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expert reaction to study identifying mutations in the H7N9 avian flu virus related to potential transmission between humans

Publishing in PLOS Pathogens scientists report that they have identified several genetic mutations that could allow the avian influenza strain H7N9 attach to human cells, although this is unlikely to happen in the wild.

 

Dr Fiona Culley, Spokesperson for the British Society for Immunology, & Senior Lecturer in Respiratory Immunology, Imperial College London, said:

“This is a good, thorough study which specifically aimed to identify which changes in bird flu would allow the virus to attach to human cells. One reason that bird flu is generally poor at infecting people is that it cannot attach to cells in human lungs.  Rarely, strains of flu which are adapted to infect animals undergo changes or mutations that allow them to jump to infecting humans. This study aimed to understand what changes a bird flu virus would need to undergo to allow it to infect and transmit between people.

“Scientists have previously studied the differences in flu viruses before and after they made the jump from infecting animals to humans. This study attempted to generate mutations in the laboratory to predict which changes might allow a flu virus to jump species. The authors found that certain combinations of three mutations were needed for the bird flu to be able to attach to human lung cells. Some of the individual mutations have been seen naturally, but these combinations of mutations have not. They could potentially happen, but there is currently no evidence that they have ever occurred and the chances of all three occurring together is relatively low.

“One thing to note is that the authors only tested whether mutations in part of the outside of the flu virus altered the ability of that part of the virus to attach to human cells. One limitation of this study is that an ability to attach to human cells does not necessarily mean that a mutated bird flu virus will be able to infect and transmit between humans. They did not incorporate these changes into a whole virus and so were not able to directly test the ability of a virus with these mutations to infect and transmit.

“Changes which allow a virus to attach to human cells on their own might not be sufficient to allow the virus to replicate and transmit in humans. Other additional changes to the virus would probably be needed to allow it to be fully compatible with the machinery of human cells. The virus must also be stable enough to survive in the environment to be transmitted between people. In fact this study suggests that acquisition of the mutations that allow the virus to attach to human cells may come at the price of reduced stability.

“Scientists want to find ways of identifying which strains of bird flu have the potential to become adapted to surviving and transmitting in the human population, so that we can better monitor and prevent infections spreading.

“Flu viruses are known to be able to mutate their outer surface fairly readily. This is a strategy used by circulating viruses which already infect humans to slowly change their appearance to avoid existing immunity within a population (in a process known as genetic drift). This continuous slow change in circulating flu viruses is why we have to produce a new flu vaccine each year to match the modified flu viruses that arise each year. Combinations of mutations that would allow a flu virus to jump from infecting one species to another are very rare.

“There is no threat posed to the UK identified in this study. These combinations of mutations have not been found naturally. The authors did not incorporate any of the mutations into whole virus particles so there is no risk of having made a new potentially dangerous virus in the lab.

“This study will help us to monitor the risk posed by bird flu in a more informed way and increasing our knowledge of which changes in bird flu viruses could be potentially dangerous will be very useful in surveillance.  Scientists are continuously on the lookout for new strains of flu which pose a danger to human health. If a new flu virus jumps from animals to humans, this is a major concern. These new viruses could spread quickly in the human population as there would be very little pre-existing immunity. Furthermore we would not be ready with a vaccine for this new flu strain and it could take a long time to manufacture sufficient quantities of vaccine. In the long term, scientists would like to develop a universal flu vaccine that would protect against all strains of flu, even when new strains make the jump from birds to humans.”

 

Prof. Wendy Barclay, Chair in Influenza Virology, Imperial College London, said:

“Predicting which influenza virus will cause the next human pandemic is both of scientific and public health interest. We can’t afford to make vaccines against all of them, so knowing which ones to worry about would allow efforts and funds to be focussed.

“H7N9 avian influenza virus is widespread in chickens in China and infects human exposed to live poultry but does not yet transmit from person to person.

“One important determinant of human to human transmissibility is the receptor binding specificity. In this paper, de Vries and co-workers have used structural information to predict which mutations would switch on the human receptor binding for the H7N9 avian influenza, and then validated the model by making artificial H7 HA proteins that now bind to sections of human airway in a similar manner as do human influenza viruses. They needed 3 mutations to achieve this.

“So the question now is could the virus recapitulate this switch in nature? Is that too few or too many? Important to note is that receptor switching is not the whole story, we know from other studies with H5N1 bird flu that protein stability is also key to allow the virus to survive the tortuous journey from one host to another. De Vries et al found that their 3 mutations actually decreased the stability of the mutant H7 HA and suggest that a virus carrying these 3 changes alone is even less likely to transmit through the air than the current H7N9 viruses. To put it another way, the 3 mutations on their own are not enough, at least one or two more are likely to be required to stabilize the new H7 HA protein.

“All of this suggests there might be quite a high barrier for H7N9 to adapt its HA protein to humans.  However we could only really know that by performing controversial Gain of Function experiments to create engineered influenza viruses carrying these mutations. The authors of this US based study are at pains to say they did not do this!

“This work comes hot on the heels of a summary (in Lancet Infectious Diseases) of this year’s H7N9 human cases in China (resulting from exposure to infected chickens), which are more numerous than ever before.  The more people infected, the higher the chance that the lethal combination of mutations could occur.  Taken along with news that some H7N9 strains became resistant to the antiviral drugs being used to treat patients, these studies keep H7N9 virus high on the list of viruses were should be concerned about. However, despite these findings this doesn’t mean that H7N9 is about to cause the next pandemic.”

 

* ‘Three mutations switch H7N9 influenza to human-type receptor specificity’ by Vries et al. will be published in PLOS Pathogens at 19:00 UK time on Thursday 15 June, which is also when the embargo will lift. 

 

All our previous output on this subject can be seen at this weblink: http://www.sciencemediacentre.org/tag/flu/

 

Declared interests

Dr Fiona Culley: No conflicts of interest.

Prof. Wendy Barclay: Prof Barclay is a member of the SMC Advisory Committee. No other conflicts of interest.

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