Longitudinal antibody correlates of SARS-CoV-2 infection in a US household cohort during Omicron waves

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 levels, 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 level after repeated 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 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.