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, 2091-94

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 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.

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 strainsSpreadCapability to cause active TB

Natural history of TB

TB immunopathogenesis

TCD4

TH1

TH2

TH1

IL-2TNFαINFγ

TH2

IL4IL10

TNFβ

Reactivationreinfection

IL 12Differenciation

Alveolare Macroph

age

Active disease

B1©

Correlates of protection

No correlate of protection identified Available data suggest:

T cell responses are paramountT 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 infectionMore protective

Meningitis (Children) Pulmonary disease

Stable efficacyLonger 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 γMore immunogenic/ safeTarget different stage of TB Should covere geneticly diverse strains

Immunologicalendpoint

Countries for phase I clinical trials

Low TB prevalence countryWithout BCG vaccine schedule since long timeEx: 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