TBVAC2020. Advancing novel & promising TB vaccine candidates from discovery to preclinical/early clinical development

Transcription

1 TBVAC2020 Advancing novel & promising TB vaccine candidates from discovery to preclinical/early clinical development Défis Scientifiques et Economiques du Développement de Vaccins pour les Pays du Sud Paris 2-3 Dec 2015

2 TBVAC2020 TBVAC2020 (H2020) NEWTBVAC (FP7) TBVAC (FP6) TB Vaccine Cluster (FP5)

3 TBVAC ( ) 4 vaccine candidates from discovery to preclinical 4 vaccine candidates tested in clinical phase I to II trials Identification of 15 candidate biomarkers Development of 3 adjuvant molecules Centralised preclinical animal models with calls to select candidates Capacity building, 2 sites for clinical trials >90 publications & >10 International Patents

4 NEWTBVAC ( ) 40 TB vaccine approaches supported 22 vaccine candidates from research to discovery 6 vaccine candidates from discovery to preclinical 4 vaccine candidates to clinical Phase I 15 candidate biomarkers further characterized & validated Identification of 18 novel candidate biomarkers > 110 publications

5 TB vaccine pipeline Discovery Preclinical Phase I Phase IIa Phase IIb Approximately 20 novel TB vaccine strategies in development, several R&D partners, TBVI HBHA Institut Pasteur Lille, Aeras, TBVI ChAdOx1.85A- MVA.85A University of Oxford, TBVI VPM1002* VPM, Germany MVA85A /Aeras-485 University of Oxford, Aeras rbcgδzmp1 University of Zurich, Aeras, TBVI MTBVAC Biofabri, University of Zaragoza, TBVI H1 + 1C31 SSI, Valneva, EDCTP M72 + ASO1E GSK, Aeras H64 + CAF01 SSI, TBVI Aerosolised MVA85A* University of Oxford, Aeras, TBVI H56 : IC31 SSI, Valneva, Aeras ChAdOxPPE15 * University of Oxford, TBVI Ad5 Ag85A McMaster University, Can Sino H4 : IC31 SSI, Sanofi Pasteur, Aeras MTBVAC+ Biofabri, University of Zaragoza, TBVI ID93 + GLA-SE IDRI, Aeras Crucell Ad35 / Aeras402 Crucell, Aeras DAR-901 Dartmouth University, Aeras RUTI Archivel Pharma Crucell Ad35 MVA85A University of Oxford, Aeras, Crucell Vaccine candidates currently supported by TBVI Vaccine candidates formerly supported by TBVI Other global vaccine candidates, not supported by TBVI

6 Most candidates ( 75-80% at the clinical trial stage) are subunit vaccines (i.e. recombinant viral vectors or protein/adjuvant) WCV candidates (i.e. live/dead (r)bcg or (r)mtb) to provide: Broader Ag coverage Natural adjuvanting properties Ease of manufacture To be used for BCG replacement, disease prevention in BCG vaccinated adults, or immunotherapy Safety concerns (rmtb, Geneva Consensus), e.g. BCG::RD1

7 BCG Δzmp1 Zmp1 inhibits: Casp1/Inflammasome & IL1β secretion Phagosome maturation Ag presentation

8 BCG Δzmp1 (mouse studies) Johansen 2011 Clin Vaccine Immunol

9 BCG Δzmp1 (GP studies) Sander 2015 Vaccine

10 TBVAC2020 ( ) Coordinator: TBVI Chair of the Steering Committee: Stefan KAUFMANN Builds on previous consortia + new partners 40 Partners (7 partners outside EU) Diversify the TB vaccine pipeline by introducing innovative approaches Select the most promising candidates by portfolio management Work in partnership (global)

11 How can we innovate the TB vaccine landscape? Head of Steering Committee S. KAUFMANN Diversity of antigens & delivery systems (WP1) O. NEYROLLES Diversity of preclinical models (WP2) F. VERRECK H2H testing in animal models & preclinical development (WP3) A. RAWKINS Clinical development (WP4) H. McSHANE Diversity of biomarkers (WP5) T. OTTENHOFF Portfolio management (WP6) TBVI

12 How can we innovate the TB vaccine landscape? Head of Steering Committee S. KAUFMANN Diversity of antigens & delivery systems (WP1) O. NEYROLLES Diversity of preclinical models (WP2) F. VERRECK H2H testing in animal models & preclinical development (WP3) A. RAWKINS Clinical development (WP4) H. MCSHANE Diversity of biomarkers (WP5) T. OTTENHOFF Portfolio management (WP6) TBVI

13 TBVAC2020 WP1 Discovery Lead Olivier Neyrolles, CNRS, Toulouse, France WP1.1 Novel antigens Lead Steffen STENGER, University of Ulm, Germany WP1.2 Novel delivery systems & immunization strategies Lead Else-Marie AGGER, Statens Serum Institute, Copenhagen, Denmark WP1.3 Novel live vaccines Lead Olivier NEYROLLES, IPBS CNRS/University of Toulouse, France Expected impact: Increase the number of TB vaccine candidates, which can be tested with the same resources thus increasing the chance of discovering an effective vaccine

14 WP1 Global Objectives Identify novel protein & (glyco)-lipid antigens, including cryptic and infection stage-specific epitopes, delivery platforms, innovative adjuvants & live vaccine candidates Down-select candidates based on : (i) safety, (ii) potent recognition by classical & non-classical human lymphocytes in human (latent) Mtb-infection & (iii) protective efficacy in mouse models of pulmonary TB Move promising (combination) vaccines forward to other animal models (GP, NHP) based on TBVI gating criteria

15 WP1.1 Novel antigens Lead Steffen Stenger Partners - 13 partners from Switzerland, Germany, Denmark, France, Belgium, The Netherlands, South Africa, Italy, Australia Objectives - Identify novel antigens and epitopes to be included in novel vectors, adjuvants and live vaccine strains Specific objectives To discover novel epitopes using innovative technologies (e.g. SWATH-MS) To discover novel stage-specific antigens using candidate-based and genomewide expression profiling To evaluate & exploit antibody-mediated protection using patient-derived antibodies and M. tuberculosis mutant library screening To discover & exploit novel lipid and glycoconjugate antigens in vitro & in vivo using innovative tools (e.g. recombinant CD1b, CD1b-Tg mice). Evaluation of vaccination using liposomes & nanoparticle-based technologies

16 Example: Lipid antigen discovery Van Rhijn et al Adv Exp Med Biol Identify CD1b-associated epitopes presented on APCs exposed to different Mtb glycolipid antigens Characterize the full spectrum of (glyco)lipid epitopes naturally presented in the context of CD1b upon infection with Mtb H37Rv Assess the immunogenicity of particular mycobacterial lipid epitopes & determine the phenotype of responsive T cells

17 WP1.2 Novel delivery systems & immunization strategies Lead Else Marie Agger Partners - 13 partners from UK, France, Switzerland, Denmark, Germany, Spain, Belgium, Australia Objectives - Develop novel vaccine vector platforms & adjuvants with a particular focus on strategies inducing humoral mucosal immunity Specific objectives To develop novel viral vector-based delivery platforms (e.g. non-integrative lentiviral vectors, ChAd, LCMV, Influenza) To develop novel nanoparticle-based delivery platforms To develop novel mucosal delivery strategies with live and sub-unit vaccines (e.g. live/inactivated MTBVAC and BCG for pulmonary delivery; novel adjuvants) To develop and exploit novel rationally designed adjuvants (e.g. novel immunomodulators; synthetic glycolipids signalling through C-type lectins; Pam 2 Cysconjugated protein signalling through TLR2 on respiratory epithelium) To evaluate differences between protective preventive and post-exposure vaccines

18 Example: Lentiviral delivery platform Dendritic cells Non replicative, integrative or non-integrative Low/no genotoxicity Very transient persistence of vector DNA in vivo No preexisting anti-vector immunity Large antigens (up to 6 8 Kb) Transduction of non mitotic cells, incl. DCs Promotes CD4, CD8 & B cell immunity Already in clinical trials in other settings Plasmodium (in mice)

19 WP1.3 Novel live vaccines Lead Olivier Neyrolles Partners - 5 from France & Spain Objectives - Improve MTBVAC; improve a promising candidate identified in NEWTBVAC (MTB Beijing-derived); generate a limited number of novel M. tuberculosis- and BCG-derived live vaccine candidates based on strong scientific rationale, in order to improve safety and/or protective efficacy Specific objectives To generate novel safer MTBVAC-based candidates using Tn mutant library screening in vivo To generate novel safer MTB Beijing-based candidates through gene inactivation To develop a novel Δpe/ppe M. tuberculosis live vaccine candidate To develop autophagy-prone BCG strains as novel live vaccines using recombinant autophagy-inducing technology To develop novel safer BCG strains based on inducibe toxin systems

20 Example: Autophagy-prone BCG Autophagy enhances the efficacy of vaccination, incl. against M. tuberculosis (Nat Med 2009, Vaccine 2013, Science 2014, Vaccine 2014) FDA-approved autophagy inducer drugs BCG Recombinant BCG secreting autophagy-inducing peptides BCG Autophagy Antigen presenting cells peptide Autophagy Enhanced vaccine immunogenicity & protection

21 How can we select better candidates? Prioritisation based on rational assessment of likely efficacy Independent selection committee (PMC/GTBVP) (WP6) Preclinical models that resemble infection in humans (WP2) Independent head-to-head animal testing (WP3) Independent phase I clinical testing (WP4)

22 Thank you! R. AEBERSOLD, Zurich P. SANDER, Zurich S. KAUFMANN, Berlin P. ANDERSEN, Copenhagen C. LOCHT, Lille F. MASCART, Brussels R. BROSCH & P. CHARNEAU, Paris T. OTTENHOFF, Leiden A. SIGAL, Durban R. NISINI, Roma O. NEYROLLES & other PIs, Toulouse S. STENGER, Ulm G. DE LIBERO, Basel W. BRITTON, Sydney H. MCSHANE, Oxford D. PINSCHEWER, Basel C. MARTIN, Zaragoza C.A. SIEGRIST, Geneva Y. PERRIE, Birmingham K. HUYGEN, Brussels M. BAIRD, Bangor J. GROOTEN, Gent