Antibodies Offer a New Path for Fighting Flu

[HenryN]

Re: Antibodies Offer a New Path for Fighting Flu

Again, my thanks Dr. Niman.

Is this paper available yet? If it is, do you have a link, sorry if I missed it in the thread

Interesting that the treatment and prophylactic dosage are so close.

I do hold out a great deal of hope that we will eventually find a universal vaccine, and it is the vaccine portion of the news item that piqued most of my interest. Treatment is only good for those who will have access to such, which, unfortunately, is not the vast majority of people when measured against the 6+ billion of us. But, I am sufficiently curious now about the prophylactic/treatment portion to have a gander at the paper myself.

I received the paper early for review. I believe it will be out tomorrow (the news embargo came off today, which is why the news stories are out now).

 

[HenryN]

Re: Antibodies Offer a New Path for Fighting Flu

SCIENTISTS HAIL WONDER JAB TO CURE ALL FLU




Experts say the breakthrough vaccine could save millions of lives
http://www.dailyexpress.co.uk/myexpress/

Monday February 23,2009

By Jo Willey, Health Correspondent


A “HOLY grail” flu vaccine that could cure all forms of the disease including deadly bird flu has moved a step closer after a major breakthrough by scientists.


Not only could it prevent several strains of the annual winter virus and the lethal H5N1 strain of bird flu, it could also be the key to halt a pandemic and save millions of lives.


So significant is the breakthrough that experts say they could create such a vaccine in just two years.


Researchers have discovered 10 antibodies that target an “Achilles heel” in most forms of influenza.

EXPRESS HEALTH: GET THE LATEST...




<TABLE style="FLOAT: none; CLEAR: both" cellSpacing=0 cellPadding=0 itxtvisited="1"><TBODY itxtvisited="1"><TR itxtvisited="1"><TD itxtvisited="1">

It is a really exciting discovery because it opens up the possibility of a vaccine against all strains.

</TD></TR><TR itxtvisited="1"><TD itxtvisited="1">Professor Peter Openshaw


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Until now, scientists have failed to find a vaccine to prevent even seasonal flu because the virus mutates and every winter new jabs need to be produced just to tackle the different circulating strains, giving manufacturers only months to produce stocks.


Current flu jabs target two proteins on the surface of the virus, but they constantly mutate in a bid to fool the immune system.


This latest ground-breaking research has found antibodies which target the weak spot in the “neck” of the virus, just below its peanut-shaped “head” which stops it shape-changing and infecting cells.
<FORM action=/posts/search/> Researchers claim that these antibodies protect against easily-transmitted H5N1 even when given to mice three days after they were infected and kept them immune for up to three weeks. Doctors fear millions of people may die from a pandemic before a vaccine is available.</FORM>


But using the antibodies, which could be made quickly and in large numbers into a single dose treatment, in combination with anti-viral drugs, they could contain the virus during the four to six months it would take to create enough quantities for a suitable vaccine.


A flu pandemic could kill 750,000, with more than six million children affected, including 750,000 under the age of five in Britain alone.


The last pandemic in 1918 was the H1N1 “Spanish flu” strain which killed 230,000 in the UK and up to 100million worldwide.


Professor Peter Openshaw, director of the Centre for Respiratory Infection at Imperial College, London, said: “This discovery is exciting and it raises the possibility that we could get a vaccine to induce your own body to produce these antibodies.


“If you could get your own immune system to make these antibodies attach to the neck, then we might be able to get a vaccine that would stop you getting any type of flu, including H5N1, which would be superb – the holy grail.


“It is a really exciting discovery because it opens up the possibility of a vaccine against all strains.


“We could imagine a vaccine that works against all winter flu strains and also protects against unknown future pandemics. That would be a major breakthrough.”


Professor Robert Liddington, from the Burnham Institute for Medical Research in La Jolla, California, one of the study’s co-authors, said: “This is crucial and very powerful knowledge because it tells us how to make antibodies against the remaining flu strains that we can’t hit at the moment.

“We certainly believe that a pandemic therapy for all kinds of influenzas maybe within our grasp.”


Dr Ruben Donis, from the Centers for Disease Control and Prevention in Atlanta, said they could not find flu viruses that were resistant to the antibodies.


He added: “We could not get the viruses to mutate and escape. These antibodies have an important therapeutic potential and also pave the way for a generation of a different kind of universal vaccine. If you have a vaccine that will develop a long-lasting immunity it will have huge cost savings for seasonal vaccination and pandemic vaccination.”


Dr Wayne Marasco, from the Dana-Farber Cancer Institute and Harvard Medical School in Boston, was one of the scientists who led the research, published online in the journal Nature Structural & Molecular Biology.


He said: “I believe that the possibility of having a pandemic therapy for influenza is certainly made more real and possible because of these discoveries.”


New drug treatments based on the proteins could be several years away, but Prof Liddington said they are working on how to turn their discovery into a
vaccination.


He said: “People tend to emphasise vaccines as the holy grail. But these anti-virals can be very effective in a pandemic outbreak setting.


“They just need to be used judiciously. They are ready to go and should be effective.”


Professor Steve Field, chairman of the Royal College of GPs, said: “The Dana-Farber institute is an internationally renowned body for research and this paper looks very interesting and potentially will be very important for the treatment of influenza, but it is at an early stage.


“We are predicting a pandemic which will be global and undoubtedly lead to many deaths around the world and therefore this sort of research could have an important effect and save lives.”

http://www.dailyexpress.co.uk/posts/view/85961

 

[HenryN]

Re: Antibodies Offer a New Path for Fighting Flu

February 23, 2009


One-shot jab for every type of flu ?ready in 5 years?



<!-- END: Module - Main Heading --><!--CMA user Call Diffrenet Variation Of Image --><!-- BEGIN: Module - M24 Article Headline with no image (a) --><!-- getting the section url from article. This has been done so that correct url isgenerated if we are coming from a section or topic --><!-- Print Author name associated with the article --><!-- Print Author name from By Line associated with the article -->Mark Henderson


<!-- END: Module - M24 Article Headline with no image --><!-- Article Copy module --><!-- BEGIN: Module - Main Article --><!-- Check the Article Type and display accordingly--><!-- Print Author image associated with the Author--><!-- Print the body of the article--><STYLE type=text/css>div#related-article-links p a, div#related-article-links p a:visited {color:#06c;}</STYLE><!-- Pagination -->A universal therapy or vaccine for every type of flu is ?within our grasp?, according to scientists who have identified proteins that can neutralise most strains of the virus that affect humans.
The discovery of three immune proteins that are effective against a broad range of influenza viruses promises to provide a new line of defence against a pandemic, and could prevent many of the 250,000 deaths from seasonal flu that occur worldwide every year.
A treatment based on the research is expected to begin patient trials during the winter of 2010-11, and could be ready for widespread use within five years.
At present, vaccines against one sub-type of the virus do not protect against others, meaning that three kinds must be incorporated in the seasonal flu jab. ?I certainly believe that a pan-therapy for all kinds of inluenza may be within our grasp,? Robert Liddington, of the Burnham Institute in La Jolla, California, who led the research, said.
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• Leap in flu cases puts hospitals under strain

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• Is it just a cold . . . or flu?

<FORM name=relatedLinksform action="" method=post></FORM>

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<!-- END: Module - M63 - Article Related Attachements -->In the new research, published in the journal Nature Structural and Molecular Biology, Dr Liddington?s team identified three monoclonal antibodies that are effective against flu viruses belonging to 10 of the 16 H subtypes. Both the H5N1 avian flu virus, which has so far infected 408 people and killed 254, and the Spanish flu virus, were neutralised by the antibodies.

http://www.timesonline.co.uk/tol/news/uk/science/article5787435.ece

 

[gsgs]

Re: Antibodies Offer a New Path for Fighting Flu

once there is a real breakthrough, will they tell us immedaiately
or only after some ournal had reviewed...accepted it ?

 

[HenryN]

Re: Antibodies Offer a New Path for Fighting Flu

once there is a real breakthrough, will they tell us immedaiately
or only after some ournal had reviewed...accepted it ?

Please. Results are presentated at scientific meetings and then published months or years later.

 

[HenryN]

Re: Antibodies Offer a New Path for Fighting Flu

Commentary

http://www.recombinomics.com/News/02230902/UVac_MM.html

 

[mixin]

Re: Antibodies Offer a New Path for Fighting Flu

Commentary

http://www.recombinomics.com/News/02230902/UVac_MM.html

Your commentary just hit Newsnow. That ought to pop a couple of bubbles of optimism.

 

[HenryN]

Re: Antibodies Offer a New Path for Fighting Flu

Your commentary just hit Newsnow. That ought to pop a couple of bubbles of optimism.

The story has widespread coverage, including multiple titles and versions of the NY times story

http://www.recombinomics.com/in_the_news.html

 

[HenryN]

Re: Antibodies Offer a New Path for Fighting Flu

Your commentary just hit Newsnow. That ought to pop a couple of bubbles of optimism.

Yes, it will replace the Tangerang story as #1 in the next few minutes.

http://www.newsnow.co.uk/h/Business+&+Finance/Industry+Sectors/Agriculture/Bird+Flu?type=ts

 

[mixin]

Re: Antibodies Offer a New Path for Fighting Flu

The story has widespread coverage, including multiple titles and versions of the NY times story

http://www.recombinomics.com/in_the_news.html

Is NY Times syndicated?

A stand-alone article with a bold headline will always command more attention than a couple of sentences buried in a lengthy article.

If your take on the study is correct, I don't understand why it was so mis-represented by either the researchers or the news reporter.

Didn't the others who were being interviewed read the study?

 

[HenryN]

Re: Antibodies Offer a New Path for Fighting Flu

Is NY Times syndicated?

A stand-alone article with a bold headline will always command more attention than a couple of sentences buried in a lengthy article.

If your take on the study is correct, I don't understand why it was so mis-represented by either the researchers or the news reporter.

Didn't the others who were being interviewed read the study?

Many papers carry NY Times stories. Those linked

http://www.recombinomics.com/in_the_news.html

are the same story with various headlines.

 

[HenryN]

Re: Antibodies Offer a New Path for Fighting Flu

Your commentary just hit Newsnow. That ought to pop a couple of bubbles of optimism.

Both Tangerang stories are in front of the Vaccine commentary, so it may not make #1

http://www.newsnow.co.uk/h/Business+&+Finance/Industry+Sectors/Agriculture/Bird+Flu?type=ts

 

[mixin]

Re: Antibodies Offer a New Path for Fighting Flu

If your take on the study is correct, I don't understand why it was so mis-represented by either the researchers or the news reporter.

Didn't the others who were being interviewed read the study?

 

[HenryN]

Re: Antibodies Offer a New Path for Fighting Flu

If your take on the study is correct, I don't understand why it was so mis-represented by either the researchers or the news reporter.

Didn't the others who were being interviewed read the study?

H5N1 is ALL about politics (no science required).

 

[AlaskaDenise]

Re: Antibodies Offer a New Path for Fighting Flu

Commentary

http://www.recombinomics.com/News/02230902/UVac_MM.html

Commentary

Universal Vaccine Media Myths

Recombinomics Commentary 12:55
February 23, 2009


One-shot jab for every type of flu ?ready in 5 years'

Researchers claim that these antibodies protect against easily-transmitted H5N1 even when given to mice three days after they were infected and kept them immune for up to three weeks.

The above headline and comment from media reports on the antibody treatment describe in today's Nature Structural and Molecular Biology, "Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses" paper unrealistically raise expectations and misrepresent the data presented in the paper. These media myths are repeated and create many misconceptions, which can be significant downside in the management of seasonal and pandemic influenza. They create an illusion of a near term universal vaccine that can lead to a single injection that will give long term protection against a wide range of influenza's, including various seasonal flu serotypes and pandemic influenza.

However, the paper does not describe a universal vaccine. It describes a panel of monoclonal antibodies that can provide protection from an influenza challenge in mice treated before or after infection. The data on treatment prior to infection is for one day, while the longest time period reported post infection was 3 days.

The approach has received widespread attention because the antibodies are directed a conserved region of HA, which inhibits viral entry into cells and this inhibition has been demonstrated for a variety of influenza A serotypes. The conserved region has been dubbed an "Achilles' heel" of the virus, but the data in the paper show that high levels of antibody are required, and virus that can partially escape from the treatment already exist in the limited number of isolates tested. Similarly, the table of variations in positions that interact with the antibody is significant, although this region is more conserved than the variable region of the molecule that is more commonly linked to immune escape.

The antibodies described in the paper are not vaccines. A vaccine would be the "Achilles heel" that would be injected into hosts to achieve long term immunity against a variety of challenges. The monoclonal antibodies in the paper were selected from a library of antibodies that were selected from an unvaccinated host. The library was screened for binding to clade 1 H5N1, and positive antibodies were expanded and subsequently tested.

When used at high concentrations, the antibodies could protect from lethal challenge, by the clade 1 H5, or other serotypes, including H1. However, full protection required high levels of antibody (10-15 mg /kg), which would translate to approximately 1 gram of antibody in an adult human. When the antibody levels were lowered to 2.5 mg / kg, challenged mice began to die. Similarly, differences were noted within sub-types, demonstrating that natural escape mutants were already in circulation.

The requirement for high levels of monoclonal antibodies present serious practical considerations. Monoclonal antibodies for the treatment of various chronic conditions already exist and provide insight into the cost an utility of antibody treatment. Humira is approved for the treatment of rheumatoid arthritis. However, it is used at a dose of 40 mg/injection, or 1/25 of the level used in the mice experiments. Of greater concern however is the duration of a therapeutic dose in vivo. Monotherapy treatment with Humira requires weekly injections.

In the Nature paper, prophylactic use of the antibodies involved a protocol calling for antibody injection one day prior to challenge. There was no data showing that the antibody treatment would produce similar results when the challenge was days, weeks, or months after treatment. Similarly, the use of the antibody for the treatment of infection, given 1-3 days post infection, shows that the antibody can prevent the virus from spreading, allowing the immune systems of the challenged mice to effectively overcome the infections. None of these experiments tests the durability of the treatment beyond one day (and not for three weeks, as described in the media quote).

However, the media myths suggest that a single injection can provide long term (lifetime?) protection, which is not supported by the data in the paper, or data for other therapeutic or prophylactic monoclonal antibodies. Similarly, the reduced activity against existing isolates suggests that resistance will develop. As was described in the supplemental material, the antibodies interact with a number of positions on the HA molecule, and the change of a single position can reduce binding (efficacy). Thus, although this region is more conserved than the head of the HA molecule, fit variants of each serotype already exist in nature, and immunological escape from a widely used treatment would not be difficult.

Thus, the current approach of using moncolonal antibodies against conserved regions of influenza is a start, but the described approach is not for a vaccine, and the practical or durable application of this approach has yet to be demonstrated.

.

 

[AlaskaDenise]

Re: Antibodies Offer a New Path for Fighting Flu

Although I view any addition to our base of knowledge as a good thing, I find myself continually befuddled by news such as this.

Being aware that there are portions of the influenza virus that are highly conserved across strains, and being aware that a natural infection of influenza produces a broader range of acquired immunity than a vaccine as it currently exists and administered, why is that a natural infection does not offer broad spectrum immunity across strains?

IOW: if these antibodies address the highly conserved portion of influenza [and I don't doubt that fact] why do we not already possess them if we've suffered a natural infection in our past? And, if we do possess them, why do they not protect us going forward? And, if they don't protect us now, why will they protect us in a future iteration of vaccine?

the fact that some people seem to never get flu may be explained if their bodies already produce broad spectrum immunity.

.

 

[Giuseppe]

Re: Antibodies Offer a New Path for Fighting Flu

CIDRAP >> Researchers find antibody that fights H5N1, seasonal flu strains

Researchers find antibody that fights H5N1, seasonal flu strains

Lisa Schnirring * Staff Writer
Feb 23, 2009 (CIDRAP News) ?

In a development that could create new tools to prevent and treat seasonal and pandemic influenza, researchers have identified and tested human monoclonal antibodies (mAbs) that can neutralize influenza A viruses, including lethal H5N1 avian influenza.


The findings raise hopes for a universal flu vaccine and shed light on new options for preventing and treating influenza infections, researchers from Dana-Farber Cancer Center, Burnham Institute for Medical Research, and the US Centers for Disease Control and Prevention (CDC) reported yesterday in an early online edition of Nature Structural and Molecular Biology. The study was supported by a grant from the National Institute of Allergy and Infectious Diseases (NIAID).

Monoclonal antibodies?highly specific infection-fighting proteins derived from the same cell lineage?are being used to treat some cancers and immunologic diseases. Physicians sometimes used a basic form of the therapy during the "Spanish flu" pandemic of 1918-19, by administering blood products from recovering patients to sick patients.

Antibody treatment, also called passive immunotherapy, has been used to prevent infectious diseases such as hepatitis A and B and respiratory syncytial virus infections.

Billions of antibodies scanned

A team from Dana-Farber Cancer Institute, an affiliate of Harvard Medical School, scanned billions of mAbs produced in bacteriophages and found 10 that were active against the four major H5N1 virus subtypes, according to a press release from NIAID. Collaborating with a researcher from the CDC's influenza division, they found that three of the mAbs had broad neutralizing effects when tested in cell cultures and mice against other known influenza A viruses, including H1 seasonal strains and the one that caused the 1918 pandemic.

At the same time, the Dana-Farber group worked with researchers at Burnham to visualize the x-ray crystal structure of an mAb that was bound to the H5N1 hemagglutinin. The image shows one arm of the mAb inserted into a genetically stable pocket in the neck of the hemagglutanin protein, which blocks the structural change needed to allow the virus to enter host cells.

Wayne Marasco, MD, PhD, associate professor of medicine at Dana-Farber, said in the press release that humans rarely make antibodies to the highly conserved region in the neck of the hemagglutinin protein. "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 producing antibodies against it, rather than against the pocket in the neck of the protein," he said.

The conserved region in the neck?rather than the constantly mutating head?of the protein could provide a useful and stable new target for vaccine developers, Marasco said, adding, "An important goal is to redirect the immune response of vaccines to this invariable region of the hemagglutinin to try to obtain durable lifelong immunity."

The new strategy would offer an advantage over current seasonal flu vaccines, which are sometimes ineffective because they don't match circulating flu strains. Though vaccines developed against the H5N1 vaccine have been promising, none have elicited a broad response in humans to different H5N1 subtypes, according to a Dana-Farber press release on the findings.

Supplementing antivirals?

Antiviral medications have been the gold standard for H5N1 treatment, but they are mainly effective when given within 24 to 48 hours of symptom onset, and health officials have voiced concerns about antiviral-resistant strains of H5N1 and seasonal influenza that have surfaced in recent years.

The human mAbs are ready for advanced preclinical testing, and the next step will be to test the antibodies in ferrets, which have sialic acid receptors in their respiratory tracts resembling those in humans, Marasco said. Then researchers will develop a clinical version of one of the mAbs for use in human trials. He said that if mAbs are safe and effective in humans, a licensed product could still be several years away.

For seasonal influenza, treatments using mAbs could be used for those who have immune-system impairments, the NIAID said. In a pandemic setting, this group and others at risk, such as first responders, healthcare workers, and those exposed to the virus, could also benefit from mAb prophylaxis or treatment.

Therapeutic mAbs are more costly to produce than other influenza drugs, but they can be readily manufactured and stockpiled, according to the Dana-Farber press release. In a pandemic, mAbs treatment could be used with antivirals until a vaccine specific to the circulating strain becomes available.

Anthony Fauci, MD, director of the NIAID, told CIDRAP News that he was very pleased with the findings, and though it can be difficult to extrapolate from mouse studies, they represent a very significant advance. He said he hopes the agency will remain involved in the group's next research steps.

"This is an elegant research finding that holds considerable promise for further development into a medical tool to treat and prevent seasonal as well as pandemic influenza," Fauci said in the NIAID press release. He added that mAbs could be used along with antivirals to contain an outbreak until a vaccine is available.

The antibodies could be frozen and have a fairly long shelf life, Fauci said. He added that mAb therapy typically provides potent protection for the first few weeks but wanes over the next few months.

Implications for vaccine development

William Schaffner, MD, chairman of the Department of Preventive Medicine at the Vanderbilt University School of Medicine in Nashville, told CIDRAP News that the findings might change the way healthcare officials approach seasonal and pandemic flu, but he cautioned that the research is still in the early stages.

Schaffner, who is also president-elect of the National Foundation for Infectious Diseases, said he sees two implications of the study, one focusing on vaccine development and the other on the development of new antibody treatments. However, he said he's a little more excited about what the findings mean for the future of vaccines.

"The holy grail of vaccine research is finding some part of the flu virus code that is conserved among different strains," he said, adding that if the protein the researchers found is successful in future trials, the method could be used to provide long-lasting immunity against a host of strains. As a result, scientists wouldn't need to develop a new vaccine every year, and people might need only periodic boosters, as in tetanus immunization, Schaffner said, adding that the prospect of saving money and having a healthier population is very exciting.

As a treatment, if mAb trials are successful in humans, it could be difficult to get the treatment to large groups of people, because it would likely be given intravenously or at least through an injection, he said. "To treat flu in advance would be logistically elaborate and expensive?it's not as easy as giving a pill."

Michael Osterholm, PhD, MPH, director of the University of Minnesota Center for Infectious Disease Research and Policy, publisher of CIDRAP News, called the new study a very important scientific development that raises hopes for a universal flu vaccine. He commended NIAID for supporting the study and said several more similarly well-done studies are needed to identify the right vaccine candidates.

However, he said the world still doesn't have an economic model or the infrastructure to support the widespread use of seasonal influenza vaccine, much less a universal flu vaccine, if early scientific findings lead to a finished product. "There's no magic bullet unless you have a gun to shoot it from and money to buy the bullets," Osterholm said.

Sui J, Hwang W, Perez S, et al. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nature Struct Mol Biol 2009 Feb 22; early online publication
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​

<cite cite="http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/feb2309monoclonal-br.html">CIDRAP >> Researchers find antibody that fights H5N1, seasonal flu strains</cite>

 

[Giuseppe]

Re: Antibodies Offer a New Path for Fighting Flu

SCIENTISTS IDENTIFY LAB-MADE PROTEINS THAT NEUTRALIZE MULTIPLE STRAINS OF SEASONAL AND PANDEMIC FLU VIRUSES [NIAID/NIH]

U.S. Department of Health and Human Services - NATIONAL INSTITUTES OF HEALTH NIH News - National Institute of Allergy and Infectious Diseases (NIAID) <http://www.niaid.nih.gov/> - Embargoed for Release: Sunday, February 22, 2009, 1:00 p.m. EST

CONTACT: Laurie K. Doepel, 301-402-1663, <e-mail: doepel@nih.gov>

SCIENTISTS IDENTIFY LAB-MADE PROTEINS THAT NEUTRALIZE MULTIPLE STRAINS OF SEASONAL AND PANDEMIC FLU VIRUSES


Scientists have identified a small family of lab-made proteins that neutralize a broad range of influenza A viruses, including the H5N1 avian virus, the 1918 pandemic influenza virus and seasonal H1N1 flu viruses.


These human monoclonal antibodies, identical infection-fighting proteins derived from the same cell lineage, also were found to protect mice from illness caused by H5N1 and other influenza A viruses. Because 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.

A report describing the research, supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health as well as the Centers for Disease Control and Prevention, appears online today in Nature Structural & Molecular Biology. Wayne Marasco, M.D., Ph.D., associate professor of medicine at the Dana-Farber Cancer Institute and Harvard Medical School in Boston led the research team, which included collaborators from the Burnham Institute for Medical Research in La Jolla, Calif., and the CDC in Atlanta.

"This is an elegant research finding that holds considerable promise for further development into a medical tool to treat and prevent seasonal as well as pandemic influenza," notes NIAID Director Anthony S. Fauci, M.D. "In the event of an influenza pandemic, human monoclonal antibodies could be an important adjunct to antiviral drugs to contain the outbreak until a vaccine becomes available."

Using standard methods of production, initial doses of a new influenza vaccine to fight pandemic influenza would be expected to take four to six months to produce.

Key to their research, Dr. Marasco and his colleagues discovered and described the atomic structure of an obscure but genetically stable region of the influenza virus to which their monoclonal antibodies bind. The hidden part of the influenza virus is in the neck below the peanut-shaped head of the hemagglutinin (HA) protein. HA and neuraminidase are the two main surface proteins on the influenza virus.

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.

Dr. Marasco, Jianhua Sui, M.D., Ph.D., and other Dana-Farber colleagues began their study with avian flu viruses. They scanned tens of billions of monoclonal antibodies produced in bacterial viruses, or bacteriophages, and found 10 antibodies active against the four major strains of H5N1 avian influenza viruses. Encouraged by these findings, they collaborated with Ruben O. Donis, Ph.D., of the CDC Influenza Division, and found that three of these monoclonal antibodies had broader neutralization capabilities when tested in cell cultures and in mice against representative strains of other known influenza A viruses.

Influenza A viruses can include any one of the 16 known subtypes of HA proteins, which fall into two groups, Group 1 and Group 2. Their monoclonal antibodies neutralized all testable viruses containing the 10 Group 1 HAs-which include the seasonal H1 viruses, the H1 virus that caused the 1918 pandemic and the highly pathogenic avian H5 subtypes-but none of the viruses containing the six Group 2 HAs.

Simultaneously, Dr. Marasco's group teamed up with Robert C. Liddington, Ph.D., professor and chair of the Infectious and Inflammatory Disease Center at Burnham, to determine the atomic structure of one of their monoclonal antibodies bound to the H5N1 HA. Their detailed picture shows one arm of the antibody inserted into a genetically stable pocket in the neck of the HA protein, an interaction that blocks the shape change required for membrane fusion and virus entry into the cell.

When they surveyed more than 6,000 available HA genetic sequences of the 16 HA subtypes, they found the pockets to be very similar within each Group but to be significantly different between the two Groups. The genetically stable pockets, they note, may be a result of evolutionary constraints that enable virus-cell fusion. This could also explain why they did not detect so-called escape mutants, viruses that elude the monoclonal antibodies through genetic mutation.

"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. Current influenza vaccines target the constantly mutating head of the HA protein and do not readily generate antibodies against the conserved region in the neck.

"An important goal is to redirect the immune response of vaccines to this invariable region of the hemagglutinin to try to obtain durable lifelong immunity," Dr. Marasco states.

The monoclonal antibodies identified in their paper are very well-characterized, Dr. Marasco notes, and he is optimistic about their further clinical development. "These are fully human monoclonal antibodies that are ready for advanced preclinical testing," he says. 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.

Despite the availability of influenza drugs and vaccines, seasonal influenza still kills more than 250,000 people worldwide each year. During seasonal flu outbreaks, monoclonal antibodies could be used to treat individuals with impaired immunity due to pre-existing medical conditions or advanced age. In the event of an influenza pandemic, these individuals plus others at risk -- for example, first responders and medical personnel and exposed family members and coworkers -- could also benefit from this type of therapy.

For more information on influenza see <http://www3.niaid.nih.gov/news/focuson/flu> and <www.cdc.gov/flu>. Also visit <http://www.PandemicFlu.gov> for one-stop access to U.S. Government information on avian and pandemic flu.

NIAID conducts and supports research-at NIH, throughout the United States, and worldwide-to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at <http://www.niaid.nih.gov>.

The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit <www.nih.gov>.
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REFERENCE: J Sui et al. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nature Structural & Molecular Biology DOI: 10.1038/nsmb.1566 (2009).

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This NIH News Release is available online at:
<http://www.nih.gov/news/health/feb2009/niaid-22.htm>.

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Re: Antibodies Offer a New Path for Fighting Flu

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2692245


Structural and Functional Bases for Broad-Spectrum Neutralization of Avian and Human Influenza A Viruses


Jianhua Sui,1* William C. Hwang,2* Sandra Perez,3 Ge Wei,2 Daniel Aird,1 Li-mei Chen,3 Eugenio Santelli,2 Boguslaw Stec,2 Greg Cadwell,2 Maryam Ali,1 Hongquan Wan,3 Akikazu Murakami,1 Anuradha Yammanuru,1 Thomas Han,1 Nancy J. Cox,3 Laurie A. Bankston,2 Ruben O. Donis,3 Robert C. Liddington,2 and Wayne A. Marasco1


Abstract
Influenza virus remains a constant public health threat, owing to its ability to evade immune surveillance through rapid genetic drift and reassortment. Monoclonal antibody (mAb)-based immunotherapy is a promising strategy for disease control. Here we use a human Ab phage display library and H5 hemagglutinin (HA) ectodomain to select ten neutralizing mAbs (nAbs) with a remarkably broad range among Group 1 influenza viruses, including the H5N1 “bird flu” and the H1N1 “Spanish flu” strains. Notably, nine of the Abs utilize the same germline gene, VH1-69. The crystal structure of one mAb bound to H5N1 HA reveals that only the heavy chain inserts into a highly conserved pocket in the HA stem, inhibiting the conformational changes required for membrane fusion. Our studies indicate that nAbs targeting this pocket could provide broad protection against both seasonal and pandemic influenza A infections.

Seasonal influenza A is a scourge of the young and old, killing more than 250,000 worldwide each year, while creating an economic burden for millions1. Pandemic influenza, which occurs when a new virus emerges and infects people globally that have little or no immunity, represents a grave threat to human health: for example, the 1918 “Spanish Flu” pandemic caused an estimated 50 million deaths2,3. Vaccines have historically been the mainstay of infection control. However, due to rapid antigenic drift, the vaccine antigen needs to be updated annually based on global influenza surveillance4,5, and it is not always fully successful. In addition, some recent H5N1 vaccines have shown promising results6-9, but none has been reported to elicit a broad neutralizing response in humans. Neuraminidase inhibitors, especially oseltamavir (Tamiflu), remain the primary antiviral treatment, but they have limited efficacy if administered late in infection, and widespread use is likely to result in the emergence of resistant viral strains10,11.
Influenza A is sub-classified by its two major surface proteins: hemagglutinin (HA or H), which mediates cell entry, first by recognizing host proteins bearing sialic acid on their surface, and second by triggering the fusion of viral and host membranes following endocytosis, allowing viral RNA to enter the cytoplasm; and neuraminidase (NA or N), which cleaves sialic acid from host and viral proteins, facilitating cell exit12. There are 16 HA subtypes and 9 NA subtypes which make up all known strains of influenza A viruses by various combinations of HA and NA12 (See Supplementary Fig. 1).
The recent spread of highly pathogenic avian influenza (HPAI), H5N1, across Asia, Europe and Africa raises the specter of a new pandemic, should the virus mutate to become readily transmissible from person-to-person. The evolution of H5N1 into a pandemic threat could occur through a single reassortment of its segmented genome or through the slower process of genetic drift12,13. Nearly 400 human H5N1 infections have been reported since 1997 from 14 countries, with a case mortality rate in the immunocompetent population above 60%4.
New therapeutic strategies that provide potent and broadly cross-protective host immunity are therefore a global public health priority. Human monoclonal antibody (mAb)-based “passive” immunotherapy is now being used to treat a number of human diseases, including Respiratory Syncytial Virus infection, and we have proposed how immunotherapy could be used strategically in a viral outbreak setting14.
In the present study, we first used a phage-display antibody library and recombinant H5 trimeric ectodomain to isolate a group of high-affinity neutralizing mAbs (“nAbs”) that were potent inhibitors of H5N1 viral infection in vitro and in vivo. Based on crystallographic and functional studies, we showed that the nAbs bind to a common epitope - a highly conserved pocket in the stem region of HA containing the “fusion peptide” - that rationalizes their ability to block membrane fusion rather than cell attachment. Sequence and structural analysis of all 16 HA subtypes points to the existence of just two variants of this epitope, corresponding to the two classic phylogenetic groupings of HA (Groups 1 and 2). We therefore tested eight further Group 1 HA subtypes, and demonstrated a remarkable and unprecedented cross-subtype binding and/or neutralization spectrum. Since we had used a Group 1 subtype (H5) for our panning, our nAbs, as expected, failed to neutralize a Group 2 subtype, H7. These results nevertheless raise the possibility that a cocktail comprising a small subset of nAbs raised against representatives of the two groups could provide broad protection against all seasonal and pandemic influenza A viruses.