Antibody titer levels and the effect on subsequent SARS-CoV-2 infection in a large US-based cohort

Abstract

Despite a growing amount of data around the kinetics and durability of the antibody response induced by vaccination and previous infection, there is little understanding of whether or not a given quantitative level of antibodies correlates to protection against SARS-CoV-2 infection or reinfection. In this study, we examine SARS-CoV-2 anti-spike receptor binding domain (RBD) antibody titers and subsequent SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) tests in a large cohort of US-based patients. We analyzed antibody test results in a cohort of 22,204 individuals, 6.8% (n = 1,509) of whom eventually tested positive for SARS-CoV-2 RNA, suggesting infection or reinfection. Kaplan-Meier curves were plotted to understand the effect of various levels of anti-spike RBD antibody titers (classified into discrete ranges) on subsequent RT-PCR positivity rates. Statistical analyses included fitting a Cox proportional hazards model to estimate the age-, sex- and exposure-adjusted hazard ratios for S antibody titer, using zip-code positivity rates by week as a proxy for COVID-19 exposure. It was found that the best models of the temporally associated infection risk were those based on log antibody titer level (HR = 0.836 (p < 0.05)). When titers were binned, the hazard ratio associated with antibody titer >250 Binding Antibody Units (BAU) was 0.27 (p < 0.05, 95% CI [0.18, 0.41]), while the hazard ratio associated with previous infection was 0.20 (p < 0.05, 95% CI [0.10, 0.39]). Fisher exact odds ratio (OR) for Ab titers <250 BAU showed OR = 2.84 (p < 0.05; 95% CI: [2.30, 3.53]) for predicting the outcome of a subsequent PCR test. Antibody titer levels correlate with protection against subsequent SARS-CoV-2 infection or reinfection when examining a cohort of real-world patients who had the spike RBD antibody assay performed.

Keywords: AUC, Area Under the Curve; Antibody; BAU, Binding Antibody Units; COVID-19; HR, Hazard Ratio; IQR, Interquartile Range; Nucleocapsid; OR, Odds Ratio; RBD, Receptor Binding Domain; ROC, Receiver operating characteristic; RT-PCR, Reverse Transcription Polymerase Chain Reaction; SARS-CoV-2; Seroprevalence; Spike.

Fig. 1

Kaplan-Meier curves showing time to positive RT-PCR tests, where negative RT-PCR tests indicate negativity, for all patients (A) and for patients categorized by previous positive (+) or negative (−) confirmed-COVID-19 before semi-quantitative anti-spike assay by RT-PCR or nucleocapsid assay (B). X-axis is days, y-axis is proportion of cohort who remains negative RT-PCR. Buckets are 0, 1–249, and 250+ representing spike antibody titer. A: All patients segmented by antibody titer level (Ab). B: All patients segmented by both antibody titer level (Ab) and evidence of previous infection through positive PCR test and/or Nucleocapsid (N) antibody test positivity.

Fig. 2

Hazard Ratio Forest plot showing log-scaled hazards for top model candidate.