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From research to clinical trials Brigitte Gicquel Institut Pasteur Coordination of TB ETHICS and

From research to clinical trials Brigitte Gicquel Institut Pasteur Coordination of TB ETHICS and TB VACCINE Cluster of the European Commission. Today, we observe an acceleration in the accumulation of knowledge: An increase of the quantity of knowledge

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From research to clinical trials Brigitte Gicquel Institut Pasteur Coordination of TB ETHICS and

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  1. From research to clinical trials Brigitte Gicquel Institut Pasteur Coordination of TB ETHICS and TB VACCINE Cluster of the European Commission

  2. Today, we observe an acceleration in the accumulation of knowledge: An increase of the quantity of knowledge Improvement of existing technologies (recent technologies) There is not an increase of discoveries

  3. During the last five years, we observe an accumulation of complete sequences of major living organisms: *The complete sequence of the Human genome *The complete sequences of most pathogenic Organisms *The technologies of mass parallel analysis (transcriptome, proteome) This doesn ’t mean we can easily derive vaccines from this knowledge

  4. During the last five years, we observe also major scientific breakthroughs: *The role of innate immunity *The biology of dendritic cells *The existence of T cell populations responding to non protein antigens (CD1 restriction) *More recently the diversity in microbial (« Beijing  ») and human populations (high or low gIFN producers, IL4 differential splicing etc…) *The role of T regulatory cells

  5. « Modern » research tends to make use of big equipements and big technical teams. This kind of research is essentially supported by big Pharma with the aim to discover new molecules and interventions for existing markets.

  6. « Modern » research tends to make use of big equipements and big technical teams. This kind of research is essentially supported by big Pharma with the aim to discover new molecules and interventions for existing markets. There is no willingness for finding molecules to solve public health problems disconnected from any market. The aims of researchers and organisations working on Poverty Related Diseases is to benefit of existing knowledge to derive molecules useful to solve public health problems of populations disconnected from The Market

  7. In the context of TB, several laboratories including big Pharma have produced Vaccine candidates. TB is not only a problem of DC countries. The disease is still present in any country of the world. However « The Market » is not existing yet. Now we have to test these vaccine candidates in clinical trials

  8. T lymphocyte Immunity 90%: no disease (90%) PPD+ Culture- (10%) 5%: disease within 0-2 years ( 30-40% in HIV+ subjects) 5%: disease during the life time (Aging, malnutrition, HIV…  Reactivation) ( 2-10%/year in HIV+ subjects) Mycobacterium tuberculosis Alveolar Macrophage Alveoli

  9. NKTcells gd T cells Mycobacterial live vaccines Mycobacterial ligands Danger signals Macrophages Apoptotic particles Immature dendritic cells Mature dendritic cells Adjuvants CD4 T cells Sub-unit vaccines and viral vaccines Induction of adaptive responses The TB Vaccine Cluster CD8 T cells Protection The new consortium: TB-VAC Under negotiation with the EC Clinical trials

  10. http://www.pasteur.fr/EC_TBvaccine/

  11. Aims of the TB vaccine cluster *To investigate different components of the immune sytem that are important in protection or disease development *To study vaccine candidates able to induce these different components 1 Vacccine candidates that have been previously isolated 2 New vaccine candidates that will be discovered during this project *To organise task forces to test vaccine candidates with standardised protocols 1 Guinea pig model (aerosol) 2 Macaque models (intratracheal) *To understand correlates of protection -> to provide parameters to follow clinical trials

  12. Rationale for a joint initiative Industry/Academy for a research project: • *The necessity to design a product that could be produced • at an industrial level. • Otherwise large scale vaccination is hopeless • *Several biological companies have been involved in research • at an early stage: • ex1: Merck for DNA vaccination in collaboration with • Institut Pasteur of Brussels • ex2: Corixa isolated vaccine candidates in collaboration • with GSK • In the TB vaccine cluster: • *Aventis participates in the TB vaccine cluster • (production and purification of antigens) • *GSK participates in the TB vaccine cluster to test • adjuvants and vaccine candidates previously isolated and tested • in in house animal models

  13. 4 projects *Coordinated by P. Andersen (DK): pre-clinical studies *Coordinated by C. Martin (ES): attenuated strains *Coordinated by J.-J. Fournié (F): non-protein antigens *Coordinated by T. Ottenhoff & J. Thole (NL): correlates of protection,Necrosis /fibrosis,Physiopathology analysis, Immune parameters Task forces for animal testing Advantages : *standardization of the protocols *testing by teams not involved in the discovery of the vaccine candidates Two industrial partners *Adjuvant *Production/purification of antigens

  14. Models of Primary TB The macaque models: Cyno/Rhesus Vaccine candidates Previously isolated (tested in mice) Task force: Guinea pigs Task force: Macaques 1 round completed 2 rounds completed 1 round is ongoing 1 round Ongoing 1 round waiting Promising antigens In different vectors Mice gd and CD1 ligants New vaccine candidates Isolated during this project Mice

  15. - BCG - Mtb PhoP mutant - BCG MVA/85A - FP/85A - Saline Survival Survival of guinea pigs up to 26 weeks post high-dose (500CFU) aerosol challenge

  16. THE TB VACCINE CLUSTER (2000-2003) *Sub-unit vaccine candidates that provide protection have been identified *Protection conferred by sub-unit vaccine candidates are superior to BCG in a murine model *However, in other animal models no protection superior to BCG or even equal to BCG was observed *Prime boost protocols including BCG, DNA and/or viral vectors showed protection *New attenuated mycobacterial live vaccines have been identified: *One provide protection superior to BCG in a murine model. *Another one provide protection in the murine and in the guinea pig model at least equal to BCG without additional safety concern

  17. From studies of bacterial populations: Important variations between strains: majors types i.e.W-Beijing, Haarlem, Manilla, etc…. Induce different immune responses From the recent discoveries in immunology: Important variations between mamal species: relevence of animal models? Important variations between individuals: Different environments (ex: BCG efficacies) Different genetic backgrounds?

  18. PPD (p=0,1) 10000 PBMC 6 100 SFC/10 1 TB HD ELISPOT IFN-g assay

  19. Importance of human systems: In vitro systems Ex vivo/in vitro systems Clinical experimentation: Study of the different populations in need of a vaccine For DC countries: *Opportunity for different countries with limited infrastructures to participate to the development of vaccines *To study the immune responses of the populations *To improve infrastructures *To establish ethical committees

  20. Two other EC FP5 projects derived from the TB vaccine cluster have been since launched : *AFTBVAC-Development of a tuberculosis vaccine in Africa *TBETHICS-Enhancing ethical evaluation, review and monitoring in international collaborative research in tuberculosis *Other ongoing FP5 projects are providing important results for the design of pre-clinical and clinical trials Mol.Epidemiolgy TB: New generation of genetic markers and techniques for the epidemiology and control of tuberculosis *Other projects will be necessary to investigate the diversity of human responses to infection and to vaccination

  21. Importance to study human immune responses as soon as possible To search for antigens that are recognised by human populations: Ex: SSI, GSK Production of antigens Pre-clinic studies Clinical studies

  22. The tendency: To fill the gap Existing knowledge Products Pre-clinical studies NGO and Public funds Industries Clinical research New drugs and vaccines

  23. Questions Knowledge Research Problems To solve Applied research Products Pre-clinical studies NGO and Public funds Industries Clinical research New drugs and vaccines

  24. The classical flow: Research to human drugs or vaccines Questions Personal curiosity Industrial problem to solve Health problem To solve Preclinical Research (efficacy) Industry (Production) Research Preclinical research (efficacy, safety) Clinical trials Safety, responses, efficacy New drugs and New vaccines

  25. DC Research Centers European Research Centers and Universities Health CareCenters in endemic area: DC DC Universities

  26. Prerequisit for human testing: The existence of epidemiological data The existence of an effective National Tuberculosis Programme The tested populations must have an immediate, mid-term and long term benefit. Immediate benefit: Improvement of diagnostic laboratories Increased access of the population to diagnosis and treatment Mid term benefit: Improvement of training capacities Technology transfer Long term benefit: Access to the vaccine that will be developed

  27. gd T cells Mycobacterial live vaccines Mycobacterial ligands Danger signals Macrophages Apoptotic particles Immature dendritic cells Mature dendritic cells Sub-unit vaccines and viral vaccines Induction of adaptive responses Different steps to investigate Protection Clinical trials

  28. Requirement of many different expertises Possibility to benefit from recent knowledge: *The complete sequences of several mycobacterial genomes *Existence of genetic tools to develop functional approaches *Biochemical characterisation of important mycobacterial compounds *Characterisation of cellular populations reacting to Mycobacterial compounds

  29. Next step: Integration of European and African countries The problematic: *To develop vaccines to protect the population in need of such a vaccine The means: *To integrate the European and African capacities *To conduct clinical studies in Africa: *To determine the reactivities of the African human populations to vaccinial antigens *To undertake phase I trials in Africa to identify immune responses and make sure of the absence of adverse effects in populations in need of vaccination

  30. VACSIS University College of London London School of Hygiene and Tropical Medecine Statens Serum Institute (Denmark) Institut Pasteur (France) M.R.C. (The Gambia) A.R.H.I. (Ethiopia) University of Zambia Institut Pasteur of Madagascar

  31. The Tuberculosis Vaccine Cluster QLK2-CT-1999-01093

  32. From Langermans et al. (2001) Proc. Natl. Acad. Sci. 98:11497-502

  33. generating new vaccines protein antigens live attenuated vaccines non-protein antigens results contribute to rational selection of new candidates results contribute to rational selection of new candidates new vaccine candidates new reagents for testing immune response understandingnew vaccines screening new vaccines model systems for assessing immune correlates immune response in man and experimental models experimental animal models of infection Candidate vaccines for Phase I clinical trials

  34. Vaccines Social value Pharmaceuticals Economic value From Rappuoli R. et al. Science 9 August 2003

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