TBVI Symposium TB Vaccines and Immunity MTBVAC, an update

Transcription

1 TBVI Symposium TB Vaccines and Immunity MTBVAC, an update Eugenia Puentes, Biofabri Annual TBVAC 2020 Meeting, 1 st 5 th February 2016, Les Diablerets

2 CONSTRUCTION OF MTBVAC Derived from a clinical isolate of M.tuberculosis (Euro-American lineage) FULFILLING 2005 Geneva Consesus Criteria: Two Independent Stable Deletion Mutations without Antibiotic Resistance Markers FROM SO2 TO MTBVAC: CONSTRUCTION STEPS Negative PDIM & PhoP Phenotypes

3 SCHEMATIC REPRESENTATION OF THE PHENOTYPIC DIFFERENCES BETWEEN MTBVAC AND WILD-TYPE M. TUBERCULOSIS M. tuberculosis MTBVAC ( phop fadd26) PDIM DAT PAT SL LAM secretion systems ESAT-6 Ag85 complex Gonnzalo-Asensio, J, N Aguilo & C Martin. Investigación y Ciencia Oct 2014

4 ATTENUATION PRECLINICAL STUDIES FROM SO2 TO MTBVAC Based on Douglas Young Roadmap : BalbC/ IT SCID Aerosol / IV SC 50 dose 6 Months C57/BL6 in H37Rv Aerosol Low dose High dose H37Rv NHP IT Erdman C57/BL6 aerosol Protection Transgenic p25 Ag85B Memory T cells PROTECTION IMMUNOGENICITY Perez et al Mol Micro 2001, Williams et al Tuberculosis 2005, Martín et al Vaccine 2006, Aguilar et al CEI 2007, Cardona et al Vaccine 2009, Verreck et al PLOs ONE 2009, Nambiar et al Eur J Immunology 2012

5 INDUSTRIAL AND CLINICAL DEVELOPMENT STATUS Preclinical Studies Phase Ia (adults) Phase Ib (adults and newborns) MTBVA transferred to BIOFABRI 23 JUL 08 Stability data GMO and IMP Authorization Process development cgmp of MTVAC Characterization & QC release of final product Manufacturing facility Design, Construction & Validation

6 INDUSTRIAL DEVELOPMENT ( ) Consistent Production process with satisfactory yields (> 20 pilot batches, 3000 vials) 1,0E+08 Stability data from GMP batches to support a shelf life > 24 months stored at C 1,0E+07 1,0E+06 1,0E+05 1,0E+04 1,0E+03 1,0E+02 1,0E ,0E Product ready to scale up

7 INDUSTRIAL DEVELOPMENT: NEW MANUFACTURING FACILITY AEMPS GMP Authorisation (Jan. 2016) Final Product Full Process and QC Validation

8 PHASE I DOUBLE BLIND, RANDOMIZED CONTROLLED, DOSE-ESCALATION STUDY TO EVALUATE THE SAFETY AND IMMUNOGENICITY OF MTBVAC IN COMPARISON WITH BCG IN ELISPOT TB (ESAT-6, CFP10, PPD) AND HIV-NEGATIVE VOLUNTEERS NCT Trial Center: Centre Hospitalier Universitaire Vaudois (CHUV) Principal Investigator: Francois Spertini Sponsor: BIOFABRI, S.L. TBVI Call: TBVI MTBVAC

9 PHASE I IN LAUSANNE VACCINATION AND SAFETY FOLLOW-UP Jan Mar May Jul Sept Nov Jan Mar May Jul Sept Nov 2015 Jan Mar First vaccination 23 Jan 13 Cohort 1 MTBVAC 5x10 3 /0.1ml n= 9 BCG SSI 5x10 5 /0.1ml n= 3 Months End of active follow-up 6 Jun 2014 End of passive follow-up 5 Nov 2014 Final data report Q2, 2015 ID inj. 23 Jan 13 1 Apr 13 DSMB 10 Apr 13 Cohort 2 MTBVAC 5x10 4 n=9 BCG SSI 5x10 5 n= 3 ID inj. 15 Apr Jun 13 DSMB 15 Jul 13 Cohort 3 MTBVAC 5x10 5 n=9 BCG SSI 5x10 5 n= 3 ID inj. 24 Jul 13 6 Nov 13 BMGF TBVI010-02

10 PHASE I IN LAUSANNE PRIMARY ENDPOINT: SAFETY Acceptable safety profile, with similar reactogenicity to BCG SECONDARY ENDPOINTS: IMMUNOGENICITY ELISPOT Negative IGRA tests 7 months after MTBVAC immunization (A transient increase in CFP-10 specific IFN-g response over the limit of positivity in two subjects from MTBVAC 5x10 4 and in one subject of MTBVAC 5x10 5 at day 28) key element for progressing MTBVAC to efficacy and prevention of sustained infection trials. WBA MTBVAC demonstrated promising immunological properties with dose-response dependent induction of polyfunctional CD4 T-cells expressing at least one cytokine (IFNg +, TNFa +, IL-2 + ). Compared to BCG, MTBVAC 5x10 5 group induced greater magnitude response in terms of IFNg+, IL-2+, and 3 cytokines+ polyfunctional T-cell. A higher number of responders were observed after MTBVAC vaccination with a peak at D28. Spertini et al 2015 Lancet Respiratory Medicine

11 Target population as prime in newborns Phase Ia and 1b Safety /Immunogenicity in Adults Safety/ Immunogenicity in neonates in endemic areas Phase II a Safety /Immunogenicity Dose selection Phase II b POC Trial IMPROVED EFFICACY OVER BCG

12 MTBVAC PHASE IB (ENDEMIC COUNTRY) A randomized, double blind, dose-escalation clinical trial of the safety, reactogenicity and immunogenicity of three doses of MTBVAC compared to BCG Vaccine SSI, in newborns (HIV-negative mothers and with no household contacts of TB) living in a tuberculosis endemic region with a safety arm in adults Trial Center: South African Tuberculosis Vaccine Initiative (SATVI) University of Cape Town Principal Investigator: Michelle Tameris Sponsor: BIOFABRI, S.L. TBVI Call: TBVI NORAD Grant SATVI-AERAS-DFI Grant

13 MTBVAC Phase Ib (endemic country) Double blind, controlled, randomized, dose-escalation study in neonates born to HIV negative mothers with a initial safety arm in adults Global injection schedule and safety and immunogenicity follow up First vaccination Oct 15 MTBVAC 5x10 5 n=9 BCG x10 5 n=9 Months End of study ID inj. Adults arm DSMB 1 Feb 16 MTBVAC 2,5x10 3 n=9 BCG x10 5 n=3 ID inj. Neonates Cohort 1 MTBVAC 2,5x10 4 n=9 BCG x10 5 n=3 ID inj. Neonates Cohort 2 MTBVAC 2,5x10 5 n=9 BCG x10 5 n=3 ID inj. Neonates Cohort 3 BCG dose rescue

14 PHASE IB IN SOUTH AFRICA: SAFETY ARM IN ADULTS Adults stage - Detailed injection schedule and safety follow up Days MTBVAC 5x10 5 /0.1ml; n=9 BCG 5x10 5 /0.1ml; n=9 D0 D7 D14 D28 D56 D90 D180 Vac. Inj Safety follow up D28-D56 SAFETY AND REACTOGENICITY IN HEALTHY BCG VACCINATED, HIV -ve, QFT -ve, ADULTS Adult stage, 9 participants from each group will be vaccinated with the highest dose of MTBVAC or BCG SSI standard human dose Acceptable safety profile

15 Target population as booster in BCG vaccinated adolescents and Young adults Phase Ia /Ib Safety /Immunogenicity in Adults Safety in Adults in endemic areas Y Phase II a Dose finding study in both QTF + and QTF individuals from endemic areas. Safety /Immunogenicity Phase II b POC Trial Prevention of sustained infection

16 Grupo de Genética de Micobacterias Prof. Carlos Martín Dr. Ainhoa Arbués Dr. Jesús Gonzalo Asensio Dr. Juan Ignacio Aguiló Dr. Dessi Marinova Ana Belén Gómez Santiago Uranga Carmen Arnal Luis Solans Bernad Dr. Jelle Thole TBVI PDT Dr. Georges Thiry Dr. Micha Roumiantzeff Dr. Barry Walker Dr. Mei Mei Ho Dr. Eddy Rommel Dr. Brijesh Patel TBVI CDT Prof. Juhani Eskola Dr. François Spertini Dr. Roland Dobbelaer Dr. Luc Hessel Dr. Bernard Fritzell Dr. Emmanuélle Gerdil Dr. François Spertini Dr. Reza Chakour Dr. Olfa Karoui Dr. Régine Audran Dr. Laure Valloton Prof. J.D. Aubert Esteban Rodríguez Oswaldo Alvarez Dr. Conchita Fernández Dr. Eugenia Puentes Dr. Alberto Parra Dr. Juana Doce DSMB Phase Ia and Ib Prof. Paul-Henri Lambert Dr. Hassan Mahomed Dr. Jaap Van Dissel Dr. D.J. Lewis Dr. Francois Spertini Dr. Brial Eley Dr. Mark Hatherill Dr. Michelle Tameris Prof. Tom Scriba Dr. Helen Mearns