BIRD flu is back. The H7N9 virus has had its deadliest year since it emerged in 2013. Since October, 714 people in China have become seriously ill, almost as many as in the previous four years combined.
More than a third of those people have died. The virus is thought to be causing milder, undiagnosed disease in far more people, and each infection is a chance for it to evolve.
The idea that H7N9 could gain the ability to spread readily via humans keeps virologists up at night. But restrictions on research into potentially pandemic viruses, put in place after concerns about another bird flu, are making it harder to study today鈥檚 threat. Isn鈥檛 it time we conquered our fears of what might happen so we can avoid a real pandemic?
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So far H7N9 has spread only in poultry across part of China, and to people who have caught it directly from birds 鈥� except for a few recent cases of .
If the virus evolves the ability to spread between humans easily, it will go pandemic and circle the world in weeks. Everyone will be at risk. Flu experts say it is likely to be much more severe than the swine flu pandemic in 2009, and could rival the 1918 flu pandemic, another bird flu that infected a third of humanity and killed 3 per cent of those who caught it.
Very few of us have ever met an H7 virus, so we have virtually no immunity. We have vaccines, but no way to make and distribute them in time. And this year, H7N9 in China acquired a mutation that makes it kill birds, and , faster.
Now, at the Scripps Research Institute in La Jolla, California, and colleagues report that a mere two mutations, added to one already in H7N9, allow the virus to bind well to human cells. (PLoS Pathogens, ).
That is one of three key changes a bird flu needs to spread from human to human. Mutations for the other two 鈥� adapting the bird virus to humans鈥� cooler and more acid cells 鈥� have already been found in circulating H7N9.
But virus genes interact in complex ways. Paulson only tested the effect of the mutations on an isolated viral protein. Such mutations can behave differently in a whole virus. 鈥淲e don鈥檛 know if all the viruses with these three traits will be airborne between mammals,鈥� says Ron Fouchier of Erasmus Medical Centre in the Netherlands, who found mutations in 2011 that allow H5N1 bird flu to spread that way.
鈥淲e need to verify by doing a transmission experiment,鈥� he says, creating a virus with these three mutations and seeing if it spreads in the air between ferrets, which get flu similarly to humans.
But that work is blocked by a temporary ban imposed in 2012 on doing such experiments with US government funding, because of controversy over Fouchier鈥檚 H5N1 work. Researchers don鈥檛 know when it will be lifted.
Making a murderer
Paulson鈥檚 team isolated the gene for haemagglutinin (HA), the protein that binds flu virus to cells, from a Chinese strain of H7N9. They found two mutations that let it attach to a sugar on mammalian cells called 2,6-sialic acid, which differs from the equivalent in birds, 2,3-sialic acid. This is needed for a virus to infect the cells.
Wild H7N9 already has one mutation in HA that lets it bind to 2,6-sialic, says Fouchier, who tested H7N9 transmission in ferrets before such experiments were banned. 鈥淏ut it also bound the avian-type receptor, so it spread poorly.鈥�
Paulson鈥檚 team found that two additional mutations make the HA bind 2,6-sialic as avidly as any human flu. Crucially, says Malik Peiris at the University of Hong Kong, it also stopped binding 2,3-sialic. 鈥淗uman mucus is very rich in 2,3-sialic and we suspect viruses that bind it get trapped and cannot reach the cells.鈥�
But the HA with all three binding mutations also became slightly less stable in more acidic conditions. To infect mammals it must be more stable.
鈥淚f the virus evolves to spread between humans easily, it will go pandemic and circle the world鈥�
Does one effect cancel out the other, making a virus unable to spread between mammals despite the binding mutations? Fouchier has found mutations that increase acid stability in natural H7N9 鈥� would one of those plus Paulson鈥檚 binding mutations let H7N9 go airborne?
鈥淭hat was the case in H5N1,鈥� says Fouchier. Researchers also need to look at the mutations in a whole virus, he says, to see if it replicates as well as the parent virus. This would also tell us if the mutations have other unexpected effects, or whether it gets other mutations influencing transmission when it infects mammals.
鈥淲ithout animal infection studies, we can only speculate what might happen,鈥� says Paulson. 鈥淏iology is complex, so we can predict that one set of mutations will influence transmission, but it is only that, a prediction.鈥�
But neither Paulson nor Fouchier are allowed to make viruses with these mutations. After Fouchier created transmissible H5N1, a regulatory committee in the US tried to stop the work being published, saying terrorists could use it to create a lethal pandemic.
There were also fears that other labs would try to copy the work without sufficient containment, and a dangerous virus might then escape. The H5N1 work was finally published, but the US halted Gain-of-Function (GOF) research for flu viruses, and for SARS and MERS.
GOF means making pathogens nastier than they currently are in nature. Testing an H7N9 virus with Paulson鈥檚 mutations in ferrets would be GOF. 鈥淣either Scripps nor we can move forward,鈥� says Fouchier.
鈥淏ecause we have not made viruses and tested for transmission, we do not know if the mutations we have identified that change receptor specificity would by themselves increase transmission, or if other mutations would be required,鈥� says Paulson.
Scared into action?
The work will eventually be done in labs that do not rely on US funding, says Fouchier, perhaps in China. But the US is a major player, and its absence slows understanding of the H7N9 threat and pathogen research generally.
In January, the and the , which grants research funding, proposed rules for vetting GOF experiments. They don鈥檛 allow the full range of this work, but Paulson thinks they would let him test the binding and stability mutations in weakened viruses unlikely to escape. But he and others don鈥檛 know what is happening with the regulations.
鈥淭he Department of 91色情片 is in the process of finalising its policy, and as soon as it release that, the National Institutes of 91色情片 is ready to start reviewing new research applications,鈥� says Carrie Wolinetz, associate director for science policy at the US NIH. 鈥淚t鈥檚 just a matter of when they get to it.鈥� She could not say when that would be. Other health experts are pessimistic about whether this is a priority amid other changes by the US administration.
鈥淭he US halted research that made flu viruses nastier than they currently are in nature鈥�
鈥淚n theory, a researcher may apply for permission to do a specific GOF experiment,鈥� says one leading flu researcher who did not wish to be named. 鈥淚n reality, this is now very difficult to achieve. The chilling effect on those trying to understand the genetics of human transmissibility is quite profound.鈥� Others agree.
Ironically, the world was alerted to the threat posed by H7N9 because it shares mutations with H5N1 that we know make that virus more dangerous 鈥� because of GOF research. Based on that, in 2013 the , and stockpiled some H7N9 vaccine, which it is . Yet it now bans the very research that drove those precautions.
鈥淭here is no doubt that natural selection will drive H7N9 virus adaptation in mammals, just like we have seen for H5N1 in ferrets and for historical pandemic strains in humans,鈥� says Fouchier. But how worried should we be? 鈥淲e need confirmation from GOF transmission studies. It is the only way.鈥�
This article appeared in print under the headline 鈥淟ethal flu two genes away鈥�
