Impact of the Intestinal Microbiome on HIV/SIV Vaccines

项目总结 在这份修订后的申请中(优先级分数为29，百分比为15%，差一点就错过了13% Payline)，我们试图定义微生物群对疫苗反应的影响，该计划涵盖了 从人类疫苗试验的观察性研究到动物模型的研究，以确定该蛋白的相关功能 微生物群。这一修订后的申请是建立在丹·巴鲁奇博士之间长达6年的密切合作基础上的 还有斯基普·维珍博士。此协作包括高效的多PI R01授权(OD011170)以定义 病原性SIV和HIV感染对肠道病毒群和细菌菌群的影响。这 协作带来了与该应用程序相关的几个方面的进步。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 开发并出版了微生物组到疫苗免疫原性的元数据。这些产品的可用性 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群调控的重要假设。数据 从现在的许多组显示，微生物群调节抗病毒免疫的关键功能是与生俱来 免疫细胞和疫苗诱导的体液和细胞免疫反应。根据有证据表明细菌 和其他微生物组分改变免疫反应，开发分析病毒的工具 和细菌微生物组，并立即获得一套独特的人类样本来自高度 相关的国际1/2a期艾滋病毒候选疫苗的临床研究，可能会进入大型- 规模疗效试验(A004/IPCAVD009；NCT02315703)，我们现在建议，以检验变量 肠道微生物群影响疫苗在人类、恒河猴和小鼠中的免疫原性。至 针对这一重要假设，我们提出了以下两个具体目标： 目的1：探讨肠道微生物群对疫苗免疫应答的影响。 人类。 目的2：确定肠道微生物组的实验性改变是否会影响疫苗- 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.