Mutations in H5N1 avian influenza viruses

Several recent media reports have included speculations about the significance of mutations in H5N1 avian influenza viruses. Some reports have suggested that the likelihood of another pandemic may have increased as a result of changes in the virus.

Since 1997, when the first human infections with the H5N1 avian influenza virus were documented, the virus has undergone a number of changes.

These changes have affected patterns of virus transmission and spread among domestic and wild birds. They have not, however, had any discernible impact on the disease in humans, including its modes of transmission. Human infections remain a rare event. The virus does not spread easily from birds to humans or readily from person to person.

Influenza viruses are inherently unstable. As these viruses lack a genetic proof-reading mechanism, small errors that occur when the virus copies itself go undetected and uncorrected. Specific mutations and evolution in influenza viruses cannot be predicted, making it difficult if not impossible to know if or when a virus such as H5N1 might acquire the properties needed to spread easily and sustainably among humans. This difficulty is increased by the present lack of understanding concerning which specific mutations would lead to increased transmissibility of the virus among humans.

Virtually all the known subtypes of influenza A viruses circulate in some wild birds, most notably wild waterfowl. In these birds, different viruses constantly mingle with each other and frequently exchange genetic material, resulting in a huge pool of constantly changing viruses. Mutations and reassortment events are commonly observed in the affected bird populations.

In animals, some recent evolutionary changes in the H5N1 virus appear to have made control efforts more difficult and further international spread of the virus in birds more likely. Such changes are fully understandable, particularly in view of the exceptionally large number of birds that have been infected with the H5N1 virus and the frequent interactions between infected free-ranging poultry and wild waterfowl.

Studies have shown that H5N1 viruses from the current outbreaks, when compared with viruses from 1997 and 2003, have become progressively more lethal in experimentally infected chickens and mice, and are also hardier, surviving several days longer in the environment. Other studies have shown that the virus is not yet fully adapted to poultry and is continuing to evolve.

Domestic ducks have acquired an ability to resist the disease caused by some strains, and are now capable of excreting large quantities of highly pathogenic virus without showing the warning signs of illness. In endemic countries, this altered role of domestic ducks is now thought to contribute to perpetuation of the transmission cycle. Research conducted in South-east Asia has recently shown that multiple distinct lineages of H5N1 virus have become established in poultry in different geographical regions, indicating the long- term endemicity of the virus in parts of Asia. That research also detected highly pathogenic H5N1 virus in apparently healthy migratory birds.

In birds, one important recent finding has been the remarkable similarity of viruses from recent outbreaks to those isolated from migratory birds that began dying at the Qinghai Lake nature reserve in central China in late April 2005. Evidence is mounting that this event, which resulted in the deaths of more than 6,000 wild birds, signalled an important change in the way the virus interacts with its natural reservoir host.

Unlike the case with mutations of human viruses (some of which have been transient), it appears that some changes have become fixed in viruses circulating in at least some species of wild birds.

Prior to the Qinghai Lake event, the highly pathogenic H5N1 virus was known to cause occasional sporadic deaths in migratory waterfowl, but not to kill them in large numbers or be carried by them over long distances.

Viruses from Qinghai Lake showed a distinctive mutation at one site experimentally associated with greater lethality in birds and mice. Viruses from the most recent outbreaks, in Nigeria, Iraq, and Turkey, as well as from earlier outbreaks in Russia, Kazakhstan, and Mongolia, are virtually identical to Qinghai Lake viruses.

It is considered unusual for an avian influenza virus causing outbreaks in birds to remain this genetically stable over so many months. This finding raises the possibility that the virus -- in its highly pathogenic form -- has now adapted to at least some species of migratory waterfowl and is co-existing with these birds in evolutionary equilibrium, causing no apparent harm, and travelling with these birds along their migratory routes.

If further research verifies this hypothesis, re-introduction of the virus or spread to new geographical areas can be anticipated when migratory birds begin returning to their breeding areas.

The recent appearance of the virus in birds in a rapidly growing number of countries is of public health concern, as it expands opportunities for human exposures and infections to occur. These opportunities increase when the virus spreads from wild to domestic birds, especially when these birds are kept as backyard flocks in close proximity to humans.

To date, no human cases have been linked to exposure to wild birds. Close contact with infected poultry and other domestic birds remains the most important source of human infections.

Some mutations have been detected in human viruses isolated in 2005 and, most recently, in one virus isolated from a fatal case in the January 2006 outbreak in Turkey. Although these mutations were found at the receptor- binding site and involved the substitution of more mammalian-like amino acids, the effect of these changes on transmissibility of the virus, either from birds to humans or from one person to another, is not fully understood. Moreover, recent studies show that these mutations were transient and did not become fixed in the circulating viruses.

Scientists do not presently know which specific mutations are needed to make the H5N1 virus easily and sustainably transmissible among humans. For example, it is not known whether the absence of a specific receptor in humans for this purely avian virus is responsible for the present lack of efficient human-to-human transmission. For this reason, virological evidence of mutational changes must be assessed together with epidemiological information about transmission patterns actually occurring in human populations. This necessity further underscores the importance of close surveillance and thorough investigation during every outbreak involving human cases.

Assessments of the outbreak in Turkey, conducted by WHO investigative teams, have produced no convincing evidence that mutations have altered the epidemiology of the disease in humans, which was similar to the pattern consistently seen in affected parts of Asia. There is no evidence, at present, from any outbreak site that the virus has increased its ability to spread easily from one person to another.