Multi-center nationwide comparison of seven serology assays reveals a SARS-CoV-2 non-responding seronegative subpopulation

Abstract

Background: An Israeli national taskforce performed a multi-center clinical and analytical validation of seven serology assays to determine their utility and limitations for SARS-CoV-2 diagnosis. Methods: Serology assays from Roche, Abbott, Diasorin, BioMerieux, Beckman-Coulter, Siemens, and Mt.-Sinai ELISA were included. Negative samples from 2391 individuals representative of the Israeli population, and 698 SARS-CoV-2 PCR positive patients, collected between March and May 2020, were analyzed Findings: Immunoassays sensitivities between 81.5%-89.4% and specificities between 97.7%-100% resulted in a profound impact on the expected Positive Predictive Value (PPV) in low (<15%) prevalence scenarios. No meaningful increase was detected in the false positive rate in children compared to adults. A positive correlation between disease severity and antibody titers, and no decrease in antibody titers in the first 8 weeks after PCR positivity was observed. We identified a subgroup of symptomatic SARS-CoV-2 positive patients (~5% of patients), who remained seronegative across a wide range of antigens, isotypes, and technologies. Interpretation: wThe commercially available automated immunoassays exhibit significant differences in performance and expected PPV in low prevalence scenarios. The low false-positivity rate in under 20 0 s suggests that cross-reactive immunity from previous CoV strains is unlikely to explain the milder disease course in children. Finding no decrease in antibody titers in the first 8 weeks is in contrast to some reports of short half-life for SARS-CoV-2 antibodies. The~5% who were seronegative non-responders, using multiple

Evaluation of Antibody Response in Symptomatic and Asymptomatic COVID-19 Patients and Diagnostic Assessment of New IgM/IgG ELISA Kits

“…This could be due to several reasons, including false-positive RT-PCR test, reactive RT-PCR with high CT value, an early-stage infection, a transient antibody response, no production of an antibody response, or production of antibodies that are below the detection level of the assays [36,37,39,48]. Some studies have indicated similar findings where they failed to detect a SARS-CoV-2 antibody response in variable portions of their COVID-19 sample cohorts [54][55][56].…”

SARS-CoV-2 reinfection in a cohort of 43,000 antibody-positive individuals followed for up to 35 weeks

“…Results were interpreted according to the manufacturer's instructions (reactive: optical density (proxy for antibody titer [24]) cutoff index ≥1.0 vs. non-reactive: optical density cutoff index <1.0).…”

The role of children in the spread of COVID-19: Using household data from Bnei Brak, Israel, to estimate the relative susceptibility and infectivity of children

“…A serological survey was conducted in Bnei Brak during June 2020. The survey was performed using a kit of the Abbott SARS-CoV-2 IgG, whose specificity was estimated as ∼100% and whose sensitivity at ≥ 21 days was estimated as ∼85% [19,20]. As part of this survey, a subset of the households in our data set could be serologically tested.…”

“…(1) We assume that all individuals who tested positive with PCR were indeed infected (even if a serological test was negative -since the serological tests have a 15% false negative rate [20]).…”