Prophylatic vaccine replacing conventional BCGDelphine NolVanessa InfanteSurendra Karki
ObjectivesStudy TB epidemiology Immunopathogenesis Immunological correlates of protection failure of BCG vaccine
To design a BCG replacement vaccine
Tuberculosis is an ancient diseaseSalo, WL. Proc.Natl.Acad.Sci.USA. 1994; 9, 2091-94
Tuberculosis is a public health threatTuberculosis, 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
Current strategy of TB controlBCG at birth+DOTS
BCGLive 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 EfficacyEffective 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%).
TB Burden9.4 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, 2010Current TB control measures are not enough!!!!
Mycobacterium Bacteria characteristic rod-shaped, non-motile, aerobic bacteria bacilli alcohol acid resistentMicobacterium groupsTbcomplex(MTb,M.africanum,M.canetti,M.bovis,M. Microti)Micobacterium other than tuberculosisTb complex strainsSpreadCapability to cause active TB
Natural history of TB
TB immunopathogenesisTCD4TH1TH2TH1IL-2TNFINFTH2IL4IL10TNFReactivationreinfectionIL 12DifferenciationAlveolare MacrophageActive diseaseB1
Correlates of protectionNo correlate of protection identifiedAvailable 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 mycobacteriaOver-attenuation of presently used strainsHelminth infectionWhy BCG failed?
Strategy of replacementTarget population for the vaccineChildren at birthPre-exposure: mtb/ environemental strains In developing countries mostly Routine vaccination schedules (EPI)Other countries: Selective vaccinationHIV exposure children
The new vaccineMore efficient than BCGIdealy prevent the infectionMore protectiveMeningitis (Children)Pulmonary diseaseStable efficacyLonger lasting protection Safe for HIV exposed children
Clinical / epidemiological impact
A superior BCG vaccine is needed
Can have a signifiant public health impact, included in broad strategyOther control measure Vaccine strategy included a booster
Chalange to replace BCGTo do a superior vaccineComplex immunopathogenisisPourly understood corelate of protectionTo show the superiority regarding BCG/ extrapolationTo make it available fo the target population (cost)
Recommandations Superior than BCG / stable efficacyIdealy prevent infectionSafe for HIV exposed children
Celular immunity Interferon More immunogenic/ safeTarget different stage of TB Should covere geneticly diverse strains
Countries for phase I clinical trials
Low TB prevalence countryWithout BCG vaccine schedule since long timeEx: Sweeden, Danemark
Vaccine control of TB-saving lifesL. Abu-Raddad, et al. PNAS 2008.
Vaccine control for TB-savings of resourcesTseng et al. BMC Public Health 2011, 11:55
*Evidence from DNA found in mummies. Tuberculosis is an ancient disease,,,600 BC,,,Egyptian mummies. Generations passed, Northern America and europe,,,,able to contain the tb quite earlier,,But,,,Passage on potato slides,,,bile salts,,for 13 yrs,,Lucky to get that,,,*Reactivation is responsible transmission and spread of infeciton.
*TB/HIV Coinfection, MDR , XDR TB, Former soviet union countries,,In 2009, mdrtb estimated to be about 0.5 million. ****One of the question to answer is why BCG , specificly in developping countries. This raison are not yet understood, but Important contributing factors might include
So now we had try to describe the problem, and exposed some element of respons, we are going to present the strategy for the replacement of BCG.
Fisrt, the target population for the vaccine for the vaccine was define regarding the epidemiological data, as the population who are going to beneficite mostly. Its also, for the first part, the population targeted today by BCG. So its . Plus HIV*Seconde,The design of the vaccine need to provide a vaccine whish are going to be:More efficient than BCG : to prevent children serious TB form (meningitis, disseminated TB)to prevent adult pulmonary TBIdealy and of course the effect with the most impact should be to prevent the installation of the diseaseFinely, the new BCG should be safe for HIV .. *Early comitment with gvt and fund institution (Available for the target population )
Seconde,We need of course a vaccine more efficiant than BCG. Again Adult *
The epidemiologcical impact :
will be depend mostly of the capacity of the new vaccine to prevent the intallation of the disease.If its not possible, because we cant expected a long life duration of the efficacy, we will not be able to prevent eficaly the risk of reactivation.
Only the neonatal portfolio vaccine,,,decrases incidence by 39-52%. A triple combination of a portfolio vaccine, drug regimen, and diagnostics reduces incidence by 71%. *BCG replacement vaccine, 70% efficacy in preventing rapid progression to TB disease after initial infection. Zambia,,5.6 million savings, decision analysis model-based simulation from the societal perspective*