Changing diapers is definitely a distraction from H5N1, but now the kid is zonked out and I have a chance to catch up a bit.

Chinese Domestic Flu Vaccine Production

Almost a year ago, I examined the implications of the lack of pandemic preparedness in Asia, particularly China.  The April 06 issue of Nature Biotechnology carried a news piece (Pubmed) that basically confirms part of what little I had been able to determine about Chinese domestic flu production capacity.  Not much new in the piece, but at least it allows me to point to a reputable news source instead of merely one of my blog entries.

Avian Flu in Felines

In early March, I was prompted by an AP story to wonder about the implications of a cat killed by H5N1 in Europe as soon as the virus showed up there (see, "Avian Flu as a Harbinger of Zoonotic Diseases").  Soon after, Declan Butler came out with a news story in Nature about this, and recently Nature carried a commentary by Albert Osterhaus and colleagues exploring the issue in more detail (Kuiken, et al., Nature 440, 741-742 (6 April 2006) | doi:10.1038/440741a).  This latter piece takes issue with the bland and unconcerned statements by the WHO and OIE that H5N1 in felines is uninteresting and, more importantly, has no influence on the spread or evolution of the virus.

Kuiken, et al., observe that fatal infections in cats are common in SE Asia and the Middle East, and:

Given the high number of infected cats in these areas, and considering their ability to excrete virus into their surroundings in sufficient quantities that transmission between cats takes place under both natural and experimental conditions (see below), cats could be more than a dead-end host for H5N1 virus.

...Apart from the role that cats may play in H5N1 virus transmission to other species, they also may be involved in helping the virus to adapt to efficient human-to-human transmission.

There isn't any evidence of this, to be sure, but it is a damn scary thought.  It is important to note that there isn't any evidence in part because we really aren't doing a very good job of looking.  Our environmental monitoring for zoonotic diseases is dramatically underfunded.  Bugs that kill humans often come from animals, and we are doing a piss poor job of understanding how and why pathogens make the jump.  (See my post "Nature is Full of Surprises, and We Are Totally Unprepared".)

More Damn Cladistics

The 27 April, 06 issue of Nature has a back-and-forth between Taubenberger, et al., and two groups disputing the assertion that the 1918 pandemic flu virus was avian in origin.  Gibbs and Gibbs assert that the virus was in fact a reassortant previously present in mammals.  If nothing else, they get this right; "In light of this alternative interpretation, we suggest that the current intense surveillance of influenza viruses should be broadened to include mammalian sources."  (The growing awareness of the effects of the virus on felines is evidence we should be doing more to monitor the virus in the wild.  Never mind that of the $1.9 billion recently pledged to prepare for a pandemic, exactly none was pointed towards better monitoring.)   Antonovics, et al., similarly, argue that Taubenberger and colleagues got the phylogenetic tree wrong and that the amino acid sequences of the RNA polymerase genes put the 1918 virus, "within...clades containing strains from other mammalian hosts."  They conclude:

By stating that the high pathogenicity of the 1918 virus is related to its emergence as a human-adapted avian influenza virus, the authors raise the possibility that an emerging avian strain could resemble the 1918 flu. This alarming implication, which is based on misinterpretation of the phylogenetic data, is completely unjustified and could seriously distort the public perception of disease risk, with grave economic and social consequences.

Fair enough, if Taubenberger, et al., have in fact come to the wrong conclusion.  Taubenberger and co-authors give what appears to be a comprehensive hearing to their detractors, and appear to answer the challenge well.  I think the best bit of their argument is as follows:

We have never maintained that the virus entered the human population in 1918: rather, as described earlier, our claim that it entered the human population "shortly" before the pandemic should be interpreted as 'at least several years before the pandemic', as stated in our discussion. The path that the precursors of the 1918 pandemic virus took before emerging in humans in 1918 remains unknown. Phylogenetic analysis on its own cannot definitively resolve the issue. As in previous analyses, we analysed the sequences of these genes for clues about their origins and found that the proteins encoded by the 1918 polymerase genes were avian-like in all cases.

I like this bit in part, of course, because I can understand it.

The argument about the origin of the virus seems half well-founded and well-measured molecular evolution, and half complete hand-waving.  (My interpretation may be influenced by the Cointreau on the rocks I am working on.  This is Uncle Sydney's drink, and I have been hoping it will rub off, though, admittedly, it doesn't seem to be working.  Yet.  Buy, hey, it's fun to try.)  I am frustrated by the cladistics story in part because there is no way to judge the merits of either side of the argument without delving into the details of not only the sequence variation and fundamental virology but also the statistical models used to generate phylogenetic trees.  This, I definitely don't have time for.  Nor, I suspect, does anyone else outside the field.  We simply have to watch the debate and see where it goes.

The real point, of course, is that we don't know where the virus came from.  It is still a mystery and will likely remain so.  Because of the evidence presented by Oxford, et al., I tend to side with Taubenberger.  It doesn't really matter, though.  Regardless of where the virus came from, the lesson today is that since we don't understand what happened before, we are completely unprepared for anything like it that may come in the future, as I have written about before.

More Vaccine Tiddlywinks

Unfortunately, as I briefly alluded in a recent post, the NIH doesn't seem to be doing much to prepare us for future outbreaks.  While the Institute has awarded just over a billion dollars to manufacturers to get cell-culture vaccine production up and running, this is simply a new way to make the old vaccine.  In interviews with those same manufacturers for the bio-era Avian Flu and Economic Impacts of Genome Design projects, they were quick to admit cell-culture production will get vaccines out the door in, optimally, four to five months instead of the six to eight month figure overused when discussing egg-based production.  This is a modest improvement, to be sure, and it is possible that cell-culture techniques can be used to produce more doses.  But this doesn't help make better vaccines.  If we used cell culture to produce the present reference vaccine, we would still be screwed because it seems very likely that the reference vaccine will be next to useless.  Where is the additional funding for alternative, or fundamentally new, vaccine technologies?

A news story in the 27 April edition of Nature offers some slight hope.  In, "Flu-vaccine makers toil to boost supply," Carina Dennis writes that, "More than a dozen groups are developing pandemic vaccines, testing a range of strategies to boost potency and production capacity."  Ms. Dennis follows with the suggestion that moving from split virus vaccines to whole virus vaccines.  That is, using intact virions instead of the standard vaccine in which the virus is disrupted with detergent.  An accompanying map shows worldwide efforts to develop new vaccines, though I note only one subunit project (Solvay) and one surface antigen project (Chiron).  There is no mention of DNA vaccines, either from PowderMed, delivered using gene guns, or from Vical, delivered via intramuscular injection, which I am waiting to hear back about from the manufacturer and from the doc in charge of a recent clinical trial.  Ms. Dennis notes that a study published by Neil Ferguson suggests that, "to curb the spread of disease, vaccinations would need to begin within one to two months of the pandemic starting."  Once again we are back to facing the need for a quick response while equipped with technology that is very slow.  And we have a crappy vaccine stock to start with.

And with that, I am tempted to start ranting again about the need to completely revamp our technological response to infectious disease, which you have all heard before.  So it is time to sleep and dream of better things.  Like changing diapers.