Community Cohort Study Maps Pre-Omicron SARS-CoV-2 Immunity Across Age Groups

When the Omicron variant swept across the world in late 2021, it met populations whose immune systems had been shaped by a patchwork of vaccinations and infections with earlier viral variants. Understanding that pre-Omicron landscape of immunity has become essential for interpreting why the variant spread so explosively and for guiding future vaccine strain selection. A new study published in PLOS One by Yangyupei Yang of the University of Michigan and colleagues now offers a detailed portrait of variant-specific antibody immunity in a well-characterized community cohort, using a battery of laboratory assays to measure how antibody responses targeted the original SARS-CoV-2 virus as well as the Delta, Beta, and Omicron variants.

The research drew on the Household Influenza Vaccine Evaluation study, known as the HIVE cohort, a longitudinal surveillance program that has followed roughly 300 households annually for acute respiratory illness. This infrastructure, originally built to study influenza transmission, proved to be a valuable resource for tracking SARS-CoV-2 immunity because participants undergo active surveillance for respiratory symptoms and provide serum samples that can be archived and analyzed retrospectively. For the present analysis, the team selected serum samples drawn between July 1 and December 31, 2021, a period that captures the interval just before Omicron displaced Delta as the dominant circulating strain.

From this collection, the researchers analyzed 156 serum samples from 117 participants. Adults accounted for 65.8 percent of the samples, and a majority of donors, 77.8 percent, had received vaccination during the analysis period. This composition reflects the reality of mid-2021 in the United States, when vaccine rollout had reached most adults but authorization for younger age groups was still limited or recent, leaving children with immunity derived almost exclusively from natural infection.

Methodologically, the study stands out for its systematic comparison of three complementary assay platforms. The first is a multiplex electrochemiluminescence assay, abbreviated ECL, which quantifies variant-specific immunoglobulin G antibodies binding to spike proteins from the original strain and from the Delta, Beta, and Omicron variants. The second is a pseudoviral neutralization assay, or PN, which uses engineered viruses carrying variant spike proteins to measure the functional ability of antibodies to block viral entry. The third is an ACE2 inhibition assay, which tests how effectively antibodies compete with the human ACE2 receptor for binding to the viral spike, a proxy for neutralizing capacity that can be run at higher throughput than live-virus neutralization.

The correlations among these platforms were strikingly high. Within the ECL IgG assays, Spearman rank correlation coefficients ranged from 0.95 to 1.00, indicating near-perfect agreement in how antibody concentrations measured against different variant antigens tracked together across samples. Within the ACE2 inhibition assays, correlations ranged from 0.70 to 0.99. Between platforms, ECL measurements correlated with pseudoviral neutralization at 0.81 to 0.83, and ACE2 inhibition correlated with neutralization at 0.88 to 0.95. These findings suggest that binding antibody titers, which are faster and cheaper to measure than functional neutralization tests, provide a reliable readout of the functional quality of the antibody response across antigenically distinct variants.

Receiver operating characteristic analysis, which evaluates how well a test discriminates between two states, was used to determine whether the assays could reliably identify vaccination status. The ECL IgG assays performed strongly, with areas under the curve between 0.84 and 0.88, sensitivity between 0.88 and 0.91, and specificity between 0.87 and 0.88. In practical terms, this means the binding assays could distinguish vaccinated from unvaccinated individuals with high accuracy. The ACE2 inhibition assays showed more variable performance, with areas under the curve ranging from 0.53 to 0.96, sensitivity from 0.17 to 0.93, and specificity from 0.91 to 1.00. Notably, some antigens related to the BA.2 sublineage of Omicron showed lower discrimination, a finding the authors attribute to the limited exposure of this cohort to Omicron antigens at the time of sampling, since most participants had never encountered Omicron through infection or vaccination with an Omicron-matched vaccine.

Beyond assay validation, the study used generalized additive mixed models to estimate how population immunity varied with age against each SARS-CoV-2 variant. The results showed that SARS-CoV-2 IgG concentrations generally increased with age and appeared to plateau in early adulthood. This age gradient reflects the combined influence of infection history and vaccination uptake, both of which were captured by the active surveillance infrastructure of the HIVE cohort. Younger children, who had fewer opportunities for infection and limited vaccine access during the study period, showed the lowest antibody concentrations, marking them as a susceptible group for continued surveillance.

The authors caution that estimates in the youngest age groups were imprecise because of small sample sizes, a limitation inherent in a cohort designed around households rather than stratified age sampling. Nevertheless, the concordance between the age-specific antibody patterns and the behavior and infection histories collected through active surveillance lends confidence to the overall picture. The study demonstrates that a high-throughput, low-volume assay strategy can describe strain-specific IgG measurement in a longitudinally followed community cohort, providing a template for ongoing serosurveillance as the virus continues to evolve.

The implications extend to vaccine strain selection, one of the most consequential decisions in pandemic response. Continued serosurveys that quantify variant-specific population immunity are critical for identifying which segments of the population lack protection against emerging variants and for informing the composition of updated vaccines. By validating that binding antibody assays correlate strongly with functional neutralization across variants, this study lowers the barrier to conducting such surveys at scale. As new variants emerge, the ability to rapidly measure strain-specific immunity in community cohorts, using small serum volumes and multiplex platforms, will remain a cornerstone of evidence-based pandemic preparedness.

Subject of Research: Evaluation of pre-Omicron population immunity for SARS-CoV-2 in the Household Influenza Vaccine Evaluation (HIVE) cohort

Article Title: Evaluation of pre-Omicron population immunity for SARS-CoV-2 in the Household Influenza Vaccine Evaluation (HIVE) cohort

Article References: Yang, Y., Juntila-Raymond, C., Callear, A., Smith, M., Atkinson, R. K., Zhao, Y., Shah, R., Santos, J. J. S., Hensley, S. E., Monto, A. S., & Martin, E. T. (2026). Evaluation of pre-Omicron population immunity for SARS-CoV-2 in the Household Influenza Vaccine Evaluation (HIVE) cohort. PLOS One, 21(10), e0360506. https://doi.org/10.1371/journal.pone.0360506

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0360506

Keywords: SARS-CoV-2, population immunity, serosurvey, HIVE cohort, variant-specific IgG, electrochemiluminescence assay, pseudoviral neutralization, ACE2 inhibition, vaccine strain selection, Omicron, Evaluation, pre-Omicron