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

Link to July Lab report: http://www.timebomb2000.com/vb/showthread.php?t=203893

Here is an important link... everything you wanted to know about influenza, by Johns Hopkins: http://www.iom.edu/Object.File/Maste... Chotani.pdf

Ferrets help understand bird flu​

ATLANTA, Georgia (CNN) -- Initial results from tests using ferrets suggest the deadly H5N1 bird flu virus has to undergo complex genetic changes before it could develop into a pandemic flu virus.

Researchers are trying to better understand what genetic changes this avian flu virus would have to undergo before it would be easily transmitted from human to human, which could lead to a pandemic.

They conducted a series of tests to see what would happen if a strain of the H5N1 virus mixed with a common human flu virus (H3N2).

"We were not able to see efficient transmission from an infected animal to a healthy animal," according to Dr. Jacqueline Katz, one of the Centers for Disease Control and Prevention (CDC) researchers working on the ferret experiments.

In addition to not seeing easy transmission from one animal to another, when an animal did get sick, the virus was "not able to cause as severe disease as the original H5N1 virus," Katz explained.

Ever since the emergence of the H5N1 avian flu virus in Asia, researchers and public health officials have been fearing it could change in a way that it would easily transmit from human to human.

If this scenario were to occur, it would cause a pandemic because humans do not have built in immunity against this particular virus.

CDC director Dr. Julie Gerberding cautioned this did not mean the deadly H5N1 virus could not turn into a pandemic virus.

"Influenza is a virus that constantly evolves," Gerberding told reporters in a teleconference last Friday.

What the research shows is that it's "probably not a simple process and more than simple genetic exchanges are necessary" for the the H5N1 virus to easily spread between humans.

Researchers used ferrets because they get the flu the same way humans do -- droplets carrying the virus are spread through coughing and sneezing and spread the disease.

Yoshihiro Kawaoka, a professor in the department of pathobiological sciences in the School of Veterinary Medicine and flu expert at the University of Wisconsin, was not involved with this research.

"This is very interesting," he said, "and we may be a bit relieved, but we shouldn't underestimate flu viruses."

Like Gerberding, Kawaoka warned that the results of this experiment did not mean that the H5N1 did not have the potential for turning into a pandemic virus.

It showed that this particular combination of the 1997 H5N1 strain and the H3N2 human flu strain did not easily spread.

Other combinations have not yet been tried.

Right now, the highly pathogenic form of the H5N1 avian virus is primarily an illness in birds.

Millions and millions of domestic and wild birds have died as a result of the spread of the virus from Asia to some parts of Europe and Africa.

According to the latest figures from the World Health Organization (WHO), there are 232 known human cases of H5N1, of which 134 have died.

Most human cases are the result of human to bird contact. Very few are the result of human to human contact.

The results of these experiments were published in the "Proceedings of the National Academies of Science."

Find this article at:
http://www.cnn.com/2006/HEALTH/conditions/07/31/birdflu.ferrets/index.html

High Levels of Human H5N1 in Ferret Upper Respiratory Tract ​

Recombinomics Commentary
August 1, 2006

Indon05 virus exhibited severe illness with substantial weight loss (18.8% mean maximum 7 days p.i.) and dyspnea but no sneezing; none of the ferrets survived past day 7 p.i. (Table 1). Although high titers of infectious virus were detected in the upper respiratory tract of Indon05-inoculated ferrets, virus was not detected in any of the nasal washes from the contact ferrets through day 9 p.c.

The above comments from the ahead of the press PNAS publication,
"Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model", indicate the human H5N1 isolate from Indonesia, A/Indonesia/5/05(H5N1), grows to high titer in the upper respiratory tract in inoculated ferrets. This property is cause for concern because the data indicate such a change can be achieved in the absence or reassortment or changes in the receptor binding domain.

WHO and consultants have been offering reassurances that new H5N1 human isolates do not have human genes or changes in the receptor binding domain. However, the publication above uses avian / human reassortants in an ferret model to monitor transmissibility of such reassortants. The data, which includes earlier data on reassortants using a 1997 isoalte, indicate that the reassorted genes do not offer selective advantage. The human genes decrease the ability of the H5N1 to grow in tissue culture or transmit under the experimental conditions that allow for transmission of human flu.

Although most of the human sequences from Indonesia have been withheld, the HA and NA genes of the above isolate have been released. The HA sequence does not have changes in the receptor binding domain. WHO and consultants have been monitoring changes at positions 226 and 228. These changes are thought to affect receptor binding specificities and increase binding for receptors found in the upper respiratory tract of mammals, However, although the human H5N1 isolate from Indonesia does not have these changes, it is able to grow to high titers in the upper respiratory tracts of the ferrets.

Thus, although the parameters being monitored by WHO and consultants have not changed in the Indonesia isolate, the high titers in the ferret upper respiratory tracts indicates other changes have led to this increased ability.

The HA sequence that has been released has a novel glycosylation and cleavage site in HA. The novel cleavage site has caused concern because it has not been reported in Indonesian poultry isolates. The frequency of H5N1 in humans or other mammals by be underestimated because surveillance in animals in Indonesia as poor and human cases are generally not tested for H5N1 bird flu unless there is a history of contact with dead or dying poultry.

Changes in the HA cleavage site can impact tissue tropism because HA cleavage is required for infection, and the cleavage is controlled by tissue specific proteases which cleavage at basic amino acids, but the surrounding sequence regulates the protease target. Most of the human isolates on the large island of Java have the novel cleavage site.

H5N1 evolves via acquisition of new sequences via recombination. The high concentration of H5N1 in Indonesia creates conditions for dual infections and H5n1 evolution. These changes do not require reassortment or changes in the receptor binding domain, the parameters being monitored by WHO.

Instead, H5N1 has been gradually changing and the number of distinct versions of H5N1 that have bee shown to cause fatal infections in humans continue to grow. None of these newly reported isolates reported reassortment with human genes. Instead the lack of such changes have been cited by governments claiming that the human isolates have not "mutated".

These reassurances are far from reassuring because H5N1 can evolve and increase efficiencies in the absence of these changes, as indicated by the high levels of H5N1 in the upper respiratory tract of experimental ferrets.

http://www.recombinomics.com/News/08010603/H5N1_Indonesia_Upper.html

China confirms 2003 bird flu death​

15:36 09 August 2006

China has announced its first confirmed human death from bird flu actually occurred in late 2003 – several months earlier than the previously reported first death from the current outbreak.

The announcement on Tuesday comes as south-east Asian nations are caught in the grip of the latest outbreak of the virus. Also on Tuesday, Indonesia reported two more human bird flu deaths, raising the toll there to 44 and making it the world's hardest hit nation.

The country reported its first bird flu deaths in July last year and has seen a steady rise in victims since then. Experts blame the escalation on Indonesia’s failure to carry out the widespread culls seen in other countries struck by the H5N1 strain.

And Thai officials have declared more than one-third of their country, including Bangkok, a disaster zone as a precautionary measure to help officials there battle bird flu. On 5 August the nation reported its 16th bird flu fatality.

Its cabinet also approved the creation of chicken "death squads" tasked with the immediately culling of any infected birds as well as all poultry within a 1-kilometre radius of any outbreaks.

Bogus email
The Chinese health ministry confirmed its first human case through laboratory tests that were carried out with the World Health Organization (WHO) and researchers from the Chinese Academy of Military Medicine, the ministry said on its website.

It identified the victim as a 24-year-old private in the People's Liberation Army, surnamed Shi. China had previously said its first human bird flu case was in November 2005.

Officials admitted their mistake after eight Chinese scientists published a letter in the New England Journal of Medicine in June 2006, claiming Shi became ill from bird flu on 25 November 2003 and later died. The journal even received a bogus email claiming to come from an author of the letter and asking for its withdrawal (see Bogus request to withdraw Chinese bird flu paper).

Stronger surveillance
Although nearly three years have passed since Shi died in Beijing, the government said there was no reason to worry about its ability to react quickly. "People shouldn't panic," said Mao Qun'an, a spokesman for the health ministry, according to the state-run Xinhua news agency. "The country's bird flu surveillance capability is much stronger now than it was two years ago."

Prior to China's announcement, the first human death from bird flu in recent years was believed to have been in Vietnam in January 2004. Since then, over 220 people have caught the virus, resulting in about 130 fatalities.

Roy Wadia, a Beijing-based spokesman for the WHO, said he did not want to speculate on any cover-up in this case, but that it highlighted weaknesses in the way officials report threats to public health: "This actually pinpoints a challenge facing the communication mechanism within the Chinese government structure."

China was widely criticised for initially covering up the deadly Severe Acute Respiratory Syndrome (SARS) outbreak in late 2002, enabling the virus to spread more easily and kill hundreds globally.

http://www.newscientist.com/article/dn9705-china-confirms-2003-bird-flu-death.html

WHO changes H5N1 strains for pandemic vaccines,
raising concern over virus evolution​

http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/aug1806vaccines.html

Lisa Schnirring * Contributing Writer

Aug 18, 2006 (CIDRAP News) – The World Health Organization (WHO) today changed the H5N1 avian influenza strains recommended for candidate vaccines for the first time since 2004, causing some experts to question how far the virus has evolved.

The WHO's new prototype strains, prepared by reverse genetics, include three new H5N1 subclades.

The hemagglutinin sequences of most of the H5N1 avian influenza viruses circulating in the past few years fall into two genetic groups, or clades. Clade 1 includes human and bird isolates from Vietnam, Thailand, and Cambodia and bird isolates from Laos and Malaysia. Clade 2 viruses were first identified in bird isolates from China, Indonesia, Japan, and South Korea before spreading westward to the Middle East, Europe, and Africa. The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006, according to WHO.

Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections:

* Subclade 1, Indonesia
* Subclade 2, Middle East, Europe, and Africa
* Subclade 3, China

On the basis of the three subclades, the WHO is offering companies and other groups that are interested in pandemic vaccine development these three new prototype strains:

* An A/Indonesia/2/2005-like virus
* An A/Bar headed goose/Quinghai/1A/2005-like virus
* An A/Anhui/1/2005-like virus

Report raises alarm, offers opportunities
Michael T. Osterholm, PhD, MPH, a leading pandemic preparedness expert, said recognition of the three subclades demonstrates how diverse the virus is and how dynamically it is evolving. He said the WHO notice is more important for the questions it raises than for the vaccine guidance it contains. "Does that mean H5N1 is closer to becoming an agent that can readily transmit human-to-human? That's the billion dollar question," he told CIDRAP News. Osterholm is director of the University of Minnesota's Center for Infectious Disease Research and Policy, publisher of the CIDRAP Web site.

Many experts who follow the ongoing analysis of the H5N1 virus sequences are alarmed at how fast the virus is evolving into an increasingly more complex network of clades and subclades, Osterholm said. The evolving nature of the virus complicates vaccine planning. He said if an avian influenza pandemic emerges, a strain-specific vaccine will need to be developed to treat the disease.

Recognition of the three new subclades means researchers face increasingly complex options about which path to take to stay ahead of the virus, he commented. Their goal is to develop a vaccine that is effective against a broad array of virus strains, one of which may be the pandemic trigger. "Does that mean one of these subclades is the lucky or unlucky one? That's the key issue," Osterholm said.

Paul Targonski, MD, PhD, a genetics epidemiology expert who works in vaccine research at the Mayo Clinic in Rochester, Minn., said that the WHO's release of the subclade strains is an important, progressive development in vaccine research. What's new for vaccine researchers is seeing the smaller differences between the H5N1 virus clades, he told CIDRAP News.

Though the information makes the development of an H5N1 vaccine more complex, it also provides good information for designing more targeted and effective vaccines, Targonski said.

Next steps for vaccine developers
Some researchers will use the WHO's new prototype strains to develop vaccines to treat regional outbreaks, while others will use them to craft a more global vaccine that addresses the most common H5N1 virus strains, Targonski predicted.

Until now, researchers have been working on prepandemic vaccines for H5N1 viruses in clade 1. In March, the first clinical trial of a US vaccine for H5N1 showed modest results. In May, French researchers showed somewhat better results in a clinical trial of an H5N1 vaccine that included an adjuvant.

Vaccine experts aren't sure if a vaccine effective against known H5N1 viral strains would be effective against future strains. Although the new viruses will now be available for vaccine research, WHO said clinical trials using the clade 1 viruses should continue as an essential step in pandemic preparedness, because the trials yield useful information on priming, cross-reactivity, and cross-protection by vaccine viruses from different clades and subclades.

See also:

Aug 18 WHO advisory on H5N1 candidate viruses

Mar 30 CIDRAP News article "H5N1 vaccine trial shows limited benefit"

April 11 CIDRAP News article "Would an imperfect vaccine be useful in a flu pandemic?"

May 12 CIDRAP News article "Sanofi reports results for H5N1 vaccine with adjuvant"

Jul 20, 2005 CIDRAP News article "WHO won't change H5N1 strains picked for vaccines"

August 30, 2006

Why blood of bird flu survivors is a lifesaver​

By Mark Henderson, Science Editor


BLOOD products taken from people who have recovered from bird flu could be useful for treating other patients in the event of a pandemic, research has suggested.

An analysis of how such transfusions were used in hospitals during the Spanish flu pandemic of 1918 has indicated that they reduced the risk of death and eased symptoms, raising the prospect that a similar approach could be used against H5N1 influenza.

Although vaccines and antiviral drugs such as Tamiflu are likely to be the front line of defence today, blood plasma transfusions could provide a valuable back-up. They could prove a particularly valuable weapon against the H5N1 virus in developing countries with poor access to vaccines and antivirals, scientists said yesterday.

The study, which is published in the journal Annals of Internal Medicine, adds weight to calls from a leading British scientist, first reported in The Times, for the Government to examine a similar blood product’s possible role in an H5N1 flu pandemic.

Sir Peter Lachmann, Emeritus Professor of Immunology at the University of Cambridge and a past president of the Academy of Medical Sciences, argues that antibodies could be taken from recovering flu patients and used to treat others who develop the disease.

The proposal differs from the blood plasma idea as it involves separating antibodies known as immunoglobulins, which are already used widely against diseases such as hepatitis A, chicken pox and measles.

Blood is removed from a patient who has recovered and the liquid plasma part is mixed with alcohol and separated into its components by fractionation. One of the resulting fractions is rich in immunoglobulins that the immune system has made to fight the pathogen in question, and these can then be given to other patients exposed to the disease.

The approach has not yet been used against flu in humans, largely because existing vaccines and antivirals are more effective and less risky. Research in mice, however, suggests that immunoglobulins would be an effective way of alleviating symptoms. In the new research, a team examined eight contemporary pieces of medical research into the Spanish flu, which killed as many as 40 million people. They found that transfusions of blood plasma from convalescents, which were sometimes performed to treat new patients, appeared to have beneficial effects.

Sir Peter said it would be sensible to start recruiting volunteers to be immunised against H5N1, whose blood could then be used to provide antibodies. “Once there is a pandemic, making immunoglobulins from convalescent patients will be a valuable thing to do. However, if the first wave is explosive there will be insufficient time. But if the initial outbreak stutters then it should work well.”

http://www.timesonline.co.uk/article/0,,3-2333845,00.html

Link to September Lab report: http://www.timebomb2000.com/vb/showthread.php?t=211354

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