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