Tuberculosis Vaccines: A strategic blueprint for the next decade

Co-editors: Michael J. Brennan and Jelle Thole

Estimated number of

cases

Estimated number of

deaths 1.45 million(range: 1.2–1.6 million)

8.8 million(range: 8.5–9.2 million)

440,000(range: 390,000–510,000)

All forms of TB

Multidrug-resistant TB (MDR-TB)

HIV-associated TB

1.1 million (13%) (range: 1.0–1.2 million)

350,000(range: 320,000–390,000)

The Global Burden of TB -2010

about 150,000

Estimated TB incidence rates, by country, 2010

TB cases per 100 000

0–24

25–49

50–99

100–299

>=300

No estimate

1/3 of the global population (2 billion) is estimated to be latently infected with TB and at risk of developing the disease later in life

1

10

100

1000

10000

2000 2010 2020 2030 2040 2050

Year

Inc

ide

nce

/mill

ion

/yr

Elimination 16%/yr

Global Plan 6%/yr

Current trajectory 1%/yr

Full implementation of Global Plan: 2015 MDGtarget reached but TB not eliminated by 2050

Elimination target: 1 /

million / year by 2050

TB incidence 10x lower than today, but >100x higher than elimination

target in 2050

Current rate of decline

0

50

100

150

200

250

2010 2020 2030 2040 2050

TB

inci

den

ce/1

00 0

0/yr

neonatal

no intervention

mass vaccination (post-exposure)

mass vaccination(pre-exposure)

A

mass vaccination(dual action)

0

50

100

150

200

250

2010 2020 2030 2040 2050

no intervention

drug treatment

mass vaccination (dual action) + drug treatment

B

mass vaccination(dual action)

periodic mass vaccination (dual action) + drug treatment

Predicted impact of new TB vaccine

Young and Dye. 2006. Cell 124:683-7 L. Abu Raddad et al, PNAS 2009

• Calmette & Guérin developed the only available TB vaccine: BCG (1906-1921)

• BCG reduces risk of severe pediatric TB disease - 40 thousand cases per year

• Protection against adult pulmonary TB, which accounts for most TB worldwide, is poor or variable at best

• Not known to protect against latent infection or prevent reactivation

• High risk of disseminated BCG in HIV positive infants

Why new TB vaccines

6

Global TB vaccine pipeline: 12 in clinical trials

Stop-TB partnership TB vaccine candidates 2009

TB vaccine candidates Tested in Clinical Trials, 2011 (Source: Stop TB Partnership)Status Products Product Description [Citations] Sponsors Indication Type of Vaccine Target Populations

Phase IIIMw [M. indicus pranii (MIP)]

Whole cell saprophytic non-TB mycobacterium [1-3]

Department of Biotechonology (Ministry of Science & Technology, Government of ), M/s. Cadila Pharmaceuticals Ltd.

Whole cell, Inactivated or Disrupted –

Phase IIb

MVA85A/AERAS-485 Modified vaccinia vector expressing Mtb antigen 85A [4-8]

Oxford-Emergent Tuberculosis Consortium (OETC), Aeras

Viral VectoredBCG-vaccinated infants and adolescents; HIV-infected adults

AERAS-402/Crucell Ad35 Replication-deficient adenovirus 35 vector expressing Mtb antigens 85A, 85B, TB10.4 [9-13]

Crucell, Aeras Viral Vectored BCG-vaccinated infants, children and adults

Phase II

M72 + AS01Recombinant protein composed of a fusion of Mtb antigens Rv1196 and Rv0125 & adjuvant AS01 [14-17]

GSK, Aeras Recombinant Protein Adolescents/adults, infants

Hybrid-I+IC31 Adjuvanted recombinant protein composed of Mtb antigens 85B and ESAT-6 [18-22]

Statens Serum Institute (SSI), TBVI, EDCTP, Intercell Recombinant Protein Adolescents; adults

VPM 1002 rBCG strain expressing listeriolysin and carries a urease deletion mutation [23-27]

Max Planck, Vakzine Projekt Management GmbH, TBVI Recombinant Live –

RUTI Fragmented Mtb cells [28-32] Archivel Farma, S.I. Whole cell, Inactivated or Disrupted

HIV+ adults, LTBI diagnosed

Phase I

AdAg85A Replication-deficient adenovirus 5 vector expressing Mtb antigen 85A [33-37] Viral Vectored Infants; adolescents;

HIV+

Hybrid-I+CAF01 Adjuvanted recombinant protein composed of Mtb antigens 85B and ESAT-6 [19-20, 38-40] SSI, TBVI Recombinant Protein Adolescents, adults

Hybrid 56 + IC31 Adjuvanted recombinant protein composed of Mtb antigens 85B, ESAT-6 and Rv2660 [41-42] SSI, Aeras, Intercell Recombinant Protein Adolescents, adults

HyVac 4/AERAS-404,+ IC31

Adjuvanted recombinant protein composed of a fusion of Mtb antigens 85B and TB10.4 [43-46]

SSI, sanofi-pasteur, Aeras, Intercell Recombinant Protein Infants

Phase III[concluded] M. vaccae

Inactivated whole cell non-TB mycobacterium; phase III in BCG-primed HIV+ population completed; reformulation pending [47-51]

NIH, Immodulon Whole cell, Inactivated or Disrupted

BCG-vaccinated HIV+ adults

Phase I [concluded]

AERAS-422Recombinant BCG expressing mutated PfoA and overexpressing antigens 85A, 85B, and Rv3407 [9-10, 52]

Aeras Recombinant Live Infants

rBCG30 rBCG Tice strain expressing 30 kDa Mtb antigen 85B [53-57] UCLA, NIH, NIAID, Aeras Recombinant Live Newborns,

adolescents, and adults

M. smegmatis Whole cell extract – Whole cell, Inactivated or Disrupted –

Why a strategic Blueprint? • Outline the major challenges and key issues for

the next decade and communicate them to broader audience

• Build consensus on key issues• Demonstrate a coordinated approach to TB

vaccine development• Use key challenges and questions in Blueprint as

a rallying point for forming new partnerships • Use issues outlined in Blueprint for soliciting

specific funding from donors.

History of TB Vaccine Development

2000 202 2009 2011

2000 2002 2009 2011

No new preventive TB vaccines in clinical trials

1st preventivevaccine enters

clinical trials (MVA85A)

1st Phase IIb proof-of-concept

of preventive vaccine initiated

15 vaccines studied in clinical trials, 12 were in

clinical trials

Global Forum IGeneva 2001

Blueprint I1998

Past Decade of Progress

Global Forum IIEstonia 2010

Annecy “Out of Box”Vancouver, Keystone TBLes Diablerets, TBVACAdvocacy StopTB WG

Blueprint IIMarch 2012

2011 2012 2013 to 2020

Next Decade of Progress

Phase III trials of preventive vaccinesOne new TB vaccine introduced

Correlate of vaccine immunity establishedNovel vaccines for all populations developed

Resources obtained that match need

Global Forum IIICape Town, 2013

Tuberculosis Vaccines: A Strategic Blueprint for the Next Decade

• A unified global strategy• Renewed, intensified and

well integrated international effort

• Outlining major scientific challenges, critical activities and crucial questions

5 priority areas / 14 critical activities

• Creativity in research and discovery• Correlates of Immunity and Biomarkers

for TB Vaccines• Clinical Trials – Harmonisation and

Cooperation• Rational Selection of TB Vaccine

Candidates• Building Support through Advocacy,

Communications and Resource Mobilisation

Creativity in Research and Discovery

• Identify mechanisms of protective immunity • Introduce new vaccine mechanisms• Facilitate translational research, comparative

preclinical studies and animal models

Correlates of Immunity and Biomarkers for TB Vaccines

• Explore novel approaches to identify correlates of immunity

• Introduce novel assays in efficacy trials to help establish correlates of immunity.

• Identify signatures of vaccine efficacy

Clinical trials: harmonization & cooperation

• Determine TB prevalence and incidence, select trial sites and choose target populations

• Design clinical trials to determine efficacy using better defined clinical endpoints

• Address regulatory, ethical and sustainability issues

Rational selection of TB vaccine candidates

• Establish global criteria for assessing vaccine candidates in clinical studies

• Obtain consensus on criteria to advance new candidates

Building support through advocacy, communications & resource mobilization

• Expand financing • Raise awareness and build

support for the role of new TB vaccines

• Broaden the base of TB vaccine advocates

Implementing the Blueprint• March 20th – Journal Publication Date and Launch

– Global Press Release from Working Group, Aeras, TBVI– Adapted press releases for South Africa and other partners also on March 20– Johannesburg Press Briefing, March 20th

– March 20th/21st – Congressional briefings in Washington, DC– March 22nd – TBVI Event in Brussels

• Companion piece developed for distribution to broader audiences

• 3rd Flobal Forum on TB Vaccines (March 2013, Cape Town) structured to address key challenges in Blueprint (www.tbvaccine2013.org)

ThanksWe are particularly grateful to all the researchers, clinicians, pharmaceutical companies, governmental and non-governmental organizations, donors and other stakeholders who completed survey questions that helped define the key priorities in TB vaccine development and to those who participated in spirited discussions at the TB blueprint meetings held in 2010 and 2011.

The following who contributed directly to the content of the Blueprint.

Erna Balk, TBVI, Lelystad, The NetherlandsLewellys Barker, Aeras, Rockville, United States of America Jerrold Ellner, Boston University and Boston Medical Center Boston, USABernard Fourie, University of Pretoria, Pretoria, South Africa Luc Hessel, TBVI, Lelystad, The NetherlandsStefan Kaufmann, Max Planck Institute for Infection Biology, Berlin, GermanyMelody Kennell, Aeras, Rockville, United States of America Hassan Mahomed, University of Cape Town, Cape Town, South AfricaTom Ottenhoff, Leiden University Medical School, Leiden, The NetherlandsJoris Vandeputte, TBVI, Lelystad, The Netherlands Barry Walker, National Institute for Biological Standards and Control, Potters Bar, UKJennifer Woolley, Aeras, Rockville, United States of America

ThanksThe Blueprint was coordinated by the Stop TB Partnership Working Group on New TB Vaccines with support from the World Health Organization, Bill & Melinda Gates Foundation, Aeras, TuBerculosis Vaccine Initiative, and the EC FP 7 framework programme.

Members of the Stop TB Partnership Working Group on New TB Vaccines Leadership Team

Michel Greco, ChairUlrich Fruth, WHO & Jennifer Woolley, Aeras, SecretaratMichael Brennan, AerasJelle Thole, TBVIHassan Mahomed, SATVISusanne Verver, KNCVPeggy Johnston, Jan Gheuens, Peter Small, Bill & Melinda Gates FdnChristine Sizemore, NIAID, NIHRobert Nakibumba, Community Representative, Working Group on New TB VaccinesTASO UgandaLucy Ghati, The National Empowerment Network of People Living with HIV/AIDS (NEPHAK), KenyaChristian Lienhardt, StopTB PartnershipDave Lewinsohn, Oregon Health and Sciences UniversityDidier Lapierre, GSK Biologicals