PHILADELPHIA - Immunologists know that human adenoviruses, a common cause of respiratory-tract infections in people, can be retooled in the laboratory to serve as effective vaccines against an array of viral diseases. When genetically engineered to express selected genes from other viruses - such as rabies, HIV, smallpox - adenoviruses infect human cells without doing them lasting damage and stimulate a vigorous, long-lasting immune response when they do so.
That's the theory, anyway. But there are significant problems with the theory. Adenoviruses are nearly ubiquitous among humans, so much so that a third or more of the population have neutralizing antibodies circulating in the blood able to inactivate an adenoviral-based vaccine.
Now, in a new proof-of-principle study in mice, researchers at The Wistar Institute and the University of Pennsylvania have shown that a vaccine based on a chimpanzee adenovirus possesses the immunological strengths of a human adenovirus vaccine without its drawbacks. The study appears in the March issue of the Journal of Virology.
"The chimpanzee adenovirus vaccine works like a charm," says Hildegund C.J. Ertl, M.D., a professor at The Wistar Institute and senior author on the study. "It's immunologically potent, and it's clear from our study that it would not be inactivated due to viral pre-exposure, as vaccines based on human adenoviruses can be."
For the study, the scientists developed two prototype vaccines against the rabies virus. One was a human adenovirus that incorporated one rabies gene, and the other was a chimpanzee adenovirus with the same gene. In mice unexposed to either type of adenovirus, the vaccines both elicited strong antibody responses. In mice pre-exposed to the human adenovirus, however, the vaccine based on the human adenovirus was severely compromised, while the one based on the chimpanzee adenovirus maintained its effectiveness.
Ertl and her coworkers are now working on similar prototype vaccines against HIV, smallpox, and other viruses.
"There are any number of viral diseases against which this approach would be effective, including many of the potential bioterror viruses," says Ertl.
A number of human adenovirus vaccines are currently under development against HIV and are considered by many to be among the most promising vaccine candidates in the field, despite the issue of viral pre-exposure.
Ertl emphasizes the inherent safety of the chimpanzee adenovirus vaccine concept she and her colleagues have developed. Concerns that a contaminant might accompany the vaccine - a virus like HIV, for example, which originated in chimpanzees - are addressed by the laboratory procedures by which the vaccine is generated.
Using techniques developed under the guidance of collaborator James M. Wilson, M.D., Ph.D., director of the Institute for Human Gene Therapy of the University of Pennsylvania, the vaccine is constructed, molecule by molecule, from the genetic code for the viral carrier - the chimpanzee adenovirus, in this case - and for the gene or genes to be incorporated, such as the rabies gene in the current study. The genes that coordinate replication of the virus are deleted. Any possible contaminant - another virus, a bacterium, even a prion - is eliminated in this process.
"Because of the laboratory methods used to generate this vaccine, there is no danger of giving people an unknown virus or other entity from the chimpanzee," says Ertl.
In addition to senior author Ertl and collaborating coauthor Wilson, the lead author on the Journal of Virology study is Zhiquan Xiang, M.D., a member of Ertl's laboratory. Arturo Reyes-Sandoval , also in Ertl's laboratory, is a coauthor. Sandoval is also affiliated with the Centro de Investigacion en Ciencia Aplicada y Tecnologia Avanzada, Mexico City, Mexico. The remaining coauthors are Guangping Gao and Yan Li of the University of Pennsylvania and Christopher J. Cohen and Jeffrey M. Bergelson of the Children's Hospital of Philadelphia.
Funding for the research was provided by the National Institutes of Health and Genovo. James M. Wilson owns equity in Targeted Genetics, formerly Genovo.
The Wistar Institute is an independent nonprofit research institution dedicated to discovering the causes and cures for major diseases, including cancer, AIDS, autoimmune disorders, and other illnesses. The Institute is a National Cancer Institute-designated Cancer Center - one of the nation's first, funded continuously since 1972, and one of only eight focused on basic research. Founded in 1892, Wistar was the first independent institution devoted to medical research and training in the nation. 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.
News releases from The Wistar Institute are available to reporters by direct e-mail or fax upon request. They are also posted electronically to Wistar's home page (http://www.wistar.upenn.edu), to EurekAlert! (http://www.eurekalert.org), an Internet resource sponsored by the American Association for the Advancement of Science.
Journal
Journal of Virology