The impact of T cell selection on vaccine durability

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Project Summary An ongoing outbreak of a novel coronavirus infection (COVID-19) has claimed millions of lives and disrupted social infrastructures around the world. Fortunately, the new mRNA vaccines from Moderna or Pfizer/BioNTech are highly effective against SARS-CoV-2. However, much remains unknown about the longevity of memory responses generated by the new mRNA-based vaccine platform in humans. With the emergence of new viral variants, there is also the need to have a flexible type of immunologic memory that is not only long-lasting but can also respond to mutated viruses. My lab studies human T cell memory. We have shown that the human pre-immune T cell repertoire for a novel pathogen is shaped by past antigen experiences and contains cross- reactive memory T cells that could compete with naïve T cells. Using a highly effective live attenuated yellow fever virus (YFV) vaccine as a model for novel infectious challenge, we tested how pre-immune repertoire impacts post-vaccine response. Multiple YFV-specific populations were identified longitudinally within the same individual using peptide-MHC (pMHC) tetramers. Extensive single-cell T cell receptor (TCR) sequencing on tetramer+ cells was used to follow progenies of the same parent cells over time. We found that vaccine selectively recruits initially rare but more responsive T cells, leading to better repertoire fitness and higher TCR diversity after vaccination. Having a diverse TCR repertoire has been directly linked to protective T cell responses and host survival in mice. For fast evolving pathogens, the diversity in T cell composition may additionally limit escape variants as mutations emerge. Here, we will use the mRNA vaccines for COVID-19 (COVID vaccines) as a model to study the durability and the breadth of T cell responses elicited by mRNA- based vaccine strategies. We hypothesize that effective peripheral T cell selection is critical for maintaining durable immunity against actively mutating viruses. Here we will build on established biological insights, resources, and donor recruitment infrastructures to determine: (1) if COVID vaccine drives effective repertoire selection and diversification, (2) how boosting enhances CD4+ T cell diversity and variant recognition, and (3) how post-vaccine memory cells are maintained and change with time. The proposed experiments will map the entire trajectory of vaccine-induced response using precise molecular and cellular tools. Data from this study will provide vital knowledge on the quality, the breadth, and the longevity of CD4+ T cell response to the mRNA vaccines in humans. Beyond COVID, insights revealed by the proposed research will be relevant for understanding how immunological memory is generated and preserved. The proposed research will therefore have broad impact and could aid future development of improved vaccine strategies for other pathogens.