Variant-specific antibody correlates of protection against SARS-CoV-2 Omicron symptomatic and overall infections

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. 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 in Nicaragua. 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. 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.