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Education: General Practitioner - FK.UNHAS 1994 Pediatrician – FK.UNHAS 2003 Fellowship Pediatric respirologist 2005

Education: General Practitioner - FK.UNHAS 1994 Pediatrician – FK.UNHAS 2003 Fellowship Pediatric respirologist 2005 -FK-UI/RSCM Diploma In Immunology 2007 -FK-UGM in collaboration with Vrije Universiteit Amsterdam Bioinformatics course –Eijkman Institute 2008

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Education: General Practitioner - FK.UNHAS 1994 Pediatrician – FK.UNHAS 2003 Fellowship Pediatric respirologist 2005

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  1. Education: General Practitioner - FK.UNHAS 1994 Pediatrician – FK.UNHAS 2003 Fellowship Pediatric respirologist 2005 -FK-UI/RSCM Diploma In Immunology 2007 -FK-UGM in collaboration with VrijeUniversiteit Amsterdam Bioinformatics course –Eijkman Institute 2008 International Board Certified Lactation Consultant – IBCLE 2008 Organization: Head of respirology division, Pediatrics dept, FK.UNHAS/RSWS Makassar Secretary of IDAI Sulawesi Selatan Member of Asian Strategic Alliance for Pneumococcal Disease ( ASAP ) Curriculum Vitae Dr. Bob Wahyudin, SpAK, IBCLC Pediatric respirologist Lactation Consultant Pediatric dept, Fac. of Medicine, Hasanuddin University

  2. Bob Wahyudin TB VACCINE: PRESENT AND FUTURE

  3. Why Vaccinated • Burden of disease: • 2 billions infected • 14 million total case • 9.1 million new cases/yr, 250.000 children • 1,7 million died/yr, 100.000 children • Emergence of MDR-TB • WHO declared “global emergency” • Vaccination might reduce morbidities/mortalities

  4. Bacterial loads difference: vaccinated/unvaccinated Russell et al. Science. 2010 May 14; 328(5980): 852–856

  5. Immunological Aspect Early interaction, early “war” Dietrich et al. APMIS 2009; 117:440-57

  6. Dheda et al. Respirology (2010) 15, 433–450

  7. TB natural cycles & potential target of vaccines Delogu & Vadda. J Infect Developing Countries 2009; 3(1): 5-15.

  8. Present situation • The only vaccine available: BCG • Most widely used vaccine • Mandatory in TB-endemic areas • “Good news” and “Bad news”

  9. Bacillus Calmette-Guerin Vaccine • AvirulentM. bovis, 13 years of passage. • (1921) per os, (1940’s) percutan • BCG incorporated into schedule (1974) • 40 or more producers worlwide • Several different “sub-strains” • Different policies between countries

  10. Currently Sub-strain used World Health Organization 1999

  11. Different Policies • BCG only at birth • recommended by Global TB  most countries • BCG once in childhood: • UK : tuberculin negative adolescents (12-13 year olds) • Repeated/booster BCG • Switzerland, Portugal  booster at school age • Eastern Europe five times,from birth to 30 years • No routine BCG use: • USA, the Netherlands, Sweden.

  12. Good news • Prevent disseminated TB and TB meningitis (especially in children) • Leprosy • Bladder Cancer • Others (malaria etc)

  13. Bad news • Unreliable against pulmonary TB • No protection against latent TB • HIV infants: not recommended • No impact on global epidemic • Wide range efficacies among countries  Need a better TB vaccine and strategies!

  14. Kauffman et al. www.thelancet.com Vol 375 June 12, 2010

  15. Normal reaction (natural history) • of BCG Vaccination Small redness: 3 wk Papul: 4-10 wk Ulceration/crusting: up to 14 wk

  16. “The Lübeck disaster” • Between 10 December 1929 and 30 April 1930, • 251 of 412 infants born in Lubeck, Germany, received virulent M.Tb instead of BCG vaccine ! • 72 died within one year. • 135 suffered from clinical tuberculosis • 44 remained well

  17. - left untreated • -Reassurance • BCG Adverse Events • Immunocompetent: left untreated • Reassurance • FNA may beneficial • Immuno compromised • Anti TB drugs • Excision : reserved for extreme cases • Local BCG disease • Abscess Ф ≥ 10x 10 mm • Persistent ulcer > 20 weeks • Regional BCG disease (BCG adenitis) • Ipsilaterallymphnodes • Ф ≥ 15x 15 mm • Search underlying immune condition • Anti TB drugs • BCG IRIS • in HIV-infected following • HAART • Distant BCG Disease • Any site beyond a local or regional ipsilateral process • Disseminated BCG (BCG-osis) • M.bovis confirmed from >1 remote site • Rapid and aggressive Anti TB drugs Other BCG Syndrome (rare): -Uveitis -Keloid formation

  18. No suspicion systemic spread: may not require anti TB • Shulld closely monitored • BCG IRIS • in HIV-infected following • HAART • May reflects hypersensitivity reaction  referred to specialist Other BCG Syndrome (rare): -Uveitis -Keloid formation, etc

  19. Future Vaccine • Goals: • Eliminate TB treat (<1 case/million) • Safe & effective in preventing TB, including HIV patients • Protect against all forms (e.g. MDR, XDR, LTBI)

  20. Appproach and Strategies • Improving BCG • Using M. tuberculosis (not M. bovis) • Sub unit vaccine • DNA Vaccine • Better adjuvant • Prime- Boost regimen strategy

  21. Type of new vaccines • New modified BCG vaccine - Genetically modified - recombinant • Modified M.tbc • DNA-based and viral vector • Killed whole cell • Sub unit • Glicolypids and carbohydrate antigens

  22. Modified BCG • Current BCG vaccines: protection wane over time • Gene modification, recombinant  enhance immune response • Strategies : as priming • Modified (gene addition, deletion) • rBCG30: overexpress antgen85B • Recombinant (Mutant BCG) : endosomal escape. • rBCGYre-Cvly, etc.

  23. Modified M. tbcstrains • Attenuated M.tbc • Safety concerns • Unlikely proceed into phase 1 • Mtb mc26020 and mc26030 • Mtb deletion of Phol and secA2

  24. DNA-Based and Viral-vectored • Protein or DNA incorporated into viral vector • Elicited both humoral and cellular immunity • Conferred significant protection • MVA85, Crucell AD35, etc

  25. Killed Whole cell • Old tactics • Recently, reported protection with adjuvanted killed bacilli • M. vaccaewhole-cell vaccine  promising data in HIV infected patients • RUTI vaccine: killed Mtb grown under stress (reportedly shorten DOTS treatment to 1 month) as immunotherapy/therapeutic TB vaccine

  26. Sub-unit vaccines • Numerous vaccine candidates • Recombinant protein/DNA encoding proteins • Need strong adjuvant • Major problem: selection of antigens need to be a ‘bouquet of antigens” • GSK M72, SSI HyVac4, etc

  27. Delogu & Vadda. J Infect Developing Countries 2009; 3(1): 5-15.

  28. Glycolipids and carbohidrates antigens • Lipoarabinomannan (LAM) recognized by DC. • LAM exerts profound biological effects • Other antigens: LM, PIMs, and other glycolypids • Need to be conjugated

  29. Approaches and concerns Svenson et al. Human Vaccines 2010. 6:4, 309-317

  30. Prime-Boost strategies Barker et al. Current Opinion in Immunology 2009, 21:331-338

  31. Delogu & Vadda. J Infect Developing Countries 2009; 3(1): 5-15.

  32. Kauffman et al. www.thelancet.com Vol 375 June 12, 2010

  33. Kauffman et al. www.thelancet.com Vol 375 June 12, 2010

  34. TB Vaccine Pipeline As of November 2009 Preclinical Phase I Phase II Phase IIb Phase III AERAS-422Aeras Mtb [∆lysA ∆panCD ∆secA2]Albert Einstein College of Medicine MTBVAC01 [∆phoP, ∆fad D26]University of Zaragoza, Institute Pasteur, TuBerculosis Vaccine Initiative (TBVI) HBHAInstitute Pasteur of Lille, INSERM, TBVI Hybrid 56Statens Serum Institute (SSI), Aeras, Intercell, TBVI HG85 A/BShanghai H&G Biotech Hybrid-I+IC31SSI, TBVI, Intercell M72GSK, Aeras MVA85A/AERAS-485Oxford-Emergent Tuberculosis Consortium (OETC), Aeras AERAS-402/ Crucell Ad35Crucell, Aeras M vaccae*Immodulon, NIH VPM 1002Max Planck, Vakzine Projekt Mgmt, TBVI rBCG30*UCLA, NIH, NIAID, Aeras AdAg85AMcMaster University Hybrid-I+CAF01SSI Hyvac 4/ AERAS-404SSI, Sanofi-Pasteur, Aeras, Intercell RUTIArchivel Farma M smegmatis* Prime Boost Post-infection Immunotherapy Preclinical vaccine candidates are not yet in clinical trials, but have been manufactured under Good Manufacturing Practice (GMP) for clinical use and have undergone some preclinical testing that meets regulatory standards. *indicates candidates that have been in clinical trials in the past, but are not currently being tested in clinical trials Source: Tuberculosis Vaccine Candidates – 2009; Stop TB Partnership Working Group on New TB Vaccines

  35. Route of vaccination • Injection: IC • Costly • Safety concerns (needle handling) • Not natural infection route • Does not elicit mucosal immunity • Oral/nasal (under development) • Least expensive • Mimic natural infection • More vigorous immune response (under evaluation)

  36. Impact prediction of the new vaccine strategies • Goal: Halves prevelance & mortalities by 2015 new case < 1/million by 2050 • Reduction prediction on incidence: Preexposure vaccines : 39-52 % reduction • New drugs: 10 -27% • New diagnostic measures: 13-42% • Combined: 71% • Combined + mass vaccination campaigns + new post exposure vaccines + drugs for LTBI : 94 %

  37. Conclusion • Present BCG vaccine inconsistently protects against M. tbcinfection • Promising new vaccines under development • New strategies: priming and boosting with different types of vaccine • Need time to full application, few has finished Phase 3 clinical trial

  38. Thank you

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