Novel Concepts Put To The Test In Three New AIDS Vaccine Trials

Volunteers are being recruited through NIAID's AIDS VaccineEvaluation Group (AVEG), which includes six clinical units located inSt.Louis, Nashville, Seattle, Birmingham, Baltimore and Rochester (NY).Thesenew trials bring the total number of vaccine protocols in humanvolunteersconducted through the AVEG to 45, using 22 different vaccine concepts. More than 2,400 volunteers have participated in AVEG preventive HIVvaccine studies since 1988.

According to Jack Killen, M.D., director of NIAID's Division of AIDS,"These three trials are part of NIAID's comprehensive approach to HIVvaccine development. Each of these studies will test a new idea orapproachtoward an effective, safe HIV vaccine."

In AVEG 027, an experimental HIV vaccine already being studied asan injected product will also be applied topically to specific mucosalsites, forexample, the moist tissues lining the nose and mouth, vagina and rectum.

Later, antibodies will be measured at those sites. Most HIV infections,suchas those acquired through sexual exposure, are transmitted acrossmucosalsurfaces. A vaccine that induces mucosal antibodies may work betterthanother types of vaccines against this most common form of exposure.

In AVEG 028, a new strategy -- based on a weakened form ofSalmonella bacteria -- will be used to present an HIV protein to theimmunesystem. Because this bacteria normally reproduces only inside humancells,it can present the HIV proteins in a way that may induce better immuneresponses than other vaccines.

In AVEG 033, a novel adjuvant, GM-CSF, is being combined with acanarypox virus-based vector containing HIV genes. GM-CSF is a drugcommonly used to improve blood cell production in cancer patients. Thisstudy will determine if GM-CSF can improve the immune response to thevector.

Additional information about each trial follows.

***AVEG 027***

AVEG 027 is evaluating sequential doses of live recombinantcanarypox ALVAC-HIV vCP205 delivered first by injection and then as a topical solution applied to the mucosa.

ALVAC-HIV vCP205 is made from a weakened canarypox virus usedas a vaccine for birds. The canarypox virus can fit large pieces offoreignDNA in its genome, infect human cells and cause them to produce foreignproteins. ALVAC-HIV vCP205 contains copies of genes for three pieces ofHIV -- the surface protein, the core protein and one enzyme. When theALVAC vaccine infects human cells, the cells make proteins from thegenesand package the proteins into HIV-like particles called pseudovirions. Although not infectious, these pseudovirions fool the immune system andtrigger an immune response. ALVAC-HIV vCP205 has already been testedin AVEG studies involving more than 700 volunteers.

Eighty-four volunteers will receive the vaccine or a placebo control atentry, one, three and six months. Volunteers will first receive anintramuscular injection to prime the immune response. Booster doseswill beadministered either intramuscularly or via a swab, nose drops or othermethod to mucosal surfaces of the nose, mouth, vagina or rectum. Thisisthe first study in humans to examine vaginal and nasal administration ofanHIV vaccine.

ALVAC vCP205 is being supplied by Pasteur Merieux Connaught(Lyon, France). The study is being conducted at all six AVEG sites:theUniversity of Alabama at Birmingham, the University of Rochester MedicalCenter, the University of Washington, Johns Hopkins University,VanderbiltUniversity and the University of St. Louis. Peter Wright, M.D., ofVanderbiltUniversity, chairs the study.

***AVEG 028***

AVEG 028 applies a new vector vaccine approach to HIV vaccineresearch. Vector vaccines use a non-disease-causing virus or bacteriatotransport HIV or other foreign genes into the body. In this case, agene forthe HIV envelope protein, gp120, is inserted into a weakened form ofSalmonella bacteria to make the vaccine, called VVG203. The weakenedSalmonella vector should retain only a transient, unsustainable abilitytoreplicate in human cells. To assess the safety of VVG203 and todeterminewhether it is sufficiently attenuated, volunteers will be closelyfollowed forsymptoms of typhoid fever.

Live-vector approaches offer many advantages over other vaccinesincluding the ability to induce long-lasting antibody and cell-mediated immune responses, and the relatively low cost of production. Inaddition, because the vaccine is administered orally, it may stimulate theproduction of mucosal antibodies.

AVEG 028 will assess if the VVG203 vaccine is safe and how thebody's immune system responds to the vaccine when it is given alone orsequentially with another AIDS vaccine, HIV-1 MN rgp120. The study willalso determine the optimal dose and immunization schedule. The 12-monthtrial, to be conducted at the Johns Hopkins University AVEG site, willenroll47 adults at low risk of HIV infection. Mary Lou Clements-Mann, M.D.,M.P.H., of Johns Hopkins University, is the study chair.

VVG203 was developed at the University of Maryland Center forVaccine Development in Baltimore by a research team led by David Hone,Ph.D., who currently is affiliated with the Institute of Human Virology,also inBaltimore. This is the first vaccine without industry sponsorship thatNIAIDhas brought from the laboratory to clinical trials. VaxGen, based inSouthSan Francisco, Calif., manufactures the MN rgp120 subunit vaccine usedinthe study.

***AVEG 033***

AVEG 033 uses a new adjuvant with ALVAC to attempt to inducebetter immune responses. An adjuvant enhances or modifies the immune-stimulating properties of a vaccine. The only licensed adjuvants foruse inhuman vaccines are alum compounds. Alum may act in part by stimulatingcertain chemical messengers, called cytokines.

In this study, volunteers are being given a recombinant cytokine,human granulocyte-macrophage colony stimulating factor (GM-CSF), as theadjuvant. GM-CSF may elicit a stronger immune response than alum whengiven directly with a vaccine.

GM-CSF is presently used to boost blood cell counts in transplant andcancer patients. It also can increase the ability of important immunesystem cellsknown as antigen presenters to initiate and direct immune responses.Whenused as an adjuvant, GM-CSF may enhance both antibody and cellularresponses to the vaccine. The vaccine being used in AVEG 033 isALVAC-HIV vCP205, which primarily stimulates the cellular immune response. Thestudy investigators will evaluate the ability of GM-CSF to enhance bothcellular and antibody responses to vCP205. The 36 volunteers enrolledinthe study will be followed for 18 months.

The study is being conducted at four AVEG sites: the University ofAlabama at Birmingham, the University of Rochester Medical Center, JohnsHopkins University and Vanderbilt University. Thomas Evans, M.D., oftheUniversity of Rochester Medical Center, chairs the study. GM-CSF isbeingsupplied by Immunex (Seattle), and ALVAC-HIV vCP205 is being supplied byPasteur Merieux Connaught.

More information about these trials can be obtained by calling theAIDS Clinical Trials Information Service (1-800-TRIALS-A) or by visiting their Web site at http://www.actis.org.

NIAID, part of the National Institutes of Health (NIH), supportsbiomedical research to prevent, diagnose and treat illnesses such asAIDS,tuberculosis, malaria, asthma and allergies. NIH is an agency of theU.S.Department of Health and Human Services. ###

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