Page 48 - MemoriaES-Eng

RESEARCH PROGRAMMES

ease. In spite of the classic theory to explain the origin and progression of LTBI, the

data obtained in recent years have generated scientific doubts. On the other hand, to
date, and despite the existence of very useful animal models to evaluate the different

characteristics of the new therapeutic candidates, the presence of a model that is
able to faithfully imitate the infection and disease in humans has not been

established. An exception is, perhaps, the model in pigs, established by Cardona

et al. Thus, research based on the development of animal experimental models plays
an ever more essential role in terms of its importance for translation.

In CIBERES researchers have been working in the field of basic research of latent

tuberculosis infection since 1997. This work is essentially based on in an effort to de-

termine its underlying mechanisms and novel animal experimental models have
been developed that can better imitate the infection and its progression into

active disease with the idea of being able to use them in the assessment of new

drug or vaccine candidates developed by other research groups, with which stable
collaboration networks can be established to facilitate the evolution of these candi-

dates into clinical development.

2. Design and evaluation of new vaccine candidates against tuberculosis

The current BCG tuberculosis vaccine offers low protection against the respiratory

forms of tuberculosis, among which are found the drug-resistant strains, as well as
the high incidence of AIDS in third world countries and the difficulties in following

treatment programmes, which makes a new, effective vaccine necessary to substi-

tute the current BCG vaccine.

Since 1999, our efforts have been invested in creating a new, attenuated tubercu-
losis vaccine, studying the test concepts and developing this new attenuated live

vaccine. An attenuated vaccine has been created based on the double deletion of

the genes phoP and fadD the MTBVAC. The first vaccine based on attenuated M.
tuberculosis satisfying the “Geneva consensus” safety criteria for entry of new TB

vaccines into clinical trials. Taken together, GMP production of freeze-dried MTBVAC

and rigorous preclinical characterization from mouse to non-human primates provide
the bases for entry into first-in-human clinical trials.

3. Design and evaluation of new therapeutic strategies against tuberculosis

(resistance, action and discovery of new drugs).

Anti-tuberculosis therapy constitutes one of the fundamental pillars in the battle

against this disease. The success of the treatment can be compromised when the
strains acquire resistance to any one of the drugs used in the treatment. Then the

active drug arsenal against this disease is extremely limited. In addition various

mechanisms of intrinsic drug resistance in M. tuberculosis could play a major role in
favouring the acquisition of mutations that confer even greater levels of resistance.

Based on these facts, discovering new, active drugs against M. tuberculosis is 13
20
one of the main priorities of tuberculosis research at a world level. Insights T
R
have been made in the usefulness of efflux inhibitors have companion drugs in the PO
therapy of tuberculosis.
E
L R
4. Design and evaluation of new diagnostic and molecular epidemiology meth- A
NU
ods in tuberculosis.
N
A
Effective control of TB is based on the rapid detection of M. tuberculosis, followed by /
ES
the implementation of an adequate anti-tuberculosis therapy. As a result of several ER
epidemiologic studies, new analytical challenges have been identified, for which a B
CI
response must be given. Mainly, greater speed to obtain the genotypes, to identify

the earliest transmission events, and thus facilitate the intervention is required. Like-
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wise, the precision in identifying the transmission environment must be improved.