Publication date: Feb 12, 2025

Background: Vaccination and prior infection elicit neutralizing antibodies targeting SARS-CoV-2, yet the quantitative relationship between serum antibodies and infection risk against viral variants remains uncertain, particularly in underrepresented regions. Methods: We investigated the protective correlation of pre-exposure serum neutralizing antibody levels, employing a panel of SARS-CoV-2 pseudoviruses (Omicron BA.1, Omicron BA.2, and ancestral D614G), and Spike-binding antibody levels, with symptomatic BA.1 or BA.2 SARS-CoV-2 infections and overall infection, in 345 household contacts from a SARS-CoV-2 household cohort study. Results: A four-fold increase in homotypic-neutralizing (e.g., BA.1-neutralizing vs. BA.1 exposure) titers was correlated with protection from symptomatic infections (BA.1 protection: 28% [95%CI 12-42%]; BA.2 protection: 43% [20-62%]), and ancestral-neutralizing titers were also correlated with protection from either variant, but only at higher average levels than homotypic. Mediation analyses revealed that homotypic and D614G-neutralizing antibodies mediated protection from infection and symptomatic infection both from prior infection and vaccination. Conclusions: These findings underscore the importance of monitoring variant-specific antibody responses and highlight that antibodies targeting circulating strains may be more predictive of protection from infection. Nevertheless, ancestral-strain-neutralizing antibodies remain relevant as a correlate of protection. Our study emphasizes the need for continued efforts to assess antibody correlates of protection. Funding: We acknowledge funding from the U.S. N.I.H., the Open Philanthropy Project, and the Bill and Melinda Gates Foundation.

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