Pegylated-interferon-{lambda} 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-{lambda}) 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-{lambda} by single cell RNA sequencing and measured SARS-CoV-2-specific T cell and antibody responses between placebo and PEG-IFN-{lambda}-treated patients. PEG-IFN-{lambda} 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-{lambda} 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-{lambda} can overcome the delay in adaptive immunity to accelerate viral clearance in patients most at risk for severe disease. Taken together, PEG-IFN-{lambda} offers an early COVID-19 treatment option for outpatients to boost innate antiviral defenses without dampening peripheral SARS-CoV-2 adaptive immunity