1. Prophylatic vaccine replacing conventional BCG Delphine Noël Vanessa Infante Surendra Karki

2. Objectives Study  TB epidemiology  Immunopathogenesis  Immunological correlates of protection  failure of BCG vaccine  To design a BCG replacement vaccine

3. Tuberculosis is an ancient disease Salo, WL. Proc.Natl.Acad.Sci.USA. 1994; 9, 2091-94

4. Tuberculosis is a public health threat Tuberculosis, caused by M. Tuberculosis remains a global health problem in developing countries TB is a global health emergency (WHO, 1993) MDG-decreasing TB incidence by 2015 Stop TB strategy: halve TB prevalence and mortality by 2015 and lower the incidence of new cases to <1 per million by 2050

5. Current strategy of TB control BCG at birth + DOTS

6. BCG Live attenuated M.bovis First Introduced in 1930s Since 1974, BCG has been included in the WHO Expanded Program on Immunization >80% coverage in developing countries > 4 billion doses- safe Not safe for HiV exposed infants

7. BCG Efficacy Effective in TB meningitis and disseminated disease in children. Wanes over time. No protection after 10-20 yrs. Does not prevent the establishment of primary infection or reactivation of latent TB. Pulmonary TB Variable, incomplete protection. North America and northern europe (60-80%). Tropical regions (0-75%). WHO, 2004.

8. TB Burden 9.4 million incident cases. 14 million prevalent cases. 2 million deaths. 0.4 million death in HIV+ 0.5 million MDR TB. 58 countries report XDRTB. WHO, 2010 Current TB control measures are not enough!!!!

9. Mycobacterium Bacteria characteristic rod-shaped, non-motile, aerobic bacteria bacilli alcohol acid resistent Micobacterium groups  Tbcomplex(MTb,M.africanum,M.canetti,M.bovis,M. Microti)  Micobacterium other than tuberculosis Tb complex strains  Spread  Capability to cause active TB

10. Natural history of TB

11. TB immunopathogenesis T CD4 TH1 TH2 TH1 IL-2 TNFα INFγ TH2 IL4 IL10 TNFβ Reactivation reinfection IL 12 Differenciation Alveolare Macroph age Active disease B1©

12. Correlates of protection No correlate of protection identified Available data suggest:  T cell responses are paramount  T cells expressing several type-1 cytokines (TNFa, IFN-g,IL-2) are associated with protection (polyfunctional T cells) Role of antibodies uncertain

13. To prevent infection/ disease To give longer protection Diversity of BCG strains Background immunity induced by non- tuberculosis environmental mycobacteria Over-attenuation of presently used strains Helminth infection Why BCG failed?

14. Strategy of replacement Target population for the vaccine Children – at birth  Pre-exposure: mtb/ environemental strains In developing countries mostly  Routine vaccination schedules (EPI)  Other countries: Selective vaccination HIV exposure children

15. The new vaccine More efficient than BCG  Idealy prevent the infection  More protective Meningitis (Children) Pulmonary disease  Stable efficacy  Longer lasting protection Safe for HIV exposed children Clinical / epidemiological impact

16. Conclusion A superior BCG vaccine is needed Can have a signifiant public health impact, included in broad strategy Other control measure Vaccine strategy included a booster Chalange to replace BCG  To do a superior vaccine Complex immunopathogenisis Pourly understood corelate of protection  To show the superiority regarding BCG/ extrapolation  To make it available fo the target population (cost)

17. Recommandations Superior than BCG / stable efficacy Idealy prevent infection Safe for HIV exposed children  Celular immunity  Interferon γ  More immunogenic/ safe  Target different stage of TB  Should covere geneticly diverse strains Immunological endpoint

18. Countries for phase I clinical trials  Low TB prevalence country  Without BCG vaccine schedule since long time  Ex: Sweeden, Danemark

19. Thank you

20. Epidemiological impact

21. Vaccine control of TB-saving lifes L. Abu-Raddad, et al. PNAS 2008.

22. Vaccine control for TB-savings of resources Tseng et al. BMC Public Health 2011, 11:55