OUTLINE OF PROTOCOL 034

Subjects: Healthy, HIV-1 uninfected adult volunteers of either gender, 18-60 years of age (no more than 10% will be older than 50 years of age) having lower risk behavior [Number of subjects = 100]

Schema:

vCP205: ALVAC-HIV (vCP205) dose of 106.3 TCID50 vCP1433: ALVAC-HIV (vCP1433) dose of 106.6 TCID50 vCP1452: ALVAC-HIV (vCP1452) dose of 106.7 TCID50			rgp160: 50 µg recombinant gp160MN/LAI-2 in PCPP Placebo: PCPP+NaCl RG: vCP65 dose of 106.3 TCID50 (ALVAC-RG)
Group	Total Volunteers	ALVAC Vector	Immunization Schedule in Months
			0	1	3	6
I	20	vCP205	vCP205	vCP205	vCP205 + rgp160	vCP205 + rgp160
II	35	vCP1433	vCP1433	vCP1433	vCP1433 + rgp160	vCP1433 + rgp160
III	35	vCP1452	vCP1452	vCP1452	vCP1452 + rgp160	vCP1452 + rgp160
IV	10	ALVAC-RG	RG	RG	RG + Placebo	RG + Placebo
Total =	100	.

Note: Amendment III (034A) outline is provided separately.

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]

ALVAC-HIV vCP1433 vaccine is a modified recombinant canarypox virus expressing the same HIV gene products as vCP205, with the addition of the known human CTL epitopes from the nef and pol gene products. [Pasteur Merieux Connaught]

ALVAC-HIV vCP1452 vaccine is a modified recombinant canarypox virus expressing the same HIV gene products as vCP205 and the human CTL epitopes from the nef and pol gene products. In addition, two vaccinia virus coding sequences have been added to enhance the overall efficiency of viral mRNA translation, with the goal of increasing expression of the HIV gene products. [Pasteur Merieux Connaught]

rgp160MN/LAI-2 is an envelope glycoprotein from HIV-1 virus expressed by VV.TG.9150 vaccinia virus on BHK21 cells. This recombinant vaccinia is a derivative of VV.TG 1163 in which the HIV-1 LAI gp120 coding sequence has been replaced by that for HIV-1 MN. [Pasteur Merieux Connaught]

Time Period: 12 months, with possibility of extension; first volunteer enrolled on 06/17/98 and the last on 08/24/98.

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

Study Chair: David Schwartz, Johns Hopkins University

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:

• Allergy to eggs or neomycin
• Prior receipt of rabies vaccine

STUDY GOALS

• Primary Objective: To evaluate the safety of each ALVAC-HIV vector, vCP205, vCP1433 and vCP1452, given alone and then simultaneously twice with gp160 MN/LAI-2 in polyphosphazene (PCPP).
  
• Secondary Objective: To compare cellular immune responses and serum antibody responses achieved by immunization with each ALVAC-HIV vector, vCP205, vCP1433 or vCP1452, given at 0 and 1 months, followed by simultaneous immunization with each ALVAC-HIV vector and subunit gp160 MN/LAI-2 in PCPP given at 3 and 6 months. By determining:
  • CD8+ and CD4+ cytotoxic T lymphocyte (CTL) activity specific for HIV-1 env, gag, pol, and nef epitopes
  • T-helper responses to HIV env and p24 proteins using lymphoproliferation
  • Neutralizing antibodies to HIV-1 MN
  • Cross-neutralizing antibodies to primary NSI and SI isolates of HIV-1
  • Antibody-dependent cellular cytotoxicity (ADCC) to HIV-1 MN
  • HIV-1 MN V3 peptide-specific, gp160 MN/LAI-specific and HIV-1 LAI p24-specific binding antibodies
  • Resistance to in vitro challenge with macrophage-trophic and T-cell trophic HIV-1 strains
  • Responses detected by ELISPOT for gamma interferon-producing CD8+ cells
  • CD4+ T cell proliferative precursor frequency enumeration by limiting dilution analysis (LDA) to both HIV-1 envelope and p24 antigens and nef, if possible