ORIGINAL RESEARCH article
Front. Immunol.
Sec. Primary Immunodeficiencies
Impaired mucosal IgA response to SARS-CoV-2 in patients with inborn errors of immunity
Provisionally accepted
Fanglei Zuo1
Samaneh Delavari2
Sima Shokri3Yating Wang1Farhad Abolnezhadian4Sara Iranparast4Fereshte Salami2Samin Sharafian5
Zahra Chavoshzadeh5
Nima Rezaei2
Hassan Abolhassani6*- 1Karolinska Institutet, Stockholm, Sweden
- 2Tehran University of Medical Sciences, Tehran, Iran
- 3Iran University of Medical Sciences, Tehran, Iran
- 4Ahvaz Jondishapour University of Medical Sciences, Ahvaz, Iran
- 5Shahid Beheshti University of Medical Sciences, Tehran, Iran
- 6Department of Medical Biochemistry and Biophysics, Karolinska Institutet (KI), Stockholm, Sweden
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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.
Keywords: Breakthrough infection, inborn errors of immunity, Mucosalimmunity, primary antibody deficiency, SARS-CoV-2
Received: 01 Sep 2025; Accepted: 09 Feb 2026.
Copyright: © 2026 Zuo, Delavari, Shokri, Wang, Abolnezhadian, Iranparast, Salami, Sharafian, Chavoshzadeh, Rezaei and Abolhassani. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Hassan Abolhassani
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