Download 2-Marie Curie Actions

Tuberculosis
Vaccine
Development
in Denmark
Joshua Woodworth
Post Doctoral Fellow
Marie Curie IIF
Research and
Innovation
Statens Serum Institut
Copenhagen, Denmark
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 Institut
Copenhagen, Denmark
Policy
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)
Policy
Research and
Innovation
Tuberculosis is global health problem
•
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
Policy
Research and
Innovation
Tuberculosis Disease and Immunity
T Cells
Chemokines
CD4/CD8
Inhalation of
aerosolized
M. tuberculosis
latency
(5%)
Control of Infection
(95%)
Infection of
Lung Alveolar
Macrophages
Reactivation
Tuberculosis
Primary
Tuberculosis
(~5% within 5 years)
Policy
Research and
Innovation
REACTIVATION
PHASE
ACUTE TB LATENT PHASE
Vaccination against
PHASE
T
cell
ACUTE
T
cell
PHASE
Infection
Bacterialload
load
Bacterial
AP
C
Infection
LATENT PHASE
REACTIVATION
PHASE
5-10%
5-10%
90-95%
90-95%
30%
Prophylactic
Prophylactic
Vaccination
Vaccination
Disease
Threshold
TIME
TIME
Post exposure (therapeutic)
Vaccination
Policy
Research and
Innovation
History of TB and Vaccines
Discovery of M.tuberculosis
1882
Development of current TB vaccine (BCG)
1921
Policy
Research and
Innovation
BCG is not effective against adult pulmonary TB
Efficacy >80%
Efficacy <20%
Rate per 100
thousand
Policy
Research and
Innovation
<10
10-24
25-49
50-99
100-249
250+
TB vaccines currently in clinical trials
EU
SSI
SSI
SSI
SSI
Policy
Research and
Innovation
Ottenhoff THM, Kaufmann SHE. (2012) PLoS Pathogens
What’s missing from BCG?
• Identification of key missing proteins
•
ESAT-6 (SSI)
• TB Patients have immune responses
to ESAT-6
Mtb
BCG
• ESAT-6 is a virulence factor
•
Adding ESAT-6 back to BCG makes it
more dangerous
(Pasteur Institute, Paris)
Policy
Research and
Innovation
Harboe et al, IAI, 1996
Vaccination with ESAT-6 protects from TB
Non-Vaccinated
15ESAT-6
ESAT-6
X
IFN (pg/ml)
15000
+
10000
5000
ESAT-6
0
Lung
Bacteria
Lung CFU (Log10)
7
**
***
ESAT6
 15-ESAT6
6
5
4
No Vaccine
Policy
Research and
Innovation
Adjuvant
(CAF01)
T cells target only one ‘epitope’ of ESAT-6
15ESAT-6
ESAT-6
X
15000
IFN (pg/ml)
T cell
response
Non-Vaccinated
+
10000
5000
ESAT-6
0
Lung
Bacteria
Lung CFU (Log10)
7
**
***
ESAT6
 15-ESAT6
6
5
4
No Vaccine
Policy
Research and
Innovation
Adjuvant
(CAF01)
T cell responses against cryptic epitopes of ESAT-6 give protection
15ESAT-6
ESAT-6
X
15000
IFN (pg/ml)
T cell
response
Non-Vaccinated
10000
5000
0
Lung
Bacteria
Lung CFU (Log10)
7
**
***
ESAT6
 15-ESAT6
6
5
4
No Vaccine
Policy
Research and
Innovation
T cell responses against cryptic epitopes of ESAT-6 give protection
15ESAT-6
ESAT-6
X
15000
IFN (pg/ml)
T cell
response
Non-Vaccinated
10000
5000
0
Lung
Bacteria
Lung CFU (Log10)
7
**
***
ESAT6
 15-ESAT6
6
5
4
No Vaccine
Policy
Research and
Innovation
T cell responses against cryptic epitopes have improved functional profile
X
15000
IFN (pg/ml)
10000
5000
0
30
T cell
‘exhaustion’
%KLRG1+ PD-1lo
T cell
response
15ESAT-6
ESAT-6
Non-Vaccinated
20
10
***
0
Non-vacc.
ESAT-6
 15 ESAT-6
Policy
Research and
Innovation
T cell responses against cryptic epitopes have improved functional profile
ESAT-6
15ESAT-6
X
15000
IFN (pg/ml)
T cell
response
Non-Vaccinated
10000
5000
0
Policy
Research and
Innovation
Look less like
TB-driven T cells
(which are associated
with disease)
Bacterial load
5-10%
Infection
90-95%
Disease
Threshold
TIME
Post-infection
Vaccination
Prophylactic
Vaccination
Policy
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
Policy
Research and
Innovation
Consortiums and Collaborative
Research Projects
Local Collaborations
•
•
•
•
•
Copenhagen University
Danish Technical University
Herlev Hospital
Hvidovre Hospital
EU Projects
•
•
NEW TB VACC
•
•
•
GENIVAC
CENTER FOR NANOVACCINES
SAFEVAC
- Max Plank, Pasteur Inst, GSK, Leiden Univ MC, more…
International Collaborations
•
•
US, South Africa, India
Policy
Research and
Innovation
Meetings
Why Europe?
Policy
Research and
Innovation
Meetings
Personal Travel
Why Europe?
I grew up in Europe, where history comes from.
- Eddie Izzard
Policy
Research and
Innovation
Work and life in Denmark…
`
Policy
Research and
Innovation
Policy
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.
Policy
Research and
Innovation
Bacterial load
ACUTE PHASE
PROTEIN
+
LATENT PHASE
PROTEIN
+
REACTIVATION
PHASE PROTEIN
5-10%
Infection
90-95%
Disease
Threshold
TIME
Post-infection
Vaccination
Prophylactic
Vaccination
Policy
Research and
Innovation