prophylatic vaccine replacing conventional bcg delphine noël vanessa infante surendra karki
TRANSCRIPT
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Prophylatic vaccine replacing conventional BCG
Delphine Noël
Vanessa Infante
Surendra Karki
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Objectives Study
TB epidemiology Immunopathogenesis Immunological correlates of protection failure of BCG vaccine
To design a BCG replacement vaccine
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Tuberculosis is an ancient disease
Salo, WL. Proc.Natl.Acad.Sci.USA. 1994; 9, 2091-94
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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
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Current strategy of TB control
BCG at birth+
DOTS
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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
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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.
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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!!!!
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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
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Natural history of TB
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TB immunopathogenesis
TCD4
TH1
TH2
TH1
IL-2TNFαINFγ
TH2
IL4IL10
TNFβ
Reactivationreinfection
IL 12Differenciation
Alveolare Macroph
age
Active disease
B1©
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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
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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?
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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
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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
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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)
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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
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Countries for phase I clinical trials
Low TB prevalence countryWithout BCG vaccine schedule since long timeEx: Sweeden, Danemark
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Thank you
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Epidemiological impact
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Vaccine control of TB-saving lifes
L. Abu-Raddad, et al. PNAS 2008.
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Vaccine control for TB-savings of resources
Tseng et al. BMC Public Health 2011, 11:55