HKU1 immune imprinting is associated with post-COVID symptoms after SARS-CoV-2 infection

The long-term health burden of SARS-CoV-2 infections remains poorly understood. In a cohort from Vancouver, Canada, we identified immune imprinting to endemic β-human coronaviruses (HCoVs), reflected by affinity-matured IgG responses that cross-reacted with the SARS-CoV-2 spike with low affinity, along with an early expansion of memory B cells recognizing HKU1 and the conserved S2 domain following the first dose of ancestral-strain vaccination. Vaccination also enhanced antibody-dependent cellular phagocytosis (ADCP), primarily directed against the HKU1 spike and SARS-CoV-2 S2 domains. In another cohort from the same region, higher HKU1 spike IgG levels and increased antibody-dependent complement deposition (ADCD) were associated with a greater likelihood of post-COVID symptoms, even though these individuals had experienced fewer SARS-CoV-2 infections at the one-year follow-up. Together, these findings suggest that β-HCoV-associated immune imprinting may simultaneously reduce infection risk and promote pathological Fc-mediated inflammation, potentially contributing to post-COVID conditions following infection with contemporary SARS-CoV-2 variants in individuals vaccinated against earlier strains.