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Thoughts about Development of HIV and HCV Gene-Based Vaccines

Thoughts about Development of HIV and HCV Gene-Based Vaccines. Britta Wahren Karolinska Institutet St Petersburg April 2012. DNA vaccines, and electroporation. Licenced, no electroportion West Nile virus for horses Hematopoietic necrosis (rhabdovirus) for salmon

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Thoughts about Development of HIV and HCV Gene-Based Vaccines

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  1. Thoughts about Development of HIV and HCV Gene-Based Vaccines • Britta Wahren • Karolinska Institutet • St Petersburg April 2012

  2. DNA vaccines, and electroporation Licenced, no electroportion • West Nile virus for horses • Hematopoietic necrosis (rhabdovirus) for salmon • Melanoma (tyrosine kinase) for dogs, humans? • Growth factor pigs (gene therapy) Clinical small trials, electroporation • HCV for chronic disease, Sällberg et al SE • Prostate heterologous antigen Pisa et al at SE • CEA heterologous and homologous antigen for gi cancer Mellstedt et al SE • HIV for healthy individuals, Ho et al US and CH • HIV for healthy individuals, Wahren et al SE

  3. A B B B B A C B B Other Other E C B A A D A E 3.2% Others 5% (F, G, H, J, NT) D 5.3% A27% C C47.2% B 12.3% Geographical distribution of 35 million HIV-1 genetic subtypes UNAIDS 2005-2012 B

  4. HIV vaccines for humans

  5. Concepts for HIVIS vaccine Containing DNA genes and avaccinia virus vector Whole genes to cover polymorphic MHC in humans All genes to cover structural and regulatory genes Several subtypes to cover virus variability and polymorphic MHC in humans Small total vector size Effective delivery, divided delivery General: whole genes representing several proteins For antibody surface antigens, for cmi interior, less variable antigens (genes, VLP, proteins, vectorized genes)

  6. Vaccine DNA clinical studies …-2005-2012 Prophylactic vaccination Phase 1 SE done HIVIS-EU, SIDA, KI, WR Phase 1 TZ done, HIVIS-EU, SIDA, WR Phase 2a TZ and Mocambique TaMoVac 1, SIDA, EDCTP and Gates Phase 2a TC and MC with EDCTP TaMoVac 2 (electroporation) Phase 1 SE, electroporation-Cellectis, id-Zetajet Phase 1 SE 3rd gen. DNA-MVA-protein gp140 Therapeutic vaccination Phase 1 mab antibody repeatedly SE Phase 3 high dose anti-HIV at birth, Uganda Phases 1/pilot studies, early antigens nef, rev, tat SE Phase 1 therapeutic SE AVIP, Dermavir Phase 1 therapeutic in children, IT

  7. p37 gag A gp160 env A p37 gag B gp160 env B RTmut B gp160 env C rev B The HIVIS plasmids. Subtypes Gp41, gp120 additional subtypes

  8. Traps • Too little protein for antibody • Delivery not optimal (intracellular) • Too few immunizations • Autoimmunity, carcinogenesis • Failed innate activation • Incorrect or not optimal cytokines • Must be delivered with drugs???

  9. Injections Biojector im id spacer Left arm: Env/rev, 3 inj +/- GMCSF sc (needle) Left arm: Env/rev, 1 inj +/- GMCSF im Right arm: Gag/RT, 1 inj Right arm: Gag/RT, 2 inj

  10. HIVIS – The Biojector Does needle free intradermal delivery of vaccine plasmids induce potent responses against vaccine antigens?

  11. 2x450V Voltage 8x110V Time Total length of pulse-train: 0,27 seconds Cellectis In vivo electroporation

  12. The HIVIS DNA vaccine, represents subtypes A, B, C Vial 1 Envelope and rev plasmids Vial 2 gag and RT plasmids Vaccine intramuscularly delivered Vial 1 in the left arm, Vial 2 in the right

  13. Vaccination schedule Late boost 3 9 Months 0 1 HIV-genes Swedish HIV DNA vaccine US poxvirus based HIV vaccine Karolinska Institutet, Smittskyddsinstitutet, Södersjukhuset, US Army, Muhimbili University, SIDA, EU

  14. IFN-g ELISpot reactivityim/id * * Many responses, ID more responders than IM Bakari et al 2011

  15. Broad persistent immune responses HIVIS03, Tanzania Broad responses to several subtypes Bakari et al 2011

  16. 3 years broad memory response after 1 or 2 HIV-MVA (n=42) 30/40 reactive 27/38 reactive Two weeks after the 1st HIV-MVA vaccination (n=30) Two weeks after the 2nd HIV-MVA vaccination (n=27) Tcell reactivity best after 1st boost Bakari et al 2011

  17. p = <0.0001 p = <0.0001 Antibody to env Antibody best after 2nd boost

  18. p = <0.0001 p = <0.0001 Antibody to gag

  19. p = 0.0149 p = 0.9103 Antibody to RT

  20. Build on previous knowledge in clinical trials 1-Prime DNA only, cellmediatedreponse ABC: Gp150env A, B, C, Gag A, B, RTdelPRi 2-Boost vectors and/or peptide/proteins, antibody and cellmediatedreponses A_E: MVA-CMDR env E gagRT A A, E:Drep env gp150 E C: NYVAC C B: ANRS peptides C: Gp140 CN54 protein

  21. A SE8891 SE6594 TH253 UG037 97TZ02 CM240 KEQ23 CAR402 A AD MSC4057 DJ264 D p2911 DJ263 ACD p1795 IbNG 9% 9% TM7808 SE7812 100 6% 6% U CAM5288 CD 100 83CD003 6% 100 100 94 BFP90 C H VI991 100 95ML8 100 AC 99 CF056 100 Z321 VI997 98 30% G6165 100 G 100 NG083 100 34% 93IN999 100 HH8793 C BR025 100 100 ETH2220 100 CY032 100 100 100 GR11 NDK GR84 100 ELI D 100 Z2Z6 SE9173 RF LAI SE9280 J CAM1 MP535c B CAM5365 EGTB117 F9363 K MP255 VI850 MP257 F F2 Vaccination against many strains of HIV E TANZANIA

  22. Acknowledgements: The volunteers Walter Reed Army Institute of Research Josephine Cox Mary Marovich Nelson Michael Merlin Robb Deborah Birx SMI/KI Britta Wahren Andreas Bråve David Hallengärd Margaret Liu Karl Ljungberg Gunnel Biberfeld Jorma Hinkula Erik Rollman Gunnel Engström Kristian Hallermalm Lindvi Gudmundsdotter Andreas Boberg Susanne Johansson Anne Kjerrström Maria Isaguliants Charlotta Nilsson Katarina Karlén Pontus Blomberg Jenny Enger Nils Carlin NIH/NIAID Bernard Moss Patricia Earl Richard Stout CytoPulse Richard Walters Anna-Karin Roos Cellectis Julia Berretta Alan King Carole Desseaux Members of the AVIP Consortium University of Munich Volker Erle Georg Gasteiger ISS, Rome Barbara Ensoli Bambino Gesú Paolo Rossi Paolo Palma Karolinska/SöS Eric Sandström Bo Hejdeman Lars Eriksson MUHAS, Dar es Salaam Muhammad Bakari Eligius Luyamuya Staffan Pauli Bartek Zuber Kopek Nihlmark Europrise Robin Shattock Natasha Polyanskaya

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