Centralized Envelope Phase I Study


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One of the major obstacles in the development of a preventive HIV-1 vaccine is the extensive genetic diversity of the virus. Designing immunogens that can induce robust T cell responses to many different strains of viruses is a major goal of the DHVI. Decades of viral sequencing has resulted in an in silico approach to HIV-1 immunogen design, which is based on the computational and mathematical modeling of HIV viral sequences. This approach has been successfully used in preclinical studies of small animals and non-human primates to identify centralized immunogens that could substantially improve the breadth of T cell reactivity to HIV, particularly that of CD8+ T cells. 

The “Centralized Envelope Phase I Study” will test these centralized immunogens in a phase I “proof-of-concept” clinical trial to determine which approach can induce superior T cell responses. In this study, the breadth and coverage of T cell responses will be evaluated using two types of centralized immunogens, consensus and mosaic Envs, versus wild-type transmitted/founder Env. In addition, the study will potentially validate the in silico approach for use in clinical trials, which would reduce the number of preclinical and human studies required to design and test HIV-1 T cell immunogens.

The vaccines that will be administered in the trial will include Env gp160s, given as DNA for priming, and Env gp120s, given as an insert in a NYVAC vector for boosting. The vaccine regimen will include two priming immunizations with the DNA inserts and two boosts with the NYVAC vaccinia vector with the same experimental inserts. The trial will include the three following arms:

I. Single wildtype transmitted/founder Env (50 subjects + 10 controls)

II. Single group M consensus Env (50 subjects + 10 controls)

III. Trivalent mosaic Env (50 subjects + 10 controls)

The manufacturing of the three gp160 DNA vaccines has been completed, and the vaccines are currently on a stability testing program. In addition, a parallel non-human primate study is underway to evaluate the immunogenicity of the clinical trial vaccines and regimens.

This project is funded by the Bill and Melinda Gates Foundation, the CAVD, the CHAVI-ID, DAIDS, the Foundation for the NIH (FNIH), and the HIV Vaccine Trials Network (HVTN). DHVI investigators will collaborate with Beth Israel Deaconess Medical Center, Fred Hutchinson Cancer Research Center, the IPPOX Foundation in Switzerland, Los Alamos National Laboratory, the NIAID, the NIH Vaccine Research Center (VRC), the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), EuroVacc, and Sanofi-Pasteur.