The impact of T cell selection on vaccine durability

项目摘要 一种新型冠状病毒感染(新冠肺炎)的持续爆发已导致数以百万计的人死亡并造成混乱 世界各地的社会基础设施。幸运的是，来自莫德纳或辉瑞/BioNTech的新型mRNA疫苗 对SARS-CoV-2非常有效。然而，关于记忆的长寿仍有许多未知之处 新的基于信使核糖核酸的疫苗平台在人类身上产生的反应。随着新病毒的出现 对于变种，还需要有一种灵活的免疫记忆类型，不仅要持久，而且 也可以对变异的病毒做出反应。我的实验室研究人类T细胞记忆。我们已经证明，人类 一种新病原体的免疫前T细胞谱系是由过去的抗原经验形成的，并包含交叉 反应性记忆T细胞可以与幼稚的T细胞竞争。使用高效的减黄活体 发热病毒(YFV)疫苗作为一种新的感染挑战的模型，我们测试了预免疫谱系 影响疫苗接种后的反应。多个YFV特异性种群被纵向鉴定在同一 使用多肽-MHC(PMHC)四聚体的个体。广泛的单细胞T细胞受体(TCR)测序 四聚体细胞被用来跟踪相同亲本细胞的后代一段时间。我们发现了疫苗 有选择地招募最初稀有但反应更灵敏的T细胞，导致更好的体能和更高的TCR 接种疫苗后的多样性。拥有不同的TCR谱系与保护性T细胞直接相关 小鼠的反应和宿主存活。对于快速进化的病原体，T细胞组成的多样性可能 此外，随着突变的出现，限制逃逸变异。这里，我们将使用新冠肺炎的mrna疫苗。 (冠状病毒疫苗)作为模型来研究由mRNA-1诱导的T细胞反应的持久性和广度 基于疫苗策略。我们假设有效的外周T细胞选择对 对活跃变异的病毒保持持久的免疫力。在这里，我们将在既定基础上再接再厉 生物学见解、资源和捐献者招募基础设施，以确定：(1)COVID疫苗是否推动 有效的谱系选择和多样化，(2)增强如何增强CD4T细胞的多样性和变异体 识别，以及(3)疫苗后记忆细胞如何维持和随时间变化。建议数 实验将使用精确的分子和细胞来绘制疫苗诱导反应的整个轨迹 工具。这项研究的数据将提供有关CD4T的质量、广度和寿命的重要知识 人类对基因疫苗的细胞反应。除了COVID，拟议研究揭示的洞察力 将与理解免疫记忆是如何产生和保存有关的。建议数 因此，研究将产生广泛的影响，并可能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.