February 8, 1999
The Ugandan Minister of Health, Crispus Kiyonga, M.B.Ch.B., adds, "This trial is part of a long-term, joint program that began in 1991 with our U.S. and French partners to develop a safe and effective HIV vaccine for Africa. Broad consultations have taken place and consensus has been reached among the various stakeholders and interested groups."
The HIV vaccine to be tested in the trial, called ALVAC vCP205, is based on a canarypox virus that cannot cause disease in humans. Canarypox-based HIV vaccines, made by Pasteur Mérieux Connaught (Rhône-Poulenc Group, France), have been tested in more than 800 volunteers in the United States and France with no serious side effects reported.
The trial is being carried out at the Joint Clinical Research Center in Kampala and the Uganda Virus Research Institute in Entebbe. Both laboratories have state-of-the-art equipment and are staffed by highly trained Ugandans who with their U.S. counterparts will be conducting the relevant investigations. The study is under the direction of Professors Roy Mugerwa, M.B.Ch.B., M.Med., of Makerere University, and Jerrold Ellner, M.D., of Case Western Reserve University in Cleveland. They also oversee one of the NIAID HIV Network for Prevention Trials (HIVNET) sites in Uganda, which conducted the groundwork studies in preparation for this and future trials of HIV vaccines.
"Every person enrolled will be fully informed by our medical staff as to what will be done in the trial and what risks or benefits may result from their participation," says Dr. Mugerwa. "The ethical standards applied in this trial are internationally accepted and are the same as those in the United States."
"Although small in size, this trial is important symbolically as a first critical step in developing an effective vaccine for Africa," says Dr. Ellner.
The Phase 1 trial, known as HIVNET 007, will enroll 40 healthy, HIV-negative adults between 18 and 40 years old who are at low risk for becoming infected with HIV. The volunteers will be randomly assigned to one of three groups: 20 individuals will receive the HIV vaccine; 10 individuals will serve as controls by receiving a similar experimental canarypox vaccine for rabies; and 10 additional control individuals will receive a placebo that does not contain any vaccine.
Each person will get four injections over six months. During the study, neither the study participants nor the health professionals involved will know which type of injection each volunteer receives. At every clinic visit, volunteers will be counseled about how to avoid HIV exposure during the study.
The study will last one year, with one additional year of follow-up to monitor safety and the durability of the immune responses to the vaccine. Specifically, they will monitor reactions to the vaccines and look for immune responses directed against HIV itself (neutralizing antibodies) or against cells infected with HIV (cytotoxic T lymphocytes, or CTLs). Apart from this information on the vaccine's safety and potential for protection, no information on its effectiveness can be obtained from this small trial.
The ALVAC vCP205 vaccine cannot cause HIV infection. First, the vaccine contains only three HIV genes, which by themselves cannot produce an infectious virus. Second, these genes are inserted into a weakened version of the canarypox virus. Canarypox virus serves solely as the gene carrier, or vector, to safely express specific HIV proteins known to elicit immune responses against HIV. Because canarypox virus can not replicate in human cells, no new canarypox viruses are formed.
The genes in the vaccine come from only clade B viruses, the predominant subtype of HIV found in the United States and Europe. However, the researchers will look for immune responses to clades A and D, as well as clade B viruses, because the former two subtypes cause most HIV infections in Uganda.
Recent experiments have revealed that CTLs taken from people naturally infected with clade A or D viruses can recognize clade B viruses in the laboratory. This is known as cross-reactivity.
"Although laboratory data suggest that some vaccines such as this canarypox vaccine stimulate broadly reactive CTLs, this needs to be evaluated in human clinical trials," says Margaret Johnston, Ph.D., assistant director for HIV/AIDS vaccines at NIAID and associate director of the vaccine and prevention research program in NIAID's Division of AIDS.
"If the answer is yes, and the levels of cross-reactivity in most volunteers are significant, then Uganda and its partners can consider moving this vaccine into larger trials," adds Dr. Johnston. "If not, we will need to more strongly encourage development of vaccines based on viruses circulating in different countries."
Notably, this study represents the first systematic test of any HIV vaccine in an African population. One of the urgent needs in HIV vaccine research, says Dr. Johnston, is to understand how human differences influence the immune response to candidate vaccines. The outcome of this study, she says, will guide NIAID's future HIV vaccine strategy and is an important step in a long process toward developing safe and effective HIV vaccines for worldwide use.
Today, Uganda's population numbers 20 million. According to Dr. Kiyonga, the rates of HIV infection range from 4 to 10 percent in rural areas to between 10 and 25 percent in urban locales. Nearly half a million Ugandans have already died of AIDS. As is true in all of Africa, the disease is primarily passed from person-to-person through heterosexual sex. A devastating consequence has been the 1 million orphaned Ugandan children.
In addition to NIAID and the government of Uganda, organizations involved in facilitating the trial include Makerere University; the Joint Clinic Research Center; the Uganda Virus Research Institute; UNAIDS; Case Western Reserve University; the Fogarty International Center of the National Institutes of Health; and Pasteur Mérieux Connaught.
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, 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 on the NIAID Web site at http://www.niaid.nih.gov.