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 about 150,000 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

Year Incidence/million/yr Elimination 16%/yr Global Plan 6%/yr Current trajectory 1%/yr Full implementation of Global Plan: 2015 MDG target 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

Predicted impact of new TB vaccine Young and Dye Cell 124:683-7

Calmette & Guérin developed the only available TB vaccine: BCG ( ) 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) StatusProductsProduct Description [Citations]SponsorsIndicationType of VaccineTarget Populations Phase III Mw [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 Vectored BCG-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, AerasViral Vectored BCG-vaccinated infants, children and adults Phase II M72 + AS01 Recombinant protein composed of a fusion of Mtb antigens Rv1196 and Rv0125 & adjuvant AS01 [14-17] GSK, AerasRecombinant 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 ProteinAdolescents; adults VPM 1002 rBCG strain expressing listeriolysin and carries a urease deletion mutation [23-27] Max Planck, Vakzine Projekt Management GmbH, TBVI Recombinant Live – RUTIFragmented 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, TBVIRecombinant ProteinAdolescents, adults Hybrid 56 + IC31 Adjuvanted recombinant protein composed of Mtb antigens 85B, ESAT-6 and Rv2660 [41-42] SSI, Aeras, Intercell Recombinant ProteinAdolescents, 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 ProteinInfants 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-422 Recombinant BCG expressing mutated PfoA and overexpressing antigens 85A, 85B, and Rv3407 [9-10, 52] Aeras Recombinant LiveInfants rBCG30 rBCG Tice strain expressing 30 kDa Mtb antigen 85B [53-57] UCLA, NIH, NIAID, AerasRecombinant Live Newborns, adolescents, and adults M. smegmatisWhole 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 No new preventive TB vaccines in clinical trials 1st preventive vaccine 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 I Geneva 2001 Blueprint I 1998 Past Decade of Progress Global Forum II Estonia 2010 Annecy “Out of Box” Vancouver, Keystone TB Les Diablerets, TBVAC Advocacy StopTB WG Blueprint II March to 2020 Next Decade of Progress Phase III trials of preventive vaccines One new TB vaccine introduced Correlate of vaccine immunity established Novel vaccines for all populations developed Resources obtained that match need Global Forum III Cape 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 20 th – 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 20 th – March 20 th /21 st – Congressional briefings in Washington, DC – March 22 nd – TBVI Event in Brussels Companion piece developed for distribution to broader audiences 3 rd Flobal Forum on TB Vaccines (March 2013, Cape Town) structured to address key challenges in Blueprint (

Thanks We 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 The following who contributed directly to the content of the Blueprint. Erna Balk, TBVI, Lelystad, The Netherlands Lewellys Barker, Aeras, Rockville, United States of America Jerrold Ellner, Boston University and Boston Medical Center Boston, USA Bernard Fourie, University of Pretoria, Pretoria, South Africa Luc Hessel, TBVI, Lelystad, The Netherlands Stefan Kaufmann, Max Planck Institute for Infection Biology, Berlin, Germany Melody Kennell, Aeras, Rockville, United States of America Hassan Mahomed, University of Cape Town, Cape Town, South Africa Tom Ottenhoff, Leiden University Medical School, Leiden, The Netherlands Joris Vandeputte, TBVI, Lelystad, The Netherlands Barry Walker, National Institute for Biological Standards and Control, Potters Bar, UK Jennifer Woolley, Aeras, Rockville, United States of America

Thanks The 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, Chair Ulrich Fruth, WHO & Jennifer Woolley, Aeras, Secretarat Michael Brennan, Aeras Jelle Thole, TBVI Hassan Mahomed, SATVI Susanne Verver, KNCV Peggy Johnston, Jan Gheuens, Peter Small, Bill & Melinda Gates Fdn Christine Sizemore, NIAID, NIH Robert Nakibumba, Community Representative, Working Group on New TB Vaccines TASO Uganda Lucy Ghati, The National Empowerment Network of People Living with HIV/AIDS (NEPHAK), Kenya Christian Lienhardt, StopTB Partnership Dave Lewinsohn, Oregon Health and Sciences University Didier Lapierre, GSK Biologicals