Scientists from the Institut Pasteur, working in collaboration with a team from Italy, have published the results of their research into the action mechanisms of a promising experimental tuberculosis (TB) vaccine in the journal PLOS Pathogens. BCG, the only currently approved TB vaccine, has been around for almost a century, but it is only partially effective and the protection it offers fades over time. Given the current emergence of adult TB cases in conjunction with the HIV epidemic and the rise in multidrug-resistant TB strains, the development of a new, more effective vaccine is a global health priority. This research was conducted in connection with the TBVAC2020 European consortium.
The Mycobacterium tuberculosis bacterium, causative agent of tuberculosis. © Institut Pasteur
Mycobacteria have a highly dense cell envelope, meaning that they have to use complex transport systems known as ESX to shuttle proteins across this barrier. Mycobacterium tuberculosis, the bacterium responsible for tuberculosis, has three such systems: ESX-1, ESX-3 and ESX-5. These systems play a vital role in TB – strains that do not have them are unable to cause the disease. The BCG strain, for example, is actually a weakened version of Mycobacterium bovis whose virulence has been attenuated by several genetic modifications, one of which has resulted in the absence of the functional ESX-1 system.
At the Institut Pasteur, Laleh Majlessi – a member of the Integrated Mycobacterial Pathogenomics Unit directed by Roland Brosch – working in collaboration with Daria Bottai from the University of Pisa, Italy, is investigating the vaccine prospects of a recently developed weakened strain of M. tuberculosis. This strain is lacking in five proteins that are shuttled by the ESX-5 transporter. These proteins are virulence factors that contribute to the pathogenicity of the bacteria. They belong to the large PE/PPE protein family, which is composed of over 160 very similar proteins.
The scientists attempted to improve their understanding of the action mechanism of this vaccine strain by using cytometry techniques to examine the arsenal deployed by cells in the immune defense system in response to the presence of virulence factors. This enabled them to produce a detailed map of the cellular and molecular mechanisms that underpin the efficacy of the vaccine strain.
Their findings show that, unlike the BCG strain, this new strain has a vast repertoire of antigens that is as comprehensive as the pathogen itself. The efficacy of this strain is a direct result of the molecular similarity of all the PE/PPE proteins. Although the strain is harmless because of its five missing virulence factors, it is still able to export the other PE/PPE proteins via its ESX-5 transport system. In mice injected with the vaccine strain, the recognition of these proteins by the immune system induced a defensive reaction against all the PE/PPE proteins, since the immune system was unable to discern the minute differences between all these closely related proteins. The weakened vaccine strain is therefore able to generate an immune response to virulence factors that it is actually missing.
The scientists' research also demonstrates that the candidate vaccine strain, which has an intact ESX-1 transport system, is better placed to stimulate the innate immune system than the BCG, which is missing ESX-1.
The increased efficacy of the new vaccine strain was also visible in the animal model. "Compared with the BCG, this new vaccine candidate gave us higher control over the intrapulmonary growth of the bacillus and the development of harmful tuberculous lesions in the preclinical mouse model," explained Laleh Majlessi. "These results pave the way for the further development of candidates in preclinical models of tuberculosis vaccination."
CD4+ T Cells Recognizing PE/PPE Antigens Directly or via Cross Reactivity Are Protective against Pulmonary Mycobacterium tuberculosis Infection, PLoS Pathog. July 28, 2016 DOI : 10.1371/journal.ppat.1005770.
Fadel Sayes (1), Alexandre Pawlik (1), Wafa Frigui (1), Matthias I. Gröschel (1), Samuel Crommelynck (1), Catherine Fayolle (2,3), Felipe Cia (4), Gregory J. Bancroft (4), Daria Bottai (5), Claude Leclerc (2,3), Roland Brosch (1), Laleh Majlessi (1)
1) Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, Paris, France
2) Institut Pasteur, Immune Regulation and Vaccinology Unit, Paris, France,
3) INSERM U1041, Paris, France,
4) London School of Hygiene and Tropical Medicine, London, United Kingdom
5) University of Pisa, Department of Biology, via S. Zeno 35-39, 56127 Pisa, Italy