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Background:  The ability of vaccines to induce mucosal immunity may be important for protection against HIV transmission. The role of vaccination route in determining systemic and mucosal immune responses is poorly understood. Because inguinal and colonic lymphatics are contiguous, inguinal vaccination may be a strategy to stimulate mucosal immunity. Here we describe the safety and immunogenicity of the vaccine candidate ALVAC-HIV vCP205 used in inguinal and deltoid vaccinations.

Methods:  This is a randomized, double-blinded, and placebo-controlled phase I trial of an intensified vaccination schedule (4 weekly vaccinations) in HIV-1-seronegative volunteers. Subjects received placebo (n = 6) or vCP205 (n = 12) via deltoid (n = 9) or inguinal (n = 9) immunization. Baseline colonic mucosal and blood samples were obtained at days –28, –14, and 0, followed by vaccinations at days 0, 7, 14, and 21, and collection of experimental samples at days 10, 17, 24, 180, and 365. Antibody responses were tested by ELISA of serum and colonic fluid. Phenotyping of CD8⁺ T cells was performed by flow cytometry on freshly isolated peripheral blood mononuclear cells (PBMC) and mucosal lymphocytes (MMC). Cytotoxic T-lymphocytes (CTL) were assessed by interferon-γ ELISpot of fresh and expanded CD8⁺ PBMC and expanded CD8⁺ MMC.

Results:  We present the still-blinded results from 18 individuals after the fourth vaccination. HIV-specific antibodies were undetectable in the serum and mucosal secretions of all subjects. Only one HIV-1-specific CTL response was detected in fresh CD8⁺ PBMC. After non-specific, polyclonal expansion of CD8⁺ PBMC, HIV-1-specific CTL responses were found in 9 participants:  3 had CTL responses only in PBMC, 3 had responses only in MMC, and 3 had responses in both compartments. In 5 cases we had reproducible responses over separate visits. Of 18 patients, 11showed a global increase in PBMC CTL against HIV-1 proteins in the vaccine, while 2 of 18 showed an increase in expanded CD8⁺ MMC HIV-1-specific CTL. Vaccination was also associated with a minor increase in HLA DR⁺/CD38⁺ PBMC CD8⁺ T cells in 8 of the 18, but not in MMC.

Conclusions:  Our results indicate that this vaccine given on an intensified schedule appears to induce HIV-1-specific CTL (but not antibody) responses detectable in the expanded CD8⁺ T cells in the majority of individuals. Important issues to be addressed when the data are unblinded include whether vaccination near inguinal lymph nodes affects the responsiveness of cellular immunity in the peripheral blood and colonic mucosa.

Keywords: HIV Vaccine; Clinical Trial; Mucosal Immunity