The University Record, January 21, 1998
By Pete Barkey
Health System Public Relations
A team of researchers has reported that it is possible to generate immunity to the deadly Ebola virus by using gene therapy.
In a study published in the January issue of the journal Nature Medicine, investigators were able to create an immune response to the Ebola virus in both mice and guinea pig models using a genetically engineered DNA vaccine. The study was conducted by researchers in the Howard Hughes Medical Institute at the U-M Health System and the Centers for Disease Control.
Ebola virus causes a rapidly progressing, often fatal, infection that can lead to vomiting, diarrhea, rash, both internal and external bleeding, and limited liver and kidney functions.
The team, lead by Gary Nabel, professor of internal medicine and of biological chemistry and an investigator at the Howard Hughes Medical Institute, injected plasmid DNA, encoding Ebola proteins, into the muscles of study animals in an attempt to stimulate an immune response. Plasmid DNA is a form of DNA carried in bacteria. It is grown under laboratory conditions and when isolated from the bacteria, it is essentially pure DNA. When injected into muscle, it directs the manufacture of the specific gene product it carries.
In the first series of tests, which were done on mice, researchers were able to generate an antibody response to a cell-surface Ebola protein, called glycoprotein, and also elicit a response to a nucleoprotein not found on the cell surface. Researchers then looked at initiating a cellular immune response, which is typically more important in providing protection against viruses.
They found that they could create a cellular response by injecting DNA containing glycoprotein, but could not with the nucleoprotein. Next, investigators performed the same tests in guinea pigs, which are susceptible to lethal infection by the virus. Ebola attacks guinea pigs and humans in much the same manner.
They examined the ability of the animals to generate an immune response and found that the results were similar to the mouse model. The guinea pigs were injected with the genetic vaccine and then transported to the Centers for Disease Control where they were lethally challenged with infectious Ebola virus. Researchers examined two separate groups for immune response:
Guinea pigs that were lethally challenged after two months showed strong immunity with both glycoprotein and nucleoprotein immunization. However, researchers found that animals challenged after four months received good immunity from the glycoprotein vaccines, but did not retain immunity from nucleoprotein.
"The news," Nabel says, "is that it is possible to generate immunity to Ebola."
Researchers examined the organs of the animals that were protected by the immunization and found no traces of the Ebola virus--meaning that immunization completely neutralized the infection in the guinea pigs. A preliminary study of the organs of animals given the DNA immunization found no toxicity, or apparent side effects. Nabel says the next step is to study the DNA vaccine in non-human primates and from there, controlled toxicity tests in humans to determine reaction to a potential vaccine.
Human subjects would not be exposed to the Ebola virus. Nabel says trials in human subjects could begin within one to two years if the next phase of studies are promising. There are four known strains of the Ebola virus and all are very closely related, but different enough, Nabel says, that it would be necessary to test a vaccine against all strains. Ebola undergoes extremely rapid replication, working so quickly, the body has little or no chance tomount an immune response.
Previous attempts to generate immunity to Ebola with either viral-based vaccines or antibody treatments have been unsuccessful. This study represents an example of the potential of recombinant DNA technology to improve the treatment of devastating human diseases.
The Ebola study is part of a larger research effort at the Center for Gene Therapy at the Health System, directed by Nabel.