Aug. 6, 2003 CHAPEL HILL -- The world's first human test of a vaccine against the prevalent subtype of HIV in sub-Saharan African and Asia, where millions have the virus that causes AIDS, is now under way. The clinical trial uses novel technology pioneered by scientists at the University of North Carolina at Chapel Hill School of Medicine and the U. S. Army Medical Research Institute of Infectious Diseases.
The phase I trial began July 17 at Johns Hopkins University. An adult male, at low risk for HIV infection, was the first of 48 volunteers in the United States to be vaccinated.
Other U.S. sites include Columbia University, Vanderbilt University and the University of Rochester. Sites in South Africa are at the University of Witwatersrand, the Chris Hani Baragwanath Hospital in Soweto and the Medical Research Council in Durban. The two-year trial will involve 48 non-HIV-infected participants in each country at four different dose levels, using a double-blind, placebo-controlled design. The primary endpoint is safety, that the vaccine does not produce significant side effects. Researchers also will look at the vaccine's ability to induce an immune response.
The vaccine is built around a disabled, safe version of Venezuelan equine encephalitis virus, or VEE. In the wild, this microbe infects horses and is sometimes carried to humans via mosquitoes.
Dr. Robert E. Johnston, professor of microbiology and immunology and director of the newly established Carolina Vaccine Institute, together with department colleague and research professor Dr. Nancy Davis studied VEE for more than 12 years, developing candidate vaccines against the virus. Their work led them to believe the virus could be modified for use as a safe vaccine vector, or delivery system for the vaccine.
Subsequent primate tests showed the technology held promise. Now, with approval from the U.S. Food and Drug Administration and the South African Medicines Control Council, a prototype HIV vaccine based on VEE technology has moved on to a human trial.
Joining Johnston and Davis in designing this "first-generation" HIV vaccine were Dr. Ronald Swanstrom, professor of biochemistry and biophysics and director of the UNC Center for AIDS Research; Dr. Jeffrey Frelinger, professor and chair of microbiology and immunology at UNC; and Drs. David Montefiore of Duke University and Phil Johnson of the Children's Hospital Research Foundation in Columbus, Ohio. Collaborating scientists in South Africa, Drs. Carolyn Williamson, Lynn Morris and Salim Karim, also were key members of this team effort.
AlphaVax, a Durham-based biotechnology spinoff of UNC, holds the commercial license for the VEE technology from the university and contributed to the design and manufactured the trial vaccine.
"It's very rare that a basic scientist gets to see something go from a concept to an actual biological product that can be tried in human beings," Johnston said.
"The VEE vector we helped develop is a means of expressing genes - in this case we're expressing a gene in vivo - inside the person vaccinated. And those gene products then immunize the person against the disease."
The vaccine contains a copy of only a small section of genetic material from HIV and does not include genetic elements needed to reconstitute live HIV, thus precluding the possibility of causing HIV infection. The vaccine material is also designed so that its VEE components cannot generate VEE virus or cause VEE infection.
The vaccine targets cells in lymph nodes, the critical tissue of the immune system. The vector will produce the immunizing protein by expressing "gag," a major protein in the HIV particle. The protein then induces the body to respond immunologically to it.
More advanced versions of the vaccine will include expression of the HIV envelope and polymerase genes.
"We hope to refine this vaccine to the point that if an individual is subsequently exposed to HIV, they will be protected from disease," Johnston said.
"This is a good first start from the standpoint of determining if the vector will work well. We can measure both cell mediated and humoral (antibody) immunity to gag. We'll be able to see if none or one or both arms of the immune response are activated during the vaccination."
The research collaboration of Johnson, Davis, Swanstrom, Montefiore and Johnson is working on subsequent generations of the vaccine. "We want to see if we can do better both from the delivery side and the gene side," Johnston said.
"I think I can speak for everybody on this team that we are extremely gratified to have this clinical trial opportunity. We're very hopeful. This is a major milestone."
Support for the early development of the vaccine came from the U. S. Army Research and Development Command, the National Institute of Allergy and Infectious Diseases (NIAID) and the International AIDS Vaccine Initiative. The trial is being conducted by the HIV Vaccine Trials Network, which is funded and supported by NIAID, a component of the National Institutes of Health.
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