Multi-center nationwide comparison of seven serology assays reveals a SARS-CoV-2 non-responding seronegative subpopulation
Open accessAbstract
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.
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- Authors
- Oved, K., Olmer, L., Shemer-Avni, Y., Wolf, T., Supino-Rosin, L., Prajgrod, G., Shenhar, Y., Payorsky, I., Cohen, Y., Kohn, Y., Indenbaum, V., Lazar, R., Geylis, V., Oikawa, M. T., Shinar, E., Stoyanov, E., Keinan-Boker, L., Bassal, R., Reicher, S., Yishai, R., Bar-Chaim, A., Doolman, R., Reiter, Y., Mendelson, E., Livneh, Z., Freedman, L. S., & Lustig, Y.
- Affiliations
- Sheba Medical Center (IL)
- Maccabi Healthcare Services (IL)
- Ministry of Defense (IL)
- Magen David Adom (IL)
- Israel Ministry of Health (IL)
- Technion – Israel Institute of Technology (IL)
- Tel Aviv University (IL)
- Weizmann Institute of Science (IL)
- Corresponding author
- Lustig, Yaniv
- ORCID
- Venue
- EClinicalMedicine
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 29-30
- Pages
- 100651
- ISSN
- 2589-5370 (ISSN-L)
- PMC
- PMC7676374
- OpenAlex
- W3099879565
- Cited by
- 129
- References
- 32
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 14 · 2022: 33 · 2021: 71 · 2020: 1
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EClinicalMedicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Health, State of Israel
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 detection and testing
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- SARS-CoV-2, immunoassay validation, antibody titers, positive predictive value, low prevalence, children, disease severity, reinfection risk, antibody half-life, immunological cross-reactivity, assay sensitivity and specificity
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