Update on H5N1 Evolution

Chen, et al., ("Establishment of multiple sublineages of H5N1 influenza virus in Asia; Implications for pandemic control" PNAS) report that:

Genetically and antigenically distinct sublineages of H5N1 virus have become established in poultry in different geographical regions of Southeast Asia, indicating the long-term endemicity of the virus, and the isolation of H5N1 virus from apparently healthy migratory birds in southern China. Our data show that H5N1 influenza virus, has continued to spread from its established source in southern China to other regions through transport of poultry and bird migration. The identification of regionally distinct sublineages contributes to the understanding of the mechanism for the perpetuation and spread of H5N1, providing information that is directly relevant to control of the source of infection in poultry. It points to the necessity of surveillance that is geographically broader than previously supposed and that includes H5N1 viruses of greater genetic and antigenic diversity.

And also that:

Our ongoing influenza virus surveillance in southern China shows that H5N1 influenza viruses have been persistently circulating in market poultry populations and also revealed that those viruses were present in apparently healthy migratory birds just before their migration. Genetic analyses reveal that the endemicity of the H5N1 viruses in domestic poultry has resulted in the establishment of distinct regional virus sublineages. The findings of this study demonstrate that H5N1 viruses can be transmitted over long distances by migratory birds. However, viruses in domestic poultry have evolved into distinct regional clades, suggesting that transmission within poultry is the major mechanism for sustaining H5N1 virus endemicity in this region.

Because some migratory ducks sampled in the study have a stronger serological response to an H5N2 probe than to H5N1, it may be that prior infection with a low pathogenic H5 virus has provide some protection against H5N1.  That is, the ducks can carry H5N1 but display no symptoms.  While this is good for those particular ducks, unfortunately it means that rather than dying the ducks can easily transport H5N1 long distances to populations that are completely immune naive for H5 viruses.

The Chen paper also reports the worrisome result that an antiserum raised in ferrets against the current human H5N1 vaccine candidate was strongly reactive against isolates from Vietnam but only weakly reactive against isolates from Indonesia and large parts of China.  Conversely, a ferret antiserum raised against an Indonesian isolate reacted only weakly with isolates from Vietnam and China.  This means the antibodies prompted by the strains from Vietnam don't work against the Indonesian and Chinese strains, and vice versa.  So there is already considerable divergence of the sequence in the wild, and some sequences are not recognized by the present human candidate vaccine.

This becomes even more troublesome with the observation by Chen, et al., of a new genotype in the wild composed of pieces of previously seen ones.  Thus not only are the avian H5N1 strains diverging in the wild to the point that they do not cross-prime mammalian immune systems, but they are also actively swapping parts on time scales that we can now resolve.  It is excellent news that we can actually see what is going on, though not in real time, but this demonstrates that the viruses are clearly able to exchange useful innovations in short time scales, thereby producing new bugs.  The authors conclude from sequence data of the new genotype that, "all eight gene segments of viruses from the Qinghai Lake outbreak in central China can be traced to the H5N1 viruses isolated from migratory ducks at Poyang Lake in southeast China, ~1,700 km distant, indicating that migratory birds can disseminate the virus over long distances."

Chen, et al., conclude the paper with:

The antigenic diversity of viruses currently circulating in Southeast Asia and southern China challenges the wisdom of reliance on a single human vaccine candidate virus for pandemic preparedness; the choice of candidate viruses for development of human vaccines must reflect the antigenic diversity observed across this wider region. Furthermore, antigenic drift observed over time within those H5N1 sublineages highlights the necessity of continually updating the candidate virus chosen for future H5N1 vaccines. These concepts are critical for the control of this pandemic threat.

Which is right on the money, as far as I am concerned.  Except, of course, it would be nice to see more people banging the DNA vaccine drum.

Meanwhile, Stevens, et al., report in an upcoming Science article that, "The hemagglutinin (HA) structure from a highly pathogenic Vietnamese H5N1 influenza virus, is more related to the 1918 and other human H1 HAs than to a 1997 duck H5 HA."  They also study specific mutations to various HA domains to gain insight into potential paths "for this H5N1 virus to gain a foothold in the human population."

The authors come to no specific conclusions about the likelihood of any given mutation, but using a recombinant system do identify a couple of changes that could lead to greater pathogenicity in humans.  A good step forward, though despite all the detailed biochemistry and molecular biology in this paper it leaves me once again feeling like we are still very poorly informed about basic flu virus biology and are simply guessing about the future course of the H5N1 in particular.