a multicenter, randomized, placebo-controlled, double-blinded, phase i trial to evaluate the safety and immunogenicity of live recombinant canarypox alvac-hiv vcp205 combined with gm-csf in healthy, hiv-1 uninfected volunteers

Conditions: HIV Infections

Summary: to evaluate the safety and immunogenicity of live recombinant canarypox alvac-hiv vcp205 in combination with recombinant human granulocyte-macrophage colony-stimulating factor (gm-csf) at 80 microg and 250 microg. \[as per amendment 4/30/99: to study the safety of following 4 alvac immunizations with a nucleic acid gag/pol hiv-1 immunogen (apl-400-047, wyeth-lederle). to assess the ability of this sequence of immunization to boost the ltl, t-helper cell, and antibody response.\] alvac-hiv candidate vaccines have induced hiv-specific ctl responses in more than half of recipients in some protocols. depending on the hiv-1 gene products expressed by the particular alvac-hiv candidate vaccine, volunteers have generated anti-envelope (vcp125, vcp205, and vcp300), anti-gag (vcp205 and vcp300), and anti-nef (vcp300) ctl activity. although 3 to 4 immunizations with the different alvac-hiv experimental vaccines induce anti-hiv-1 neutralizing antibodies in a portion, often the majority, of volunteers, the geometric mean titers of these antibodies are modest, usually less than 50. this study will determine whether there is an increase in the anti-hiv antibody titers when gm-csf is used as an adjuvant with alvac-hiv vcp205 and will also examine the kinetics and magnitude of the hiv-specific ctl response.

alvac-hiv candidate vaccines have induced hiv-specific ctl responses in more than half of recipients in some protocols. depending on the hiv-1 gene products expressed by the particular alvac-hiv candidate vaccine, volunteers have generated anti-envelope (vcp125, vcp205, and vcp300), anti-gag (vcp205 and vcp300), and anti-nef (vcp300) ctl activity. although 3 to 4 immunizations with the different alvac-hiv experimental vaccines induce anti-hiv-1 neutralizing antibodies in a portion, often the majority, of volunteers, the geometric mean titers of these antibodies are modest, usually less than 50. this study will determine whether there is an increase in the anti-hiv antibody titers when gm-csf is used as an adjuvant with alvac-hiv vcp205 and will also examine the kinetics and magnitude of the hiv-specific ctl response. in this randomized, placebo-controlled, double-blinded study volunteers receive alvac-hiv vcp205 at 10\^6.3 tcid50 or placebo and gm-csf or placebo by intramuscular injection at months 0, 1, 3, and 6 as follows: group a: vcp205 plus gm-csf placebo (10 volunteers) group b: vcp205 plus 80 microg gm-csf (10 volunteers) group c: vcp205 plus 250 microg gm-csf (10 volunteers) group d: vcp205 placebo plus gm-csf placebo (6 volunteers). \[as per amendment 04/30/99: boosting with apl-400-047 hiv-1 gag/pol dna is added for volunteers who have received all scheduled immunization in the original protocol. volunteers in groups a, b, and c will receive booster intramuscular injections of dna vaccine at months 0 and 1, those in group d will receive dna control (bupivacaine carrier alone) at months 0 and 1\].

Eligibility criteria:
inclusion criteria volunteers must have: * negative elisa for hiv within 8 weeks prior to immunization. * cd4 count of 400 cells/mm3 or higher. * normal history and physical examination. * viable ebv line prior to initial immunization. \[as per amendment 4/30/99: * negative anti-dsdna antibodies (for volunteers receiving booster vaccine).\] exclusion criteria co-existing condition: volunteers with the following conditions or symptoms are excluded: * medical or psychiatric condition or occupational responsibilities that preclude compliance with the protocol. * recent suicidal ideation or psychosis. * active syphilis. note: * if the serology is documented to be a false positive or due to a remote (greater than 6 months) treated infection, the volunteer is eligible. * active tuberculosis. note: * volunteers who have a positive ppd and a normal chest x-ray showing no evidence of tb and who do not require inh therapy are eligible. * positive for hepatitis c antibody or hepatitis b surface antigen. * allergy to eggs, neomycin, or thimerosal. \[as per amendment 4/30/99: * hypersensitivity to bupivacaine or other amide-type anesthetics (e.g., lidocaine, mepivacaine) for volunteers receiving booster vaccine).\] concurrent medication: excluded: lithium or cimetidine. volunteers with the following prior conditions are excluded: * history of immunodeficiency, chronic illness, or autoimmune disease. * history of cancer unless there has been surgical excision with reasonable assurance of cure. * history of suicide attempts or past psychosis. * history of anaphylaxis or other serious adverse reactions to vaccines. * history of serious allergic reaction to any substance requiring hospitalization or emergent care (e.g., stevens-johnson syndrome, bronchospasm, or hypotension). \[as per amendment 11/13/97: * history of cardiac disease or cardiac arrhythmias.\] prior medication: excluded: * live attenuated vaccines within 60 days of study. note: * medically indicated subunit or killed vaccines (e.g., influenza, pneumococcal) are not exclusionary, but should be given at least 2 weeks away from hiv immunizations. * experimental agents within 30 days prior to study. * blood products or immunoglobulin in the past 6 months. * hiv-1 vaccines or placebo as part of a previous hiv vaccine trial. * immunosuppressive medications. risk behavior: excluded: volunteers with an identifiable higher-risk behavior for hiv infection (i.e., aveg risk group c or d), including a history of injection drug use within 12 months prior to enrollment or higher-risk sexual behavior as defined by the aveg.

Keywords: reference values granulocyte-macrophage colony-stimulating factor aids vaccines hiv seronegativity dose-response relationship, immunologic hiv preventive vaccine