July 12, 2004 PHILADELPHIA – Researchers at The Wistar Institute and the University of Pennsylvania report success in monkeys of an innovative triple-vaccine strategy aimed at creating an effective anti-HIV vaccine regimen. In a test of the new approach, the scientists sought to maximize the immune response to a truncated HIV gene called Gag and succeeded in dramatically stimulating the production of CD8+ T cells responsive to Gag. Many scientists believe that CD8+ T cells will be an important key to creating an effective HIV vaccine.
"For a variety of reasons, it may not be possible to create a vaccine that generates antibodies able to neutralize HIV," says Hildegund C.J. Ertl, M.D., professor and immunology program leader at Wistar and senior author on the report published in the July issue of the Journal of Virology. "The next best thing may be to develop a vaccine that stimulates the production of anti-HIV CD8+ T cells, which have been shown in other studies to reduce viral load, although they do not prevent infection. The new vaccine regimen we tested induced unprecedented levels of CD8+ T cells in monkeys."
The experimental vaccines developed by Ertl and her colleagues take advantage of sophisticated bioengineering technologies and the special characteristics of a class of viruses called adenoviruses to create a series of three vaccines that, when given in sequence, build on each other to generate a stronger immune response than might otherwise be possible.
Many current vaccine development programs rely on human adenoviruses engineered to include elements from disease-causing agents, in part because adenoviruses are relatively easy to manipulate in the laboratory and readily enter a wide variety of cells, including important cells of the immune system, to stimulate a vigorous, long-lasting immune response.
A number of these vaccines based on common strains of human adenoviruses, including some against HIV, have returned positive results in early clinical trials. An unaddressed problem with this vaccine-development approach, however, is that many people are exposed to adenoviruses in childhood and carry neutralizing antibodies against the viruses that would interfere with the effectiveness of any vaccine based on them. About 45 percent of adults in the United States, for example, have pre-existing immunity to the most prevalent strains of adenovirus, and similar or higher levels have been reported in other parts of the world.
To circumvent this potential difficulty, the researchers at The Wistar Institute and the University of Pennsylvania developed a series of vaccine vectors based on chimpanzee adenovirus strains, which possess the immunological strengths of human adenoviruses without their drawbacks. Previously published proof-of-principle studies in mice showed that the new vectors were able to avoid the problem of pre-existing immunity.
In the current study, the scientists created three vaccines, each with a different adenovirus as a backbone but all containing the same truncated HIV gene, Gag. Two of the vaccines were based on chimpanzee adenoviruses, and the third was based on a human adenovirus. The vaccines were administered to two groups of four rhesus macaques each. One group received the human adenovirus vaccine first, followed by the two chimpanzee adenovirus vaccines. The other group received one of the chimpanzee adenovirus vaccines first, followed by the other chimpanzee adenovirus vaccine and then the human adenovirus vaccine.
Both triple immunization regimens sparked high frequencies of CD8+ T cells against Gag that remained remarkably stable over time, demonstrating the potential of the new strategy. For eventual clinical use, vaccines incorporating more elements of HIV would be needed to elicit sufficiently broad T-cell responses to be fully effective.
A unique advantage of the triple-vaccine approach tested by the researchers is that it avoids generating pre-existing immunity to the vaccine backbone, which is new to the immune system at each stage of the regimen. The immune system does respond with increasing vigor, however, to the repeating Gag element of the three vaccines.
In addition to Ertl, the other Wistar-based authors on the Journal of Virology study are first authors Arturo Reyes-Sandoval, Ph.D., also affiliated with Instituto Politecnico Nacional in Mexico City, Mexico, and Julie C. Fitzgerald, both of whom contributed equally to the work, as well as Zhi Quan Xiang, M.D., and Yan Li. The University of Pennsylvania co-authors include James M. Wilson, M.D., Ph.D., professor of medicine and medical genetics, Rebecca L. Grant, D.V.M., Soumitra Roy, M.D., and Guangping Gao, Ph.D.
Support for the research was provided by the National Institute of Allergy and Infectious Diseases, one of the National Institutes of Health.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center – one of only eight focused on basic research. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools.
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