A NOVEL PD1 DNA-BASED VACCINATION STRATEGY TO MIMIC GAG-SPECIFIC RESPONSES FOUND IN HIV ELITE CONTROLLERS – PD1VAX

This project aims at developing an innovative DNA vaccination strategy against HIV. The development of an effective HIV vaccine represents a major public health objective, as HIV remains one of the most devastating infectious agents, with over 35 million people currently living with the virus worldwide (UNAIDS 2013 global report). An HIV vaccine candidate has for the first time shown a moderate efficacy in a phase III trial, which energized the vaccine research field but also demonstrated the need for improved vaccine strategies against HIV. One of the obstacles remaining for candidate vaccine evaluation is that correlates of protection against HIV remain poorly defined. However, a series of recent studies have shed light on the particular nature of the antiviral immune response in HIV-infected patients who spontaneously control the virus in the absence of therapy. Our groups (teams FR1 and FR2) have shown that these rare patients, called HIV Elite Controllers, develop T cell responses that are particularly efficient at sensing low amounts of virus and at eliminating infected cells (Almeida, J. Exp. Med. 2007 and Blood 2009; Vingert, PLoS Pathogens 2010). This efficiency arises from the selection and expression of particular T cell receptors (TCRs) with a high avidity for epitopes located in the capsid of HIV, the Gag p24 protein (Ladell, Immunity 2013). Developing a vaccine that induces Gag responses similar to those seen in Controllers represents a key objective, as such high sensitivity responses are needed to contain limiting amounts of infecting HIV virions at a very early stage, before the virus has time to spread systemically.

Our project will build on a novel vaccination platform that was shown to induce high frequency, high-sensitivity, and persistent Gag responses in mice (Zhou, J. Clin. Invest. 2013). This vaccination platform, developed by team HK1, relies on a DNA vector that encodes a soluble PD1-Gag fusion protein. The soluble PD1 moiety (sPD1) markedly enhances Gag immunogenicity, due to an efficient targeting of the immunogen to dendritic cells (DC) that express ligands of the PD1 receptor. The strategy chosen is based on in vivo electroporation of the sPD1 DNA vector, because this technique induces the recruitment of DC to the site of vaccination. Electroporation represents one of the most promising approaches for DNA vaccine delivery, as it increases immunogen expression 10-100 fold as compared to simple DNA injection. For this project, we will use the TERESA electroporation device developed by our industrial partner (team HK2), who is conducting a clinical phase IIb trial for DNA vaccination in China.

The project will focus on a preclinical evaluation of the sPD1-Gag vaccine in three systems, including human cell cultures, a mouse model, and a non-human primate model. Evaluation in human cells will take advantage of a rapid in vitro vaccination system developed by team FR2, with the objective of comparing the repertoire of Gag-specific TCRs induced by vaccination to the repertoire of HIV Elite Controllers. The mouse model will make use of the EcoHIV virus, which expresses the native HIV-1 Gag protein with a murine retroviral envelope, and is a suitable challenge virus to test the efficacy of the sPD1-Gag vaccine. The most promising sPD1-Gag vaccination strategy will then be evaluated in rhesus macaques challenged by the mucosal route with pathogenic SIVmac239, based on the extensive expertise acquired by team HK3 in this animal model. At each step, we will use the responses measured in HIV or SIV Elite Controllers as a benchmark for optimal vaccine responses. These experiments will provide preclinical data to support a future trial of the sPD1-Gag vaccine in humans, and will further the development of DNA vaccination strategies against HIV.