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.

摘要 疫苗接种是保护高危人群免受 新兴病原体然而，FDA批准的疫苗缺乏绝大多数新兴的 因此，需要新的疫苗和疫苗接种策略来保护易感的 来自MERS-CoV、埃博拉病毒（EBOV）、基孔肯雅病毒（CHIKV）和寨卡病毒等病毒的群体 （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 基于类颗粒（VLP）的疫苗在缺乏佐剂介导的先天免疫原性的情况下免疫原性差， 免疫刺激事实上，越来越多的证据表明， 多种先天免疫途径能够引发广泛的保护性、长期免疫应答 类似于自然感染所刺激的那些。然而，到目前为止，只有少量的佐剂已经被应用于临床。 批准用于人类使用，我们对它们的作用机制或宿主了解甚少 易感性等位基因来调节他们的表现。这种知识的缺乏阻碍了我们开发新产品的能力。 佐剂，同时也限制了我们合理联合收割机不同佐剂的能力， 保护性疫苗制剂。此外，由于两种FDA靶向的先天免疫途径 批准的和实验的佐剂是高度多态性的，宿主遗传变异很可能将 显著地影响单个佐剂在不同人群中的功效和安全性。因此，我们认为， 开发安全有效的佐剂和疫苗配方需要了解 特定的佐剂/疫苗在不同人群中发挥作用。重要的是，我们还可以利用这一点 多样性的反应，以确定多态性基因和遗传网络，调节反应， 特异性佐剂，然后使用该信息合理选择佐剂组合， 在高危人群中引发持久的保护性免疫。因此，我们的计划，它利用我们的 研究小组在佐剂开发，疫苗学和复杂性状遗传学方面的专业知识，建议使用 先进的系统疫苗学和遗传学方法来定义多态性基因/基因网络， 调节对特定佐剂的反应。然后，我们将使用这些信息来识别特定的佐剂或 在疫苗接种风险增加的人群中引发保护性免疫的佐剂组合 失败该计划将产生几项高影响力的可交付成果，包括：1）广泛有效的IND前 针对几种高后果新出现病原体的疫苗，包括EBOV、流感、MERS-CoV和 ZIKV，2）新的佐剂制剂，其被设计为在遗传学上安全地引发持久的保护性免疫， 不同的人群，包括有疫苗失败风险的个体3）改进的动物模型， 测试疫苗的安全性和有效性，以及4）佐剂免疫调节基因的一般知识， 为开发具有新型作用机制和改善疗效/安全性的新型佐剂提供信息 数据区.