Respiratory Virus Vaccine and Adjuvant Exploration

疫苗接种代表着最有效的公众之一 保护高危人群免受新出现病原体侵袭的卫生措施。然而，FDA批准了 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等病毒的侵袭， 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，基础疫苗的免疫原性很差 刺激。事实上，越来越多的证据表明，刺激作用的佐剂组合 多种先天免疫途径能够引起广泛保护性的、长寿的免疫。 与自然感染刺激的反应相似。然而，到目前为止，只有少数人 佐剂已被批准用于人类，但我们对其作用机制知之甚少 或控制其表现的寄主易感等位基因。这种对知识的缺乏 阻碍我们开发新佐剂的能力，同时也限制了我们合理结合的能力 开发具有广泛保护性的疫苗配方的不同佐剂。此外，由于先天的 FDA批准的佐剂和实验佐剂靶向的免疫途径都具有高度多态， 宿主遗传变异很可能会对个体的疗效和安全性产生重大影响。 不同人群的佐剂。因此，开发安全有效的佐剂和 疫苗配方需要了解特定佐剂/疫苗如何在不同的 人口。重要的是，我们还可以利用这种响应的多样性来确定 多态基因和遗传网络，调节对特定佐剂的反应，然后使用 这些信息有助于合理选择旨在安全地产生持久保护作用的佐剂组合 高危人群的免疫力。因此，我们的项目，它利用了我们研究团队的 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 定义多态基因/基因网络的系统疫苗学和遗传学方法 调节对特定佐剂的反应。然后，我们将使用此信息来确定特定的 佐剂或佐剂组合将在符合条件的人群中诱导保护性免疫 增加了疫苗失败的风险。该计划将产生几项影响较大的交付成果，包括： 1)对几种高后果新出现的病原体广泛有效的IND前疫苗，包括 EBOV、流感、MERS-CoV和ZIKV，2)安全设计的新型佐剂配方 在包括高危人群在内的遗传多样性人群中激发持久的保护性免疫 疫苗失败的3)改进的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，将为新佐剂的开发提供信息 新的作用机制和改进的疗效/安全概况。

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.