Press release
World
Tuberculosis Day (March 24)
The Institut Pasteur engaged in the fight
With a third of the
world's population infected, 2 million deaths and 8.5 million new cases each
year, tuberculosis (TB) is the number two infectious disease in the world after
AIDS, without sparing France, where 6300 new cases occurred last year. The prevalence
of the resistance to antibiotics and the emergence of multiresistance are worrying
at the international level, and is a risk for checkmating treatments in many
countries.
Vaccines, treatments, diagnosis, and surveillance: on all of these fronts, the
Institut Pasteur is seeking to improve the resources for fighting against the
scourge. Several laboratories of international renown are conducting advanced
research on its Paris campus, while worldwide, a TB Network brings together
ten institutes from the International Network of Instituts Pasteur that are
taking an active part in the national programmes in different countries to control
TB.
SURVEILLANCE
The Institut Pasteur in Paris: a National Reference Centre
The National Reference Centre of Mycobacteria at the Institut Pasteur is one
of two French centres in charge of epidemiological surveillance of TB in France,
where each year about 6,000 new cases and 700 deaths are recorded. Each year
it receives 2,000 samples to analyse, a tenth of which come from abroad, often
sent by NGOs like Doctors Without Borders. Currently, a large study is underway
in the Seine Saint-Denis department to characterize the circulating strains
and thereby to understand exactly how individuals are infected: this work involves
laboratory analyses like field surveys in affected families. It should be remembered
that the Ile-de-France has 3-4 times more cases than the national average, and
5-6 times more within Paris. The NRC belongs to the network of laboratories
set up by the WHO for the surveillance of resistance to TB antibiotics in the
world.
The Instituts
Pasteur in the world: an active network on the forefront of the fight
Algeria, Morocco, Tunisia, Ivory Coast, Central African Republic, Cameroon,
Madagascar, Cambodia, Vietnam, Russia, etc.-the Instituts Pasteur present in
these countries that are especially affected by TB have reference centres actively
participating in diagnosis and surveillance of the disease. A number of them
are involved in the National Programmes to Control TB, even managing them, like
the Institut Pasteur of Algiers, which is the standard for the World Health
Organization in the areas of Africa or Madagascar, one of the most affected
countries.
VACCINES
Doing better than BCG
The only vaccine at our disposal against tuberculosis is BCG (Calmette-Guérin
Bacillus, a vaccine developed at the Institut Pasteur in 1921). It is effective
in nearly 90% of cases in preventing the serious forms of tuberculosis in children
(tuberculous meningitis and disseminated form). But in adults, vaccinated individuals
are only protected in half of the cases. As a result, vaccination by BCG is
insufficient to prevent transmission of the disease, which is the only way of
curbing the epidemic. To bring tuberculosis under control throughout the world,
it is therefore necessary to develop more effective vaccines. Several teams
from the Institut Pasteur in Paris are combining their efforts in this direction.
Thanks to Franco-British efforts coordinated by Prof. Stewart Cole at the Institut
Pasteur, the complete genome sequence of Mycobacterium bovis (BCG is
a weakened form of this bacterium responsible for bovine tuberculosis)have been
obtained in 2002, after the one of the bacterium responsible for tuberculosis
(Mycobacterium tuberculosis) in 1998, considerably facilitating this
research. Furthermore, the Institut Pasteur is now sequencing the BCG Pasteur
strain, whose genome should be deciphered by the end of the year.
It is precisely due to the comparison of the genes of these mycobacteria that
a good avenue for research is now being explored-adding genes lost during BCG
development at the begining of the 20th century to give it a superior protective
power. Results in animals for this improved BCG are encouraging. It still remains
to the researchers to better define the targeted genes in order to build a BCG
that is more successful, without being more virulent.
Another avenue for research studied in Prof. Brigitte Gicquel's laboratory consists
in screening thousands of mutant tubercle bacilli, selecting those that do not
multiply in the human target cells (macrophages), and that are therefore not
pathogenic, before testing their protective power in mice. About a hundred mutants
stemming from this screening will now be studied one by one.
In other respects, the receptor that allows the bacterium to attach itself to
certain key cells of our defence system-a stage that engages our immune reactions-was
discovered last year in the same laboratory : the studies conducted around this
receptor could provide tools to modulate the organism's defences, either during
vaccination or during the illness.
In the meantime, an alternative, developed by Prof. Gilles Marchal's staff,
also consists in better administration of the BCG, for example rectally (suppositories),
avoiding abscesses and syringe use in particular. The preliminary results obtained
at the Institut Pasteur show the effectiveness of this course in animals.
Clinical
trials over the world
In the world today, only one clinical trial (phase I) is under way, resulting
from a European programme, the TB Vaccine Cluster, that was coordinated for
four years by Prof. Brigitte Gicquel from the Institut Pasteur (now the coordinator
of TB Ethics, an organisation of researchers, philosophers and experts in ethical
questions responsible for considering the deployment of clinical trials throughout
the world). The TB-VAC project funded by the European Commission and now coordinated
in the Netherlands regroups most of the laboratories of the TB Vaccine Cluster
project and sets up phase-I clinical trials. Two phase-I trials will be launched
in the United States. This small number of trials illustrates the difficulty
for the scientific community in developing new vaccines, which will only see
the light of day several years from now.
DIAGNOSIS
Developing new tools is urgent
The method currently used for diagnosing the disease-examining sputum under
the microscope-has not changed for a century, and it only permits diagnosing
a third of the TB cases under the best conditions, even if it allows the diagnosis
of the most contagious patients. The diagnostic of the patients whom sputum
are negative needs 4 to 6 weeks of cultures. Testing for susceptibility to antibiotics
made from theses cultures takes 3 to 4 more weeks. The lack of tools for a rapid
and performing diagnostic is a major problem in controlling the epidemic, especially
in a setting where an effective treatment exists. Pr Gilles Marchal at the Institut
Pasteur has a number of promising leads that should eventually make it possible
to improve and facilitate diagnosis: one consists in detecting molecules secreted
precociously by the bacteria responsible for the infection; the other aims to
reveal specific defence reactions of the patient that signal infection.
TREATMENTS
New molecules to fend off resistance
An effective treatment against tuberculosis does exist, a combination of four
antibiotics. However, this is an unwieldy treatment that must be followed for
at least six months. Moreover, the emergence of multi-resistant tubercle bacilli
to these antibiotics, also the subject of significant molecular epidemiological
studies at the Institut Pasteur, worries the medical authorities. For these
reasons it now appears crucial to find new antibiotics to fight the infection.
Historically, the Institut Pasteur has been committed in the search for new
TB drugs, since the sulfonamides-among the first synthetic antibiotics to be
used against TB in the 30s-were developed there.
Today, several laboratories are working in synergy. Brigitte Gicquel's laboratory
is seeking new therapeutic targets, particularly in the bacterial envelope,
and others, specially Prof. Pierre-Etienne Bost's laboratory, are testing active
molecules on these targets in various ways. Two targets are already being investigated.
One of the objectives is to obtain their structure in three dimensions (3D)
by crystallography, then to make a 'molecular design'. Bioinformatics makes
it possible to obtain the 3D structure of the target molecule on the computer
and to research through the 'analytical drawing' the ideal inhibitor molecule
that could block this target. The candidates are then synthesized and tested.
In addition, 'virtual screening' methods make it possible to test entire libraries
of virtual molecules. Parallel to this highly rational research, the anti-TB
power of entire collections of molecules from 'combinatorial libraries' is being
tested. To accelerate this strategy, the Institut Pasteur is currently being
equipped with a high-speed molecular screening platform that should be operational
by the end of 2004: this will make it possible to test tens of thousands of
molecules in several weeks, compared to the thousands currently tested in the
same period of time. Starting next year, the Institut Pasteur could multiply
its molecular screening capacities by a factor of 10.
The researchers thus hope to obtain through these various avenues more effective
antibiotics that could then be administered for shorter period : indeed, the
longer the treatment, the less the patient adhere, increasing the risk of therapeutic
check and of resistance to antibiotics. Shortening the current treatment, on
top of the logistical importance and the added comfort for the patient, will
make it possible to considerably curb the development of the bacilli's resistance
to antibiotics.
A COALITION OF
RESEARCHERS FOR A BETTER STRIKE FORCE
Besides the TB Network of the International Network of Instituts Pasteur, several
teams from the Institut Pasteur in Paris have combined their efforts to increase
the effectiveness of their research. In particular, a Major Horizontal 'TB'
Programme, coordinated by Prof. Stewart Cole, was launched in 2003: it brings
together no less than 14 of the campus's laboratories. The main ones involved
are:
Bacterial Molecular Genetics Unit, directed by Stewart Cole
Mycobacterial Genetics Unit, directed by Brigitte Gicquel
Organic Chemistry Unit, directed by Pierre-Etienne Bost
Protein Folding and Modelling Unit, directed by Michel Goldberg
Structural Biochemistry Unit, directed by Pedro Alzari
National Reference Centre of Mycobacteria, directed by Véronique Vincent
and Gilles Marchal
And technical platforms of the Institut Pasteur
Press Contacts :
Nadine Peyrolo - Tel.:
+33(0)1 45 86 81 47 -E-mail : npeyrolo@pasteur.fr
Corinne Jamma - Tel: +33 (0)1 40 61 33 41 - E-mail: cjamma@pasteur.fr