A new serological study reports that acute SARS-CoV-2 infection rapidly raises antibody levels not only against the pandemic virus but also against the seasonal human coronaviruses that cause common colds. The finding, published in the journal Discover Viruses, adds to evidence that the immune response to SARS-CoV-2 departs from the classical antibody trajectory, in which immunoglobulin M appears first before the body class-switches to immunoglobulin G and immunoglobulin A. That atypical pattern, the authors argue, complicates the long-standing practice of using IgM as a marker of recent infection.
The research team, led by Guadalein Tanunliong and colleagues at the British Columbia public health laboratory network, analyzed serum samples from 51 people with nucleic acid amplification test-confirmed SARS-CoV-2 infection, collected between 0 and 14 days after symptom onset, and compared them with 30 pre-pandemic control samples collected before COVID-19 first appeared in British Columbia, Canada. All 51 infected participants were tested for IgA and IgM, while 26 of the 51 available samples were also tested for IgG. The infected individuals were hospitalized patients with a median age of 68 years, and the study was conducted under a provincial mandate to validate SARS-CoV-2 serological assays for outbreak investigations and seroprevalence work.
The investigators used a multiplex immunoassay, the V-PLEX Coronavirus Panel 2 from Meso Scale Discovery, to quantify antibodies against the spike proteins of the four endemic human coronaviruses, HCoV-229E, HCoV-NL63, HCoV-HKU1 and HCoV-OC43, as well as against the spike, nucleocapsid and receptor binding domain of ancestral SARS-CoV-2. Serum specimens were diluted 1:5000 and run on multi-spot plates with isotype-specific detection antibodies, and seropositivity thresholds were interpreted relative to validated signal cut-off values. The four endemic coronaviruses have circulated in humans since the 1960s, two of alpha lineage and two of beta lineage, and typically reinfect people every two to three years, so antibodies against them often persist at detectable levels throughout life.
The results confirmed that the antibody response to SARS-CoV-2 starts early and moves fast. Serum collected at both 0 to 7 days and 8 to 14 days after onset showed higher IgA, IgG and IgM levels against SARS-CoV-2 spike, receptor binding domain and nucleocapsid than the pre-pandemic controls, with statistically significant differences. Levels trended higher at 8 to 14 days than at 0 to 7 days across all three isotypes, with the difference reaching statistical significance for IgM. Percent seropositivity also climbed over time: at 0 to 7 days, IgA seropositivity ranged from 73 to 82 percent, slightly above IgG at 56 to 78 percent and IgM at 58 to 76 percent, while by 8 to 14 days IgG seropositivity reached 100 percent for all three SARS-CoV-2 targets, exceeding IgM rates of 83 percent for nucleocapsid and 94 percent for spike and receptor binding domain.
The cross-reactive signal emerged most clearly for the beta-lineage seasonal coronaviruses, HCoV-OC43 and HCoV-HKU1. IgM, IgA and IgG antibodies against these two viruses were elevated in infected individuals compared with pre-pandemic controls. At 0 to 7 days, IgM against HCoV-OC43 and IgG against HCoV-HKU1 were already significantly higher in the infected group, while other isotypes trended higher without reaching significance. By 8 to 14 days, all three isotypes against both beta coronaviruses were significantly higher in cases than controls. In contrast, most IgA and IgG responses against the alpha-lineage viruses HCoV-229E and HCoV-NL63 were not significantly different between groups, although IgM against HCoV-NL63 was significantly elevated at both time points.
To probe the association further, the team stratified infected individuals by their early SARS-CoV-2 antibody status. Among the 13 people who were seropositive for SARS-CoV-2 spike IgG at 0 to 7 days, the so-called early IgG responders, spike IgG levels correlated positively with IgG levels against the beta coronaviruses, with a Pearson correlation coefficient of 0.62 for HCoV-HKU1 and 0.81 for HCoV-OC43. Among the 5 early IgG non-responders, only HCoV-NL63 showed a significant correlation, and it was negative. The authors describe these analyses as exploratory, given the small subgroup sizes, but the pattern is consistent with the idea that a rapid early IgG response to SARS-CoV-2 may reflect recall of humoral memory from prior exposure to related seasonal coronaviruses.
IgM showed a parallel cross-reactive association. Among all 51 individuals tested for IgM, high SARS-CoV-2 spike IgM correlated positively with IgM against the seasonal coronavirus spike proteins during acute infection. At 0 to 7 days after onset, the correlation coefficients were highest for HCoV-HKU1 and HCoV-NL63, each at 0.76, followed by HCoV-229E at 0.49 and HCoV-OC43 at 0.45. Similar correlations held at 8 to 14 days, with the exception of HCoV-OC43, which did not correlate significantly at that later window. Linear regression models for the infected groups explained a moderate share of the variability, with R-squared values between 0.21 and 0.59, and were generally stronger at 0 to 7 days for HCoV-HKU1 and HCoV-NL63. Among pre-pandemic controls, by contrast, no correlation between seasonal coronavirus IgM and SARS-CoV-2 IgM was observed.
An exploratory comparison of IgM to IgG ratios reinforced the picture of an IgG-dominated early response to SARS-CoV-2. Infected individuals showed significantly lower IgM:IgG ratios against SARS-CoV-2 nucleocapsid and spike than controls, as early as 0 to 7 days after infection, and no significant shift in the ratios occurred between the two time windows. For the seasonal coronaviruses, anti-spike IgM:IgG ratios showed no significant differences between infected individuals and controls, remaining uniformly low for HCoV-229E, HCoV-HKU1 and HCoV-OC43. The exception was HCoV-NL63, where the IgM:IgG ratio was elevated in infected individuals, reaching statistical significance at 8 to 14 days, mirroring the elevated IgM levels against that virus.
The study also documented baseline cross-reactivity in the pre-pandemic controls. No pre-pandemic seropositivity was observed for SARS-CoV-2 spike for any isotype, but the controls did show seropositivity for the receptor binding domain, at 17 percent for IgG, 10 percent for IgA and 13 percent for IgM, and low-level seropositivity for nucleocapsid in 3 percent for IgA and IgG. The authors note that the receptor binding domain is a smaller protein that yields lower signals and lower positivity thresholds, increasing the likelihood of false positives, and that pre-pandemic cross-reactivity rates can vary with age, year and region.
The authors are careful about what the findings do and do not show. The cohort consisted of unvaccinated individuals infected with ancestral SARS-CoV-2, which the authors describe as a valuable reference point for defining early antibody kinetics without confounding from vaccination or reinfection, but the sample was small, drawn largely from hospitalized cases, and lacked clinical data on severity, comorbidities and sex-stratified analyses. There were no paired specimens for individual-level longitudinal follow-up, and the assay measured antibody quantities rather than function, so the cross-reactivity cannot be tied to neutralization or protection. The authors also cannot determine whether the early seasonal coronavirus responses reflect true antibody cross-reactivity or recall of conserved epitopes from prior exposures. Even so, they conclude that the early IgG, IgA and IgM responses to SARS-CoV-2 were associated with seasonal coronavirus responses, supporting earlier pandemic reports that IgM-based tests for recent infection are unreliable for SARS-CoV-2, and underscoring the importance of accounting for cross-reactivity when interpreting serological assays and assessing correlates of protection.
Subject of Research: Cross-reactive antibody responses to seasonal human coronaviruses following acute SARS-CoV-2 infection
Article Title: Cross-reactive IgM, IgA, and IgG antibody responses to seasonal human coronaviruses following acute SARS-CoV-2 infection
Article References: Tanunliong, G., Márquez, A. C., Krajden, M., Morshed, M., Jassem, A. N., & Sekirov, I. (2026). Cross-reactive IgM, IgA, and IgG antibody responses to seasonal human coronaviruses following acute SARS-CoV-2 infection. Discover Viruses, 3(1), Article 1. https://doi.org/10.1007/s44370-026-00036-1
Image Credits: AI Generated
DOI: 10.1007/s44370-026-00036-1
Keywords: SARS-CoV-2, human coronaviruses, cross-reactivity, IgM, IgG, IgA, serology, antibody kinetics, HCoV-OC43, HCoV-HKU1, multiplex immunoassay, immune imprinting
News Source: Kristina Jarvis. (October 30, 2026). Early SARS-CoV-2 infection triggers cross-reactive antibodies against seasonal coronaviruses. Scienmag.
