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

• Evaluate the safety of intranasal administration of Vacc-4x with Endocine as adjuvant at three different dose levels [ Time Frame: 2 months after completion of last patient. ] [ Designated as safety issue: Yes ]
  Record adverse events including severe adverse events according to GCP
  
  

• Evaluate cellular immune response to Vacc-4x in vivo by Vacc-4x DTH skin test [ Time Frame: Up to 2 months after completion of last patient ] [ Designated as safety issue: No ]
  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
  
  
• Evaluate cellular immune response to Vacc-4x in vitro [ Time Frame: Up to 6 months after completion of last patient ] [ Designated as safety issue: No ]
  Measure changes in Vacc-4x-specific T cell proliferation and activation compared with baseline values for each individual participant, i.e. before vaccination
  
  
• Evaluate the effect on CD4+ T cell counts and viral load (HIV-1 RNA) in peripheral blood [ Time Frame: Up to 2 months after completion of last patient ] [ Designated as safety issue: No ]
  Measure individual changes in CD4 counts and viral loads at baseline
  
  

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.