Pantaleo Vaccine Discovery Consortium

OVERVIEW:

The primary goal of the Pantaleo-led VDC is to generate replication-restricted poxvirus vectors that would substantially improve the breadth of HIV-1-specific vaccine induced immune responses. This strategy is also combined with the deletions of certain poxvirus genes known to interfere with the induction of the immune response. These newly generated vectors in addition to improving the magnitude and the quality of the vaccine induced HIV-1-specific T cell response, may serve potent priming strategies for envelope protein-based vaccines and thus for the induction of potent antibody responses.

RESEARCH OBJECTIVES:

1. Development of poxvirus-based vaccine candidate(s) with at least a 10-fold increase in immunogenicity as measured by the frequency of vaccine induced T-cells compared to the current poxvirus vectors and of novel formulation/delivery strategies.

2. Development of validated pre-clinical in vitro assays and in vivo models that serve as filters for the selection of improved vectors; understanding the mechanisms of generation and maintenance of memory T-cells to help develop strategies to elicit durable vaccine-induced T-cell responses; and delineation of the factors regulating the patterns of T cell function.

3. Selection of the most immunogenic among the current poxvirus vectors that offers the most potential for future development; assessment of novel T-cell adjuvants for improving the immunogenicity of poxvirus vectors; and evaluation of ‘best-in-class’ poxvirus vectors. The aim of the consortium is to advance one or more candidates to enter Phase I clinical trials by year 5.

PROGRESS:

Substantial progress has been made on the generation of replication competent viruses as well as combined viruses (combining replication competency and gene deletion strategies). Pathogenicity studies in new born mice have demonstrated a satisfactory safety profile of the lead replication competent poxvirus vector.

The researchers are also working on improvement of HIV transgenes to be expressed in the novel poxvirus vectors.

The VDC has put in place standard operating procedures and selection algorithm that are crucial for the comparison of the biological effects of the different NYVAC and MVA mutants.  The selection algorithm comprises a combination of innate and adaptive immunity filters/assays including transcriptional analysis in in vitro experimental models and pre-clinical evaluation in the non-human primate model.

The large set of in vitro immunological data has enabled us to identify the lead replication competent poxvirus vectors which we are moving rapidly to further evaluation in non-human primates and to clinical studies.

The Phase II study EV03/ANRSVAC20 is fully enrolled and all volunteers have completed the immunization.  Immunogenicity data is expected early 2010.