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Induction of CD8+ cytotoxic T cells is considered one of the important correlates for the protective efficacy of candidate human immunodeficiency virus type 1 (HIV-1) vaccines. To induce CD8+ cytotoxic T lymphocytes (CTLs) along with neutralizing antibody and CD4+ T cell help, a live canarypox virus construct expressing gp120, transmembrane gp41, the gag and protease genes, and sequences containing CTL epitopes in nef and pol was given simultaneously with, or followed by, rgp120 SF2. CD8+ CTLs were detected in 61% of volunteers at some time during the trial. Three to 6 months after the last immunization, the gene-specific responses were gag, 26/81; env, 17/77; nef, 12/77; and pol, 3/16. Simultaneous immunization with the canarypox vector and the subunit, beginning with the initial immunization, resulted in earlier antibody responses. In summary, a strategy of immunization with a canarypox vector expressing multiple genes of HIV-1 given with gp120 results in durable CD8+ CTL responses to a broad range of epitopes.

We evaluated prime-boost immunization with two recombinant envelope glycoprotein subunit vaccines (HIV-1MN recombinant gp160 vaccine in alum adjuvant [MN rgp160] and HIV-1MN recombinant gp120 vaccine in alum adjuvant [MN rgp120]) for safety and immunogenicity in healthy, HIV-1-uninfected adults. The rationale was to combine the helper T cell memory and binding antibody responses typically induced by rgp160 vaccines with the superior neutralizing antibody responses induced by rgp120 vaccines. In a double-blinded, controlled trial, volunteers were randomly assigned to receive MN rgp160 or adjuvant placebo, and a subset later received MN rgp120. The two vaccines were safe, but reactions to MN rgp160 and its adjuvant placebo exceeded those to MN rgp120. MN rgp160 induced IgG binding antibodies, including all IgG subclasses, to MN rgp160 in all vaccine recipients. HIV-1MN-neutralizing and anti-V3 MN peptide-binding antibodies were observed in a majority of volunteers after the fourth MN rgp160 immunization, but at lower levels compared with immunization with MN rgp120 in historical controls. HIV-1-binding, neutralizing, and fusion inhibition antibodies were boosted to the highest levels among MN rgp160 recipients after MN rgp120 booster injections. MN rgp120 boosting appeared to alter the distribution of MN rgp160 vaccine-induced, anti-MN rgp160 IgG subclass antibodies. MN rgp160 induced helper T cell memory, measured by lymphocyte proliferation, Thl and Th2 cytokine production, and skin testing. Strategies including both subunit vaccines may help maximize antibody and helper T cell memory responses to HIV-1 envelope glycoprotein.

A safety and immunogenicity trial was conducted in vaccinia-immune and vaccinia-naive human immunodeficiency virus (HIV)-uninfected adults who were randomized to receive 10(6) or 10(7) TCID50 of canarypox (ALVAC) vector expressing HIV-1MN gp160 or 10(5.5) TCID50 of ALVAC-rabies virus glycoprotein control at 0 and 1 or 2 months and ALVAC-gp160 or 50 microg of HIV-1SF2 recombinant (r) gp120 in microfluidized emulsion at 9 and 12 months; others received rgp120 at 0, 1, 6, and 12 months. All vaccines were well-tolerated. Neither vaccinia-immune status before vaccination nor ALVAC dose affected HIV immune responses. HIV-1MN and HIV-1SF2 neutralizing antibodies were detected more often (100%) in ALVAC-gp160/rgp120 recipients than in recipients of ALVAC-gp160 (<65%) or rgp120 (89%) alone. ALVAC-gp160/rgp120 also elicited more frequent HIV V3-specific and fusion-inhibition antibodies, antibody-dependent cellular cytotoxicity, lymphoproliferation, and cytotoxic CD8+ T cell activity than did either vaccine alone. Trials with ALVAC expressing additional HIV components and rgp120 are underway.

The safety and immunogenicity of HIV-1MN recombinant gp160 (MN rgp160) vaccine in healthy, uninfected volunteers was tested in a double-blind study with a factorial design. By random assignment, 20 volunteers received three 200 micrograms doses of MN rgp160 and four volunteers received placebo at days 0, 28, and 168 or 0, 56, and 224. Of the 24 volunteers, 16 received 200 micrograms or 800 micrograms of MN rgp160 and two received placebo at day 532 (month 18). The vaccine was safe. It induced T cell memory measured by Th1 cytokine production and lymphocyte proliferation, and serum anti-MN rgp160 IgG (all subclasses) and IgA antibodies. Fifteen of 20 vaccinees developed neutralizing antibody. The regimen including immunizations on days 0, 28, and 168 followed by the 800 micrograms fourth dose was most immunogenic.

Twenty-two human immunodeficiency virus type 1 (HIV-1)-infected, asymptomatic volunteers with CD4 cell counts of >600 cells/mm3 who were enrolled in a phase I immunotherapy trial comparing two schedules of immunization of an HIV-1 IIIB-based recombinant gp160 (rgp160) experimental vaccine were evaluated for rgp160-specific antibodies in parotid saliva, genital secretions, and serum. When the study was unblinded, it was determined that five volunteers had received rgp160 on a month 0, 1, 2, 3, 4, and 5 immunization schedule, seven volunteers had received rgp160 on a month 0, 1, 2, and 5 schedule, five had received alum/deoxycholate placebo, and seven had received a licensed hepatitis B virus vaccine. Five volunteers consented to the donation of parotid saliva but not genital secretions. Prior to immunization, parotid saliva specimens were available for 11 of 22 volunteers, seminal plasma (SP) specimens were available for 7 of 22 volunteers, cervicovaginal lavage (CVL) specimens were available for 5 of 22 volunteers, and serum was available for 22 of 22 volunteers. These baseline specimens and specimens collected at 1 and 7 months after the final immunizations were assessed by enzyme-linked immunosorbent assay for immunoglobulin G (IgG) and IgA antibodies specific for HIV-1 LAI rgp160 or HIV-1 MN rgp160. No augmentation in HIV rgp160-specific IgG or IgA antibody production in either parotid saliva or serum specimens of vaccinees compared to that in controls was observed after immunization. There were insufficient numbers of SP or CVL specimens available for statistical comparisons between vaccinees and controls. Overall, anti-LAI rgp160 IgG antibodies were detected in the parotid saliva specimens of 20 of 22 volunteers, the seminal plasma specimens of 11 of 11 volunteers, and the CVL specimens of 6 of 6 volunteers and in 21 of 22 serum specimens. Fewer volunteers expressed anti-LAI rgp160 IgA antibodies in mucosal or serum specimens: 11 of 22 parotid saliva specimens, 3 of 11 SP specimens, 3 of 5 CVL samples, and 12 of 22 sera.

The inability of antibodies induced by experimental human immunodeficiency virus type 1 (HIV-1) vaccines to neutralize HIV-1 primary isolates may be due to a failure to elicit such antibodies, antigenic differences between the vaccine and the strains tested, insensitivity of the assays used, or to a combination of factors. New neutralization assays were used to determine the ability of candidate AIDS vaccines to generate neutralizing antibodies for clade B primary isolate BZ167, which is closely related in portions of its envelope to the immunizing strains. Sera from HIV-uninfected volunteers in vaccine trials were tested, and neutralizing activity was found in recipients of recombinant (r) gp120MN or of rgp160MN-containing canarypox boosted with rgp120SF-2. Detection of antibodies that neutralize primary isolate BZ167 correlated with neutralizing activity for homologous vaccine strains. These data demonstrate that certain candidate AIDS vaccines can elicit antibodies that neutralize a primary isolate of HIV-1.

Phase I studies of volunteers not infected with human immunodeficiency virus type 1 (HIV-1) have shown that immunization with envelope subunit vaccine products elicits antibodies that neutralize laboratory-adapted (prototype) HIV-1 strains in vitro. Prototype strains are adapted to grow in continuous (neoplastic) cell lines and are more susceptible to neutralization than are primary isolates cultured in human peripheral blood mononuclear cells. In this study, 50 sera from nine phase I vaccine trials and 16 from HIV-1-infected persons were evaluated for neutralizing antibody activity against 3 laboratory-adapted and 5 primary HIV-1 isolates. Of 50 sera, 49 neutralized at least 1 of the prototype strains; however, none displayed neutralizing activity against primary isolates of HIV-1. Serum from most HIV-1-infected persons neutralized both laboratory-adapted and primary HIV-1 isolates. These data demonstrate a qualitative, or large quantitative, difference in the neutralizing antibody response induced by envelope subunit vaccination and natural HIV-1 infection.