Research and Innovation Research and Innovation Tuberculosis Vaccine Development in Denmark Joshua Woodworth Post Doctoral Fellow Marie Curie IIF Statens.

Research and Innovation


Tuberculosis Vaccine Developmentin Denmark

Joshua Woodworth

Post Doctoral FellowMarie Curie IIF

Statens Serum InstitutCopenhagen, Denmark

PolicyPolicy 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



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)



• 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



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



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



Discovery of M.tuberculosis1882

Development of current TB vaccine (BCG)1921

History of TB and Vaccines



BCG is not effective against adult pulmonary TB

Rate per 100 thousand

<1010-2425-49

100-249250+

50-99

Efficacy >80%

Efficacy <20%



TB vaccines currently in clinical trials

Ottenhoff THM, Kaufmann SHE. (2012) PLoS Pathogens

EU

SSI

SSI

SSI

SSI



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



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



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


4

5

6

7

** ***

Lu

ng

CF

U(L

og

10

)

0

5000

10000

15000

IFN

(p

g/m

l)


+ESAT-6 Adjuvant

(CAF01)

T c

ell

resp

on

se

LungBacteria



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


4

5

6

7

** ***

Lu

ng

CF

U(L

og

10

)

0

5000

10000

15000

IFN

(p

g/m

l)


T c

ell

resp

on

se

LungBacteria



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


4

5

6

7

** ***

Lu

ng

CF

U(L

og

10

)

0

5000

10000

15000

IFN

(p

g/m

l)


T c

ell

resp

on

se

LungBacteria



0

5000

10000

15000

IFN

(p

g/m

l)


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



0

5000

10000

15000

IFN

(p

g/m

l)


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)



TIME

Bac

teri

allo

ad

90-95%

5-10%

Prophylactic

Vaccination


Post-infection

Vaccination



Why Europe?

• Science is science everywhere

• Strong research and technology an innovation environment

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



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



Meetings

Why Europe?



Why Europe?

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

Meetings

Personal Travel



`

Work and life in Denmark…





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.



TIME

ACUTE PHASE PROTEIN

LATENT PHASEPROTEIN

REACTIVATIONPHASE PROTEIN

Bac

teri

allo

ad

90-95%

5-10%

Prophylactic

Vaccination


Post-infection

Vaccination

+ +

Research and Innovation Research and Innovation Tuberculosis Vaccine Development in Denmark Joshua Woodworth Post Doctoral Fellow Marie Curie IIF Statens.

Documents

innovation research

policy research

innovation bcg

tb slide

innovation discovery

denmark slide

tb deaths

history of tb