{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:39:47Z","timestamp":1791333587665,"version":"4.3.1"},"reference-count":28,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ng Teng Fong Healthcare Innovation Project FY2021 grant","award":["NTF_AUG2021_2C2_CR_05"],"award-info":[{"award-number":["NTF_AUG2021_2C2_CR_05"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objectives: Neutralizing autoantibodies against type I interferons, particularly interferon-alpha (IFN-\u03b1), have been implicated in severe COVID-19 outcomes. This study investigated the prevalence and functional significance of anti-IFN-\u03b1 autoantibodies (AAbs) in hospitalized unvaccinated COVID-19 patients and their association with COVID-19 disease severity. Methods: We retrospectively analyzed serum samples from 122 hospitalized COVID-19 patients (asymptomatic\/mild: n = 69, moderate: n = 35, severe\/critical: n = 18) and 32 healthy uninfected controls. Anti-IFN-\u03b1 AAbs were quantified using a commercial enzyme-linked immunosorbent assay (ELISA) kit, with functional neutralization assessed via competitive ELISA and STAT1 phosphorylation inhibition. Statistical comparisons were performed using one-way ANOVA for parametric data and the Kruskal\u2013Wallis test for non-parametric variables. Results: Anti-IFN-\u03b1 AAbs were detected in 24.6% of COVID-19 patients, with all clinical subgroups showing significantly higher titers compared to healthy controls (p &lt; 0.05). Although no significant differences in anti-IFN-\u03b1 AAb levels were found between mild, moderate, and severe cases, patients with severe or critical COVID-19 had markedly higher mean titers (10,511.3 ng\/mL) compared to non-severe (mild + moderate) cases (375.2 ng\/mL, p &lt; 0.001). Strongly neutralizing anti-IFN-\u03b1 AAbs, with high titers (&gt;20,000 ng\/mL) and the ability to inhibit STAT1 phosphorylation, were identified in three severe COVID-19 cases. Anti-IFN-\u03b1 AAb levels correlated positively with CRP (r = 0.80, p &lt; 0.0001), LDH (r = 0.80, p = 0.001), and neutrophil count (r = 0.52, p = 0.003), and negatively with lymphocyte count (r = \u22120.59, p = 0.0006). Conclusions: Elevated and functionally neutralizing anti-IFN-\u03b1 AAbs were associated with severe COVID-19. These findings support their role as a risk factor for poor outcomes and emphasize the importance of early COVID-19 vaccination. Screening may help identify high-risk individuals, particularly those unvaccinated or with immune vulnerabilities.<\/jats:p>","DOI":"10.3390\/vaccines13070742","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T13:44:19Z","timestamp":1752241459000},"page":"742","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Role of Anti-Interferon-\u03b1 Autoantibodies in Severe COVID-19: Implications for Vaccination Prioritization"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1167-353X","authenticated-orcid":false,"given":"Xin Rong","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore 308433, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore 308433, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2656-136X","authenticated-orcid":false,"given":"Hwee Siew","family":"Howe","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore 308433, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khai Pang","family":"Leong","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore 308433, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elampirai","family":"Elangovan","sequence":"additional","affiliation":[{"name":"National Centre for Infectious Disease, Tan Tock Seng Hospital, Singapore 308442, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiung-Hui","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2635-4715","authenticated-orcid":false,"given":"Kok Ooi","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore 308433, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard Yu Hor","family":"Thong","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore 308433, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7812-9881","authenticated-orcid":false,"given":"Shawn","family":"Vasoo","sequence":"additional","affiliation":[{"name":"National Centre for Infectious Disease, Tan Tock Seng Hospital, Singapore 308442, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1119-4934","authenticated-orcid":false,"given":"Bernard Pui Lam","family":"Leung","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore 308433, Singapore"},{"name":"Health and Social Sciences, Singapore Institute of Technology, Singapore 828608, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Negishi, H., Taniguchi, T., and Yanai, H. 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