Can cross-protective airway-resident immunity be harnessed for SARS-CoV-2 variant protection in UK and Malawian populations with or without HIV infection?

Coinciding with >70% seroprevalence in Malawi and >75% vaccination coverage in the UK, the omicron variant has had lower mortality than the delta variant. Both prior infection and vaccination protect against severe COVID-19, and vaccination combined with infection induces highly cross-reactive hybrid immunity. Pre-existing cross-reactive T cells targeting highly conserved replication proteins abort SARS-CoV-2 infection before PCR positivity or antibody seroconversion, leading to protection against COVID-19. Our unpublished data suggest that this rapid immune-surveillance is attributable to pre-existing cross-reactive SARS-CoV-2 T cells that are highly enriched in the human airways. Furthermore, lung-resident B cells elicit antibodies that cross-neutralise influenza variants and recent work has highlighted the protective potential of mucosal IgA against COVID-19. These data suggest that cross-reactive airway immune responses could be critical in defence against emerging variants. We hypothesise that airway-compartmentalised T and B cells provide an enriched long-lived reservoir of cross-reactive immunity against emerging variants than can protect against COVID-19, and we postulate that is impacted by background exposure, vaccination status and pre-existing HIV infection, in Malawi and UK adults. An understanding of tissue-resident long- lived, broadly cross-reactive immunity is vital for development of next generation mucosal-targeted vaccines and for future studies predicting susceptibility to novel variants.