The Common Cold Is Associated With Protection From SARS-CoV-2 Infections

BACKGROUND: Adults and children often respond differently to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with adults facing a higher risk of symptomatic and severe illness. We hypothesize that children's protection from symptomatic SARS-CoV-2 may be due to more frequent respiratory viral infections, which prime their airway antiviral defenses. METHODS: Using case-cohort and case-control analyses in the Human Epidemiology and Response to SARS-CoV-2 cohort, we evaluated whether infection with common respiratory viruses protects against SARS-CoV-2 infections and investigated airway molecular mechanisms by which this protection is achieved. We tested 10 493 longitudinal nasal swabs from 1156 participants for 21 respiratory pathogens. We performed RNA sequencing on 147 swabs (n = 144 participants) collected prior to SARS-CoV-2 infection and 391 swabs (n = 165 participants) during and before rhinovirus infection. RESULTS: Participants with rhinovirus infection in the previous 30 days were at 48% lower risk of SARS-CoV-2 infection (adjusted hazard ratio, 0.52; P = .034). Among participants with SARS-CoV-2 infection, recent rhinovirus infection was associated with 9.6-fold lower SARS-CoV-2 viral load (P = .0031). Higher preinfection expression of 57 genes was associated with lower SARS-CoV-2 viral load, including 24 antiviral defense genes; 22 of these were induced by rhinovirus infections. Relative to adults, children expressed higher levels of the antiviral gene signature (P = .014) and were at 2.2-fold increased risk for rhinovirus infections. CONCLUSIONS: Rhinovirus infections, which trigger increased expression of antiviral airway genes, are linked to a lower risk of SARS-CoV-2 infection. Frequent rhinovirus infections may enhance this protective gene profile, partially explaining why children experience milder SARS-CoV-2 infections compared to adults. CLINICAL TRIALS REGISTRATION: NCT04375761.