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TB VACCINES:
THE GLASS HALF FULL
END TB 2019: 23RD ANNUAL CONFERENCE OF THE UNION-
NORTH AMERICA REGION
David Lewinsohn, MD, PhD
Feburary 23, 2019
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Disclosures
• David Lewinsohn:
• OHSU inventor, CD8+ T cell vaccines and diagnostics
• ViTi Inc., CEO, current
• Spouse Deborah Lewinsohn:
• OHSU inventor, CD8+ T cell vaccines and diagnostics
• ViTi Inc., President, current
• OHSU and Drs. Deborah and David Lewinsohn have a financial interest in ViTi,
a company that may have a commercial interest in the results of this research.
This potential individual and institutional conflict of interest has been reviewed
and managed by OHSU.
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½ Empty ½ Full
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Ending TB
• Guiding Principles
• TB elimination not
achievable without new
tools
• While these tools are not
widely at present,
investments NOW is key
WHO Global Tuberculosis Report2018
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Effect by year up to 2050 of interventions and strategies begun in 2015 on TB (all-types) incidence per million (A, C, E, and G) and TB (all types) related mortality per million (B, D, F, and H).
Abu-Raddad L J et al. PNAS 2009;106:13980-13985
©2009 by National Academy of Sciences
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9
Stopping the cycle of
transmission in adults will
prevent the spread of TB to
children as well
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10
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“…evaluating cost
effectiveness found new TB
vaccines to be an
overwhelmingly cost effective
intervention, whether from the
health system or societal
perspective.”
11
Over the first ~25 years of use, a
prevention of disease vaccine could
avert over 50 million cases of TB
globally (Murray et al. 1998)
As low as 20% efficacy and 5 years
duration of protection could be cost
effective if delivered to
adolescents/adults (Knight et al. 2014)
Harris R, et al 2016, Human Vaccines and Immunotherapeutics. 12:2813-2832.
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www.stoptb.org
Pre-Clinical
IV BCG
William Barclay
Sally Sharpe
Frank Verreck
Bob Seder and
JoAnne Flynn
Pulmonary BCG
Frank Verreck
CMV
Louis Picker
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13
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IV BCG
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Mtb challenge (5-15 CFU): 6months after BCG vaccination
Bob Seder, Patricia Darrah, Joanne Flynn
Experimental Protocol
Vaccine Route Dose
BCG
ID (low) 5x105
ID (high) 5x107
AE 5x107
IV 5x107
ID + AE 5x105 + 5x107
Do
seR
ou
te
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Mycobacterial Burden (CFU) at Necropsy
Low
-ID
Hig
h-I
D
AE IV
ID/A
E
Un
vax
Tota
l CFU
(l
og
scal
e)
Lung
sterile
Unvax (n = 4)
Low-ID (n = 10)
High-ID (n = 8)
IV (n = 10)
AE (n = 10)
ID/AE (n = 10)
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M72/AS01E
GSK, Aeras
Vaccae TM
Anhui Zhifei Longcom
DAR-901
Dartmouth Medical School,
GHIT
VPM1002
Max Planck, VPM, SII
Completed (April 2017)
Awaiting for resultsPhase III 10000 PPD+ 15-65y Prevention of disease China 2-
3Q2018
Phase II 990 Q- 12-17y Prevention of
infection
South Africa
1Q2018
Phase IIb 3573 Q+ 18-50y Prevention of disease South Africa, Kenya, Zambia
2Q2018
Phase IIb 650 Q- 13-15y Prevention of
infection
Tanzania 4Q2019
Phase II/III 2000 TB+ 18-65y Prevention of
recurrence
India
4Q2019
Turning a Corner: recent and upcoming data in
TB vaccine efficacy trials PHASE PARTICIPANTS EFFICACY LOCATION
RESULTS
H4:IC31/BCG revacc
SP, SSI, Aeras
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Recent Results are Game-Changing
19
TB vaccines
are
achievable
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990 QFT- adolescents
• high-risk setting
• neonatal BCG
• H4:IC31 vaccine
• BCG revaccination
• Placebo
Primary outcomes
• Safety
• Acquisition of Mtb Infection (QFT conversion; q6 months over two years)
Secondary outcomes
• Immunogenicity
• Sustained QFT conversion to a positive test without reversion to negative status at 3 months and 6
months after conversion
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QFT conversion
• H4:IC31
• 44 of 308 participants (14.3%)
• BCG
• 41 of 312 participants (13.1%)
• Placebo
• 49 of 310 participants (15.8%)
Sustained conversion
• H4:IC31 8.1%
• BCG 6.7%
• Placebo 11.6%
Efficacy (sustained conversion)
• BCG
45.4% (P = 0.03)
• H4:IC31
30.5% (P = 0.16).
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Recent Results are Game-Changing
23
TB vaccines
are
achievable
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1999
2004 2009
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Antigen Discovery
• Dillon et al., I&I 1999
• Skeiky et al., I&I 1999
Animal Studies
• Skeiky et al., JI 2004
• Reed et al., PNAS 2009
Human Studies
• I. Leroux-Roels et al., Improved CD4(+) T cell responses to Mycobacterium tuberculosis in PPD-negative adults by M72/AS01 as compared to the M72/AS02 and Mtb72F/AS02 tuberculosis candidate vaccine formulations: a randomized trial. Vaccine 31, 2196-2206 (2013).
• J. Montoya et al., A randomized, controlled dose-finding Phase II study of the M72/AS01 candidate tuberculosis vaccine in healthy PPD-positive adults. Journal of clinical immunology 33, 1360-1375 (2013).
• O. T. Idoko et al., Safety and immunogenicity of the M72/AS01 candidate tuberculosis vaccine when given as a booster to BCG in Gambian infants: an open-label randomized controlled trial. Tuberculosis (Edinb) 94, 564-578 (2014).
• E. G. Thacher et al., Safety and immunogenicity of the M72/AS01 candidate tuberculosis vaccine in HIV-infected adults on combination antiretroviral therapy: a phase I/II, randomized trial. Aids 28, 1769-1781 (2014).
• A. Penn-Nicholson et al., Safety and immunogenicity of candidate vaccine M72/AS01E in adolescents in a TB endemic setting. Vaccine 33, 4025-4034 (2015).
• P. Gillard et al., Safety and immunogenicity of the M72/AS01E candidate tuberculosis :vaccine in adults with tuberculosis A phase II randomised study. Tuberculosis (Edinb) 100, 118-127 (2016).
• N. Kumarasamy et al., A Randomized, Controlled Safety, and Immunogenicity Trial of the M72/AS01 Candidate Tuberculosis Vaccine in HIV-Positive Indian Adults. Medicine (Baltimore) 95, e2459 (2016).
• N. Kumarasamy et al., Long-term safety and immunogenicity of the M72/AS01E candidate tuberculosis vaccine in HIV-positive and -negative Indian adults: Results from a phase II randomized controlled trial. Medicine (Baltimore) 97, e13120 (2018).
• O. Van Der Meeren et al., Phase 2b Controlled Trial of M72/AS01E Vaccine to Prevent Tuberculosis. N Engl J Med 379, 1621-1634 (2018).
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• Randomized, double-blind, placebo-controlled, phase 2b trial of the M72/AS01E
tuberculosis vaccine• Human (HIV)–negative adults 18
to 50 years of age with LTBI (QFT)
• M72/AS01E 1786 (1660)
• Placebo 1787 (1623)
• Kenya, South Africa, and Zambia
Outcomes
• Safety
• Efficacy
• Progression to bacteriologically
confirmed active pulmonary
tuberculosis disease
• Polymerase-chain-reaction test,
mycobacterial culture, or both
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27
10 vs 22 cases (p=0.04)
Efficacy 54%
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ID93 + GLA-SEIDRI, Wellcome Trust
Global Pipeline of TB Vaccine Candidates
29
Phase 3Phase 2bPhase 2aPre-Clinical
VaccaeTM
Anhui Zhifei Longcom
MTBVAC
Biofabri, TBVI, Zaragosa
Ad5 Ag85A
McMaster, CanSino
ChAdOx185A/MVA85A (ID/IM/Aerosol)
U. Oxford
DAR-901
Dartmouth, GHIT
RUTI
Archivel Farma, S.L
H56: IC31
SSI, Valneva, Aeras
H4: IC31Sanofi Pasteur, SSI, Aeras
M72 + AS01E
GSK, Aeras
Viral Vector
Protein / Adjuvant
Mycobacterial – Whole Cell or Extract
Information on candidates in clinical development is self-reported by vaccine sponsors, coordinated
by the Working Group on New TB Vaccines
Candidates in preclinical development are representative and include those in the Aeras and/or TBVI
portfolios that have completed Gate 1 as published in Barker L, Hessel L, Walker B, Tuberculosis,
92S1 (2012) S25–S29
Mycobacterial – Live
TB/FLU-04L
RIBSP
Cysvac2
U. Sydney, TBVI
BCG-ΔZMP1
U. Zurich, TBVI, Aeras
MVA-based Mutiphasic
VaccineTransgene, TBVI
ChAdOx1.85A/PPE15U. Oxford, TBVI
H64+CAF01 SSI, TBVI
CMV-6Ag Aeras, Vir Biotech, OHSU
ChAd3/MVA-5AgAeras, GSK, Transgene
Phase 1
Revised on September 28, 2017
VPM 1002
SII, Max Planck, VPM, TBVI
(Phase 2/3)
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Novel Partnerships Will Be Key to Success
30
TB VACCINE ACCESS
Advocates and Communities
Funders
WHO and Regulators
Governments
Manufacturers
Vaccine Developers-private and
public sector
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The Way Forward
• Populations• Neonates
• Pre-infection
• Novel mechanisms• Prevention of infection
• Mucosal
• Animal models that reflect human disease• Natural transmission
• Stochastic approaches
• Correlates of protection• Clinical trials
• Human challenge model