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New Antibody Could Supress Flu Viruses

Posted on: Thursday, 26 February 2009, 15:40 CST

Scientists employed by a Dutch drug company are developing an antibody that would give humans lifelong protection against several influenza viruses, including the H5N1 avian flu virus.

The team of scientists from Scripps Research and the biopharmaceutical company Crucell reported their findings in the journal Science on Thursday. The report marks the second in a week to find antibodies that can disrupt a range of flu strains.

"This is very exciting because it marks the first step toward the Holy Grail of influenza vaccinology -- the development of a durable and cross-protective universal influenza virus vaccine," Ian Wilson, a researcher at the Scripps Research Institute in La Jolla, California, said in a statement.

"Such a flu vaccine could be given to a person just once and act as a universal protectant for most subtypes of influenza, even against pandemic viruses."

More than 200,000 people are hospitalized due to flu complications each year in the US, according to the US Centers for Disease Control and Prevention. About 36,000 people die from the illness during a normal year. But during the last century, the Spanish Flu of 1918-1919, the Asian Flu of 1957-1958, and the Hong Kong Flu of 1968-1969 resulted in the deaths of 50-100 million people globally.

Crucell’s antibody, CR6261, is a naturally occurring immune system protein that grabs onto a hidden part of flu viruses, stopping them from infecting cells, scientists said.

"A new therapy for the often deadly flu virus is much needed", said Jaap Goudsmit, CSO of Crucell. "The continuous mutation of the influenza virus means that vaccine developers are always playing catch-up when it comes to choosing the correct virus. In addition, these vaccines tend to perform less effectively in the elderly. The almost universal oseltamivir resistance of the H1N1 virus presently circulating and the reported cases of H5N1 oseltamivir-resistance illustrate the urgency for a universal therapy against flu."

"We can see exactly how and where the antibody grabs on to these influenza viruses," said the study’s first author, Damian Ekiert, a graduate student in the Scripps Research Kellogg School of Science and Technology working in the Wilson laboratory.

"And we can see that this same mode of interaction occurs in viruses that are very different from each other."

Wilson said he has been working with influenza antigens since 1987.

“I find it just amazing to suddenly see antibodies now appear that we had no idea existed," he said.

In an effort to understand exactly how CR6261 recognized and responded to such a broad array of influenza viruses, Ekiert worked to solve two crystal structures: one with the antibody bound to the hemagglutinin H1 virus that caused the 1918 pandemic and another with the antibody glued to the hemagglutinin from the 2004 Vietnam H5 avian influenza.

Influenza antibodies “target mushroom-shaped proteins known as hemagglutinin (HA) that stud the outer coat of a virus particle to help the virus infect cells of a host organism, such as humans,” researchers said.

The antibodies discovered by the scientists attach to the “stalk” of the hemagglutinin particle, near where the protein juts out from the viral coat, and that this binding area, known as an epitope, is the same in both the H1 and H5 viruses.

The scientists then analyzed the genome of more than 5,000 different influenza viruses and found the epitope's sequence is nearly identical in all of them, which means that this part of the virus could be more effectively attacked than the virus’s constantly mutating cap.

"The epitope it needs to latch on to is at the base of the stalk of the hemagglutinin protein, so it is difficult to get to because these proteins are packed together tightly on the viral coat," said Ekiert.

"Plus, most antibodies try to attack the mushroom cap of the hemagglutinin proteins because that is much more accessible, and so this probably sets up a huge competition between antibodies."

"Certain regions of the hemagglutinin protein are like big red flags to the immune system, but they are functionally unimportant," Wilson said. "The task now is to figure out how to suppress reactivity with those regions and enhance the immune system's attack on this conserved epitope."

Both teams have demonstrated that the antibody can suppress 16 different subtypes of influenza viruses, including every H1 virus tested. The antibody also worked on the H5 bird viruses that are not yet circulating in humans.

However, the CR6261 antibody is not effective for the H3 subclass, which is a common human influenza virus, because a sugar molecule blocks the epitope, scientists said.

"If a sugar is the only impediment in the way, we think there is a way around that in vaccine design," Wilson said.

"Even so, this antibody could still potentially hit 12 out of the 16 influenza viral subtypes. We now have a blueprint upon which to design the next generation of anti-virals, and that is why we are so enthusiastic about these findings as they give hope that it may indeed be possible to generate a universal vaccine against influenza virus, as well as provide immediate protection when used as an antibody therapeutic."

Patents for these antibodies have been filed worldwide, based on the first filing date of September 7, 2006, Crucell said in a statement.

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On the Net:

• Scripps Research Institute
• Crucell
• Science

Source: redOrbit Staff & Wire Reports

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