High prevalence of undocumented SARS-CoV-2 infections revealed by analysis of nucleocapsid-specific IgG responses in diagnosed and undiagnosed individuals.
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Blom K, Galanis I, Bacchus P, Sondén K, Bujila I, Efimova T, Garli F, Mansjö M, Movert E, Pettke A, Rapp M, Sperk M, Söderholm S, Valentin Asin K, Zanetti S, Gisslén M, Bråve A, Groenheit R, Klingström J
PLOS Glob Public Health 5 (1) e0003300
[2025-01-22; online 2025-01-22]
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 for 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.
PubMed 39841747
DOI 10.1371/journal.pgph.0003300
Crossref 10.1371/journal.pgph.0003300
pmc: PMC11753678
pii: PGPH-D-24-01077