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Dr. Klaus Reither Swiss Tropical and Public Health Institute AIDS 2014 - Melbourne - 21.07.2014

Safety and immunogenicity of H1/IC31 ® , an adjuvanted TB subunit vaccine , in HIV-infected adults with CD4+ lymphocyte counts greater than 350 cells/mm 3 : a phase II, multi-centre , double-blind , randomized , placebo-controlled trial. Dr. Klaus Reither

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Dr. Klaus Reither Swiss Tropical and Public Health Institute AIDS 2014 - Melbourne - 21.07.2014

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  1. Safety and immunogenicity of H1/IC31®, an adjuvanted TB subunit vaccine, in HIV-infected adults with CD4+ lymphocyte counts greater than 350 cells/mm3: a phase II, multi-centre, double-blind, randomized, placebo-controlled trial Dr. Klaus Reither Swiss Tropical and Public Health Institute AIDS 2014 - Melbourne - 21.07.2014 On behalf of the Aurum102/THYB05 team

  2. Background Tuberculosis: 8.6 million new active TB cases and 1.3 million TB deaths in 2012 (WHO). Urgent need to develop safe and effective TB vaccines to accelerate progress towards TB elimination. Essential to evaluate the safety and immuno-genicityof TB vaccines in HIV-infected persons. Abu Raddadet al, PNAS 2009

  3. Background The H1/IC31 vaccine: recombinant fusion protein Ag85B-ESAT-6 TBvaccine [Hybrid (H1)] , adjuvanted with IC31®

  4. Background

  5. Trial sites Ifakara Health Institute: Bagamoyo, TZ Aurum Institute: Tembisa, SA

  6. Trial design Randomisation H1/IC31 vaccine or placebo was randomly allocated in a 5:1ratio. Blinding The investigators, study monitors and participants were blinded. The study pharmacists prepared the investigational product. Syringes were masked in order to conceal a slight difference in the appearance of the H1/IC31 and placebo.

  7. Trial design Schedule of events (summary) Primary immunogenicity endpoint

  8. Consort diagram Screened (n=167) Excluded (n=119) - Screening failure (n=109) - Withdrawn consent (n=1) - Sleep apnoea, persistent shortness of breath (n=1) - Enrolment closed (n=8) Randomised (n=48) Placebo arm (n=8) Received 1st vaccination (n=8) H1/IC31arm(n=40) Received 1st vaccination (n=40) Received 2nd vaccination (n=8) Received 2nd vaccination (n=39) Did not receive 2nd vaccination (n=1), because of pregnancy Lost to follow-up (2nd vaccination and end of study) (n=0) Lost to follow-up (2nd vaccination and end of study) (n=1) Safety analysis (n=40) Safety analysis (n=8) Samples from TembisaSite did not meet internal quality control standards Immunogenicity analysis (n=4) Immunogenicity analysis (n=20)

  9. Demographic and baseline characteristics

  10. Safety • Local injection site reactions were more common in H1/IC31 versus placebo recipients (65.0% vs. 12.5%, p=0.015) • 3 serious adverse events (malaria, perianal abscess and pregnancy with death of premature child): not related to the investigational product • No effect on CD4+ T cell count and HIV viral load

  11. Immunogenicity - whole blood intracellular cytokine assay H1/IC31 vaccination group (n=20): IFN-γ, TNF-α, IL-2 and IL-17 expressing CD4+ T cells after stimulation with H1 Durable immune response: CD4+ T cell expressing IFN-γ, IL-2 or TNF-α Response independent of CD4 count or QFT status. Data not shown

  12. Immunogenicity - whole blood intracellular cytokine assay H1/IC31 vaccination group (n=20): H1 specific CD4+ T cells expressing any combination of IFN-, TNF- and IL-2 Predominately IFN-γ/TNF-α/IL-2 or TNF-α and IL-2 Poor CD8+ T cells responses. No humoral responses. Data not shown

  13. Conclusions • Safety • H1/IC31was well tolerated and safe in HIV-infected adults, with CD4+ lymphocyte counts greater than 350 cells/mm3, from TB endemic areas. • Similar to safety profiles of previous trials in HIV-uninfected TB-uninfected, BCG vaccinated or latently TB-infected participants. • Immunogenicity • H1/IC31 induced a persistent Th1-immune response with predominately TNF-α and IL-2 co-expressing CD4+ T cells and polyfunctionalIFN-γ, TNF-α and IL-2 expressing CD4+ T cells. • Future clinical TB vaccine development • Multistage vaccine H56/IC31will continue in clinical development, • might prevent acute TB disease as well as re-activation of LTBI. • H1/IC31 data has been and will be used as supportive data. Aagaard C et al., Nat Med. 2011

  14. Acknowledgment Claudia Dauben-berger Nicole Lenz Christian Pohl Katherine L Fielding Hannah Jeffery Benjamin M Kagina Elisabeth J Hughes Willem A Hanekom Thomas J Scriba Sponsor: SSI Peter Andersen Søren T Hoff Peter Bang Ingrid Kromann PI: Gavin J Churchyard Lynn Katsoulis Trevor Beattie Nicolene Gardiner Khadija Said ElirehemaMfinanga Funded by the European Developing Countries Clinical Trials Partnership (EDCTP)

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