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

BackgroundVaccination 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. MethodsWe 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. ResultsA 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. ConclusionsThese 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. FundingWe acknowledge funding from the U.S. N.I.H., the Open Philanthropy Project, and the Bill and Melinda Gates Foundation. Research In Context Evidence before this studyBased on searches of Google Scholar and PubMed, not restricted to English-language articles, using search terms including "correlates of protection," "SARS-CoV-2," "COVID-19," "BA.1," "BA.2," "neutralizing antibodies," "immune response," and "thresholds of protection" we identified multiple studies, primarily based on randomized clinical trials or prospective cohort designs, which have shown that serum SARS-CoV-2-neutralizing antibodies are informative correlates of protection from overall or symptomatic infection after vaccination or infection. Our search was limited to 2020 and later, and included several high-quality RCTs and cohort studies, as well as consideration of published meta-analyses. Often the serum correlates used were spike-binding or -neutralizing peak titers or baseline titers months before infection waves, and specific viral exposures for participants remained unknown. Most prior evidence related to neutralizing antibodies focused on neutralizing titers against the ancestral strain even when participants were challenged with later viral variants, although a small number of groups have also investigated neutralizing antibody titers directed against contemporaneous strains, such as Omicron BA.1. Furthermore, most studies of correlates of protection focused on vaccines widely available in North America and Europe; few serum antibody correlates of protection studies have included globally used COVID-19 vaccines, such as Soberana or Sputnik. Relatedly, Central America as a region has had no known studies of SARS-CoV-2 serum neutralizing antibody correlates of protection, to the best of our knowledge, despite the unique vaccine exposure histories of its residents and widespread infections before such vaccines became available. Added value of this studyIn this study, we used a household-based cohort study design with an embedded transmission study, in which we collected serum from household members just before they were exposed to a co-resident in the household who developed COVID-19. This design enabled correlates of protection analysis of serum antibody titers at the time of known exposure, relatively homogeneously across the cohort. Our study was conducted in Managua, Nicaragua, during Omicron BA.1 and BA.2 infection waves, presenting the first such study in Central America, and the first such study including participants who received some global vaccines. We conducted pseudovirus neutralization assays against the ancestral SARS-CoV-2 strain and contemporaneous Omicron BA.1 and BA.2 variants, allowing for parallel analyses of anti-Omicron titers as correlates of protection and more widely available ancestral-neutralizing titers. Implications of all the available evidenceOverall, the results in this study, in combination with the prior available evidence, continue to point to serum neutralizing antibodies as an informative correlate of protection from overall and symptomatic infection. Titers against contemporaneous variants (BA.1 and BA.2 in this case), were protective at lower levels than those against the ancestral strain, but ancestral-neutralizing titer was still informative as a correlate of protection. Lastly, for any known vaccination or prior infection history studied with such an analysis, neutralizing antibodies appear to mediate protective effects of prior SARS-CoV-2 exposure on overall or symptomatic infection.