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February 24, 2009

Monoclonal Antibodies Can Provide Durable Immunity to Against Avian Flu and Other Flu


Researchers have discovered human antibodies that neutralize not only H5N1 bird flu but other strains of influenza as well and say they hope to develop them into lifesaving treatments.

Flu at wikipedia. Flu kills about 250,000 people every year. This can increase to 1-2 million during a pandemic. The spanish flu killed over 50 million This treatment could potentially be expanded to immunize against all flu and remove the threat of flu pandemic.

The antibodies -- immune system proteins that attach to invaders such as viruses -- also might be used to protect front-line workers and others at high risk in case a pandemic of flu broke out, the researchers said.

In tests on mice the viruses neutralized several types of influenza A viruses, including the H5N1 avian influenza virus, the researchers reported in Sunday's issue of the journal Nature Structural & Molecular Biology.

"We were surprised and actually delighted to find that these antibodies neutralized a majority of other influenza viruses, including the regular seasonal (H1N1 strain of) flu," Robert Liddington of the Burnham Institute for Medical Research in La Jolla, California, told reporters in a telephone briefing


UDPATE:

US News and world report has an interview that indicates the timing of the deployment of this work. 2010-2011 for clinical trials. 3-5 years for the research to make a universal flu vaccine and then another 2 years for that universal flu vaccine to get to clinical trials.

How do you know that this antibody works against both bird flu and seasonal flu?
We tested the antibody against bird flu, against 1918 pandemic flu; we tested it against all 10 different types of flu viruses, multiple strains, both in tissue culture and in animals. The antibody was not only active in preventing infection; you could give it to animals that got a lethal dose of the flu virus as late as three days after infection, when they were clearly getting sick, and they recovered and survived.

This is exciting science, but it's not yet a cure for the flu. What's the next step?
With the additional testing that's required, there should be a very potent anti-influenza drug that will come out of this work. We are planning to be in clinical trials in the 2011-2012 flu season, which is about as fast as you can go. This is the actual drug that will wind up going into people. The antibodies are produced in cell factories. We need to pass our antibodies on to a manufacturer that will complete the animal studies and conduct the clinical trials.

How would this treatment work, if it's approved as a flu treatment?
The antibodies have to be given by injection or inhalation, and they last in your body for 21 days. Monoclonal antibodies are currently being used to treat cancers and inflammatory diseases, including Herceptin for the treatment of breast cancer, Avastin or Erbitux for the treatment of colon cancer, and Retuxin for the treatment of lymphoma.

The other question is whether we can turn this into a universal vaccine. The research involved in making that next step will probably take three to five years. The goal will be to develop lifelong immunity to flu, rather than developing seasonal immunity as we do now.








The new antibodies attach to a less mutation-prone part of the virus, on the "stick" part of the lollipop, the researchers said. It appears to be similar across various strains.

"It forms part of a complex molecular machinery with many moving parts," Liddington said. "All the parts must work perfectly together if the virus is to enter the cell and establish an infection."

The antibodies gum up the works, the researchers found by making atomic images of the antibodies attacking the virus. They hope to use this knowledge to engineer or find other monocolonal antibodies that can neutralize the six strains of flu not affected by this latest discovery -- including the H3N2 strain of seasonal flu now circulating.

Dr. Ruben Donis of the U.S. Centers for Disease Control and Prevention said the antibodies, called monoclonal antibodies because they attack one specific target only, protected mice from what should have been a lethal target of H5N1 avian flu virus -- even up to three days later after infection.

"When we tried to select viruses that were resistant to the activity of these antibodies, we failed," Donis told the briefing. "We could not get the virus to mutate and escape."

Dr. Wayne Marasco of Dana-Farber said it should be straightforward to develop the antibodies as drugs, because they are already used broadly in cancer therapy.

A single injection protects for three weeks. "It provides durable immunity," Marasco said.


Video Explaining the Spread of Flu and the Immune Response


A little over one minute into the two minute video is where antibodies are presented. After macrophages, T-cells and killer T-Cells.

FURTHER READING
Science Daily has coverage

Large quantities of monoclonal antibodies can be made relatively quickly, after more testing, these influenza-specific monoclonal antibodies potentially could be used in combination with antiviral drugs to prevent or treat the flu during an influenza outbreak or pandemic.

"One of the most remarkable findings of our work is that we identified a highly conserved region in the neck of the influenza hemagglutinin protein to which humans rarely make antibodies," says Dr. Marasco. "We believe this is because the head of the hemagglutinin protein acts as a decoy by constantly undergoing mutation and thereby attracting the immune system to produce antibodies against it rather than against the pocket in the neck of the protein."



Their findings could also assist vaccine developers.

He currently is arranging to use NIAID research resources to take the next steps: first, testing the antibodies in ferrets, the gold standard animal model for influenza, and then developing a clinical grade version of one antibody that could enter human clinical trials as soon as 18 months from when the development program begins. Should the antibodies prove safe and effective in humans, it could take several years to develop a licensed product.

The scientists also identified a new mechanism of antibody action against influenza: Once the antibody binds, the virus cannot change its shape, a step required before it can fuse with and enter the cell it is attempting to infect.

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