Seropositivity to Nucleoprotein to detect mild and asymptomatic SARS-CoV-2 infections: A complementary tool to detect breakthrough infections after COVID-19 vaccination?

Lotus L. van den Hoogen*, Gaby Smits, Cheyenne C.E. van Hagen, Denise Wong, Eric R.A. Vos, Michiel van Boven, Hester E. de Melker, Jeffrey van Vliet, Marjan Kuijer, Linde Woudstra, Alienke J. Wijmenga-Monsuur, Corine H. GeurtsvanKessel, Susanne P. Stoof, Daphne Reukers, Lisa A. Wijsman, Adam Meijer, Chantal B.E.M. Reusken, Nynke Y. Rots, Fiona R.M. van der Klis, Robert S. van BinnendijkGerco den Hartog

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Background: With COVID-19 vaccine roll-out ongoing in many countries globally, monitoring of breakthrough infections is of great importance. Antibodies persist in the blood after a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Since COVID-19 vaccines induce immune response to the Spike protein of the virus, which is the main serosurveillance target to date, alternative targets should be explored to distinguish infection from vaccination. Methods: Multiplex immunoassay data from 1,513 SARS-CoV-2 RT-qPCR-tested individuals (352 positive and 1,161 negative) without COVID-19 vaccination history were used to determine the accuracy of Nucleoprotein-specific immunoglobulin G (IgG) in detecting past SARS-CoV-2 infection. We also described Spike S1 and Nucleoprotein-specific IgG responses in 230 COVID-19 vaccinated individuals (Pfizer/BioNTech). Results: The sensitivity of Nucleoprotein seropositivity was 85% (95% confidence interval: 80–90%) for mild COVID-19 in the first two months following symptom onset. Sensitivity was lower in asymptomatic individuals (67%, 50–81%). Participants who had experienced a SARS-CoV-2 infection up to 11 months preceding vaccination, as assessed by Spike S1 seropositivity or RT-qPCR, produced 2.7-fold higher median levels of IgG to Spike S1 ≥ 14 days after the first dose as compared to those unexposed to SARS-CoV-2 at ≥ 7 days after the second dose (p = 0.011). Nucleoprotein-specific IgG concentrations were not affected by vaccination in infection-naïve participants. Conclusions: Serological responses to Nucleoprotein may prove helpful in identifying SARS-CoV-2 infections after vaccination. Furthermore, it can help interpret IgG to Spike S1 after COVID-19 vaccination as particularly high responses shortly after vaccination could be explained by prior exposure history.

Original languageEnglish
Pages (from-to)2251-2257
Number of pages7
Issue number15
Publication statusPublished - 1 Apr 2022

Bibliographical note

Funding Information:
This work was supported by the Dutch Ministry of Public Health, Welfare, and Sports (VWS).

Publisher Copyright: © 2022 The Authors


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