Impaired mucosal IgA response to SARS-CoV-2 in patients with inborn errors of immunity

Background: Patients with inborn errors of immunity (IEI) often exhibit impaired responses to vaccination and infection, yet their systemic and mucosal antibody dynamics against SARS-CoV-2 remain incompletely understood. Methods: We investigated humoral immunity in 93 IEI patients recruited during the early phase of the pandemic, including pediatric patients with confirmed infection (n=64) and adult patients who received complete inactivated COVID-19 vaccination (n=29). Patients were classified as having primary antibody deficiency (PAD), combined immunodeficiency, or innate immune defects. Results: Receptor-binding domain (RBD)-specific IgG levels were comparable between infected children and vaccinated adults; however, PAD patients exhibited the weakest systemic and mucosal humoral responses, with markedly reduced salivary IgA. To validate these findings, we conducted a two-year follow-up of 15 PAD patients compared with 15 healthy controls. Despite regular intravenous immunoglobulin (IVIg) therapy, PAD patients had a ~4-fold higher re-infection rate than controls, with persistently low IgA and IgM in mucosal secretions. IVIg normalized IgG in serum, saliva, and nasal fluids but failed to restore mucosal IgA, which strongly correlated with re-infection frequency. Moreover, IgG responses to the latest emerging variants at the time of study (XBB.1.5, JN.1) declined in both groups, while mucosal IgA was more durable in controls. Conclusion: These findings underscore the critical role of mucosal IgA in protection and highlight persistent vulnerability in PAD patients despite IgG replacement therapy.