Immunogenicity and Safety of 4 Prime-boost Combinations of HIV Vaccine Candidates in Healthy Volunteers

Study Overview
=================
Brief Summary
-----------------
The development of a safe and effective HIV-1 vaccine strategy would probably be the best solution for the ultimate control of the worldwide AIDS pandemic. Heterologous prime-boost immunisations are today considered promising HIV prophylactic vaccine strategies. It is thus relevant to pursue the development of different candidate vaccines in prime-boost vaccine strategies to identify the most promising prime-boost combinations and to integrate scientific inquiry into trial protocols from the beginning to maximize learning opportunities.

Detailed Description
-----------------
Phase I/II, multicenter, national, open-label, randomized trial HIV including 4 prophylactic prime-boost HIV vaccines strategies: Volunteers are randomly allocated in a 1:1:1:1 ratio at trial entry to 4 parallel arms with the following prime-boost strategies: Arm 1. MVA HIV-B primes at Week 0 and Week 8 + LIPO-5 boosts at Week 20 and Week 28 Arm 2. LIPO-5 primes at Week 0 and Week 8 + MVA HIV-B boosts at Week 20 and Week 28 Arm 3. GTU-MultiHIV B primes at Week 0, Week 4 and Week 12 + LIPO-5 boosts at Week 20 and Week 28 Arm 4. GTU-MultiHIV B primes at Week 0, Week 4 and Week 12 + MVA HIV-B boosts at Week 20 and Week 28

Official Title
-----------------
Phase I/II Open-label Randomized Multicenter Trial to Assess Immunogenicity and Safety of 4 Prime-boost Combinations of HIV Vaccine Candidates (MVA HIV-B/ LIPO-5; LIPO-5/MVA HIV-B; GTU®-MultiHIV B / LIPO-5; GTU®-MultiHIV B/MVA HIV-B) in Healthy Volunteers at Low Risk of HIV Infection

Conditions
-----------------
HIV Infection

Intervention / Treatment
-----------------
* Biological: LIPO-5
* Biological: MVA HIV-B (MVATG17401)
* Biological: GTU®-MultiHIV B: 0.5 mL IM via Biojector® 2000 and 0.5mL IntraDermic, 3 shots


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written and signed informed consent Subject at low risk to contract HIV i.e. no history of injecting drug use in the previous ten years; no gonorrhea or syphilis in the last six months; no high risk partner (e.g. injecting drug user, 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/presumed to be HIV negative ; no unprotected vaginal intercourse in the last six months outside a relationship with a regular known/presumed HIV negative partner Available for follow-up for the duration of the study (56 weeks from screening) 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; contraceptive implant/patch; IntraUterine Contraceptive Device (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 Subject registered in French Health ministry computerised file and authorised to participate in a clinical trial Subject covered by Health Insurance Exclusion Criteria: Clinically relevant abnormality on history or examination including history of: uncontrolled infection; autoimmune disease; immunodeficiency or use of immunosuppressive drugs within 3 months prior to screening; cancer; chronic diseases requiring long-term treatment whose interruption during the trial has no impact on the health status in the short or long-term Receipt of live attenuated vaccine within 60 days or other vaccine within 14 days prior to W0 Planned receipt of other vaccines than those planned by the protocol and those recommended in France (excluding live attenuated vaccines) during the trial follow-up (reference : Weekly Epidemiological Newsletter 14-15 dated on April 10th, 2012 (Bulletin Epidémiologique hebdomadaire 14-15 / 10 avril 2012)) Receipt of blood products or immunoglobin within 4 months prior to screening History of severe local or general reaction to vaccination defined as local: extensive, indurated redness and swelling involving most of the antero-lateral thigh or the major circumference of the arm, not resolving within 72 hours general: fever ≥ 39.5°C within 48 hours; anaphylaxis; bronchospasm; laryngeal oedema; collapse; convulsions or encephalopathy within 72 hours Positive for ANA antibodies at a titer considered clinically significant: titer ≥ local cut-off associated with positive anti-native DNA and extractable nuclear antigen antibodies HIV-1 or HIV-2 positive or indeterminate at screening Woman expecting to conceive during the study period Pregnant or breastfeeding woman Symptoms, physical signs or laboratory values suggestive of systemic disorders, including renal, hepatic, cardiovascular, pulmonary, skin, immunodeficiency, psychiatric, which could interfere with the interpretation of the trial results or compromise the health of the volunteers Clinically significant grade 1 routine laboratory parameters Grade 2 or above routine laboratory parameters Known hypersensitivity to aminoglycosides and eggs (as used in the vaccine production processes) Known hypersensitivity to one of the trial vaccine components, the metabolites or formulation excipients Anticipated non-compliance with the protocol Participation in another clinical trial with an on-going exclusion period at screening Participation in a HIV preventive vaccine clinical trial (unless participant were randomized in placebo arm) Subject under legal guardianship or incapacitation Subject who is an active blood donor and unwilling to interrupt blood donations during the his/her participation in the trial

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MVA HIV-B and LIPO-5 vaccines<br>MVA HIV-B primes 0,5 milliliter (mL) Intramuscular at Week 0 and Week 8 LIPO-5 1mL Intramuscular boosts at Week 20 and Week 28 | Biological: LIPO-5<br>* LIPO-5: 1mL IntraMuscular, 2 shots;<br>* Other names: FIT Biotech GTU-MultiHIV B vaccine candidate;Biological: MVA HIV-B (MVATG17401)<br>* MVA HIV-B (MVATG17401): 0.5mL IntraMuscular, 2 shots;<br>|
| Experimental: LIPO-5 and MVA HIV-B vaccines<br>LIPO-5 primes 1mL intramuscular at Week 0 and Week 8 and MVA HIV-B 0,5mL intramuscular boosts at Week 20 and Week 28 | Biological: LIPO-5<br>* LIPO-5: 1mL IntraMuscular, 2 shots;<br>* Other names: FIT Biotech GTU-MultiHIV B vaccine candidate;Biological: MVA HIV-B (MVATG17401)<br>* MVA HIV-B (MVATG17401): 0.5mL IntraMuscular, 2 shots;<br>|
| Experimental: GTU-MultiHIV B and LIPO-5 vaccines<br>GTU-MultiHIV B 0,5mL intramuscular via Biojector 2000 and 0,5mL intradermic primes at Week 0, Week 4 and Week 12 and LIPO-5 1mL intramuscular boosts at Week 20 and Week 28 | Biological: LIPO-5<br>* LIPO-5: 1mL IntraMuscular, 2 shots;<br>* Other names: FIT Biotech GTU-MultiHIV B vaccine candidate;Biological: GTU®-MultiHIV B: 0.5 mL IM via Biojector® 2000 and 0.5mL IntraDermic, 3 shots<br>* GTU®-MultiHIV B: 0.5 mL IM via Biojector® 2000 and 0.5mL IntraDermic, 3 shots<br>|
| Experimental: GTU-MultiHIV B and MVA HIV-B vaccines<br>GTU-MultiHIV B 0,5mL intramuscular via Biojector 2000 and 0,5mL intradermic primes at Week 0, Week 4 and Week 12 and MVA HIV-B 0,5mL intramuscular boosts at Week 20 and Week 28 | Biological: MVA HIV-B (MVATG17401)<br>* MVA HIV-B (MVATG17401): 0.5mL IntraMuscular, 2 shots;<br>Biological: GTU®-MultiHIV B: 0.5 mL IM via Biojector® 2000 and 0.5mL IntraDermic, 3 shots<br>* GTU®-MultiHIV B: 0.5 mL IM via Biojector® 2000 and 0.5mL IntraDermic, 3 shots<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the safety of MVA HIV-B at Week 2 in arm 1 | • Proportion of participants without any grade 3 or 4 adverse events (clinical or biological) related to MVA-vaccine immunisation, reported from Week 0 to Week 2 in arm 1 | Visit Week 2 | 
| To discard vaccine strategies with an insufficient level of immunogenicity, defined by HIV-specific IFN-γ-ELISPOT responses, among 4 HIV prophylactic prime-boost combinations in healthy volunteers at low risk of HIV infection | Proportion of participants with a HIV-specific Interferon-gamma Enzyme Linked Immunosorbent SPOT (IFN-γ ELISPOT) response in each of the 4 arms, defined by a positive response to at least one of the stimulating HIV peptide pools (15-mer pools covering Env, Gag, Pol, and Nef) measured in stimulated Peripheral Blood Mononuclear Cell (PBMC) by a standard IFN-γ ELISPOT assay at Week 30, i.e. 2 weeks after the last vaccine immunisation. | Visit Week 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the tolerance of each prime-boost combination | Grade 1 or more clinical and laboratory adverse events related to vaccine immunisation: proportion of participants with an event; number, nature, grade and time of occurrence. Any event related to vaccine immunisation, leading to discontinuation of the immunisation regimen: proportion of participants with an event; number, nature, grade and time of occurrence. Grade 3 or 4 clinical and laboratory adverse events, validated by the Endpoint Review Committee, regardless of the relationship to vaccine immunisation: proportion of participants with an event; number, nature, grade and time of occurrence. Serious adverse events, regardless of the relationship to vaccine immunisation: proportion of participants with an event; number, nature, grade and time of occurrence. | visit Week 52 | 
| To assess for each prime-boost combination the type of vaccine-induced T cell response | In all participants having received at least 1 dose of vaccine: Proportion of HIV-specific IFN-γ-ELISPOT responders Ex-vivo transcriptome analysis In participants having received at least 1 dose of vaccine and a positive IFN-γ-ELISPOT response at the considered timepoint: • Magnitude and breadth of HIV-specific IFN-γ-ELISPOT responses, measured following stimulation of PBMC with HIV-1 peptide pools 2 weeks after each vaccine immunisation. In a random sample of participants, having received at least 1 dose of vaccine, with random sampling stratified on trial arm and ELISPOT response at Week 30: Production of cytokine (IFN- γ, Interleukin-2 (IL-2), Tumor Necrosis Factor-alfa (TNF-alfa)) by HIV-specific Cluster of Differentiation 8 (CD8+) and Cluster of Differentiation 4 (CD4+) T cells Secretion of cytokines by PBMC measured by Luminex® Gene expression profile of PBMC measured by transcriptome analysis | Visit Week 30 |