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Pantaleo: Poxvirus-Based Vaccine Development

OVERVIEW

The primary goal of the Pantaleo-led research consortium is to generate highly attenuated replication-competent 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 as potent priming strategies for envelope protein-based vaccines and thus for the induction of potent antibody responses.

​Furthermore, Pantaleo/CHUV was awarded with a 2nd grant to develop DNA/NYVAC platform. The DNA/NYVAC platform has been tested in multiple phase I and II clinical trials in Europe and has shown to be highly immunogenic. This part of the project represents further development of the DNA/NYVAC platform targeted to improve both the magnitude of the T-cell response (particularly CD8 T cell response) and breadth of the response. The primary goal of the project is to investigate whether the 2nd generation DNA-C/NYVAC-C vaccine combination together with novel immunization strategies is able to increase response magnitude and breadth and induce balanced Env versus Gag, Pol and Nef HIV-1-specific T cell response in humans.

​The researchers are investigating in the non-human primate model the immunogenicity of the 2nd generation DNA-C/NYVAC-C regimen. The combined clinical and NHP challenge study data will provide the scientific basis for moving the DNA-C and NYVAC-C vaccine candidates to a phase IIB trial in Africa.

​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 ‘best-in-class’ poxvirus vector(s) through validated in vivo and in vitro filters for Phase I clinical evaluation

4. GMP manufacturing of the 2nd generation DNA and NYVAC vaccine candidates developed under the PTVDC program.

5. Conduct toxicity studies as requested by the regulatory authorities in preparation for the clinical development of the 2nd generation DNA and NYVAC vaccine candidates

6. Conduct NHP immunogenicity and efficacy studies as well as PhI safety and immunogenicity study with the 2nd generation DNA and NYVAC vaccine candidates, to generate data for the ph IIB study in Sub-Saharan Africa.

PROGRESS

To date, the researchers have successfully developed a series of new poxvirus vectors and identified the "best-in-class" replication competent vectors following a stringent selection algorithm with pre-defined criteria. This selection algorithm, containing a series of in vitro and in vivo testing, has been the result of a collective effort of the consortium and has demonstrated to be very effective in selecting candidate vaccines.

At present, the research consortium has:  1) released the DNA and NYVAC  (replication deficient) GMP lots; 2) completed the large NHP study that demonstrated the new NYVAC vaccines developed within PTVDC are highly immunogenic both in terms of T-cell and B-cell responses; 3) Completed several several other NHP studies to further evaluate and compare different vaccine combinations, inserts and regimens, which have provided pivotal data for the design of future clinical studies; 4) completed the selection of the replication competent NYVAC further clinical development.   Furthermore, in collaboration with HVTN, two phase I clinical studies have been initiated with the new DNA and NYVAC (replication deficient) vaccines.  The goal of the study is to evaluate the safety and immunogenicity of the new DNA and NYVAC as well as to compare the different protein immunization schedule. 

All these data will be instrumental for the design of the next phase IIb efficacy study.  

 

 

Grant at a Glance

Principal Investigator

Giuseppe Pantaleo, MD

Grantee Institution

Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland 

Project Title

Poxvirus Vaccine Regimen Design

Grant Awards

First grant: $21.1M over 6 years, awarded in August 2006

Second grant: $5.7M over 5 years, awarded in November 2009

Collaborating Institutions

  • Arizona State University, USA
  • CHU Henri Mondor, University Paris 12, France
  • Consejo Superior de Investigaciones Cientificas, Spain
  • Institute for Research in Biomedicine, Switzerland 
  • IPPOX Foundation, Switzerland
  • Leiden University Medical Centre, The Netherlands
  • Murdoch University, Australia
  • Oregon Health Sciences University, VGTI, USA
  • Sanofi Pasteur, Canada
  • University of Cambridge, UK
  • University of Montreal, Canada
  • University of Regensburg, Germany
  • University of Washington, USA
  • Vaccine and Gene Therapy Institute of Florida, USA

External Scientific Advisory Board

  • Rafi Ahmed, Emory Vaccine Centre
  • Andrew McMichael, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital
  • Stanley Plotkin, Sanofi Pasteur
  • Nina Russell, Bill & Melinda Gates Foundation

Progress to Date

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