Haynes: Centralized Envelope Phase I Study
This project aims to solve a fundamental and central problem blocking the development of a successful HIV-1 vaccine—how to design vaccine immunogens from a T-cell epitope perspective to successfully address the broad genetic diversity of HIV-1. If successful, this project will enable the field to accelerate vaccine development by ‘validating’ an
in silico approach for optimizing HIV-1 T cell immunogens for testing in clinical trials. Over the past two decades, extensive viral sequencing has enabled an
in silico approach to immunogen design to be developed, and substantial preclinical progress has been made. Centralized genes have now been identified which, as predicted
in silico, have been proven to substantially improve the breadth of T cell reactivity, particularly CD8+ T-cells, in small animals as well as in non-human primates. The regimen that will be used to test the centralized genes in humans consists of two priming immunizations with DNA inserts, and then two boosts with the NYVAC vaccinia vector containing the same experimental inserts.
The arms of the trial will include:
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 vaccines will be Env gp160s given as DNAs for priming and Env gp120s given as an insert in NYVAC vector as a boost. Building upon the previous human experience from the EuroVacc trials, the anticipated immunization regimen will be two injections of DNA at weeks 0, and 4 followed by two injections of NYVAC at weeks 20 and 24. Doses of DNA and NYVAC are anticipated to be ~4mg and ~1x107 pfu respectively. Controls will be given the empty vaccine diluent control.
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.
There has been significant progress in advancing to the Phase I clinical trial, comprising the submission of the IND to the FDA in July 2013 and subsequent approval to initiate the start of the trial. Part A of the trial is slated to begin enrollment in November 2013.
A significant critical milestone was met in October 2013 with the finding that one of the arms of the HVTN 096 clinical trial that incorporated a DNA prime and NYVAC+AIDSVAX boost, which is a similar regimen to HVTN 099, demonstrated adequate immunogenicity to support the initiation of HVTN 099.