Immune memory to SARS2 in a changing landscape

PROJECT SUMMARY – Project 2 SARS-CoV-2 (SARS2) remains a fundamental threat to global health and a leading cause of death. Here, we will address a number of important outstanding questions in the field of T cell memory to SARS2. Accordingly, we’ve established novel donor cohorts, including the Multiple Vaccinations and Infections (MVI) Cohort, with over 450 donors enrolled in an ongoing longitudinal study (total of 8 years). These samples reflect the real-life evolution of memory responses, from donors with up to 5 distinct immunizations and up to 4 different infections. The Breakthrough Infection (BTI) Cohort includes donors who provided large blood donations (leukapheresis) during the Delta and Omicron waves, and on-going recruitment as new variant waves arise. The Discordant Pairs (DP) cohort enrolled people sharing living arrangements where one individual experienced BTI infection, while the other tested negative. First, we will determine the evolution of memory T cell responses over repeated exposures and vaccinations in a real-life study spanning several years, using a multifaceted approach. We hypothesize that a history of immunization plus infection is associated with broad responses against antigens beyond S (spike), indicating a qualitative advantage in T cell responses. We will also consider the alternative, that previous immunizations imprint T cell responses and a pre-existing S response inhibits development of T cell responses against other SARS2 antigens. We will also study long term evolution of T cell memory responses as a function of type and number of exposures. We hypothesize that we will observe progressive functional maturation of memory T cells. Alternatively, we might observe progressive exhaustion and loss of functionality. We will also measure T cell memory longevity as a function of type and number of exposures. Finally, we will assess the impact of age on real-life evolution of SARS2-specific memory T cells in the context of repeated vaccinations and reinfections, by comparing responses between donors aged 20-39, 40-59, and 60 and over. We will further determine memory T cell responses in the BTI cohort utilizing apheresis samples collected in a shorter pre/post-infection time frame, leveraging knowing the exposure window and variant wave of exposure. We will probe if broad responses are detected against antigens beyond S, or if a pre-existing S response inhibits development of responses to other antigens. Further, is the epitope repertoire modulated with new, variant- specific epitopes being recognized? We will also determine SARS2-specific T cell responses from donors in the DP cohort. To explain why SARS2 exposed donors do not develop overt infection, we hypothesize that they might be higher vaccine responders; might be associated with previous asymptomatic infections and/or high levels of pre-existing immunity; and/or might have experienced an abortive infection. Finally, we will test the hypothesis that BTIs are associated with selective expansion of different T cell memory subpopulations, defined by varied antigen sensitivity and cross-reactivity patterns, and defined by different methodologies.