Given the highly complex nature of HIV, including the challenges of protecting mucosal surfaces from transmission and high variability of the virus, developing innovative vaccination strategies is crucial. Indeed, despite extensive research, a fully efficacious vaccine to prevent HIV transmission remains elusive, and there is limited understanding of correlates of protection, particularly at mucosal surfaces. Recently, the importance of the microbiome in mucosal immunity have become appreciated, and here we hypothesize that we can exploit the microbiome to induce protective vaccine responses. Here we propose a novel HIV vaccination approach that uses persistent probiotic therapy as an adjuvant to enhance immunogenicity and protection induced by a potent combined vaccine strategy. Our vaccine consists of concurrently administered SIV (gag p55) and HIV (gp140) DNA + HIV gp140 trimer protein. Recent studies have provided evidence that combining DNA and protein for vaccination elicits increased vaccine specific cellular and humoral immunity, In addition, our preliminary studies provocatively demonstrated that probiotic treatment in SIV-uninfected macaques results in increased T follicular helper cells in lymph nodes, IgA expressing B cells in mucosal tissues, increased antigen presenting cells in mucosal tissues, and increased multifunctional T cells, as well as decreased proliferation and activation of CD4+ T cells. Thus, we hypothesize that combining the potent immunomodulatory effects of beneficial microbiota manipulation with a novel vaccine platform that should induce robust cellular and humoral immunity will result in unprecedented high levels of vaccine specific responses in both mucosal and systemic tissues, resulting in protection from rectal SHIV challenge. There are several innovative aspects of this vaccine design, including: (i.) Modulation of the microbiota with probiotics to enhance mucosal vaccine responses; (ii.) utilization of a novel dual SHIV DNA-HIV gp140 protein vaccination platform; (iii.) novel measurements of potential vaccination correlates will be measured including microbiome morphogenesis, homeostatic mucosal responses, innate immune responses, and T follicular helper and germinal center B cell responses, in addition to standard correlates of vaccination (antibody and T cell responses).

Public Health Relevance

Here we propose a novel vaccination strategy using microbiota manipulation with probiotic therapy as an adjuvant to vaccination with combined SIV DNA and HIV Env gp140 trimer protein. We hypothesize that this innovative vaccine platform will result in robust vaccine-induced innate and adaptive immunity both in mucosal and systemic sites, and will ultimately provide enhanced protection from intrarectal SHIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI120712-04
Application #
9404871
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Dang, Que
Project Start
2015-07-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Hensley-McBain, Tiffany; Zevin, Alexander S; Manuzak, Jennifer et al. (2016) Effects of Fecal Microbial Transplantation on Microbiome and Immunity in Simian Immunodeficiency Virus-Infected Macaques. J Virol 90:4981-9
Manuzak, Jennifer A; Hensley-McBain, Tiffany; Zevin, Alexander S et al. (2016) Enhancement of Microbiota in Healthy Macaques Results in Beneficial Modulation of Mucosal and Systemic Immune Function. J Immunol 196:2401-9