| The TB Vaccine Cluster: From Research to
Clinical Trials Dr Brigitte GICQUEL
Mycobacterial
Genetics Unit, Institut Pasteur, France Infectious diseases
are the cause of more than 33% of the deaths worldwide. Only vaccination was able
to eradicate an infectious disease. This had happened with the eradication of
small pox thanks to the utilisation of a live vaccine the Vaccinia virus of which
we will speak as a vector later on during this workshop. Other infectious diseases
like polio are under elimination thanks to vaccination. A vaccine against tuberculosis
(TB) was discovered early during the 20th Century. However its protective efficacy
was only very well proven in children. It protects against the severe forms of
disseminated tuberculosis. Its efficacy against the adult pulmonary forms of TB
was shown to be variable following the different clinical trials, ranging from
85% to 0% with a medium estimate of 50%. As a consequence new vaccines are urgently
needed to protect efficiently against tuberculosis. During the last ten years
the research dynamism has moved toward big consortium and the accumulation of
data that need important bio-informatic structures to be used appropriately. We
hope that the fight against TB will benefit of them. Defining
Research We need research to find the new vaccines, but what
is research? The general press gives us the impression that there is an acceleration
in the accumulation of knowledge. We have the impression that we know more and
more every day. However, this is simply an increase in the quantity of knowledge
due to the improvement in existing technologies. This does not mean that there
is an increase in discoveries, which is quite different. In
biology, for example, we have the complete human genome sequence, and the complete
sequences of most pathogenic organisms. We have different technological approaches
to study these organisms. However, knowing how to make a vaccine based on this
knowledge is still a difficult step. Knowledge is not tantamount to discoveries. However,
in the past five years, we have observed several major scientific breakthroughs,
for example, in relation to tuberculosis, leprosy and immunology. We have discovered
the role of innate immunity, the biology of dendritic cells, the existence of
T cell populations that are CD1 restricted, the role of T regulatory cells, and
the diversity of microbial and human populations. These discoveries should help
us for the design of new vaccines. Such a goal will require the association of
these different expertises. Today, the general press seems to
suggest that "modern" research means big technical teams, big equipment in big
pharmaceutical companies. This big effort of research is derived from the important
efforts in genomic. It requests enourmous financial supports that will be essentially
used for the design of products for existing markets. There is no real willingness
to discover new molecules for public health problems disconnected from the market.
This is why we need initiatives to fight against poverty-related diseases and
to develop molecules for public health problems by associating public and private
partners with Non governmental Organisation (NGO) and international agencies that
could help at the different steps, research, development, production, pre-clinical
and clinical trials until the implementation of new more efficient pharmaceutical
products. In the context of tuberculosis, several laboratories
funded by national and intenational agencies like the National Institutes of Health
of America (N.I.H.) the European Commissison (E.C.), but also major pharmaceutical
companies, have participated to the production of vaccine candidates, Merck and
Glaxo SmithKline together with CORIXA. Several vaccine candidates have showed
very promising results in pre-clinical studies. We now have to test them in clinical
trials to determine their ability to induce protective immunity to tuberculosis.
Immunology has moved from the study with animal models to humans. This will help
to study correlates of protection after vaccination. We do not know the real efficacy
of these vaccine candidates in human beings. We therefore need more research to
improve these vaccine candidates but also to identify new vaccine candidates in
case the few candidates that we have fail after a number years of testing due
to the discovery of unknown parameters that have to be fulfilled for a real efficient
vaccine. Stefan Kauffmann has published an excellent paper in
Nature Reviews/Immunology on immunity to tuberculosis. This is a significant problem
because, after vaccination or after infection responses the induction of various
T cell population, which could be protective. Only a small fraction of infected
but not immunocompromised individuals will develop the disease instead of being
protected. We therefore need more research on this issue. During infection, the
bacilli will be phagocytosed by macrophages and dendritic cells. In about 90%
of cases, immunity will arise and the disease will be controlled. This shows that
infection is protective against the disease. Only in 10% of cases will the disease
arise, for various reasons. However infected individuals remain at risk to dévelop
the disease at any time during their life. The issue of protection is therefore
very complicated. It will require probably different interventions according to
the various populations. The TB Vaccine Cluster Consortium European
researchers have come together in the TB Vaccine Cluster consortium. This consortium
is transformed into a new consortium known as TB-VAC within the 6th Frame Work
Programme of the European Commission and now includes partners from developing
countries in need of such vaccines. Its aim is to improve vaccines candidates
issued from the TB Vaccine Cluster of the 5th Frame Work of the European Commission,
to isolate new ones and to test them in Phase 1 clinical trials in Europe. An
important goal will be to understand parameters important in protection and/or
development of the disease so that correlates of protection could be discovered
and help to monitor any immune intervention. We also need adjuvants for an efficient
vaccination. We need to understand both adaptive immunity and innate immunity,
and the role of the newly discovered unconventional T cell populations. Vaccine
Candidates The work of the TB Vaccine Cluster was funded by
the European Commission, and involved 38 laboratories in Europe. Its aim was to
investigate the different components of the immune system, to study various vaccine
candidates, and to discover new vaccines. These vaccines were tested by laboratories
not involved in their discovery and acting as task forces. Laboratories that had
developed promising vaccine candidates using the mouse animal model were requested
to test the vaccine candidates in guinea pigs before being tested in Non Human
Primates (NHP). The best vaccines will then be tested in human beings after completion
of all tests related to inocuity. A big emphasis is put on the definition of correlates
of protection that will be required to estimates phase 1/2 trials.
The TB Vaccine Cluster involves laboratories from academies, institutions and
pharmaceutical companies such as GlaxoSmithKline and Aventis Pasteur. We felt
it was important to bring together pharmaceutical companies and research institutions
from the very beginning of the project to promote vaccine candidates that could
be manufactured in conditions of scale production suitable for mass vaccination. Results During
the TB vaccine cluster project we generated sub-unit vaccine candidates that provided
protection, which is superior to BCG in a murine model but not in other models.
We also generated new attenuated mycobacterial live vaccines, that provided better
protection than BCG in some cases. Finally a protocol of immunisation including
BCG and recombinant pox virus provided protection superior to BCG in the highly
sensitive guinea pig model. This vaccine candidate is being tested in phase 1
clinical trials. Interactions between the host and the pathogen were studied at
a molecular level thanks to genomic, genetic, cell biology, and biochemical approaches.
to propose new intervention strategies. A more detailed list of results obtained
during the TB vaccine cluster is indicated at its WEB site Other
EC Projects The European Commission has also supported a number
of other projects with the aim of developing new vaccines and understanding immune
responses after infection: AFTBVAC and VACSIS. An ongoing project on molecular
epidemiology "New generation genetic markers and techniques for the epidemiology
and control of tuberculosis" (2000-2003) emphasised the variation of M-tuberculosis
strains: the W-Beijing, Haarlem and Manilla families produced different immune
responses. In addition we know that all mammal species are not equal at the immunological
level: they do not induce the same responses. This is a problem for strategies
going from pre-clinical to clinical trials. There exist also many differences
between human individuals regarding their responses to medical treatments. These
variations could be due to genetic backgrounds but are essentially due to the
environments of the various populations being infected by different microorganisms.
There is also a great diversity in the mycobacterial world. Therefore it appears
extremely important to consider such variations by undertaking different clinical
trials with different populations of different geographic origin. This should
be an opportunity for developing countries with limited infrastructures to participate
in the development of vaccines. We have to study the immune responses of these
populations in need of vaccines, and help to improve infrastructures for all initiatives.
It should lead to the establishment of ethics committees that will be useful not
only for TB research. Conclusion People
believe that we have enough knowledge that simply needs to be applied. However,
a gap exists between knowledge and its application, and we need research to obtain
more appropriate knowledge to get more information on correlates of protection
to follow any vaccination trial. However vaccine candidates that showed promising
results in pre-clinical studies are ready to be tested in phase 1 clinical trials
and some immune molecular parameters can be followed.We should work together to
associate research centres in Europe and in developing countries. We also need
to work with health care centres with a view to improving their control of disease.
In order to study vaccines and immunology, we need regions with epidemiological
data. We need to work in association with countries having effective national
tuberculosis programmes, and to ensure that everyone obtains immediate, mid-term
and long-term benefits. The immediate benefits for developing countries may include
the improvement of diagnostic laboratories leading to increased access of populations
to diagnosis and treatment. The medium term benefits may include the improvement
in training capacities, and the technology transfer of useful technologies. Finally,
a long term benefit will involve access to the vaccines that will be developed. | 
