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Crucell's Revolutionary Antibody for Universal Therapy Against Flu

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Ik weet niet of dit al gepost is, het originele wetenschappenlijke artikel:

Heterosubtypic Neutralizing Monoclonal Antibodies Cross-Protective against H5N1 and H1N1 Recovered from Human IgM+ Memory B Cells


www.plosone.org/article/info%3Adoi%2F...

Interessant commentaar:

www.virology.ws/2009/02/25/influenza-...
flosz
0
quote:

Gert50 schreef:


Ik weet niet of dit al gepost is, het originele wetenschappenlijke artikel:

Heterosubtypic Neutralizing Monoclonal Antibodies Cross-Protective against H5N1 and H1N1 Recovered from Human IgM+ Memory B Cells


www.plosone.org/article/info%3Adoi%2F...

Interessant commentaar:

www.virology.ws/2009/02/25/influenza-...

Een paar vbtjes:
www.iex.nl/forum/topic.asp?forum=228&...
www.iex.nl/forum/topic.asp?forum=228&...
www.iex.nl/forum/topic.asp?forum=228&...

Commentaar is idd ook interessant en nieuw imo.
flosz
0
quote:

flosz schreef:


[quote=pim f]
In de NY Times wordt de aandacht gevestigd op het feit dat de concurrent zijn antilichamen al op muizen heeft getest...

[/quote]
The most potent antibody (CR6261) was protective in mice when given before and after lethal H5N1 or H1N1 challenge and could be used as a broad spectrum agent for prophylaxis or treatment of human or avian influenza infections without prior strain characterization.
hugin.info/132631/R/1208066/249155.pdf

The research was conducted on mice. Treated with CR6261, the mice recovered from lethal doses of bird flu as late as five days after infection. Still, Wilson cautioned that more research and testing are needed, including clinical trials, before either an antibody-based flu treatment or a universal vaccine becomes available for human use.
www3.signonsandiego.com/stories/2009/...

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.
www.thespec.com/News/article/518226

www.youtube.com/watch?v=12U2AqvM57I


Vergeet nog wat moois, met excuses.

Uit de presentatie van vandaag(hoe laat is het in Hong Kong...)


• Prophylactic and therapeutic efficacy data in ferrets.

www.crucell.com/page/downloads/090227...
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Staat in een artikel in de Volkskrant van zaterdag 28e, katern 'kennis' erover. Op zich weinig nieuws. 'k Heb geen toegang tot digitale editie helaas, misschien dat iemand anders kan plakken?
www.volkskrant.nl/vk-online/today.html
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quote:

Nul N. Noppes schreef:


Staat in een artikel in de Volkskrant van zaterdag 28e, katern 'kennis' erover. Op zich weinig nieuws. 'k Heb geen toegang tot digitale editie helaas, misschien dat iemand anders kan plakken?
www.volkskrant.nl/vk-online/today.html


Het artikeltje uit de VK
Bijlage:
MeawandMoo1
1
quote:

Arabica k. schreef:


Durft iemand een gokje te doen t.a.v. de vraag wanneer dit de kliniek in kan. Maxen?

Zie laatste zin uit de Volkskrant (Nx4nX) en als correctie op mijn eerdere posting.

"Crucell denkt binnen twee jaar met proeven bij mensen te kunnen beginnen".
pim f
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quote:

Nx4nX schreef:


Het artikeltje uit de VK

aanbevolen en bedankt

nu vraag ik me wel af of je iemand met griep met monoclonale antilichamen zult gaan behandelen, ik bedoel: de kosten zullen prohibitive zijn. Dus je zult een vaccin proberen te maken - neem ik aan. Punt 1: dit ondergraaft de lucratieve jaarlijkse griepspuiten carroussel (dus daarmee worden de toekomstige winsten van bv Sanofi gedecimeerd). Punt 2: de H3-variant is nog niet gecoverd, dus universeel zal het hierop te ontwikkelen vaccin niet wezen. Maar interessant is het wel...
MeawandMoo1
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quote:

pim f schreef:


nu vraag ik me wel af of je iemand met griep met monoclonale antilichamen zult gaan behandelen, ik bedoel: de kosten zullen prohibitive zijn. Dus je zult een vaccin proberen te maken - neem ik aan. Punt 1: dit ondergraaft de lucratieve jaarlijkse griepspuiten carroussel (dus daarmee worden de toekomstige winsten van bv Sanofi gedecimeerd).
[/quote]
Mogelijke oplossing zou vergelijkbaar met rabies kunnen zijn. Gebruik maken van vaccine van Sanofi, met toevoeging van de antilichamen van Crucell.
Noem het een win-win situatie.

[quote=pim f]
Punt 2: de H3-variant is nog niet gecoverd, dus universeel zal het hierop te ontwikkelen vaccin niet wezen. Maar interessant is het wel...

Zie twee artikelen.
Persbericht crucell:
Recently we expanded our set of influenza antibodies by discovering antibodies targeting also the H3 seasonal influenza strains, says Ronald Brus, CEO of Crucell.

Artikel uit de volkskrant:
"Griep wordt meestal veroorzaakt door H1 en H3 virussen. Recentelijk hebben we aantilichamen ontdekt die ook het H3-virus neutraliseren.
We zijn hierover een publicatie aan het schrijven.

Wel denk ik dat, in combinatie met (uit persbericht Crucell):

Patents for these antibodies have been filed worldwide, based on the first filing date of September 7, 2006. The claims encompass the unique conserved region to which the antibodies bind, the unique features of the neutralizing antibodies, their mode of binding, as well as their use in diagnosing, treating and preventing influenza virus infection and associated symptoms.

een potentiele kaskraker in huis heeft die de griepomzet van de concurentie kan doen decimeren.
Echter, zoals door Crucell aangegeven, d'r is meer onderzoek nodig, en zeker om meer patenten rondom CR6261 te verkrijgen en daarmee andere onderzoekers /bedrijven compleet de wind uit de zeilen te halen.
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Niet iedereen overlijdt aan griep. Er wordt straks een risicogroep gedefinieerd, die in aanmerking komt voor een behandeling met mab's.
In feite is het nog ingewikkelder, omdat er talloze onschuldige virale infecten zijn (niet-griep, banale verkoudheid) die je wel moet differentiëren van een echte griep. Tante Beppie die de eerste verschijnselen krijgt van een verkoudheid moet niet gelijk om de mab's gaan gillen.

Dus het vaststellen van een echte griep is een voorwaarde om je dure mab,s in te zetten.
Daarnaast is er onder andere vanuit de reumatologie bekend dat de mab's bepaald niet zonder bijwerkingen zijn.

Fantastische uitvinding, maar geen panacee.
MeawandMoo1
1
quote:

soldaat schreef:


Niet iedereen overlijdt aan griep. Er wordt straks een risicogroep gedefinieerd, die in aanmerking komt voor een behandeling met mab's.
[/quote]
In mijn ogen hoef je niet tot de risicogroep te behoren om een behandeling te ontvangen. In mijn ogen gaan namelijk ook economische en tactische belangen spelen.
Indien een bedrijf zijn medewerkers laat inenten, is het voordeliger omdat eenmalig te laten doen in plaats van jaarlijks. Daarnaast kan ik mij voorstellen dat verzekeraars bereidt zijn om een premiekorting te geven voor bedrijven die zo'n behandeling doorvoeren. Minder verzuimrisico.
Daarnaast in bepaalde beroepen zoals het sturen van een soldaat naar het front, wil je ook niet dat hij met een niesbui zijn maten prijsgeeft. (geintje)

[quote=soldaat]
In feite is het nog ingewikkelder, omdat er talloze onschuldige virale infecten zijn (niet-griep, banale verkoudheid) die je wel moet differentiëren van een echte griep. Dus het vaststellen van een echte griep is een voorwaarde om je dure mab,s in te zetten
[/quote]
Ik mis je punt even, zeker indien een combinatie mab die de H1 tot en met H16 aanpakt.
Indien vanuit Percivia een hoger rendament gaat halen (bijvoorbeeld al van 27 naar 40, of zelfs, zoals in Crucells presentatie miscchien wel naar 100)dan weegt dat enorm op het kostenaspect. De marges en/of het kostenaspect kunnen worden aangepast, zeker in een situatie van massaproductie.
Wat was het huidige rendament van een regulier griepvaccine? 2 to 4?

[quote=soldaat]
Daarnaast is er onder andere vanuit de reumatologie bekend dat de mab's bepaald niet zonder bijwerkingen zijn.
[/quote]
Zou kunnen, voor mij onbekend terrein en nog geen refererende documenten gelezen

[quote=soldaat]
Fantastische uitvinding, maar geen panacee.

Time will tell, misschien wordt het iets en mischien wel een nieuwe fakor V L/C.
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Geachte M.

Bedankt voor uw opbouwende kritiek.


Ik mis je punt even, zeker indien een combinatie mab die de H1 tot en met H16 aanpakt.
Indien vanuit Percivia een hoger rendament gaat halen (bijvoorbeeld al van 27 naar 40, of zelfs, zoals in Crucells presentatie miscchien wel naar 100)dan weegt dat enorm op het kostenaspect. De marges en/of het kostenaspect kunnen worden aangepast, zeker in een situatie van massaproductie.
Wat was het huidige rendament van een regulier griepvaccine? 2 to 4?


Wat ik bedoelde met een gewone verkoudheid is, dat deze altijd overgaat en doorgaans door andere virussen dan de influenza of para-influenza virussen wordt veroorzaakt.


flosz
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Another antibody against diverse flu strains found
Robert Roos News Editor
Feb 27, 2009 (CIDRAP News) – For the second time this week, scientists have reported the discovery of a human antibody that, at least in theory, could lead to development of a vaccine or drug effective against most types of influenza A, including the deadly H5N1 avian flu virus.
A team from the Scripps Research Institute in La Jolla, Calif., and the Dutch company Crucell Holland BV describe the new antibody, called CR6261, in a report in Science. They write that the antibody recognizes a stable, or nonmutating, region of the hemagglutinin (HA) protein in the 1918 pandemic flu virus and a 2004 strain of the H5N1 virus.
As it is described, the antibody targets the same general region of the HA protein as do the monoclonal antibodies described in the report published Feb 22: the stem or neck of the molecule, which sits on the surface of the virus and helps it bind to host cells. And like the earlier report, the new one says the antibody neutralizes the virus by blocking it from fusing with cells.
"The antibody neutralizes the virus by blocking conformational rearrangements associated with membrane fusion," the Science report states. "Identification of the CR6261 epitope [the HA site the antibody targets] provides a lead for the design of antivirals and takes a significant step towards the development of a durable and cross-protective 'universal' vaccine against influenza A," it concludes.
The National Institute of Allergy and Infectious Diseases, which provided funding for both studies released this week, said in a statement yesterday, "Taken together, these studies provide a blueprint for efforts to develop new antiviral drugs as well as a potential universal flu vaccine."
The scientists, with Damian C. Ekiert of Scripps as first author, write that they isolated CR6261 from a healthy, vaccinated person by mixing a serum sample with HA from an H5 virus. In a previously reported study, they found that CR6261 neutralized several influenza A subtypes, including H1, H2, H5, H6, H8, and H9. They also found that it protected mice from H1N1 and H5N1 viruses when administered up to 5 days after infection.
To determine which part of the HA molecule the antibody targets and how it neutralizes the virus, the team studied the crystal structures of the antibody in combination with HAs from the 1918 H1N1 virus and a 2004 Vietnam strain of the H5N1 virus. They found that the antibody attaches to the base of the proteins rather than to the mushroom-shaped head—the portion targeted by existing flu vaccines.
In further experiments, the scientists concluded that the antibody prevents HA from initiating the process of fusing the viral membrane with the host cell membrane. "CR6261 appears to neutralize the virus by stabilizing the pre-fusion state and preventing the pH-dependent fusion of viral and cellular membranes," the report says.
The researchers also analyzed more than 5,000 HA genetic sequences in a flu database in an effort to learn why certain flu subtypes, such as H3 and H7, are not neutralized by CR6261. They concluded that the masking of a certain site on the HA molecule by glycoproteins (glycosylation) is the probable reason. From this analysis, they concluded that the antibody probably can neutralize HAs from 12 of the 16 influenza A subtypes: H1, H2, H4-H6, H8, H9, H11-H14, and H16.
The presence of the CR6261 epitope in a wide range of influenza viruses "suggests a critical role in membrane fusion," indicating the possibility of using it to develop new antiviral drugs and a broadly protective vaccine, the researchers write.
Experts who were not involved in the study said the latest findings are very similar to those reported earlier this week in Nature Structural and Molecular Biology.
John Treanor, MD, a vaccine researcher and professor of microbiology and immunology at the University of Rochester in New York, called the idea of using the "fusion region" of HA to develop a vaccine interesting, though not entirely new. "It's a long way to go between knowing you have an antibody that can recognize that region and making a vaccine," he said.
If the CR6261 target region were used to make a vaccine designed to induce the immune system to generate similar antibodies, immunogenicity could be a challenge, Treanor said. "Bear in mind that you don't really make this antibody when you're exposed [to flu viruses], or you don't make much of it. So presumably you'd have to cook up some way of presenting the epitope in such a way as to make it immunogenic."
He said the findings certainly raise the possibility making CR6261 antibodies for use as a flu treatment. "I don't have any doubt that we could do that. I will say that if the experience with palivizumab is any guide, you'd expect this type of passive antibody approach to be much more effective for prevention than for treatment."
Palivizumab is a human monoclonal antibody used to protect certain vulnerable children from serious infections with respiratory syncytial virus, he said.
Dr. Richard Webby, a virologist, flu researcher, and associate member of the Department of Infectious Diseases at St. Jude Children's Research Hospital in Memphis, called the latest findings "great stuff."
Given that monoclonal antibodies are already used to treat certain diseases, the findings certainly point to a possibility of antibody-based therapies for flu, he said.
"There are some limitations on the wider use of this approach, cost being the major one," he said. "As production techniques improve and costs come down, it becomes a little bit more viable."
Webby added that antibody-based flu therapies have been "very, very effective" in animal models, surpassing other drugs. "So I absolutely think it's an avenue that needs to be pursued aggressively."
As for the vaccine possibilities, he noted that a number of researchers are trying to make vaccines that induce immunity to more stable parts of influenza viruses, including sites on the HA, and have had mixed success. "There's no doubt that if we want to produce a more cross-reactive vaccine against influenza, we have to understand more about these cross-reactive epitopes," he said.
www.cidrap.umn.edu/cidrap/content/inf...

flosz
0
Published Online February 26, 2009
Science DOI: 10.1126/science.1171491
REPORTS
Submitted on January 27, 2009
Accepted on February 19, 2009

Antibody Recognition of a Highly Conserved Influenza Virus Epitope
Damian C. Ekiert 1, Gira Bhabha 1, Marc-André Elsliger 1, Robert H. E. Friesen 2, Mandy Jongeneelen 2, Mark Throsby 2, Jaap Goudsmit 2, Ian A. Wilson 3*
1 Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Crucell Holland BV, Archimedesweg 4-6, 2301 CA Leiden, The Netherlands.
3 Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
* To whom correspondence should be addressed.
Ian A. Wilson , E-mail: wilson@scripps.edu
Influenza virus presents a significant and persistent threat to public health worldwide, and current vaccines provide immunity to viral isolates similar to the vaccine strain. High-affinity antibodies against a conserved epitope could provide immunity to the diverse influenza subtypes and protection against future pandemic viruses. Co-crystal structures were determined at 2.2 and 2.7 Å resolutions for broadly neutralizing human antibody CR6261 Fab in complexes with the major surface antigen (hemagglutinin, HA) from viruses responsible for the 1918 H1N1 influenza pandemic and a recent lethal case of H5N1 avian influenza. In contrast to other structurally characterized influenza antibodies, CR6261 recognizes a highly conserved helical region in the membrane-proximal stem of HA1/HA2. The antibody neutralizes the virus by blocking conformational rearrangements associated with membrane fusion. The CR6261 epitope identified here should accelerate the design and implementation of improved vaccines that can elicit CR6261-like antibodies, as well as antibody-based therapies for the treatment of influenza.
www.sciencemag.org/cgi/content/abstra...

Thursday, Feb. 26, 2009
NIAID MEDIA AVAILABILITY
Flu Virus Foiled Again
Second Research Team Finds Same Common Achilles’ Heel in Seasonal and Pandemic Flu Viruses

WHAT: Researchers at The Scripps Research Institute in La Jolla, California, supported in part by the National Institutes of Health, have identified a common Achilles’ heel in a wide range of seasonal and pandemic influenza A viruses. The study found an infection-fighting protein, or human antibody, that neutralizes various influenza A virus subtypes by attaching to these viruses in the same place. This common attachment site provides a constant region of the flu virus for scientists to target in an effort to develop a so-called universal flu vaccine. Such a vaccine would overcome the annual struggle to make the seasonal flu vaccine match next year’s circulating flu strains and might help blunt emerging pandemic influenza viruses as well.
The study provides data about the antibody attachment site that are similar to the findings of another research group, reported on February 22, 2009. Taken together, these studies provide a blueprint for efforts to develop new antiviral drugs as well as a potential universal influenza vaccine.

The Scripps research team, led by Ian A. Wilson, Ph.D., in collaboration with researchers at the biopharmaceutical company Crucell Holland (The Netherlands), discovered the potent antibody during a systematic examination of blood samples taken from healthy individuals who previously had been vaccinated with the ordinary seasonal flu vaccine. Using sophisticated screening technologies, the scientific team isolated antibodies that recognize flu viruses to which the average person has never been exposed, such as H5N1 avian flu viruses. Through this process, the scientists found one antibody called CR6261 that had broad neutralizing capabilities. Subsequently, they found several antibodies similar to CR6261 in other donors as well. With the help of a robotic crystallization laboratory, the Scripps team quickly determined the detailed three-dimensional structures of this antibody when bound to the H1 virus that caused the 1918 pandemic flu as well as to an H5 virus with pandemic potential. CR6261 bound to a relatively hidden part in the stem below the mushroom-shaped head of the hemagglutinin protein, one of two major surface proteins found on the flu virus.
The National Institute of Allergy and Infectious Diseases, the National Institute of General Medical Sciences, and the National Cancer Institute, all components of the National Institutes of Health, provided funding to this study.
ARTICLE: DC Ekiert et al. Antibody recognition of a highly conserved influenza virus epitope. Science DOI 10.1126/science.1171491 (2009).
WHO: NIAID Director Anthony S. Fauci, M.D., is available to comment on this study.
CONTACT: To schedule interviews, please contact Laurie K. Doepel, 301-402-1663, or niaidnews@niaid.nih.gov.

flosz
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March 2, 2009
Volume 87, Number 09
p. 11
Structural Biology
Skeleton Key May Defuse Flu
Antibodies bind a flu protein nook common to many viral strains
Carmen Drahl
A FAMILY OF ANTIBODIES neutralizes multiple types of flu by targeting a weak spot in the virus, according to a pair of studies. The discovery could point the way to treatments that shield people from both seasonal and pandemic flu.
Every new year brings a new flu season and a new flu vaccine to go with it. Flu vaccines are developed by predicting which types of flu will dominate the coming season, structural biologist Ian A. Wilson of the Scripps Research Institute says. "If anything different comes along, the vaccine won't be as effective," he says.
Most vaccines elicit antibodies to hemagglutinin, a protein on the virus's surface. But the region of hemagglutinin that the antibodies target mutates rapidly, allowing viruses to elude human immune systems. Now, independent teams led by Wilson and Wayne A. Marasco of the Dana-Farber Cancer Institute, in Boston, have found antibodies targeting a portion of hemagglutinin that is less variable and is consistent in many types of flu.
Each team started with a library containing large numbers of antibodies compiled from human volunteers. Marasco's library was built in-house, whereas Wilson collaborated with Dutch biotechnology company Crucell. They fished out antibodies of interest by using avian flu hemagglutinin as their lure. With Ruben O. Donis of the Centers for Disease Control & Prevention, Marasco found that his handful of hits suppressed disparate types of flu in mice, a finding replicated by Wilson's team.
The antibodies are versatile because they don't interact with hemagglutinin's variable region. Two other groups found similar antibodies last year, but they didn't unambiguously describe their mechanism of action.
Now, to get at the mechanism, Marasco and Dana-Farber colleague Jianhua Sui teamed with Robert C. Liddington and William C. Hwang of the Burnham Institute for Medical Research, in La Jolla, Calif., to obtain a crystal structure of an antibody bound to avian flu hemagglutinin (Nat. Struct. Mol. Biol., DOI: 10.1038/nsmb.1566).
Independently, Wilson and Damian C. Ekiert obtained that structure, as well as one of an antibody bound to hemagglutinin from the 1918 epidemic flu (Science, DOI: 10.1126/science.1171491). In every structure, the antibody targets the same pocket, which is in the stem of hemagglutinin rather than its variable head.
The stem pocket is conserved because it is involved in a conformational change that's crucial for viral infection, Wilson says. With an antibody bound in this pocket, hemagglutinin can no longer change its shape, a step required before the virus can fuse with a cell and send in its genetic material.
Physicians might someday be able to inject this type of antibody into people infected with the flu, or the stem pocket could be used to make a new vaccine that doesn't need retooling every year, Marasco says.
"Hopefully, these works will provide a starting point for rational vaccine design and ultimately improve the therapeutic treatment of influenza," says Zihe Rao, an expert in crystallography of flu proteins at Tsinghua University, in Beijing.
pubs.acs.org/cen/news/87/i09/8709notw...

Dana-Farber video:
pubs.acs.org/cen/multimedia/87/flu/in...
flosz
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Team Finds Immune Molecule that Attacks Wide Range of Flu Viruses
By Renee Twombly and Mika Ono
Researchers at The Scripps Research Institute report the characterization of an immune system molecule that targets what appears to be an "Achilles heel" of a wide range of influenza viruses – including the viruses responsible for past global pandemics, those causing current common infections, and strains of bird flu believed to pose future world threats.
The discovery of the molecule, an antibody known as CR6261, is good news for researchers who hope to design a flu vaccine that would give humans lifelong protection against a majority of influenza viruses. The antibody also has the potential to treat those who are unvaccinated and become infected with the flu.
The team's findings were published in the February 26, 2009, issue of Science Express, an advance, online publication of selected research papers from the prestigious journal Science.
"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," says the study's senior investigator, Ian Wilson, a professor in the Department of Molecular Biology and a member of The Skaggs Institute for Chemical Biology at Scripps Research. "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."
Flu vaccines now offer protection only for the specific strains of influenza that public health officials believe to be currently circulating in the population. This involves a lot of guesswork about which strains will be most prevalent and, because the virus is constantly mutating, this guesswork must be repeated year after year.
According to the U.S. Centers for Disease Control, in the United States more than 200,000 people are typically hospitalized from flu complications every year, and about 36,000 people die from the illness. But that is in a normal year. Over the past century, three major human influenza pandemics (the Spanish Flu of 1918-1919, the Asian Flu of 1957-1958, and the Hong Kong Flu of 1968-1969) have devastated the human population, killing around 50-100 million people worldwide.
Broad Action
In the new research paper, the scientists, composed of a team from Scripps Research and the biopharmaceutical company Crucell, in the Netherlands, show that the CR6261 antibody attaches to the virus that caused the devastating 1918 "Spanish flu" and to a virus of the "H5" class of avian influenza that jumped from chickens to a human in Vietnam in 2004 The scientists at Crucell previously demonstrated in laboratory experiments that this antibody can neutralize common, seasonal flu viruses.
"We can see exactly how and where the antibody grabs on to these influenza viruses," says 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 says the discovery was possible because of the modern tools that the research team employed, such as phage display to isolate antibodies from human blood, and a state-of-the-art robotic crystallization laboratory that helps solve the structures of microbial antigens much more quickly than in the past.
"I have been working with influenza virus antigens since 1987, and I find it just amazing to suddenly see antibodies now appear that we had no idea existed," Wilson says.
Researchers at Scripps Research and collaborating institutions have long been looking for influenza antibodies with a broader spectrum of action. To find these antibodies, the researchers extracted white blood cells from a healthy immunized volunteer to make a library of antibodies to look for antibodies that interact with viruses that the donors could not have come into contact with before, such as H5 avian influenza that has spread only from chickens to humans, but not from humans to humans.
The researchers found one such antibody in the blood of a donor who had recently been vaccinated with a flu shot to protect against H1 influenza virus, one of the seasonal subtypes that most commonly circulates in humans. That antibody was isolated and named CR6261—although some of the researchers later dubbed it "Supermantibody" when they began to realize how effective it was.
CR6261-like antibodies have now also been found in other people. According to Ekiert, it is likely that many people, if not all, have these antibodies, but the body doesn't always produce or use them efficiently.
Solving the Puzzle
The next step for the researchers was to understand exactly how CR6261 recognized and responded to such a broad array of influenza viruses.
To do that, Ekiert led the successful effort 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, including those induced by current vaccines, 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.
What the Scripps Research scientists found is that CR6261 latches on to the "stalk" of the mushroom-like 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, suggesting that this part of the virus is much more highly conserved than the virus's constantly mutating cap.
This insight into the way the CR6261 antibody binds to the virus's structure makes sense, the researchers say. It helps explains why the antibody may not be as powerful as it needs to be to attack influenza. "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," Ekiert says. "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 says. "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."
Bijlage:
flosz
0
vervolg.
It may also be possible that some people who rarely if ever contract the flu may have CR6261-like antibodies that are more efficient than others in neutralizing influenza viruses.
So far, the researchers have shown the CR6261 antibody works against many of the 16 different subtypes of influenza viruses. The antibody neutralized every H1 virus that the group tested, including those that have caused pandemics over the past 100 years. 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.
"If a sugar is the only impediment in the way, we think there is a way around that in vaccine design," Wilson says. "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."
In addition to Wilson and Ekiert, authors of the paper "Antibody recognition of a highly conserved epitope across influenza viruses" are Gira Bhabha and Marc-André Elsliger of Scripps Research, and Robert Friesen, Mandy Jongeneelen, Mark Throsby, and Jaap Goudsmit of Crucell Holland BV, Leiden, The Netherlands.
The work was funded by a grant from the National Institutes of Health, a predoctoral fellowship from the ARCS Foundation and the Skaggs Institute. Facilities supporting this work were funded by the NIH National Institute of General Medical Sciences, the National Cancer Institute, and the U.S. Department of Energy.
www.scripps.edu/newsandviews/e_200903...
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0
Hebben ze nu die mAb's alleen ontdekt en geisoleerd, of zou C hem ook al produceren?
flosz
1
Tamiflu-Resistant H1N1 Flu Virus Prevalence Increasing
By John Gever, Senior Editor, MedPage Today
Published: March 02, 2009
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.
ATLANTA, March 2 -- More than 12% of H1N1 influenza A infections in the U.S. last season were resistant to oseltamivir (Tamiflu) and the prevalence appears to be rising dramatically, according to a team of CDC-led researchers.

Moreover, the resistant strains appear no less virulent, debunking earlier suggestions that oseltamivir resistance would make the virus less dangerous.

Those findings emerged from a study of 1,155 H1N1 isolates from the 2007-2008 season by Nila J. Dharan, M.D., of the CDC, and colleagues from that agency and from several state public health laboratories, and reported online in the Journal of the American Medical Association
Mid-season data reported in February 2008 showed oseltamivir resistance on the rise generally among all flu virus serotypes. (See: Resistance to Oseltamivir (Tamiflu) Grows Higher)
Dr. Dharan examined records of 274 individual infections with H1N1 viruses, including 99 showing oseltamivir resistance.
"We found no significant difference in our comparison of the clinical symptoms and outcomes of untreated patients with oseltamivir-resistant and oseltamivir-susceptible influenza A(H1N1) infections," the researchers wrote.
One exception was that fewer hospitalizations were seen among those with resistant strains (2% versus 8%, P=0.005).
But virtually identical percentages of untreated patients took medications for fever and missed work or school, the researchers found.
Among patients who received antiviral agents, illness severity and outcomes were also similar.
Of 47 patients with resistant strains who received oseltamivir, five were hospitalized and four died.
Patient factors including demographics and flu vaccination history did not affect the likelihood of contracting oseltamivir-resistant H1N1 strains.
Dr. Dharan and colleagues also determined that rates of oseltamivir usage within a state did not correlate with the prevalence of resistant strains.
Of 22 states analyzed, only one had records of high oseltamivir usage (as measured by filled prescriptions) and high proportions of resistant strains, whereas four had high drug usage and low rates of resistant infection. Six states had relatively low levels of oseltamivir use and high rates of resistant infection.
The researchers also noted that early surveillance data for the current season have suggested that more than 90% of H1N1 viruses -- the most common now in circulation -- are resistant to oseltamivir. (See: Mild Flu Season So Far May Still Have Punch)
In an accompanying editorial, David M. Weinstock, M.D., and Gianna Zuccotti, M.D., both from Harvard, said the study helps "dispel the notion that oseltamivir resistance compromises virulence."
They also pointed to a small Dutch study, also reported online this week in JAMA, suggesting that one particular oseltamivir resistant strain may be even deadlier than normal for H1N1 viruses.
"The widespread belief that oseltamivir would retain activity against epidemic influenza strains has crumbled," Drs. Weinstock and Zuccotti wrote.
They added that this should not be surprising, given that a variety of studies have shown rising resistance to the drug beginning in the 2006-2007 season.
"For now, the best tools to mitigate influenza infection are tried-and-true -- vaccination, social distancing, hand washing, and common sense," they concluded.
www.medpagetoday.com/InfectiousDiseas...

jama.ama-assn.org/cgi/reprint/2009.29...
jama.ama-assn.org/cgi/reprint/2009.29...
*****************************

This makes it a potentially powerful antibody against a broad range of influenza strains. Fears of a flu pandemic are fuelled by the rising number of flu strains that have mutated in ways that make them resistant to oseltamivir.

Importantly, the study showed that CR6261 provides immediate protection against the influenza virus, suggesting that it will be able to prevent disease spread. In contrast, oseltamivir was less efficacious and in some cases not effective at all.

The advantages of the mAb over oseltamivir may also be important for protecting or treating people at risk of severe illness or death due to seasonal flu. These include the elderly and immune-suppressed individuals.
investors.crucell.com/C/132631/PR/200...
www.plosone.org/article/fetchObjectAt...
hugin.info/132631/R/1208066/249155.pdf

Preclinical study demonstrated antibody strongly outperformed oseltamivir
Provides immediate protection against influenza virus, suggesting ability to prevent
disease spread. Oseltamivir less efficacious and in some cases not effective at all
hugin.info/132631/R/1287817/289432.pdf

Oseltamivir will not be reliable in preventing viral spread as resistance may emerge
hugin.info/132631/R/1156548/223246.pdf
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quote:

flosz schreef:


They also pointed to a small Dutch study, also reported online this week in JAMA, suggesting that one particular oseltamivir resistant strain may be even deadlier than normal for H1N1 viruses.

??? Enigszins degenererend niet waar?
flosz
0
Nee hoor, helemaal niet en ook niet denigrerend imo. (Deze studie is overigens geen verwijzing naar Crucell zoals je kunt zien).
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