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
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
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.
½ Empty ½ Full
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
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
9
Stopping the cycle of
transmission in adults will
prevent the spread of TB to
children as well
10
“…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.
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
13
IV BCG
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
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)
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
Recent Results are Game-Changing
19
TB vaccines
are
achievable
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
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).
Recent Results are Game-Changing
23
TB vaccines
are
achievable
1999
2004 2009
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).
• 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
27
10 vs 22 cases (p=0.04)
Efficacy 54%
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)
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
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