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

Kfir Oved, Liraz Olmer, Yonat Shemer-Avni, Tamar Wolf, Lia Supino-Rosin, George Prajgrod, Yotam Shenhar, Irina Payorsky, Yuval Cohen, Yishai Kohn, Victoria Indenbaum, Rachel Lazar, Valeria Geylis, Michal Tepperberg Oikawa, Eilat Shinar, Evgeniy Stoyanov, Lital Keinan-Boker, Ravit Bassal, Shay Reicher, Ruti YishaiAdina Bar-Chaim, Ram Doolman, Yoram Reiter, Ella Mendelson, Zvi Livneh, Laurence S. Freedman, Yaniv Lustig*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 an in-house RBD 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: The commercially available automated immunoassays exhibit significant differences in performance and expected PPV in low prevalence scenarios. The low false-positivity rate in under 20′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 assays in a population-wide manner, represents the proportion of patients that may be at risk for re-infection. Funding: Israel Ministry of Health.

Original languageEnglish
Article number100651
JournalEClinicalMedicine
Volume29-30
DOIs
StatePublished - Dec 2020

Funding

FundersFunder number
Chaim Sheba Medical Center
Nehemia Rubin Excellence in Biomedical Research

    Keywords

    • Antibodies
    • COVID-19
    • IgG
    • SARS-CoV-2
    • Serology
    • Seronegative subpopulation
    • Validation study

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