Opeyemi Oludada, University of Calgary

Opeyemi E. Oludada (Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada), Magen E. Francis (Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada), Baweleta Isho (Department of Immunology, University of Toronto, Toronto, Ontario, Canada), Salma Sheikh-Mohamed (Department of Immunology, University of Toronto, Toronto, Ontario, Canada), Albert Nguyen (Department of Immunology, University of Toronto, Toronto, Ontario, Canada), Cynthia Swan (Vaccine and Infectious Disease Organization - International Vaccine Centre (VIDO-InterVac), Saskatoon, Saskatchewan, Canada), Angie Rassmussen (Vaccine and Infectious Disease Organization - International Vaccine Centre (VIDO-InterVac), Saskatoon, Saskatchewan, Canada), and Alyson A. Kelvin (Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada)

Fighting & Responding

Secondary exposure outcomes to SARS-CoV-2 depend on the variant match, yet the cellular correlates of protection remain unclear. C57BL/6J mice were primed with the SARS-CoV-2 Alpha variant virus and homologously re-challenged with Alpha (Alpha→Alpha) or heterologously re-challenged with Beta (Alpha→Beta) at various time points over 1 year post-primary infection (ppi). We assessed clinical disease, viral burden, lung pathology, neutralizing antibodies, and germinal center (GC) and T follicular helper (Tfh) dynamics up to 84 days ppi. Homologous re-challenge suppressed infection in the lungs and nasal turbinates at 21 and 56 days post-infection, with waning protection by 84 days post-infection. In contrast, heterologous Beta re-challenge consistently induced weight loss and peribronchiolar thickening, whereas primary Beta infection alone did not cause weight loss, supporting productive viral replication across time points. Although neutralizing antibody titers declined over time, they did not fully account for the patterns of protection across re-challenge intervals, suggesting the involvement of additional mechanisms. Transcriptional regulators of GC/Tfh, including BCL6, AID, and IL-6, varied with timing and challenge type, and an early rise in the lymph node GC B cells by day 2 post-secondary inoculation was associated with protection. Taken together, these data identify rapid GC activation as a potential cellular correlate of protection and suggest that cross-variant gaps arise from qualitative and kinetic differences in GC-Tfh responses. We are now analyzing one-year post-primary infection transcriptomics to define the cross-reactive GC/MBC repertoires and map out conserved epitopes across coronaviruses using single-cell profiling, recombinant mAb cloning/epitope mapping, and human tonsil organoids.