In Vivo Electroporation Enhances the Immunogenicity of ADVAX, a DNA-based HIV-1 Vaccine Candidate, in Healthy Volunteers

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1 In Vivo Electroporation Enhances the Immunogenicity of ADVAX, a DNA-based HIV-1 Vaccine Candidate, in Healthy Volunteers Aaron Diamond AIDS Research Center

2 ADVAX Clade B /C DNA Vaccine 8.7 kb 8.2 kb

3 In Vivo Electroporation () Enhances Humoral and Cellular Immunogenicity = in vivo propagation of electrical fields to enhance the intracellular uptake of DNA, resulting in: Higher transfection efficiency Higher antigen expression Enhanced cellular and humoral immunogenicity Recruitment of immune cells to injection sites Dose sparing of vaccine enhances humoral responses to DNA vaccines by 1 2 logs, confirmed reproducibly with multiple antigens in mice and rabbits Cellular responses increase by 2-4 fold

4 ADVAX Electroporation Clinical Trial Design Priming Vaccination Boosting Vaccination 3 rd Vaccination for 4.0mg Group Only Study Conclusion Week 0 Week 8 Week 36 Week 56 Group/Route Dose Subjects Placebo/ Saline 8 IM 4.0mg 8 Low 0.2mg 8 Mid 1.0mg 8 High 4.0mg 8 Healthy males and females aged at low risk for HIV-1 infection

5 TriGrid TM In Vivo Electroporation Device

6 TriGrid TM In Vivo Electroporation Procedure

7 Clinical Trial Progress and Safety To Date Trial began October 2007 All 40 volunteers enrolled and all vaccinations complete One SAE to date not related to vaccine Safety labs unremarkable Last volunteer visit completed October 2009

8 Electroporation Tolerabililty Number of Responses None Light Uncomfortable Intense Severe 0 Post Injection Immediately Following Electrical Stimulation 30 Minutes Post Vaccination Total of 75 administrations in 32 volunteers

9 Electroporation Acceptability 100 Percentage of Responses Yes No Not Sure Yes No Not Sure is acceptable if it protects against a serious disease, such as HIV, for which there is no vaccine is acceptable if it improves protection against a serious disease, such as influenza, for which we already have a vaccine

10 Improves IFNγ ELISpot Response Rate Dose Group Response Rate IM 4.0mg 0/8 0% 0.2mg 3/8 37.5% 1.0mg 7/8 87.5% 4.0mg 6/8 75% 4.0mg 3 shots 8/8 100%

11 Improves IFNγ ELISpot Response Rate Dose Group Response Rate IM 4.0mg 0/8 0% 0.2mg 3/8 37.5% 1.0mg 7/8 87.5% 4.0mg 6/8 75% 4.0mg 3 shots 8/8 100%

12 Induces Durable IFNγ ELISpot Responses Vaccination Vaccination Vaccination (high dose) Vac Assays in Progress High Dose SFC/million SFC/million Mid Dose Low Dose Week W1 W2 W4 W8 W9 W W12 W16 W24 W36 W48 W56

13 Increases the Breadth of the IFNγ ELISpot Antigen Response Percentage of responding volunteers IM Low Mid High Number of Positive Antigens

14 Boosts the Magnitude of the Dominant IFNγ ELISpot Response to Envelope Envelope 500 SFC/million IM Low Mid High 2 Shots High 3 Shots

15 Boosts the Magnitude of the Sub-Dominant IFNγ ELISpot Responses 150 Polymerase Gag Nef-Tat SFC/million IM Low Mid High 2 High 3 IM Low Mid High 2 High 3 IM Low Mid High 2 High 3

16 ICCS Analysis of High Dose Volunteers at Peak ELISpot Response Both CD4 and CD8 responses were elicited, with slight CD4 predominance Co-secretion of IFNγ and IL-2 is evident in both CD4+ and CD8+ responses Strong correlation with ELISpot Responses Highest cytokine secretion in response to env, although the majority of responses were to more than one antigen

17 Conclusions TriGrid TM delivery of ADVAX: Is safe, tolerable, and acceptable Improves the total IFNγ ELISpot response rate Improves the magnitude of IFNγ ELISpot responses Improves the breadth of IFNγ ELISpot responses Improves the duration of IFNγ ELISpot responses Induces IFNγ/IL-2 CD4+ and CD8+ T cell responses to multiple antigens

18 Acknowledgements Our Dedicated Clinical Trial Volunteers ADARC Clinical Team David Ho Arlene Hurley Daniel Dugin Rockefeller Clinical Team Sarah Schlesinger Marina Caskey Johanne Andersen IAVI Clinical Team Pat Fast Claudia Schmidt Harriet Park Angela Lombardo ADARC Laboratory Yaoxing Huang David Gardiner Mar Boente-Carrera Roselle Vittorino Faye Yu Yang Song IAVI HIL Jill Gilmour Jo Cox Tony Tarragona Dilbinder Gill Lorna Clark Hannah Cheeseman Phil Bergin ICHOR Medical Systems Bob Bernard Drew Hannaman Ryan Betts Barry Ellefsen Claire Evans Karen Dolter Brian Livingston EMMES, Inc. Len Dally Kelley Loghran Carol Smith Rockefeller University Clinical and Translational Science Award