Abstract

The long-range objectives of Project 2 are to develop HlV-1 vaccine regimens that stimulate broadly directed immune responses and that block HIV-1 infection in humans and control viral replication In individuals who become infected. Although the precise correlates of immunity remain undefined, significant progress has been made in this area, and it appears that both humoral and cellular immune responses may be required for an optimal HIV-1 vaccine. In this project, we will test the hypothesis that mosaic antigens will induce increased breadth of cellular and/or humoral immune responses compared with natural sequence antigens in humans. We will also test the hypothesis that boosting responses primed with our optimal vector regimen with our stable clade 0 gp140 trimer will markedly augment antibody responses. To evaluate these hypotheses, we propose the following two Specific Aims:
Specific Aim 1 : To determine the optimal vector regimen in humans. Study IA: A phase 1 trial to compare natural and mosaic antigens in the context of Ad26/MVA vectors. Study IB: A phase 1 trial to compare the homologous Ad26 vector regimen with a heterologous Ad26/MVA vector regimen.
Specific Aim 2 : To determine the impact of a protein boost with our novel Env gpl40 trimer in humans. Study 2A: A phase 1 dose escalation trial of our novel trimeric Env gp140 protein. Study 2B: A phase 1 study to compare the best vector regimen with and without a protein trimer boost.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI096040-02
Application #
8487359
Study Section
Special Emphasis Panel (ZAI1-EC-A)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$511,546
Indirect Cost
$132,222

  Institution

Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

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
Martinot, Amanda J; Abbink, Peter; Afacan, Onur et al. (2018) Fetal Neuropathology in Zika Virus-Infected Pregnant Female Rhesus Monkeys. Cell 173:1111-1122.e10
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
Iampietro, M Justin; Larocca, Rafael A; Provine, Nicholas M et al. (2018) Immunogenicity and Cross-Reactivity of Rhesus Adenoviral Vectors. J Virol 92:
Badamchi-Zadeh, Alexander; Tartaglia, Lawrence J; Abbink, Peter et al. (2018) Therapeutic Efficacy of Vectored PGT121 Gene Delivery in HIV-1-Infected Humanized Mice. J Virol 92:
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
Baden, Lindsey R; Walsh, Stephen R; Seaman, Michael S et al. (2018) First-in-Human Randomized, Controlled Trial of Mosaic HIV-1 Immunogens Delivered via a Modified Vaccinia Ankara Vector. J Infect Dis 218:633-644
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
Blass, Eryn; Aid, Malika; Martinot, Amanda J et al. (2018) Adenovirus Vector Vaccination Impacts NK Cell Rheostat Function following Lymphocytic Choriomeningitis Virus Infection. J Virol 92:

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