Discovering Durable Pan-Coronavirus Immunity

总体总结 严重急性呼吸综合征(SARS)冠状病毒(CoV)-2是对人类的毁灭性威胁。而当 成功的疫苗项目正在进行中，基因漂移和免疫逃避已经开始颠覆 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 在过去的二十年里有所增加--这表明可能用不了多久就会有另一次CoV泄漏 寄主物种进入人类的屏障。下一代疫苗设计战略能够提供强大的 除了其他冠状病毒外，还迫切需要针对不断演变的SARS-CoV-2毒株的保护。整体而言 该计划的目标是提供下一代设计和测试所需的关键信息 疫苗策略，在整个冠状病毒范围内提供尽可能广泛的保护效果 一家人。总体计划假设是对人类异质性的免疫学识别 对SARS-CoV-2感染和疫苗接种的反应将阐明影响疗效和广度的因素 冠状病毒疫苗策略。这一假设得到了最近的出版物和来自我们的 一队。在这方面，尽管数百种疫苗正在开发中，但与泛美卫生组织最相关的目标是 冠状病毒免疫可以克服诱导中和抗体反应的简单需要，这在很大程度上 结合到病毒尖峰蛋白(S)的S1区域的非保守区--容易病毒逃逸。 来自我们团队的新证据指出了S2区域的重要性，该区域在 COVS。我们的团队发现，快速诱导抗S2抗体与重症患者较少的死亡有关 疾病，更多的交叉反应的记忆B细胞反应，在轻度疾病中迅速愈合，以及改善的抗体 疾病解决后的耐用性。一些人获得更好的临床结果的潜在因素 相关的交叉反应抗-S2免疫反应仍未完全确定。我们已经组建了一支 多学科团队，在免疫学、病毒学、遗传学、医学、生物化学、结构 完成生物和数学课程的总体目标。的互补和综合专业知识 该团队将共同努力：1)精细绘制对SARS-CoV-2变种的体液和细胞反应图，并 自然感染或接种后出现的冠状病毒亲属，2)定义机制(S) 这些反应提供了保护，以及3)利用免疫的这些机械性关联来激励切割 边缘，结构稳定的天然类S抗原，将在逐步改进方法中用于 疫苗接种和保护研究。总的来说，该小组产生的数据将(A)确定免疫学 抗冠状病毒广度的相关性预计将指导疫苗设计；(B)定义最保守的靶点 S冠状病毒对人类适应性免疫系统的可获得性及其识别机制的洞察；(C) 产生包含上述(a-c)所告知的B和T细胞策略的新免疫原；以及(D)在 计划优化交付方法的背景下，最大限度地保护、持久的冠状病毒免疫。

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.