Antibody cures West Nile virus in mice

A newly developed monoclonal antibody can cure mice infected with the West Nile virus, according to University scientists.

If further studies confirm the effectiveness and safety of the antibody, it could become one of the first monoclonal antibodies used as a treatment for an infectious disease.

In a strain of mice that normally has only about a 10 percent survival rate after West Nile infection, scientists found that single doses of the antibodies given soon after infection could boost survival rates to 90 percent or higher.

Michael Diamond
Michael Diamond

“To our knowledge, these experiments are the first successful demonstration of the use of a humanized antibody as a post-exposure therapy against a viral disease,” said senior investigator Michael S. Diamond, M.D., Ph.D., assistant professor of molecular microbiology, of pathology and immunology and of medicine. “They also suggest antibody-based therapeutics may have a broader utility against other infectious diseases.”

He pointed out that Macrogenics Inc. of Rockville, Md., a company that contributed to the study and licensed the antibody from the University, must complete other preliminary studies before the antibody can be tested in humans. But Diamond and his colleagues are excited both by the apparent potency of the antibody and its potential to help them explore new possibilities for treating related viruses that are more prolific causes of human disease and death.

“We could give a single dose of this antibody to mice as long as five days after infection, when West Nile virus had entered the brain, and it could still cure them,” Diamond said. “It also completely protected against death from the disease.”

Researchers will report their results in the May issue of Nature Medicine.

In 2004, West Nile virus reportedly caused 2,470 infections and 88 deaths in the United States. Most infections with the virus are mild or symptom-free, but infections in people with weakened immune systems and those over 50 sometimes lead to serious complications or death.

Antibodies typically work by attaching to a piece of a foreign cell or substance, which causes immune-system cells known as macrophages to pick up the substance and clear it from the body.

Binding to the invader is just the beginning of the battle, though. Some antibodies bind to invaders in ways that fail to slow down the invader or trigger a response from macrophages.

From the panel of West Nile virus antibodies they initially produced from mouse cells, researchers identified 46 that could bind to the West Nile virus’ envelope protein. Further testing showed that 12 could bind to the virus in a way that consistently neutralized it, shutting down infections in cell cultures and in mice.

The human immune system would clear out these foreign antibodies quickly, so scientists at Macrogenics clipped out the genetic material that controls the targeting of one of the potent antibodies and cloned it into a human antibody. The “humanized” antibody should be less likely to induce an adverse human immune system response.

A second round of tests in mice confirmed that the new antibodies retained their ability to stop West Nile virus.

Other monoclonal antibodies are in development or are used as anti-cancer and anti-inflammatory treatments. An antibody against respiratory syncytial virus is approved for use as a prophylactic treatment in children at risk of the disease in hospitals. Unlike the West Nile virus antibody, though, this antibody has to be given prior to infection.

West Nile virus belongs to a family of viruses known as flaviviruses, several of which are spread by mosquito bites.

Other flaviviruses include the virus that causes dengue fever, a potentially life-threatening infection prevalent in tropical cities. Epidemiologists at the Centers for Disease Control and Prevention estimate there are annually 100 million cases of dengue worldwide.

“A lot of what we’re learning from the West Nile virus antibody will be of consequence for the development of a pediatric dengue vaccine,” said co-author Daved H. Fremont, Ph.D., associate professor of biochemistry and molecular biophysics and of pathology and immunology. “Currently there are no safe vaccines for dengue infections.”

In follow-up studies, Fremont and others are detailing the precise mechanisms that allow the new West Nile antibody to block viral infection.

Diamond and Fremont are looking for other areas of the West Nile virus E protein that antibodies can bind to and neutralize the virus.

Researchers at Macrogenics were co-authors on this paper, and Diamond now serves as a consultant for the company.