HIV DNA vaccines for humans

Transcription

1 HIV DNA vaccines for humans Vaxgen phase III Gp160 protein B HIV proph Immunogenic, No protection Sanofi-Thailand Alvac boost B HIV proph Moderate NIH, VRC I DNA ABC high dose and adeno HIV proph High response similar to HIVIS Merck I, II Phambili Adenovector, clade B HIV proph Over 70% resp No protection KI/SMI-HIVIS DNA ABC high dose, MVA boosts A, B, C, (D), E HIV proph High (100%) broad immunogenicity Eurovacc DNA+Nyvac C HIV proph High env response several DNA followed by vaccinia HIV proph

2 Vaccine DNA clinical studies Phase 1 SE done HIVIS-EU, SIDA, KI, WR Phase 1 TZ done, HIVIS-EU, SIDA, WR Phase 2a TZ and Mocambique TaMoVac 1, with SIDA, EDCTP and Gates Phase 2a with EDCTP TaMoVac 2 Phase 1 SE, electroporation-cytopulse, id-biojector In parallell, need to develop next generation Phases 1/pilot studies, early antigens nef, rev, tat Phase 1 therapeutic SE AVIP, Dermavir Phase 1 therapeutic in children, IT

3 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

4 The HIVIS plasmids. Subtypes p37 gag A p37 gag B RTmut B gp160 env A gp160 env B gp160 env C rev B

5 Deliveries HIV DNA vaccine by Biojector/Zetaject Id or im Electroporation id Vector delivery of HIV by Vaccinia MVA-CMDR id or im, high dose

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

7 Divided doses, HIV DNA vaccine Vial 1 Envelope and rev plasmids Vial 2 gag and RT plasmids To avoid antigenic competition, vaccine delivered Vial 1 env in the left, Vial 2 gag in the right arm

8 HIVIS 03 Results after 1 MVA boost

9 ELISpot after 1 MVA Im Low dose 1 mg i.d. priming as good as higher dose 4 mg i.m. Responses against many peptides broad T-cell reactivity Id

10 Env and gag antibody titers after 3 DNA and 2 MVA immunizations, Swedish cohort. RT titers occur, na. Everybody obtains HIV-specific antibody- Volunteer env 2w 2MVA env 1m 2MVA gag 2w 2MVA gag 1m 2MVA N/A N/A N/A N/A N/A 1723 N/A Highest titers Lowest titers

11 Lessons learnt Added potency by heterogenous prime-boost To divide vaccine components Young individuals Route id/im, dose Vaccinia vector immunity minor role for insert immunogenicity Different from preclinical Serology --- electroporation Type of adjuvant---gm-csf, detergents, interleukins? Never give up

12 Safety and immunogenicity of a multigene multiclade HIV-1 DNA plasmid vaccine boosted with heterologous HIV-1 MVA among healthy volunteers in Dar es Salaam, Tanzania M Bakari 1, F Mhalu 1, S Aboud 1*, C Nilsson 2, J Francis 1, M Janabi 1, E Lyamuya 1*, EA Aris 1, J Mbwana 1*, D Buma 1, L Mwanyika 3, B Hejdeman 4, A Bråve 2, M Robb 5, M Marovich 5, N Michael 5, P Earl 6, B Moss 6, B Wahren 2, G Biberfeld 2, K Pallangyo 1, E Sandström 4, for the HIVIS study group. 1 Muhimbili University of Health and Allied Sciences and Muhimbili National Hospital, Dar es Salaam, 2 Swedish Institute for Infectious Disease Control (SMI) and Karolinska Institute (KI), Stockholm, Sweden; 3 Tanzania Police Force; 4 Venhälsan, Karolinska University Hospital, Sweden; 5 US Military HIV Research Program, Rockville, MD, USA and 6 National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH), Bethesda, MD, USA. Presentation to the 5th EDCTP forum, 12 AICC, Arusha, Tanzania, 12 th 14 th October 2009, Paris 2009

13 IFN-g ELISpot reactivity in 34 responders 2 weeks after HIV-1 MVA boost, 100% Any Gag 34 (100%) Any Env 31 (89%) Gag and Env 19 (56%) Gag or Env 26 (76%)

14 CD8+ and CD4+ T-cell IFN-g ELISpot two weeks after HIV- MVA boost in 13 vaccinees Responses to Gag CD8+ CD4+ 9/13 13/13 Responses to Env CD8+ CD4+ 3/11 11/11 CD4+ reactivity 100 %, CD8+ reactivity %, antibody 100 % Gag is a more potent antigen 14

15 To do Characterization of antibodies IgG; binding to epitopes, neutralization (class, ADCC, affinity) IgA Modify DNA env to prime for neutralizing antibodies against conserved epitopes Use old env constructs as backbones Produce modified gp120 + gp41 in human cells react with known neutralization sites Continue to use MVA A_E as boost Nasal DNA boosting of primed volunteers in HIVIS 05 Induction of IgA antibodies? Protein env boosting

16 Therapeutic

17 Exfoliation on large surfaces of skin, direct HIV DNA application in pouches, the Dermavir study, Gudmundsdotter et al 2009

18 Dermavir study, AVIP Immune responses but poor viral control Safe, laborious Vaccine gave good immunogenicity, despite low antigen dose (1 mg id x 6) Enhanced exsisting epitope reactions New vaccine-specific epitope reactions Long drug holiday, median 18 months Decreased viral setpoint in the whole material, including placebo!! No viral reduction by vaccination a disappointment Too few patients recruited?? or just enough Patients recruited too late in disease course? Next study, continuous protection by antiviral drugs

19 WORKING HYPOTHESIS Ongoing, well controlled HIV infection in children aged 4-16 years profs Rossi and Palma, Bambino Gesù, Rome We hypothesize there will be maintenance and increase of immunological benefits obtained with previous successful HAART, and that vaccination may further reduce viral load

20 Acknowledgements: The volunteers SMI/KI Britta Wahren Andreas Bråve 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 Reinhold Benthin Margareta Hagelin Karolinska/SöS Eric Sandström Bo Hejdeman Lars Eriksson Viveca Holmberg SMITTSKYDDSINSTITUTET Swedish Institute for Infectious Disease Control Walter Reed Army Institute of Research Josephine Cox Mary Marovich Nelson Michael Merlin Robb Deborah Birx NIH/NIAID Bernard Moss Patricia Earl Members of the AVIP Consortium University of Munich Volker Erle Georg Gasteiger ISS, Rome Barbara Ensoli Aurelio Cafaro FIT Biotech, Tampere Kai Krohn MUHAS, Dar es Salaam Fred Mhalu Muhammad Bakari Willy Urassa Pontus Blomberg Jenny Enger Nils Carlin Richard Stoutt Novartis Susan Barnett Indresh Srivastava CytoPulse Richard Walters Anna-Karin Roos Staffan Pauli Bartek Zuber

21 HIV vaccines and microbicides PhD education, how it works 20 students in over 20 projects, collaborations between all Europrise groups Registered at home university, follow those rules, works well Stipend/salary of 30000/year, 3 years, rated on collaboration and project Travel, lodging and course participation of both students and tutors arranged by course leaders and paid by Europrise Other courses and conferences, 2-3/student/year Checkpoints: After each course Course arranger around 3000 e/course, also local sponsoring (for school and yearly meetings 4 milj euro for 5 years)

22 Europrise PhD school, Competion for 3-year stipend. 1. Collaborations between over 20 projects 2. Basic and specialized training 3. Learned how to present science as posters, abstracts, talks, how to write articles, grant applications, scientific and review papers. 4. Time for individualized training, accomplishments and additional travel grants 20 stipends, attendees, 5-7 passed PhD examination, 6-7 expected next year Around 20 % students each year can expect to meet aim of 20 graduated Europrise PhD students during 5 years. Collaboration teachers, students, Europrise general works well.

23 Europrise PhD school, course plan 1. Basic virology, immunology KI/Stockholm Nov Mucosal immunology, vector virology KI/Stockholm May Basic and applied immunology, range of methods Imp Coll/St Georges, London Sept Adults clinical trials on site, EP mucosal workshop KI/KUS, Stockholm May 09 Learn teaching and workshop participation 5. Pediatric HIV and vaccination in childhood Univ of Rome, Novartis Sept In comb with annual meeting Budapest, reviews Budapest annual meeting Nov B-cells and antibody workshop and teaching Milan (Scarlatti) with Tanzanian particip. Antibody technology, dev. country trials June day prep and annual meeting, presentations Athens Nov Conference invitations Nobel Forum series, Stockholm series 2011 May 10. Annual meeting in X-city Nov 2011

24 Students, projects and teachers at start Nicolas Ruffin Antibodies in HIV and SIV infection Chiodi SE Kevin Mendonca Vaginal delivery of bioactive proteins Pozzi UK Nada Chaoul Baff and HIV-specific versus nsp B-cell Richard FR Sarah Brinkmann Optimisation of a novel adjuvant Sattentau UK Annette Sköld Activators of Notch signalling Spetz SE Julia Hornig Novel assays for cytokines-mucosal samples Gotch UK Ke Xu HIV transfer immature DC- CD4+ Moog, FR Andreas Boberg Drug escape vaccine vaccine Wahren SE Joanna Said Microbicide biochemistry Bergström SE Paolo Palma Pediatric vaccination Rossi IT Andrea Gorlani Cross-neutralization lama ab Verrips NL Adam Coleman Innate immunity assays Goodier UK Katharina Bohnhorst Dendritic cell activation Stahl-Henning DE Katja Klein Microbicides and immunology Shattock UK Caroline Weber TLR agonists Verrier FR Heribert Quendler Antibody immunochemistry Katinger AU Elena Pettini CD4 and CD8 activation Medaglini IT Hannes Uchtenhagen HIV epitope structure Spetz SE Kelly DaCosta HIV and SIV neutralization Cranage UK Stefania Dispenseri Antibody biochemistry Scarlatti IT Samanta Mariani Co-receptor usage Poli IT Marie Borggren HIV DC interactions Fenyö SE halo students