Th169 - Longitudinal Antigen-specific Immune Profiling During sars-cov-2 Breakthrough Infection Highlights Early Activation of Memory CD8 T Cells Followed by Later Activation of Memory B Cells

Timothy Johnston; Rishi Goel; Sokratis Apostolidis; Divij Mathew; Allison Greenplate; E. John Wherry

Abstract Text: SARS-CoV-2 infection of vaccinated individuals has become commonplace due to waning antibody and the evolution of immune evasive variants. Nevertheless, the risk of severe disease is lower in people who are vaccinated, likely due to the enhanced potency and accelerated kinetics of memory T and B cell responses. To date, there is little detailed data profiling the kinetics of memory T cell, B cell, and antibody responses during the early stages of infection. To evaluate the kinetics of recall immune responses during SARS-CoV-2 infection, we longitudinally sampled omicron-infected individuals during the days and weeks following symptom onset. The early response engaged Spike-specific plasmablasts and CD8 T cells, which were activated within 7 days of symptom onset. Activation of CD8 T cells was dominated by central memory cells but was observed in effector memory subsets as well, demonstrating that vaccination primes multi-functional memory CD8 T cells that respond during the first week of infection. Activation of Spike-binding memory B cells followed during the second week after symptom onset, marked by amplification of variant-binding and IgA class-switched memory B cells. Despite early detection of plasmablasts, neutralizing antibody titers did not increase until 15 days post-symptom onset. Responses targeting non-Spike proteins from SARS-CoV-2 had delayed kinetics and lesser magnitude compared to Spike-specific responses, supporting the notion that vaccine-primed recall responses are more potent than primary responses. These data demonstrate the functionality of mRNA vaccine-induced memory B and T cell populations and highlight CD8 T cells as first responders during SARS-CoV-2 breakthrough infection.