Transient anti-interferon autoantibodies in the airways are associated with efficient recovery from COVID-19

Pre-existing anti-interferon alpha (anti-IFN-α) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti-IFN-α autoantibodies in the airways -- the initial site of infection -- can also determine disease outcomes. In this study, we developed a new multiparameter technology, flowBEAT, to quantify and profile the isotypes of anti-IFN-α and anti-SARS-CoV-2 antibodies in longitudinal samples collected over 20 months from the airway and matching blood of 129 donors with mild, moderate, and severe COVID-19. We found unexpectedly that nasal anti-IFN-α autoantibodies were induced post-infection onset in more than 70% of mild to moderate COVID-19 cases and associated with robust anti-SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti-IFN-α autoantibodies followed the peak of host IFN-α production and waned with disease recovery, revealing a regulated balance between IFN-α and anti-IFN-α response. Notably, only a subset of mild to moderate patients progressed to develop systemic anti-IFN-α, which correlated with systemic inflammation and worsened symptoms. In contrast, patients with life-threatening COVID-19 sustained elevated anti-IFN-α in both airways and blood, coupled with uncontrolled viral load and IFN-α production. Our studies thereby reveal a novel protective role for nasal anti-IFN-α autoantibodies in the immunopathology of COVID-19 and, more broadly, suggest that anti-IFN-α may serve an important regulatory function to restore homeostasis following viral invasion of the respiratory mucosa. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) awards R21AI167032 (E.E.B.G.) and R01AI123126-05S1 (E.E.B.G.); and by the Program for Breakthrough Biomedical Research Award (N.R.R., S.A.L., E.E.B.G.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board (IRB) of Emory University gave ethical approval for this work under IRB protocol #00003368 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. The code will be available on the Ghosn Lab GitHub page: github.com/Ghosn-Lab.