Immunotherapies for cancer and infectious diseases
MVA TECHNOLOGY IN THE DEVELOPMENT OF
HIGHLY COMPLEXED TB VACCINE CANDIDATES
Journée infections nosocomiales
15 décembre 2016
Lyon
Aurélie Ray
Infectious Diseases Department, Lyon
- CONFIDENTIAL - 2
Different outcomes of M. tuberculosis infection and underlying
immune mechanisms
Kaufmann and McMichael, Nat Medecine, 2005
- CONFIDENTIAL - 3
TB in the world
In 2015,
- One-third of the world's population has latent TB
- 10.4 million new TB cases
- 1.8 million died from TB (including 0.4 million among people with HIV)
- 580 000 new cases of MDR-TB (including 100 000 cases of rifampicin resistant TB)
- 60% of TB cases worlwide occured in just 6 countries : China, India, Indonesia, Nigeria, Pakistan and South Africa
Global Tuberculosis Report WHO, 2015.
sel16
Diapositive 3
sel16 Il faut citer ta source : "WHO, Global TB report 2016"SeL; 13/12/2016
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TB in the world
Global Tuberculosis Report WHO, 2015.
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TB current treatments
An estimated 49 million lives were saved through TB diagnosis and treatment between
2000 and 2015.
Drug-sensitive TB
~10 M new cases in 2015
MDR-TB
Multidrug-resistant TB
~580,000 new cases in 2015
• Definition
Mtb strain susceptible to the
first-line drugs
• Treatment: First-line drugs
• Isoniazid
• Rifampicin
• Pyrazinamide
• Ethambutol
• Duration: 6m
• Efficacy: 85%-95%
• Definition
Mtb strain resistant to both
isoniazid and rifampicin
• Treatment: Second-line drugs
• Fluoroquinolones
• Bedaquiline
• ρ-Aminosalicylic acid
• Amikacin/Kanamycin
• Moxifloxacin
• …
• Duration: 24m
• Efficacy: 45%-65%
6- CONFIDENTIAL -
2: Adult vaccines prophylactic and post-exposure
1: Pediatric vaccineprophylactic
INFECTION PHASES AND DISEASE OCCURRENCE
3: Immunotherapeutic (P3) (combination with antibiotics)
3: Therapeutic vaccinesin combination with antibiotics: Increase/acceleration of cure and/or
prevention of rebound or re-infection
Vaccine approaches in the fight against tuberculosis
7- CONFIDENTIAL -
Therapeutic vaccines
• Definition : Manipulation of the immune system in an antigen specific
fashion to treat disease
� enhancement of immunity: cancers, infectious diseases
� attenuation of an immune response: autoimmune diseases
• Aims of therapeutic vaccines targeting chronic infectious diseases :
� Add a mechanism of action poorly used by current therapies (enroll the host’s
immune system to participate in viral/bacterial clearance)
� Mimic major immune features found in resolvers/controllers
� Avoid exacerbation of diseases
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Global pipepline of TB vaccine candidates
Vaccine
candidate
Partners Description Current
phase
Attenuated,
Inactivated or
fragmented
mycobacteria
VPM 1002 Serum Institute of India (India) Recombinant BCG Phase Iib/III
MTBVAC Biofabri (Spain) Live attenuated M.TB Phase I/IIb
Vaccae Anhui Zhifei Longcom (China) Heat-inactivated M. vaccae Phase III
RUTI Archivel Farma (Spain) Fragmented M.TB Phase II
Adjuvanted
recombinant
proteins
ID93+GLA-SE Infectious Disease Research
Institute (United States)
Rv3619, Rv3620, Rv1813 and
Rv2608
Phase IIb
H56:IC31 Statens Serum Institut (Denmark), Ag85B, ESAT-6, Rv2660c [H56] Phase II
M72/ASO1E GSK Vaccines (UK° MTB 32A and 39A Phase IIb
H4:IC31 Sanofi Pasteur (France) Ag85B and TB10.4 Phase II
Viral vectors
based vaccine
Ad5 Ag85A McMaster University (Canada) human ad5 - Ag85A Phase II
ChAdOx1-85A/
MVA85A
University of Oxford (UK) Chimp adenovirus/MVA
heterologous prime–boost
expressing M. TB Ag85A
Phase I
MVA85A/
MVA85A
University of Oxford (UK) MVA intradermal followed by
aerosol; prime–boost vaccine
Phase I
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TB vaccine candidates positioned as post-exposure vaccine
Vaccine
candidate
Partners Description Current
phase
Attenuated,
Inactivated or
fragmented
mycobacteria
VPM 1002 Serum Institute of India (India) Recombinant BCG Phase Iib/III
MTBVAC Biofabri (Spain) Live attenuated M.TB Phase I/IIb
Vaccae Anhui Zhifei Longcom (China) Heat-inactivated M. vaccae Phase III
RUTI Archivel Farma (Spain) Fragmented M.TB Phase II
Adjuvanted
recombinant
proteins
ID93+GLA-SE Infectious Disease Research
Institute (United States)
Rv3619, Rv3620, Rv1813 and
Rv2608
Phase IIb
H56:IC31 Statens Serum Institut (Denmark), Ag85B, ESAT-6, Rv2660c [H56] Phase II
M72/ASO1E GSK Vaccines (UK° MTB 32A and 39A Phase IIb
H4:IC31 Sanofi Pasteur (France) Ag85B and TB10.4 Phase II
Viral vectors
based vaccine
Ad5 Ag85A McMaster University (Canada) human ad5 - Ag85A Phase II
ChAdOx1-85A/
MVA85A
University of Oxford (UK) Chimp adenovirus/MVA
heterologous prime–boost
expressing M. TB Ag85A
Phase I
MVA85A/
MVA85A
University of Oxford (UK) MVA intradermal followed by
aerosol; prime–boost vaccine
Phase I
10- CONFIDENTIAL -
ActiveActive
LatentLatent
Resuscitation
High plasticity of the MVA has allowed to generate highly complexed candidates
MVA / ACT-LAT-RES
Modified Vaccinia
Ankara virus
(MVA)- Very high safety
profile (150 000
vaccinations
agains small pox)
- High inducer of
innate immune
response
- In clin.trials
malaria, HIV, ..
Multi-phase
antigens covering
all phases of
infection (active,
resuscitation,
latent)
Phases of infection
17 Mtb antigens
evaluated
TB-therapeutic vaccine developed at Transgene
11- CONFIDENTIAL -
MVA-TB lead candidates
� Six genetically stable MVA-TB candidates with at least 5 antigens belonging to the 3 phases of
disease generated.
� All shown to be immunogenic in naïve mouse strains
Vaccines Antigens # cassettes # Ag
MVATG18639 Rv2626/Ag85B - CFP10/ESAT6 - TB10.4/Rv0287 - RpfB/D – Rv3407/Rv1813 5 10
MVATG18598 Rv2626/2A/Ag85B - CFP10/ESAT6 - TB10.4/Rv0287 - RpfB/D – Rv3407/2A/Rv1813 5 10
MVATG18633 Ag85B - ESAT6 - RpfB/D - Rv2626 - Rv1813 5 6
MVATG18690 RpfB/D/Ag85B/TB10.4/ESAT6 - Rv2626/Rv3407 2 7
MVATG18692 RpfB/D/Ag85B/TB10.4/ESAT6 - Rv3478/2A/Rv1733 2 7
MVATG18827 SS-Rv2029/TB10.4/ESAT6/Rv0111 - SS-RpfB/D 2 6
Active – Resuscitation – Latent
Heterodimeric partners
SS: signal sequence
2A: auto-cleavage peptide
RpfB-D= fusion of RpfB (30-284) and RpfD (54-154)
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�Model typically used to evaluate efficacy of novel antimicrobials (antibiotics)
� Endpoints : 1. Primary: Reduction of bacterial load in relapsing animals;
2. Secondary: Prevention of Relapse/ Reactivation of Mtb infection;
Vaccine candidates move to therapeutic efficacy testing in TB Post-exposure
mouse model (E Nuermberger, JHU)
2
4
6
8
CF
U p
er
lun
g(l
og
10)
Time
Control group Sub-optimal
antibiotic
regimen
Mtb
(H37Rv)
Novel treatment
modality
Bacterial load
Relapse/Reactivation
A typical experiment will last 7-8 months
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Kruskal-Wallis: p=0.011
Mann-Whitney test:
• §: p<0.05; §§: p<0.01 as comp. with RHZ group
• *: p<0.05; **: p<0.01
Bacterial load Protection[CFU log10 – Mean CFU log10 (RHZ)]
Testing of the 6 MVA-vaccines: measure of primary end-point ie bacterial load in
Relapser mice (Lung CFU counts)
� 3:6 MVA display significant efficacy
� Highest efficacy with MVATG18633 (1.5 log mean
CFU reduction, p=0.004)
CF
U (
log 1
0)(m
ean
±S
EM
)
0
1
2
3
4
5
LLoD
+ RHZ
p=0.061 **§ § §§
** p=0.061
Pro
tect
ion
(∆∆ ∆∆lo
g 10)
(mea
n±
SE
M)
0.0
0.5
1.0
1.5
2.0
+ RHZ
p=0.061 **
§
§ §§** p=0.061
14- CONFIDENTIAL -
Other lead players Vaccines Preclinical models
Main results
Relapse (%)
Vaccine vs. Control
CFU (log10)
Vaccine vs. Control
Serum Statens Institut
(SSI)
H56 / CAF01
(3 Ags)
(Aagaard, Nat Med, 2011)
• Bacterial load post-
antibiotherapy arrest
100% vs 100%
(5/73 vaccinated mice
did not relapse)
1.5-3 vs 2-4
(p<0.05)
Protection: ~1 log10
Vakzine Projekt Management
(VPM)
VPM1002
(Modified BCG)
(Gengenbacher, Microb
Infect, 2016 )
• Bacterial load post-
antibiotherapy arrest
100% vs 100% 4.4 vs 5.5
(p<0.05)
Protection: ~1 log10
Infectious Disease Research
Institute
(IDRI)
ID93-GLA-SE
(4 Ags)
(Coler, JID, 2013)
• Bacterial load post-
antibiotherapy arrest
• Survival
100% vs 100%
+ Vaccination
improved survival
4.3 vs 5.0
(p<0.05)
Protection: ~0.5 log10
Examples of therapeutic efficacy with adjuvanted recombinant protein
and live-based vaccines
H56 VPM1002 ID93
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Ongoing efficacy study to test Transgene candidates
● TB post-exposure mouse model, comparison head to head with partner’s candidates.
● TBVAC2020 consortium program
● Mouse model of latent infection
● Supported by Aeras
● Prophylactic heterologous prime-boost in non-human primates including a multi-antigen
MVA-TB vaccine
● Collaboration with GSK
● Supported by Aeras
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Host Directed Therapies (HDT): other Immune Players to improve TB
treatment
Treatment of multidrug-resistant tuberculosis (MDR-TB) is extremely challenging
due to :
� the virulence of the etiologic strains
� the aberrant host immune responses
� the diminishing treatment options with TB drugs.
To improve the clinical management outcomes, new treatment regimens is
needed that incorporate therapeutics targeting of both :
� M. tuberculosis : therapeutic vaccine
� Host factors : Host directed therapy
In TB, HDTs may neutralize excessive inflammation in organs and decrease M. tb
proliferation while facilitating tissue repair.
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Host Directed Therapies (HDT): other Immune Players to improve TB
treatment
Lancet, Volume 16, Issue 4, 2016, e47–e63
Host-targeted therapies focus on ameliorating the severity of disease
and improving treatment outcomes
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CD4+
T cells
Host directed therapy (HDT) in TB
1 Augmenting cellular anti-microbial mechanisms :
- Promote phagolysosome fusion (Metformin) and
phagosome maturation (Imatinib)
- Induce antimicrobial peptides (Vit D, HDAC inhibitors)
- Induce autophagy (Gefitinib, VitD, mTOR inhibitors)
Inflammatory
pathways activation
2 Reducing inflammation and
preventing lung damage :
- Corticosteroids
- TNF blocker
- Statins
- COX and leukotriene inhibitors
- MMP inhibitors
Adapted from Wallis and Hafner, 2015
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Host directed therapy (HDT) in TB
1. Augmenting cellular anti-microbial
mechanisms
Inflammatory
pathways activation
2. Reducing
inflammation and
preventing lung
damage
TB patient
Intranasal administration of
the HDT-MVA
Migration to the lung
Lung epithelial cells
HDT-MVA
Adapted from Wallis and Hafner, 2015
3. Modulating anti-M-tuberculosis protective innate and adaptative
Administration of specific immune mediators (cytokines, chemokines)
• can enhance survival of mice after Mtb infection and decrease bacterial
load
• Induce antimicrobial peptides
• decrease lung pathology
NK
NK cell homeostasis, B
cell immunoglobulin
class switch
DC
Increase CPA
function of DC
Development, proliferation and
activation of NK cells, mature
and memory T cells.
CD8+
T cells
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Positioning of MVA-HDT in the treatment of tuberculosis
Active TB
Pre-exposure vaccine
- BCG, M72, MTBVAC, H4
Therapeutic treatment
- Antibiotics
- Therapeutic vaccine
(M. Vaccae, MVA-TB)
Post-exposure vaccine
- M72, H56, ID93
Weakness
- Resistance (MDR, XDR)
- duration
- relapse
- Lung damage
HDT
- Enhance the quality of
the memory response
and prevent risk of
reinfection
- Enhance efficacy of
existing therapy
- Prevent tissue damages
Weakness
- Poor efficacy of BCG
- Selected on their
ability to induce a
CD4 Th1 response.
Weakness
- Selected on their
ability to induce a CD4
Th1 response
Adapted from Kaufmann et al, 2015
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MVA technology, a comprehensive toolbox
● In the last century vaccination has dramatically reduced death and morbidity caused by
infectious diseases (smallpox, polio, rabies, diphtheria, tetanus, HAV, HBV mumps,
measles …)
● There is still major unmet medical needs HIV, malaria, TB, cancer
● MVA is an interesting technology to develop the next generation of vaccine
● Safe with a high plasticity that allow large transgene
● Strong inducer of innate immunity
● Mimic a live infection by expressing antigen in situ after immunization, thereby
facilitating the induction of a strong T-cell responses
● MVA technology can be adapted to different pathologies
● To induce an immunity specific of a pathogen
● To target host factor and improve the clinical management outcomes
22- CONFIDENTIAL -
Acknowledgements
TRANSGENE
Lyon, France
• Marie Gouanvic
• Charles-Antoine Coupet
• Aurélie Ray
• Clément Levin
• Audrey Glaize
• Cécile Bény
• Emmanuel Tupin
• Stéphane Leung-Theung-Long
• Geneviève Inchauspé
• Romain Micol
• Valentina Ivanova-Segura
• Ludovic Dendane
Strasbourg, France
• Martine Marigliano
• Jean-Baptiste Marchand
• Nathalie Silvestre
• Thierry Menguy
• Joan Foloppe
• Doris Schmitt
• Chantal Hoffmann
• Murielle Klein
• Véronique Koerper
• Sophie Steinbach
• Fabrice Le Pogam
• Patricia Kleinpeter
• Dominique Villeval
• Sophie Jallat
• Annick Hoh
NIH support through grant awarded to
Emergent BioSolutions/Transgene
subcontractor
• Eric Nuermberger
• Paul Converse
• Sandeep Tyagi
• Tom Evans
• Barry Walker
• Nathalie Cadieux