Clinical trial NCT01473810: Intranasal Modified Vacc-4x Gag Peptides With Endocine as Adjuvant
Official title: Immunotherapy of HIV-infected Patients: A Single-blinded, Randomized, Immunogenicity, Pilot Study of Intranasal Administration of Vacc-4x With Endocine as Adjuvant
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV Infection
Keywords: HIV
vaccination
T cells
mucosal immunity
safety
nasal administration
DTH skin test
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: Bionor Immuno AS
name: Eurocine Vaccines AB
First posted: 2011-11-17
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Evaluate the safety of intranasal administration of Vacc-4x with Endocine as adjuvant at three different dose levels
timeFrame: 2 months after completion of last patient.
Secondary outcomes:
measure: Evaluate cellular immune response to Vacc-4x in vivo by Vacc-4x DTH skin test
timeFrame: Up to 2 months after completion of last patient
measure: Evaluate cellular immune response to Vacc-4x in vitro
timeFrame: Up to 6 months after completion of last patient
measure: Evaluate the effect on CD4+ T cell counts and viral load (HIV-1 RNA) in peripheral blood
timeFrame: Up to 2 months after completion of last patient
Other outcomes:
Locations:
city: Oslo
country: Norway
facility: Department of Infectious Diseases, Oslo University Hospital
Study officials:
affiliation: Oslo University Hospital
name: Dag Kvale, Professor/MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Brekke K, Lind A, Holm-Hansen C, Haugen IL, Sorensen B, Sommerfelt M, Kvale D. Intranasal administration of a therapeutic HIV vaccine (Vacc-4x) induces dose-dependent systemic and mucosal immune responses in a randomized controlled trial. PLoS One. 2014 Nov 14;9(11):e112556. doi: 10.1371/journal.pone.0112556. eCollection 2014.