The AIDS Vaccine Evaluation Group (AVEG) is comprised of six AIDS Vaccine Evaluation Units (AVEUs), the Data Coordinating and Analysis Center (DCAC), a Central Immunology Laboratory (CIL), a Mucosal Immunology Laboratory (MIL), and a Viral Immunology Laboratory (VIL). AVEG activities are conducted under contract and active coordination with the Clinical Development Branch of the Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID).

Division of the Acquired Immunodeficiency Syndrome (DAIDS)

DAIDS was formed in 1986 to address the national research needs created by the advent and spread of the HIV/AIDS pandemic. Integral to the mission of DAIDS is ensuring that scientific investigation of HIV infection is focused on the most critical biomedical research issues engendered by the epidemic. Specifically, DAIDS works to increase basic knowledge of the pathogenesis, natural history and transmission of HIV disease, and to promote progress in its detection, treatment, and prevention. DAIDS accomplishes this through planning, initiating and evaluating programs in: 1) fundamental basic and clinical research, 2) discovery and development of therapies for HIV infection and its complications, 3) discovery and development of vaccines and other preventative interventions, and 4) training of researchers in these activities.

The discovery and development of a vaccine to prevent HIV infection is a key of DAIDS-supported research. Basic laboratory research studies are expanding knowledge of the mechanisms of HIV immunity and providing information on the most promising candidate vaccines. A substantial, collaborative effort supports animal studies that examine the effects of a wide range of potential vaccines in several retroviral models. Because of this important work, several vaccine candidates are being evaluated in human clinical trials through the AVEG.

In addition, research in preparation for efficacy trials of candidate vaccines is underway through the HIV Vaccine Efficacy Trials Network (HIVNET). DAIDS is working with various communities to determine the feasibility of performing vaccine efficacy trials in specific populations. Other DAIDS HIV prevention research efforts are currently focused on the development of immunologic and chemoprophylactic agents, barrier methods, and other biomedical and behavioral interventions.

AIDS Vaccine Evaluation Group (AVEG)

The AVEG was established in 1988 to conduct Phase I and II clinical trials to determine the safety and immunogenicity of vaccines for HIV/AIDS. To date, over 25 candidate vaccines have undergone analysis in AVEG Phase I trials in over 2,850 volunteers not infected with HIV and who are also at low risk of exposure to and infection with HIV-1. Two rgp120 vaccine candidates were evaluated in a Phase II trial in approximately 300 volunteers. A Phase II trial of a canarypox vaccine in conjunction with a rgp120 vaccine is now underway. Phase II trials are designed to further evaluate the safety and immunogenicity of the vaccines in larger and more heterogenous populations, including volunteers whose history or circumstances suggest that they might be at higher risk of exposure to HIV. Such Phase II studies will provide further information about suitability of vaccines for entry into Phase III (efficacy) trials. An additional 164 HIV-1 infected volunteers participated in four Phase I therapeutic trials.

The AVEG consists of the following contract-supported components, each with clearly defined roles and responsibilities.

AIDS VACCINE EVALUATION UNITS (AVEUs)

Johns Hopkins University, Baltimore, MD - D. Burke, D. Schwartz
St. Louis University, St. Louis, MO - R. Belshe, G. Gorse, S. Frey
University of Alabama at Birmingham, Birmingham, AL - M. Mulligan
University of Rochester, Rochester, NY - M. Keefer, T. Evans
University of Washington, Seattle, WA - L. Corey, J. McElrath
Vanderbilt University, Nashville, TN - B. Graham, P. Wright

DATA COORDINATING AND ANALYSIS CENTER (DCAC)

The Statistical Center for HIV/AIDS Research and Prevention (SCHARP) at the Fred Hutchinson Cancer Research Center, Seattle, WA

CENTRAL IMMUNOLOGY LABORATORY (CIL)

Duke University, Durham, NC - K. Weinhold

MUCOSAL IMMUNOLOGY LABORATORY (MIL)

University of Alabama at Birmingham, Birmingham, AL - J. Mestecky

VIRAL IMMUNOLOGY LABORATORY (VIL)

BBI-Biotech Research Laboratories, Inc., Gaithersburg, MD - M. Cosentino

CENTRAL REPOSITORIES

Clinical Specimens: BBI-Biotech Research Laboratories, Inc. Gaithersburg, MD
Vaccines: McKesson Bioservices Corp., Rockville, MD

Coordination among the AVEG components is critical to its effective operation and is achieved by several mechanisms. The DCAC is pivotal to ensuring a coordinated effort through its collection and management of data from the clinical sites and laboratories and through the logistical support it provides in arranging meetings and disseminating information. The AVEG also has established the following groups, which foster communication and coordination of AVEG activities through frequent conference calls and regularly scheduled meetings:

• The Executive Committee is primarily composed of the NIAID Project Officer, AVEU Principal Investigators (PIs), the laboratories, and the DCAC. This group provides overall direction and management for the AVEG.
• A Community Advisory Board (CAB) has been established at each AVEU to assist in community outreach, recruitment and retention of volunteers, and review of AVEG protocols. CAB members are representatives from the communities participating in Phase I/II vaccine trials. An at-large CAB representative serves as a liaison to the Executive Committee.
• Clinic Coordinators consists of the head nurses and recruiters from each AVEU who address issues relevant to protocol implementation, recruitment and retention of volunteers, including women and minorities, and site operations.
• The Immunology Committee includes one or more immunologist from each AVEU, the CIL, and a representative from the DCAC. This group discusses and plans the immunological studies performed at the sites and laboratories, and makes recommendations regarding potential collaborations.

These groups usually meet at the regularly scheduled meetings of the full AVEG and at the annual conference on AIDS vaccine development. The larger meetings also provide important forums for all AVEG participants to discuss ongoing studies and future plans.

Frequent contacts with industry, other government agencies, and expert groups are also important to the AVEG's effectiveness. The AVEG works closely with vaccine manufacturers to identify promising vaccine candidates and facilitate their entry into clinical trials based on defined scientific and administrative criteria. Interactions with the Food and Drug Administration (FDA) ensure that vaccine products are tested in compliance with all regulatory requirements.

The primary goals of the AVEG are to:

• evaluate promising new vaccine candidates in Phase I/II clinical trials
• determine the safety and toxicity of each potential candidate vaccine
• compare the immunogenicity of different HIV vaccine candidates
• test combination vaccine strategies with different products
• optimize dose and schedule for different products and different subject populations or strategies.

AIDS Vaccine Evaluation Units (AVEUs)

Phase I/II clinical trials of candidate AIDS vaccines are conducted at six AVEUs located in different geographic areas in the United States. Promising vaccines are tested for safety and immunogenicity. Different doses and immunization schedules are evaluated in an attempt to determine optimal humoral and cell-mediated responses induced by each candidate AIDS vaccine. Volunteers are recruited, vaccinated and followed at the AVEUs. Clinical specimens from volunteers are collected, and safety assessments and some immuogenicity assays are conducted at the AVEUs. The CIL performs a standard set of immunological evaluations for each trial.

Each AVEU is responsible for: 1) recruitment of appropriate volunteers into each vaccine protocol, obtaining informed consent, registration and randomization; 2) continuous counseling of volunteers regarding avoidance of exposure to HIV infection; 3) medical management of the volunteers, including vaccine administration, medical monitoring, collection of specimens and prompt reporting of adverse reactions; 4) maintaining confidentiality of all volunteer records; 5) collection and management of all study data collected on volunteers, including completion of data forms, data entry and timely transmission to the central data base; 6) collection of specimens and performance of laboratory assays as specified in each protocol; 7) aliquoting, labeling and transfer of specimens to the Clinical Specimen Repository (CSR), CIL and MIL; and 8) maintaining a pharmacy inventory of vaccines and accountability of records to ensure proper storage and tracking of all vaccine materials.

In addition, each AVEU participates in protocol development. The Protocol Chair for each protocol is an investigator at one of the AVEUs and is responsible for ensuring compliance and timely completion of the study. The Protocol Chairs are chosen from among the AVEU Principal Investigators or their Co-Investigators on a rotating basis.

Institutions:

Johns Hopkins University, Baltimore, Maryland
St. Louis University, St. Louis, Missouri
University of Alabama at Birmingham, Birmingham, Alabama
University of Rochester, Rochester, New York
University of Washington, Seattle, Washington
Vanderbilt University, Nashville, Tennessee

Data Coordinating and Analysis Center (DCAC)

Clinical trials of candidate AIDS vaccines conducted at the AVEUs utilize common protocols tailored to the specifications of each vaccine and done in a multicenter format. Given the complexity of the trials and that multiple vaccines are being tested concurrently, facilitating coordination and communication among the component parts of the AVEG is the paramount responsibility of the DCAC.

The DCAC provides statistical scientific leadership to the AVEG. The DCAC develops appropriate study designs for the AVEG protocols and, when requested, for ancillary studies. The DCAC has a major role in protocol development, designing case report forms and data screens, reviewing manuscripts, and advising on the appropriateness of statistical methods and analyses proposed. The DCAC is responsible for ensuring protocol compliance by monitoring the AVEUs and the CIL for compliance, completeness and accuracy of records. Deficiencies are noted, as well as recommendations to correct any problems.

Data collection and management for the clinical trials is provided by the DCAC through preparation of data forms, and collection, processing and editing of data received from the AVEUs, the CIL and the MIL. The DCAC thus provides quality control regarding data entry, accuracy and transmission. In addition, the DCAC designed and maintains a distributed data management system, data screens and protocol-specific software. The DCAC has written and maintains an AVEG Manual of Operations (MOP) and AIDES User's Guide for computer operations, which are provided to the AVEUs and other members of the AVEG. The DCAC also provides logistical support for the AVEG, such as meeting planning, and disseminates study information, protocols, minutes and other materials, as needed.

Institution:

The Statistical Center for HIV/AIDS Research and Prevention (SCHARP) at the Fred Hutchinson Cancer Research Center, Seattle, WA

Central Immunology Laboratory (CIL)

The Phase I/II clinical trials being conducted by the AVEG include a comprehensive evaluation of the immunogenicity of candidate vaccines. These studies include an increasingly sophisticated array of assays of humoral and cell-mediated immune responses to HIV.

The CIL performs evaluations of humoral responses, including binding antibody and functional antibody (including virus neutralization and cell fusion inhibition) assays, and evaluates certain cellular immune responses, such as HIV-specific cytotoxic T lymphocyte (CTL) activity and antibody-dependent cell-mediated cytotoxicity. The CIL provides quality assurance for designated immunologic assays performed at the AVEUs and conducts training in the implementation of assays for humoral and cell-mediated immune responses to HIV.

Institution:

Duke University, Durham, North Carolina

Mucosal Immunology Laboratory (MIL)

The MIL provides centralized assessment of humoral and cellular mucosal immune responses induced by vaccination of volunteers with candidate AIDS vaccines. It is estimated that HIV is spread by sexual transmission at mucosal surfaces in 80% of cases worldwide. New candidate AIDS vaccines are being developed to specifically induce mucosal responses--this laboratory evaluates immune responses induced by these vaccines at mucosal sites.

The MIL performs varied immunological evaluations on specimens from vaccinees to assess the induction of humoral and cellular HIV-specific mucosal immune responses. These evaluations include antibody binding assays for analysis of HIV-specific IgA1, IgA2, sIgA and IgG antibody responses, and detection of IgA, IgG and IgM antibody-secreting cells in fluid, cell or tissue specimens primarily obtained from gut-associated mucosal sites, reproductive tract mucosal sites or blood.

Institution:

University of Alabama at Birmingham, Birmingham, Alabama

Viral Immunology Laboratory (VIL)

The VIL has expertise in high throughput/high volume assay, large-scale production of standardized reagent and clinical assay support. The VIL's role in supporting the AVEG's HIV vaccine research agenda is to:

• Perform FDA-approved commercial assays to detect HIV-1 infection, including HIV-1 ELISA, Western Blot, immunofluorescence, RIPA, RNA and subtype PCR and detect IgG subclasses and specific antibodies to HIV-1 in other body fluids (e.g., urine, saliva, seminal and vaginal fluids)
• Perform evaluations of humoral immune responses induced by immunization with candidate AIDS vaccines, including HIV-1 neutralization assay with vaccine strains of HIV-1 and primary field isolates, to prepare and maintain stocks of HIV-1 from PBMCs or monocytes, to isolate and expand primary HIV-1 isolates for neutralization assays, and to perform TCID₅₀ and bioburden determinations on virus stocks
• Process and maintain an inventory of volunteer specimens arriving for evaluation.

Institution:

BBI-Biotech Research Laboratories, Inc., Gaithersburg, Maryland