The impact of T cell selection on vaccine durability

项目摘要 新型冠状病毒感染（COVID-19）的持续爆发已夺去数百万人的生命， 世界各地的社会基础设施。幸运的是，来自Moderna或辉瑞/BioNTech的新mRNA疫苗 对SARS-CoV-2非常有效。然而，关于记忆的寿命， 新的基于mRNA的疫苗平台在人类中产生的反应。随着新病毒的出现 变体，还需要有一种灵活的免疫记忆类型，不仅是持久的， 也能对变异病毒做出反应。我的实验室研究人类T细胞记忆我们已经证明， 针对新病原体的免疫前T细胞库是由过去的抗原经历形成的， 反应性记忆T细胞可以与幼稚T细胞竞争。使用高效减毒活黄 发热病毒（YFV）疫苗作为新的感染性攻击的模型，我们测试了免疫前的剧目如何 影响疫苗接种后的反应。多个YFV特异性群体在同一个区域内纵向鉴定， 个体使用肽-MHC（pMHC）四聚体。广泛的单细胞T细胞受体（TCR）测序， 使用四聚体+细胞随时间跟踪相同亲本细胞的后代。我们发现疫苗 选择性地募集最初罕见但反应更灵敏的T细胞，从而获得更好的库适应性和更高的TCR 疫苗接种后的多样性具有多样化的TCR库与保护性T细胞直接相关， 反应和宿主存活率。对于快速进化的病原体，T细胞组成的多样性可能 此外，当突变出现时，限制逃逸变体。在这里，我们将使用针对COVID-19的mRNA疫苗 （COVID疫苗）作为模型来研究由mRNA-1引起的T细胞应答的持久性和广度。 疫苗战略。我们假设，有效的外周T细胞选择是关键， 保持对活跃变异病毒的持久免疫力。在这里，我们将建立在 生物学见解、资源和捐赠者招募基础设施，以确定：（1）COVID疫苗是否能推动 有效的库选择和多样化，（2）加强如何增强CD 4 + T细胞的多样性和变异 识别，以及（3）疫苗后记忆细胞如何维持并随时间变化。拟议 实验将使用精确的分子和细胞技术， 工具.这项研究的数据将提供关于CD 4 + T细胞的质量、广度和寿命的重要知识。 细胞对mRNA疫苗的反应。除了COVID，拟议研究揭示的见解 将有助于理解免疫记忆是如何产生和保存的。拟议 因此，研究将产生广泛的影响，并有助于未来开发改进的疫苗战略， 其他病原体。

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.