Broad neutralization of pandemic threat coronaviruses

摘要-总体 冠状病毒从动物宿主中反复出现，以及由此导致的COVID 19大流行， 因此，有必要制定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力手段之一，但需要很大的广度， 最大化对抗未知病毒威胁的有效性。目前，第一代疫苗 正在部署以对抗SARS-CoV-2，但它们对紧急SARS-CoV-2变种的有效性， 重要的是，对其他潜在的人畜共患冠状病毒是未知的。该计划将侧重于中和 抗体作为保护性免疫应答的证明和关键组分。该方案将改善 预防冠状病毒，采用渐进的多步骤方法， 疫苗保护。这项研究的一个关键组成部分将是了解中和抗体如何 在自然感染或接种疫苗后引起的人类反应针对SARS-CoV-2包膜 以及抗体进化如何导致效力和广度的增加。确定和 使用多种方法，对SARS-CoV-2中和抗体靶向的表位进行表征， 指导免疫原的设计，旨在引发中和抗体靶向不同的光谱， 冠状病毒尽可能。将在小鼠和仓鼠中测试几种免疫原和递送策略 将用真正的SARS-CoV-2或一系列新开发的挑战模型进行挑战 整合了不同的冠状病毒刺突蛋白。将分析在这些动物中引发的抗体， 与在SARS-CoV-2免疫的人中发现的那些相比，免疫原逐步完善， 向下选择，目的是在非人灵长类动物中进行疫苗攻击实验， 有前途的候选人每个参与团队的专业知识是高度互补的，该计划将 利用和加强现有的科学协同作用，以确保有效和及时地完成 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.