Burnham Scientists Share in Landmark Flu-Fighting Effort

Sunday, Feb. 22, 2009 | Scientists at the Burnham Institute for Medical Research are part of a team that has engineered human antibodies that attack influenza viruses — including the deadly bird flu — and could end up significantly reducing the threat of future flu pandemics.

Not only could the newly discovered antibodies lead to far more effective antiviral drugs than Tamiflu and others currently on the market, but possibly to a robust vaccine that will bring an end to the “yearly scramble” for a flu shot to fight the latest version of the virus.

“Flu is an annual killer on a large scale — so this is a really big deal if it pans out, and I don’t see why it won’t,” said Robert Liddington, director of Burnham’s Infectious and Inflammatory Disease Center, and one of the lead researchers on the study, published online Sunday in the journal Nature Structural & Molecular Biology. The Burnham team collaborated with scientists from the Centers for Disease Control and Prevention, and Harvard’s Dana-Farber Cancer Institute.

The antibodies protected mice that were injected with highly lethal doses of the bird flu, as well as those infected by several other strains of the influenza virus, including the deadly Spanish flu that killed tens of millions worldwide in 1918 and 1919.

Liddington said if clinical trials go well, an antiviral based on the antibody could be approved by the U.S. Food and Drug Administration and go into production within two to three years.

Other infectious disease specialists are lauding this discovery as a landmark in the fight against influenza. “This is excellent work,” said Robert T. Schooley, head of the University of California, San Diego’s infectious disease division. “This research provides an opportunity to develop new classes of drugs … and get around the yearly scramble for ‘this year’s vaccine.’”

Influenza kills more than a quarter-million people each year. And, say infectious disease experts, the world is overdue for a flu pandemic like the Spanish flu, or the Hong Kong flu of the late 1960s that killed 34,000 in the United States.

In recent years, public health officials have been particularly worried about the H5N1, or bird flu virus. Human infections of H5N1 have been rare, and limited to people who work closely with poultry. But it has an extremely high mortality rate, with more than 60 percent of the 400 known cases resulting in death.

Antibodies, the foot soldiers of our immune system, are proteins normally produced by white blood cells that locate and attach to viruses and other invaders so they can be destroyed by white cells. The key to the new discovery was that the antibodies developed by the scientists target the stems of the lollipop-shaped hemaglutinin molecules that are packed tightly on the outer surface of the flu virus.

Until now, antivirals and vaccines have targeted the heads of the molecules because they are the most visible to the body’s defenses. However, targeting the head is ineffective in the end because the head is constantly mutating. This is why a new flu vaccine has to be developed every year.

And even a yearly vaccine is limited in its effectiveness, because the mutations do not abide by the Gregorian calendar. “The head of the flu changes every time it reproduces itself, and changes can happen within one season,” Liddington said. Antivirals like Tamiflu also target the head, which is why they have been less effective in recent years.

The stem is a different story. Described by Liddington as a “sophisticated molecular machine” the stem facilitates the “fusing” of the virus to the membranes of a cell. When that happens, the genetic material of the virus spews out into the cell, and people get sick, Liddington said.

But because of the stem’s complexity, it does not mutate like the head. So antibodies that target the stem can have long-lasting effect because they aren’t dealing with a constantly changing form. But until now, researchers have not been able to develop such antibodies because the virus stem stays hidden under the head, and unrecognizable to the antibodies that fight the virus.

What helped the researchers make the discovery was that they made synthetic versions of the hemaglutinin molecule, which were less dense than they are on the virus. This gave the antibodies the ability to identify the stem.

And as fate would have it, the bird flu hemaglutinin is what led the scientists to the set of antibodies that hit the stem. “Had we used the hemaglutinin from a different virus we might not have readily found this set of antibodies,” Liddington said. “It’s a bit of an irony that the scariest virus is leading us down the path to a universal cure.”

The researchers are confident that the antiviral therapy will have a reasonably fast track to FDA approval because human monoclonal antibodies are widely accepted in the medical community, and form the basis of several other drugs that have already been approved. “The pathway to the clinic is straight forward,” said Wayne Marasco, who headed up the team from the Dana-Farber Institute. “In practical terms (they could be ready) for the 2011 or 2012 winter seasons.”

The development of a long-lasting flu vaccine is farther down the road, but the discovery has pointed researchers in a “new direction for vaccine research,” Marasco said.

A potential hurdle is the high cost to manufacture drugs based on human monoclonal antibodies. This means that if a drug results from this discovery, it would not be one that ends up in everyone’s medicine cabinet, Liddington said. It would be more likely strategically stockpiled by public health agencies.

However, Marasco said the manufacturing costs might not be as high as expected because large pharmaceutical companies have built plants in recent years and could take advantage of economies of scale. And the need for vast quantities of the drug would be mitigated by the fact that people would likely need only one dose of the drug.

Although the researchers have secured patents for the antibodies, they do not yet have a partner for the development and manufacture of the potential drug. Both Liddington and Marasco raised the possibility of a partnership among private entities and the federal government.

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