Respiratory Virus Vaccine and Adjuvant Exploration - Equipment Supplement

呼吸道病毒疫苗及佐剂探索-设备补充

基本信息

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
项目类别：
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

项目摘要

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高危人群免受感染的最有效的公共卫生措施之一新出现的病原体。然而，绝大多数新兴疾病都缺乏 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者来自中东呼吸综合征冠状病毒 (MERS-CoV)、埃博拉病毒 (EBOV)、基孔肯雅病毒 (CHIKV) 和寨卡病毒等病毒的人群（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在缺乏佐剂介导的先天性免疫的情况下，基于类颗粒（VLP）的疫苗的免疫原性很差免疫刺激。事实上，越来越多的证据表明，刺激的佐剂组合多种先天免疫途径能够引发广泛的保护性、长期的免疫反应与自然感染所刺激的类似。然而，迄今为止，只有少数佐剂被开发出来。已批准用于人类，但我们对其作用机制或宿主了解甚少调节其表现的易感性等位基因。这种知识的缺乏阻碍了我们开发新产品的能力助剂的发展，同时也限制了我们合理组合不同助剂的广泛发展保护性疫苗制剂。此外，由于 FDA 和 FDA 均针对先天免疫途径已批准和实验的佐剂具有高度多态性，宿主遗传变异很可能会显着影响不同人群中单个佐剂的功效和安全性。所以，开发安全有效的佐剂和疫苗配方需要了解如何特定的佐剂/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反应的多样性，以确定调节反应的多态性基因和遗传网络具体的佐剂，然后利用该信息合理选择旨在安全地设计的佐剂组合在高危人群中引发持久的保护性免疫力。因此，我们的计划利用了我们的优势研究团队在佐剂开发、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佐剂组合将在疫苗风险增加的人群中引发保护性免疫力失败。该计划将产生几个高影响力的成果，包括：1）广泛有效的预 IND 针对几种严重后果的新兴病原体的疫苗，包括埃博拉病毒、流感、中东呼吸综合征冠状病毒和 ZIKV，2）新型佐剂配方，旨在安全地引发持久的遗传保护性免疫力不同人群，包括有疫苗失败风险的个体 3) 改进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常识为开发具有新颖作用机制和提高功效/安全性的新佐剂提供信息配置文件。