Longitudinal antibody correlates of SARS-CoV-2 infection in a US household cohort during Omicron waves
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Background
SARS-CoV-2 vaccines have been updated based on circulating variants and the antibody protection from prior vaccination and infection against emerging variants. We evaluated longitudinal antibody correlates of SARS-CoV-2 infection risk during Omicron waves.
Methods
We used data from a longitudinal cohort study from 2021 through 2025 with prospective surveillance for acute respiratory illness, and repeated blood collection. A subset of participants also provided weekly respiratory specimens to identify asymptomatic infections. Serum samples were tested using multiplex assays measuring anti-Spike (S) binding IgG and angiotensin-converting enzyme 2 (ACE2) inhibition (a measure of inhibition of the ACE2 receptor interaction) across multiple SARS-CoV-2 variants. Cox models were used to evaluate associations between antibody, prior vaccination and infection, and SARS-CoV-2 infections.
Findings
Among 119 participants who contributed 438.8 person-years of follow-up, 81 symptomatic SARS-CoV-2 infections and 4 asymptomatic infections (from 33 participants with weekly swabs) were detected. Each two-fold increase in anti-S IgG concentration was associated with a 15% lower hazard of symptomatic infection (hazard ratio [HR]=0.85, 95%CI:0.82–0.88). Similarly, each 10% increase in ACE2 inhibition was associated with a 7% lower infection hazard (HR=0.93, 95% CI:0.90–0.95). After adjusting for antibody levels, prior SARS-CoV-2 infection remained protective, while recent vaccination was not associated with infection hazard. The peak predicted antibody after repeat COVID-19 vaccinations was estimated to confer 62–65% protection against symptomatic infection.
Interpretation
Higher levels of binding and functional antibodies were associated with reduced the risk of SARS-CoV-2 infections across multiple waves between 2021—2025. These findings support the use of longitudinal serologic surveillance to inform vaccine evaluation and future booster strategies against evolving SARS-CoV-2 variants.
Research in Context
Evidence before this study
We searched PubMed and Google Scholar for studies published between January 1, 2020 and May 1, 2026 using combinations of the terms “SARS-CoV-2”, “COVID-19”, “correlates of protection”, “antibody correlates”, “Omicron”, and “longitudinal cohort”. Previous studies consistently demonstrated that SARS-CoV-2 antibody levels, particularly neutralizing antibodies, are associated with protection against infection. Most evidence was from vaccine clinical trials, healthcare worker cohorts, or observational studies evaluating a single epidemic wave or variant period. In many studies, antibody measurements were obtained at a single time point, often shortly after vaccination, and related to subsequent infection risk months later. Few studies incorporated repeated antibody measurements over time, and most focused on either binding antibodies or neutralizing antibodies alone. During the Omicron era, correlates of protection studies were frequently limited to specific subvariants such as BA.1 or BA.5, and relatively little evidence exists on how antibody correlates perform across successive waves characterized by rapidly changing variants. To our knowledge, no previous study in the United States has evaluated longitudinal antibody correlates of protection across the multiple Omicron waves using repeated serologic measurements, comprehensive vaccination and infection histories, and both symptomatic and asymptomatic infection surveillance.
Added value of this study
This study used data from a prospective longitudinal U.S. household cohort, enabling evaluation of antibody correlates of protection across multiple Omicron waves from January 2022 through January 2025. More than 90% of participants had been enrolled before the start of the COVID-19 pandemic, providing detailed pre-pandemic baseline information and complete longitudinal histories of SARS-CoV-2 vaccination and infection. Unlike most previous studies that relied on a single antibody measurement, we incorporated all available serum specimens (median 5 [IQR 3-8] specimens per participant) and modeled antibody levels as time-varying exposures. We evaluated both spike-binding IgG antibodies and ACE2 binding inhibition, a functional measure closely related to neutralizing activity, and examined multiple composite antibody definitions to assess the robustness of findings. In addition to symptomatic infections identified through active respiratory illness surveillance, a subset of participants underwent weekly respiratory sampling, allowing inclusion of asymptomatic infections. Across all analyses, higher antibody levels were consistently associated with reduced infections, and findings were similar across binding and functional antibody measures and across alternative composite antibody definitions.
Implications of all the available evidence
Together with previous studies, these findings support SARS-CoV-2 variant-specific antibody responses as correlates of protection against infection, particularly against dominant circulating variants. The consistency of associations across multiple Omicron waves, evolving variants, and alternative antibody measurements suggests that longitudinal serologic surveillance can provide meaningful information about population susceptibility even in settings with complex vaccination and infection histories. After adjustment for measured antibody levels, recent vaccination was not associated with additional reduction in infection hazard, whereas prior infection remained associated with lower infection hazard. In other words, the protection associated with recent vaccination was largely captured by measured antibody responses, while prior infection was associated with protection beyond that captured by measured antibody levels. These results have implications for vaccine evaluation, interpretation of serosurveys, and future booster vaccine strategies as SARS-CoV-2 continues to evolve.
