"There is no scientifict basis to predict [the course of the avian flu]".

There is an excellent news story by Dennis Normile in the 18 November 05 issue of Science about  present uncertainty over the course of the avian flu, "Pandemic Skeptics Warn Against Crying Wolf".

As I have written here previously (for example, "How long does it take the flu to evade a vaccine?"), we have very little data on the evolution of pandemic flu viruses.  For instance, we can't make general conclusions about the intervals between pandemics because there just aren't many data points.  Moreover, historical pandemic strains are quite different from each other, with some being obviously of avian origin while others arose through recombination or reassortment of avian and mammalian strains.  Differences amongst the viruses also obscure the mechanism(s) by which pandemic strains arise.

In the lead for his article, Normile asks, "Is the H5N1 virus now circulating in Asia really the one to watch? How soon will the next pandemic occur? And will it trigger a wave of mortality, as did the 1918 flu, or a just small ripple in the annual influenza death toll?"  He quotes well known virologists and evolutionary biologists as doubting whether the presently circulating H5N1 flu bug has the capacity to become a pandemic strain.  The article then delves into the role of World War I in generating and spreading the 1918 virus.

Most interesting for me, however, are the straightforward comments concerning how little we know about what is going on:

Although the historical data are interesting, [Mary Lipsitch of Harvard] and others add, they simply aren't conclusive enough to rule an H5N1 pandemic in or out. "We don't know what viruses circulated in the past [among humans], except for the most recent 150 years," says Yoshihiro Kawaoka, a virologist at the University of Tokyo and the University of Wisconsin, Madison. What's more, he says, H5N1 is shattering historical precedents. Never before has a virus so highly lethal for poultry become so widespread and continued in circulation for such a long time. And with the virus continuing to spread, "the risk of mutation is increasing accordingly," says Masato Tashiro, director of WHO's Collaborative Center for Influenza Surveillance and Research at Japan's National Institute of Infectious Diseases in Tokyo. There are so many gaps in what is known about how virulence and pathogenicity evolve, Kawaoka says, that "there is no scientific basis to predict anything." (emphasis added)  [The University of Washington's Carl Bergstrom] agrees: "We, as scientists, need to do a good job of something slightly tricky here, which is to convey that our predictions are probabilistic."

Not an easy job, particularly when politicians demand (and promise) unrealistic certainty and the public has an ever poorer understanding of the very nature of science.  But because pandemics do historically occur, everyone who knows anything about the flu agrees we need to prepare for the future.  The article concludes:

[Paul Offit, of the University of Pennsylvania School of Medicine] hopes the concerns about H5N1 will lead to efforts to strengthen the U.S. infrastructure for vaccine development and production, which he says has deteriorated over the last 50 years. He thinks the message scientists should be sending "is not that we're going to protect you from the bird flu pandemic, but that we're going to be protecting you from a pandemic which may be 20 years from now."

As if that weren't enough to worry about, Oliver Sacks reminds us that the 1918 flu was accompanied by at least one other disease that under other circumstances would have itself been seen as a tragic pandemic.  In "Waking to a New Flu Threat" (NY Times, 16 November 05), Sacks and Joel Vilensky note:

The influenza pandemic of 1918 was followed by another epidemic. The disease was encephalitis lethargica, or the "sleepy sickness," and like influenza it spread through most of the world. Its symptoms were extraordinarily varied - most commonly there was lethargy, but sometimes there was insomnia, and even frenzy; sometimes there were paralyses, sometimes mental disorders...  In 1982 it was shown that irregularly spaced waves of influenza-pneumonia deaths in Seattle during the early 20th century epidemic were followed approximately one year later by corresponding waves of encephalitis fatalities.

...No cure or causative agent had ever been found and most of the remaining survivors were housed in chronic-care hospitals and forgotten.

...No funds have been allocated to try to better understand this mysterious disease and its relationship to epidemic influenza. Encephalitis lethargica is a particularly insidious disease because it is so variable; any early cases in a new outbreak would almost certainly be misdiagnosed as they were 100 years ago.

It is not unlikely that this disease will return. Perhaps with the imminent influenza epidemic, perhaps not. Regardless, we would do well to re-awaken ourselves to what may be a formidable gathering threat.

Which, as I watch the sun set over Mt. Rainier, Lake Union, and downtown Seattle, will not help me sleep any better tonight.

Direct Biological Production of Diesel

Based on the number of Google searches that lead to my post Algae into Biodiesel, there seems to be significant interest in direct biological production of diesel.  National Geographic, c|net, and Technology Review all have carried stories recently about new approaches for generating biofuels and new catalysts for reducing costs and improving yield.

Perhaps this research will finally help land a turbo diesel roadster on my doorstep.

Avian Flu, and vaccination, in China

Everyone has probably  heard that China has confirmed human cases of the H5N1 flu ("China Reports Second Bird Flu Death", Reuters via NY Times).  The Chinese government now acknowledges that they have a "serious epidemic" (CNN), and has culled more than twenty million birds in response to localized outbreaks.

In an attempt to keep control of the situation, "China Threatens Police Action in Fight on Bird Flu" (Reuters via NY Times).  I find particularly interesting the new regulations forbidding actions that restrict accurate reporting of the progress of the virus; "Any practices which affect the reporting of epidemic diseases, including deception, false or late reporting, are forbidden," according to Vice Agriculture Minister Yin Chengjie.  As I wrote last spring (The Economic Consequences of Chinese Pandemic Un-Preparedness), the structure of governmental power in China appears to have changed significantly over the last few years.  According to people who spend significant amounts of time in country, the central government is no longer able to exert much authority over local governments, nor can it count on accurate information coming in from the provinces.  It will be interesting to see if the new regulations have an impact on disease reporting.  With less than clear initial explanations of the enormous benzene spill near Harbin (NY Times), it may be awhile before up front communication is the norm.

The government has also announced plans to vaccinate 14 billion birds to combat further spread.  Of course, the first question everyone is asking is where they are going to come up with that much vaccine.  Everyone in the west seems to agree that the domestic Chinese poultry vaccine production capacity is only in the neighborhood of several hundred million doses annually, which suggests they face significant challenges in vaccinating more than 10 billion birds anytime soon.  An article in the International Herald Tribune casts doubt on the feasibility of this strategy, with veterinary experts expressing blunt skepticism; "Dr. Leon Russell, president of the World Veterinary Association, said '..For the life of me, I can't figure out how China will vaccinate billions of chickens'."

(UPDATE 28 November 05):  Last Thursday's Nature has a short news piece claiming that China has already vaccinated 8 billion birds and that "the country's ten vaccine producers can make 16 billion doses of vaccine per year".  That is quite a contrast to other numbers I've read, and definitely disagrees with the rest of this post.

Wired Magazine's version of the Global DNA Foundry Map

Wired 13.12 (December 2005) contains the magazine's version ("A Genome Shop Near You") of the Global Distribution of Commercial DNA Foundries map I helped make this past summer.  Not all of the foundries on my map are on Wired's version, and they found a few more, but the gist is the same.  Jerry Epstein and Anne Yu at the Center for Stratetic and International Studies contributed to making the original map.

Phase I Results of PowderMed's H3 DNA Vaccine

I'm still stuck waiting for publication of the relevant journal paper, but I now have a copy of poster presented by PowderMed earlier this year.

The summary: with 1, 2, and 4 microgram injections of an H3 gene vaccine via gene gun, PowderMed has shown that even the single microgram dose was safe and generated an anti-influenza antibody response.  Each dose was trialed on a group of 12 volunteers.  "The titres achieved at day 21 of the 4 microgram dose group were sufficient to meet the requirements of the CHMP [Committee for Medical Products for Human Use of Europe] for licensing of annual influenza vaccines."  Thus falls the "primate barrier" to DNA/gene vaccines.

As I understand it, human challenge trials for H3 Panama influenza will begin early next year.  So the pieces are falling into place, but there seems to be so much unfounded resistance against DNA/gene vaccines that it may take a painfully long time just to get funders and regulators tuned in to the possibilities.

I'll post more here when additional trial data is no longer embargoed.

Bio-ERA's US Senate Testimony on Pandemic Flu

Last week Jim Newcomb, my colleague from Bio Economic Research Associates (www.bio-era.net), testified before the Senate Foreign Relations Committee on potential economic damage from a flu pandemic.  Here is the PDF (bio-era, US Senate), replete with excellent figures.  Much of the testimony is based on extensive analysis by bio-era of the SARS episode.  The upshot for the flu is that fear induced by infectious disease can cause significant damage by itself.  The SARS virus killed just short of 800 people and cost as much as $50 billion.  The H5N1 avian flu had by March 2005 already caused an estimated $10 billion in damage, with those costs now much higher and sure to rise even if the bug doesn't evolve to become more infectious in humans.

"Preventing a Pandemic Flu"

I am presently sitting in the "Preventing a Pandemic Flu" working group at the National Academy of Sciences/Keck Futures Intiative.  These discussions are embargoed for the time being, so I can't relate them here, but we are coming up with an interesting strategy that fills significant holes in the present US Gov't plan.  My greatest fear is that President Bush's announcement has sucked all the air out of the room for other options.  But perhaps we will attract sufficient attention to get some money spent.

We'll see.

How long does it take the flu to evade a vaccine?

With all the recent Presidential attention to the threat from the H5N1 Avian Flu, and the many billions now earmarked for stockpiling vaccines and drugs, it seems like a good idea to ask on what time scale the virus might be able to evade these countermeasures.  Vaccination is of particular interest, as it is regarded as by far the best tool to combat viral infection at the population level.

Last February, I examined how little is known about the evolution of pandemic strains of influenza ("Avian Flu Uncertainties").  At the time, there was very little data concerning either the origin of pandemic strains or how often they should arise.  Forensic work on the 1918 pandemic flu suggested that virus was entirely avian in origin, which has now been confirmed by sequence analysis.  The WHO Global Influenza Program Surveillance Network published a paper in the journal Emerging Infectious Disease in October, "Evolution of H5N1 Avian Influenza Viruses in Asia", which states that:

Genomic analyses of H5N1 isolates from birds and humans showed 2 distinct clades with a nonoverlapping geographic distribution. All the viral genes were of avian influenza origin, which indicates absence of reassortment with human influenza viruses.

The WHO team also notes that:

Genetic and antigenic analyses have shown that, compared to previous H5N1 isolates, 2004-2005 isolates share several amino acid changes that modulate antigenicity and perhaps other biological function.  Furthermore, our molecular analysis of the HA from isolates collected in 2005 suggests that several amino acids located near the receptor-binding site are undergoing change, some of which may affect antigenicity or transmisibility.

That is, the currently circulating strain of H5N1 is in the process of becoming something else.  Of course, everything subject to variation and selection (e.g. evolution) is in the process of becoming something else, but the future of H5N1 is of particular interest since understanding it may help us plan for a pandemic.  (Incidentally, CNN.com is just now sporting the most excellent headline, "WHO: Human flu pandemic inevitable".)

Despite the recent "Isolation of drug-resistant H5N1 virus," (Nature, 20 October 2005), the WHO Global Influenza team determined that recent isolates are "sensitive to 2 neuraminidase inhibitors that are recommended for prophylactic or therapeutic intervention against human infections."  So obviously the specific details of which viral isolate one is working with determine its sensitivity to drugs.  In the case of the drug-resistant strain, it was isolated in February 2005 from a Vietnamese girl who may have contracted the virus while she cared for her brother.  Human-to-human transmission is supported by the girl's lack of contact with poultry and the fact that the neuraminidase gene from virus isolated from the girl was virtually identical to that isolated from her brother.  Thus there are evidently drug resistant strains running around in the wild.

As far as I can tell, it just isn't yet clear how fast drug-resistance traits can spread.  There is now at least a little data about how long it takes a particular viral strain to find work-arounds for vaccines.  A recent initial effort to sequence many flu strains in parallel indicates that mutations that provide ways around vaccines can rapidly dominate a population of flu viruses. 

In, "Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution," (Nature, 25 October, 2005) Ghedin et al., find:

Perhaps the most dramatic finding in our data is the discovery of an epidemiologically significant reassortment that explains the appearance, during the 2003-2004 season, of the 'Fujian/411/2002'-like strain, for which the existing vaccine had limited effectiveness. ...Phylogenetic analysis of 156 H3N2 genomes from our project revealed the clear presence of multiple, distinct clades circulating in the population. Through a reassortment event, a minor clade provided the haemagglutinin gene that later became part of the dominant strain after the 2002-2003 season.

That is, exchange of gene segments between subpopulations within a particular strain can provide the means for the strain to escape a previously effective vaccine.  Here is the important bit:

This finding illustrates not only that the influenza virus population contains multiple lineages at any given time, but also that alternate, minor lineages can contribute genetic variation to the dominant lineage, resulting in epidemiologically significant, antigenically novel strains. It is worth emphasizing that our sequence-based sampling approach--in contrast to traditional serologically based sampling--will reveal co-circulating strains even before they become antigenically novel.

In other words, the authors assert that amongst viruses that we give the same name there is considerable variation that may be hard to distinguish using traditional techniques.  Sequencing the genomes of many isolates can provide a map of how a population of viruses is changing in response to vaccines.  Ghedin, et al., note that their work demonstrates significant change of the dominant flu strain even within the 2003-2004 flu season.  That variation appeared to originate and then dominate the population of viruses within 12 months.

Which brings me to the core of this post, namely that we now have real-world data demonstrating that flu viruses can escape vaccines in less than a year, far shorter than the time it takes to produce significant quantities of effective vaccines.  It is important to note that this is a different problem than producing a new vaccine for new annual flu strains every year.  If a pandemic strain emerges, our problem is not planning ahead just far enough to deploy a vaccine for next year's strain, but rather to combat a strain already killing people worldwide.  It took most of a year for the CDC and Sanofi to come up with a hypothetical H5N1 vaccine, and the new National Strategy for Pandemic Influenza contains the expectation of years to accumulate enough vaccine to be useful for large populations.  Never mind that the existing whole virus vaccine may not be effective against a pandemic strain.

There is another significant point of concern embedded in the Ghedin paper:

The fact that the minor Fujian-like clade has donated its HA to the previously dominant strain rather than itself becoming the dominant circulating virus indicates that there may be important amino acid co-substitutions in the other proteins essential for viral fitness.

Which needs to be combined with another important bit:

...Even within a geographically constrained set of isolates, we have found surprising genetic diversity, indicating that the reservoir of influenza A strains in the human population -- and the concomitant potential for segment exchange between strains -- may be greater than was previously suspected.

We cannot think of the H5N1, or any other strain, as either a clonal population experiencing selection or as a bunch of individuals producing descendants that may accumulate mutations leading to a pandemic strain.  Rather, flu viruses exists as elements of a population that appear to be constantly innovating and trading parts.  This is a critical distinction, particularly in light of rapid human and avian intercontinental travel.  Not only have we now learned that there is greater variation in any given set of geographically linked isolates, but because of human travel we can expect all kinds of novel parts to show up in populations that were otherwise isolated and appeared to be of no immediate threat.

The Ghedin paper doesn't necessarily teach us directly about the evolution of pandemic flu strains, but it does suggest our current plan for pandemic vaccination is not well suited for the problem at hand.

After studying synthetic vaccines for Bio-ERA, amongst other clients, I think DNA vaccines are the best bet for rapid response on a time scale shorter than flu strains seem to evolve.  I've a draft paper on synthetic vaccines in for consideration at Biosecurity and Bioterrorism, and will shortly embark on another paper specifically about distributed manufacture of DNA vaccines.  PowderMed is waiting for publication of their (already accepted) first paper on their plasmid vaccine for the annual flu and will be starting trials of an H5N1 DNA vaccine early next year.  Unfortunately, it seems the folks in DC aren't taking this technology seriously, and instead blowing billions on developing cell culture production of whole virus vaccines.  Even the folks who manufacture vaccines in cell culture acknowledge this will only cut a month or two off the response time. 

Inventing Throughout Life

Technology Review has a short article by Ed Tenner on the productivity of inventors and scientists as they age, "Megascope: Live Long and Tinker".  The article seems to take seriously the myth that mathematicians and physicists do all their best work before the age of 40.  But most of the experimental scientists and engineers I know, including the majority of biologists I've run into, just get better with age.  It takes quite a while to learn all the tricks of the trade and to accumulate enough knowledge to start putting together pieces that don't obviously fit.  The same, I find, is true of inventing.  The more you know, and the more skills you acquire, the more you are able to produce.

This doesn't mean the process of inventing gets any faster, unfortunately...