Mucosal and systemic immune correlates of viral control after SARS-CoV-2 infection challenge in seronegative adults.

Human infection challenge permits in-depth, early, and pre-symptomatic characterization of the immune response, enabling the identification of factors that are important for viral clearance. Here, we performed intranasal inoculation of 34 young adult, seronegative volunteers with a pre-Alpha severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain. Of these participants, 18 (53%) became infected and showed an interferon-dominated mediator response with divergent kinetics between nasal and systemic sites. Peripheral CD4⁺ and CD8⁺ T cell activation and proliferation were early and robust but showed distinct kinetic and phenotypic profiles; antigen-specific T cells were largely CD38⁺Ki67⁺ and displayed central and effector memory phenotypes. Both mucosal and systemic antibodies became detectable around day 10, but nasal antibodies plateaued after day 14 while circulating antibodies continued to rise. Intensively granular measurements in nasal mucosa and blood allowed modeling of immune responses to primary SARS-CoV-2 infection that revealed CD8⁺ T cell responses and early mucosal IgA responses strongly associated with viral control, indicating that these mechanisms should be targeted for transmission-reducing intervention. Editor's summary: The COVID-19 pandemic has provided unprecedented immunological insight into how humans fight respiratory virus infections, but the earliest stages of SARS-CoV-2 infection remain poorly characterized. Wagstaffe et al. conducted a human SARS-CoV-2 infection challenge study, enabling analysis of the innate and adaptive immune responses during the early postexposure period. Of 34 seronegative young adults inoculated, 18 developed sustained infections, which were accompanied by a systemic interferon-dominated inflammatory response preceding that in nasal lining fluid. Modeling of the immune response identified CD8⁺ T cell and early mucosal IgA responses as strongly associated with viral control, suggesting that vaccines that optimally induce these responses may help reduce transmission. —Claire Olingy [ABSTRACT FROM AUTHOR]