This project aims to address a fundamental problem blocking the development of a successful HIV-1 vaccine. The goal is to understand how best to design T cell immunogens to address the broad genetic diversity of HIV-1. Extensive viral sequencing has enabled the development of in silico approaches to immunogen design that are predicted to improve the breadth of T cell reactivity.  The CECI project will test two such centralized approaches (consensus and mosaic versions of the HIV envelope gene Env) versus a single wild type Env in a Phase 1 clinical trial.  Validation of in silico immunogen design as a method of enhancing the breadth and coverage of T cell responses to HIV could speed the development of a practical vaccine.

The CECI project is a landmark collaboration among major stakeholders in the Global HIV Enterprise.  Its members include the Collaboration for AIDS Vaccine Discovery (CAVD), the Center for HIV/AIDS Vaccine Immunology (CHAVI) at Duke University, the National Institute of Allergy and Infectious Diseases (NIAID) Division of AIDS, the NIAID HIV Vaccine Trials Network (HVTN), the IPPOX Foundation and others. This $6 million grant from the Bill & Melinda Gates Foundation will support the preparation of experimental immunogens to be used in the clinical trial. NIAID will provide substantial in-kind support for the project through its manufacturing, quality control and clinical trials capabilities.

RESEARCH OBJECTIVES:
This research project will includes a phase I proof-of-concept study be initiated to test two centralized approaches (consensus and mosaic Envs) versus single wildtype Env, as a means of enhancing the breadth and coverage of T cell responses to HIV. The critical scientific questions to be addressed in the clinical trial include:

1. Is consensus Env superior to wildtype transmitted/founder Env for induction of T cell breadth?
2. Is consensus Env superior to trivalent mosaic Env for induction of T cell breadth?
3. Can the predictions of superiority of induced breadth of T cell responses by consensus and mosaic immunogens that are predicted in silico, be validated in humans in vivo?

If the above three questions can be answered expeditiously in one phase I human clinical trial, the results will propel the field forward in terms of immunogenic design for HIV T cell responses. Furthermore, results from this study will validate the in silico design approach, and in doing so, will open an important new path towards HIV-1 vaccine development, wherein fewer comparative preclinical and human trials would need to be performed in order to choose or optimize immunogen design for induction of the broadest HIV T-cell responses for optimal vaccine immunogenicity.

Partner
Bill & Melinda Gates Foundation