Discovering Durable Pan-Coronavirus Immunity

总体汇总 严重急性呼吸系统综合征（SARS）冠状病毒（CoV）-2是一种毁灭性的人类威胁。而 成功的疫苗计划正在进行中，遗传漂变和免疫逃逸已经开始颠覆 免疫力，更多的变种可能会继续出现。此外，人畜共患冠状病毒的传播率 在过去的二十年里， 宿主物种进入人类的屏障下一代疫苗设计策略，能够提供强大的 除了其它CoV之外，还迫切需要针对进化的SARS-CoV-2毒株的保护。整体 该计划的目标是为下一代导弹的设计和测试提供必要的关键信息 在整个CoV中提供最大可能广度的保护效力的疫苗策略 家人总的程序假设是，免疫识别异质性在人类 对SARS-CoV-2感染和疫苗接种的反应将阐明可能影响疗效和范围的因素 冠状病毒疫苗策略。这一假设得到了最近出版物和我们的初步数据的支持。 团队在这方面，尽管正在开发数百种疫苗，但与泛非最相关的目标是： CoV免疫可能无视诱导中和抗体应答的简单需要， 与病毒刺突（S）蛋白S1区的非保守区域结合-易受病毒逃逸影响。 来自我们团队的新证据指出了S2区域的重要性，该区域在整个基因组中更为保守。 冠状病毒。我们的研究小组发现，快速诱导抗S2抗体与严重急性胰腺炎患者的死亡率降低有关。 疾病，更多的交叉反应记忆B细胞反应，轻度疾病的快速愈合，以及改善的抗体 疾病消退后的持久性。为什么有些人会有更好的临床结果的潜在因素- 相关的交叉反应性抗-S2免疫应答仍有待完全确定。我们组建了一个 多学科团队，具有免疫学、病毒学、遗传学、医学、生物化学、结构 生物学和数学，以实现总体计划目标。的互补性和综合性专门知识 该小组将共同致力于：1）精细绘制SARS-CoV-2变异体的体液和细胞反应， 冠状病毒的亲属在自然感染或接种疫苗后出现，2）定义了 这些反应提供保护，3）利用这些免疫机制的相关性来激发切割 边缘，结构稳定的天然样S抗原，将用于逐步改善的方法， 疫苗接种和保护研究。总的来说，该团队产生的数据将（a）确定免疫学 预期告知疫苗设计的抗CoV宽度的相关性;（B）定义上最保守的靶标， 人类适应性免疫系统可及的CoV S及其识别机制;（c） 产生新的免疫原，所述新的免疫原包含由上述（a-c）告知的B和T细胞策略;以及（d）在以下中测试它们： 计划优化的交付方法的背景下，以最大限度地提高保护性，持久的CoV免疫的广度。

OVERALL SUMMARY Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV)-2 is a devastating human threat. While successful vaccine programs are underway, genetic drift and immune escape have already begun to subvert immunity, with more variants likely to continue to emerge. Moreover, the rates of zoonotic CoV transmission have increased over the past two decades—indicating that it may not be long before another CoV breaches host-species barriers into humans. Next generation vaccine design strategies that are able to provide robust protection against evolving SARS-CoV-2 strains in addition to other CoVs are urgently needed. The overall goal of this program is to produce critical information necessary for the design and testing of next generation vaccine strategies that provide protective efficacy with the greatest possible breadth across the CoV family. The overall Program hypothesis is that immunological discernment of heterogeneity in human responses to SARS-CoV-2 infection and vaccination will illuminate factors that can impact efficacy and breadth of CoV vaccine strategies. This hypothesis is supported by recent publications and preliminary data from our team. In this regard, although hundreds of vaccines are under development, the targets most relevant for pan- CoV immunity may defy the simple need for the induction of neutralizing antibody responses, which largely bind to non-conserved areas in the S1 region of the viral Spike (S) protein—susceptible to viral escape. Emerging evidence from our team points to the importance of the S2 region, which is more conserved across CoVs. Our team has found that rapid induction of anti-S2 antibodies is connected to less death in severe disease, more cross-reactive memory B cell responses, swift healing in mild disease, and improved antibody durability after disease resolution. The factors underlying why some people develop better-clinical-outcome- associated crossreactive anti-S2 immune responses remains to be fully defined. We have assembled a multidisciplinary team with expertise in immunology, virology, genetics, medicine, biochemistry, structural biology and mathematics to achieve the overall Program goal. The complementary and integrative expertise of the team will come together to: 1) finely map the humoral and cellular responses to SARS-CoV-2 variants and coronaviral relatives that emerge after natural infection or vaccination, 2) define the mechanism(s) by which these responses confer protection, and 3) utilize these mechanistic correlates of immunity to inspire cutting edge, structurally stable native-like S antigens that will be used in a step-wise improvement approach in vaccination and protection studies. Collectively, the data generated by this team will (a) identify immunological correlates of anti-CoV breadth expected to inform vaccine design; (b) define the most conserved targets on CoV S accessible to the human adaptive immune system and mechanistic insights into their recognition; (c) generate novel immunogens incorporating B and T cell strategies informed by (a-c) above; and (d) test them in the context of Program-optimized delivery methods to maximize breadth of protective, durable CoV immunity.