research and innovation research and innovation tuberculosis vaccine development in denmark joshua...

Research and Innovation

Research and Innovation

Tuberculosis Vaccine Developmentin Denmark

Joshua Woodworth

Post Doctoral FellowMarie Curie IIF

Statens Serum InstitutCopenhagen, Denmark

PolicyPolicy Research and Innovation

Research and Innovation

About Me…

• - From Detroit, MI

• - B.S. in Biology, University of Michigan

• - PhD in Immunology, Harvard Medical School• “T cell immune response to Tuberculosis Infection”

• - Post Doc, TB Vaccine Development Statens Serum InstitutCopenhagen, Denmark

PolicyPolicy Research and Innovation

Research and Innovation

Staten Serum Institut (SSI)Copenhagen, Denmark

• •       Governmental Institute•Epidemiology•Medical sample Testing

Academics and Industry•Vaccine Development

• HIV,TB, Malaria, Chlamydia, Strep A• Polio vaccine, BCG (TB vaccine)

•Diagnostics• TB skin test (tuberculin)

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Research and Innovation

• 1/3 World Population latently infected

• 8 million new TB cases annually

• 1.5 million TB deaths annually

• TB is the major cause of death of people with HIV/AIDS

Tuberculosis is global health problem

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Research and Innovation

Infection ofLung AlveolarMacrophages

PrimaryTuberculosis

(~5% within 5 years)

Control of Infection(95%)

ReactivationTuberculosis

(5%)latency

Inhalation of aerosolized

M. tuberculosis

Chemokines

T CellsCD4/CD8

Tuberculosis Disease and Immunity

PolicyPolicy Research and Innovation

Research and Innovation

TIME

ACUTE PHASE

LATENT PHASE REACTIVATIONPHASE

Bac

teri

allo

ad

90-95%

5-10%

Prophylactic

Vaccination

TIME

ACUTE PHASE

LATENT PHASE REACTIVATIONPHASE

Bac

teri

allo

ad

Infe

ctio

n

APC

T cellT

cell

APC

T cellT

cell

30%

90-95%

5-10%

ProphylacticVaccination

Post exposure (therapeutic)Vaccination

DiseaseThresholdInfection

Vaccination against TB

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Discovery of M.tuberculosis1882

Development of current TB vaccine (BCG)1921

History of TB and Vaccines

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BCG is not effective against adult pulmonary TB

Rate per 100 thousand

<1010-2425-49

100-249250+

50-99

Efficacy >80%

Efficacy <20%

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Research and Innovation

TB vaccines currently in clinical trials

Ottenhoff THM, Kaufmann SHE. (2012) PLoS Pathogens

EU

SSI

SSI

SSI

SSI

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Research and Innovation

What’s missing from BCG?

Harboe et al, IAI, 1996

• Identification of key missing proteins• ESAT-6 (SSI)

• TB Patients have immune responses to ESAT-6

• ESAT-6 is a virulence factor• Adding ESAT-6 back to BCG makes it

more dangerous (Pasteur Institute, Paris)

BCGMtb

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Research and Innovation

Vaccination with ESAT-6 protects from TB

No Vaccine ESAT6 15-ESAT6

4

5

6

7

** ***

Lu

ng

CF

U(L

og

10

)

0

5000

10000

15000

IFN

(p

g/m

l)

Non-Vaccinated ESAT-6 15ESAT-6X

+ESAT-6 Adjuvant

(CAF01)

LungBacteria

PolicyPolicy Research and Innovation

Research and Innovation

T cells target only one ‘epitope’ of ESAT-6

No Vaccine ESAT6 15-ESAT6

4

5

6

7

** ***

Lu

ng

CF

U(L

og

10

)

0

5000

10000

15000

IFN

(p

g/m

l)

Non-Vaccinated ESAT-6 15ESAT-6X

+ESAT-6 Adjuvant

(CAF01)

T c

ell

resp

on

se

LungBacteria

PolicyPolicy Research and Innovation

Research and Innovation

T cell responses against cryptic epitopes of ESAT-6 give protection

No Vaccine ESAT6 15-ESAT6

4

5

6

7

** ***

Lu

ng

CF

U(L

og

10

)

0

5000

10000

15000

IFN

(p

g/m

l)

Non-Vaccinated ESAT-6 15ESAT-6X

T c

ell

resp

on

se

LungBacteria

PolicyPolicy Research and Innovation

Research and Innovation

T cell responses against cryptic epitopes of ESAT-6 give protection

No Vaccine ESAT6 15-ESAT6

4

5

6

7

** ***

Lu

ng

CF

U(L

og

10

)

0

5000

10000

15000

IFN

(p

g/m

l)

Non-Vaccinated ESAT-6 15ESAT-6X

T c

ell

resp

on

se

LungBacteria

PolicyPolicy Research and Innovation

Research and Innovation

0

5000

10000

15000

IFN

(p

g/m

l)

Non-Vaccinated ESAT-6 15ESAT-6X

Non-vacc. ESAT-6 15 ESAT-60

10

20

30

***%K

LR

G1+ P

D-1lo

T cell responses against cryptic epitopes have improved functional profile

T cell‘exhaustion’

T c

ell

resp

on

se

PolicyPolicy Research and Innovation

Research and Innovation

0

5000

10000

15000

IFN

(p

g/m

l)

Non-Vaccinated ESAT-6 15ESAT-6X

T cell responses against cryptic epitopes have improved functional profile

T c

ell

resp

on

se

Look less like TB-driven T cells(which are associated with disease)

PolicyPolicy Research and Innovation

Research and Innovation

TIME

Bac

teri

allo

ad

90-95%

5-10%

Prophylactic

Vaccination

DiseaseThresholdInfection

Post-infection

Vaccination

PolicyPolicy Research and Innovation

Research and Innovation

Why Europe?

• Science is science everywhere

• Strong research and technology an innovation environment

• Collaborative research projects• Shared knowledge and tools• Build professional network

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Research and Innovation

Consortiums and Collaborative Research Projects

• Local Collaborations• Copenhagen University• Danish Technical University• Herlev Hospital• Hvidovre Hospital

• EU Projects• NEW TB VACC

- Max Plank, Pasteur Inst, GSK, Leiden Univ MC, more…• GENIVAC• CENTER FOR NANOVACCINES • SAFEVAC

• International Collaborations• US, South Africa, India

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Research and Innovation

Meetings

Why Europe?

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Research and Innovation

Why Europe?

I grew up in Europe, where history comes from.- Eddie Izzard

Meetings

Personal Travel

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Research and Innovation

`

Work and life in Denmark…

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Research and Innovation

PolicyPolicy Research and Innovation

Research and Innovation

Themes to include

• •       Europe has a vibrant and attractive science, technology and innovation culture;

• •       Europe provides opportunities for career development and advancement;

• •       Europe's industry and research organizations offer challenging opportunities to work in world-class environments.

PolicyPolicy Research and Innovation

Research and Innovation

TIME

ACUTE PHASE PROTEIN

LATENT PHASEPROTEIN

REACTIVATIONPHASE PROTEIN

Bac

teri

allo

ad

90-95%

5-10%

Prophylactic

Vaccination

DiseaseThresholdInfection

Post-infection

Vaccination

+ +