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).

Big Day for Bird Flu News

Today brings news that a live, infectious strain of the 1918 flu has been reconstructed in the lab.  The press has responded smartly this time (New York Times, AP via Wired News, CNN, The New Scientist) -- with fairly decent reporting -- no doubt in part because President Bush addressed the situation in a press conference, suggesting that the U.S. military might be involved in managing a pandemic.  There is quite the political hullabaloo in Washington DC, too boot, with the New York Times reporting that in response to closed door briefing last week a Pentagon appropriations bill has been boosted by USD 3.9 Billion solely for dealing with the flu (it's unclear from the story whether that money is intended for use by the Pentagon or by the NIH).  Politicians, and political parties, are evidently trying to outdo one another in being out front on this issue, despite the fact that we are hopelessly behind.  No surprise there.

As far as the biology goes, for those who have been paying attention, or even just reading this blog, there isn't that much new in today's reports.  As related by the Times, papers in Science and Nature basically confirm at least part of the molecular detective story told by Oxford et al., namely that the 1918 flu jumped directly from birds to humans.  Thus, "The Swine Flu" is a misnomer for the disease caused by this particular bug.  There is no further progress on figuring out when and where the bug evolved, as far as I can tell.

The Nature paper, from Jeffrey Taubenberger's group, describes his work in extracting flu sequences from preserved lung tissue and from a corpse frozen in permafrost.  This paper is a bioinformatic comparison (i.e. no experiments) that characterizes the 1918 flu polymerase genes.  The Science article describes infecting mice with a reconstructed virus, which turned out to be considerably more lethal than expected.  The article will be out on 7 October.  I will write more when I've had a chance to carefully ready both papers.

The publication of the viral sequence, with accompanying descriptions of how to reconstruct live virus, obviously raise questions about safety.  Every story above mentions that the investigators and journal editors balanced the benefits and threats, and asked for a review from the National Science Advisory Board for Biosecurity (NSABB), before going to press.  Fortunately, everyone came to a conclusion in favor of publishing.  Press reports, including one in Nature, give voice to critics of publishing the sequence and construction methods.  In particular, there are complaints that the 1918 strain could be reconstituted for use as a weapon or that it could simply escape back into the wild.  I am obviously not the only one not much convinced by these arguments.  While very few people alive today have been exposed to the 1918 strain, related strains are often included in annual flu vaccines.  So humans is no longer immune naive for that set of bugs.  As for the use of 1918 as a weapon, the reverse genetics required to produce a live RNA virus from DNA plasmids are decidedly non trivial at the time being.  No doubt, this process will get simpler, but this isn't something you are going to do in your garage.

 

Tamiflu Resistant H5N1?

CNN is reporting that Tamiflu-resistant strains of H5N1 are appearing in Asia, and that "resistance to anti-flu drugs [is] growing worldwide."  It is a typical CNN story, and therefore leaves one wanting more facts, but at least it's enough to start a Google adventure.

In another story, CNN is repeating the forecast by Dr. David Nabarro of up to 150 million deaths from H5N1.

Taking Issue With Henry Niman

Henry Niman has made quite a lot of bother about the Avian Flu in the last year at his site Recombinomics.  It is still unclear whether he has a better handle on the future of the virus than does the WHO, the CDC, the FAO, and the UN, in part because he has yet to publish anything in a peer reviewed article.  But it is clear some folks are getting touchy about Niman's vocal assertions of doom -- here is a blog entry rebutting some of Niman's claims, and otherwise taking him to task for his behavior.  There's more, for those interested in this sort of thing, at drmartinwilliams.com.

UPDATE (24 October 2005):  Here is a previous post of mine that includes an attempt to figure out whether Niman has interesting or useful contributions to the Avian Flu problem, and a post attempting to sort out the difference, if any, between recombination and reassortment.  Also an early commentary on how little data we have about what evolutionary mechanisms result in pandemic flu strains.

UPDATE (1 November 2005):  Here is a post illustrating the gap between Niman's claims and conclusions based on sequencing data from the World Health Organization.

PowderMed's H5N1 DNA Vaccine

The news service at Nature is reporting ("Bird flu vaccine not up to scratch" -- subscription required) that an egg-based whole virus Avian Flu vaccine, recently announced with fanfare as solving all our problems, is unlikely to be useful.  Fortunately, there is an alternative.  Alas, regulatory issues may prevent PowderMed from distributing it's DNA vaccine for the Avian Flu for some years yet.

The whole virus vaccine was announced with great fanfare just a few months ago.  But as I've written previously (here and here), egg-based vaccine production will never be sufficient for rapid responses to quickly evolving viruses like the flu.  Moreover, to produce a decent immune response the whole virus vaccine must be administered in 2 doses, each 6 times larger than an annual flu shot.  While this is in part because humans have never been exposed to an H5 virus (we are "immune naive"), it also appears that it just isn't a great vaccine.

While it is true that enthusiasm for DNA vaccines has gone through a bit of a boom and bust cycle, early results requiring high dose intramuscular injection are not representative of how the current technology works.  Genes coding for antigens for new viruses are slotted into a plasmid vector that has been proved safe in humans, the plasmids are loaded onto micron-sized gold particles, and the particles are injected into the skin using a high-pressure helium blast.  At Bio-ERA, we've been studying the vaccine and its utility, and it looks like the real deal.  An article in Red Herring quotes the CEO of PowderMed as saying;

What we really believe we’ve got is not just a vaccine; we actually have the ability to produce a capability for a country to cover anything really.  We have designed, with the help of contract manufacturers, a facility that would be able to produce 150 million doses in three months.

The key to the value of PowderMed technology is that the DNA vaccine is delivered directly in the nucleus of dendritic cells in the epidermis.  By getting dendritic cells to express coat proteins from pathogens and then present those proteins in complexes with MHC molecules, the vaccine directly stimulates a cellular immune response; T-cells are thereby primed to recognize and dispose of the virus and infected cells.

Vaccine production in chicken eggs or in cell culture requires at least 6 months to even begin cranking out doses, and requires significant infrastructure to do so.  PowderMed suggests that within three months of sequencing a new pathogen they can have vaccines ready to go.  But my estimates suggest it could be much faster than this.  Included in PowderMed's estimate is the time required to load the vaccine into their proprietary delivery system (a helium powered injector about the size of a flashlight).

My own estimate of the time required to fabricate the plasmids, followed by enzymatic amplification, is more like a week or two.  Injection of the vaccine does require particular technology (a "gene gun") but as it happens those have been used for ~10 years to genetically modify plants and animals.  There are gene guns scattered all across the developed and developing world.  If we had to, if the Avian Flu started to cause real problems in the human population, we could synthesize the vaccine in a widely distributed fashion (anywhere around the globe where people have access to large scale DNA synthesis) and deliver it using gene guns.  True, those instruments were intended for research use only, and were not designed for (or at least not marketed for) use on humans.  But if things start to go south, I'll be first in line.

Commentary on Flu Vaccine News and Epidemiological Models

I've been mulling whether to wade into the fray generated by recent reports of "effective" H5N1 vaccines and computer models that suggest a pandemic might be stoppable.  Fortunately, I see that the folks at EffectMeasure took care of most of what I wanted to say.  Basically, the media is distorting news of minimal (and possible irrelevent) progress on the vaccine to make it sound like we are all set and ready for whatever comes, while the models show that only if we are very lucky will anti-virals and quarantines slow a pandemic (the comments on both posts are worth reading, too).  I feel so much safer.

"Influenza Pandemic: Challenges Remain in Preparedness"

On 26 May, 2005, Marcia Crosse, Director of Health Care at the Government Accountability Office(GAO), testified (PDF) before the Subcommittee on Health, and the Committee on Energy and Commerce of the U.S. House of Representatives on pandemic preparedness in the US.  The news is not good.

Some of the choicer comments:

Challenges regarding the nation’s preparedness for and response to an influenza pandemic remain. Specifically, our prior work has found that although CDC participated in an interagency working group that developed the U.S. plan for pandemic preparedness that was posted for public comment in August 2004, as of May 23, 2005, the plan had not been finalized. Further, we found that the draft plan does not address certain critical issues, including how vaccine for an influenza pandemic will be purchased, distributed, and administered; how population groups will be prioritized for vaccination; what quarantine authorities or travel restrictions may need to be invoked; and how federal resources should be deployed. At the state level, we found that most hospitals across the country lack the capacity to respond to large-scale infectious disease outbreaks.

...The draft plan delegates to the states responsibility for distribution of vaccine. The lack of a clearly defined federal role in distribution complicates pandemic planning for the states. Furthermore, among the current state pandemic influenza plans, there is no consistency in terms of their procurement and distribution of vaccine and the relative role of the federal government. Approximately half of the states handle procurement and distribution of the annual influenza vaccine through the state health agency. The remainder either operate through a third-party contractor for distribution to providers or use a combination of these two approaches.

Most annual influenza vaccine distribution and administration are accomplished within the private sector, with relatively small amounts of vaccine purchased and distributed by CDC or by state and local health departments. In the United States, 85 percent of vaccine doses are purchased by the private sector, such as private physicians and pharmacies. HHS has not yet determined how influenza vaccine will be distributed and administered during an influenza pandemic.

There are many issues surrounding the production of influenza vaccine, which will only become exacerbated during an influenza pandemic. Vaccines, which are considered the first line of defense to prevent or reduce influenza-related illness and death, may be unavailable or in short supply. Producing the vaccine is a complex process that involves growing viruses in millions of fertilized chicken eggs. Experience has shown that the vaccine production cycle takes at least 6 to 8 months after a virus strain has been identified, and vaccines for some influenza strains have been difficult to mass-produce, causing further delay. The lengthy process for developing a vaccine may mean that a vaccine would not be available during the initial stages of a pandemic.

Here is a wee bit of good news, namely that the US Government is spending money to guarantee purchase of vaccine so that manufacturers will maintain more production infrastructure:

...The agency’s fiscal year 2006 budget request includes an increase of $30 million for CDC to enter into guaranteed purchase contracts with vaccine manufacturers to ensure the production of bulk monovalent influenza vaccine. If supplies fall short, this bulk product can be turned into a finished trivalent influenza vaccine product for annual distribution. If supplies are sufficient, the bulk vaccine
can be held until the following year’s influenza season and developed into vaccines if the circulating strains remain the same. In addition, according to CDC, this guarantee will help to expand the influenza market by providing an incentive to manufacturers to expand capacity and possibly
encourage additional manufacturers to enter the market. In addition, the fiscal year 2006 budget request includes an increase of $20 million to support influenza vaccine purchase activities.

But, of course, the testimony basically ends on a downer:

Even if sufficient quantities of the vaccine are produced in time, vaccines against various strains differ in their ability to produce the immune response necessary to provide effective protection against the disease. Studies show that it is uncertain how effective a vaccine will be in preventing or controlling the spread of a pandemic influenza virus.

At least with this testimony, and the remarks  of Senate Majority Leader Dr. Frist at Harvard Med School last week, it seems the right noises are being made in Washington DC.