Transcript Aucun titre de diapositive

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
Improvement of existing technologies
(recent technologies)
There is not an increase of discoveries
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
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
« 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.
« 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
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
Mycobacterium tuberculosis
Alveolar
Macrophage
T lymphocyte
Immunity
Alveoli
(10%)
5%: disease within 0-2 years
( 30-40% in HIV+ subjects)
90%: no disease (90%)
PPD+ Culture-
5%: disease during the life time
(Aging, malnutrition, HIV…  Reactivation)
( 2-10%/year in HIV+ subjects)
NKTcells
Mycobacterial
live vaccines
gd T cells
Mycobacterial ligands
Danger signals
Macrophages
Apoptotic particles Immature dendritic
Mature dendritic cells
cells
Adjuvants
CD4 T cells
Sub-unit vaccines
and viral vaccines
Induction of adaptive
responses
The TB Vaccine Cluster
Protection
The new consortium: TB-VAC
Under negotiation with the EC
Clinical trials
CD8 T cells
http://www.pasteur.fr/EC_TBvaccine/
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
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
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
Models of Primary TB
Vaccine candidates
Previously isolated
(tested in mice)
Promising antigens
In different vectors
New vaccine candidates
Isolated during this project
The macaque
models:
Cyno/Rhesus
Task force:
Guinea pigs
2 rounds completed
1 round is ongoing
Task force:
Macaques
1 round
completed
1 round
Ongoing
1 round
waiting
Mice
gd and
CD1 ligants
Mice
Survival
Survival of guinea pigs up to 26 weeks post high-dose (500CFU) aerosol
challenge
- BCG
- Mtb PhoP
mutant
- BCG MVA/85A FP/85A
- Saline
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
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?
ELISPOT IFN-g assay
PPD (p=0,1)
SFC/106PBMC
10000
100
1
TB
HD
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
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
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
The tendency: To fill the gap
Existing knowledge
Products
Pre-clinical studies
Industries
Clinical research
New drugs and vaccines
NGO and
Public funds
Knowledge
Applied research
Research
Questions
Problems
To solve
Products
Pre-clinical studies
Industries
Clinical research
New drugs and vaccines
NGO and
Public funds
The classical flow: Research to human drugs or vaccines
Questions
Personal curiosity
Industrial problem
to solve
Health problem
To solve
Research
Preclinical
Research
(efficacy)
Industry
(Production)
Preclinical research
(efficacy, safety)
New drugs and
New vaccines
Clinical trials
Safety, responses,
efficacy
European Research
Centers and Universities
DC Universities
DC Research
Centers
Health CareCenters
in endemic area:
DC
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
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
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
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
VACSIS
University College of Londo
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
The Tuberculosis Vaccine Cluster
QLK2-CT-1999-01093
From Langermans et al. (2001) Proc. Natl. Acad. Sci.
98:11497-502
generating new vaccines
protein
antigens
results contribute
to rational
selection of new
candidates
live
non-protein
attenuated
antigens
vaccines
new vaccine
candidates
new reagents
for testing
immune response
understanding new vaccines
screening new vaccines
experimental animal
models of
infection
results contribute
to rational
selection of new
candidates
model systems
for assessing
immune correlates
immune response
in man and
experimental models
Candidate vaccines for Phase I clinical trials
Vaccines
Social
value
Pharmaceuticals
Economic value
From Rappuoli R. et al. Science 9 August 2003