"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...

Is Annual Influenza a Bigger Killer Than We Think?

In a short paper in the Journal of the Royal Society of Medicine in July, 2003, Madjid et al., note that influenza immunization significantly reduces the risk of recurrent myocardial infarction, sudden cardiac death, and stroke.  They suggest that rather than the oft quoted figure of 20,000 deaths per year in the U.S., influenza should probably be credited with more like 90,000 deaths per year.

Madjid et al., go on to question whether influenza should be considered a bioweapon risk, particularly in light of the project (now completed) to sequence the 1918 flu strain.  As I wrote last week, I think publishing the 1918 sequence is critical to scientific progress and that the risks are overstated.  Still, the notion that flu accounts for many more annual deaths than is typically acknowledged is interesting.

More on Henry Niman's claims about the H5N1 Avian Flu

Here is an article in the 30 October Pittsburgh Tribune-Review by Jennifer Bails profiling Henry Niman and his ideas; "Fox Chapel researcher says bird flu coming faster than expected."  I'm quoted towards the end of the article, once again pointing out the lack of peer-reviewed anything from Niman.  I find it increasingly odd that Niman claims the H5N1 strain currently circulating carries portions of genes imported from mammalian flu strains, particularly since recent sequence analysis indicates the virus is entirely avian in origin.

Specifically, the WHO Global Influenza Program published a paper in the journal Emerging Infectious Disease in October, "Evolution of H5N1 Avian Influenza Viruses in Asia", which states quite explicitly 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.

So, Dr. Niman, what gives?

By the way, even after no less a figure than Sydney Brenner explained cladistics to me, I still don't understand.  Anyone care to enlighten me in, say, 30 words or less?

I'll have another post on the evolution of flu viruses by tomorrow.

On the Threat of the 1918 Flu

What do you do when a vanquished but still quite deadly foe reappears?  To further complicate the situation, what if the only way to combat not just that particular foe, but also fearsome cousins who show up every once in a while, is to invite them into your house so as to get to know them better?  Chat.  Suss out their strengths and weaknesses.  Sort out the best way to survive an inevitable onslaught.  This is our situation with the 1918 Influenza virus and and its contemporary Avian relatives

Over the last couple of weeks, several academic papers have been published containing the genomic sequence of the 1918 "Spanish" Flu.  These reports also contained some description of the mechanism behind that flu's remarkable pathogenicity.  (Here is the 1918 Influenza Pandemic focus site at Nature, and here is the Tumpey, et al., paper in Science.)  In response, several high visibility editorials and Op-Ed pieces have questioned the wisdom of releasing the sequence into the public domain.

Notably, Charles Krauthammer's 14 October column in The Washington Post, entitled "A Flu Hope, Or Horror?", suggests:

Biological knowledge is far easier to acquire for Osama bin Laden and friends than nuclear knowledge. And if you can't make this stuff yourself, you can simply order up DNA sequences from commercial laboratories around the world that will make it and ship it to you on demand. Taubenberger himself admits that "the technology is available."

I certainly won't debate the point that biological skills and knowledge are highly distributed (PDF), nor that access to DNA fabrication is widely distributed.  However, while I am sure that Dr. Taubenberger is familiar with the ubiquity of DNA synthesis, I seriously doubt he suggested to anyone that it is easy to take synthetic DNA and from it create live, infectious negative strand RNA viruses such as influenza.  I've written to him, and others, for clarification, just to make sure I've got that part of the story correct.

Krauthammer also asserts that, "Anybody, bad guys included, can now create it," and that, "We might have just given it to our enemies."  These statements border on being inflammatory.  They are certainly inaccurate.  The technology to manipulate flu viruses in the lab has been around for quite a few years, but not many research groups have managed to pull it off, which suggests there is considerable technical expertise required.  (I will clarify this point in my blog as I hear back from those involved in the work.)

The other commentary of note appeared in the 17 October New York Times, "Recipe for Destruction", an Op-Ed written by Ray Kurzweil and Bill Joy.  They call publication of the sequence "extremely foolish":

The genome is essentially the design of a weapon of mass destruction. No responsible scientist would advocate publishing precise designs for an atomic bomb, and in two ways revealing the sequence for the flu virus is even more dangerous.

First, it would be easier to create and release this highly destructive virus from the genetic data than it would be to build and detonate an atomic bomb given only its design, as you don't need rare raw materials like plutonium or enriched uranium. Synthesizing the virus from scratch would be difficult, but far from impossible. An easier approach would be to modify a conventional flu virus with the eight unique and now published genes of the 1918 killer virus.

Second, release of the virus would be far worse than an atomic bomb. Analyses have shown that the detonation of an atomic bomb in an American city could kill as many as one million people. Release of a highly communicable and deadly biological virus could kill tens of millions, with some estimates in the hundreds of millions.

These passages are rife with technical misunderstanding and overheated rhetoric.  My response to Joy and Kurzweil arrived late at the Times, but on the same day a number of other letters made points similar to mine.  For the record, here is my letter:

The Op-Ed by Ray Kurzweil and Bill Joy, celebrated inventors and commentators, is misleading and alarmist.
    The authors overstate the ease of producing a live RNA virus, such as influenza, based on genomic information.  Moreover, their assertion that publishing the viral genome is potentially more dangerous than publishing instructions to build nuclear weapons is simply melodramatic.
    The technology to manipulate and synthesize influenza has been in the public domain for many years.  Yet despite copious U.S. government funds available for such work, only a few highly skilled research groups have demonstrated the capability.  Restricting access to information will only impede progress towards understanding and combating the flu.  Obscuring information to achieve security makes even less sense in biology than in software development or telecommunications, fields Kurzweil and Joy are more familiar with.
    Dealing with emerging biological threats will require better communication and technical ability than we now possess.  Open discussion and research are crucial tools to create a safer world.

Dr. Rob Carlson, Senior Scientist, Department of Electrical Engineering, University of Washington, and Senior Associate, Bio-Economic Research Associates

I was, of course, tempted to go on, but alas the Times limits letters to 150 words.  ("Alas" or "fortunately", depending on your perspective.  Of course, I've no such restriction here.)  Kurzweil and Joy commit the same error as Krauthammer of confounding access to DNA synthesis with producing live RNA virus in the lab.  Fundamentally, however, both the opinion pieces are confused about the threat from a modern release of the 1918 Flu virus.  In a Special Report, Nature described the work by Terrence Tumpey at the CDC to recreate and test the virus:

[Terrence Tumpey] adds that even if the virus did escape, it wouldn't have the same consequences as the 1918 pandemic. Most people now have some immunity to the 1918 virus because subsequent human flu viruses are in part derived from it. And, in mice, regular flu vaccines and drugs are at least partly effective against an infection with reconstructed viruses that contain some of the genes from 1918 flu.

Thus, without minimizing any illness that would inevitably result from release of the original flu virus, the suggestion that any such event would be as deadly as the first go round is inaccurate.  To further clarify the threat, I asked Brad Smith, at the Center for Biosecurity and the University of Pittsburgh Medical Center for some assistance.  He returned, via email, with a story less comforting than that in Nature:

Rob,
       
After speaking with my colleagues DA Henderson and Eric Toner, here are my thoughts on this:
       
The 1918 flu was an H1N1 strain.  The most prevalent seasonal flu strain for the last several decades has been based on H3N2.  Note that there are many flavors of any given H and N type, the hemaglutinin and neauraminidase are constantly mutating and each has a series of antigenic sites.  For example, while the recent predominant seasonal flu has been H3N2, each season it is a slightly different H3N2.  We do retain some residual immunity from last year's H3N2, so we do get sick, but only the weakest that are infected die.  This is the difference between common antigenic drift, and the less common antigenic shift to an entirely new H and N that results in a new pandemic flu strain. (You already know this, but I'm just trying to lay it all out.)
   
H1N1 variants had been major annual strains until the 1957 H2N2 pandemic strain emerged, and has continued as a minor annual strain.  (The H3N2 strain emerged as the 1968 pandemic strain.)  It is accurate that a version of H1N1 is a component of the annual trivalent flu vaccine that we use today and some of the internal proteins of H3N2 strains are derived from H1N1 through reassortment.
       
However, most people in the US born after 1957 have never been exposed to H1N1 in the "wild" and most people do not get flu shots either (in the US or worldwide) - so they would not have been exposed to the H1N1 variant in the vaccine.
       
So, I am not completely sanguine that a reintroduction of the 1918 flu virus into today's relatively naive population would be tempered by some degree of residual immunity.  If there is residual immunity, or some effectiveness of today's vaccine and anti-virals, what would that translate into with respect to a decrease in the numbers of people sick and dying?  1918 flu caused 500,000 deaths in the US and perhaps 50 million deaths worldwide over an amazingly short 18 months.  So, even if only a few percent (relative to what happened in 1918) of the people who are infected by an escaped 1918 flu virus died, the toll would be in the millions.
   
This does not mean that the cost/benefit of studying 1918 flu means it shouldn't be studied, but it certainly isn't as de-fanged as one might hope.

-Brad

Truth be told, the diversity of opinions amongst people well educated on the details means we can't really estimate what would happen if the original virus were released.  So what do we do about the this and other threats?  One answer is to spin up a well-funded effort to improve our technical capabilities.

Echoing Senate Majority Leader Bill Frist, Joy and Kurzweil go on call in their Op-Ed for "a new Manhattan Project to develop specific defenses against new biological viral threats, natural or human made."  This is fine and all, but the Manhattan Project is decidedly the wrong model for an effort to increase biological security.  Far better as a metaphor is the Apollo Program; massive and effective but relatively open to public scrutiny.  Quoting briefly from my 2003 paper on how to improve security amidst the proliferation of biological technologies:

Previous governmental efforts to rapidly develop technology, such as the Manhattan and Apollo Projects, were predominantly closed, arguably with good reason at the time. But we live in a different era and should consider an open effort that takes advantage of preexisting research and development networks. This strategy may result in more robust, sustainable, distributed security and economic benefits.  Note also that though both were closed and centrally coordinated, the Manhattan and Apollo Projects were very different in structure. The Apollo Project took place in the public eye, with failures plainly writ in smoke and debris in the sky. The Manhattan Project, on the other hand, took place behind barbed wire and was so secret that very few people within the US government and military knew of its existence. This is not the ideal model for research that is explicitly aimed at understanding how to modify biological systems. Above all else, let us insist that this work happens in the light, subject to the scrutiny of all who choose to examine it.

Which, I think, is quite enough said on this issue (for now).

Beamed Power

Wired News has a story today mentioning a fresh examination of beamed power.  Most of the piece is about a $500 billion project to generate power on the moon and then beam it back to Earth (oy), though it does mention the space elevator eventually.  NASA is partnering in set of Centennial Challenges aimed to promote development of technologies such as beamed power, strong tethers, and climber robots.

The Rise of Chinese Biotech

On the theme of increased participation of developing countries in biological technology, Rik Wehbring pointed me to a Reuters story, "Low Cost Spearheads China Drive Into Biotech".  As I have written previously here, in addition to investment by Western companies China is putting considerable effort into developing both domestic R&D and domestic clinical expertise.

The Reuters story notes that

China already boasts more than 20 biotech parks dotted around the country and 500 biotech enterprises.  Some 300 of these companies are focused on medicine, with the balance mainly targeting agriculture.  The Chinese government and local governments have both been active in supporting the sector, with total state funding last year reaching the equivalent of 270 million euros ($325 million).

Because "the cost of biomedical research in China is only about 20 percent of the cost in Western countries", that $325 million goes quite a long ways.

We can expect drug development and biomedical research to take off in India as well.  A friend of mine with investments in the U.S., Europe, and in India cites cost figures for India identical to those for China.

So I ask you, without considerably greater investment in education and domestic R&D, how are either the U.S. or Europe going to compete?  What is it going to take for policy (politicians) to catch up to reality?