Live from Synthetic Biology 2.0

I'm sitting in Synthetic Biology 2.0 at UC Berkeley.  Talks started off with energy applications, which is interesting.  Evidently there was also a big VC meeting in the last few days that focused on SB applications to producing energy.

Steve Chu (Nobel Laureate in Physics and Director of LBL) led off the talks with proposals that "excess" crop land in US could be used to "grow energy", by producing appropriate plants and methods via synthetic biology.  He mentioned that despite global population expansion by a factor of ~2.5 in the last 60 years, cultivated land has only increased by ~10-15% due to increases in productivity.  But Chu made no mention of the problem that we have trashed lots of crop land in the last 50 years, and it isn't obvious that we could use large amounts of land to grow energy given the state of the soil.  More importantly, he made no mention of where we would get all the water to grow those energy crops.

I am all for growing our energy sustainably, of course, but I don't think that terrestrial crops have a hope of being the right answer.  Best meme from Chu's talk was starting off with the most efficient engine design, figuring out the best fuel for that engine, then designing an organism to produce that fuel.  Cool.

Craig Venter is speaking now.  Lots on minimal genomes and looking at alternative pathways for directly producing energy.  Directly photosynthetic production of methane, etc.

More soon.

Avian Flu Catch-Up

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.

Best Synthetic Biology Project Ever

After a rather sudden onset of full labor Tuesday afternoon, we have 
been joined by a lovely little girl.

Pascale is 3170 grams.

Comments on new FDA rules for expedited development of pandemic influenza vaccines

I'm a bit behind on the blog, having spent most of the last four weeks on the road, battling a norovirus (Yuck.  Don't get this bug  Hey Ralph, where the hell is my vaccine?), doing my taxes, and buckling down in the lab trying to get devices fabricated.  Cool progress on the later, which, alas, has to be disclosed to the University, written up for publication, and a patent application filed before I can discuss it here.  Harrumph.

A great deal has transpired on the influenza front, including news that the current H5N1 vaccine is as useless (NY Times) as predicted, which means that the need for alternative vaccine technologies is now even greater (more on this in a forthcoming post).  But I will start with the FDA's new draft guidelines on accelerated licensing of influenza vaccines, which I briefly addressed at the beginning of March.  The suggested guidelines were officially announced a few days later.  What follows is my take after a quick once over.

Here is how the document (PDF warning) starts off:

This document is intended to provide to you, sponsors of pandemic influenza vaccines, guidance on clinical development approaches to facilitate and expedite the licensure of influenza vaccines for the prevention of disease caused by pandemic influenza viruses.  The approaches apply to "split virus" and whole virus inactivated pandemic vaccines propagated in embryonated chicken eggs, and are also applicable to cell-culture derived, recombinant hemagglutinin-based protein, and adjuvanted pandemic influenza vaccines.  We, FDA, also address live attenuated influenza vaccines. This document does not address influenza vaccines that do not contain a hemagglutinin component.  Current U.S. licensed influenza vaccines are trivalent vaccines approved for the prevention of seasonal influenza illness.  Two classes of vaccines are licensed, "split virus" trivalent inactivated vaccines and a live attenuated trivalent vaccine. (pg. 1)

Beginning on page 2, by the way, is a short and very nice introduction to the biology and history of pandemic influenza viruses.

Here are some interesting quotes from the press release:

The FDA provides manufacturers with clear guidance on developing and submitting clinical data to show safety and effectiveness for new vaccines.  Consistent with the aims of FDA's Critical Path Initiative to get products to market more quickly and to advance the development and use of new technologies, these documents outline specific approaches that vaccine developers may follow.

...In issuing this advice, FDA aims to facilitate manufacturers in increasing the number of doses to ensure that enough influenza vaccine is available to vaccinate each person in the at-risk population. Having additional diversity in our vaccine supply helps enhance the capacity to produce more doses of influenza vaccine and contributes to the nation's pandemic preparedness.

...The release of these guidances is part of the comprehensive effort that FDA is undertaking to work with manufacturers to facilitate the development of vaccines.  Other examples include a recent CBER advisory committee meeting to discuss novel approaches to develop influenza vaccine such as using cell technology rather than eggs, frequent interactions with vaccine manufacturers to provide both scientific and regulatory guidance, as well as CBER's preparation of material for testing the potency of new vaccines, which are made available to manufacturers.

All in all, an exceptionally conservative document, given the magnitude of the problem we are facing.  The recommendations should do very nicely in all circumstances save the emergence of an actual pandemic.

The main problem I have with this announcement is that it appears to be geared towards easing the way for approval and use of particular technologies -- namely vaccine production by cell-culture, split virus vaccines, and specific recombinant protein vaccines -- rather than defining engineering and immunological goals that any given technology should meet to be approved.  For example, PowderMed's DNA vaccine does not appear to fit into the new guidelines, despite arguments the company is likely to make that injecting a plasmid coding for the hemagglutinin is equivalent to injecting the protein itself.  I hope I am wrong about this, because DNA vaccines look to be the only technology that can be used to respond on short time scales to rapidly spreading diseases.

No doubt I will return to this issue as the rules are discussed and developed.

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.

"The Knowledge"

Mark Williams' article about the likelihood of bioterrorism, "The Knowledge", is now online at MIT's Technology Review.  I make a brief appearance in the penultimate paragraph.

Most of the article deals with the achievements of the former (we hope) Soviet bioweapons program, and whether new synthetic techniques could be used to reproduce these results in the garage or basement.  I've not much to say about the article.  The text repeats a number of my own observations over the years about the ease of obtaining used equipment, skills, and reagents (in Wired, at Future Brief, and in Biosecurity and Bioterrorism (via Kurzweilai.net), for example).  Williams does explore the issue that increased funding of biosecurity work increases the number of experts and explicitly amounts to proliferation.  Experts are consulted.  I disagree with them.  Enough said.

Technology Review went to the trouble of having Allison Macfarlane, an MIT research associate in the Science, Technology, and Global Security Working Group in MIT's Program in Science, Technology, and Society, give a "rebuttal" to Williams.  Macfarlane begins:

Could terrorists, intent on causing as much harm and societal disruption as possible, use new biotechnology processes to engineer a virulent pathogen that, when unleashed, would result in massive numbers of dead? Mark Williams, in his article "The Knowledge," suggests we should be contemplating this doomsday scenario in the 21st century. Williams's article might make you sleep less soundly, but are the threats real? The truth is that we do not really know.

While most of the rebuttal is well argued, I have to disagree with the last point above: We know the threat is absolutely real, because we know pathogens have been genetically modified in the past.  The question, then, is the timing of the threat becoming imminent.  While it is not technologically challenging to synthesize organisms, or to insert novel genes into viruses or bacteria, it can be technically quite difficult.  That is, the laboratory widgets and reagents necessary to create new pathogens or even to resurrect the 1918 flu are easy to come by, but actually implementing the procedures correctly to produce infectious organisms is quite difficult.  In other words, this activity is still art.  For the time being.

For example, I've explicitly asked around about the difficulty of reproducing the 1918 flu, and responses have varied.  Some people have ignored outright my queries, and others have actively discouraged me from even exploring how hard this might be.  It seems there is a great reticence to discuss this possibility in public.  (I think this is a grave mistake.)  But after prodding people I know who have built RNA viruses in the lab, I would summarize the situation by reiterating that the difficulties lie in laboratory protocols -- skills -- rather than in any technological barrier.  Publishing the 1918 sequence didn't make much difference in this regard: once you know how to make one flu bug you can make any of them.  Worse, you could make a great many flu variants all at once, and let nature sort out which ones are worthwhile weapons.  This isn't news to anyone who has thought about the problem, and the only barrier is trial and effort in the lab/garage/basement/cave.

Thus the threat is very real, and it is probably only a matter of time before the first bug shows up.  How much time, I will not predict.  But I do know we are totally unprepared for naturally occurring threats, let alone the artificial ones that Williams focuses on.  Slowing research will simply leave us ignorant and, when the inevitable happens, struggling to mount even a minimal defense.

What is the Sound of a Cat Dying from Avian Flu?

"Aaargh Plop", it turns out.  Declan Butler has a story in tomorrow's Nature about the apparent spread of H5N1 among felines.  Evidently, until recently, the "WHO argued that cats are not naturally susceptible to flu, and thateven if infected they would not shed large quantities of virus."

But as I observed a few days ago, it is odd that cats are dying in Europe so soon after the virus arrived there.  Dr. Butler notes that H5N1 is not behaving as expected in cats:

...With bird flu it may be different. Later in 2004, Albert Osterhaus's team from Erasmus University in Rotterdam showed experimentally that domestic cats do die from H5N1 and do transmit it to other cats (T. Kuiken et al. Science 306, 241; 2004). And in January this year, the virus was found not only in sputum but also in faeces of experimentally infected cats, suggesting that infected animals may shed the virus extensively (G. F. Rimmelzwaan et al. Am. J. Pathol.168, 176–183; 2006).

It is unclear how these findings relate to cats in their natural environment. But in next month's issue of Emerging Infectious Diseases, Thai researchers describe a cat that died of H5N1 after eating a pigeon carcass. It showed similar pathology to cats experimentally infected with the virus.

It gets worse:

Andrew Jeremijenko, head of influenza surveillance at the US Naval Medical Research Unit 2 in Jakarta, Indonesia, detected H5N1 in a kitten he found near a poultry outbreak in Cipedang, West Java, and tested out of curiosity on 22 January. The virus from the kitten is closely related to recent H5N1 strains isolated from humans in Indonesia: it shares genetic changes found in human strains that are not present in samples from birds.

Interesting.  The standard explanation for the sequence variation would be that the virus propagated at low levels in a cat after it consumed the bird.  But I wonder about another possibility.  Speculation Warning: The flu is very error prone during reproduction, which means that during infection in birds a great many sequences are produced that don't actually survive/reproduce in avians.  But it is possible that a bird can carry a small number of sequences better adapted to mammals that do not proliferate in the bird.  When consumed by a cat, the new sequences might be ready to go in the new host.  That might -- might! -- account for the speed with which the virus started killing mammals in Europe.

Dr. Butler concludes his article with an anecdote about how prevalent feline H5N1 deaths may be in the wild.  The confusion over cat deaths in Europe may simply be another example of ignorance about how H5N1 is actually behaving in nature:

Scientists may just be learning what is already common knowledge among Indonesian villagers. Peter Roeder, a consultant for the UN Food and Agriculture Organization, says locals have an onomatopoeic name for bird flu "that sounds like 'plop', the sound of a chicken hitting the ground when it falls out of a tree. They also have a name for the cat form of avian flu — 'aaargh plop' — because cats make a screaming noise before they fall out of the tree."

Nature is Full of Surprises, and We Are Totally Unprepared

The SARS coronavirus came out of nowhere.  It is an example of the speed with which a zoonotic disease can leap to the fore of international attention.  We were completely surprised.  Fortunately, the virus was not quite as virulent as first feared, and it burned itself out before causing greater havoc.  This is an important misconception about the SARS episode.  Yes, the virus was identified and sequenced in a hurry, but all our technology was of little help in responding.  We got lucky.

According to an epidemiological modeling paper published a year after the epidemic:

We conclude that the control of SARS through the use of simple public health measures was achieved because of the efficacy with which those measures were introduced and the moderate transmissibility [R0] of the pathogen coupled with its low infectiousness prior to clinical symptoms[theta].

[Fraser, et al., PNAS | April 20, 2004 | vol. 101 | no. 16 | 6146-6151]

That is, it is quite possible that the much vaunted public health measures used to battle the SARS virus were only effective because the virus wasn't actually that bad.  Not to minimize the death, disease, and the at least US$ 50 billion in economic damage, but it could well have been a lot worse.

This conclusion comes out of a modeling paper, and describes the development of a methodology similar to the one now being used to plan responses to a pandemic flu outbreak.  Unfortunately, there isn't a great deal of data to constrain the model, and as Tara O'Toole and her colleagues at the Center for Biosecurity at UPMC point out (PDF), present monitoring and quarantine policy is simply "inconsistent with available scientific understanding of the nature of person-to-person disease transmission."  There is also a distinct question as to how far we should trust the model.  Fortunately, we can look at distinct historical events to figure out whether preparations are on the right track.

Below is a time line of events starting in the fall of 2002, when the SARS coronavirus first emerged.  (Sources:  WebMD, Science, Nature, PNAS, Journal of Virology.)

Note that while the virus appears to have emerged in November of 2002, it wasn't until February of 2003 that Carlo Urbani saw his first patient.  The diagnosis in November is entirely forensic in nature.  That is, working backwards this seems to be when the virus first jumped to humans.  Koch's postulates, which must be met in order to conclusively link a pathogen and the disease it causes, are not met until the middle of April.  The sequence is then announced at the height of the pandemic, though it isn't published until after most deaths from the initial outbreak have already happened.  Ralph Baric's group at UNC publishes the first paper in October demonstrating control of the virus in the lab, which is a prerequisite to doing any biology, figuring out how the virus works, and developing vaccines.  (Ralph told me at a meeting last week they were ready go to with the paper a few months before it came out.  This delay was probably due to academic publishing BS, as far as I can tell, though it might have gone faster if people were still dying at that point.)  The first vaccine takes another year to test and publish (some of this interval is also due to the dynamics of academic publishing, but the point remains).

Thus the pandemic was basically over by the time we could do any biology and even start to think about vaccines.  But Ralph Baric wouldn't have been able to move as fast as he did in 2003 had he not worked out the packaging strains for the coronavirus reverse genetics system years earlier, published in November of 2000 (Yount, et al., J. Virology).  As it happened, Ralph thought the viruses were interesting, and he put in the time and effort to sort out how to work with them in the lab.  It is only through Ralph's efforts that the rest of us have the good fortune to know as much as we do now about the virus.

What about the next time?  The reverse genetics system for influenza was published in 1999, and we are still trying to figure out how the virus works.  If a flu pandemic hits we might, just maybe, be ready with useful vaccines and antivirals, particularly if the FDA's new flu vaccine licensing rules turn out to be as well thought out as has been reported.  Future flu pandemics are a near certainty, if only because we have historical examples.  Thus there is a clear motivation to get ready for the next one.  We have a choice about whether to prepare, and the flu is an understood threat.  But what about the next true surprise, the next SARS coronavirus?  And what if it is just a little bit worse than SARS? 

We have to be able to detect the threat, understand it, and respond much more rapidly than is now possible.

New Rules for Expedited Flu Vaccine Licensing

CNN is reporting that on Thursday the FDA will announce new draft rules intended to accelerate the approval of new flu vaccines.  This is excellent news.  According to the story, "Eventually, the guidelines could knock one to two years off the time it takes to develop and license a new flu vaccine."

Here is all the good stuff:

...The guidelines make clear there are a variety of approaches to creating vaccines to fight the next pandemic.

The guidelines allow for emergency approval if a completely new super-strain of flu suddenly appears. Or, manufacturers could systematically create and stockpile a library of vaccines against brewing new strains.

They even allow for the possibility of one day vaccinating people against a potential future pandemic strain at the same time they get their regular winter flu shot.

The last point is interesting, because it is an example of explicitly trying to get out in front of a pandemic strain before it appears.  The biggest reason H5N1 is a threat is that humans have never been exposed to a virus like it.  We are "immune naive", which means we have no preexisting antibodies or lymphocytes primed to respond to this particular virus.

Additional interesting policy tidbits:

In the case of a previously approved flu vaccine, manufacturers could tweak the vaccine for use against a new flu strain without having to seek a new license from the FDA, according to the draft documents.

Additionally, a manufacturer could receive "accelerated approval" for a new flu vaccine by performing studies showing that recipients experienced a surge in protective immune-system cells.

This is all good stuff, and comes not a moment too soon.  Okay, it comes a couple of years late.  We're way behind in preparing technological responses either to large outbreaks of infectious disease or to bioterror attacks.  The draft rules are putatively open for comment for 90 days -- if the rules turn out to be as well constructed as CNN is reporting, then everyone should enthusiastically support these proposed changes.

I'll post more when the official documents are released.

Avian Flu as a Harbinger of Zoonotic Diseases

As most people have heard by now, H5N1 has reached Germany and is confirmed to have killed a cat (AP via the NY Times).  I think the time scale is of interest here.  The virus has only just reached Western Europe, evidently via migrating birds, and already it has jumped to mammals.  In contrast, there appear to have been few cases in felines in Asia, despite the amount of exposure mammals have had there.  From the AP report:

In addition to the large cats infected in Thailand, three house catsnear Bangkok were found to be infected with the virus in February 2004. In that case, officials said one cat ate a dead chicken on a farm where there was a bird flu outbreak, and the virus apparently spread to the others.

I suppose its possible cat deaths are going unreported throughout Asia, but if the AP report is correct then  transmission to cats is very low probability, and I find it odd that the virus is already confirmed to have killed a cat in Germany.  It makes one wonder how the sequence is changing.

Fortunately, there are as of yet no known cases of cat-to-human transmission.  But human exposure to the virus has only just begun in Europe, and the coming months will increase this contact.

All news reports seem to agree that the virus arrived in France and Germany via migrating wild birds.  In an article focusing on the effects of the virus on the French poultry industry, Craig Smith notes in the New York Times that:

...The real threat, many experts fear, may come in the weeks ahead as pintail, garganey and shoveler ducks begin arriving from their wintering grounds in Africa, where the virus has already spread among poultry. The annual migration toward northern breeding grounds is expected to last until the end of May.

Smith also describes how migration patterns have been somewhat unusual this year due to extremely cold weather.  Thus the spread of the virus may be enhanced by changing weather patterns, increasing the likelihood of transportation into areas of the world densely populated by both humans and domesticated animals.  This sort of thing is only going to happen more often.

The AP (via the NY Times) recently picked up this thread with an article entitled, "Scientists See Growing Animal - Disease Risk."  The article begins, "Humans risk being overrun by diseases from the animal world, according to researchers who have documented 38 illnesses that have made that jump over the past 25 years," and winds up:

One explanation may be the recent and wide-scale changes in how people interact with the environment in a more densely populated world that is growing warmer and in which travel is faster and move extensive, Marano said. Those changes can ensure that pathogens no longer stay restricted to animals, she added. Examples from recent human history include HIV, Marburg, SARS and other viruses.

That prospect leaves open the question of what future threats await humans.

''It always surprises us. We think that avian flu will be the next emerging disease. My guess is something else might come out before that,'' said Alan Barrett, of the University of Texas Medical Branch at Galveston. ''It's very hard to anticipate what comes next.''

SARS, in particular, is an excellent example of surprise from nature.  It is also an example of how ill prepared we are for emerging diseases.  It is clear from recent work that if the SARS coronavirus had been just a little more virulent, and if it had spread just a little more before symptoms emerged, then the epidemic would likely not have been held in check by public health measures.  Moreover, it is only because coronaviruses caught the attention of a talented virologist several years before that the community was able to get a handle on the virus as quickly as it did.  More on this in an upcoming post.

(UPDATE, 5 March 06: Ralph Baric is the virologist mentioned above.  Here's the story.)