Project 2: PanbetaCoV protein vaccine design

项目2：PanbetaCoV蛋白疫苗设计

基本信息

批准号：
10842503
负责人：
Kevin Wiehe
金额：
$ 282.88万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-16 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10842503
关键词：
2019-nCoV Address Adjuvant Alphavirus Animal Model Animals Antibodies Antibody Response Antibody titer measurement Antigens Avidity Binding COVID-19 vaccine Cell surface Chiroptera Complex Coronavirus Coronavirus spike protein Cross Reactions Cryoelectron Microscopy Development Disease Outbreaks Ensure Epitopes Ferritin Follicular Dendritic Cells Future Goals HIV HIV vaccine Health Human Immunity Immunize Immunologic Monitoring Influenza Macaca Mediating Merbecovirus Messenger RNA Methods Middle East Respiratory Syndrome Molecular Conformation Mus Mutation Peptides Persons Proteins SARS coronavirus Sarbecovirus Site Structure Structure of germinal center of lymph node Surface System Techniques Testing Therapeutic Translating Vaccine Design Vaccines Variant Viral Wild Type Mouse Work aluminum sulfate betacoronavirus betacoronavirus vaccine coronavirus pandemic cross reactivity design expectation immunogenic influenza virus vaccine lipid nanoparticle nanoparticle neutralizing antibody nonhuman primate novel pandemic coronavirus pandemic disease pandemic potential pandemic preparedness phase III trial prevent programs protein structure rational design receptor binding research clinical testing spillover event trafficking vaccine candidate vaccine development vaccine-induced antibodies zoonotic coronavirus

项目摘要

Abstract – Project 2 Animal betacoronaviruses (betaCoVs), such as those that gave rise to SARS-CoV-1, MERS, and now SARS- CoV-2, represent a significant, continuous threat to human health. Vaccines can provide pre-existing immunity to future zoonotic coronaviruses. A major limitation of the current effective vaccines to SARS-CoV-2 is that they likely will only protect SARS-CoV-2 isolates that are nearly identical to the Wuhan isolate used in the vaccines. Thus, the world remains vulnerable to SARS-CoV-2 mutational escape variants and from future animal betacoronavirus spillover events that have pandemic potential. Vaccine development that addresses this vulnerability is urgently needed. Project 2 will support this Program’s overall goal to develop vaccines that will prevent future betaCoV pandemics and SARS-CoV-2 escape variants by designing vaccine immunogens that elicit broadly neutralizing antibodies (bnAb) to provide protective immunity across the betaCoV genus. Structurally conserved neutralizing epitopes exist on betaCoV spike proteins, and we hypothesize that vaccines that elicit broadly protective antibodies to these sites can be developed. In preliminary studies, we have isolated cross-reactive neutralizing antibodies from SARS-CoV-1 or SARS-CoV-2-infected or recovered humans and used structural determination to precisely define their betaCoV bnAb epitopes. Our vaccine design strategy involves using computational and structural- based design techniques to develop immunogens that preferentially present these and additionally identified bnAb epitopes. Each immunogen design will be displayed on the surface of nanoparticles to enhance antigen avidity and antigen trafficking to germinal centers and follicular dendritic cells. We have demonstrated a proof-of-concept for our strategy using a multimerized SARS-CoV-2 receptor binding domain (RBD)- ferritin nanoparticle that induces high titers of antibodies that neutralize diverse human and animal Sarbecoviruses (group 2b) in immunized macaques. In Aim 1, we will isolate new antibodies to define additional bnAb epitopes and establish the full spectrum of regions on the surface of betaCoV S proteins that are capable of inducing bnAbs to animal betaCoVs in groups 2b and 2c. In Aim 2, we will utilize cutting-edge computational immunogen design methods to design broadly neutralizing epitope-focused immunogens. These immunogens have the spike protein fixed in conformations that expose neutralizing epitopes or are spike subunits that are truncated or resurfaced to remove irrelevant, non-neutralizing, or betaCoV strain-specific neutralizing epitopes while retaining broadly neutralizing epitopes. In Aim 3, we will immunize wild-type mice with these novel immunogens and evaluate their ability to induce human betaCoV bnAbs that can protect animals from viral challenge. Project 2 will impact the field by generating cross-reactive neutralizing antibodies that could be translated into therapeutics, elucidating new broadly neutralizing epitopes on the betaCoV spike protein, and defining the design principles for epitope-focused immunogens that elicit protective immunity to betaCoVs.

摘要 – 项目 2 动物 β 冠状病毒 (betaCoV)，例如引起 SARS-CoV-1、MERS 和现在的 SARS-的病毒 CoV-2 对人类健康构成重大、持续的威胁，疫苗可以提供预先存在的免疫力。针对未来的人畜共患冠状病毒，目前有效的 SARS-CoV-2 疫苗的一个主要限制是它们。可能只会保护与研究中使用的武汉分离株几乎相同的 SARS-CoV-2 分离株因此，世界仍然容易受到 SARS-CoV-2 突变逃逸变体的影响。以及未来具有大流行潜力的动物乙型冠状病毒溢出事件。迫切需要解决此漏洞的项目 2 将支持该计划的总体开发目标。疫苗将预防未来 betaCoV 大流行和 SARS-CoV-2 逃逸变种设计可引发广泛中和抗体 (bnAb) 的疫苗免疫原，以提供保护性 betaCoV 属中存在结构保守的中和表位。关于 betaCoV 刺突蛋白，我们捕获了能够引发针对这些蛋白的广泛保护性抗体的疫苗在初步研究中，我们已经分离出交叉反应中和抗体。 SARS-CoV-1 或 SARS-CoV-2 感染或康复的人类，并使用结构测定精确地定义其 betaCoV bnAb 表位我们的疫苗设计策略涉及使用计算和结构- 基于设计技术来开发优先呈现这些的免疫原，另外识别出的bnAb表位将显示在纳米粒子的表面以增强。我们已经证明了抗原亲和力和抗原向生发中心和滤泡树突细胞的运输。使用多聚化 SARS-CoV-2 受体结合域 (RBD) 对我们的策略进行概念验证 - 铁蛋白纳米颗粒可诱导高滴度抗体，中和不同的人类和免疫猕猴中的动物 Sarbecoviruses（2b 组）在目标 1 中，我们将分离新的抗体来定义。额外的 bnAb 表位并在 betaCoV S 蛋白表面建立全谱区域能够在 2b 组和 2c 组中诱导动物 betaCoV 的 bnAb。在目标 2 中，我们将利用尖端技术。计算免疫原设计方法来设计广泛中和表位的免疫原。免疫原将刺突蛋白固定在暴露中和表位的构象中或者是刺突蛋白被截断或重新出现的亚基，以去除不相关的、非中和的或 betaCoV 菌株特异性的在目标 3 中，我们将免疫野生型小鼠。使用这些新型免疫原并评估它们诱导人类 betaCoV bnAb 的能力，从而保护项目 2 将通过产生交叉反应中和抗体来影响该领域。可以转化为治疗方法，阐明 betaCoV 刺突上新的广泛中和表位蛋白质，并定义引发保护性免疫的针对表位的免疫原的设计原则 β冠状病毒。