What causes influenza?
Influenza or flu for short is caused by a family of viruses, which can be called influenza A or influenza B.
Influenza A viruses are found in humans, animals – like swine and horses- and mostly aquatic birds. Influenza B is only found in humans.
How do flu viruses infect cells and spread to others?
Flu viruses are covered in hundreds of protein spikes on their surface. There are two different types, called the hemagglutinin and the neuraminidase.
In order to infect cells flu viruses bind on to sugar receptors on the surface of the cells by the hemagglutinin. The cell then engulfs the virus, and the viruses’ protective coat is removed to expose its genes.
The information in these genes is then copied by the cell, resulting in the production of all the new building blocks to produce 1000’s of new flu virus progeny.
These new viruses then force their way out of the cell, however they all bind onto the sugar receptors once outside the cell.
The second spike, the neuraminidase, removes these sugars, allowing the viruses to release and spread to infect healthy cells.
Please can you give an introduction to the new drug you have developed that is effective in preventing the spread of different strains of influenza? How does this drug work?
The new drug is based on the natural sugars that the virus neuraminidase removes, called sialic acid.
Dr Steve Withers at the University of British Columbia modified the sialic acid to make an artificial sialic acid with two fluorines, so that they are called di fluoro sialic acids (DFSAs).
As it looks very similar to the natural sugars, the neuraminidase tries to break these DFSAs down, but in doing so they form a tight link to the neuraminidase, thus blocking it from removing sugars on the cell. The virus remains bound to the cell, thus preventing it from spreading.
How was this drug developed?
Dr Withers and Dr Watts at the University of Bath, developed a series of drugs by starting with the modified sialic acid DFSA, but since our bodies also have neuraminidases the DFSA had to be further modified to make the drugs specific for the flu neuraminidase.
Each time a new drug was made we tested it against a number of different flu virus strains to see firstly if it could block the function of their neuraminidases, secondly to see if it could stop the viruses reproducing in cells in the laboratory, thirdly to make sure they didn’t harm healthy cells, fourthly to see if it was effective against viruses which were known to be resistant to the other flu drugs already available, Tamiflu and Relenza.
Dr Streltsov also from CSIRO used the Australian synchrotron to actually visualise how the drugs were binding in crystals of the neuraminidase, to understand what interactions were occurring between the drug and the neuraminidase.
Those that showed the greatest potency in the laboratory models were then tested in a lethal model of flu infection in mice by Dr Niikura at Simon Fraser University in Canada. The two drugs tested protected mice from death.
Thus development of the drugs has been an evolutionary process from the starting DFSA, requiring diverse skills.
What stage of development is the drug currently at?
We can see that it works well in the mouse model, but mice get flu in the lungs. A better model for human infections is the ferret model as they get an upper respiratory tract infection like humans. Hence one of the next steps is to test the most potent drug in ferrets against some different flu strains.
We also need to determine whether different strains of influenza can become resistant to these drugs after prolonged exposure of viruses to the drugs in the laboratory.
The best method of taking the drugs will also have to be investigated. Currently it would have to be inhaled like Relenza, but there are modifications to see if we can make it into a drug that could be easily swallowed like Tamiflu or if it could be modified so one single inhaled dose could be sufficient, like the recently released Inavir, which is a long acting modified Relenza.
How does this new drug differ from the seasonal flu vaccine that needs to be updated every year?
The flu vaccine, jab or shot as it is known, contains 3 different strains of flu and is given as a preventative before the flu season arrives. It cannot be used to treat you once you get flu.
When you are given this vaccine your body makes an immune response, and you develop antibodies specifically to these 3 viruses. While these antibodies will circulate in your body for months, because flu viruses are constantly evolving, by the time people start getting flu in the late winter, the strains may be different to those that were in the vaccine.
This means you may not be protected against one or more of the new strains that are circulating. Hence you can still get flu despite being vaccinated.
In contrast, the drugs are taken as a treatment when you develop symptoms, such as fever, headache, sore throat, muscular aches, lethargy.
The mechanism flu viruses use to remove the sugars from the cells is the same in all flu strains. Since the drugs use this mechanism to bind the virus it should be difficult for the virus to evolve to stop binding the drug, without affecting its own means of spreading. This means the drugs should be effective against all current and future strains of flu.
How long does the flu vaccine take to produce and can this be problematic?
Once the strains are selected for the seasonal flu vaccine, it takes at least 6 months to produce the millions of doses required. When a new pandemic strain emerges it would take at least the same time or longer, as the strains may have to be modified to grow well under the manufacturing conditions for large scale production.
This means that during the first several months of a pandemic there would be no vaccines available. This is when treatments would have a role to play as the first line of defence, until vaccines become available.
The new drug that you have developed is said to be effective against resistant flu strains. Please can you explain why some flu strains are resistant to current treatments and how the new drug overcomes this resistance?
Flu viruses are constantly evolving, they make mistakes when they copy their genes, resulting in mutations. Sometimes these mutations are harmless and have no effect, but other times they may result in changing a part of the virus. If there is an advantage to the changes then this virus may become the dominant one in a population.
Some flu viruses have evolved with mutations which give resistance to Tamiflu and Relenza. We are seeing many more viruses with mutations which make them resistant to Tamiflu compared to Relenza. This is because these two drugs are chemically different.
Both of these drugs bind reversibly to the flu neuraminidase, also blocking the spread of the virus. However, the difference with our drugs is that because they are a sugar, the virus tries to break it down, but this leads to the drug binding tightly to the neuraminidase.
We have tested our drugs against a number of different viruses resistant to Tamiflu and Relenza, and because ours work by a different mechanism they are still effective against these other resistant viruses.
What further research needs to be done to determine the efficacy of the new drug against a broader range of flu strains?
We have tested the drugs in mice but mice get a lung infection, so we need to test in ferrets, which get an upper respiratory infection more like humans. So we need to test different strains in ferrets.
We need to see if viruses can mutate and become resistant to these drugs by exposing viruses to the drugs in the laboratory over an extended period of time, trying to force the viruses to change.
We believe it will be difficult for viruses to become resistant to these drugs, since if they mutate so they don’t break down these artificial sugars, it means they would no longer be able to remove the natural sugars on the cells, and hence could not spread.
We need to work out how best to take the drug, which may need further chemistry, to make changes to the artificial sugars if we aim to make it suitable for example for taking as a pill, or if a single dose will do the job, instead of twice daily for 5 days as is currently used for the other drugs.
While both Relenza and Tamiflu are effective, because Tamiflu is taken as a capsule it has had greater psychological acceptance, than Relenza which is inhaled as a dry powder.
So how you take the drug is also an important part of any drug development.
How many people does influenza affect each year and what impact do you think this new drug will have on these figures?
It is estimated there are between 3-5 million cases globally, with up to 0.5 million deaths per year.
Because the drugs won’t stop you catching flu, you may not see any significant decrease in the numbers of cases. But you would hope that if people take the drug early enough after developing symptoms that you will reduce the length and severity of symptoms, so that people can resume their normal activities sooner.
This should lead to reductions in use of the healthcare systems, as well as economic impacts on businesses due to staff taking fewer days of sick leave.
Should flu viruses be considered to be living organisms?
A highly philosophical question! They contain genetic material, hence if the definition of life is containing the necessary genetic material to reproduce then yes.
However, they need a living host cell in which to reproduce, so they do not have the ability to reproduce by themselves. Hence the answer would be no.
Where can readers find more information?
The paper has been published ahead of print in Science Express, but will be out in print in the coming weeks.
Mechanism-Based Covalent Neuraminidase Inhibitors with Broad Spectrum Influenza Antiviral Activity.
Kim JH, Resende R, Wennekes T, Chen HM, Bance N, Buchini S, Watts AG, Pilling P, Streltsov VA, Petric M, Liggins R, Barrett S, McKimm-Breschkin JL, Niikura M, Withers SG. Science. 2013 Feb 21.
About Dr Jenny McKimm-Breschkin
Dr. McKimm-Breschkin is a Chief Research Scientist and Project Leader in Virology at the Commonwealth Scientific and Industrial Research Organisation (CSIRO) in Victoria, Australia.
After completing a first class honours degree at Monash University, Melbourne, Victoria, in 1974 Dr. McKimm-Breschkin won a Fulbright postgraduate award to the Microbiology department at Pennsylvania State University, Hershey Medical Centre, where she obtained her PhD in virology in 1978.
She returned to Melbourne University Microbiology department as a Queen Elizabeth II Post-doctoral fellow with research focussed on the recently discovered rotaviruses. A second postdoctoral position followed at the Walter and Eliza Hall Institute of Medical Research, as a Colin Syme Junior Fellow under the supervision of Jacques F. A. Miller working in the field of cellular immunology.
She then worked for the Australian Commonwealth Health Department for two years working on animal viruses, before joining CSIRO in 1987. She was part of the team involved in the development of Relenza, providing neuraminidase proteins for X-ray crystallography studies, as well as carrying out pre-clinical resistance studies as part of the drug registration.
She has continued to work in the evolving field of drug resistance, integrating both structural and functional approaches to understanding the mechanisms of resistance.
Using the knowledge gained from the design of Relenza and understanding how influenza viruses can become resistant to Tamiflu and Relenza, she has collaborated with groups at the University of British Columbia, Canada and the University of Bath, UK in the development of newer mechanism based inhibitors, which are currently undergoing laboratory testing.
Dr McKimm-Breschkin is a member of the Australian and American Societies for Microbiology and a member of the Antiviral Group of the International Society for Influenza and Other Respiratory Viruses, an international group interested in the development and use of antivirals and mechanisms of resistance.
Dr McKimm-Breschkin was awarded a Bachelor of Science with first class honours in Microbiology, from Monash University, Melbourne, Victoria, Australia, in1974.
She was awarded a doctorate in Microbiology, from Pennsylvania State University, USA, in 1978.
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