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.
It is currently unknown whether the intestinal microbiome impacts immune responses to vaccines. In this proposal, we will assess the impact of the intestinal microbiome on the immunogenicity of candidate HIV vaccines in human samples and in animal models. These data will contribute to our understanding of the relationship of the microbiome and the host immune system.
| Barouch, Dan H; Tomaka, Frank L; Wegmann, Frank et al. (2018) Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19). Lancet 392:232-243 |
| Badamchi-Zadeh, Alexander; Moynihan, Kelly D; Larocca, Rafael A et al. (2018) Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy. J Immunol 201:2744-2752 |
| Alter, Galit; Barouch, Dan (2018) Immune Correlate-Guided HIV Vaccine Design. Cell Host Microbe 24:25-33 |
| Borducchi, Erica N; Liu, Jinyan; Nkolola, Joseph P et al. (2018) Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys. Nature 563:360-364 |
| Abbink, Peter; Kirilova, Marinela; Boyd, Michael et al. (2018) Rapid Cloning of Novel Rhesus Adenoviral Vaccine Vectors. J Virol 92: |
