Respiratory Virus Vaccine and Adjuvant Exploration

疫苗接种是最有效的公共 采取卫生措施，保护高危人群免受新出现的病原体的侵害。然而，FDA批准 绝大多数新出现的病原体缺乏疫苗，因此新的疫苗和 需要疫苗接种策略来保护易感人群免受MERS-CoV等病毒的侵害， 埃博拉病毒（EBOV）、基孔肯雅病毒（CHIKV）和寨卡病毒（ZIKV）。佐剂代表一种 现代疫苗学的基本组成部分，因为重组蛋白或病毒样颗粒（VLP） 在缺乏佐剂介导的先天免疫的情况下， 刺激.事实上，越来越多的证据表明， 多种先天性免疫途径能够引发广泛的保护性、长寿命的免疫应答。 类似于自然感染刺激的反应。然而，迄今为止，只有少数 佐剂已被批准用于人类，但我们对其机制的了解很少 或调节其性能的宿主易感性等位基因。人们缺乏了解 阻碍了我们开发新佐剂的能力，同时也限制了我们合理联合收割机的能力， 不同的佐剂，以开发广泛的保护性疫苗配方。此外，由于先天 FDA批准的和实验性佐剂靶向的免疫途径是高度多态的， 宿主遗传变异可能会显著影响个体的有效性和安全性， 佐剂在不同人群中的应用因此，开发安全有效的佐剂和 疫苗制剂需要了解特定佐剂/疫苗在不同环境中的作用 人口。重要的是，我们还可以利用这种多样性来确定 多态性基因和遗传网络，调节对特定佐剂的反应，然后使用 合理选择佐剂组合的信息， 在高危人群中的免疫力。因此，我们的计划，利用我们的研究团队的优势， 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。我们将使用这些信息来识别特定的 佐剂或佐剂组合将在处于以下状态的人群中引发保护性免疫力： 增加疫苗失败的风险。该计划将产生几个高影响力的可交付成果，包括： 1)广泛有效的IND前疫苗，用于几种高后果的新出现的病原体，包括 EBOV、流感病毒、MERS-CoV和ZIKV，2）设计用于安全地 在遗传多样性人群中引发持久的保护性免疫，包括处于风险中的个体 3）改进了用于测试疫苗安全性和有效性的动物模型，以及4）一般 佐剂免疫调节基因的知识，这将为新佐剂的开发提供信息， 新的作用机制和改善的功效/安全性特征。

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.