Blom Kim, Galanis Ilias, Bacchus Philip, Sondén Klara, Bujila Ioana, Efimova Tatiana, Garli Fredrik, Mansjö Mikael, Movert Elin, Pettke Aleksandra, Rapp Marie, Sperk Maike, Söderholm Sandra, Valentin Asin Karin, Zanetti Sarah, Gisslén Magnus, Bråve Andreas, Groenheit Ramona, Klingström Jonas
Public Health Agency of Sweden, Solna, Sweden.
Lund University, Lund, Sweden.
PLOS Glob Public Health. 2025 Jan 22;5(1):e0003300. doi: 10.1371/journal.pgph.0003300. eCollection 2025.
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.
急性严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染并非总能得到诊断；因此，所有感染中未被记录的比例不明。SARS-CoV-2可诱导刺突蛋白和核衣壳蛋白特异性IgG抗体，可在血清流行率研究中检测到这些抗体，以确定既往感染情况。然而，随着含有刺突蛋白的疫苗的引入，不再可能将刺突-IgG用作感染标志物。在许多国家，市售疫苗不包含核衣壳蛋白，这使得可以将核衣壳特异性IgG（N-IgG）用作既往感染的特异性标志物。然而，重要的是，并非所有感染SARS-CoV-2的个体都会产生可检测到的N-IgG反应，并且有报告称既往感染个体的N-IgG滴度会下降，这使得N-IgG在血清流行率研究中的应用变得复杂。在此，我们的目的是研究N-IgG作为既往感染标志物的情况。为此，我们分析了一个特征明确的队列（n = 2583；于2022年3月采样），其中包括612名既往诊断并记录有SARS-CoV-2感染的参与者。我们发现，75%（460/612）确诊感染SARS-CoV-2的参与者N-IgG呈阳性，并且在最近一次记录的SARS-CoV-2感染后至少105周内，血清阳性频率保持稳定。在没有记录SARS-CoV-2感染的参与者中，32.6%（642/1971）N-IgG呈阳性，提示既往感染。假设既往诊断和未诊断个体中N-IgG血清阴性病例的频率相似，我们进一步估计，1329例未诊断且N-IgG阴性的病例中有214例曾被感染，表明该队列中的总感染率为56.8%（1468/2583），明显高于记录的23.7%的感染率。总之，我们的结果表明，虽然N-IgG是既往SARS-CoV-2感染的良好标志物，但既往感染的N-IgG阴性个体比例较大，存在低估人群中既往感染个体总数的风险。考虑到这一无法诊断的病例数可以更好地估计人群中感染个体的总数。
