The second of two highly-controversial academic papers on the H5N1 avian influenza has now been published, showing the virus is just four mutations away from an airborne version that could pass from human to human.
Currently, the virus can be transmitted from birds to humans, but only very, very rarely from human to human. However, the first of the two papers, published last month, showed that it could become transmissible in mammals - and the second, published today, that these mutations could take place in the wild.
The Cambridge researchers analysed all of the bird flu surveillance data from the last 15 years, focusing on birds and humans - and found that two of the five mutations seen in the experimental viruses had already occurred in numerous existing avian flu strains. A number of the viruses even had both mutations.
"Viruses that have two of these mutations are already common in birds, meaning that there are viruses that might have to acquire only three additional mutations in a human to become airborne transmissible," says Colin Russell of the University of Cambridge. "The next key question is 'is three a lot, or a little?'"
The scientists used a mathematical model of how viruses replicate and evolve within a mammalian host. And they found several factors that increased the likelihood of mutations evolving, including random mutation and a long period of infection.
They also concluded that the sets of substitutions identified by Fouchier and Kawaoka in the first paper are unlikely to be the only combinations that produce an aerosol transmissible virus.
There's also the possibility that the viruses from a bird that infect a human might have a mutation that would not be detected by routine surveillance. For example, if 100 virus particles from a bird infect a human and one of those particles had a key mutation, it would increase the probability of the mutation reaching high levels within a host, even though routine sequencing wouldn't detect it.
Finally, the team points out that if mammals are capable of transmitting viruses that have some but not all of the necessary substitutions, it could increase the probability of an airborne transmissible virus evolving.
"With the information we have, it is impossible to say what the exact risk is of the virus becoming airborne transmissible among humans. However, the results suggest that the remaining three mutations could evolve in a single human host, making a virus evolving in nature a potentially serious threat," said Derek Smith, Professor of Infectious Disease Informatics at the University of Cambridge.
"We now know that it is in the realm of possibility that these viruses can evolve in nature, and what needs to be done to assess the risk more accurately of these mutations evolving in nature."