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Ana Guimar ã es- Walker,

Safe administration of DNA (pTHr.HIVA) and MVA.HIVA to 169 HIV-1 uninfected volunteers enrolled in Phase I/II trials in the UK. Ana Guimar ã es- Walker, I. Cebere, N. Mackie, T. Hanke, P. Fast, L. Dally, J. Weber and A. J. McMichael. XVI International AIDS Conference Toronto, Canada.

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Ana Guimar ã es- Walker,

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  1. Safe administration of DNA (pTHr.HIVA) and MVA.HIVA to 169 HIV-1 uninfected volunteers enrolled in Phase I/II trials in the UK. Ana Guimarães- Walker, I. Cebere, N. Mackie, T. Hanke, P. Fast, L. Dally, J. Weber and A. J. McMichael. XVI International AIDS Conference Toronto, Canada.

  2. DNA vaccine (pTHr.HIVA) Plasmid Modified Vaccinia Ankara (MVA.HIVA) Non-replicant live attenuated vector Vaccine Candidates HIVA-A Clade A HIV-1 gag p17 and p24 25 CTL epitopes linked end-to-end (env, gag, pol and nef) • Humoral and cellular responses in rodents and macaques. Hanke T, Nat Med 2000 • SIV-specific CTL response in rhesus monkeys. Wee EG, J Gen Virol 2002 • Multifunctional HIV-1 specific T-cell responses in healthy seronegative subjects. Goonetilleke N, J Virol, May 2006 • Specific T-cell responses in HIV-1 infected subjects. Dorrell L., J Virol, May 2006 MRC Human Immunology Unit - WIMM - Oxford University

  3. Study Design DNA 0.1 mg DNA 0.1 mg END 001 n=18 DNA 0.5 mg DNA 0.5 mg END MVA 5x107pfu MVA 5x107pfu END 003 n=8 MVA 5x107pfu MVA 5x107pfu END 005 (n=9) Early boost Late boost DNA 0.5 mg DNA 0.5 mg 006 n=18 MVA 5x107pfu MVA 5x107pfu MVA 5x107pfu MVA 5x107pfu END DNA 2 mg DNA 2 mg DNA 4 mg DNA 4 mg MVA 1x108pfu END 016 n=18 MVA 1x108pfu MVA 1x108pfu END MRC Human Immunology Unit - WIMM - Oxford University

  4. Demographics (n=155) (n=3) (n=6) (n=73) (n=96) (n=5) MRC Human Immunology Unit - WIMM - Oxford University

  5. Clinical Definitions • Adverse Events: • Vaccine reactions  Other AEs • Solicited events Unsolicited events • “Reactogenicity”  “Ongoing reactogenicity”  Grading criteria  cutaneous reactions: • Types of cutaneous reactions: • Pain, tenderness, itchiness • Erythema • Swelling x induration • Blister, vesicle  ulceration • Rash • Grading parameters: • % of Arm circumference • Size • Duration • Use of medication • Other MRC Human Immunology Unit - WIMM - Oxford University

  6. Maximum Local Reactions(per volunteer during the 28 days post vaccination) • Typical local reactions: • Following DNA.HIVA Following MVA.HIVA • Pain/tenderness Pain/tenderness • Erythema • Induration # Trial 016 (n=24) N vol MRC Human Immunology Unit - WIMM - Oxford University

  7. Maximum Systemic Reactions(per volunteer during the 28 days post vaccination) • Typical local reactions: • Following DNA.HIVA Following MVA.HIVA • None Malaise/ myalgia • Headache # Trial 016 (n=24) N vol n=8 n=8 n= 16 MRC Human Immunology Unit - WIMM - Oxford University

  8. Non-Serious Adverse Events (Excludes Local and Systemic Vaccine Reactions) Severity Relationship % DNA MVA DNA MVA % Over 1000 AEs reported across trials ~ 30% of AEs considered possibly or probably related to vaccine < 10% of events related to vaccine graded as moderate or severe MRC Human Immunology Unit - WIMM - Oxford University

  9. Serious Adverse Events (SAEs) Days (n) Enrolment Days (n) Last vac • SAEs reported for 6 volunteers: • Hospitalization: fever, malaise, nausea & headache • 2. Removal of gallbladder • Umbilical hernia repair • 3. Hospitalization: cycle accident 4. Excavation of sinuses • Removal of nasal polyps • Realignment of nasal septum • Mesothelioma • Hysterectomy and bilateral oophorectomy 04 04 30 02 175 91 179 03 78 50 78 50 78 50 313-448 261-126 30 30  No SAES caused by Vaccine. MRC Human Immunology Unit - WIMM - Oxford University

  10. Laboratory assessment • No positive ELISA HIV results. • No evidence of induction of auto-immune antibodies. • Liver function tests • Grade 3 or greater laboratory values leading to discontinuation of vaccinations (n=02 volunteers). MRC Human Immunology Unit - WIMM - Oxford University

  11. Ex vivo 3 IFN - Cultured H Thymidine ELISPOT CFSE Subject ELISPOT ELISPOT Proliferation +IL - 7/IL - 15 PROLIF. WBICS DNA-MVA - 2 1 7769 224.21 959 2165 0.56 0.46 3 2 2 10431 11.6 103 166 0.07 0.01 2 4 3 3206 44.41 514 ND ND 0.02 2 4 4181 7.33 36 86 0.03 0.01 2 5 1463 8.50 31 128 0.01 0.03 2 6 388 4.28 30 96 0.00 0.02 2 7 413 0.93 4 18 0.01 0.01 2 8 1769 1.59 5 13 0.01 0.01 MVA 9 2494 0.36 28 165 ND 0.01 (CTL ) 10 1250 0.15 - 1 - 3 ND ND (CTL ) 11 356 0.97 0 15 ND 0.00 (CTL ) 12 3838 0.55 6 ND ND 0.00 13 ND 1. 01 0 16 ND 0.00 14 ND 0.30 3 - 18 ND 0.00 15 ND 0.69 - 1 31 ND 0.00 16 ND Immunogenicity of DNA.HIVA and MVA.HIVAPositive Responders across assays in 016 Trial n=8 n=8 n=8 0.17 11 16 ND 0.00 PLACEBO n=8 No positive responses 1 Background subtracted responses to Gag (CTL string response indicated in brackets). Responses shown are from Wk9 in the DNA/MVA arm and Wk1 in the MVA only arm 2 Response from Wk10 (2 weeks post MVA) 3 Response from W12 (4 weeks post MVA) 4 ND= no data available for Pool 90 specific responses MRC Human Immunology Unit - WIMM - Oxford University

  12. Conclusions – Safety • Overall both DNA.HIVA and MVA.HIVA vaccines were safe and well tolerated. • Most local or systemic reactions following vaccination with DNA or MVA vaccinations were mild. • Local and systemic reactions were more frequently observed following MVA vaccination, compared to DNA-HIVA vaccination. • Ensuring consistency in the grading criteria is crucial within a programme consisting of overlapping trials. MRC Human Immunology Unit - WIMM - Oxford University

  13. Acknowledgments: • IAVI Dr Claudia Schmidt Dr Jill Gilmour Dr Patricia Fast Mr Carl Verlinde Mr Dani Voojis • Imperial College London Professor Frances Gotch Professor Jonathan Weber Dr Nicola Mackie Dr Peter Hayes Dr Tristan Barber Mr Carl DeSouza Mr Ken Legg Ms Miranda Cowen • MRC Human Immunology Oxford Professor Andrew McMichael Dr Inese Cebere Dr Jo Roberts Dr Nilu Goonetilleke Dr Susana Pinheiro Dr Thomas Hanke Ms Althea Thomas Ms Denise Brown Ms Nicola Winstone Mr Stephen Moore Ms Vanessa Loach ALL VOLUNTEERS • EMMES Dr Leonid Gibianski Ms Carol Smith Ms Kelley Loughran Mr Len Dally Ms Sophia Pallas • MRC Clinical Trials Unit London Dr Sheena McCormack Ms Elizabeth Brodnicki Mr Patrick Kelleher • Origin Ms Stephanie Miall MRC Human Immunology Unit - WIMM - Oxford University

  14. Safe administration of DNA (pTHr.HIVA) and MVA.HIVA to 169 HIV-1 uninfected volunteers enrolled in Phase I/II trials in the UK. Additional Slides XVI International AIDS Conference Toronto, Canada.

  15. Number of Volunteers who received each vaccination as scheduled – Trial 006 119 Enrolled Volunteers DNA PRIMING 40/40 2 mg DNA 39/39 0.5 mg DNA 40/40 Placebo 17/17 MVA 1/2 Placebo 16/19 MVA 2/2 Placebo 17/18 MVA 2/2 Placebo EARLY boost OR 16/19 MVA 2/2 Placebo 17/17 MVA 1/1 Placebo 18/18 MVA 2/2 Placebo LATE boost

  16. Demographics MRC Human Immunology Unit - WIMM - Oxford University

  17. Distribution of Responses according to Age Trial #006 MRC Human Immunology Unit - WIMM - Oxford University

  18. Local & Systemic Reactions- Trial 006(per volunteer during the 28 days post vaccination) Systemic Reactions Local Reactions % % DNA MVA DNA MVA Reactions post MVA were not altered by DNA priming MRC Human Immunology Unit - WIMM - Oxford University

  19. Non-Serious Adverse Events – Trial 006(Excludes Local and Systemic Reactogenicity) Severity Relationship % % DNA MVA MVA DNA MRC Human Immunology Unit - WIMM - Oxford University

  20. HIV.A Peptides HIV-1 gag CTL epitopes p24 p17 Pool 9 Pool 1 Pool 2 Pool 3 Pool 4 Pool 90 (1+2+3+4) Responder = volunteer with a positive response in at least one pool on at least one occasion. MRC Human Immunology Unit - WIMM - Oxford University

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