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Rencontre HIV 11.11.2009

Rencontre HIV 11.11.2009. Ballade au long du temps dans les méandres des vaccins HIV. PLAN. Ad5. ALVAC. HVTN 072, 077, 078. NYVAC. gp120. STEP. Problèmes liés au Développement de Vaccins HIV. Adénovirus Smallpox. rgp-120. VAX 004 : AIDSVAX B/B (7 injections)

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Rencontre HIV 11.11.2009

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  1. Rencontre HIV11.11.2009 Ballade au long du temps dans les méandres des vaccins HIV

  2. PLAN Ad5 ALVAC HVTN 072, 077, 078 NYVAC gp120 STEP

  3. Problèmes liés au Développement de Vaccins HIV

  4. Adénovirus Smallpox

  5. rgp-120

  6. VAX 004 : AIDSVAX B/B (7 injections) 5095 MSM & 308 WHR (18-62 yo) Flynn NM et al., JID 2005

  7. AIDSVAX B/E (7 injections) IVDU

  8. PLAN Ad5 ALVAC HVTN 072, 077, 078 NYVAC gp120 STEP

  9. rAd5

  10. rAd5 HIV Clinical Studies VRC-006 (rAd5 alone, n=30) VRC-008 (DNA prime by two devices, rAd5 boost, n=39) VRC-009 (roll-over prior receipt of DNA prime, n=10) VRC-011 (route comparison, n=52) VRC-015 (rAd5 by two devices, n=3) HVTN-054 (rAd5 alone, n=40) HVTN-057 (roll-over prior receipt of DNA prime, n=60) HVTN-068 (DNA prime/rAd5 boost, n=60) HVTN-069 (DNA prime/rAd5 boost, route comparison, n-61) RV156A (roll-over, DNA prime/rAd5 boost in E. Africa, n=4) RV172 (rAd5 alone & DNA prime/rAd5 boost in E. Africa, n=187*) IAVI V001 (DNA prime/rAd5 boost in E. & S. Africa, n=84) HVTN-204 (DNA prime/rAd5 boost in U.S., Caribbean, & S. Africa, n=240*)

  11. VRC 006

  12. rAd5 HIV Vaccine Candidate Boost Clinical Safety Data At high dose of HVTN 078, i.e., 1010 PU Local symptoms: ~17% none ~78% mild 5-10% moderate None severe No SAEs or non-reactogenicity AEs Systemic symptoms 16-55% none 28-74% mild 10-17% moderate None severe

  13. Phase I

  14. Escalating doses : w0, w4 and w26

  15. STEP Study (HVTN 502) Phase IIb trial with the Merck Ad5 experimental vaccine(Gag-Pol-Nef HIV-1 clade B) Population: 3000 high risk HIV-negative volunteers (low and high Ad5 titers). Primary endpoints: Safety Reduction in HIV-1 infection rate and/or viral load at 3 months post-diagnosis.

  16. STEP Study results Number of infections in vol. with pre-existing immunity against Ad5 Total number of HIV infections

  17. PLAN Ad5 ALVAC HVTN 072, 077, 078 NYVAC gp120 STEP

  18. HVTN 077 Overview A phase 1b clinical trial to evaluate the safety and immunogenicity of recombinant Ad35 and Ad5 HIV-1 vaccines as a prime-boost regimen or as boosts to a DNA priming regimen in healthy Ad5-naïve and Ad5 exposed, low risk, HIV-1 uninfected adult participants Chair: Jonathan Fuchs, SFDPH/UCSF Co-Chair: Pierre-Alexandre Bart, CHUV/ Lausanne

  19. Trial Rationale • While no efficacy with MRK Ad5 approach, the VRC’s multigene, multiclade DNA prime/Ad5 boost regimen has a distinct immunologic profile • Substantial pre-existing immunity to Ad5 worldwide may limit immunogenicity and clinical utility of Ad5 products • Ad35 significantly less prevalent in the population • Recent non-human primate SIV challenge model data demonstrates a reduction in SIV viral load and improved survival using alternative adenoviral serotypes (Liu, Nature, 2008)

  20. rAd5 - rAd35 rAd35 - rAd5 2000 1500 SFC/10e6 PBMC 1000 500 0 2 4 8 11 13 15 19 23 27 INF ELISPOT response after boost with the heterologous vector in macaques Env-A peptide pool Initial rAd immunization After heterologous boost Heterologous Vectors can Boost Cellular Immune Responses

  21. HVTN 077 Schema Ad5 naive Ad5 exposed

  22. ALVAC

  23. Phase 2, clade B

  24. We need efficacy trials !

  25. NYVAC

  26. Clinical Experience with rNYVAC HIV CLINICAL STUDIES NYVAC-B:phase I study in 10 infected patients (TheraVac01) NYVAC-C: EV01 (completed): A phase I trial to assess the safety and immunogenicity of NYVAC-C in 24 HIV-1 negative healthy volunteers EV02 (completed):A phase I trial to assess the safety of 4mg DNA C (IM) and the safety and immunogenicity of DNA-C followed by NYVAC-C (IM) in an open randomised comparison to NYVAC-C alone in 40 healthy volunteers at low risk of HIV infection EV03/ANRSVAC20 (ongoing): A phase II trial to compare the immunogenicity and safety of 3 DNA-C prime followed by 1 NYVAC-C boost to 2 DNA C prime followed by 2 NYVAC-C boost in 140 HIV-1 negative healthy volunteers OTHER STUDIES NYVAC-JEV vaccine - phase I trial, conducted by WRAIR NYVAC-Pf7 (Malaria vaccine) – phase I/IIa, conducted by WRAIR NYVAC-Rabies

  27. Ad5 and Poxvirus Combination NHP Studies Clinical Study

  28. NHP Immunogenicity Studies • Studies conducted by Merck and Sanofi Pasteur • Study Products: • Ad5 expressing codon-biased HIV-1 (strain CAM1) gag gene • MVA expressing CAM1 gag gene • ALVAC expressing CAM1 gag gene • NYVAC expressing CAM1 gag gene

  29. NHP Immunogenicity Studies – Study 2 FIG. 2. ALVAC and MVA vectors as boosters, following priming with Ad vectors. Macaques were immunized at weeks 0, 4, and 26 with either 109 vp of Ad5-gag (animals 99C117 and 99D227), 107 vp of Ad5-gag (animals 99D021 and 99D156), 109 vp of Ad6-gag (animals 99D126 and 99D128), or 107 vp of Ad6-gag (animals 99D147 and 99D151). At weeks 56 and 119, animals were given either 108 PFU of ALVAC-gag or 108 PFU of MVA-gag. Numbers of SFC/106 PBMC were calculated as noted in the legend to Fig. 1.

  30. NHP Immunogenicity Studies – Study 3 FIG. 3. Comparison of the Gag-specific cellular immune response elicited by heterologous poxvirus priming-Ad5 boosting and Ad5 primingpoxvirus boosting. Priming doses of the gag-expressing ALVAC and NYVAC vectors were given at weeks 0 and 4, followed by the Ad5 booster at week 27; dose levels are indicated. MVA-gag was given at week 0, 4, and 27, and the Ad5 booster was given at week 65. In the final group, the Ad5 vector priming inoculations were delivered at weeks 0 and 4, with the MVA vector boosting delivered at week 27. The frequencies are expressed as the numbers of SFC/106 PBMC and were calculated as the differences in responses between the PBMC stimulated with the Gag 20-aa peptide pool and the mock-treated PBMC. These values were determined at the start of the treatment (pre), at week 8 (post-prime), at the timeof the boosting (pre-boost), and at 4 and 8 weeks postboosting; animals are indicated along the x axis.

  31. Ad5 and Poxvirus Combination • NHP Studies • Clinical Study

  32. Clinical Study – Ad5+ALVAC • Ad5-gag prime/ALVAC-gag (vCP205) boost • Study Rationale • Cell mediated immune (CMI) responses may be key to control of HIV • Adenovirus vectors elicit potent CMI responses, but: • Pre-existing immunity may blunt response rate • Induced immunity may impair subsequent boost • Heterologous prime/boost regimen may overcome immunity to vector • Supported by preliminary data in macaques

  33. Clinical Study – Ad5+ALVAC • Study Population: 135 subjects who have previously participated in Merck protocol 007 (Ad5 HIV-1 gag) or protocol 012 (MRKAd5 HIV-1 gag), receiving 3 doses of Ad5 at various dose levels. • Study regimen: a single booster dose of either • ALVAC vCP205 vaccine at 1x106.78 TCID50 OR • MRKAd5 HIV-1 gag at 1 x 1010 vp

  34. Clinical Trial – Ad5+ALVAC -Summary • Both vaccines were generally safe and well tolerated • Recall responses were elicited by both vaccines • No significant differences in the proportion of responders or the magnitude of the ELISpot responses between the treatment groups

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