$13 million grant puts new herpes-based AIDS vaccine on fast track

August 01, 2003

In an unlikely twist in the fight against AIDS, scientists have re-engineered a herpes virus - stripping most of its DNA and replacing it with small snippets of DNA from the AIDS virus - in a bid to create a new type of AIDS vaccine.

Early tests in mice suggest that the new vaccine could help the immune system make more infection-fighting antibodies and killer T-cells than other vaccines, which could make it more effective. The University of Rochester researchers who have pioneered the new approach have been awarded a $13 million grant from the National Institutes of Health to complete the additional testing necessary to move the vaccine into clinical trials.

"We've known for some time that the herpes virus is a very effective vehicle for delivering material into cells," said Howard Federoff, M.D., Ph.D., a University of Rochester scientist who has spent the last decade developing the new vaccine approach. "We've recently been able to harness one of the virus' most useful features, giving us a new tool that appears to have strong potential as an AIDS vaccine."

That feature is a string of DNA, called an amplicon, that causes the virus' DNA to be copied many times over before the virus infects a healthy cell. When Federoff and his colleagues re-engineered the herpes virus for use as a vaccine, they removed most of the herpes DNA and replaced it with snippets of DNA from the AIDS virus. That DNA provided the instructions for making key protein molecules that are found in the AIDS virus.

When the re-engineered herpes virus was injected into mice, healthy cells in the mouse began making those proteins. The immune system, in turn - recognizing the proteins as foreign - began producing antibodies and killer T-cells to attack and destroy them. Should an HIV infection strike, the researchers hope that those antibodies and killer T-cells would mount an aggressive attack against the infection before it can take hold and cause AIDS.

Other potential AIDS vaccines have used a similar approach, but most produced just small quantities of the desired proteins from the AIDS virus. By using the herpes virus - and by harnessing the DNA-copying ability of its amplicon - the researchers have engineered the virus to deliver many times the DNA of earlier vaccines. In their prototype AIDS vaccine, the researchers have packaged enough DNA to produce fragments of six different proteins from the AIDS virus. The amplicon then amplified those six DNA segments, producing 10 to 15 copies of each.

"Think of the virus as an envelope that delivers written pages," said Stephen Dewhurst, Ph.D., a virologist who serves as co-principal investigator for the project. "Most envelopes can deliver a few pages. This envelope can deliver a book."

Dewhurst and his colleagues believe that the large number of DNA segments will cause cells to produce a greater number of AIDS-virus protein fragments, and that the immune system will, in turn, produce a larger number of antibodies and killer T-cells. As a result, the immune system should be much better armed against a potential HIV infection.

At the same time, the vaccine is likely to be safe. No live virus is used, and all of the disease-causing genes from the herpes virus have been removed. The DNA segments from the AIDS virus have been carefully selected and have been proven not to cause AIDS.

The goal of the five-year, $13 million grant is to complete the early development of the vaccine and prepare it for the first tests in people. Michael Keefer, M.D., a vaccine researcher who specializes in clinical testing of AIDS vaccines, is the principal investigator on grant. He will coordinate a team of more than a dozen scientists working in two groups. One, led by Federoff, will work to fine tune the re-engineered herpes virus and the packaging of its DNA payload for use as a vaccine. William Bowers, Ph.D., a virologist and molecular biologist, will lead an effort to ensure that the vaccine can be "scaled up" - that is, manufactured in large quantities without quality problems that could diminish the vaccine's effectiveness or safety. A second group, led by Dewhurst, will test the vaccine in laboratory animals to assess its safety and effectiveness. In particular, they will try to determine how well the vaccine spurs the immune system to produce antibodies and killer T-cells and how long those effects last.

"Using the herpes virus amplicon is one of the most innovative approaches I've seen in the effort to develop an AIDS vaccine," said Keefer. "It's exciting to help move this technology forward and to see what its capabilities are. This is cutting-edge vaccine work that may prove useful against HIV as well as a range of other diseases."

Federoff's laboratory is also pursuing the development of amplicon vaccines for use against several types of cancer and neurological disorders such as Alzheimer's and Parkinson's disease.
-end-


University of Rochester Medical Center

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