TORONTO - American scientists have found human antibodies that kill a broad range of influenza A viruses, a discovery that raises hopes of both better flu drugs and a more effective, longer lasting flu shot.
The discovery of monoclonal antibodies that target what some researchers believe may be flu's Achilles heel suggests medicine finally may be able to find a way to neutralize the virus's maddening ability to evade the immune system through constant mutation.
The wily virus's trick of continually altering its external appearance is why people don't develop life-long immunity after catching the flu and why flu shots have to be reformulated almost annually to keep pace.
"I certainly believe a pan therapy for influenza may be within our grasp," one of the authors, Dr. Robert Liddington, said of the findings, which were published Sunday in the journal Nature Structural and Molecular Biology.
Preliminary results have been promising. The monoclonal antibodies protected mice against what should have been lethal doses of several variants of avian H5N1 and human H1N1 flu viruses. Later this year their protective potential will be tested in ferrets, which are believed to be the best animal model for flu.
The work was done by researchers from the Dana-Farber Cancer Institute in Boston, the Burnham Institute for Medical Research in La Jolla, Calif., and the U.S. Centers for Disease Control in Atlanta, with funding from the U.S. National Institute of Allergy and Infectious Diseases.
The monoclonal antibodies have already been patented. And Dr. Wayne Marasco, of the Dana-Farber Institute, said the group will seek a pharmaceutical partner with which to begin the expensive work of human clinical trials.
As Liddington described the antibodies he focused on the near-term prospect of a drug that could be given to prevent infection or as a treatment to cut short illness after infection.
That therapy, in the form of an injection, would be useful in the early days of a flu pandemic, when pandemic vaccine isn't yet ready, said Liddington, director of the infectious diseases program at the Burnham Institute.
Because these antibodies kill a range of influenza A viruses -- 10 of 16 influenza A subtypes -- they could be stockpiled by countries which could use them to protect critical workers in the early days of a pandemic, regardless of the strain that triggered the outbreak, he said.
But another author, Dr. Ruben Donis, saw new hope for the Holy Grail of influenza science -- a single vaccine that targets all forms of the flu.
"My heart is with vaccines. For me, this is more important conceptually for the potential to target this as a vaccine," said Donis, the CDC's chief of the molecular virology and vaccines.
But he admitted that while the antibodies have been shown to kill viruses, it's not yet clear that a safe and effective vaccine can be designed to target the unchanging part of the key protein on the virus's surface revealed by this work.
"To say `Hey, you know, we can illicit an immune response to this' -- we still haven't gotten there," Donis said. "We're still quite a ways away."
On the drug front, challenges remain as well. Most monoclonal antibody therapies developed to date are enormously expensive. Cancer drugs like Avastin and Herceptin, for instance, cost in the tens of thousands of dollars for treatment.
Dr. Frederick Hayden, an antiviral expert at the University of Virginia, said any monoclonal antibody treatment would have to be price competitive with existing flu drugs and a number of others that are in development.
"The (drug) pipeline is not robust but it's certainly not empty, either," said Hayden, who was not involved in this research.
The head of the National Institute of Allergy and Infectious Diseases acknowledged monoclonal antibody therapies have been expensive, but suggested with time prices will come down.
Dr. Anthony Fauci added that while right now these findings may be more a conceptual advance than an immediate step forward, figuring out whether something can be done is a crucial first step.
"I'd rather have the concept down and work out the technical details than not even know if something was conceptually possible," he said.
The work started with a search of a library of 27 billion human antibodies compiled from the blood of 57 health volunteers in Boston about a decade ago.
Using a virus foreign to the immune systems of those volunteers -- the H5N1 avian flu -- as a sort of bait, the authors found a few antibodies that rose up to neutralize it. They were "surprised and delighted," Liddington said, to discover the same antibodies also acted against nine other subtypes of influenza A viruses.
Liddington called the antibodies "natural antiviral agents."
The authors believe corresponding antibodies can be found to neutralize the six other known influenza A virus subtypes and the influenza B viruses.
The scientists found the antibodies target a portion of the hemagglutinin, the key protein on the surface of the virus. The target is a stalk-like part that attaches the protein's globular head to the surface of the virus.
Donis used the analogy of a lollipop, with the target being the stick.
Influenza viruses are covered with these lollipop-shaped proteins. Because the head of the protein is so dominant, the immune system targets it, churning out antibodies to attack it.
But each subtype of virus has a different hemagglutinin protein. And even within a subtype, the head of the protein is constantly altering to evade immune systems, drugs and vaccines.
To use the lollipop analogy, it's as if the antibodies are only programmed to recognize a lollipop with a head of a specific colour, shape and size. But the monoclonal antibodies this team has identified target the stick, which is virtually identical among 10 of the 16 virus subtypes.
People make these antibodies, but in limited supplies, the scientists said. They aren't sure why.
Researchers at the CDC tried to see if they could force viruses to create mutations in the stalk, but they could not. It appears its design is critical: without it, the virus is unable to enter human cells.
"The virus cannot mutate it because by mutating it, it would commit suicide," Donis explained.
If that's true, it would mean the viruses might not be able to develop resistance to a drug made from the monoclonal antibodies. And if scientists can figure out how to make an effective vaccine targeting the stalk part of the hemagglutinin, in theory it should convey long-term protection against a variety of flu viruses.
