Pantaleo: RepliVax Vaccine Platform
The development of an efficacious HIV vaccine is of paramount importance for the control and prevention of HIV infection. The RV-144 trial has shown a modest effect of the ALVAC-HIV (vCP1521) in combination with a recombinant gp120 subunit alum-adjuvanted vaccine (AIDSVAX B/E) in preventing infection, i.e. 31.2% efficacy thus providing evidence that an HIV vaccine may prevent HIV infection. Preliminary data from the immune correlates case control study from the RV-144 trial have shown that high plasma binding IgG antibody titers specific to Env V1/V2 are associated with reduced risk of infection. Therefore, the main focus of novel immunization strategies should be the substantial improvement of the vaccine-induced antibody response.
Building on the large experience accumulated within the Poxvirus T-cell Vaccine Discovery Consortium under the CAVD program for development of the replication competent NYVAC vector and the industrial competences at Sanofi Pasteur, Pantaleo's VDC will focus on the development of novel replication competent platforms for optimal priming of antibody responses.
The overarching goal of the work performed for this grant is to develop a replication competent self-limiting single cycle flavivirus vector based HIV vaccine candidate, ie RepliVax®,
for use in a prime-protein boost regimen with a strong emphasis on eliciting optimal, robust and durable/boostable antibody responses. In parallel to the RepliVax® development, the VDC will also focus on the development of novel delivery systems for Env proteins and generation of novel Env immunogens. Two main approaches to this end are planned: (i) target ENV antigen(s) to dendritic cells (DCs) using a DC-specific antibody and (ii) use bioinformatics to generate ENV immunogens (ENV) with improved epitopes selected basd on binding to broadly neutralizing antibodies. DC-targeting may be considered as a platform technology that could contribute to the development of improved vaccines, either as a stand-alone approach or used in combination with other components.
1. To develop a RepliVax® based viral vector platform for delivering HIV antigens
2. To generate novel Env immunogens and delivery systems for Env proteins
3. Immunological characterization of the RepliVax® vectors and prime/boost immunization strategies
In year 1, the main progress of RepliVax include: 1) Generation of prototype RepliVax HIV recombinants and initiation of optimization process; 2) Completion of pilot NHP study with anti-Lox-1 DC targeting vaccine candidate combined with NYVAC-KC; selection of the most promising candidates for the next DC Targeting Selection Study in NHP; 3) Obtained the initial in vitro immunogenicity data on DCs and monocytes with RepliVax-ZM96gag, which suggested that RepliVax has a distinct different immunological profile compared to pox vectors; 4) initiated the generation of improved Env immunogens with enhanced bNMAbs binding.