Influenza is classified by the World Health Organisation as ‘a virus that attacks mainly the upper respiratory tract'1 with symptoms including fever, cough, headache, muscle pain and sore throat. The influenza virus is an RNA virus which is subdivided into the genera Influenza A, B and C. Of the three, Influenza A is the most virulent and produces the most severe illness.
Structure and Properties
The three genera of Influenza share a similar structure, with a diameter of 80-120nm in a roughly spherical shape 2. The virion consists of an outer envelope containing two main types of glycoproteins, covering a central core containing the RNA and other viral proteins 3. Unusually, the genome consists of more than one strand of RNA, instead being comprised of seven or eight strands which each code for either one or two genes. The genome of Influenza A codes for 11 different proteins: haemagglutinin, neuraminidase, nucleoprotein, M1, M2, NS1, NS2, PA, PB1, PB1-F2 and PB2 4. Influenza A is able to be subclassified based on the antibody responses to haemagglutinin (HA) and neuraminidase (NA) in the format HxNy 5. Currently, there are 16 different HA and 9 different NA subtypes that are known, but only H1, 2 and 3 and N1 and 2 are commonly found in humans 6.
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The role of HA is to bind to the surface of the target cell, resulting in the engulfing of the virus in an endosome. The cell then attempts to digest the contents of the endosome, however, once the pH has dropped to roughly 6.0 the structure of HA becomes unstable, causing it to partially unfold. This exposes a highly hydrophobic portion known as the “fusion peptide” which inserts into the intracellular membrane. The HA molecule then refolds into a more stable structure under low pH conditions resulting in the virus membrane and that of the lysosome to be pulled together. The new arrangement of HA then causes the membranes to fuseallowing the viral RNA into the cell, initiating infection 7.
Neuraminidase is responsible for removing the terminal sialic acid residues from the host cell and progeny viruses to prevent binding to the surface of the host cell 8. This allows the virions to spread out and infect other cells without being wasted on pre-infected cells.
After the virus has entered the host cell by the action of HA, the viral nucleoplasmid is released, having been signaled to do so by the change in structure of HA, and travels to the host nucleus 9.
Once within the nucleus, the negative sense viral RNA (vRNA) is transcribed into positive sense vRNA by RNA polymerase 10. The vRNA is then either exported to the cytoplasm to be translated or remains in the nucleus. The newly formed viral proteins are then either secreted via the Golgi apparatus onto the cell surface, or transported back to the nucleus for the purpose of constructing new genomic particles 10.
During this process, different viral proteins which have been released perform roles such as inhibiting host mRNA translation within the cell and breaking down the host mRNA to release nucleotides to be used in vRNA synthesis 11.
Due to the lack of RNA proofreading enzymes within the virion, the RNA polymerase makes an error in transcription approximately every 10,000 nucleotides, which is also roughly the length of the Influenza vRNA 12. The result of this is that almost all of the new virions will be mutated from the parent vRNA. This is referred to as antigenic shift which is a gradual change of the surface antigens presented by the virus.
Influenza is also able to mutate by a method known as Antigenic Shift. This occurs when more than one type of influenza infects one cell. Due to the segmentation of the vRNA, if this occurs, the genes of each strain of the virus can be swapped. This can occur with a mix of human and non-human influenza or solely non-human influenza which, when combined, mutates to have the ability to infect humans 13. This form of mutation poses the greatest public health risk as it can create novel strains of the virus to which the public has no immunity, causing epidemics and pandemics.
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It should be noted that although both influenza A and B can mutate by antigenic drift, only influenza A is able to mutate by antigenic shift 14.
There are three main methods of transmission for the Influenza Virus:
- Direct Transmission – This is where an infected person coughs or sneezes directly into the eyes nose or mouth or another person.
- Airborne Transmission – When a person inhales the aerosolised droplets produced by the coughing or sneezing of an infected individual
- Contact Transmission – Where the virus is picked up from another surface and transferred to the uninfected person by hand to mouth, eye or nose contact.
In airborne transmission, even though the droplets are typically 0.5 to 5µm, inhalation of just one droplet may be enough to cause infection. It is possible for one sneeze to contain tens of thousands of droplets, however most of these will settle on surfaces as they are too large to be suspended in the air 15.
Once the droplets have settled on a surface, the survival time of the virus varies dramatically depending on the surface, varying from 5 minutes on skin and 15 minutes on dry tissue paper16 to up to 17 days on banknote17. The implications of this are that it becomes very easy for transmission to occur, particularly in urban environments.
Symptoms and Pathophysiology
Influenza is able cause a range of symptoms which can leave people bedridden for days. The most common symptoms of influenza include fever, chills, coughing, myalgia, fatigue and nasal congestion.
One of the ways it is thought that influenza causes these symptoms is through its inhibition of adrenocorticotropic hormone (ACTH) which leads to lowered levels of cortisol 18, this means that the immune response is stronger as cortisol can weaken the activity of the immune system through actions such as preventing proliferation of T-cells. Most of the symptoms listed above are caused by vast amounts of cytokines and chemokines such as interferon and TNF produced by the infected cells 19. The coughing and nasal congestion caused in influenza can also be partially attributed to the cell damage caused by the infection, as opposed to being solely caused by the inflammatory response 20 22. The massive immune response can also potentially lead to hypercytokinemia or cytokine storm.
This is when the body loses control of the production of cytokines in an immune response, normally in reaction to a new highly pathogenic infection, resulting in a cascade of T-cells and macrophages being recruited to the site of infection potentially resulting in multiorgan failure 21. It is believed that it may be hypercytokinemia that is responsible for the high mortality in both H5N1 bird flu cases 23 and in the 1918 Spanish influenza pandemic 24. Others however have suggested that the large volume of cytokines is due to the massive viral replication and is being controlled appropriately as opposed to the loss of control in cytokine storm 25.
Treatment and Vaccination
During the winter in temperate area of the world, levels of influenza reach epidemic levels. This results in a large loss to the economy of affected nations, with studies showing that the annual seasonal Influenza epidemic costs the USA over $80 billion 26. Combined with the potential cost to human life this highlights the need for effective treatments for influenza.
The main focus of treatment currently is neuraminidase inhibitors, these work by preventing the mature virions from detaching from the infected host cell and spreading throughout the body. As NA is found on both influenza A and B, neuraminidase inhibitors are effective against both genera. Drugs within this group include Oseltamivir (Tamiflu) and Zanamivir (Relenza).
Oseltamivir is a prodrug which undergoes hydrolysis in the liver to become the activated free carboxylate which acts as a competitive inhibitor to the reaction between NA and sialic acid. Currently Oseltamivir is becoming less effective as the circulating strains of seasonal influenza become resistant to it, as shown in a recent WHO study of the 2008-2009 seasonal influenza strains of H1N1 found that 95% of the tested strains were resistant to the drug 27. Similar studies by the CDC found an even higher 99.6% rate of resistance 28. Resistance in the 2009 pandemic strain of H1N1 is currently shown to be 1.3% 30.In cases of non-resistant influenza the reduction in time to symptom alleviation is 0.5 to 1 day 29.
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Zanamivir, unlike Oseltamivir, is not a prodrug and is instead taken in the active form. The method of inhibition is the same as that of Oseltamivir in that it binds competitively to the active sit of NA. Studies by the CDC have shown that over the same 2008-2009 period as above, the resistance to Zanamivir was 0% 28. The resistance in the 2009 pandemic H1N1 strain is also 0% 30. Zanamivir is also shown to be able to reduce the time to symptom alleviation by 1.5 days.
A further group of anti-influenza drugs are M2 inhibitors. These function by preventing protons entering the virus from the acidic lysosomal environment. This stops the dissociation of proteins vital in the un-coating of the virion resulting in the inability to release the contents into the cytoplasm. M2 inhibitors are only effective against influenza A, not B. Many strains of influenza have now developed resistance to M2 inhibitors such as Adamantane, however, for the 2008-2009 period seasonal influenza had only 0.5% resistance, compared to the 100% resistances for H3N2 and the novel H1N1 responsible for the 2009 pandemic 28.
Due to the ever changing nature of Influenza's antigenic representation, it is necessary to provide a new vaccine every flu season. The flu season occurs during the colder part of the year so varies between the northern and southern hemisphere. The consequence of this is that 2 versions of the seasonal flu vaccine must be produced for each year, one for the Northern hemisphere flu season and one for the Southern hemisphere flu season.
The vaccine consists of three different vaccines to protect against the most common strains in that year of influenza A (H1N1), influenza A (H3N2) and Influenza B. The vaccine strains are identified by population sampling carried out in laboratories across the world such as the CDC in America and the National Institute for Medical Research in the UK. Due to the lengthy process of vaccine production, the sampling is used to try and predict which strains will be prevalent in six months time when the vaccine is completed. This can potentially result in the most prevalent strain not being fully immunised against, however it is likely that the vaccine will still provide partial protection.
The process of growing the vaccine begins with first adapting the wild virus for usage in manufacturing a vaccine. To reduce the virulence and aid growth in the allantois of the hens' eggs, where the vaccine strains are grown, the wild virus is mixed with a strain of laboratory Influenza A. After being allowed to grow together a hybrid of the two strains is formed which contains the less harmful internal structures found in the laboratory strain but which presents with the antigens of the wild strain. This process takes roughly three weeks 31.
After testing to ensure that the antigens presented on the hybrid virus match the wild virus, the vaccine manufacturers test the growth rate of the virus in the eggs under varying conditions to find the optimal conditions, taking another three weeks. The main vaccine manufacturing then starts by inserting the virus into 9-12 day old fertilised hens' eggs and incubated at the previously determined optimal conditions for 2 to 3 days.The allantois of the egg, which now contains millions of virions, is extracted. The virus is then killed by use of chemicals and the Antigens purified. Each lot of antigen takes roughly two weeks to produce, with a new batch being started every few days 31. The vaccine then undergoes clinical trials to ensure it is safe to use which requires at least 4 weeks more before being approved by the regulatory authority and put on sale.
This type of vaccine is referred to as a ‘dead whole organism' vaccine. The benefits of this type of vaccine are that it can be even be administered to immunocompromised people as there is no chance of a reversion of virulence occurring, however it does result in a weaker level of immunity.
A second type of vaccine has recently started to be used known as FluMist or Live attenuated influenza vaccine. This works by delivering an aerosolised spray of a weakened version of the influenza virus intranasally. The advantage of this method is that the level of immunity induced is high, with a single dose usually being enough to provide long term immunity. However, there is a risk that the weakened virus may revert to its more virulent form meaning it is not suitable for immunocompromised patients.
Of the two genera of influenza that commonly cause illness in humans (A and B) only influenza A has the potential to cause pandemics. The main reason for this is how influenza A is able to mutate so rapidly by antigenic shift but also the potential for novel strains to appear via antigenic drift in previously animal origin strains.
The WHO pandemic phases outline a pandemic as follows; ‘the same identified virus has caused sustained community level outbreaks in two or more countries in one WHO region and at least one other country in another WHO region'32.
In the last 100 years there have been four notable influenza pandemics:
- Spanish Flu – 1918-20
- Asian Flu – 1957-58
- Hong Kong Flu – 1968-69
- Swine Flu – 2009-present
The most severe of these pandemics was the Spanish flu which is estimated to have killed between 50 and 100 million people worldwide 33. Reports from the time indicate that on top of the usual symptoms of influenza there was also haemorrhage of mucous membranes 33. The main cause of death was bacterial pneumonia due to the damage caused by the influenza virus to the ciliated epithelial cells in the respiratory system allowing bacteria to migrate to the lungs 34.
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