1. Global progress in tuberculosis vaccine development
Helen McShane
The Jenner Institute
University of Oxford

2. Global Plan to Stop TB: 2006 - 2015
Targets (from MDGs)
> 70% with infectious TB will be diagnosed
>85% of those will be cured
By 2015, global prevalence of TB will be
reduced to 50% of 1990 levels
By 2050, global incidence will be
<1/million population
How?
Use of current tools
DOTS; DOTS-plus; DOTS expansion
New tools
New drugs
New diagnostics
New vaccines
Total cost of plan: US$ 56 billion – US$ 31 billion funding gap 2

3. BCG Live attenuated Mycobacterium bovis First used in 1921 (per os)
Efficacy:
Good
Disseminated TB and TB meningitis
Leprosy
Bad
Lung disease
Boosting (Rodrigues et al, Lancet 2005)
Efficacy highly variable (0 – 80%) 3

4. Why is the efficacy of BCG so variable?
Different strains of BCG
Nutrition
Exposure to environmental mycobacteria
Masking (Black et al, 2002)
Blocking (Brandt et al, 2002) 4

5. Other problems with BCG
Safety in immuno-suppressed
Contra-indicated in HIV-infected adults
Risk of disseminated BCG disease in HIV-infected infants
Change of WHO policy
Relative balance of risks

6. What do we know about protective immunity
Essential:
CD4+ T cells
IFN γ
TNF
Probably important:
CD8+ T cells
γδ T cells
CD-1 restricted T cells
IL-17
Il-2
Probably not a major role
B cells and antibodies 6

7. Design of an improved vaccine against TB
Include BCG in new regime
Needs to induce cellular immune response
3 possible strategies:
Enhance BCG with a subunit vaccine
Protein + adjuvant
Viral vector
Replace BCG with improved BCG / attenuated M. tb
Enhance an improved BCG

8. Recombinant BCG strains
rBCG-30 (UCLA/AERAS)
First time in man February 2004
Not currently active
ΔureC hly+ (MPI Berlin / VPM)
Phase I study in Berlin complete
Phase I/IIa in South Africa ongoing
Aeras 422:
rBCG expressing Ag85A, B and Rv3407
Phase I study commenced in Q1 2011
Now withdrawn for safety reasons 8

9. Attenuated M.tb strains
Pho p-/- (Martin, Zaragosa)
Pantothenate auxotroph (Jacobs, HHMI)
IKE-PLUS (Sweeney et al, NM 2011)

10. Booster vaccines: MTB 72F / M72
GSK
32/39kDa antigens
AS01 adjuvant.
First time in man February 2004
In Phase IIa in South Africa and The Gambia
Antigen-specific CD4+ T cell responses
Von Eschen et al, 2009 10

11. Booster vaccines: SSI fusion proteins
Hybrid 1 (ESAT6/85B)
IC31 novel adjuvant
First time in man November 2005
Confounds diagnostic tests
HyVac 4 (TB10.4/85B)
Phase I in Europe complete
Phase I/IIa in South Africa ongoing
Hybrid 56 (ESAT6/85B/Rv2660)
Phase I underway in South Africa
Van Dissel et al, 2010

12. Booster vaccines: Aeras 402
Ad35-85A,B,TB10,4
Aeras/Crucell
First time in man Oct 2006
Phase I/IIa study in South Africa complete
High antigen-specific CD8+ T cell responses
Phase IIb in infants underway
Abel et al, AJRCCM 2010

13. MVA85A BCG - MVA85A regimen Modified vaccinia Ankara (MVA)
Poxvirus
No replication in mammalian tissues
Good T cell boosting vector
Excellent safety record
M.tb antigen 85A
Mycolyl transferase
Major target antigen
Protective in small animals
In all environmental mycobacteria
Doesn’t interfere with new diagnostic tests
BCG - MVA85A regimen 13

14. MVA85A can improve BCG induced protection in preclinical animal models
MICE
NHP
Goonetilleke et al, JI 2003
Verreck et al, PLoS ONE 2009
GUINEA PIGS
CATTLE
Williams et al, I&I 2005
Vordermeier M et al, I&I 2009

15. Summary of clinical trials with MVA85A since 200215

16. MVA85A is highly immunogenic in UK trials
Pre-MVA85A
Wk 1
Wk 2
Wk 8
Wk 24
McShane H et al, NM 2004
Beveridge N et al, EJI 2007
Sander C et al, AJRCCM 2009
Minassian A et al, BMJ Open 2011

17. 100 miles

18. MVA85A is immunogenic in South African trials
Hawkridge A et al, JID 2008
Scriba T et al, EJI 2010
Scriba T et al, JID 2011

19. Co-administration of MVA85A with EPI vaccines reduces MVA85A immunogenicity in Gambian infants
MVA85A + EPI
3 groups of infants:
EPI alone
EPI + MVA85A
MVA85A alone
MVA85A alone
Ota et al, STM 2011

20. Infant Phase IIb efficacy trial
Objectives:
Safety
Immunogenicity
Efficacy (against disease & infection)
Immune correlates
Design:
BCG vaccinated infants in Worcester, South Africa
Randomised at weeks to receive either:
MVA85A (1 x 108pfu)
placebo (Candin)
Sample size = 2784 (1392/arm)
Cumulative TB incidence of 3%
90% power to detect 60% improvement over BCG alone
Status
Fully enrolled
2 DSMB reviews
Due to unblind in Q4 2012 20

21. Trials in HIV-infected adults
TB010
TB011
TB019
Location
Oxford, UK
Worcester,
South Africa
Dakar, Senegal
Dose
10 with 5x107 pfu
10 with 1x108 pfu
5x107 pfu
1x108 pfu
Participants
M. tb coinfected 20 4 36 15 24 17
CD4 count
>350
>300
Viral load
<100,000
Not specified
ARV treatment? No
24 – No
12 – Yes
Group 1 (n=12) : No
Group 2 (n=12) : Yes
Second dose?
Group 1 at 12 months
Group 2 at 6 months
Check how many Mtb infected

22. HIV safety data No effect on HIV RNA load No effect on CD4 count
AE profile as in HIV- subjects
No evidence of immune activation
No effect of MVA85A on CCR5 co-receptor expression
No change in unstimulated serum beta-chemokines
No higher levels of HIV gag DNA in Ag85A-specific cells than in CMV-specific cells
No evidence for bystander activation following MVA85A vaccination
Minassian et al, BMJ Open 2011

23. A second MVA85A at 12 months enhances duration and magnitude of immunity in HIV-infected subjects
* P < 0.05
Summed peptide pool responses
Single peptide pool responses * * * * * *
Dieye et al, unpublished data

24. Vaccine induced immune responses higher in subjects on ARVs
Single peptide pool responses
Summed peptide pool responses
P<0.0138 ns
P=0.0029
P=0.0027
P<0.0001
P=0.0024
P=0.0002
P=0.0003
Put p values in
Dieye et al, unpublished data

25. Phase IIb trial in HIV+ adults
Proof of concept study in HIV+ adults
protection against TB disease and M. tb infection
safety & immunogenicity
immune correlate samples stored
Two sites
South Africa: Cape Town (Robert Wilkinson)
Senegal: Dakar (Souleymane Mboup)
Design:
HIV-infected adults +/- ARV
1400 subjects randomised to receive either:
2 doses of MVA85A, 6-9 months apart or
2 doses of placebo (candin)
Annual incidence assumed to be 2.5%
80% power to detect 60% improvement
Follow-up for 2 years
Status:
Enrolment commenced August 2011

26. Progress 14 vaccines evaluated in clinical trials
Two vaccines being evaluated in efficacy trials
No immunopathology issues identified in any clinical trials to date

27. Challenges No immunological correlate No validated animal models
Difficulty with end-points
Finite capacity to do efficacy testing

28. Acknowledgements

29. Funders and partners Oxford Emergent Tuberculosis Consortium
European Commission
Study participants 29