The study represents significant progress in two important areas. First, it encourages hope that a human HIV-1 vaccine may prove possible in time, and, second, it shows that the genetic vaccine strategy -- now in clinical trials against herpes, influenza, certain cancers, and HIV-1 at Penn and other institutions -- will likely be able to deliver on its early promise.
"We will have to wait to see whether this vaccine will become an HIV-1 vaccine," says David B. Weiner, PhD, an associate professor of pathology and laboratory medicine and senior author on the study. "A great deal of additional work remains to be done before we can say that. But these results do give us confidence to go forward. And they strongly suggest that this new technology will find its place in the treatment of human disease."
What is novel about the vaccine used in Dr. Weiner's small-scale chimpanzee study is that it directly incorporates attenuated HIV-1 genes rather than proteins produced by the viral genes, as is the case with the usual live- or killed-virus vaccines against various diseases.
For the new vaccine, the genes are integrated into a laboratory construct called a plasmid, mixed with a local anesthetic called bupivacaine -- which improves the transfection, expression, and immunogenicity of the genes -- and then injected into the muscle. There is no expectation that the vaccine genes will be permanently integrated into the recipient's genome -- a goal of gene therapy -- only that they will be retained in the body long enough to provoke an infection-fighting immune response.
Three chimpanzees were immunized with the vaccine containing the attenuated HIV-1 genes in the experimental trial. As a control, a fourth chimpanzee was given a vaccine preparation identical in every way except that it did not include the HIV-1 genetic material. Two of the three immunized chimpanzees and the control chimpanzee were then exposed to 250 times the amount of virus known to be sufficient for infection, using an HIV-1 strain different from the one used to prepare the vaccine to more closely simulate non-laboratory conditions. The third immunized animal was kept as a negative control, unchallenged with virus. All were then monitored for 48 weeks.
Using an assay capable of detecting as few as 500 copies of virus per milliliter of blood -- one commonly used to measure HIV-1 infection in humans -- the scientists were unable to detect virus in the two immunized, virus-challenged animals over that period. The control chimpanzee, however, demonstrated viral loads in excess of 10,000 copies per milliliter.
With another, extremely sensitive laboratory assay, however -- one that can detect as few as 50 copies of virus per milliliter -- the two protected animals were found to be HIV-positive at one time-point each, at weeks 6 and 8 respectively, before reverting to an HIV-negative status. From an immunological perspective, this observation has important implications concerning the vaccine's protection cycle.
"Following a traditional vaccination, the recipient may encounter the virus against which they've been vaccinated," Weiner explains. "The virus can infect cells and begin to replicate. But the immune system, based on a kind of memory put in place by the vaccine, sees the infection, responds vehemently, and destroys the infected cells and the virus. This is similar to what we saw with our vaccine. There was some limited replication, but the immune system was ultimately able to effectively control that infection."
Co-lead author on the paper is Penn research associate Jean D. Boyer, PhD, with Kenneth E. Ugen, PhD, at the University of South Florida, Tampa, FL. The collaborative study also involved researchers from the Coulston Foundation, Alamogordo, NM; Harvard University, Cambridge, MA; and Apollon Inc., Malvern, PA. The work was supported in part by a Strategic Program for Innovative Research on AIDS Treatment (SPIRAT) grant from the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health (NIH).
The University of Pennsylvania Medical Center's sponsored
research ranks fifth in the United States, based on grant
support from the National Institutes of Health, the primary
funder of biomedical research in the nation -- $149 million
in federal fiscal year 1996. In addition, for the second
consecutive year, the institution posted the highest growth
rate in its research activity -- 9.1 percent -- of the top
ten U.S. academic medical centers during the same period.
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