Avian Influenza APRIL Lab Report: Scientific Developments In The Fight Against H5N1

Link to March Lab report: http://www.timebomb2000.com/vb/showthread.php?t=190070

In Bird Flu Vaccine Hunt, 1976 Tragedy Looms
Scientists Are Working Toward an Effective Bird Flu Vaccine, but Want to Avoid Harm of Swine Flu Shots​

April 1, 2006 — - For nearly nine years, infectious disease specialists at Rochester University Medical Center in Rochester, N.Y., have been conducting tests as part of a broad national effort to develop a bird flu vaccine.

Beginning in late 1997, the human trials have tested 30 different vaccines, all pegged to the H5N1 virus. The testing is funded by National Institute of Allergy and Infectious Diseases at Rochester and six other centers around the country.

Volunteers like Jamal Khal are acutely aware of the growing talk that avian flu may be the next pandemic. As he received an injection at Strong Memorial Hospital, Khal said, "I just wanted to be prepared in case it comes to this country."

As infected birds are found closer and closer to the United States, moving from Asia through the Middle East to Europe, scientists also are feeling a sense of urgency.

"When you are trying to be ready for a disaster, you have to be prepared for the worst-case scenario," said Dr. John Treanor who heads the Rochester program.

Vaccine Would Require Two Shots

So far, there has been limited success. The latest vaccines have been effective when given in large doses -- four to 12 times normal. And two shots would be required, straining the ability of pharmaceutical companies to produce enough to protect the U.S. population.

Since the bird flu virus has yet to mutate so that the illness can be transmitted from person to person, instead of bird to person, Treanor and other specialists do not believe that a pandemic is inevitable. But they are preparing, nevertheless.

"The goal would be to have a vaccine that's safe, first of all -- that would be effective, at least preventing the most severe manifestations of bird flu," Treanor said, "and that could be made widely available."

He also sees part of the scientist's job to gather enough information to guide those in Washington who would decide whether to stockpile a vaccine and when to order inoculations.

Avoiding a Repeat of Harmful 'Swine Flu' Vaccine

What's happening in Rochester and elsewhere is a reminder of another pandemic scare 30 years ago.

The pandemic never occurred, but the vaccine produced to protect Americans had tragic consequences.

In 1976, three American soldiers at Ft. Dix, N.J., died from swine flu, raising fears of a pandemic. Unlike bird flu, the swine flu virus was transmitted person to person.

The administration of President Gerald R. Ford mounted a national campaign urging Americans to get swine flu shots. In a famous photo opportunity that year, Ford himself rolled up his sleeve and was inoculated.

But the vaccine was unsafe. Thirty-two people died and hundreds of other developed paralysis from Guillain-Barre syndrome.

Patty Tipton was 32 in 1976, when she was inoculated.

"I didn't know anything about the side effects," she says today at her home in Owensboro, Ky. "It has been such a life-changing event."

After being inoculated with the swine flu vaccine, she developed Guillain-Barre and is confined to a wheel chair. She has lost her fine motor skills and can no longer sew or embroider, things that once gave her pleasure -- let alone play softball or ride a horse, her main outdoor pursuits in 1976.

Her constant thought is what might have been had she not had the vaccine.

"I could have survived the swine flu," she says. "I was young, I was healthy."

What would she recommend about the bird flu vaccine? Find out first if there are side effects.

The decision to inoculate is still defended by Dr. David Sencer, director of the Centers for Disease Control in 1976.

"If there was a pandemic and we hadn't done anything," he says today, "there would have been a lot more deaths than we saw."

Sencer says the big mistake in 1976 was ceding the decision making to politicians, a mistake he hopes is not repeated.

"The more it's recognized as a health problem and decisions are made by health personnel," he adds, "the better of we'll be."

Which Bird Flu Strain Will It Be?

Today in Rochester and at the other centers, there is confidence the mistakes of 1976 won't be repeated with bird flu.

"We have demonstrated that the vaccine is safe," says Treanor, "the name of the game now is finding a vaccine that is equally effective."

Treanor says scientists have had time they did not have in 1976 to follow the development of the bird flu. But underscoring the difficulty is the notorious ability of a flu virus to change its characteristics rapidly.

"If a pandemic were to arise," he says, "it's very possible that the pandemic strain would not be exactly the strain as the one in the vaccine we're testing."

In that case, Treanor says it might take four to six months to develop the proper vaccine.

But unlike 1976, he says, nothing in 2006 will be done in panic.

"I think the commitment right now is not to immunize until there is clear evidence of person to person to person transmission," he says. "And that, I think, would be a singal suggesting that pandemic is inevitable. And would probably be a good time to start vaccinating people."

http://abcnews.go.com/WNT/AvianFlu/story?id=1794656&page=1&CMP=OTC-RSSFeeds0312

Science of the flu ​

This story was published Monday, April 10th, 2006

By John Trumbo, Herald staff writer

The pandemic flu of 1918-19 raced around the globe after jumping from being a bird-to-bird flu to a human-to-human virus. That leap across the genetic firewall made it possible for the bug to kill an estimated 50 million people.

But that small leap is a huge challenge for a flu virus.

First, it begins with wild birds, where it may or may not pose a threat to humans, depending on the type of fowl. It then migrates into domestic birds, where it is more deadly because it can infect people who handle those birds.

This is the current stage for H5N1, the avian flu strain that so far has killed millions of chickens and other fowl in 45 countries. It's also infected about 200 people who have been in close contact with infected birds, and at last count 108 of those people had died.

But so far no human victim has passed the virus to another person.

H5N1 has infected people who contacted the feces or bodily fluids of infected birds. The virus also has infected various mammals, including tigers, domestic cats and pigs.

The real danger is when the virus makes the genetic leap that allows it to be transmitted human to human. This happens through either genetic drift or genetic shift.

Drift is a random mutation of the genome, with the virus generally remaining within the affected species. Drift happens continuously, and is why the human flu virus changes from year to year, requiring new vaccines for each flu season.

Genetic shift involves a more fundamental change in the virus' genetic code that makes it possible for it to enter a new species. When that happens, the new pathogen is highly virulent because the body has not built up any defenses against the bug.

And this is what has health officials and medical researchers so concerned. There is no telling when or where that jump will happen, said Dr. Larry Jecha, health officer for the Benton-Franklin Health District.

"We don't know for sure how this will happen," said Julie Gerberding, director of the Centers for Disease Control and Prevention, in an interview with public television's Charlie Rose last week. "You need (to know) the biology of the virus and the biology of the specific species affected."

Super bug fear

Some people believe that because H5N1 has been known to exist for more than 10 years without having developed the ability to make the genetic jump, chances are it won't happen.

But if the virus does become a new super bug through genetic shift, the resulting pandemic would hit humans hard.

The deadly virus invades cells in the respiratory passages. Its genetic RNA then replicates itself in the host cell, expanding to the point where the cell bursts, exploding more viruses into the body and exponentially repeating the process. Viral pneumonia is the result.

There is currently very little defense available from antiviral medicines or a flu vaccine.

The antivirals Tamiflu and Relenza are effective in reducing severity of the disease, say experts. The medicines help block an enzyme the virus needs to escape from an infected cell to another. But antiviral supplies are limited.

Having a vaccine is the best line of defense, but there is no effective vaccine for H5N1 yet. And there is always the possibility that genetic shift of the virus could occur before researchers can develop a silver bullet vaccine -- which would then likely make it ineffective.

It normally takes six months or more to perfect a flu vaccine once the pandemic virus has been identified, and by then it can infect millions.

Pandemic survivors

Some people who have had a pandemic flu survived without ill effects.

Geneva Murray, 82, of Richland, got sick with the Asian flu in 1957 while living in Ventura, Calif., where she was a cafe waitress trying to raise three girls on her own.

"I was pretty sick for several days," said Murray, who remembers a doctor making a house call to her bedside.

"He didn't know what it was at first, but thought it might be diphtheria," she said. "He didn't tell me it was the Asian flu until later."

Murray recovered, although she didn't have the benefit of a vaccine or flu-specific medication. But she went through the flu while pregnant with her first son, who was born seven months later in 1958 with brain damage. Doctors suspected the damage was caused by the flu virus.

Her son never talked, walked and gradually lost the ability to eat. He died in 1961.

Owen Kruger, 73, of Richland also is a pandemic flu survivor, along with his wife, Patricia.

They and their two young children were stricken while living in Park Forest, Ill., where Kruger worked as a materials science engineer at the Argonne National Laboratory.

"It was very devastating for us," Kruger said. The entire family was laid low for nearly a week while the flu ran its course.

Kruger said they each took cold-water baths to combat fevers that raged up to 104 degrees. "In those days, people just suffered through it," he said.

http://www.tri-cityherald.com/tch/local/story/7614628p-7525771c.html

Chipping

Digital Angel gets patent approval for thermal microchip​

Minneapolis/St. Paul Business Journal - 10:09 AM CDT Mondayby Lauren WilbertStaff Writer

Digital Angel Corp. said today that the U.S. Patent and Trademark Office awarded the medical technology company with a patent for Bio-Thermo implantable microchips, which can monitor temperatures in animals. The St. Paul-based company said the chip can be used for early detection of infectious diseases, such as avian bird flu in birds.

The microchips, which can be embedded using a syringe into cats, dogs, livestock and horses, and poultry, keep track of an animal's body temperature via a scanner.

Patents covering the same bio-thermo technology are pending in several other countries. Digital Angel (AMEX: DOC) is selling the microchips in South Africa and is in discussions to offer it in Japan as well.

http://twincities.bizjournals.com/twincities/stories/2006/04/10/daily2.html?t=printable

http://www.twincities.com/mld/twincities/news/nation/14347296.htm

Posted on Sat, Apr. 15, 2006

Scientists go beyond eggs to make bird flu vaccine
But big supplies won't be ready anytime soon
BY ROBERT S. BOYD
Washington Bureau

CLEVELAND — Health scientists and engineers are racing to find new ways to produce a vaccine that will protect people from the threat of a worldwide bird-flu pandemic.

They're working with plants, insects and bacteria that they hope can churn out huge quantities of vaccine more efficiently than the present, agonizingly slow system of using millions of chicken eggs.

An adequate supply of vaccine for the lethal H5N1 flu virus won't be available for years, experts from seven countries, 44 universities and 60 biotechnology companies agreed at a conference this week in Cleveland sponsored by the National Academy of Sciences.

"We're not ready," said Bruce Gellin, the director of the National Vaccine Program Office at the Department of Health and Human Services. "If it happens tomorrow or next year, we're in trouble. It's a sobering picture."

Klaus Stohr, the head of the World Health Organization Influenza Team, said that one dose of a safe, effective vaccine for H5N1 was "going to be much more valuable than diamonds."

In the past three years, bird flu — also known as avian flu — has killed millions of birds, a small number of mammals and 109 humans in Asia, Europe and Africa. So far, it's overwhelmingly a bird disease, but it's mutating rapidly and might change into a form that could pass among humans.

The 2006 spring bird-migration season is just beginning, raising fears that the virus could reach the Western Hemisphere this year.

"It's routine for a virus to cross hemispheres from Russia to Canada via the Arctic," said Michael Callahan, the manager of avian influenza surveillance for the Department of State.

Ducks and other wild birds can carry a virus along an established "flyway" through Alaska to Washington state, Oregon, California, Arizona and Mexico. A sick or dead duck could be a warning signal.

About 30 potential vaccines are being tested for safety and effectiveness in the United States and Europe, but the results have been disappointing, Stohr said.

The tests show that very high doses of vaccine — and at least two shots — are needed to prevent infection, which means much greater quantities will be necessary, far more than can be produced by current technology.

There will be no breakthrough this year, Stohr said. "It will take six years to have enough vaccine for 20 percent of the world's population. It may take eight to 10 years to solve the problem."

Futhermore, the virus keeps changing, so a vaccine developed for one type of flu may not work against another variant. The H5N1 type that began in Asia already has split into two main branches.

"They are different enough that we may need two stockpiles of vaccine," said James Matthews, the senior science-policy director at Sanofi Pasteur, a vaccine manufacturer in Swiftwater, Pa.

To meet the challenge, scientists are trying to grow vaccines in various kinds of cells, which they multiply in giant vats, instead of in eggs. Yeast, tobacco leaf, soybeans and duckweed cell cultures avoid many of the problems encountered with eggs, but that still doesn't speed up the process much.

"You can't make cells divide any faster," said Patrick Scannon, the chief scientist at Xoma Ltd., a biotechnology firm in Berkeley, Calif.

Researchers also are seeking novel methods to deliver vaccine to patients without the necessity of refrigeration and sterile needles, which can pose obstacles in many parts of the world.

"Theoretically you could have a vaccine in a tomato," said Alan Shaw, the president of VacInnate, a biotechnology company in New Haven, Conn. Eating the tomato would provide additional protection after the first inoculation, like a booster shot, he said.

Another idea is to insert the genes for the virus in the DNA of a bacterial cell and then inject it into a human cell. Once there, the DNA generates the proteins that block infection.

"You make the vaccine all by yourself," Shaw said.

Given the lack of an adequate vaccine, experts at the conference stressed the importance of a strong surveillance system to detect a local flu outbreak promptly, before it can spread into a pandemic. Such a system helped limit the SARS epidemic, which killed 774 people in Canada and Asia in 2003.

"We need a computerized system to collect events and spot clusters," said Roy Anderson, an epidemiologist at London's Imperial College. "Two days is the critical threshold for a quarantine to control H5N1."

"The key to our survival in the next two or three years is good surveillance," Shaw said.

"We need to be on a wartime footing," Gellin said. "Innovation comes out of crisis."

threat to bird and mammal biodiversity

Bird flu's 'risk to biodiversity' ​

By Helen Briggs
BBC News science reporter


The spread of bird flu poses serious risks to biodiversity, say scientists who have detailed an outbreak of the virus in Owston's civets.

The mammal is a small, endangered carnivore that lives in the forests of Vietnam, Laos and southern China.

Three animals died at a conservation centre in northern Vietnam last summer. It is not known how they contracted the virus, as they do not eat poultry.

The scientists report the cases in a journal of the UK's Royal Society.

The team - from the UK, Vietnam and China - call for better monitoring of the H5N1 virus in wild animals.

"H5N1 could pose a risk to a variety of wild birds and mammals," lead author Diana Bell, of the Centre for Ecology, Evolution and Conservation at the University of East Anglia, Norwich, UK, told the BBC News website.

"We need to be screening wild birds and mammals in those countries where the virus has been present for some time.

"We mustn't be totally anthropocentric in our focus on H5N1. It doesn't only kill humans and poultry; it also kills a wide variety of wild birds and carnivorous mammals."

Biodiversity threat

H5N1 has killed birds in at least 11 of the 27 avian orders, including gulls, storks, pigeons, eagles, cranes, pelicans, parrots and owls.

It has also infected tigers, leopards and domestic cats fed contaminated meat, and ferrets and mice in laboratory studies.

Dr Bell's team warns that the disease poses a threat to bird and mammal biodiversity in many Asian countries that are "global hotspots" for conservation.

"This report illustrates the ease with which this influenza A H5N1 virus can cross species barriers and reinforces the pandemic concern engendered by its progressively increasing geographic range," they write in the Proceedings of the Royal Society B: Biological Sciences.

The civets that died were part of a conservation scheme in Cuc Phuong National Park that coordinates an international breeding programme for the species.

Owston's civet ( Chrotogale owstoni ) is listed as globally threatened and is losing numbers to hunting and trapping.
Its meat is prized by bushmeat restaurants, its body parts by traditional medicine makers and its skin by taxidermists in Vietnam and China.

Story from BBC NEWS:
http://news.bbc.co.uk/go/pr/fr/-/1/hi/sci/tech/4920546.stm

Published: 2006/04/19 10:46:54 GMT

Info on current testing methods

Editorial

Early Diagnosis of Avian Influenza​

Peter S. Lu*

The current wave of pandemic avian influenza looks likely to spread via-migrating ducks into North America by early fall of this year. Although this form of influenza A virus primarily targets wild birds and poultry, it can infect some mammals. In the few human cases that have been reported (usually only after intimate contact with domestic birds), the infection followed an unusually aggressive course and more than half of the victims have died (on 24 March 2006, the World Health Organization reported 186 human cases and 105 fatalities). The danger is that if the virus adapts sufficiently to allow serial human-to-human transmission, a global human pandemic may rapidly develop.

Vaccination, drug treatment, and containment are all under consideration for influenza preparedness (and are discussed in some detail in the special section in this issue), but their use cannot be optimized unless infection is quickly detected. Early stages of influenza, when transmission first begins, lack distinguishing clinical symptoms and thus require a biochemical test. Because such a test will most likely be used under diverse conditions, ranging, for example, from emergency rooms to airports, it needs to be as straightforward and robust as possible. It should give an answer quickly, ideally in about 5 minutes. It should not require special storage, reagents, instruments, or personnel, nor generate hazardous byproducts such as more virions. It should work on a sample specimen that is easy to obtain and should provide specific information that will distinguish an emerging pandemic strain from seasonal influenza. Perhaps the most challenging requirement is that the test should be resistant to the mutational changes that are characteristic of influenza, allowing us to detect today's virus, not just yesterday's.

Unfortunately, current detection technologies--PCR (polymerase chain reaction), viral culture, and immunoassays--fall short of these requirements. PCR, which analyzes the viral genome, is the most sensitive but is slow (minimum time, 2 hours), requires highly trained personnel, and can miss new viral strains. Viral culture is the gold standard for diagnosis but is even slower (minimum time, several days), is more difficult to perform than PCR, and requires special high-security labs to minimize the risk of release of virions that are formed during the test. Immunoassays, like those used for the familiar home pregnancy test, give rapid results and are easy to perform but currently lack the necessary sensitivity and specificity to distinguish avian from seasonal influenza reliably. The few such immunoassay-based tests that claim to detect avian influenza are purportedly insensitive and are thus unlikely to pick up newly evolving strains.

Is all lost? There are glimmers of hope. Our understanding of the avian influenza virus is growing rapidly, and some of these early insights may be leveraged to facilitate its early detection. Especially important are viral diagnostic targets, such as the abundantly expressed NS1 viral protein that may be used by influenza to inhibit interferon-related host defenses and contribute to its virulence. It appears that this protein exists in a specific form in avian influenza. It could therefore be detected in a rapid diagnostic test by agents that are capable of binding to it but not to the NS1 proteins of typical non-avian human influenza. Such target-based tests will not only permit detection of today's avian influenza but may also be able to detect tomorrow's.

Early diagnosis in the form of a quick point-of-care test is a vital element in our defense against avian influenza. Efforts to develop vaccines and drugs must surely continue, but we cannot rely solely on these interventions. Vaccination presently suffers from the inability to target tomorrow's influenza. Drug treatment can limit influenza's spread, but only when the infection is quickly identified. The power of containment is still our traditional first line of defense against an epidemic, but rapid identification of infectious individuals or animals is crucial to treatment and to containment strategies. Accordingly, we need to put a major effort behind the development of tests that are quick, sensitive, specific, simple, and inexpensive. This may also alleviate the need to extensively train the personnel who administer and interpret these tests. We may or may not need such a test this year, but we will surely have to have it in the future.

10.1126/science.1128199



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Peter S. Lu is the president and chief executive officer of Arbor Vita Corporation in Sunnyvale, CA. The company's focus is the use of PDZ domains in human therapeutics and diagnostics in oncology, neurology, and influenza. He also has patent applications in the area of influenza diagnostics and therapy.

http://www.sciencemag.org/cgi/content/summary/sci;312/5772/337

H5N1 Mutation could make it more "human friendly"......

Structure and Receptor Specificity of the Hemagglutinin from an H5N1 Influenza Virus


James Stevens,1* Ola Blixt,1,2 Terrence M. Tumpey,4 Jeffery K. Taubenberger,5 James C. Paulson,1,2 Ian A. Wilson1,3*

The hemagglutinin (HA) structure at 2.9 angstrom resolution, from a highly pathogenic Vietnamese H5N1 influenza virus, is more related to the 1918 and other human H1 HAs than to a 1997 duck H5 HA. Glycan microarray analysis of this Viet04 HA reveals an avian 2-3 sialic acid receptor binding preference. Introduction of mutations that can convert H1 serotype HAs to human 2-6 receptor specificity only enhanced or reduced affinity for avian-type receptors. However, mutations that can convert avian H2 and H3 HAs to human receptor specificity, when inserted onto the Viet04 H5 HA framework, permitted binding to a natural human 2-6 glycan, which suggests a path for this H5N1 virus to gain a foothold in the human population.

1 Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

2 Glycan Array Synthesis Core-D, Consortium for Functional Glycomics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

3 Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

4 Influenza Branch, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.

5 Department of Molecular Pathology, Armed Forces Institute of Pathology, Rockville, MD 20306, USA.

* To whom correspondence should be addressed. E-mail: wilson@scripps.edu (I.A.W.) and jstevens@scripps.edu (J.S.)

The editors suggest the following related resources on Science sites:

In Science Magazine
Introduction to special issue:
Influenza: The State of Our Ignorance
Caroline Ash and Leslie Roberts

Science 21 April 2006: 379 Summary » PDF »

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Link to May Lab report: http://www.timebomb2000.com/vb/showthread.php?t=195858