Evaluation in cynomolgus macaques challenged with SHIV-SF162-p3 of the protective efficacy of a measles-based SHIV vaccine combined with a peptide-based vaccine targeting 3 retroviral functions – ARTT-HIVAC

The repeated failures of previous clinical HIV-1 vaccine candidates and the moderate efficacy of the RV144 vaccine (31% at 42 months) have emphasized the need of new vectors inducing new immune functions and the setup of vaccine regimens combining several pre-existing immunogens/vaccine strategies. Measles virus (MV) vector priming combined with protein boosts could fulfill these conditions. In fact, in an initial study we demonstrated that vaccination with MV vectors expressing Gag, Env and Nef simian-human immunodeficiency virus immunogens (MV-SHIV) controlled the SHIVSF162p3 challenge virus in cynomolgus macaques. Indeed, the peak viral load median of the vaccinated monkeys was nearly 2 logs lower compared to the placebo group, and plasma virus load was strongly reduced within a week (p=0.0001, Wilcoxon test). Moreover in contrast to the control monkeys, the vaccinated monkeys maintained plasma CD4+ T-cell counts >1000 cells/µl following challenges. Consequently, the MV-SHIV vaccine markedly reduced the reservoir size in PBMCs, spleen, axillary and inguinal lymph nodes and rectum, as evidenced by 50% of the animals exhibiting = 10 proviral DNA copies per million of cells. Interestingly, the control of SHIV162p3 found in the vaccinated monkeys was correlated with the Gag-specific cellular immune responses. However MV-SHIV vaccine alone was not able to delay SHIV acquisition after repeated intrarectal challenges, which is crucial for a HIV-vaccine to prevent virus integration. This could be attributed to the lack of induction of plasma neutralizing IgG (against tier-2 SHIV162p3) and mucosal IgA (in rectal secretions), which are known to be associated in vivo with a sterilizing protection against SHIV and SIV challenges, or at least with a delay of acquisition. Thus, we propose in this study to combine the MV-SHIV vaccine with protein boosts of the external region of the HIV gp41 envelope subunit. That gp41 polypeptide will include 3 highly conserved functional domains: the immunosuppressive domain ISD (the target of IgA antibodies in “Exposed Uninfected” patients), the “3S-motif” (anti-3S antibodies inhibit NK activity and cytotoxicity) and the membrane-proximal external region MPER (recognized by neutralizing and anti-HIV transcytosis antibodies in macaques challenged by the SHIVSF162p3). Chemically synthesized gp41 polypeptide in the presence of PLGA-based nanoparticles and TLR4 and TLR7/8 agonists adjuvants, or recombinant gp41 expressed by measles virus vector will be first assessed in mice to define the protein-boost regimen yielding the highest levels of circulating and mucosal antibodies. Then, cynomolgus macaques will be primed with the previously assessed MV-SHIV vaccine and boosted with the best protein-boost regimen before intravaginal challenges with the SHIVSF162p3 strain. We aim to provide the proof of concept of the protective efficacy for this new vaccine regimen/combination in the perspective of a first-in-man Phase I clinical trial. The final objectives of this project are the evaluation in patients of this vaccine candidate as a prophylactic and therapeutic vaccine.