Prophylatic vaccine replacing conventional BCG Delphine Noël Vanessa Infante Surendra Karki

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

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

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

Current strategy of TB control BCG at birth + DOTS

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

BCG Efficacy Effective in TB meningitis and disseminated disease in children. Wanes over time. No protection after 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.

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!!!!

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

Natural history of TB

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©

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

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?

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

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

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)

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

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

Thank you

Epidemiological impact

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

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