education: general practitioner - fk.unhas 1994 pediatrician – fk.unhas 2003 fellowship...

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