Cross-reactive IgM, IgA, and IgG antibody responses to seasonal human coronaviruses following acute SARS-CoV-2 infection

Abstract Background Antibody kinetics following SARS-CoV-2 infection differs from the classical trajectory, where infection initially elicits IgM responses before subsequent class-switching to IgG and IgA, complicating the use of IgM as a marker of recent SARS-CoV-2 infection. This atypical pattern may reflect cross-reactive memory responses against highly-related human coronaviruses (HCoV). Here, we investigated the interplay between early IgG, IgM, and IgA responses to SARS-CoV-2 infections and HCoV antibody responses. Methods Serum IgM, IgA, and IgG responses against the spike (S) of four HCoVs; and the S, nucleocapsid (N), and receptor binding domain (RBD) of SARS-CoV-2 were quantified by a multiplex immunoassay in acute SARS-CoV-2 cases (N = 51) 0–14 days post onset and pre-pandemic controls (N = 30). Results SARS-CoV-2 IgG levels and percent seropositivity were higher at 0–7 days compared to controls, increasing further at 8–14 days. Beta-HCoV IgA, IgG, and IgM were higher in cases than controls, increasing between 0 and 7 and 8–14 days. Among early (0–7 days) SARS-CoV-2 S IgG responders, IgG levels correlated positively with beta-HCoV S IgG (HCoV-HKU1: R = 0.62, P = 0.023 and HCoV-OC43: R = 0.81, P < 0.001) for IgG. High SARS-CoV-2 S IgM among infected individuals correlated positively with HCoV S IgM levels. Significance SARS-CoV-2 infection elicits cross-reactivity across IgM, IgG, and IgA responses to HCoVs, suggesting limitations in the use of IgM as a serological marker of recent infection. These findings highlight the complexity of immune responses to SARS-CoV-2 and the importance of accounting for potential cross-reactivity to related viruses when investigating serological markers of infection and assessing correlates of protection.