Early HHV-6 IgG and IgA responses during acute SARS-CoV-2 infection in relation to long COVID: a multicohort observational study

BACKGROUND: Long COVID is a heterogeneous condition associated with both early immune responses to SARS-CoV-2 and antibody responses to herpesviruses. However, herpesvirus-directed antibody responses during acute SARS-CoV-2 infection and their relationship to subsequent long COVID remain poorly understood. METHODS: We developed a multiplex bead-based serologic assay using recurrent, public peptide epitopes spanning all eight human herpesviruses. Antibody responses were profiled in longitudinal samples from acute SARS-CoV-2 infection and in early post-infection samples from participants in the NIH RECOVER observational cohort. IgG, IgA, and IgM responses were analysed using peptide-, virus-, and factor-level approaches. FINDINGS: During acute SARS-CoV-2 infection, a subset of individuals exhibited increased herpesvirus-directed IgA responses, particularly against beta-herpesviruses, without corresponding increases in IgG or IgM. In RECOVER participants, subsequent long COVID was associated with herpesvirus- and isotype-specific enrichment of high responders, most prominently HHV-6 IgA and HHV-1/HHV-2 IgG. Unsupervised factorisation identified distinct HHV-6 IgG- and IgA-dominant antibody programs with differing clinical and demographic associations. HHV-6 IgG responses were associated with lower symptom burden and relative enrichment among participants without long COVID, whereas HHV-6 IgA responses were associated with greater symptom burden. HHV-6 IgG responses also declined with increasing age, with the association more readily detected among females. INTERPRETATION: Early herpesvirus-directed antibody responses following SARS-CoV-2 infection exhibit distinct virus- and isotype-specific patterns associated with long COVID. These findings suggest that heterogeneity in long COVID may be linked to differential herpesvirus-directed humoural immune responses that emerge early after infection. FUNDING: This study was funded by Stanford Post-Acute Recovery Cohort; NIH and RECOVER grants; the Henry Gustav Floren Family Trust; the Stanford Department of Medicine Team Science Program; Stanford Institutes of Medicine Summer Research Program (SIMR); the Doris Duke Charitable Foundation; the SPARK Program; Nucleate Dojo; the Jessica Lynn Saal Memorial Award; the William and Marissa Rastetter Research Scholar Fund through the Robinson Life Sciences, Business, and Entrepreneurship Program; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health Award.