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