Single-Cell Profiling of the Antigen-Specific Response to BNT162b2 SARS-CoV-2 RNA Vaccine

Kramer, Kevin J.; Wilfong, Erin M.; Voss, Kelsey; Barone, Sierra M.; Shiakolas, Andrea R.; Raju, Nagarajan; Roe, Caroline E.; Suryadevara, Naveenchandra; Walker, Lauren; Wall, Steven C.; Paulo, Ariana; Schaefer, Samuel; Dahunsi, Debolanle; Westlake, Camille S.; Crowe, James E.; Carnahan, Robert H.; Rathmell, Jeffrey C.; Bonami, Rachel H.; Georgiev, Ivelin S.; Irish, Jonathan M.

RNA-based vaccines against SARS-CoV-2 are critical to limiting COVID-19 severity and spread. Cellular mechanisms driving antigen-specific responses to these vaccines, however, remain uncertain. We used single-cell technologies to identify and characterized antigen-specific cells and antibody responses to the RNA vaccine BNT162b2 in longitudinal samples from a cohort of healthy donors. Mass cytometry and machine learning pinpointed a novel expanding, population of antigen-specific non-canonical memory CD4+ and CD8+ T cells. B cell sequencing suggested progression from IgM, with apparent cross-reactivity to endemic coronaviruses, to SARS-CoV-2-specific IgA and IgG memory B cells and plasmablasts. Responding lymphocyte populations correlated with eventual SARS-CoV-2 IgG and a donor lacking these cell populations failed to sustain SARS-CoV-2-specific antibodies and experienced breakthrough infection. These integrated proteomic and genomic platforms reveal an antigen-specific cellular basis of RNA vaccine-based immunity. ONE SENTENCE SUMMARY Single-cell profiling reveals the cellular basis of the antigen-specific response to the BNT162b2 SARS-CoV-2 RNA vaccine.