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• Aeras 422:– rBCG expressing Ag85A, B and Rv3407– Phase I study commenced in Q1 2011– Now withdrawn for safety reasons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