Respiratory Virus Vaccine and Adjuvant Exploration - Equipment Supplement

呼吸道病毒疫苗及佐剂探索-设备补充

• 批准号: 10242434
• 负责人: Ralph S Baric
• 金额: $ 108.85万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242434
• 关键词: 2019-nCoV; Adjuvant; Adult; Animal Model; Antibody Response; Biological Assay; Chikungunya virus; Communicable Diseases; Complex Genetic Trait; Consultations; Data Set; Development; Ebola virus; Equipment; Evaluation; FDA approved; Failure; Formulation; Future; Genes; Genetic; Genetic Variation; Glycoproteins; Goals; Human; Human Volunteers; Immune response; Immunity; Immunization; Immunologic Adjuvants; Individual; Infection; Knowledge; Laboratories; Measures; Mediating; Messenger RNA; Middle East Respiratory Syndrome Coronavirus; Modernization; Performance; Phase; Population; Population Heterogeneity; Populations at Risk; Public Health; Recombinant Proteins; Regulator Genes; Research; Risk; Safety; Sampling; Serum; Subfamily lentivirinae; Susceptibility Gene; Universities; Vaccinated; Vaccination; Vaccines; Virus; Virus-like particle; Zika Virus; advanced system; base; biosafety level 3 facility; design; genetic approach; immunogenic; improved; influenzavirus; innate immune pathways; nanoparticle; neutralizing antibody; novel; novel vaccines; pathogen; programs; recombinant virus; respiratory virus; response; vaccination strategy; vaccine development; vaccine efficacy; vaccine evaluation; vaccine safety; vaccine trial; vaccinology

ABSTRACT Vaccination represents one of the most effective public health measures for protecting at risk populations from emerging pathogens. However, FDA approved vaccines are lacking for the vast majority of emerging pathogens, and therefore new vaccines and vaccination strategies are needed to protect susceptible populations from viruses such as MERS-CoV, Ebola virus (EBOV), chikungunya virus (CHIKV) and Zika virus (ZIKV). Adjuvants represent an essential component of modern vaccinology, since recombinant protein or virus like particle (VLP) based vaccines are poorly immunogenic in the absence of adjuvant-mediated innate immune stimulation. In fact, a growing body of evidence suggests that combinations of adjuvants that stimulate multiple innate immune pathways are capable of eliciting broadly protective, long-lived immune responses similar to those stimulated by natural infections. However, to date, only a small number of adjuvants have been approved for human use, and we have a poor understanding of their mechanisms of action or the host susceptibility alleles that regulate their performance. This lack of knowledge impedes our ability to develop new adjuvants, while also limiting our capacity to rationally combine different adjuvants to develop broadly protective vaccine formulations. Furthermore, since the innate immune pathways targeted by both FDA approved and experimental adjuvants are highly polymorphic, it is likely that host genetic variation will significantly impact both the efficacy and safety of individual adjuvants across diverse populations. Therefore, the development of safe and effective adjuvants and vaccine formulations requires an understanding of how specific adjuvants/vaccines perform in diverse populations. Importantly, we can also take advantage of this diversity in responses to identify the polymorphic genes and genetic networks that regulate the response to specific adjuvants, and then use that information to rationally select adjuvant combinations designed to safely elicit durably protective immunity in at risk populations. Therefore, our Program, which takes advantage of our research team's expertise in adjuvant development, vaccinology, and complex trait genetics, proposes to use advanced Systems Vaccinology and Genetics approaches to define the polymorphic genes/gene networks that regulate the response to specific adjuvants. We will then use this information to identify specific adjuvants or adjuvant combinations that will elicit protective immunity in populations who are at increased risk of vaccine failure. This program will results in several high impact deliverables, including: 1) broadly efficacious pre-IND vaccines for several high consequence emerging pathogens, including EBOV, influenza, MERS-CoV, and ZIKV, 2) novel adjuvant formulations that are designed to safely elicit durable protective immunity in genetically diverse populations, including individuals who are at risk of vaccine failure 3) improved animal models for testing vaccine safety and efficacy, and 4) general knowledge of adjuvant immune regulatory genes that will inform the development of new adjuvants with novel mechanisms of action and improved efficacy/safety profiles.

抽象的 疫苗接种是保护处于风险人群免受风险的最有效的公共卫生措施之一 新兴病原体。但是，对于绝大多数新兴的疫苗，FDA批准的疫苗 病原体，因此需要新的疫苗和疫苗接种策略来保护易感 来自MERS-COV，埃博拉病毒（EBOV），Chikungunya病毒（Chikv）和Zika病毒等病毒的种群 （zikv）。佐剂是现代疫苗学的重要组成部分，因为重组蛋白或病毒 像粒子（VLP）的疫苗一样，在没有辅助介导的先天物的情况下，免疫原性很差 免疫刺激。实际上，越来越多的证据表明刺激的佐剂的组合 多种先天免疫途径能够引起广泛的保护性，长期的免疫反应 与自然感染刺激的类似。但是，迄今为止，只有少数佐剂 被批准用于人类使用，我们对他们的行动机制或主机的理解很差 调节其性能的敏感性等位基因。缺乏知识阻碍了我们发展新的能力 佐剂，同时还限制了我们合理结合不同佐剂以广泛发展的能力 保护性疫苗配方。此外，由于FDA靶向的先天免疫途径 批准和实验佐剂是高度多态的，宿主遗传变异可能会 显着影响各种人群中各个佐剂的功效和安全性。所以， 安全有效的佐剂和疫苗配方的开发需要了解 特定的佐剂/疫苗在不同人群中进行。重要的是，我们也可以利用这一点 反应的多样性以识别调节对反应的多态性基因和遗传网络 特定的佐剂，然后使用该信息合理选择旨在安全的辅助组合 在风险种群中引起持久的保护性免疫。因此，我们的计划利用了我们 研究团队在辅助开发，疫苗学和复杂性状遗传学方面的专业知识建议使用 先进的系统疫苗科学和遗传学方法来定义多态基因/基因网络 调节对特定佐剂的反应。然后，我们将使用此信息来识别特定的佐剂或 辅助组合将在疫苗风险增加的种群中引起保护性免疫 失败。该计划将导致几个高影响可交付成果，包括：1）广泛有效的预点 几种高后果新兴病原体的疫苗，包括EBOV，流感，MERS-COV和 ZIKV，2）旨在安全地在遗传上安全发挥耐用的保护性免疫的新型辅助配方 不同的人群，包括有疫苗衰竭风险的人3）改善动物模型 测试疫苗的安全性和功效，4）辅助免疫调节基因的一般知识将 通过新颖的作用机理和提高功效/安全性，告知新佐剂的开发 概况。