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The avian influenza virus

The virus:

A virus is made up of a package of genetic material bounded by a protein and lipid shell. The avian influenza virus, classified as a type A influenza virus, consists of ten proteins encoded by eight strands of ribonucleic acid. The lipid shell of the virus contains surface proteins that are able to bind to membrane receptors located in epithelial cells of the respiratory tract and lungs of the victim.

When bound to the receptors, the virus is drawn into the cell membrane, fusing and moving through it, after which the shell opens and the RNA is released into the cytoplasm. The genome exists as negative RNA - it must be transcribed before protein synthesis can occur, thus it translocates to the nucleus of the host cell where this transcription to mRNA, or positive RNA, occurs. Some mRNA re-enters the cytosol to be translated into the viral proteins, using the host cells own ribosomal machinery, while some remains in the nucleus and is used to synthesise further copies of the negative RNA for the virus's propagation. The new viral RNA then moves back into the cytoplasm where it joins with the newly made proteins to be packaged into new copies of the complete virus. The assembly occurs on the inside of the cell membrane, and as the process is completed, the virus moves through the cell membrane by exocytosis. The new virus is either released into the airway to find another host cell to infect or is ejected in a cough or sneeze and launched to find a new host. Virus replication dominates the cell's machinery and resources to the extent that the host cells die; it is these dead cells in the airways that result in the symptomatic rhinorrhea and irritated throat. A very large number of dead cells in the lungs can result in complications leading to death.

Drug and vaccine action:

Two antiviral medications, oseltamivir and zanamivir, are likely to be successful in treating influenza caused by the H5N1 virus, but additional studies are needed to demonstrate their current and ongoing effectiveness. They are Neuraminidase (N - one of the viral proteins) inhibitors, which block the release of the newly formed virions from the infected cells, preventing spread to other cells. These drugs are only useful within 1-2 days of infection in controlling spread, thus rely on prompt diagnosis which may not always be possible given the similarities between symptoms of influenza and other illnesses such as the common cold.

A vaccine has been developed to protect humans against the avian influenza virus, but due to the low transmission rate of avian influenza it is has not been used by the general public. The vaccine contains an antigen with an adjuvant (a chemical that stimulates the immune system) in order to prepare the immune system for the virus by storing antibodies to destroy the virus upon infection.

Spread of the virus:

Most cases of avian influenza infection in humans have resulted from contact with infected poultry or surfaces contaminated with excretions from infected birds. The spread of avian influenza viruses from one ill person to another has been reported very rarely, and has been limited. Infection of a host cell requires a specific receptor, which birds possess but on the whole humans do not. It's limited spread from birds to humans could be accounted to the fact that receptor mutations in some individuals or populations can lead to ability of the avian influenza virus to bind - for example in the asian population that suffered an outbreak, or to a mutation in the virus.

Mutation:

All Type A Influenza viruses, which includes those that infect humans and birds, mutate easily because the virus lack mechanisms that prevent changes in its genetic code during replication, and are unable to repair any changes that do occur. As a result of these uncorrected errors, the genetic composition of the virus changes (mutation) during replication and the existing strain is replaced with a new mutant virus, properly known as an antigenic variant. These constant, permanent and usually small changes in the antigenic composition of Influenza A Viruses are known as antigenic drift. The danger in antigenic drift is that Influenza Viruses that are mildly pathogenic can mutate into forms that become highly pathogenic to an increased number of species, leading to high mortality rates in humans.

Epidemiology:

History of Avian influenza epidemic:

Outbreaks of avian influenza occurred among poultry in eight countries in Asia during late 2003. Over 100 million birds in the affected countries either died from the disease or were killed in order to try to control the outbreaks. In March 2004, the outbreak was considered to be under control. However in June 2004, new outbreaks of the H5N1 virus among poultry and wild birds were reported in Asia. Since that time, the virus has spread geographically. Human cases of influenza A (H5N1) infection have been reported mainly in Asia and Africa. There have been 282 cases of confirmed mortality and 467 cases of morbidity caused by the virus.

Preparation for epidemic:

  • Stockpiling of antiviral drugs is necessary in order to reduce the strain on pharmaceutical companies.
  • Vaccines should be issued to government officials and healthcare workers in order to maintain bureaucracy and health services during an avian influenza epidemic.
  • Funding of the development of new antiviral drugs. The seasonal influenza has shown new resistance against amantadine and oseltamivir due to mutation.
  • Development of strategies for the phases of the epidemic such as no human-human transmission and low human-human transmission.

Oseltamivir

Efficacy/resistance

Due to high rates of mutation and multiple strains of influenza some strains have appeared to be resistant to Oseltamivir. The clinical efficacy is currently unknown against H5N1.

Supply chain/availability

  • Shikimic acid supply from China is very limited
  • 90% of all star anise is already used in Tamiflu manufacture by Roche
  • Tamiflu has been stockpiled worldwide as 400million doses (2006)
  • Dosage dependant supply is required

Vaccines can be stored before the epidemic reaches the UK, however these vaccines will not be well matched to the specific strain causing the epidemic. Research shows that mismatched vaccines may provide up to 30% defence against the virus and lower transmission rates by up to 50%. A vaccine designed to target the exact strain of the virus provides around 70% protection and can reduce transmission by 80%. This data shows that if the entire population was vaccinated against the virus, even with a mismatched vaccine, the already low transmission rates would be lowered significantly, decreasing the likelihood of the onset of a pandemic.

Antiviral drugs have the ability to provide both prevention (chemoprophylaxis) and treatment of the influenza if administered within 48 hours of the onset of symptoms. Antivirals are a useful combination with vaccines in order to relieve the strain on the health service and lower the economic burden of an influenza epidemic. Neuraminidase inhibitors are however costly due to the lack of raw material (star anise). They have very little adverse effects and low evidence of drug resistance, and therapeutic value in decreasing lower respiratory tract complications making them an ideal solution. Research proves that treatment with neuraminidase inhibitors reduces virus shedding, but the full impact on transmission needs further investigation. Zanamivir suffers from poor bioavailability and it has to be administered through an inhaler device, making it difficult for mass distribution.

Manufacturing Issues:

Stockpiled vaccines and antiviral drugs will be used up in the initial period of the epidemic, placing great strain on manufacturing. Production of vaccines via the egg based method lasts at least six months, so supply of more vaccines will be in waves of 6 months. This means in the mean time there will be a great dependence on antiviral drugs.

Plant location is critical to ensure quick distribution, however in the current economic crisis the UK is not a favourable location for the investment of pharmaceutical companies. Firms will look to set up production capacities in countries where labour is cheap and raw material is available; China is highly desirable for this reason (large star anise resources).

Timescale of manufacturing rel. to epidemic timeframe

Distribution

Workers plan in epidemic

Social Planning Issues

Guidelines should be published in paper format and on the internet available to all members of the population in the case of an epidemic. A hotline should be set up to inform the public of to keep them updated. Advice on which people who should avoid leaving home should be announced regularly. As per previous practices closure of schools and offices should coordinate with government procedure. Instructions on how to handle raw poultry and eggs should be published.

  • Wash hands with soap and warm water after contact with raw poultry and eggs.
  • Thoroughly wash cutting boards and utensils with soap and hot water.
  • Cook poultry to a temperature of at least 165 degrees F.
  • Cook eggs until firm.

In order to slow the spread of avian flu in an epidemic biosecurity practices should be employed by poultry farmers.

  • Farmers disinfect their clothing and shoes as well as their farm equipment.
  • They should separate domestic birds and wild birds.
  • Infected birds should be quarantined.

The stockpiled antiviral drugs should be prioritised to be available to the army and police in order to maintain law and order. Surgical masks should be issued to officers who may be in contact with people who have contracted the virus, as they help prevent the virus from entering the breathing tract of the host. Health workers who will more than likely come into contact with patients with the H5N1 virus should be vaccinated and take precautions such as wearing surgical masks while being on a ward and they should wash their hands thoroughly after patient contact

Ethics:

When new drugs are manufactured by companies they obtain a patent which restricts other companies from manufacturing the drug for a certain period of time. In an epidemic the government may forcefully grant other companies to patented information of the manufacturing process to create a treatment for avian flu to meet high demand. However the legality and ethical principle of this conduct may be breached. The company with the patent will lose large sums of revenue which will have to be reimbursed.

Will it be morally correct to issue remedies which have not been completely tested (Eg. plasmid based therapy). These remedies will have not been extensively tested for side effects and may cause severe damage to the user. However they do have their pro's in that they can be manufactured in a 2 week period to meet demand. The clinical efficacy of these treatments will also be unknown.

The current manufacturing plant capacity is insufficient to supply vaccines and antivirals in the case of an epidemic or pandemic crisis. Pharmaceutical companies looking to expand their capacity should be helped by the government with grants in order to achieve higher outputs in return for company loyalty in the form of free drugs to add to the current insufficient stockpile. Should non validated manufacturing plants be commissioned depends on the level of the crisis, suffering may be reduced if such plants are allowed to be commissioned however these production capacities may produce 'bunk' products due to a lack of testing of equipment.

Another ethical dilemma is raised when considering if the government should provide treatment to high risk groups such as the elderly first. Should those in a position of power be allowed to receive treatment first? This is morally incorrect as each life is as valuable as another however during an epidemic the lives of those involved in stopping the virus spread are critical to save lives and suffering on a larger scale.

Bibliography:

http://www.news.cornell.edu/stories/Oct05/avianflu.thevirus.ws.html

http://health.howstuffworks.com/bird-flu2.htm

http://www.medicinenet.com/bird_flu/page3.htm

http://www.cdc.gov/flu/avian/gen-info/facts.htm

http://www.ringsurf.com/online/2210-mutation_of_avian_flu_virus.html

http://www.nature.com/nrd/journal/v5/n12/full/nrd2175.html

http://docs.google.com/viewer?a=v&q=cache:UsYy1gJ-AJkJ:www.who.int/entity/csr/disease/avian_influenza/Antivirals_their_use_and_availability.pdf+limitation+of+antivirals+avian+influenza+advantages&hl=en&gl=uk&pid=bl&srcid=ADGEESh_vzISuk2y5XnfK9_H9LsuuFtk0YR2MeJ4D1oVY8dGCk4Lq5PfM8VhZomcAvBEtdyiOM-jRf7g6ICwACb5CRq7iN4mRtx0pjnnkxh6lAG81LJ5bmqAXMExFaGotxcb8cxeKmm0&sig=AHIEtbTAUUarBpYJZGUCHN0Hz9Uq0BUaaw


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