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High prevalence of undocumented SARS-CoV-2 infections revealed by analysis of nucleocapsid-specific IgG responses in diagnosed and undiagnosed individuals

Blom, Kim ; Galanis, Ilias ; Bacchus, Philip LU ; Sondén, Klara ; Bujila, Ioana ; Efimova, Tatiana ; Garli, Fredrik ; Mansjö, Mikael ; Movert, Elin LU and Pettke, Aleksandra , et al. (2025) In PLOS global public health 5(1).
Abstract

Acute SARS-CoV-2 infections are not always diagnosed; hence an unknown proportion of all infections are not documented. SARS-CoV-2 can induce spike and nucleocapsid protein specific IgG antibodies, which can be detected in seroprevalence studies to identify a previous infection. However, with the introduction of vaccines containing the spike protein it is no longer possible to use spike-IgG as a marker of infection. In many countries marketed vaccines do not include the nucleocapsid protein, allowing the use of nucleocapsid-specific IgG (N-IgG) as a specific marker for previous infection. Importantly however, not all SARS-CoV-2-infected individuals develop detectable N-IgG responses and there are reports of waning of N-IgG titers in... (More)

Acute SARS-CoV-2 infections are not always diagnosed; hence an unknown proportion of all infections are not documented. SARS-CoV-2 can induce spike and nucleocapsid protein specific IgG antibodies, which can be detected in seroprevalence studies to identify a previous infection. However, with the introduction of vaccines containing the spike protein it is no longer possible to use spike-IgG as a marker of infection. In many countries marketed vaccines do not include the nucleocapsid protein, allowing the use of nucleocapsid-specific IgG (N-IgG) as a specific marker for previous infection. Importantly however, not all SARS-CoV-2-infected individuals develop detectable N-IgG responses and there are reports of waning of N-IgG titers in previously infected individuals, complicating the use of N-IgG in seroprevalence studies. Here, our aim was to investigate N-IgG as a marker for previous infection. To this end we analyzed a well characterized cohort (n = 2,583; sampled in March, 2022), including 612 participants with a previously diagnosed and documented SARS-CoV-2-infection. We show that 75% (460/612) of the confirmed SARS-CoV-2-infected participants were N-IgG positive, and that the frequency of seropositivity was stable for at least 105 weeks after the latest documented SARS-CoV-2-infection. Among participants with no documented SARS-CoV-2-infection, 32.6% (642/1971) were N-IgG-positive, suggesting a previous infection. Assuming similar frequency of N-IgG-seronegative cases in previously diagnosed and undiagnosed individuals we further estimate that 214 of the 1329 undiagnosed and N-IgG-negative cases had been previously infected, indicating a total infection rate of 56.8% (1,468/2,583), clearly higher than the documented 23.7% rate of infection, in this cohort. In conclusion, our results suggest that while N-IgG is a good marker of previous SARS-CoV-2-infection the large proportion of previously infected N-IgG-negative individuals introduces a risk forFunding: This work was funded by grants provided to the Public Health Agency of Sweden (grant nos. S2020/0281/FS and S2020/08532 FS); by the Swedish state, under an agreement between the Swedish government and the county councils (ALFGBG-965885; MG); by the Swedish Research Council (2021-05045 & 2021-06545; MG); and by King Gustaf V:s and Queen Victoria´s Foundation (MG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Competing interests: The authors have declared that no competing interests exist.underestimations of total level of previously infected individuals in a population. Accounting for this dark number of undiagnosable cases can provide better estimates of total level of infected individuals in a population.

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published
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PLOS global public health
volume
5
issue
1
article number
e0003300
publisher
Public Library of Science (PLoS)
external identifiers
  • pmid:39841747
  • scopus:85215573458
ISSN
2767-3375
DOI
10.1371/journal.pgph.0003300
language
English
LU publication?
yes
id
9817ea67-e4c1-40bd-8c23-c41ffaa05ecc
date added to LUP
2025-04-02 10:33:59
date last changed
2025-07-09 18:29:14
@article{9817ea67-e4c1-40bd-8c23-c41ffaa05ecc,
  abstract     = {{<p>Acute SARS-CoV-2 infections are not always diagnosed; hence an unknown proportion of all infections are not documented. SARS-CoV-2 can induce spike and nucleocapsid protein specific IgG antibodies, which can be detected in seroprevalence studies to identify a previous infection. However, with the introduction of vaccines containing the spike protein it is no longer possible to use spike-IgG as a marker of infection. In many countries marketed vaccines do not include the nucleocapsid protein, allowing the use of nucleocapsid-specific IgG (N-IgG) as a specific marker for previous infection. Importantly however, not all SARS-CoV-2-infected individuals develop detectable N-IgG responses and there are reports of waning of N-IgG titers in previously infected individuals, complicating the use of N-IgG in seroprevalence studies. Here, our aim was to investigate N-IgG as a marker for previous infection. To this end we analyzed a well characterized cohort (n = 2,583; sampled in March, 2022), including 612 participants with a previously diagnosed and documented SARS-CoV-2-infection. We show that 75% (460/612) of the confirmed SARS-CoV-2-infected participants were N-IgG positive, and that the frequency of seropositivity was stable for at least 105 weeks after the latest documented SARS-CoV-2-infection. Among participants with no documented SARS-CoV-2-infection, 32.6% (642/1971) were N-IgG-positive, suggesting a previous infection. Assuming similar frequency of N-IgG-seronegative cases in previously diagnosed and undiagnosed individuals we further estimate that 214 of the 1329 undiagnosed and N-IgG-negative cases had been previously infected, indicating a total infection rate of 56.8% (1,468/2,583), clearly higher than the documented 23.7% rate of infection, in this cohort. In conclusion, our results suggest that while N-IgG is a good marker of previous SARS-CoV-2-infection the large proportion of previously infected N-IgG-negative individuals introduces a risk forFunding: This work was funded by grants provided to the Public Health Agency of Sweden (grant nos. S2020/0281/FS and S2020/08532 FS); by the Swedish state, under an agreement between the Swedish government and the county councils (ALFGBG-965885; MG); by the Swedish Research Council (2021-05045 &amp; 2021-06545; MG); and by King Gustaf V:s and Queen Victoria´s Foundation (MG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Competing interests: The authors have declared that no competing interests exist.underestimations of total level of previously infected individuals in a population. Accounting for this dark number of undiagnosable cases can provide better estimates of total level of infected individuals in a population.</p>}},
  author       = {{Blom, Kim and Galanis, Ilias and Bacchus, Philip and Sondén, Klara and Bujila, Ioana and Efimova, Tatiana and Garli, Fredrik and Mansjö, Mikael and Movert, Elin and Pettke, Aleksandra and Rapp, Marie and Sperk, Maike and Söderholm, Sandra and Asin, Karin Valentin and Zanetti, Sarah and Gisslén, Magnus and Bråve, Andreas and Groenheit, Ramona and Klingström, Jonas}},
  issn         = {{2767-3375}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLOS global public health}},
  title        = {{High prevalence of undocumented SARS-CoV-2 infections revealed by analysis of nucleocapsid-specific IgG responses in diagnosed and undiagnosed individuals}},
  url          = {{http://dx.doi.org/10.1371/journal.pgph.0003300}},
  doi          = {{10.1371/journal.pgph.0003300}},
  volume       = {{5}},
  year         = {{2025}},
}