Cross-reactive T cell immunity against novel coronaviruses with pandemic potential, predictable from spike sequence conservation

Widespread SARS-CoV-2 infection and vaccination have reshaped global immunity to coronaviruses. Whether this immunity extends to animal sarbecoviruses with spillover potential remains unknown. We assessed cross-reactive memory T-cell responses to spike proteins from five relevant human angiotensin-converting enzyme 2 (hACE2)-dependent sarbecoviruses and MERS-CoV in healthcare workers in the UK and Vietnam. Limited SARS-CoV-2 specific or cross-reactive responses were seen in pre-pandemic samples. However, in samples collected from vaccinated donors at 3-24 months after booster vaccination, cross-reactive T-cell responses across the hACE2-dependent sarbecoviruses were detected. There was a strong correlation between the magnitude of responses and the level of viral sequence identity. This relationship was reproduced across cohorts in the UK and Vietnam. These findings indicate that post-pandemic populations possess measurable cellular immunity to genetically related sarbecoviruses and suggest that the degree of T-cell cross-recognition can be predicted from the spike protein sequence conservation. Such data provide an immunological framework for assessing vulnerability to future sarbecovirus spillover.