Novel TB Vaccine could Replace BCG

Gary Cross, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0SP

The attenuated strain of Mycobacterium tuberculosis, bacille Calmette-Guerin (BCG) is used as a tuberculosis vaccine. Although efficacious (1) this efficacy has been questioned and currently NCIE recommend the vaccine is not used routinely, reserved for use in “high risk” patients (2). Additionally, the vaccine can lead to the development of disseminated tuberculosis in individuals already latently infected (3). The relative risk is several hundred. Clearly, this makes the vaccine of limited use in areas where tuberculosis is endemic.

The search for a novel effective vaccine against tuberculosis is continuing. A team from the USA have recently published their findings in Nature Medicine (4), and the results look promising. They show that a conserved set of genes within Mycobacteria, known as the esx-3 region, play a vital role in evading host innate immunity. Infecting mice with a normal esx-3 positive strain of Mycobacteria resulted in rapid death; infection with an esx-3 negative strain (M. smegmatis) provoked a host bactericidal response and the avoidance of disease. These results implement the esx-3 locus in bacterial virulence.

Next, the researchers introduced esx-3 genes into the M. smegmatis strain and found that not only was the mouse immune system still able to clear the strain, but that subsequent challenge with esx-3 positive M. tuberculosis stimulated a marked bactericidal response. This additional result suggests that the M. smegmatis mycobacterial strain may be useful as a vaccine for M. tuberculosis. Interestingly, the researchers were able to isolate CD4+ cells from the vaccinated population and found transferring these cells to host mice also transferred the immunity. This suggest M. smegmatis challenge produces a unique CD4+ population which confers this immunity.

Clearly, further studies need to be performed to establish the precise mechanism of this effect. Nevertheless, results such as this raise hopes that a safe and effective tuberculosis vaccine is on the horizon.

References: 

1. Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV, Mosteller F. Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. J. Am. Med. Assoc 1994; 271: 698–702.
doi: 10.1001/jama.1994.03510330076038

2. National Institute for Health and Clinical Excellence. CG117 Tuberculosis: full guidance. [Internet] National Institute of Clinical Excellence 2011 [cited 10 November 2011] Available from http://guidance.nice.org.uk/CG117/NICEGuidance/pdf/English

3. Hesseling AC, Marais BJ, Gie RP, Schaaf HS, Fine PEM, Godfrey- Faussett P, Beyers N . The risk of disseminated bacille Calmette-Guerin (BCG) disease in HIV-infected children. Vaccine 25, 14–18.
doi: 10.1016/j.vaccine.2006.07.020 

4. Sweeney KA, Dao DN, Goldberg MF, Hsu T, Venkataswamy MM et al. A recombinant Mycobacterium smegmatis induces potent bactericidal immunity against Mycobacterium tuberculosis. Nature Med 2011; 17: 1261-1268.
doi: 10.1038/nm.2420

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