Hybrid immunity-based induction of durable pan-endemic-coronavirus immunity in the elderly

Repeated vaccinations and infections have led to diverse states of hybrid immunity against SARS-CoV-2 in the global population. However, age and comorbidities can compromise protection against severe disease, and antibody-mediated immunity is undercut by viral immune escape mutations. Whether and to what extent durable T cell responses compensate for reduced humoral immunity, particularly in the elderly, have not been investigated. Here, we utilize SARS-CoV-2-specific and pan-coronavirus-derived peptide pools, including or excluding spike glycoprotein-derived epitopes, to measure vaccination and infection induced pan-human endemic coronavirus (PHEC)-directed T cell immunity. In contrast to vaccinated individuals, hybrid immunity induced by vaccination and SARS-CoV-2 infection comprises high frequencies of PHEC-reactive T cells with comparable frequencies and functional TCR avidities across all age groups. With waning humoral immunity and vulnerability to escape mutations, PHEC-reactive T cells may provide critical protection. Our findings underscore the importance of incorporating pan-coronavirus T cell epitopes in future vaccine strategies.