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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 VitaeCurriculum VitaeDr. Bob Wahyudin, SpAK, IBCLCPediatric respirologistLactation ConsultantPediatric dept, Fac. of Medicine, Hasanuddin University
TB VACCINE: PRESENT AND FUTURE
Bob Wahyudin
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
Bacterial loads difference: vaccinated/unvaccinated
Russell et al. Science. 2010 May 14; 328(5980): 852–856
Immunological Aspect
Early interaction, early “war”
Dietrich et al. APMIS 2009; 117:440-57
Dheda et al. Respirology (2010) 15, 433–450
TB natural cycles & potential target of vaccines
Delogu & Vadda. J Infect Developing Countries 2009; 3(1): 5-15.
Present situation
The only vaccine available: BCG
Most widely used vaccine
Mandatory in TB-endemic areas
“Good news” and “Bad news”
Bacillus Calmette-Guerin Vaccine
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
Currently Sub-strain used
World Health Organization 1999
• 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
Good news
Prevent disseminated TB and TB
meningitis (especially in children)
Leprosy
Bladder Cancer
Others (malaria etc)
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!
Kauffman et al. www.thelancet.com Vol 375 June 12, 2010
Small redness: 3 wk Papul: 4-10 wk Ulceration/crusting: up to 14 wk
Normal reaction (natural history)of BCG Vaccination
“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
BCG Adverse Events
Local BCG disease- Abscess Ф ≥ 10x 10
mm- Persistent ulcer > 20
weeksRegional BCG disease (BCG adenitis)- Ipsilateral lymphnodes- Ф ≥ 15x 15 mm
Distant BCG Disease- Any site beyond a
local or regional ipsilateral process
Disseminated BCG (BCG-osis)- M.bovis confirmed
from >1 remote site
BCG IRIS- in HIV-infected following HAART
Other BCG Syndrome (rare):-Uveitis-Keloid formation
- left untreated-Reassurance- Immunocompetent
: left untreated- Reassurance- FNA may beneficial- Immuno
compromised• Anti TB drugs• Excision :
reserved for extreme cases
- Search underlying immune condition
- Anti TB drugs
- Rapid and aggressive Anti TB drugs
BCG IRIS- in HIV-infected following HAART
Other BCG Syndrome (rare):-Uveitis-Keloid formation, etc
- No suspicion systemic spread: may not require anti TB
• Shulld closely monitored
- May reflects hypersensitivity reaction referred to specialist
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)
Appproach and Strategies
Improving BCG
Using M. tuberculosis (not M. bovis)
Sub unit vaccine
DNA Vaccine
Better adjuvant
Prime- Boost regimen strategy
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
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.
Modified M. tbc strains
Attenuated M.tbc
Safety concerns
Unlikely proceed into phase 1
Mtb mc26020 and mc26030
Mtb deletion of Phol and secA2
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
Killed Whole cell
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
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
Delogu & Vadda. J Infect Developing Countries 2009; 3(1): 5-15.
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
Approaches and concerns
Vaccine Type Concerns
Genetically modified BCG Safety, particularly in HIV patients
Nucleid –acid base (naked DNA or viral vectored)
Safety, immunity to vector
Adjuvanted killed whole cell Which adjuvant
Sub unit vaccines(recombinant antigens)
Which? How many combinations?Which adjuvant?
Carbohydrate-protein conjugate
Which? How many combinations?Which adjuvant?
Svenson et al. Human Vaccines 2010. 6:4, 309-317
Prime-Boost strategies
Strategy Prime Boost Immunotherapy/latency vaccine
Prevention of clinical pathology
Meningitis/miliary TB
Pulmonary TB Reactivation TB (pulmonary)
Vaccine candidates
Live rBCG expressing Mtb antigens
Viral vectored Live 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
Delogu & Vadda. J Infect Developing Countries 2009; 3(1): 5-15.
Kauffman et al. www.thelancet.com Vol 375 June 12, 2010
Kauffman et al. www.thelancet.com Vol 375 June 12, 2010
TB Vaccine PipelineVPM 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*
Hybrid-I+IC31SSI, TBVI, Intercell
M72GSK, Aeras
MVA85A/AERAS-485Oxford-Emergent Tuberculosis Consortium (OETC), Aeras
AERAS-402/ Crucell Ad35Crucell, Aeras
M vaccae*Immodulon, NIH
Preclinical Phase II Phase IIIPhase IIbPhase I
*indicates candidates that have been in clinical trials in the past, but are not currently being tested in clinical trialsSource: Tuberculosis Vaccine Candidates – 2009; Stop TB Partnership Working Group on New TB Vaccines
As of November 2009
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
Prime
Boost
Post-infection
ImmunotherapyPreclinical 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.
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)
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 %
Conclusion
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
Thank you