Intranasal Modified Vacc-4x Gag Peptides With Endocine as Adjuvant

Study Overview
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Brief Summary
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HIV-specific cellular immunity is hampered in most HIV-infected individuals. Therapeutic immunization in HIV aims to strengthen the HIV-specific cellular immunity, usually in the absence of replicating HIV with antiretroviral drugs. The aims of this strategy can be to decrease the mass of latently infected CD4+ T cells, better tolerance of drug-free periods, and better select candidates for preventive HIV vaccines. Vacc-4x is one of the few peptide-based therapeutic vaccines tested, and consists of four, slightly modified HIV Gag p24 consensus peptides. Vacc-4x was first tested by intradermal injections using GM-CSF as adjuvant. A recent multinational placebo-controlled study found improvement of vaccine-specific T cell immunity and decrease in viral loads (presented at the AIDS vaccine 2011 conference, Bangkok). In this study the investigators hypothesize that the Vacc-4x peptides, deposited on the nasal mucosal surfaces in conjunction with Endocine, a newly developed and documented mucosal adjuvant, will induce T cell responses to HIV and improve HIV-specific immunity both systemically and at mucosal surfaces (oral, rectal, vaginal).

Detailed Description
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HIV-specific cellular immunity is hampered in most HIV-infected individuals, partly because the virus infects CD4+ T cells, the key cell subset in all immune responses. CD4 is the primary HIV receptor (CD4), but infection requires a co-receptor (CCR5) which is carried mainly by activated T cells. During primary HIV-infection, two types of CD4+ T cells mainly become infected: (i) Sub-activated T cells of all specificities within the mucosal linings, particularly in the gut; and (ii) HIV-specific T cell clones, that proliferates and are activated as a normal response to HIV infection itself. The HIV-specific immunity therefore becomes severely compromised early in the infection. Patients having better T cells specific to parts of the HIV Gag matrix protein usually progress slower towards AIDS than patients with poor T cell responsitivity towards Gag. Therapeutic immunization in HIV aims to strengthen the HIV-specific cellular immunity, usually in the absence of replicating HIV with antiretroviral drugs. The aims of this strategy can be to decrease the mass of latently infected CD4+ T cells, better tolerance of drug-free periods, and better select candidates for preventive HIV vaccines. The latter point may be important since clinical trials with preventive vaccine candidates may challenge our ethical standards: Such trials must be very large and conducted in poor areas with high prevalence of HIV, in order to have as many (placebo) or few (vaccine candidate) new HIV infections as fast as possible. Preventive vaccine trials might therefore compete with introduction of western access to HIV drugs. Vacc-4x is one of the few peptide-based therapeutic vaccines tested, and consists of four, slightly modified HIV Gag p24 consensus peptides. Vacc-4x was first tested by intradermal injections using GM-CSF as adjuvant. In a dose study at our Hospital, the investigators found induction of robust cellular immune responses both in vitro and in vivo by skin testing, indications of improved viral control, long-lasting immunity and lack of mutational changes in the HIV strains within the study cohort. A recently completed multinational placebo-controlled study found improvement of viral loads (presented at the AIDS vaccine 2011 conference, Bangkok). In this study the investigators hypothesize that the Vacc-4x peptides, deposited on the nasal mucosal surfaces in conjunction with Endocine, a newly developed and documented mucosal adjuvant, will induce T cell responses to HIV and improve HIV-specific immunity both systemically and at mucosal surfaces (oral, rectal, vaginal). This route of application may even simplify mass vaccination. The study is primarily a dose-study focused on adverse events, which have been negligible when Vacc-4x was given parenterally, as well as induction of systemic and mucosal immunity.

Official Title
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Immunotherapy of HIV-infected Patients: A Single-blinded, Randomized, Immunogenicity, Pilot Study of Intranasal Administration of Vacc-4x With Endocine as Adjuvant

Conditions
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HIV Infection

Intervention / Treatment
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* Biological: Vacc-4x low dose
* Biological: Vacc-4x medium dose
* Biological: Vacc-4x high dose
* Biological: Zero dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age above 18 years, both genders. HIV positive at least one year. Clinically stable on ART for the last 6 months (changes in therapy is allowed as long as the viral load is stable). Documented viral load (HIV-1 RNA) less than 50 copies/mL for the last six months. Documented stable CD4 cell count ≥ 400x106/L. Nadir (lowest ever) CD4 cell count ≥ 200x106/L. Signed informed consent. Exclusion Criteria: Reported pre-study AIDS-defining illness within the previous year. Malignant disease. On chronic treatment with immunosuppressive therapy. Unacceptable values of the hematologic and clinical chemistry parameters, as judged by the Principle Investigator (or designee), including creatinine values >1.5x upper limit of normal (ULN), and AST (SGOT), ALT (SGPT) and alkaline phosphatase values >2.5x ULN. Concurrent chronic active infection such as chronic viral hepatitis B or C or active tuberculosis. Pregnant or breastfeeding women. Women of childbearing potential not using reliable and adequate contraceptive methods (defined as: use of oral, implanted, injectable, mechanical or barrier products for the prevention of pregnancy; practicing abstinence; sterile) during the study, or sexually active male patients with partners of childbearing potential unwilling to practice effective contraception during the study. Current participation in other clinical therapeutic studies. Incapability of compliance to the treatment protocol, in the opinion of the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vacc-4x low dose<br>80 µg Vacc-4x (20 µg pr. peptide) in 300 µl Endocine divided into two administrations, one for each nose cavity | Biological: Vacc-4x low dose<br>* 80 µg Vacc-4x (20 µg pr. peptide) in 300 µl Endocine divided into two administrations, one for each nose cavity, administrated once weekly for four weeks<br>* Other names: Endocine;|
| Experimental: Vacc-4x medium dose<br>400 µg Vacc-4x (100 µg pr. peptide) in 300 µl Endocine divided into two administrations, one for each nose cavity | Biological: Vacc-4x medium dose<br>* 400 µg Vacc-4x (100 µg pr. peptide) in 300 µl Endocine divided into two administrations, one for each nose cavity, administrated once weekly for four weeks<br>* Other names: Endocine;|
| Experimental: Vacc-4x high dose<br>1200 µg Vacc-4x (300 µg pr. peptide) in 300 µl Endocine divided into two administrations, one for each nose cavity | Biological: Vacc-4x high dose<br>* 1200 µg Vacc-4x (300 µg pr. peptide) in 300 µl Endocine divided into two administrations, one for each nose cavity, administrated once weekly for four weeks<br>* Other names: Endocine;|
| Placebo Comparator: Zero dose<br>Adjuvant only, i.e. 300 µl Endocine divided into two administrations, one for each nose cavity | Biological: Zero dose<br>* 300 µl Endocine divided into two administrations, one for each nose cavity, administrated once weekly for four weeks<br>* Other names: Endocine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety of intranasal administration of Vacc-4x with Endocine as adjuvant at three different dose levels | Record adverse events including severe adverse events according to GCP | 2 months after completion of last patient. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate cellular immune response to Vacc-4x in vivo by Vacc-4x DTH skin test | Record intradermal Vacc-4x-associated delayed-type hypersensitivity test (DTH) in vivo by measuring skin induration (area) 2 days after injecion qt end of study week 8, in comparison with 38 historical unvaccinated HIV seropositive controls | Up to 2 months after completion of last patient | 
| Evaluate cellular immune response to Vacc-4x in vitro | Measure changes in Vacc-4x-specific T cell proliferation and activation compared with baseline values for each individual participant, i.e. before vaccination | Up to 6 months after completion of last patient | 
| Evaluate the effect on CD4+ T cell counts and viral load (HIV-1 RNA) in peripheral blood | Measure individual changes in CD4 counts and viral loads at baseline | Up to 2 months after completion of last patient | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, vaccination, T cells, mucosal immunity, safety, nasal administration, DTH skin test