Early Mucosal Type II Interferon Limits SARS-CoV-2 Replication in Humans

COVID-19 vaccines markedly reduce disease severity, but their ability to block infection and transmission remains limited and variable.1 A better understanding of early mucosal immune programs that constrain viral replication at susceptible upper respiratory sites is needed to develop more effective antiviral strategies. However, temporal and anatomical antiviral dynamics are difficult to resolve without longitudinal, paired-site sampling beginning before infection onset. We quantified longitudinal viral load by RT-qPCR and human gene expression by mRNA sequencing in 1,237 samples prospectively collected daily from the nasal cavity, oral cavity, and oropharynx of 16 individuals starting from the onset of naturally acquired SARS-CoV-2 infection, and 16 age-, sex-, and vaccination-matched uninfected individuals. Here we show that Type I interferon (IFN) responses are initiated concurrently across these upper respiratory sites, even before local viral detection. In contrast, Type II IFN initiation is more spatially variable, and earlier nasal Type II IFN initiation is associated with reduced viral replication, prior COVID-19 vaccination, and higher tissue-resident memory T cell (TRM) signature expression. These findings demonstrate that in addition to humoral immunity, prior vaccination primes rapid, inducible mucosal Type II IFN responses, likely mediated by rare TRM upon viral encounter, to limit viral replication and spread.