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

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Presentation on theme: "Thoughts about Development of HIV and HCV Gene-Based Vaccines Britta Wahren Karolinska Institutet St Petersburg April 2012."— Presentation transcript:

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 C B E B C B B B A BA A D OtherB A Other A B C Others 5% (F, G, H, J, NT) D 5.3% C C 47.2% E E 3.2% B B 12.3% A A 27% Geographical distribution of 35 million HIV-1 genetic subtypes UNAIDS 2005-2012

4 HIV vaccines for humans Vaxgen phase III Sanofi-Thailand Gp160 protein B Alvac boost B HIV proph Immunogenic, No protection Moderate NIH, VRC IDNA ABC high dose and adeno HIV prophHigh response similar to HIVIS Merck I, II Phambili Adenovector, clade B HIV prophOver 70% resp No protection GeovaxDNA B followed by poxvirus B HIV prophProtection in macaques EurovaccDNA+Nyvac CHIV prophHigh env response KI/SMI-HIVISDNA ABC high dose, MVA boosts A, B, C, (D), E HIV prophHigh (100%) broad immunogenicity

5 Concepts for HIVIS vaccine Containing DNA genes and a vaccinia 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


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

9 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???

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

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

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

13 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

14 01 Months 39 Swedish HIV DNA vaccine US poxvirus based HIV vaccine HIV-genes Vaccination schedule Karolinska Institutet, Smittskyddsinstitutet, Södersjukhuset, US Army, Muhimbili University, SIDA, EU Late boost

15 IFN-g ELISpot reactivity im/id ** Many responses, ID more responders than IM Bakari et al 2011

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

17 3 years broad memory response after 1 or 2 HIV-MVA (n=42) Two weeks after the 1 st HIV-MVA vaccination (n=30) Two weeks after the 2 nd HIV-MVA vaccination (n=27) 30/40 reactive27/38 reactive Tcell reactivity best after 1st boost Bakari et al 2011

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

19 p = <0.0001 Antibody to gag

20 p = 0.0149 p = 0.9103 Antibody to RT

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

22 Vaccination against many strains of HIV E A 9% D 6% C 30% AC 34% CD 6% ACD 6% AD 9% TANZANIA

23 Acknowledgements: The volunteers 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 Karolinska/SöS Eric Sandström Bo Hejdeman Lars Eriksson Walter Reed Army Institute of Research Josephine Cox Mary Marovich Nelson Michael Merlin Robb Deborah Birx Richard Stout Pontus Blomberg Jenny Enger NIH/NIAID Bernard Moss Patricia Earl Members of the AVIP Consortium University of Munich Volker Erle Georg Gasteiger ISS, Rome Barbara Ensoli Bambino Gesú Paolo Rossi Paolo Palma MUHAS, Dar es Salaam Muhammad Bakari Eligius Luyamuya CytoPulse Richard Walters Anna-Karin Roos Cellectis Julia Berretta Alan King Carole Desseaux Nils Carlin Staffan Pauli Bartek Zuber Kopek Nihlmark Europrise Robin Shattock Natasha Polyanskaya

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