OUTLINE OF PROTOCOL 201

Subjects: Healthy, HIV-1 uninfected individuals allocated to one of six population strata based on responses to a questionnaire concerning medical history and sexual activity, with randomization to the four treatment groups within each population stratum.

Schema:

Product Description:

CHO cell-derived HIV-1 SF-2 rgp120 combined with MF59 adjuvant emulsion [Chiron/BIOCINE]
CHO cell-derived HIV-1 MN rgp120 in alum [Genentech]

Time Period: First volunteer enrolled 12/09/92 and the last on 12/07/93; follow-up extended to 4 years.

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

Study Chairs: Lawrence Corey and Julie McElrath, University of Washington

DEFINITION OF SEXUAL RISK CATEGORIES FOR PROTOCOL 201

Higher Risk:

• A newly acquired higher risk-associated STD within past 6 months
• Unsafe sexual activity (standard AVEG definition) with 4 or more partners within the past 6 months or more than 15 times with 3 different partners in the last 6 months
• Possibly safe or unsafe sex (standard AVEG definition) with a known HIV+ individual in the past 6 months
• Possibly safe sexual activity (standard AVEG definition) with 12 or more partners in the past 6 months

Lower Risk:

• Mutually monogamous relationship with a known or presumed HIV seronegative partner for the last 6 months
• Safest sexual activity (standard AVEG definition) with unlimited number of partners
• No unsafe sexual activity AND possibly safe sexual activity with less than three partners within the last 6 months.

Intermediate Risk: All remaining individuals

INCLUSION CRITERIA

• Age: 18-60 [Except for Group A where age range is 1628 (03/93)] **
• Sex: Males or nonpregnant females
• Normal history and physical examination
• Normal complete blood count and differential defined as:
  • HCT >34% for women, >38% for men
  • WBC >3500 cells/mm³ with normal differential
  • Total lymphocyte count >800 cells/mm³
  • Absolute CD4 count >400 cells/mm³
  • Platelets (120,000-550,000)
• For females, negative pregnancy test at time of entry

  NOTE: Either urine or serum pregnancy test may be used.

• ALT <3X institutional upper normal limit
• Creatinine <1.6 mg/dl
• Negative ELISA for HIV
• Member of eligible risk group
• Availability and commitment for 18 months of follow-up
• Live attenuated vaccines within 60 days of enrollment

  NOTE: Medically indicated subunit or killed vaccines are not exclusionary; but should be given at least two weeks away from HIV immunization.

• Active syphilis (at prescreen)
• Active tuberculosis (at prescreen)

EXCLUSION CRITERIA

• Clinically significant medical disease
• History of immunodeficiency, autoimmune disease, or use of immunosuppressive medications

  NOTE: IDUs with fever, night sweats, weight loss and diarrhea not attributable to disease (e.g., TB or HIV) will not be excluded from the study.

• Use of experimental agents within 30 days prior to study
• Previous use of HIV vaccines
• 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.

• Active syphilis [see Prescreen]
• Active TB [see Prescreen]

STUDY GOALS

This Phase II trial is directed at expanding the available data regarding the reactogenicity and immunogenicity of two candidate HIV-1 vaccines: SF-2 rgp120 (CHO) [BIOCINE/Chiron] in MF59 Adjuvant; and MN rgp120 [Genentech] in Alum Adjuvant [Genentech]. These vaccines, both recombinant envelope subunit proteins, have been tested 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, particularly targeting those individuals who are at higher risk for acquiring HIV infection and thus potential recipients of an HIV vaccine in the future. The feasibility of conducting vaccine trials in higher risk groups will be assessed. The study will examine the safety and immunogenicity of the candidate vaccines in the higher risk target population, and these responses will be compared to those of the lower risk populations of this trial and to those participants in previous and ongoing AVEG trials.

The major goals of the protocol are:

• To demonstrate in a large sample the safety of and tolerance to the vaccines, as a prelude to large scale efficacy trials.
• To evaluate the level of humoral response induced by vaccination, and to compare the two vaccines with respect to immune responses induced by these specific formulations.
• To determine whether the immune response differs among different population groups.
• To evaluate compliance to candidate vaccine regimens.

Study extensions:

• To measure the safety, immunogenicity and durability of an additional dose of the candidate vaccines among the six risk groups.
• To compare the immune responses elicited by a third boost administered at two different time periods, 12 months or 18 months.