Global progress in tuberculosis vaccine development
description
Transcript of Global progress in tuberculosis vaccine development
Global progress in tuberculosis vaccine development
Helen McShaneThe Jenner InstituteUniversity 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 HIV-
infected 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• Aeras 422:– rBCG expressing Ag85A, B and Rv3407– Phase I study commenced in Q1 2011– Now withdrawn for safety reasons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
Modified vaccinia Ankara (MVA)PoxvirusNo replication in mammalian tissuesGood T cell boosting vectorExcellent safety record
M.tb antigen 85AMycolyl transferaseMajor target antigenProtective in small animalsIn all environmental
mycobacteriaDoesn’t interfere with new
diagnostic tests
MVA85A
BCG - MVA85A regimen
MVA85A can improve BCG induced protection in preclinical animal models
Vordermeier M et al, I&I 2009
CATTLE
NHP
Verreck et al, PLoS ONE 2009
GUINEA PIGS
Williams et al, I&I 2005
Goonetilleke et al, JI 2003
MICE
Summary of clinical trials with MVA85A since 2002
MVA85A is highly immunogenic in UK trials
McShane H et al, NM 2004
2+
1+
4+
3+
Number of functions:Pre-MVA85A Wk 1 Wk 2 Wk 8 Wk 24
Pre-MVA85A Wk 1 Wk 2 Wk 8 Wk 24
Beveridge N et al, EJI 2007
Sander C et al, AJRCCM 2009 Minassian A et al, BMJ Open 2011
100 miles
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
MVA85A alone
Ota et al, STM 2011
3 groups of infants:• EPI alone• EPI + MVA85A• MVA85A alone
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
TB010 TB011 TB019Location Oxford, UK
Worcester, South Africa
Dakar, Senegal
Dose 10 with 5x107 pfu10 with 1x108 pfu
5x107 pfu 1x108 pfu
Participants M. tb coinfected
20 4
3615
2417
CD4 count >350 >300 >300Viral load <100,000 Not specified <100,000
ARV treatment? No24 – No12 – Yes
Group 1 (n=12) : NoGroup 2 (n=12) : Yes
Second dose? No No Group 1 at 12 monthsGroup 2 at 6 months
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
7(1)
7(2)
28(1)
28(2)
84(1)
84(2)
168 (
1)
168 (
2)0
200
400
600
800
1000
1200
Days post vaccination
SFC
s/m
illio
n PB
MC
7(1)
7(2)
28(1)
28(2)
84(1)
84(2)
168 (
1)
168 (
2)0
1000
2000
3000
4000
5000
6000
Days post vaccination
SFC
s/m
illio
n PB
MC
Summed peptide pool responses Single peptide pool responses
*
**
*
**
* P < 0.05
Dieye et al, unpublished data
Vaccine induced immune responses higher in subjects on ARVs
Summed peptide pool responses Single peptide pool responses
Dieye et al, unpublished data
ARV naive (
0)
ARV+ (0)
ARV naive (
7)
ARV+ (7)
ARV naive (
28)
ARV+ (28)
ARV naive (
84)
ARV+ (84
)0
2000
4000
6000
8000
SFC
/ 10
^6 P
BM
C
ARV naive (
0)
ARV+ (0)
ARV naive (
7)
ARV+ (7)
ARV naive (
28)
ARV+ (28
)
ARV naive (
84)
ARV+ (84
)0
500
1000
1500
SFC
/ 10
^6 P
BM
C
P<0.0001 P=0.0024 P=0.0002 P=0.0003P<0.0138 ns P=0.0029 P=0.0027
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