Impact of the Intestinal Microbiome on HIV/SIV Vaccines

项目摘要 在这个修订后的申请（优先级得分29和百分位数15%，这勉强错过了13%， payline），我们试图确定微生物组对疫苗反应的影响， 从人用疫苗试验的观察性研究到动物模型研究，以确定 微生物组此修订后的应用程序是建立在强大的6年合作博士丹Barouch 和斯基普·维珍博士这项合作包括一项高效的多PI R01赠款（OD011170）， 致病性SIV和HIV感染对肠道病毒组和细菌微生物组的影响。这 合作导致了与这一应用相关的若干进展。重要的是，评估 微生物组，包括细菌微生物组和病毒组，并用于定义 微生物组疫苗免疫原性元数据已经制定并公布。网站或资源的可用性 方法为我们提供了一个独特的机会，利用正在进行的人类疫苗试验来探索 疫苗反应的性质和程度受微生物组调节的重要假设。数据 现在表明，微生物组调节抗病毒免疫，关键的先天免疫功能， 免疫细胞和疫苗诱导的体液和细胞免疫应答。基于细菌 和其他微生物组成分改变免疫反应，病毒组分析工具的开发 和细菌微生物组，以及立即获得一组独特的人类样本， 一项HIV候选疫苗的相关国际1/2a期临床研究，该研究可能会进入大规模- 我们现在提议进行大规模疗效试验（A004/IPCAVD 009; NCT 02315703），以检验变异 在肠道微生物组中的作用影响疫苗在人类、恒河猴和小鼠中的免疫原性。到 针对这一重要假设，我们提出以下两个具体目标： 目的1：评估肠道微生物组对疫苗引起的免疫应答的影响， 人类 目的2：确定肠道微生物组的实验改变是否影响疫苗- 在动物模型中引发免疫反应。

PROJECT SUMMARY In this revised application (priority score 29 and percentile 15%, which narrowly missed the 13% payline), we seek to define the impact of the microbiome on vaccine responses in a program spanning from observational studies in a human vaccine trial to studies in animal models to define the relevant functions of the microbiome. This revised application is built upon the strong 6 year collaboration between Dr. Dan Barouch and Dr. Skip Virgin. This collaboration included a highly productive multi-PI R01 grant (OD011170) to define the effects of pathogenic SIV and HIV infection on the enteric virome and bacterial microbiome. This collaboration led to several advances relevant to this application. Importantly, the technologies to evaluate the microbiome including the bacterial microbiome and virome and for defining the relationship of components of the microbiome to vaccine immunogenicity metadata were developed and published. The availability of these methods provides us with a unique opportunity to leverage an on going human vaccine trial to probe the important hypothesis that the nature and extent of vaccine responses is regulated by the microbiome. Data from many groups now show that that the microbiome regulates antiviral immunity, functions of key innate immune cells and vaccine-induced humoral and cellular immune responses. Based on evidence that bacterial and other microbiome constituents alter immune responses, the development of tools for analysis of the virome and bacterial microbiome, and the immediate availability of a unique set of human samples from a highly relevant international phase 1/2a clinical study of an HIV vaccine candidate that will likely advance into large- scale efficacy trials (A004/IPCAVD009; NCT02315703), we now propose, to test the hypothesis that variations in the intestinal microbiome influence vaccine immunogenicity in humans, rhesus monkeys, and mice. To address this important hypothesis, we propose the following two Specific Aims: Aim 1: To assess the impact of the intestinal microbiome on vaccine-elicited immune responses in humans. Aim 2: To determine whether experimental alterations of the intestinal microbiome impact vaccine- elicited immune responses in animal models.