Topic of the month: Bird Flu

Every month, the Gate2Biotech will deal with current topics associated with biotechnologies.

The topic of this month, is the avian influenza (bird flu). During April, the portal´s visitors will find useful information about its signs, locations with a high risk of infection, and the stadium of medicine and vaccine development.

We will provide you with the most complex and recent information regarding the H5N1 virus.

• Czech version
• Chronological overview of events connected with bird flu

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The H5N1 avian influenza signs

One of the key signs of the bird flu in people is a high fever exceeding 38°C. The patient suffers from cough, sore throat, muscle pains, also possibly conjunctivitis, pnemonia, in the advanced stadium also acute breath insufficiency and other directly life-threatening states.

The incubation time of this illness is usually two to four days. When the patients first visit the doctor, they are usually asthmatic, have a fever, and cough blood and mucus. Diarrhoea is another common sign. The patients however do not have to suffer from all of these problems. It was characteristic of the recent mass cases that the patients didn´t have a rash, conjuctivitis or a stuffed nose.

Unlike the usual influenza, where the infection is expressed by mild breathing problems, H5N1 causes a very serious state leading to a quick life function disruption and death. Viral pnemonia and multi-organ failure are also extremely common.

A type H5 stem influenza or directly H5N1 is proven by at least one of the following laboratory tests: a. positive RT-PCR for A/H5 or A/H5N1 influenza b. positive virus cultivation for A/H5N1 influenza (Comment: Viral cultivation of the specimen with a H5N1 suspicion should be done only in BL-3 level laboratories); c. positive immunofluorescent antibody test (IFA) using monoclonal antibodies against A/H5 influenza; d. an at least four-fold advancement of H5-specific antibody titres in pair serum specimens.

Avian flu is an animal disease caused by viruses infecting mostly birds and less commonly pigs. It causes two basic types of illness in domestic poultry - a high and low pathogenic form. The so-called low-pathogenic form is expressed only by mild signs (such as „ruffled“ feathers, a decrease in egg production) and can be overlooked easily. The high-pathogenic form is expressed far more dramtically. It spreads quickly and a affects many internal organs in the infected poultry. The death rate is as much as a hundred procent in the first forty-eight hours.

The danger of infection

The risk of infection is elevated especially during contact with infected poultry or wild birds, in close contact (in a one-meter range ) with a person reported as a suspected or confirmed case, or in a laboratory dealing with the A/H5N1 virus. Regarding the current situation in the Czech Republic, infected or dead birds pose the most acute threat. Therefore we recommend not to come close to any birds that are dead or appear sick (do not fly, have difficulty moving). Staying at farms or houses in an affected area, where sick or dead poultry had been reported in the preceding six weeks is also risky.

Infected birds carry the virus via their saliva, nose secretions and feces. The infection is spread further by contact with these sick birds and their excrements. It can spread to people only by contact with contaminated birds or surfaces polluted by them.

The most common cases of the disease spreading to man originate from the country, where the breeders let their poultry loose. The infection is then spread to the farmhouse and also to children´s playgrounds. Especially bird droppings are dangerous, as they contain a large amount of the virus particles. No case of infection from eggs or cooked food has been reported yet. Regardless of these dangers, it seems that the transfer of the disease to man is not quite easy. For various so far unknown reasons, a lot of people living in the affected locations do not contract the disease. We expect thousands to millions of human contacts with the virus, but no sign of the disease has appeard in the majority of the cases.

Also the role of migrating birds in carrying the highly-pathogenic form is not quite known yet. Wild waterfowl is a natural reservoir of all A type flu subtypes. They have apparently been carrying the virus for hundreds of years with no signs of the disease. The H5 and H7 subtypes are usually carried by birds in their low pathogenic form, and this form can be infiltrated into poultry breeding farms, where the highly pathogenic form gradually develops.

Earlier, highly pathogenic variants from dead migrating birds (several dead birds) were very rarely isolated, usually in a location affected by a poultry infection. This detection has supported the long-term opinion that migrating birds do not spread the highly pathogenic form. But the last months have shown that the migrating birds may indeed play a role in spreading these highly pathogenic forms. Spreading of this subtype into new areas cannot be ruled out.

Epizoocies (animal epidemics) in poultry that have been reported in southeastern Asia since mid 2003 are historically most widespread and serious. Never before in history has such a large area been affected and so many birds have died.

The possibility of human to human transfer has not yet been proven, nevertheless some cases with this suspicion exist. It concerns a five-member family in Vietnam, a transfer from a girl to her aunt in Thailand, or the possible infection of three people in the Netherlands. But even in these cases, the disease transfer is only speculative. No infections of medical staff treating bird flu patients have been reported.

Treatment

No vaccine or a hundred percent effective medicine against avian flu exists yet, though many biotechnological laboratories are making an effort in their development. None of the different types of vaccines against the usual types of influenza protect against a pandemic threat.

Effective medicine development including their testing takes up to several years before they are let into free sales. The World Health Organization (WHO) has publicized the vaccinal bird flu strain for use in human vaccine in April 2004, clinical tests of the developed vaccines were launched the following year. Currently, several clinical tests are going on, they are supposed to test the sufficient protection of experimental vaccines and state the minimal amount of vaccine in a dose to ensure this protection. Because the vaccine itself must be effective against a particular pandemic virus, its rapid development in such an enormous amount is closely related to the origin of a pandemic from an economical point of view. Not even the current common influenza vaccine production would come close to meeting the requirements of a pandemic. Protection against influenza can be ensured via vaccination. Because the influenza virus undergoes frequent mutations, every year a temporary vaccine is produced.

With the bird flu, fortunately, only a slow mutation speed has been observed, which doesn´t require changes in the prototype pandemic vaccination strains.

Pandemic H5N1 vaccine development

• April 2004 - WHO provides the strain prototype for the producers
• NIAID (USA) - launches two projects aiming for clinical testing
• 6.8.2005 - preliminary results -the vaccine was immunogenic, but an increase in the dosage from 180 micrograms (in a 2x 90 μg) versus the usual 15ug in a standard vaccine was necessary
• 4.8.2005 - ACAMBIS publishes a report concerning the development of a „universal“ influenza vaccine targeted to the M2e domain (a highly conservative extracellular M2 ion channel domain)
• M2e was incorporated into a virosome particle, the project proceeds into the preclinical tests.

Today, 9 companies from Australia, Canada, France, Germany, Italy, the Netherlands, England, Switzerland and the USA produce an anti-influenza vaccine. The world production during the period from 2000 to 2003 has increased from 230 million doses to 300 million. Regardless of this increase, the current production would not be sufficient to cover the consumption even in the case of a monovaccine production, in addition to that, the doses are not distributed equally.

Today two products that may decrease the seriousness of a season virus infection exist: Oseltamivir (Tamiflu) and zanamivir (Relenza). They are effective in the case of their use within 48 hours from the appearance of the first signs of infection. With the H5N1 infection, this medicine may improve the prognosis for survival in the case of its early, nevertheless so far not enough clinical data are available yet.

The earlier on known group of antivirotics, the so-called M2 channel inhibitors, that is amantadin and rimantadin, could be used in the treatment of pandemic influenza, but resistency against these agents often quickly arises. This may significantly reduce its efficiency during pandemic influenza treatment.

Some of the momentarily circulating H5N1 virus variants are fully resistent against M2 inhibitors. Nevertheless producing a pandemic variant via reassortment still leaves a possibility that these agents will be efficient. In the case of neuraminidase inhibitors, the main significant and limiting drawbacks for mass use in the case of a pandemic are its insufficient production capacity, also its relatively high sales price, which can make these agents entirely inaccessible for some countries.

With its current production capacity, that has been recently quadrupled, it would take ten years, before the amount of oseltamivir sufficient to treat 20 % of the population would be produced. The oseltamivir production process is complex, longlasting and is not easy to transfer to other production facilities. Most of the so far reported fatal cases of pnemonia were a result of the effect of a virus and not a secondary bacterial infection. It was therefore impossible to treat it with antibiotics.

When can a pandemic arise

Three conditions would have to be fulfilled in order for a pandemic to start: a new influenza virus subtype appears, this strain may cause serious illness in humans and is followed by an easy and persistent transfer from human to human. According to the latest results, the H5N1 fulfills the first two conditions. It is a new virus for humans (the H5N1 virus has not yet circulated in the human population). If this subtype infiltrates into the human population, no-one will have antibodies.

All mutations of the virus leading to the origin of a pandemic variant must therefore lead toward the easy transfer from human to human. The risk of such a mutation exists, also the possibility of human to human transfer exists. This possibility will persist during the time of the virus´s circulation in the bird reservoir, therefore this variant may become pandemic in the future.

The virus´s transfer from man to man may be facilitated by a so-called reassortment, where a genetic material exchange of the „human“ and „bird“ influenza virus during the parallel infection of a human or pig takes place. Reassortment may lead to an immediate creation of a virus completely adapted to humans and is followed by an abrupt increase in the number of cases.

The second mechanism is a much more gradual process of so-called adaptive mutations, where the capability of the virus to infect humans increases in association with other cases of human diseases. Adaptive mutations in their origin appear as small clusters of disease within one community with some human to human transfer, this may gradually lead to the origin of the fully adapted variant. The second type of virus adaptation grants the world some time to prepare.

The WHO considers the risk of a pandemic starting serious. The H5N1 virus now firmly anchored in a large part of Asia presents a persisting risk of human to human disease transfer. Every following case of human infection gives the virus another possibility to improve its expressibility within the human population and therefore its chance of transforming into a pandemic strain. The current spread of the virus in poultry and in the population of wild birds into new areas increases the opportunity for more virus transfers to humans. Whereas the seriousness (mortality) and the time of a pandemic variant emerging cannot be estimated, the possibility of the actual start of the pandemic is actually increasing.

Flu pandemics are auspiciously rapidly spreading diseases in practically all the countries of the world. As soon as such a spreading occurs, stopping the pandemic is almost out of the question, because the virus spreads very rapidly via the droplet infection. The fact, that the virus may be exudated even before the first signs are shown, contributes to the risk of its rapid spread all over the world for example via air traffic.

The seriousness and death rate regarding the pandemic virus infection cannot be estimated. During the past pandemics, 25 to 35 percent of the entire population had been infected. Under the most favourable conditions, that means that the new virus will cause only a mild disease, 2 - 7.4 million deaths are expected worldwide (using data from 1957). In 1918 during an exceptional pandemic of Spanish influenza, at least 40 million people died, in the US, the death rate was about 2,5 percent.

A pandemic may cause a rapid increase of infected people requiring hospitalization or at least medical examination and aid, which can temporarily exceed the capacity of the medical facilities. Also a high percentage of infected people at work may affect basic services (such as police, transportation and others). Because the population will be quite sensitive to a new variant, the infection rate within a certain community may increase extremely rapidly, which may cause temporary breakdowns in the social and economic sphere. Nevertheless due to the current globalization (connection of services, media and market), these breakdowns may have a more pronounced effect. On the basis of the recent experiences, a second pandemic wave is expected within a year.

Because in the case of a pandemic outbreak all the countries will be subject to emergency conditions, it is probable that the possibilities of providing international help to countries will be limited. Also the individual governments will see a priority in protecting their own inhabitants.

Author: Gate2Biotech.com using NRL information regarding influenza viruses, information from WHO and the ptaci-chripka.cz server.

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