The goal of this IPCAVD program is to develop Ad26/Env vaccines for HIV-1 by a highly collaborative and multifaceted research program involving leading investigators in academia and industry. Our overall hypothesis is that an optimized Ad26/Env mosaic vaccine will induce highly functional antibodies that will protect humans against acquisition of multiple HIV-1 clades. The significance of this program is the potential actual development of a safe and effective global HIV-1 vaccine, the unparalleled commitment of a major pharmaceutical company to this HIV-1 vaccine, and the opportunity for major scientific advances in our understanding of immune correlates of protection. In our current IPCAVD program (U19 AI096040), we have developed alternative serotype adenovirus vectors, bioinformatically optimized HIV-1 mosaic antigens, and stable Env gp140 protein immunogens. We have shown that the Ad26-Env/Gag/Pol prime, Env gp140 protein boost (Ad26/Env) vaccine afforded unprecedented protective efficacy against acquisition of infection following heterologous SIVmac251 challenges in rhesus monkeys, as well as robust protection against SHIV-SF162P3 challenges. Protection correlated with polyfunctional antibody responses as determined by systems serology. We have also advanced the Ad26/Env, Ad26/MVA, and Ad26/MVA/Env mosaic vaccines into phase 1/2a clinical trials in the United States, East Africa, South Africa, and Thailand. Over the next 5 years of this IPCAVD program, we propose to define the extent and mechanism of protection achieved by our lead Ad26/Env vaccine regimen in rhesus monkeys, to advance our lead vaccine regimen into phase 2b/3 efficacy studies in humans, and to develop an improved next generation HIV-1 vaccine candidate. To accomplish the goals of this IPCAVD program, we propose the following Projects and Cores: Project 1. Preclinical Development of Ad26/Env Vaccines for HIV Project 2. Manufacturing and Clinical Development of Ad26/Env Vaccines for HIV Core A. Administrative Core Core B. Immunology Core Core C. NHP Core

Public Health Relevance

The development of a safe and effective HIV-1 vaccine is a global health priority. We have demonstrated that the Ad26/Env mosaic HIV-1 vaccine affords protection against viral challenges in rhesus monkeys and is safe and immunogenic in humans. In this IPCAVD program, we propose to evaluate the protective efficacy of this vaccine in humans and to develop simplified and improved next generation HIV-1 vaccine candidates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI128751-03
Application #
9853715
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Pensiero, Michael N
Project Start
2018-02-01
Project End
2023-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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
Bricault, Christine A; Kovacs, James M; Badamchi-Zadeh, Alexander et al. (2018) Neutralizing Antibody Responses following Long-Term Vaccination with HIV-1 Env gp140 in Guinea Pigs. J Virol :
Whitney, James B; Lim, So-Yon; Osuna, Christa E et al. (2018) Prevention of SIVmac251 reservoir seeding in rhesus monkeys by early antiretroviral therapy. Nat Commun 9:5429
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
Barouch, Dan H (2018) A step forward for HIV vaccines. Lancet HIV 5:e338-e339