Study to Compare the Immunogenicity and Safety of Two HIV Preventive Vaccinations in Healthy Volunteers (EV03/ANRSVAC20)

• Immunogenicity parameter: presence of CD8/CD4+ T cell responses defined according to internationally agreed criteria for evaluation of IFNgamma ELISPOT assays, in response to env plus at least one of the gag, pol, nef peptide pools [ Time Frame: week 26 and week 28 ] [ Designated as safety issue: No ]
• Safety parameter: grade 3 or above local adverse event, grade 3 or above systemic adverse event, grade 3 or above other clinical or laboratory adverse event,any event attributable to vaccine leading to discontinuation of the immunisation regimen. [ Time Frame: within 72 weeks ] [ Designated as safety issue: No ]

• Immunogenicity parameter: presence of CD8/CD4+ T cell responses defined according to internationally agreed criteria for evaluation of IFNgamma ELISPOT assays, in response to env plus at least one of the gag, pol, nef peptide pools [ Time Frame: week 26 and week 28 ]
• Safety parameter: grade 3 or above local adverse event, grade 3 or above systemic adverse event, grade 3 or above other clinical or laboratory adverse event,any event attributable to vaccine leading to discontinuation of the immunisation regimen. [ Time Frame: within 72 weeks ]

• Cellular responses: CD8/CD4+ T cell mean IFNgamma Spot Forming Units (SFU) per million cells across the peptide pools [ Time Frame: at weeks 26 and 28 ] [ Designated as safety issue: No ]
• Cellular responses: CD8/CD4+ T cell mean Spot Forming Units (SFU) per million cells across the peptide pools [ Time Frame: at any week following the first immunisation including weeks 48 and 72 ] [ Designated as safety issue: No ]
• Cellular responses: mean proportion of CD4/CD8+ T cells producing IL-2 and/or IFNgamma following ex-vivo stimulation with HIV-1 peptide pools [ Time Frame: at weeks 26 and 28, 48 and 72 ] [ Designated as safety issue: No ]
• Cellular responses: number of different epitopes that can be characterised [ Time Frame: to be determined at a later stage ] [ Designated as safety issue: No ]
• Antibody responses [ Time Frame: to be determined at a later stage ] [ Designated as safety issue: No ]
• All grade 1 and 2 adverse events [ Time Frame: within 72 weeks ] [ Designated as safety issue: No ]
• All events including those considered unrelated [ Time Frame: within the 72 weeks ] [ Designated as safety issue: No ]

• Cellular responses: CD8/CD4+ T cell mean IFNgamma Spot Forming Units (SFU) per million cells across the peptide pools [ Time Frame: at weeks 26 and 28 ]
• Cellular responses: CD8/CD4+ T cell mean Spot Forming Units (SFU) per million cells across the peptide pools [ Time Frame: at any week following the first immunisation including weeks 48 and 72 ]
• Cellular responses: mean proportion of CD4/CD8+ T cells producing IL-2 and/or IFNgamma following ex-vivo stimulation with HIV-1 peptide pools [ Time Frame: at weeks 26 and 28, 48 and 72 ]
• Cellular responses: number of different epitopes that can be characterised
• Antibody responses
• All grade 1 and 2 adverse events [ Time Frame: within 72 weeks ]
• All events including those considered unrelated [ Time Frame: within the 72 weeks ]

The purpose of the trial is to evaluate the effect upon immune system of two regimens of preventive HIV vaccination in healthy adult volunteers. Volunteers will be vaccinated by DNA-C and NYVAC-C vaccines, and the immune changes will be assessed, as well as safety of the vaccines. Volunteers will be followed during 72 weeks.

Methods: randomised phase I/II international trial with a parallel group design, open to participants and investigators but blind to laboratory personnel, in healthy volunteers.

Vaccines strategies: 70 volunteers will receive 3 DNA-C vaccinations and 1 NYVAC-C vaccination; 70 volunteers will receive 2 DNA-C vaccinations and 2 NYVAC-C vaccination.

DNA-C: 2x2ml intra muscular in right and left vastus lateralis; NYVAC-C: 1 ml intramuscular in non-dominant deltoid.

Main outcome:

1. the presence of CD8/CD4+ T cell responses defined according to internationally agreed criteria for evaluation of IFNgamma ELISPOT assays:

   • in response to env plus at least one of the gag, pol, nef peptide pools,
   • at weeks 26 or 28;
2. the safety parameters.

Secondary outcomes:

• cellular responses,
• antibody responses,
• all grade 1 and 2 adverse events,
• all events including those considered unrelated.

Sample size: 140 volunteers

Enrollment period: 9 months

Patient's participation duration: 78 weeks

Study duration: 27 months

• Biological: DNA-C
  1.0mg per ml of DNA HIV-C vaccine 2x2 ml IM
• Biological: NYVAC-C
  NYVAC-C 1 ml IM

• Experimental: 3 DNA-C + 1 NYVAC-C
  Interventions:

  • Biological: DNA-C
  • Biological: NYVAC-C
• Active Comparator: 2 DNA-C + 2 NYVAC-C
  Interventions:

  • Biological: DNA-C
  • Biological: NYVAC-C

Inclusion Criteria:

• age between 18 and 55 years on the day of screening
• available for follow-up for the duration of the study (78 weeks from screening)
• able to give written informed consent

• at low risk of HIV and willing to remain so for the duration of the study low risk of HIV infection defined as:

  • no history of injecting drug use in the previous ten years
  • no gonorrhoea or syphilis in the last six months
  • no high risk partner (e.g. injecting drug use, HIV positive partner) either currently or within the past six months
  • no unprotected anal intercourse in the last six months, outside a relationship with a regular partner known to be HIV negative
  • no unprotected vaginal intercourse in the last six months outside a relationship with a regular known/presumed HIV negative partner
• willing to undergo a HIV test
• willing to undergo a genital infection screen
• if heterosexually active female, using an effective method of contraception with partner (combined oral contraceptive pill; injectable contraceptive; IUCD; consistent record with condoms if using these; physiological or anatomical sterility in self or partner) from 14 days prior to the first vaccination until 4 months after the last, and willing to undergo urine pregnancy tests prior to each vaccination
• if heterosexually active male, using an effective method of contraception with their partner from the first day of vaccination until 4 months after the last vaccination

• for French volunteers only :

  • subjects registered in French Health ministry computerised file and authorised to participate in a clinical trial
  • subjects covered by Health Insurance
  • subjects included in the ANRS vaccine research network of volunteers

Exclusion Criteria:

• pregnant or lactating
• clinically relevant abnormality on history or examination including history of grand-mal epilepsy; severe eczema; allergy to eggs or gentamicin; severe allergic diseases; liver disease with inadequate hepatic function; haematological, metabolic or gastrointestinal disorders; uncontrolled infection; autoimmune disease, immunodeficiency or use of immunosuppressives in preceding 3 months
• receipt of live attenuated vaccine within 60 days or other vaccine within 14 days of enrolment
• receipt of blood products or immunoglobin within 4 months of screening
• participation in another trial of a medicinal product, completed less than 30 days prior to enrolment

• history of severe local or general reaction to vaccination defined as

  • local: extensive, indurated redness and swelling involving most of the anterolateral thigh or the major circumference of the arm, not resolving within 72 hours
  • general: fever >= 39.5oC within 48 hours; anaphylaxis; bronchospasm; laryngeal oedema; collapse; convulsions or encephalopathy within 72 hours
• HIV 1/2 positive or indeterminate on screening
• positive for hepatitis B surface antigen, hepatitis C antibody or serology indicating active syphilis requiring treatment
• positive for DNA/ANA antibodies at titre considered clinically relevant by immunology laboratory
• grade 1 or above routine laboratory parameters (see section 4.1.4 & appendix 4 for definitions) Note of clarification 18th april 2008: hyperbilirubinemia has to be considered as an exclusion criterion only when confirmed to be conjugated bilirubinemia
• unlikely to comply with protocol