Pegylated-interferon-λ treatment-induced peripheral interferon stimulated genes are associated with SARS-CoV-2 viral load decline despite delayed T cell response in older individuals

Interferons (IFNs) are antiviral cytokines induced very early after SARS-CoV-2 infection and are crucial for viral clearance, shaping immunity, and preventing the development of severe COVID-19. We previously demonstrated that a single injection of peginterferon-lambda1 (PEG-IFN-λ) accelerated viral clearance in COVID-19 patients. To determine if the rapid viral decline was mediated by enhanced immunity, we assessed in vivo responses to PEG-IFN-λ by single cell RNA sequencing and measured SARS-CoV-2-specific T cell and antibody responses between placebo and PEG-IFN-λ-treated patients. PEG-IFN-λ treatment induced interferon stimulated genes in peripheral immune cells expressing IFNLR1 , with plasmacytoid dendritic cells having the greatest response, followed by B cells. PEG-IFN-λ did not significantly affect SARS-CoV-2-specific antibody levels in plasma or the magnitude or functionality of virus-specific T cells. However, we identified a delayed T cell response in older adults, suggesting that PEG-IFN-λ can overcome the delay in adaptive immunity to accelerate viral clearance in patients most at risk for severe disease. Taken together, PEG-IFN-λ offers an early COVID-19 treatment option for outpatients to boost innate antiviral defenses without dampening peripheral SARS-CoV-2 adaptive immunity ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by The Toronto COVID-19 Action Initiative (JJF), CIHR operating grant (COVID-19 Rapid Research Funding Opportunity) (DLT, JJF), University of Toronto (JJF), Ontario First COVID-19 Rapid Research Fund (JJF), Toronto General (JJF), Western Hospital Foundation (JJF) and University of Manitoba start-up funding (DS). ### 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: Patients were recruited into the Phase II clinical trial ([NCT04354259][1]) approved by Health Canada and provided written, informed consent under protocols approved by the University Health Network ethics board. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon request to the authors. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04354259&atom=%2Fmedrxiv%2Fearly%2F2022%2F03%2F03%2F2022.02.24.22271438.atom