Discovering Durable Pan-Coronavirus Immunity

发现持久的泛冠状病毒免疫力

基本信息

批准号：
10328116
负责人：
Duane R. Wesemann
金额：
$ 1181万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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/10328116
关键词：
2019-nCoV Adaptive Immune System Adjuvant Animals Antibodies Antibody Response Antibody-mediated protection Antigens Area B-Lymphocytes Binding Biochemistry Boston CD4 Positive T Lymphocytes COVID-19 patient COVID-19 vaccination COVID-19 vaccine Cell Communication Cellular Structures Cessation of life Chiroptera Clinical Cohort Studies Coronavirus Coupled Data Development Disease Dose Effectiveness Epitopes Evaluation Exhibits Family Future Generations Genetic Drift Genetic Medicine Goals Heterogeneity Human Immune Immune response Immunity Immunologics Immunology Infection Knowledge Laboratories Link Lymphocyte MHC Class I Genes Maps Mathematics Memory B-Lymphocyte Methods Monoclonal Antibodies Outcome Preclinical Testing Preparation Proteins Publications Recording of previous events Recovery Research Resolution Route SARS-CoV-2 immunity SARS-CoV-2 infection SARS-CoV-2 variant Serology Severities Site Specificity Structure Symptoms Syndrome System T cell response T-Lymphocyte T-Lymphocyte Epitopes Technology Testing Tissues Translating Vaccination Vaccine Design Vaccines Variant Viral Virion Virus Work antibody test base cohort coronavirus vaccine cross reactivity data hub design efficacy evaluation enhancing factor genome-wide glycosylation healing improved in vivo insight multidisciplinary mutant neutralizing antibody next generation novel novel coronavirus novel vaccines pandemic disease pre-clinical prevent programs protective efficacy respiratory response stem structural biology transmission process universal coronavirus vaccine vaccine development vaccine evaluation virology zoonotic coronavirus

项目摘要

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.

总体总结严重急性呼吸系统综合症 (SARS) 冠状病毒 (CoV)-2 是一种毁灭性的人类威胁。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，可能会继续出现更多变种，此外，人畜共患冠状病毒的传播率也会增加。过去二十年里有所增加——这表明不久之后就会出现另一次冠状病毒破坏能够提供强大的下一代疫苗设计策略。除了其他冠状病毒外，还迫切需要针对不断演变的 SARS-CoV-2 病毒株提供保护。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可在冠状病毒范围内提供最大可能广度的保护功效总体计划假设是人类异质性的免疫学辨别。对 SARS-CoV-2 感染和疫苗接种的反应将阐明影响功效和广度的因素这一假设得到了我们最近发表的文章和初步数据的支持。在这方面，尽管有数百种疫苗正在开发中，但与泛相关的目标最为相关。冠状病毒免疫可能无法满足诱导中和抗体反应的简单需求，这在很大程度上与病毒刺突 (S) 蛋白 S1 区域的非保守区域结合，容易导致病毒逃逸。我们团队的新证据表明了 S2 区域的重要性，该区域在整个过程中更加保守我们的团队发现，快速诱导抗 S2 抗体与重症患者死亡人数减少有关。疾病、更多的交叉反应性记忆 B 细胞反应、轻度疾病的快速愈合以及抗体的改善疾病解决后的持久性。一些人取得更好临床结果的潜在因素。相关的交叉反应性抗 S2 免疫反应仍有待完全定义。多学科团队拥有免疫学、病毒学、遗传学、医学、生物化学、结构学方面的专业知识生物学和数学以实现总体计划目标的互补和综合专业知识。该团队将齐心协力：1）精细绘制对 SARS-CoV-2 变体的体液和细胞反应图谱，自然感染或疫苗接种后出现的冠状病毒亲属，2) 定义其机制这些反应提供保护，并且 3）利用这些免疫的机械相关性来激发切割边缘、结构稳定的类天然 S 抗原，将用于逐步改进方法总的来说，该团队生成的数据将 (a) 识别免疫学。预期为疫苗设计提供信息的抗冠状病毒广度的相关性；(b) 确定最保守的靶点；人类适应性免疫系统可接触到的 CoV S 及其识别机制 (c) 产生结合上述 (a-c) 所告知的 B 和 T 细胞策略的新型免疫原，并 (d) 对其进行测试；计划优化的交付方法，以最大程度地扩大保护性、持久的冠状病毒免疫力。