Discordant Outcomes of SARS-CoV-2 Exposure in Household Contacts

We investigated discordant SARS-CoV-2 infection outcomes among household contacts. 95 recently-exposed household contacts were recruited from June 2020 to February 2023 in a prospective study of "discordant pairs", where one individual experienced documented SARS-CoV-2 infection while another close contact consistently tested negative despite shared living arrangements. We collected pre- and post-infection samples and analyzed both SARS-CoV-2 and common cold coronavirus (CCC)-specific T cell responses, as well as spike RBD neutralizing and nucleocapsid-binding antibody titers. Antibody and cellular immune responses did not identify a single predominant mechanism explaining discordant outcomes. Instead, we observed distinct immunological patterns that could be associated with protection from infection across different household contacts. In ∼40% of cases, uninfected individuals showed pre-existing immunity to non-spike antigens and CCC sequences. Moreover, 30% of uninfected individuals displayed evidence suggestive of abortive infections, characterized by increased T responses without detectable changes in antibody levels. The remaining cases showed no clear changes in immunological patterns. Multiple immunity-associated factors operate in household settings for SARS-CoV-2-exposed individuals who do not develop overt infection, including both pre-existing immunity and abortive or transient infections. Although causality cannot be established without additional functional assays, this diversity of protective immune responses might help explain why some individuals remain uninfected despite close contact with SARS-CoV-2-positive household members.