WHO update on H5N1 mutations

WHO has an update with their view of the genetic status of the H5N1 virus. Given the "two mutations to a pandemic" statement by Nabarro followed by the furious backpedal, it's not surprising. The WHO statement is interesting, mainly informative -- and very carefully worded. Can't complain about that.

Here's the opening:

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.

Here's my translation:

The virus is mutating and the mutations have affected its biological behavior but not at this point affected its transmission from human to human. The statement is silent on whether mutations have affected transmission from bird to human

WHO goes on to say (correctly) we know too little about the relationship between the genetic sequences and the biology to be able to know what properties it needs to acquire to become a full-fledged pandemic strain. We do see genetic changes that have affected its behavior in animals however.

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.

WHO goes on to say that the genetic changes seen in these birds have become fixed in the circulating virus, something they say has not (yet) happened in mutations in a single human isolate in Turkey, which they characterize as "transient." The relative stability of the mutation seen since the Qinghai outbreak may signal adaptation to wild migratory birds, and its geographically widespread occurrence may be evidence of spread via bird flyways. This carries with it the probability the virus will be reintroduced into cleared areas when birds return on their migration cycles. WHO does not believe any human cases have so far been "associated with" exposure to wild birds versus domesticated poultry.

Finally comes the money section:

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.

I can't disagree with any of this. In my view, it states accurately and precisely what we do and don't know (mainly what we don't know). Unfortunately the effect is somewhat spoiled by the last paragraph:

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.

The first sentence doesn't say there is no evidence that the epidemiology is altered, only that if there is evidence it is not convincing. Since we don't know what it takes to convince WHO (I have previously suggested a whack on the head with a two-by-four might be needed to get their attention), this is neither comforting nor informative. Is there some "non convincing" evidence? If so, what is it? And if the last sentence is completely accurate -- no evidence whatsoever, anywhere -- then why the qualification? Saying there is no evidence of any kind is different than saying there no convincing evidence, or that there is scant evidence, or there is some evidence but it hasn't risen to a level of concern, or some evidence WHO is arguing about amongst themselves but not ready to discuss publicly, or . . . what?

One of the two sentences in that paragraph is wrong. I'd be willing to lay odds it's the last one.