Investigators supported by the National Institute of Allergy and Infectious Diseases (NIAID) have begun enrolling volunteers in three new clinical trials of novel HIV vaccine approaches. The trials are testing a novel route of immunization, an innovative vaccine strategy and a new adjuvant, or vaccine booster.
Volunteers are being recruited through NIAID's AIDS Vaccine Evaluation Group (AVEG), which includes six clinical units located in St. Louis, Nashville, Seattle, Birmingham, Baltimore and Rochester (NY). These new trials bring the total number of vaccine protocols in human volunteers conducted through the AVEG to 45, using 22 different vaccine concepts. More than 2,400 volunteers have participated in AVEG preventive HIV vaccine 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 HIV vaccine development. Each of these studies will test a new idea or approach toward an effective, safe HIV vaccine."
In AVEG 027, an experimental HIV vaccine already being studied as an injected product will also be applied topically to specific mucosal sites, for example, the moist tissues lining the nose and mouth, vagina and rectum.
Later, antibodies will be measured at those sites. Most HIV infections, such as those acquired through sexual exposure, are transmitted across mucosal surfaces. A vaccine that induces mucosal antibodies may work better than other types of vaccines against this most common form of exposure.
In AVEG 028, a new strategy -- based on a weakened form of Salmonella bacteria -- will be used to present an HIV protein to the immune system. Because this bacteria normally reproduces only inside human cells, it can present the HIV proteins in a way that may induce better immune responses than other vaccines.
In AVEG 033, a novel adjuvant, GM-CSF, is being combined with a canarypox virus-based vector containing HIV genes. GM-CSF is a drug commonly used to improve blood cell production in cancer patients. This study will determine if GM-CSF can improve the immune response to the vector.
Additional information about each trial follows.
AVEG 027 is evaluating sequential doses of live recombinant canarypox 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 used as a vaccine for birds. The canarypox virus can fit large pieces of foreign DNA in its genome, infect human cells and cause them to produce foreign proteins. ALVAC-HIV vCP205 contains copies of genes for three pieces of HIV -- the surface protein, the core protein and one enzyme. When the ALVAC vaccine infects human cells, the cells make proteins from the genes and package the proteins into HIV-like particles called pseudovirions. Although not infectious, these pseudovirions fool the immune system and trigger an immune response. ALVAC-HIV vCP205 has already been tested in AVEG studies involving more than 700 volunteers.
Eighty-four volunteers will receive the vaccine or a placebo control at entry, one, three and six months. Volunteers will first receive an intramuscular injection to prime the immune response. Booster doses will be administered either intramuscularly or via a swab, nose drops or other method to mucosal surfaces of the nose, mouth, vagina or rectum. This is the first study in humans to examine vaginal and nasal administration of an HIV vaccine.
ALVAC vCP205 is being supplied by Pasteur Merieux Connaught (Lyon, France). The study is being conducted at all six AVEG sites: the University of Alabama at Birmingham, the University of Rochester Medical Center, the University of Washington, Johns Hopkins University, Vanderbilt University and the University of St. Louis. Peter Wright, M.D., of Vanderbilt University, chairs the study.
AVEG 028 applies a new vector vaccine approach to HIV vaccine research. Vector vaccines use a non-disease-causing virus or bacteria to transport HIV or other foreign genes into the body. In this case, a gene for the HIV envelope protein, gp120, is inserted into a weakened form of Salmonella bacteria to make the vaccine, called VVG203. The weakened Salmonella vector should retain only a transient, unsustainable ability to replicate in human cells. To assess the safety of VVG203 and to determine whether it is sufficiently attenuated, volunteers will be closely followed for symptoms of typhoid fever.
Live-vector approaches offer many advantages over other vaccines including the ability to induce long-lasting antibody and cell-mediated immune responses, and the relatively low cost of production. In addition, because the vaccine is administered orally, it may stimulate the production of mucosal antibodies.
AVEG 028 will assess if the VVG203 vaccine is safe and how the body's immune system responds to the vaccine when it is given alone or sequentially with another AIDS vaccine, HIV-1 MN rgp120. The study will also determine the optimal dose and immunization schedule. The 12-month trial, to be conducted at the Johns Hopkins University AVEG site, will enroll 47 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 for Vaccine Development in Baltimore by a research team led by David Hone, Ph.D., who currently is affiliated with the Institute of Human Virology, also in Baltimore. This is the first vaccine without industry sponsorship that NIAID has brought from the laboratory to clinical trials. VaxGen, based in South San Francisco, Calif., manufactures the MN rgp120 subunit vaccine used in the study.
AVEG 033 uses a new adjuvant with ALVAC to attempt to induce better immune responses. An adjuvant enhances or modifies the immune- stimulating properties of a vaccine. The only licensed adjuvants for use in human vaccines are alum compounds. Alum may act in part by stimulating certain chemical messengers, called cytokines.
In this study, volunteers are being given a recombinant cytokine, human granulocyte-macrophage colony stimulating factor (GM-CSF), as the adjuvant. GM-CSF may elicit a stronger immune response than alum when given directly with a vaccine.
GM-CSF is presently used to boost blood cell counts in transplant and cancer patients. It also can increase the ability of important immune system cells known as antigen presenters to initiate and direct immune responses. When used as an adjuvant, GM-CSF may enhance both antibody and cellular responses to the vaccine. The vaccine being used in AVEG 033 is ALVAC-HIV vCP205, which primarily stimulates the cellular immune response. The study investigators will evaluate the ability of GM-CSF to enhance both cellular and antibody responses to vCP205. The 36 volunteers enrolled in the study will be followed for 18 months.
The study is being conducted at four AVEG sites: the University of Alabama at Birmingham, the University of Rochester Medical Center, Johns Hopkins University and Vanderbilt University. Thomas Evans, M.D., of the University of Rochester Medical Center, chairs the study. GM-CSF is being supplied by Immunex (Seattle), and ALVAC-HIV vCP205 is being supplied by Pasteur Merieux Connaught.
More information about these trials can be obtained by calling the AIDS 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), supports biomedical research to prevent, diagnose and treat illnesses such as AIDS, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
Press releases, fact sheets and other NIAID-related materials are available via the NIAID home page at http://www.niaid.nih.gov.