If two recently emerged avian influenza virus strains mutate and acquire the ability to become easily human transmissible, they could create a pandemic flu, researchers from MIT reported in the journal Cell.

The two bird (avian) flu strains – H5N1 and H7N9 – do not currently transmit easily from human-to-human. However, it would only take one or just a few genetic mutations to change all that.

In these two studies, scientists from MIT (Massachusetts Institute of Technology) focused on the H7N9 and H5N1 flu strains. They said their findings should help public health officials monitor how the viruses evolve, regarding their potential for human-to-human transmission.

Senior author of the two papers published in Cell this week, Ram Sasisekharan, the Alfred H. Caspary Professor of Biological Engineering, believes their findings could also help guide the development of new vaccines.

Influenza viruses are classified according to the type of HA (hemagglutinin) protein they contain. Humans are most commonly infected by the H1 and H3 proteins. The human immune system is not naturally prepared to fight off other HA types, and some of these other types can eventually evolve to attack human respiratory cells.

Sasisekharan and team wanted to determine H7N9’s and H5N1’s ability to infect humans and transmit from human-to-human. They analyzed the structure of their HA proteins.

Sasisekharan had already demonstrated in previous studies that an influenza virus’ ability to infect humans depends on its HA protein. The protein binds to glycan (sugar) receptors that exist on the surface of respiratory cells. These receptors are either umbrella-shaped or resemble a cone. The virus needs to bind to the umbrella-shaped receptors in order to infect humans, and in order to infect humans easily and transmit from person-to-person easily it will need to bind to those receptors efficiently.

There is no evidence so far that either H5N1 or H7N9 can bind to human glycan receptors efficiently.

H5N1 is the highly pathogenic bird flu virus that has caused serious outbreaks in domestic poultry in parts of the Middle East and Asia. H5N1 does not typically infect humans. However, there have been nearly 600 reported cases of human infection from 15 countries since 2003. In the majority of cases, infected people had been in close contact with sick or dead poultry. About 60% of the people who became ill with H5N1 died.

H5N1 would not need many mutations to become easily human transmissible

The MIT researchers studied the HA protein structures from hundreds of H5N1 virus strains. They identified three HA regions where just a couple of genetic mutations would make it possible for the HA to bind to the human receptors efficiently. In the majority of cases, the base of the receptor-binding site is affected.

Since 2005, the H5N1 strain has been evolving. However, none of the strains currently in circulation have all the necessary mutations to become human transmissible.

The scientists identified one strain, though, that only requires a single amino-acid switch to become a highly infections virus for human populations. Several others only required two amino-acid switches. Sasisekharan said “There are multiple different ways that this can happen.”

Current H5N1 vaccines are probably ineffective now

Sasisekharan added that the H5N1 vaccines that governments around the world have stockpiled would probably be useless now, because the virus has evolved rapidly since 2005.

Sasisekharan said:

“There is cause for concern. Yet these findings open opportunities to make sure that some of these newer strains do become part of the stockpiling, because they are closer to human adaptation.”

H7N9 is a relatively new bird flu virus strain. It has been infecting people in China this year (2013) and has caused serious illness. Approximately 20% of infected humans have died. According to most available data, the majority of people who became ill had been in contact with poultry or environments that might have been contaminated with the H7N9 bird flu virus strain, such as live bird markets.

At least 132 people have been infected with the H7N9 flu virus strain, most of them in China. Thirty-seven of them have died, says the World Health Organization (WHO). H7N9 has a lower mortality rate than H5N1.

The scientists point out that it would take just one amino-acid change to dramatically increase the HA protein’s binding strength, thus making H7N9 highly human transmissible. However, they stress that the current circulating forms of the virus bind weakly to human receptors.

Sasisekharan said “It was not a marginal increase; we saw a pretty significant increase in receptor binding. Our research provides insights to help keep track of potentially important mutations so that proactive steps can be taken to be better prepared against dangerous viruses.”

As H7 typically infects non-human animals, when a human is infected with H7N9 he/she is not able to mount much of an immune response. Sasisekharan thinks that the current H7 vaccines now in development will not offer humans much protection because the strains being used in them are very different from H7N9.

An article published in The Lancet reported that the H7N9 avian flu virus strain is resistant to treatment with oseltamivir (Tamiflu) in some cases.

Experts from China, the USA and Canada pointed out in the journal Science (May 2013 issue) that the H7N9 virus strain may already be human transmissible through direct contact as well as through airborne exposure.

The information provided in the two articles published in this week’s Cell should have a direct impact on vaccine development and flu risk assessment, writes Linfa Wang, director of the program in emerging infectious disease at the Duke-NUS Graduate Medical School in Singapore.

Wang, who was not involved in this research, said “Their unique approach, incorporating structural topology of the host receptor glycan bound to key viral surface protein (HA) and the inter-residue interaction network in the receptor binding site of HA, is extremely powerful in providing crucial information within a short time period.”

Both studies were funded by the NIH (National Institutes of Health) and the Singapore-MIT Alliance for Research and Technology.

Scientists have been talking about the avian influenza virus’ potential for becoming a serious pandemic for years. One year ago, two papers described the pandemic potential of the H5N1 bird flu virus strain. One paper identified four genetic mutations that the virus would have to undergo before it could become easily human transmissible, while the other identified five changes. Another paper suggested that some of these changes were already evident in circulating strains.

Written by Christian Nordqvist