Seroincidence of SARS-CoV-2 Infection Prior to and During the Rollout of Vaccines in a Community-based Prospective Cohort of U.S. Adults

Background: Infectious disease surveillance systems, which largely rely on diagnosed cases, underestimate the true incidence of SARS-CoV-2 infection, due to under-ascertainment and underreporting. We used repeat serologic testing to measure N-protein seroconversion in a well-characterized cohort of U.S. adults with no serologic evidence of SARS-CoV-2 infection to estimate the incidence of SARS-CoV-2 infection and characterize risk factors, with comparisons before and after the start of the SARS-CoV-2 vaccine and variant eras.

Methods: We assessed the incidence rate of infection and risk factors in two sub-groups (cohorts) that were SARS-CoV-2 N-protein seronegative at the start of each follow-up period: 1) the pre-vaccine/wild-type era cohort (n=3,421), followed from April to November 2020; and 2) the vaccine/variant era cohort (n=2,735), followed from November 2020 to June 2022. Both cohorts underwent repeat serologic testing with an assay for antibodies to the SARS-CoV-2 N protein (Bio-Rad Platelia SARS-CoV-2 total Ab). We estimated crude incidence and sociodemographic/epidemiologic risk factors in both cohorts. We used multivariate Poisson models to compare the risk of SARS-CoV-2 infection in the pre-vaccine/wild-type era cohort (referent group) to that in the vaccine/variant era cohort, within strata of vaccination status and epidemiologic risk factors (essential worker status, child in the household, case in the household, social distancing).

Findings: In the pre-vaccine/wild-type era cohort, only 18 of the 3,421 participants (0.53%) had ≥1 vaccine dose by the end of follow-up, compared with 2,497/2,735 (91.3%) in the vaccine/variant era cohort. We observed 323 and 815 seroconversions in the pre-vaccine/wild-type era and the vaccine/variant era and cohorts, respectively, with corresponding incidence rates of 9.6 (95% CI: 8.3-11.5) and 25.7 (95% CI: 24.2-27.3) per 100 person-years. Associations of sociodemographic and epidemiologic risk factors with SARS-CoV-2 incidence were largely similar in the pre-vaccine/wild-type and vaccine/variant era cohorts. However, some new epidemiologic risk factors emerged in the vaccine/variant era cohort, including having a child in the household, and never wearing a mask while using public transit. Adjusted incidence rate ratios (aIRR), with the entire pre-vaccine/wild-type era cohort as the referent group, showed markedly higher incidence in the vaccine/variant era cohort, but with more vaccine doses associated with lower incidence: aIRR=5.3 (95% CI: 4.2-6.7); aIRR=5.1 (95% CI: 4.2-7.3); aIRR=2.5 (95% CI: 2.1-3.0), and aIRR=1.65 (95% CI: 1.3-2.1). These associations were essentially unchanged in risk factor-stratified models.

Interpretation: In SARS-CoV-2 N protein seronegative individuals, large increases in incidence and newly emerging epidemiologic risk factors in the vaccine/variant era likely resulted from multiple co-occurring factors, including policy changes, behavior changes, surges in transmission, and changes in SARS-CoV-2 variant properties. While SARS-CoV-2 incidence increased markedly in most groups in the vaccine/variant era, being up to date on vaccines and the use of non-pharmaceutical interventions (NPIs), such as masking and social distancing, remained reliable strategies to mitigate the risk of SARS-CoV-2 infection, even through major surges due to immune evasive variants. Repeat serologic testing in cohort studies is a useful and complementary strategy to characterize SARS-CoV-2 incidence and risk factors.