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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) - PowerPoint PPT Presentation
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Rencontre HIV11.11.2009
Ballade au long du temps dans les méandres des vaccins HIV
Flynn NM et al., JID 2005
VAX 004 : AIDSVAX B/B (7 injections)5095 MSM & 308 WHR (18-62 yo)
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*)
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
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.
STEP Study resultsTotal number of HIV infections Number of infections in vol. with
pre-existing immunity against Ad5
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/UCSFCo-Chair: Pierre-Alexandre Bart, CHUV/ Lausanne
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)
Heterologous Vectors can Boost Cellular Immune Responses
INF ELISPOT response after boost with the heterologous vector in macaques
rAd5 - rAd35rAd35 - rAd5
500
1000
1500
2000
0 2 4 8 11 13 15 19 23 27
SFC
/10e
6 PB
MC
Initial rAd immunization After heterologous boost
Env-A peptide pool
NYVAC
Clinical Experience with rNYVACHIV 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
NHP Immunogenicity StudiesStudies 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
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 and99D128), 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.
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.
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
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
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
HVTN 078 Overview
A phase 1b clinical trial to evaluate the safety and immunogenicity of heterologous
prime/boost vaccine regimens (NYVAC-B/rAd5 vs rAd5/NYVAC-B) in healthy,
HIV-1 uninfected, Ad5 seronegative adult participants
Chair: Giuseppe Pantaleo, CHUVCo-chair: Pierre-Alexandre Bart, CHUV
HVTN 078 Design: Design: Phase 1b, single center, randomized, Phase 1b, single center, randomized,
double-blind trial.double-blind trial.
Participants: Participants: 80 healthy, HIV-1 and Ad5 seronegative volunteers aged 18 to 45 years (75 vaccinees / 5 placebo recipients)
Duration per participant: 12 months + annual follow-up during 4 years
Sponsor: EuroVacc, Lausanne, Switzerland
Study products: vectors and insertsAdenoviral vector vaccine:
HIV-1 recombinant adenoviral serotype 5 (rAd5) vector vaccine VRC-HIVADV014-00-VP containing: clade B Gag-Pol fusion clades A, B, C Env
NYVAC-HIV-B vaccine vector:Modified pox viral vector (New York Vaccinia).HIV genes are derived from clade B viruses: BX08 (French R5 clade B isolate) for env HIV-1IIIB (TCLA clade B) for gag-pol-nef
HVTN 078 Schema Nbr Week 0
Month 0Week 4Month 1
Week 20Month 5
Week 24Month 6
Group 1
30
2
NYVAC-B (107)
Placebo
NYVAC-B (107)
Placebo
Placebo
Placebo
rAd5 (1010)
Placebo
Group 2 15
1
rAd5 (108)
Placebo
Placebo
Placebo
NYVAC-B (107)
Placebo
NYVAC-B (107)
Placebo
Group 3 15
1
rAd5 (109)
Placebo
Placebo
Placebo
NYVAC-B (107)
Placebo
NYVAC-B (107)
Placebo
Group 4 15
1
rAd5 (1010)
Placebo
Placebo
Placebo
NYVAC-B (107)
Placebo
NYVAC-B (107)
Placebo
108
109
1010
Inclusion criteria
Age of 18 to 45 years Able and willing to provide informed consent At low risk for HIV infection Good general health Neutralizing Ab titers Ad5 <18 Negative HIV-1 and HIV–2 blood test Negative Hepatitis B and C tests Negative pregnancy test
Exclusion criteria (1)
Excessive daily alcohol use HIV vaccine received in a prior HIV vaccine trial STD within 12 months prior to enrollment Immunosuppressive medication Live attenuated vaccines received within 30 days Allergy treatment with antigen inject. within 30 days Current anti-tuberculosis (TB) prophylaxis or therapy Active syphilis infection Clinically significant medical condition
Exclusion criteria (2) Serious adverse reactions to vaccines Allergy to eggs and/or egg products History of, or known active cardiac disease ECG with clinically significant findings, Autoimmune disease Asthma BMI>40 (or >35 if 2 or more Cardiac Risk Factors) Hypertension Diabetes mellitus type 1 or 2 Pregnant or breastfeeding
Endpoints Primary endpoints: Safety and TolerabilityPrimary endpoints: Safety and Tolerability
Local and systemic reactogenicity signs & symptomsLocal and systemic reactogenicity signs & symptoms Laboratory measurements of safetyLaboratory measurements of safety Adverse eventsAdverse events Serious Adverse Events meeting Expedited Adverse Serious Adverse Events meeting Expedited Adverse
Events criteriaEvents criteria
Secondary endpoints: ImmunogenicitySecondary endpoints: Immunogenicity Magnitude and frequency of HIV-1 specific CD4 and Magnitude and frequency of HIV-1 specific CD4 and
CD8 T cell resp. as measured by CD8 T cell resp. as measured by ELISpotELISpot and/or and/or intracellular cytokine staining (intracellular cytokine staining (ICSICS) assay 2 weeks ) assay 2 weeks post 4post 4thth vaccination (w26) vaccination (w26)
