Transcript Tuberculosis Screening

Global progress in tuberculosis vaccine
development
Helen McShane
The Jenner Institute
University of Oxford
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
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%)
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)
Other problems with BCG
• Safety in immuno-suppressed
• Contra-indicated in HIV-infected adults
• Risk of disseminated BCG disease in HIVinfected infants
• Change of WHO policy
• Relative balance of risks
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
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
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– Now withdrawn for safety reasons
Attenuated M.tb strains
• Pho p-/- (Martin, Zaragosa)
• Pantothenate auxotroph (Jacobs, HHMI)
• IKE-PLUS (Sweeney et al, NM 2011)
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
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
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
MVA85A
Modified vaccinia Ankara (MVA)
M.tb antigen 85A
Poxvirus
No replication in mammalian tissues
Good T cell boosting vector
Excellent safety record
Mycolyl transferase
Major target antigen
Protective in small animals
In all environmental
mycobacteria
Doesn’t interfere with new
diagnostic tests
BCG - MVA85A regimen
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
Summary of clinical trials with MVA85A since 2002
MVA85A is highly immunogenic in UK trials
Wk 1
Pre-MVA85A
Pre-MVA85A
Wk 1
Wk 2
Wk 2
Wk 8
Wk 8
Wk 24
Wk 24
Number of functions:
McShane H et al, NM 2004
Sander C et al, AJRCCM 2009
Beveridge N et al, EJI 2007
Minassian A et al, BMJ Open 2011
4+
2+
3+
1+
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
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
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
– 2 DSMB reviews
– Due to unblind in Q4 2012
Trials in HIV-infected adults
Location
Dose
Participants
M. tb coinfected
TB010
TB011
TB019
Oxford, UK
Worcester,
South Africa
Dakar, Senegal
5x107 pfu
1x108 pfu
36
15
24
17
10 with 5x107 pfu
10 with 1x108 pfu
20
4
CD4 count
>350
>300
>300
Viral load
<100,000
Not specified
24 – No
12 – Yes
<100,000
Group 1 (n=12) : No
Group 2 (n=12) : Yes
No
Group 1 at 12 months
Group 2 at 6 months
ARV treatment?
No
Second dose?
No
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
A second MVA85A at 12 months enhances duration and
magnitude of immunity in HIV-infected subjects
* P < 0.05
Summed peptide pool responses
6000
Single peptide pool responses
1000
SFCs/million PBMC
5000
SFCs/million PBMC
*
1200
*
4000
3000
*
2000
*
1000
800
*
600
*
400
200
0
0
1)
7(
2)
7(
)
(1
28
)
(2
28
)
(1
84
)
(2
84
Days post vaccination
8
16
)
(1
8
16
)
(2
1)
7(
2)
7(
)
(1
28
)
(2
28
)
(1
84
)
(2
84
8
16
)
(1
8
16
)
(2
Days post vaccination
Dieye et al, unpublished data
Vaccine induced immune responses higher in
subjects on ARVs
Single peptide pool responses
Summed peptide pool responses
6000
4000
2000
P=0.0029
P=0.0027
500
0
iv
e
na
R
V
A
na
iv
e
(0
A
)
R
A
V
R
+
V
na (0)
iv
e
(7
A
)
A
R
R
V
+
V
(7
na
)
iv
e
(2
A
8)
R
A
V
R
+
V
na (28
)
iv
e
(8
A
4
R
V+ )
(8
4)
R
V
ns
1000
0
A
P<0.0138
1500
P=0.0003
(0
)
R
A
V+
R
V
na (0)
iv
e
(7
)
A AR
R
V
+
V
(7
na
)
iv
e
(2
A
8)
R
A
V
R
+
V
na (28
)
iv
e
(8
A
4
R
V+ )
(8
4)
P=0.0002
A
P=0.0024
SFC / 10^6 PBMC
SFC / 10^6 PBMC
8000
P<0.0001
Dieye et al, unpublished data
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
Progress
• 14 vaccines evaluated in clinical trials
• Two vaccines being evaluated in efficacy trials
• No immunopathology issues identified in any
clinical trials to date
Challenges
• No immunological correlate
• No validated animal models
• Difficulty with end-points
• Finite capacity to do efficacy testing
Acknowledgements
Funders and partners
Oxford Emergent Tuberculosis Consortium
European Commission
Study participants