OUTLINE OF PROTOCOL 033

Subjects: Healthy, adult volunteers of both sexes, 18-60 years of age, who have no identifiable higher-risk behavior for HIV-1 infection

Schema: Amendment pending to boost consenting volunteers with APL-400-047 HIV-1 gag-pol DNA vaccine [Wyeth-Lederle Vaccine and Pediatrics]

ORIGINAL STUDY

.	A: ALVAC-HIV vCP205,106.3 TCID50 (PMC) G80: 80 µg GM-CSF (IMMUNEX) G250: 250 µg GM-CSF (IMMUNEX) PG: Placebo GM-CSF(IMMUNEX) PA: Placebo-ALVAC (PMC)
Group	N	SCHEDULE (Months)
		0	1	3	6
A	10	A+PG	A+PG	A+PG	A+PG
B	10	A+G80	A+G80	A+G80	A+G80
C	10	A+G250	A+G250	A+G250	A+G250
D	6	PA+PG	PA+PG	PA+PG	PA+PG
Total	36	.

The GM-CSF or Placebo GM-CSF will be given IM at the same deltoid inoculation site at the same depth, just prior to the ALVAC-HIV vCP205 or Placebo-ALVAC injection.

AMENDMENT II

Original Study Group	N	Original Vaccine Regimen (0, 1, 3, 6 months)**	Amendment II Regimen
			Month 0	Month 1
A	10	A + GM-CSF placebo	DNA (IM)	DNA (IM)
B	10	A + GM-CSF (80 µg)
C	10	A + GM-CSF (250 µg)
D	6	PA + GM-CSF placebo	DNA Control	DNA Control
** See original protocol schedule for details			.
DNA boost: 1000 µg APL-400-047, formulated with bupivacaine as a facilitating agent - given IM DNA control: Bupivacaine carrier alone

Note: It is anticipated that most Protocol 033 volunteers have completed follow-up through Day 336 of the original protocol. The booster immunizations in Amendment II should begin as soon as possible, but at least 2 weeks after the volunteers last protocol visit.

Product Description: ALVAC-HIV vCP205 is a recombinant canarypox vector into which the following genes have been inserted: HIV-1 envelope gp120 (strain MN) linked to the transmembrane portion of HIV-1 gp41 (strain LAI) and the HIV-1 LAI genes encoding the entire gag protein and a portion of the pol sequence, sufficient to evoke the protease portion. [Pasteur-Merieux/Connaught]

Recombinant human GM-CSF (Leukine), produced by recombinant DNA technology in yeast from a DNA sequence obtained from human T cells using a murine GM-CSF cDNA probe. [Immunex Corporation]

Amendment II: The APL 400-047 DNA plasmid vaccine expresses the human immunodeficiency virus type-1 core structural proteins, and partially deleted nonfunctional reverse transcriptase and integrase proteins, derived from the HIV-1 strain HXB2 and inserted into the GENEVAX^® DNA plasmid backbone. APL 400-047 is formulated with the facilitating agent bupivacaine, an amide-type local anesthetic agent. [Apollon]

Time Period: 18 months; volunteers participating in Amendment II will have follow-up extended to 3 months after the last immunization in the extended study. First volunteer enrolled 01/21/98 and the last on 06/03/98. Amendment II boosts began 07/99.

Clinical Sites: University of Rochester, Johns Hopkins University, University of Alabama at Birmingham, Vanderbilt University

Study Chair: Thomas Evans, University of Rochester

INCLUSION CRITERIA

Standard inclusion criteria, with the addition of:

• Viable EBV line prior to initial immunization

EXCLUSION CRITERIA

Standard exclusion criteria, with the addition of:

• Positive for Hepatitis C antibody
• Allergy to eggs, neomycin or thimerosal
• Use of lithium or cimetidine

STUDY GOALS

• Primary Objective: To generate safety data on the use of GM-CSF as an adjuvant in combination with ALVAC-HIV vCP205
• Secondary Objective: To evaluate the adjuvant effect of the GM-CSF on the immunogenicity of ALVAC-HIV vCP205.
  • Study whether GM-CSF used in combination with ALVAC-HIV vCP205 can improve either the kinetics or magnitude of the binding and neutralizing antibody responses.
  • Study whether GM-CSF used in combination with ALVAC-HIV vCP205 can improve the kinetics, magnitude or durability of the HIV-specific cytotoxic T lymphocyte (CTL) response.
  • Assess whether other vaccine-induced HIV-specific T cell immune responses are altered, as measured by lymphoproliferation, Delayed Type Hypersensitivity (DTH) skin testing and other laboratory tests.
• Amendment II: The study was amended in April 1999 to study the safety of following the four ALVAC immunizations with a nucleic acid gag/pol HIV-1 immunogen (APL-400-047, Wyeth-Lederle). In addition, the ability of this sequence of immunizations to boost the CTL, T helper cell, and antibody response will be assessed.