Clinical development of ID93 + GLA-SE as a prophylactic or...
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idri.org Clinical development of ID93 + GLA-SE as a prophylactic or therapeutic vaccine for tuberculosis Tracey Day, PhD Senior Scientist Infectious Disease Research Institute 5 th Global Forum on TB Vaccines SG Reed 1 , RN Coler 1 , C Casper 1 , TA Day 1 , A Penn-Nicholson 2 ; M Tameris 2 ; R Ellis 3 ; M Hatherill 2 , Z Sagawa 1 , AM Beckmann 1 , AM Ginsberg 3 , TJ Scriba 2 , R Cho 4 , H Lee 4 , YA Kang 4 , E Cho 5 , R Oh 5 , YH Choi 5 , and the TBVPX-113, 114, and 203 Study Teams 1,2,3 1 IDRI, Seattle, Washington; 2 South African Tuberculosis Vaccine Initiative, University of Cape Town, South Africa; 3 Aeras, Rockville, Maryland; 4 Yonsei University College of Medicine, 5 Quratis, Seoul, South Korea
Transcript of Clinical development of ID93 + GLA-SE as a prophylactic or...
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Clinical development of ID93 + GLA-SE as a prophylactic or therapeutic vaccine for tuberculosis
Tracey Day, PhDSenior Scientist
Infectious Disease Research Institute5th Global Forum on TB Vaccines
SG Reed1, RN Coler1, C Casper1, TA Day1, A Penn-Nicholson2; M Tameris2; R Ellis3; M Hatherill2, Z Sagawa1, AM Beckmann1, AM Ginsberg3, TJ Scriba2, R Cho4, H Lee4, YA Kang4, E Cho5, R Oh5, YH Choi5, and the TBVPX-113,
114, and 203 Study Teams1,2,3
1IDRI, Seattle, Washington; 2South African Tuberculosis Vaccine Initiative, University of Cape Town, South Africa; 3Aeras, Rockville, Maryland; 4Yonsei University College of Medicine, 5Quratis, Seoul, South Korea
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Strategies for TB Vaccine Development
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ProphylacticPre-infection‐ prevent infection and/or disease‐ either initial or sustained infection
Post-infection ‐ prevent disease ‐ prevent reactivation from latency
Immunotherapy‐ shorten the course of
chemotherapy for active TB ‐ decrease relapse or reinfection
ratesAdapted from BMGF
Initial infection
Early disease
Latency
Reactivation
Treatment
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What Type of Immune Response Should be Elicited by an “ideal” TB Vaccine
Prophylactic
▪ Elicit a protective response from a naïve-like baseline
▪ Pulmonary tissue resident T-cell memory
▪ Functional antibodies patrolling lung spaces
– Orchestrate Mtb killing
– Attract and activate innate cells
– Antibody-dependent cellular phagocytosis
– Antibody-dependent cellular cytotoxicity
▪ Rapid recall response that traffics to lung
▪ Long-lasting memory response
Therapeutic
▪ Elicit an immediate effector response through boosting and redirect existing response
▪ T cells trafficking to lung and inside lesions
– Lethal effector functions within inflamed environment and amidst moderate antigen load
– Avoid exacerbating disease and inducing harmful pathology
▪ Functional antibodies reach lesion interior
▪ Durable memory to protect from re-infection
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Current TB Vaccine Landscape
Type of Vaccine Candidate Stage Potential Advantages / Disadvantages
Protein Subunit M72/AS01E Phase 2b Safety - safety/reacto varies
Immunology - offers multivalency, both T cell and Ab response
Manufacture – easy, locally produced, cost varies by adjuvant
H56:IC31 Phase 2a
H4:IC31 Phase 2a
ID93 + GLA-SE Phase 2a
Viral Vector Ad5 Ag85A Phase 1 Safety - safety/reacto varies
Immunology – few antigens, strong T cell response, low antibody response
Manufacture – ease? cost?
ChAdOx185A/MVA85A
Phase 1
TB/FLU-04L Phase 2a
Killed / Inactivated / Extract
Vaccae Phase 3 Safety - safety/reacto could vary?
Immunology – many antigens but individual variability?
Manufacture – ease? consistency? in country? cost?
DAR-901 Phase 2b
RUTI Phase 2a
Live / Attenuated VPM 1002 Phase 3 Safety - safety/reacto could be an issue
Immunology – many antigens but individual variability?
Manufacture – ease? consistency? In country? cost?
MTBVAC Phase 1
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ID93 + GLA-SE
▪ ID93 is a fusion of 4 Mtb antigens with diverse roles, recognized in exposed individuals, protection in mouse models, and no human sequence homology • Rv1813 - Up-regulated under hypoxic conditions
• Rv2608 - PPE protein, outer-membrane associated
• Rv3619 - EsX protein family of secreted virulence factors
• Rv3620 - EsX protein family of secreted virulence factors
▪ GLA-SE is a synthetic TLR-4 agonist adjuvant formulated in a squalene oil in water nano-emulsion• Demonstrated safety thus far– another TLR4 ligand adjuvant has been
approved for licensure
• Induces Th1-biasing response (even in existing strong Th2 environment)
• Readily scalable for local production at low cost
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ID93 Rv3619 Rv1813 Rv3620 Rv2608
GLA-SE
Total people
ID93 + GLA-SE > 200
GLA-SE > 1000
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Pre-Clinical Data: Proof of principle in mice, guinea pigs, and non-human primates
Coler R et al. J Infect Dis. 2013 6
Prophylactic
Therapeutic
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TBVPX-113: Phase 1a Study in the US
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▪ Design: first in human, phase 1,
randomized, double-blind, dose-
escalation
▪ Population: 60 BCG-, QFT-, healthy
adults
▪ Safety: good
▪ Immunogenicity results:
– GLA-SE increases T cell magnitude
and polyfunctionality
– GLA-SE increases antibody
response; IgG1 and IgG3 but not
IgG2 or IgG4
– Multi-functional antibodies post
ID93+GLA-SE vaccination
Poster by Day et al.
Outer circlePie chart
TNF+ IFNg + IL-2 +
IFNg + IL-2 +
TNF+ IL-2 +
TNF+ IFNg +
TNF+
IFNg +
IL-2 +
3 cytokines
1 cytokine
2 cytokines
2 mg ID93 + 2 mg GLA-SEN = 12Median cytokine+ CD4 T cell frequency = 1.062%
2 mg or 10 mg ID93N = 6Median cytokine+ CD4 T cell frequency = 0.127%
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GLA-SE increases antibody functionality
ID9
3
Day
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Day
84
Day
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Day
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0.0
0.2
0.4
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0.8
1.0
NK IFNg
ID93 ID93+GLA
NK
Ifn
g
Day
0
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Day
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84
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NK MIP1b
ID93 ID93+GLA
NK
MIP
1b
Day
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Day
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NK CD107a
ID93 ID93+GLA
NK
CD
107a
Day
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50
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ID93 ADCP
ID93 ID93+GLA
AD
CP
(ph
ag
osco
re)
Day
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84
Day
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Day
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80
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RV1813 ADCP
ID93 ID93+GLA
AD
CP
(ph
ag
osco
re)
ID93 *** *** ***
***
***
*
*
Day
0
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Day
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10
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NKDegran 1813
ID93 ID93+GLA
NK
CD
107a
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Day
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Day
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Day
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MIP1b 1813
ID93 ID93+GLA
NK
MIP
1b
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Day
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Day
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0.0
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NK
IF
Ng
IFNg 1813
RV1813
******
*
ID93
ID93
+GLA
0
1
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Po
lyfu
ncti
on
ality
IFNγ MIP1β CD107a ADCP
IFNg MIP1b CD107a ADCP
IgG1
IgG2
IgG3
IgG4
IgM
IgA1
IgA2
A
B C
Data Courtesy of Lennette Lu and Galit Alter, Ragon Institute
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TBVPX-114: Phase 1b in South Africa▪ Design: randomized, double-blind, dose-escalation ▪ Population: 66 BCG+, QFT+/-, adults ▪ Safety: good▪ Immunogenicity:
– More robust CD4 responses in QFT+ adults suggests boosting from natural infection– QFT+ express more IFN-g– Multivalent vaccine increases complexity of T-cell response– Tem (immediate effect) + Tcm (long lasting)
9Whole blood ICS, Adam Penn-Nicholson, SATVI Poster by Penn-Nicholson et al.
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0.00
0.05
0.10
0.15
0.20
0.25
0.5
1.0
1.5
2.0
CD
4+ T
cells (
%)
Cytokine coexpression
in Rv2608 stimulated CD4+ T cells
DAY 0DAY 14DAY 42DAY 112DAY 126DAY 196DAY 294
IFN-g +++
IL-2TNF-a
++-
+-+
+--
-+-
--+
-++
< 0.0001 < 0.0001 0.0098 < 0.0001 < 0.0001 < 0.0001 0.0014
Multivalency lends complexity for CD4 T cell responses
Rv2608
Vaccination on Day 0,Day 28, Day 112
Rv3620
0.00
0.05
0.10
0.15
0.20
0.25
0.5
1.0
1.5
2.0
CD
4+ T
cells (
%)
Cytokine coexpression
in Rv3619 stimulated CD4+ T cells
IFN-g +++
IL-2TNF-a
++-
+-+
+--
-+-
--+
-++
DAY 0DAY 14DAY 42DAY 112DAY 126DAY 196DAY 294
< 0.0001 < 0.0001 0.0002 0.0045 < 0.0001 < 0.0001 0.2707
TBVPX-114: Phase 1b
A spectrum of T cell phenotypes are induced by individual antigens: potentially with diverse functionalities
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Whole blood assay data from Adam Penn-Nicolson and team, SATVI
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TBVPX-203: Phase 2a in South Africa
▪ Design: randomized, double-blind, placebo-controlled
▪ Population: 60 HIV-, BCG+, treated TB patients
▪ Safety: good
▪ Interim immunogenicity data on 1st
cohortA. CD4 T cells boosted similarly to QFT+
individualsB. Antibody responses appear higher than in
QFT+ individuals
Preliminary conclusion: Post TB treatment patients are not immunosuppressed in ways that impair T-cell or antibody responses to ID93 + GLA-SE
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A
Whole blood ICS, Adam Penn-Nicholson, SATVI
BWhole blood ICS, Adam Penn-Nicholson, SATVI
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Clinical Trials with ID93 + GLA-SE
Phase 1TBVPX-113
N=60
Phase 1bTBVPX-114N=66
Phase 2aTBVPX-203N=60
PoRPhase 2bTBVPX-204N=840
BCG+ QFT-BCG+ QFT+
BCG- QFT- BCG+ QFT+TB patients
BCG+ QFT+TB patients
BCG+ QFT+BCG+ DS TB patientsBCG+ MDR patients
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BCG+ QFT-Healthcareworkers
PoIPhase 2N=180Quratis
TherapeuticPhase 1/2
Phase 1TBVPX-120Lyophilized
N=48
BCG- QFT-
Phase 1DMID 12-0109
LiposomalN=70
BCG- QFT-
Completed Trials
BCG+ MDR patients
TherapeuticPhase 1/2
Planned Trials
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Conclusion:▪ ID93 antigens are unique and diverse: Rv2608, Rv3619, Rv3620, Rv1813
• PE/PPE family, ESX-family, hypoxia-related
▪ GLA-SE adjuvant appears safe and is amenable to low cost local manufacture
• TLR4-agonist target
• Synthetic
— readily scalable, low cost
— is being manufactured in endemic countries
• Dose sparing
▪ Immune response profile – Th1 with strong functional antibody responses
• Spectrum of CD4 T cell differentiation and memory profiles
• Most functional IgG subclasses against all 4 antigens
▪ Acceptable safety profile in Mtb-naïve, Mtb-infected, and TB patients at end of treatment
▪ Poised for
• Phase 2b proof of concept testing for prevention of recurrence in treated TB patients, prevention of infection/disease
• Safety testing in TB patients during treatment (DS and MDR)
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AcknowledgementsTBVPX-113, -114, -203, DMID 12-01009
participants, study teams, clinical sites
IDRI Clinical/Regulatory
Anna Marie Beckmann
Jill Ashman
Zachary Sagawa
Aude Frevol
IDRI Clinical Immunology
Julie Vergara
Tom Rolf
Sarah Albertson
Fan-Chi Hsu
IDRI GMP Operations
IDRI Adjuvants & Formulations
Rhea Coler
Corey Casper
Steve Reed
Desmond Tutu HIV Foundation
Linda Gail-Bekker
Stellenbosch University SU-IRG
Gerhard Walzl
Andreas Diacon
Nelita Du Plessis
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TASK
SATVI Adam Penn-NicholsonErica Smit Thomas Scriba Michele TamerisMark HatherillAngelique LuabeyaJustin Shenje
AerasAnn Ginsberg Dave Hokey Kathryn RutkowskiRuth Ellis Tom Evans
Ragon InstituteLennette LuGalit Alter
Yonsei University Ray ChoHyejon Lee
QuratisYu Hwa Choi Rosa OhEd Cho
Gennova BiopharmaceuticalsAfrigen Biologics
