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 Vrije Universiteit 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

3.  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. Russell et al. Science. 2010 May 14; 328(5980): 852–856

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

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

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

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

9.  Avirulent M. 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. 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. Different Policies

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

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

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

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

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

22.  Improving BCG  Using M. tuberculosis (not M. bovis)  Sub unit vaccine  DNA Vaccine  Better adjuvant  Prime- Boost regimen strategy

23.  New modified BCG vaccine - Genetically modified - recombinant  Modified M.tbc  DNA-based and viral vector  Killed whole cell  Sub unit  Glicolypids and carbohydrate antigens

24.  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.

25.  Attenuated M.tbc  Safety concerns  Unlikely proceed into phase 1  Mtb mc 2 6020 and mc 2 6030  Mtb deletion of Phol and secA2

26.  Protein or DNA incorporated into viral vector  Elicited both humoral and cellular immunity  Conferred significant protection  MVA85, Crucell AD35, etc

27.  Old tactics  Recently, reported protection with adjuvanted killed bacilli  M. vaccae whole-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

28.  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

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

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

31. Vaccine Type Concerns Genetically modified BCGSafety, particularly in HIV patients Nucleid –acid base (naked DNA or viral vectored) Safety, immunity to vector Adjuvanted killed whole cellWhich adjuvant Sub unit vaccines(recombinant antigens) Which? How many combinations? Which adjuvant? Carbohydrate-protein conjugateWhich? How many combinations? Which adjuvant? Svenson et al. Human Vaccines 2010. 6:4, 309-317

32. StrategyPrimeBoostImmunotherapy/late ncy vaccine Prevention of clinical pathology Meningitis/miliary TBPulmonary TBReactivation TB (pulmonary) Vaccine candidatesLive rBCG expressing Mtb antigens Viral vectoredLive or acelluler containing latent antigens Live r BCG with enosomal escape Proteins with adjuvants Live attenuated Mtb Barker et al. Current Opinion in Immunology 2009, 21:331-338

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

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

36. TB Vaccine Pipeline VPM 1002 Max Planck, Vakzine Projekt Mgmt, TBVI rBCG30* UCLA, NIH, NIAID, Aeras AdAg85A McMaster University Hybrid-I+CAF01 SSI Hyvac 4/ AERAS-404 SSI, Sanofi-Pasteur, Aeras, Intercell RUTI Archivel Farma M smegmatis* Hybrid-I+IC31 SSI, TBVI, Intercell M72 GSK, Aeras MVA85A/ AERAS-485 Oxford-Emergent Tuberculosis Consortium (OETC), Aeras AERAS-402/ Crucell Ad35 Crucell, Aeras M vaccae* Immodulon, NIH Preclinical Phase IIPhase IIIPhase IIbPhase I *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 As of November 2009 AERAS-422 Aeras Mtb [∆lysA ∆panCD ∆secA2] Albert Einstein College of Medicine MTBVAC01 [∆phoP, ∆fad D26] University of Zaragoza, Institute Pasteur, TuBerculosis Vaccine Initiative (TBVI) HBHA Institute Pasteur of Lille, INSERM, TBVI Hybrid 56 Statens Serum Institute (SSI), Aeras, Intercell, TBVI HG85 A/B Shanghai H&G Biotech 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.

37.  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)

38.  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 %

39.  Present BCG vaccine inconsistently protects against M. tbc infection  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