Search

To test the safety and immunogenicity of a high-titered preparation of ALVAC-HIV vCP205 in both high-risk and low-risk persons and to evaluate variations in dosing schedule, we conducted a multicenter, randomized, double-blind trial of this vector in combination with recombinant subunit gp120 in 150 HIV-1-seronegative volunteers. The high-titered ALVAC vaccine was well tolerated; adverse events were minimal and not influenced by dosing. At day 728, the cumulative probability of a cytotoxic T-lymphocyte (CTL) response was 76% (95% confidence interval [CI]: 64%-89%) among volunteers receiving vaccine, and the net amount attributable to vaccination was 50% (CI: 16%; 74%). The net probability of a repeated positive CTL response by day 728 was 50% (CI: 21%; 64%). There was a significant difference in CTL response at day 182 between volunteers who had received four doses versus three doses of vCP205 (42% vs. 24%, p =.052). The CTL response was similar in high-risk volunteers and vaccinia-naive volunteers compared with vaccinia-immune volunteers. Neutralizing antibody responses were detected in 95% of vaccinees at day 287, with higher geometric mean titers in recipients of sequential versus simultaneous dosing of the two vaccines and in vaccinia-naive volunteers. This high-titered preparation of ALVAC-HIV vCP205 in combination with gp120 was safe and immunogenic in a diverse group of HIV-1-seronegative volunteers.

The principal neutralizing determinant (PND) of human immunodeficiency virus HIV-1 is part of a disulfide bridged loop in the third variable region of the external envelope protein, gp120. Analysis of the amino acid sequences of this domain from 245 different HIV-1 isolates revealed that the PND is less variable than thought originally. Conservation to better than 80 percent of the amino acids in 9 out of 14 positions in the central portion of the PND and the occurrence of particular oligopeptide sequences in a majority of the isolates suggest that there are constraints on PND variability. One constraining influence may be the structural motif (beta strand--type II beta turn--beta strand--alpha helix) predicted for the consensus PND sequence by a neural network approach. Isolates with a PND similar to the commonly investigated human T cell lymphoma virus IIIB (HTLV-IIIB) and LAV-1 (BRU) strains were rare, and only 14 percent of sera from 86 randomly selected HIV-1 seropositive donors contained antibodies that recognized the PND of these virus isolates. In contrast, over 65 percent of these sera reacted with peptides containing more common PND sequences. These results suggest that HIV vaccine immunogens chosen because of their similarity to the consensus PND sequence and structure are likely to induce antibodies that neutralize a majority of HIV-1 isolates.