Antibody Levels From High-Throughput Variant-Specific SARS-CoV-2 Anti-Spike Immunoglobulin G and Angiotensin-Converting Enzyme 2 Neutralization Assays Correlate With COVID-19 Infection Risk in a Large Population.

Background: SARS-CoV-2 antibody levels have been proposed as a correlate of protection from infection. Yet, large-scale prospective studies of cost-effective scalable antibody measures as predictors of infection under real-world conditions are limited. We examined whether antibody levels measured by high-throughput variant-specific SARS-CoV-2 anti-spike immunoglobulin G (IgG) and angiotensin-converting enzyme 2 (ACE2) neutralization assays correlate with cell-based neutralizing antibody measurements and whether they can serve as a reasonable correlate of protection from SARS-CoV-2 infection.

Methods: We conducted a large institutional cohort study between January 2022 and March 2023. Participants (N = 2513) provided dried blood spot (DBS) samples for assessment of anti-spike IgG and ACE2 inhibition levels through high-throughput assays. Comparison with authentic cell-based SARS-CoV-2 neutralizing antibody assays was conducted with serum samples (n = 105). Associations between antibody levels and risk of infection were evaluated.

Results: Correlation between serum and DBS sampling and between cell-based neutralizing and high-throughput antibody binding assays was high for anti-spike IgG and ACE2 neutralization, though the degree of correlation varied by variant. Longitudinal evaluation suggested that DBS-based IgG and ACE2 inhibition levels were anticorrelated with infection risk, with higher sensitivity noted for ACE2 inhibition and variant-matched measures. IgG and ACE2 inhibition levels decreased over time, with more durable responses observed in participants whose most recent priming event was infection vs vaccination.

Conclusions: Findings suggest that variant-specific SARS-CoV-2 antibody levels may be a useful correlate of protection for infection, which has important implications for vaccination recommendations and evaluating infection risk. High-throughput assays measured via DBS may have utility in timing of boosters at the population or individual level.