Broad neutralization of pandemic threat coronaviruses

摘要--总体 从动物储藏室反复出现冠状病毒，以及由此导致的COVID19大流行， 因此有必要开发针对各种大流行威胁冠状病毒的干预措施。 疫苗是缓解病毒流行的最有效手段之一，但需要极大的广度 最大限度地提高对未知病毒威胁的有效性。目前，第一代疫苗是 部署用于抗击SARS-CoV-2，但它们对新出现的SARS-CoV-2变种的有效性， 重要的是，对其他潜在的人畜共患病冠状病毒的抵抗力尚不清楚。这项计划将重点放在中和 抗体被证明是保护性免疫反应的关键组成部分。该计划将有所改进 防范冠状病毒，采用循序渐进的多步骤方法，以增加 疫苗保护。这项研究的一个关键组成部分将是理解中和抗体如何 自然感染或接种疫苗后在人类身上引发的针对SARS-CoV-2包膜的反应 以及抗体进化如何导致效力和广度的增加。身份识别和 用多种方法表征SARS-CoV-2中和抗体靶向的表位 指导免疫原的设计，旨在诱导针对不同光谱的中和抗体 冠状病毒尽可能多。几种免疫原和递送策略将在老鼠和仓鼠身上进行测试 这将受到真正的SARS-CoV-2或一整套新开发的挑战模型的挑战 整合不同的冠状病毒刺突蛋白。在这些动物体内产生的抗体将被分析并 与SARS-CoV-2免疫的人和免疫原相比，逐步提纯和 向下选择，目标是在非人类灵长类动物中进行疫苗挑战实验， 很有前途的候选人。每个参赛团队的专业知识具有很强的互补性，该计划将 充分利用和加强现有的科学协同作用，以确保高效和及时地完成 目标。

ABSTRACT-OVERALL The recurrent emergence of coronaviruses from animal reservoirs, and the resulting COVID19 pandemic, necessitates the development of interventions that can target diverse pandemic-threat coronaviruses. Vaccines are among the most powerful means for mitigating viral epidemics but require significant breadth to maximize the probability of effectiveness against unknown viral threats. Currently, first generation vaccines are being deployed to combat SARS-CoV-2, but their effectiveness against emergent SARS-CoV-2 variants and, importantly, against other potential zoonotic coronaviruses is unknown. This program will focus on neutralizing antibodies as a demonstrated and key component of protective immune responses. The Program will improve preparedness against coronaviruses, employing a progressive multistep approach to increase the breadth of vaccine protection. A key component of the research will be to comprehend how neutralizing antibody responses, elicited in humans following natural infection or vaccination, target the SARS-CoV-2 envelope spike and how antibody evolution leads to increased potency and breadth. The identification and characterization of epitopes targeted by SARS-CoV-2 neutralizing antibodies, using multiple approaches, will guide the design of immunogens that aim to elicit neutralizing antibodies targeting as diverse a spectrum of coronaviruses as possible. Several immunogens and delivery strategies will be tested in mice and hamsters that will be challenged with authentic SARS-CoV-2 or a panoply of newly developed challenge models incorporating divergent coronavirus spike proteins. Antibodies elicited in these animals will be analyzed and compared with those found in SARS-CoV-2 immunized humans and immunogens progressively refined and down-selected with the goal of performing vaccine-challenge experiments in nonhuman primates with the most promising candidates. The expertise of each participating team is highly complementary and the program will capitalize and build on the already existing scientific synergy to ensure the efficient and timely completion of the goals.