hagen 1 , Alexandra Hinchcliff 2 , Matilda Clark 2 , Caitlin Kent 2 , Malet Aban 3 , Heidi Peck 3 , Hayley A McQuilten 1 , Arnold Reynaldi 4 , Ashleigh I Holloway 1 , Angelica Tan 2 , Vanessa Rigas 2 , Erin Gargan 2 , Miles P Davenport 4 , Stephen J Kent 1 , Ian Barr 3 , Hyon-Xhi Tan 1 , Adam K Wheatley 1 , Amy W Chung 1 , Jane Nelson 2 , Adrian Miller 5 , Oanh Nguyen 1 , Jane Davies 2 , Louise C Rowntree 1 , Katherine Kedzierska 1
  1. Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
  2. Menzies School of Health Research, Darwin, Northern Territory, Australia
  3. WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, Victoria, Australia
  4. Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia
  5. Indigenous Engagement, CQUniversity, Townsville, Queensland, Australia

Indigenous populations globally have increased morbidity and mortality from influenza viruses, together with disproportionate rates of chronic diseases, including diabetes, respiratory and renal disorders. Yet, the impact of chronic diseases on immunity towards influenza vaccination in Indigenous people is unknown. We recruited Australian First Nations and non-Indigenous people vaccinated with seasonal inactivated influenza vaccines (IIVs) in 2022-2024, and assessed their humoral and cellular responses in context of comorbidities at baseline and after immunization. Our study highlights the prevalence of multimorbidity in our Australian First Nations cohort, associated with highly elevated baseline NK cell and T cell activation, IL-6, IL-18 and MCP-1 inflammation levels, and pro-inflammatory agalactosylated IgG antibodies. Participants with multimorbidity, irrespective of ethnicity, also had higher HAI titres at baseline, potentially reflecting health-seeking behaviour and repeated vaccination. Following IIV, all vaccinees, including participants with multimorbidity, had increased HAI antibody titres against all vaccine components and higher influenza HA-specific IgD- B cell frequencies as compared to baseline levels. However, for the first time, we revealed increased prevalence of pro-inflammatory atypical CD21-CD27- B cells (atBCs) within influenza-specific HA-positive IgD- B cells and lack of significant cTFH1 cell activation in individuals with comorbidities, correlating with multimorbidity-associated baseline inflammatory features. Our findings thus reveal that vaccinees with multiple chronic diseases, both Australian First Nations and non-Indigenous participants, can mount antibody responses following influenza vaccination, although their cellular immune features, HA-specific B cell and cTFH1 compartments, display pro-inflammatory signatures post-IIV, linked to multimorbidity-associated inflammation and IgG glycosylation patterns at baseline. Our study supports influenza vaccination for individuals with chronic diseases, especially relevant to Indigenous populations with high prevalence of multimorbidity. Our data also suggest that individuals with chronic comorbidities potentially need different formulation, dose and/or schedule for influenza immunization.