Protocol 202

OUTLINE OF PROTOCOL 202

A PHASE II SAFETY AND IMMUNOGENICITY TRIAL OF LIVE RECOMBINANT CANARYPOX ALVAC-HIV VCP205 WITH OR WITHOUT HIV-1 SF-2 RGP120 IN HIV-1 UNINFECTED ADULT VOLUNTEERS

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), identified as belonging to one of two risk groups for HIV infection: 1) individuals having lower-risk behavior or 2) individuals having higher-risk behavior. [Total Number of Subjects = 420]

Schema:

Group	Total Volunteers	Clinical Sites and Risk Groups			Immunization Schedule in Months
		AVEG		HIVNET	Immunization Schedule in Months
		Lower	Higher	Higher	0	1	3	6
A	140	20	40	80	A+gp120	A+gp120	A+gp120	A+gp120
B	140	20	40	80	A+Sal	A+Sal	A+Sal	A+Sal
C	140	20	40	80	PA+Sal	PA+Sal	PA+Sal	PA+Sal
TOTAL	420**	60	120	240**	A: ALVAC vCP205, 10^6.3 TCID₅₀gp120: SF-2 rgp120 (50 µg) in MF59 PA: Placebo-ALVAC Sal: Saline Placebo

** A total of 255 volunteers were enrolled in the HIVNET cohort for a total of 435 volunteers enrolled in the protocol

ACCRUAL AND IMMUNIZATIONS COMPLETED

Product Description:

ALVAC-HIV vCP205 is a recombinant canarypox vector vaccine 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]
CHO cell-derived SF-2 rgp120 in combination with MF59 adjuvant emulsion. [Chiron Vaccines]

Time Period: 24 months with two additional annual follow-up visits and the possibility of extension; first volunteer enrolled 05/22/97 and the last on 01/26/98.

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

HIVNET: Denver Department of Public Health (CO), Fenway Community Health Center (MA), Memorial Hospital/NEBHS (RI), Howard Brown Health Center (IL), New York Blood Center (NY), New York University Medical Center (NY), San Francisco Department of Public Health (CA), University of Pennsylvania, University of Washington

Study Co-Chairs: Robert Belshe and Geoffrey Gorse, Saint Louis University; Cladd Stevens, New York Blood Center; Susan Buchbinder, San Francisco Department of Public Health

INCLUSION CRITERIA

Standard AVEG inclusion criteria, with the following exceptions:

Negative Hepatitis B (Hepatitis B surface antigen is measured at prescreen but is not an eligibility criterion)

Variations to standard criteria:

Risk status: Enrollment into the protocol will be stratified by risk status.
- HIVNET Volunteers: Participants at HIVNET sites will be eligible for the study if they meet the eligibility criteria for the HIVNET Vaccine Preparedness Study (VPS) [see Appendix A, HIVNET Criteria for Defining High Risk]. At HIVNET sites with women among their baseline study participants, at least one-third of the enrollees will be women.
- AVEG Volunteers: Lower risk participants at the AVEG sites will be enrolled using the same risk behavior criteria applied in Phase I AVEG studies [see Appendix A, AVEG Risk Categories A and B]. If potential AVEG volunteers do not meet the criteria for AVEG risk category A or B, they may be enrolled in the higher risk group if they meet the HIVNET criteria for defining high risk.
Numbers of female volunteers: a minimum of 20% females will be enrolled into each of the risk strata (lower and higher risk groups)
Normal complete blood count and differential defined as:
- Hematocrit 30% for women; 38% for men
- White count 3,500 cells/mm³ and 12,000 cells/mm³
- Differential within institutional normal limits or approval of site physician
- Total lymphocyte count 800 cells/mm³
- Absolute CD4 count 400 cells/mm³
- Platelets (125,000550,000/mm³)
Normal ALT (3 x institutional upper normal limit)
Negative Hepatitis B
Negative ELISA for HIV within 8 weeks of immunization
Hepatitis B surface antigen is measured at baseline (rather than prescreen eligibility testing)

EXCLUSION CRITERIA

Standard exclusion criteria, with the following exceptions:

Variations to standard criteria:

Criteria for risk behavior are described above
Persons with a history of suicide attempts within 3 years

Addition:

Immediate type hypersensitivity reaction to egg products or neomycin (used to prepare ALVAC vaccines)

STUDY GOALS

This Phase II trial is directed at expanding the available data regarding the safety and immunogenicity of two HIV-1 vaccine strategies: canarypox vector vCP205 (Pasteur-Merieux Connaught) or vCP205 with SF-2 rgp120 (Chiron Vaccines). These vaccine strategies have been evaluated in Phase I studies in healthy immunocompetent adults and have been shown to be well tolerated and immunogenic. The goal of this vaccine trial is to expand testing into a larger population base, in order to estimate the safety profile and immunogenicity with more precision than possible from Phase I study data. The study will include individuals who are at higher risk for acquiring HIV infection and thus representative of potential HIV vaccine recipients in the future. Aspects of the feasibility of conducting larger vaccine efficacy trials in higher risk groups will be assessed with the proposed vaccine candidates.

Primary Objectives

Expand the data on safety of ALVAC vCP205 alone and ALVAC vCP205 with SF-2 rgp120, comparing vaccine and placebo recipients. These evaluations will be made in:
- participants at lower risk for HIV-1 infection
- participants at higher risk; i.e., the proposed populations for possible subsequent efficacy trials
Expand the data on immunogenicity of ALVAC vCP205 alone and ALVAC vCP205 with SF-2 rgp120 in:
- participants at lower risk for HIV-1 infection
- participants at higher risk; i.e., the proposed populations for possible subsequent efficacy trials

Secondary Objectives

Assess readiness and develop and pilot test procedures for future efficacy trials.
Describe volunteers' behavior and resulting events during the study which might impact on feasibility of future vaccine efficacy trials.
- assess recruitment success; i.e., rate of enrollment in a Phase II trial, including relationship to previously expressed willingness to participate in vaccine trials (HIVNET subset of volunteers).
- determine the frequency and types of social harms experienced by trial participants, how they are addressed, and if they are addressed to the satisfaction of trial participants.
- compare the risk taking behavior in vaccine and placebo recipients at enrollment and over time.
- assess the quality of blinding: 1) Assess the participants' belief regarding their assignment to vaccine or placebo groups; 2) Monitor the frequency of HIV antibody testing (compulsory and voluntary) outside of the trial.