Global progress in tuberculosis vaccine development

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)
• gt 70 with infectious TB will be diagnosed
• gt85 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
• lt1/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

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)

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)

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 ?
• TNF
• Probably important
• CD8 T cells
• ?d T cells
• CD-1 restricted T cells
• IL-17
• Il-2
• Probably not a major role
• B cells and antibodies

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
• ?ureC 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• Now withdrawn for safety reasons

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
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

• 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
• Doesnt interfere with new diagnostic tests

BCG - MVA85A regimen
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
Vordermeier M et al, II 2009
Williams et al, II 2005
15
Summary of clinical trials with MVA85A since 2002
16
MVA85A is highly immunogenic in UK trials
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
MVA85A alone

• 3 groups of infants
• EPI alone
• EPI MVA85A
• 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 18-26 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

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 gt350 gt300 gt300
Viral load lt100,000 Not specified lt100,000
ARV treatment? No 24 No 12 Yes Group 1 (n12) No Group 2 (n12) Yes
Second dose? No No Group 1 at 12 months Group 2 at 6 months
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 lt 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
Plt0.0138
ns
P0.0029
P0.0027
Plt0.0001
P0.0024
P0.0002
P0.0003
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