Staff Scientist Vaccine Research Center, NIH New York, New York, United States
Abstract Text: Continued immune escape by newly evolving SARS-CoV-2 variants has led to concerns that antigenic imprinting toward earlier variants may limit the efficacy of updated vaccines. However, most studies to date have examined this phenomenon primarily via serum reactivity and/or phenotypic characterizations of memory B cells. Here, we leverage a previous study of homologous versus heterologous boosting in nonhuman primates (NHPs) to investigate the immunogenetic underpinnings of imprinting. Two groups of NHPs were immunized with the clinical mRNA-1273 primary vaccine regimen and then boosted 6 months later with either mRNA-1273 (homologous) or mRNA-1273.β (heterologous). A third group received a primary vaccine series using mRNA-1273.β without boosting. All groups were then challenged with a β-variant virus. We used variant-specific antigenic probes and single-cell sequencing using the 10X Chromium platform to assess the longitudinal development of cross-reactivity in all three cohorts. Notably, we found a specific increase in the usage of heavy chain V gene IGHV3-ABA in the group primed with mRNA-1273.β. When paired with IGLV3-AED, these antibodies bound to an epitope in RBD. Most were able to weakly bind to and neutralize Omicron variant BA.1 and two demonstrated modest neutralization even against modern Omicron variants JN.1, KP.2, and KP.3. Negative-stain electron microscopy was used to understand the structural basis for imprinting. Overall, we show how different primary exposures can impact the immunogenetic characteristics of the antibody response, thus driving antigenic imprinting.
