TB Vaccine Research and Development: Progress, Strategies ...

TB Vaccine Research and Development:

Progress, Strategies and Controversies

Lewis Schrager, M.D.

V.P., Scientific Affairs

Rockville, MD

USA

15 March 2016

GVIRF Global Forum

Johannesburg, South Africa

2Source: WHO Global TB Report 2015

Outline

• Progress

• Major challenges in TB vaccine R&D efforts

• Controversies in the TB vaccine R&D field

Phase I Phase IIa Phase IIb Phase III

Ad5 Ag85A

McMaster CanSino

RUTI

Archivel Farma, S.L

M72 + AS01E

GSK, Aeras

Vaccae™

Anhui Zhifei Longcom, China

DAR-901

Dartmouth, Aeras

ID93 + GLA-SE

IDRI, Aeras, Wellcome Trust

VPM 1002 (rBCG)

Max Planck, VPM, TBVI, SII

TB / FLU-04L

RIBSP

MTBVAC (Attenuated M.Tb)

TBVI, Zaragoza, Biofabri

Crucell Ad35 / MVA85A*

Crucell, Oxford, Aeras

H1: IC31

SSI, TBVI, EDCTP

ChAdOx1.85A / MVA85A*

Oxford, Birmingham

H4: IC31

SSI, Sanofi-Pasteur, Aeras

MVA85A / MVA85A (ID, Aerosol)*

Oxford

H56 + IC31

SSI, Aeras

The Global Clinical Pipeline of TB Vaccine Candidates

Viral Vector

Protein / Adjuvant

Mycobacterial – Whole Cell or Extract

Experimental medicine tools / platforms*

Last updated 8/31/15

TB Vaccine Candidates: Summary of Status

CandidateCandidateCandidateCandidate DescriptionDescriptionDescriptionDescription StatusStatusStatusStatus CommentsCommentsCommentsComments

Vaccae™ (M. vaccae) Heat killed WC Phase 3 PoD (China) Data due 2016

VPM-1002 Recombinant BCG -Phase 2b BCG

replacement (S.A.)

-Phase 3 PoR (India)

Potential licensure

submission(s) 2019

M72:AS01E Adjuvanted fusion

protein

-Phase 2b PoD (S.A.,

Kenya, Zambia)

Data due 2018

H4:IC31 Adjuvanted fusion

protein

-Phase 2 PoI (S.A.) Primary data due

2016;

BCG comparator arm


protein

-Phase 2 safety,

immunogenicity (S.A.)

-Promising NHP data

-PoI study in planning

ID93:GLA-SE Adjuvanted fusion

protein

-Phase 2a in treated TB

patients ongoing (S.A.)

-Phase 2b PoR study

planned

MTBVAC Live, attenuated

Mtb

-Phase 1 completed -Primary pathway:

BCG replacement

(infants)

DAR-901 Heat-killed M.

obuense

-Phase 1 completed -Follow-on to SRL-172

-Phase 2 PoD in

planning

5PoD: Prevention of Disease; PoR: Prevention of Recurrent Disease; PoI: Prevention of Sustained Infection





replacement (S.A.)


Potential licensure

submission(s) 2019


protein


Kenya, Zambia)

Data due 2018


protein


2016;

BCG comparator arm


protein

-Phase 2 safety,


-Promising NHP data



protein



-Phase 2b PoR study

planned


Mtb


BCG replacement

(infants)


obuense


-Phase 2 PoD in

planning






replacement (S.A.)


Potential licensure

submission(s) 2019


protein


Kenya, Zambia)

Data due 2018


protein


2016;

BCG comparator arm


protein

-Phase 2 safety,


-Promising NHP data



protein



-Phase 2b PoR study

planned


Mtb


BCG replacement

(infants)


obuense


-Phase 2 PoD in

planning






replacement (S.A.)


Potential licensure

submission(s) 2019


protein


Kenya, Zambia)

Data due 2018


protein


2016;

BCG comparator arm


protein

-Phase 2 safety,


-Promising NHP data



protein



-Phase 2b PoR study

planned


Mtb


BCG replacement

(infants)


obuense


-Phase 2 PoD in

planning






replacement (S.A.)


Potential licensure

submission(s) 2019


protein


Kenya, Zambia)

Data due 2018


protein


2016;

BCG comparator arm


protein

-Phase 2 safety,


-Promising NHP data



protein



-Phase 2b PoR study

planned


Mtb


BCG replacement

(infants)


obuense


-Phase 2 PoD in

planning






replacement (S.A.)


Potential licensure

submission(s) 2019


protein


Kenya, Zambia)

Data due 2018


protein


2016;

BCG comparator arm


protein

-Phase 2 safety,


-Promising NHP data



protein



-Phase 2b PoR study

planned


Mtb


BCG replacement

(infants)


obuense


-Phase 2 PoD in

planning






replacement (S.A.)


Potential licensure

submission(s) 2019


protein


Kenya, Zambia)

Data due 2018


protein


2016;

BCG comparator arm


protein

-Phase 2 safety,


-Promising NHP data



protein



-Phase 2b PoR study

planned


Mtb


BCG replacement

(infants)


obuense


-Phase 2 PoD in

planning






replacement (S.A.)


Potential licensure

submission(s) 2019


protein


Kenya, Zambia)

Data due 2018


protein


2016;

BCG comparator arm


protein

-Phase 2 safety,


-Promising NHP data



protein



-Phase 2b PoR study

planned


Mtb


BCG replacement

(infants)


obuense


-Phase 2 PoD in

planning






replacement (S.A.)


Potential licensure

submission(s) 2019


protein


Kenya, Zambia)

Data due 2018


protein


2016;

BCG comparator arm


protein

-Phase 2 safety,


-Promising NHP data



protein



-Phase 2b PoR study

planned


Mtb


BCG replacement

(infants)


obuense


-Phase 2 PoD in

planning


High-Interest Pre-clinical Candidate:

CMV-Vectored TB (Louis Picker, OHSU)

• Live, attenuated, persistent CMV vector

• Also used for HIV vaccine development (IAVI)

• Unique characteristics

– Stimulates tissue effector memory

– UL 128-130 deletion stimulates MHC II-

restricted CD8+ T-cell responses

• Encouraging results in Rhesus macaque Mtb

challenge studies

• Will need to address regulatory hurdles re:

safety of live, persistent CMV14

Non

Human

primates

Whole Cell

Vaccines

Aerosol

and

mucosal

vaccination

B-cells and

antibodies

Conventional

T-cells

Funders’

Community

Donor

Unrestricted

T cells

TB Vaccine R&D: Challenges

• Mono-focus on CD4+ T-cell responses; lack of immunological diversity

• Lack of immune correlate of protection

• Lack of a reliable, reproducible functional assay

• Lack of a human challenge model– Human challenge consortium formed (Harvard, AECOM, Imperial College, Cornell, Rutgers, Aeras)

– Key issues• Develop safe challenge strains (auxotrophs; genetic kill switches)

• Develop reporter methodology (blood-borne substrates; volatile aromatics)

• Achieve regulatory guidance/approval

16

TB Vaccine R&D: Challenges

• Poor predictive power and lack of

standardized animal models that reliably

predict human clinical outcomes

• Lack of funding*

– HIV vaccine funding, 2014: $841 million

– Malaria vaccine funding, 2014: ~$170 million

– Total TB vaccine funding, 2004-2014: ~$600

million

*From Vaccines and Alternative Approaches: Reducing our Dependence on

Antimicrobials. Review on Antimicrobial Resistance, Jim O’Neill, Chair. February

2016

17

TB Vaccine R&D: Controversies

• Resource allocation balance: experimental vs. vaccine product development

• Role of small animal models (mice, guinea pig, rabbit) in vaccine candidate evaluation

• Target patient population– Infant-targeted vaccine (BCG replacement)

– Adolescent/adult targeted vaccine (prevention of infection and/or disease; reduce transmission)

• Choice of endpoint/indication– Prevention of established Mtb infection (feasible/licensable?)

– Prevention of TB disease (IGRA-’s vs. IGRA+’s)

– Prevention of recurrent disease (many variables; too high a bar?)

• Infant BCG vaccination – effect of prior sensitization to vaccine development

• Effect of co-factors (e.g., DM, NTM exposure) on vaccine response

18

Acknowledgments

• Ann Ginsberg, Aeras

• Bernard Landry, Aeras

• Jessica Eisner, Aeras

• Zhongkai Shi, Aeras

• Nathalie Cadieux, Aeras

• Ravi Anantha, Aeras

• Thomas Scriba, UCT/SATVI

19

Recent Major Funders and R&D Partners

20And special thanks to the sites and participants And special thanks to the sites and participants And special thanks to the sites and participants And special thanks to the sites and participants

in in in in our clinical trials!our clinical trials!our clinical trials!our clinical trials!

Thank You.

Potential Worldwide Impact of New TB Vaccines

22

Immunization of infants, adolescents, adults with a 60% efficacious vaccine:

20% coverage rate for adolescents and adults90% coverage rate for infants

Source: Aeras –Not for circulation; estimates subject to change

TB Vaccine Research and Development: Progress, Strategies ...

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