Effect Measure

Swine flu: pandemic pre-history

However this pandemic evolves, we are going to learn a lot about how pandemics evolve — or maybe even start. A paper just published online in Nature sets out a bit more of what we know about this pandemic strain (yes, we can officially refer to it that way now) and makes some observations about its prehistory (its history before it became known and documented by we mortals). Maryn McKenna has an excellent run-down over at CIDRAP News, which you should read. Here’s our take on it.

First, we’d like to make a “meta-science” observation. This paper is unusual in several ways. The least remarkable is that it is a multi-continent collaboration of scientists (Hong Kong, UK, US). Not so unusual these days, but worth remembering. Science publishing and collaboration is changing and digital communications via the internet is enabling it. That’s not to say that even in those new clothes the old world isn’t still present. Too many of today’s top flu scientists are still keeping their sequences private until publication, a habit sometimes justified as “protecting post docs, young faculty and graduate students.” St. Jude, Mt. Sinai and CDC itself are all guilty of this deplorable (and in the context of a pandemic, frankly unethical) practice. We’ve called them on it multiple times. And that’s the second way this paper is unusual. The authors have been openly sharing and collaborating (via a multi-author wiki platform). The analysis reported in this paper has been done bit by bit out in the open, for all to see. They still were able to publish in one of the highest profile journals in the world (Nature). No post docs or junior faculty or graduate students got hurt by it. On the contrary, by working together they had a much stronger result. The third observation is that Nature published the paper without embargo, meaning it wasn’t provided ahead of time to a favored list of reporters (and often science bloggers; we are on several embargo lists and we abide by the terms. But we hate the idea of it). It is still getting plenty of press. Press embargoes are deplorable and any scientific journal that values transparency and the objective evaluation of merit and interest shouldn’t do it. If they want to call attention to themselves or certain papers they can always issue a press release.

So much for meta-science. What about the contents of the paper? The authors make two interesting points. By a detailed analysis of genetic sequences from 2 outbreak (now pandemic) virus genomes, 15 newly sequenced swine viruses from a Hong Kong surveillance project that goes back into the 1990s and 796 other flu virus genomes representing a diverse spectrum of influenza (285 human, 100 swine, 411 avian isolates) they showed that each of the 8 segments of the new pandemic virus came from an established swine lineage (established meant circulating for more than 10 years before this outbreak). A very nice figure in the paper illustrates the braided origin of the current virus. It has pieces from a 1979 Eurasian swine virus (which in turn was likely of avian origin) and a triple-reassortant North American swine virus (which in turn had pieces of avian H1N1 virus, classical swine virus [which itself may have been derived from humans] and human seasonal H3N2 and later mixed again with classical swine virus replacing H3 with H1). This much was already known. But inclusion of the 15 Hong Kong surveillance sequences showed that combinations of Eurasian swine, North American triple reassortant and classical swine segments were already present, although not the exact combination seen in the outbreak. One that was the same in 7 of 8 segments was isolated in Hong Kong in 2004, referred to by the authors as a sister lineage to the one in the outbreak. They conclude that the components of the pandemic strain have been circulating in swine for years and were widely distributed geographically.

The authors were still not able to say where the final combination came together and then jumped to humans because the genetic record from swine is too sparse. There are long gaps at places where things were likely happening, but we don’t know when or where. Using some assumptions about the rate of molecular evolution, the authors suggest the species jump (to us) may have happened somewhere around the first of the year or perhaps a few months earlier, but the virus may have been circulating undetected for years in pigs.

The final paragraph of the paper is being widely quoted on the newswires:

As reported recently, all three pandemics of the twentieth century seemto have been generated by a series of multiple reassortment events in swine or humans, and to have emerged over a period of years before pandemic recognition. Our results show that the genesis of the S-OIV [swine-origin influenza virus] epidemic followed a similar evolutionary pathway: H1N1 viruses with human pandemic potential had been identified, transmission from swine to humans was known and the disease had been made notifiable. Yet despite widespread influenza surveillance in humans, the lack of systematic swine surveillance allowed for the undetected persistence and evolution of this potentially pandemic strain for many years. (Smith et al., Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature 2009 (advance online publication Jun 11 [cites omitted])

In our view it’s unlikely that even with systematic swine surveillance we would have been able to predict this event because our knowledge of the relationship of the genetics to the biology is still primitive. It is interesting that the authors imply that the 1918 virus was also the result of multiple reassortment in swine and humans. Taubenberger has maintained that the 1918 virus jumped to humans from birds, displacing the earlier view expressed here. There is a citation to a paper in press at PNAS by the senior author of this paper (Smith), so we’ll have to wait for it to appear to see what this is about.

An influenza pandemic is a public health calamity. But for flu science, it is also a golden opportunity.

Addendum: Just noticed Ed Yong’s terrific post on this paper over at scienceblogs Not Exactly Rocket Science. He includes the figure I referred to above. Some detailed and clear explanaiton of this paper. Highly recommended.

Comments

  1. #1 Lowlander
    June 12, 2009

    Hi Revere,

    Yes, we know little, and possibly not enough to predict pandemic potential by simple genomic analysis. However, if you don’t have surveillance then you will not improve that knowledge, or putting in other terms, without data from the field, your research is necessarily impaired and will not improve at its full potential.
    On another note, surveillance of pigs by it self WOULD improve chances of detection of probable suspects. At the very least it would trigger veterinary attention to the units which could impair or abort transmission cycles, would improve health status transparecy in livestock trade which is necessarily the main way for different strains to be transported over the world. This by itself would probably at least delay the evolution of the virus and limit somewhat re-assortments of strains from different species (which is clearly the main concern here from the perspective of an emergent zoonosis).
    Coupled up with surveillance of workers would improve your chances of prediction. Or even comparing samples from pigs with the Human isolations in the geographical area of pig production units

  2. #2 CSplat
    June 12, 2009

    Speaking of surveillance; My wife took our 7 year old for his yearly wellness visit yesterday. Doctor made a statement about how nice it was to see a ‘well child’ for a change. She asked about the flu, his comment: ‘You have no idea.’

    The second interesting piece was that the doctor mentioned they are no longer testing for flu (NC, it is unclear if this is only limited to pediatric patients). He said that those with flu symptoms could call in and they would issue a Tamiflu prescription without seeing the patient.

    It seems to me that this is both an excellent way to infer Tamiflu resistance as well as a missed opportunity to quantify the spread of the novel strain.

  3. #3 Lowlander
    June 12, 2009

    Hi Csplat,

    The simple fact is that governments in developed nations are, and have been for quite some time now absolutelly myopic in their political choices regarding public and animal health. This not just an American problem I assure you. The whole of Europe is copying American policies regarding public funding.
    Nobody wants to spend money, period. Taxophobia has become an ideology. Even research clearly indicates that this is not really expenditure it is an investment with very good returns on the medium to long term. But to people living in a mentality of yearly bottom line (or 4 legislature bottom line) such exercises are meaningless.

  4. #4 Richard Hendricks
    June 12, 2009

    I thought we didn’t have a firm grasp on what defines virulence and how a flu virus develops human-human transmission ability? Would knowing about the virus 2 months early have made a difference? If scientists were given 20 novel flu viruses could they point to the one or two that were most likely to cause problems?

  5. #5 Lisa the GP
    June 12, 2009

    I’m very disappointed in the CDC flu figures for this week. 17,500 cases or so across the nation?

    Yeah. Riiiight.

    As has been pointed out, they’ve effectively stopped counting.

  6. #6 CSplat
    June 12, 2009

    I just saw the CDC figures as well… Average increase of 663 cases/day ?!? I guess the policy of Don’t Ask / Don’t Tell just isn’t for the military anymore.

    It seems that not testing is missing out on a tremendous opportunity to advance the study of the rate of efficacy.

    In my opinion, this simply further erodes my confidence of the posted ‘facts’. Any further information regarding the pandemic must now be appropriately ‘scaled’. (I’m starting to get downright cynical!)

    I’m assuming that the US-Death figure isn’t also being ‘gamed’; the 4/day rate is an increase. Sadly, I don’t expect this to remain constant.

  7. #7 Phillip Huggan
    June 12, 2009

    Any flu analysis of any type that can be safely extracted from pre-1918 corpses would be invaluable. The bodies of dead and frozen mountain-climbers would fill the tiniest amount of 20th century flu gaps. I get the impression a dead mountain climber would’ve been more than willing to have made such a herioc contribution, but I’m sure there are established descendants protocols for this. Does no one any good if a scientist too dies on those slopes…

  8. #8 Jamie
    June 12, 2009
  9. #9 Peer
    June 12, 2009

    I’m amazed that Nature published this paper under the creative commons license. The entire paper is freely available and the figures can be reproduced as long as cited. Maybe it’s a ploy to increase impact factors but a huge step towards fully open access science!

  10. #10 Peer
    June 12, 2009

    “H1N1 viruses with human pandemic potential had been identified, transmission from swine to humans was known and the disease had been made notifiable. Yet despite widespread influenza surveillance in humans, the lack of systematic swine surveillance allowed for the undetected persistence and evolution of this potentially pandemic strain for many years.”(Smith et al., Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature 2009)

    That’s akin to monitoring H5N1 bird flu by only looking at human infections!

    I’m sorry revere, but I disagree with your statement

    “In our view it’s unlikely that even with systematic swine surveillance we would have been able to predict this event because our knowledge of the relationship of the genetics to the biology is still primitive.”

    It certainly wound not have hurt!

    This disease was identified through the surveillance network for of disease in humans, that specifically was looking for humans infected with swine influenza viruses! The virus currently circulating in humans is very similar to those previously identified from human infections as early as 2005 (CDC papers in Science, NEJM, MMWR). So if we know there’s a threat then swine workers and swine should be monitored so we’re not caught unaware.

    In this case, it was the knowledge gained through years of pandemic planning which includes training scientists that allowed this virus to be identified and characterized so rapidly. This happened despite the lack of data.

    In fact, the area where pandemic preparedness plans are lacking is in surveillance of animal hosts, be it swine, poultry or wild birds. There remains ten years or more of missing data prior to the generation of this virus. If that data was available people would not have been calling this virus a franken-flu made up of avian, swine, human influenza genes. And control plans may have been in place to contain the spread of the disease or protocols available for the rapid diagnosis may have been available – as they’re available for bird flu. We could even have had potential vaccine strains available prior to the outbreak.

    There has not been a paper on the systematic surveillance of influenza in swine hosts for years. The potential for swine hosts to facilitate the combination of genetic elements from different viruses that could potentially infect humans and cause a pandemic has been known. Specifically highlighted by the fact that humans infected with swine influenza (triple reassortant) viruses has been a nationally notifiable disease in the USA since 2007.

  11. #11 revere
    June 12, 2009

    Peer: I expressed the opinion that swine surveillance would not have predicted the pandemic. I didn’t say I thought it was a bad idea or that it would hurt. On the contrary, I have been quite clear here that surveillance of animals and people is a key part of public health infrastructure. At some point we may indeed even be able to make the leap to anticipating a pandemic strain by looking at animals. We can’t do that today so I think it is unlikely it would have predicted this pandemic. Which is all my comment said.

    The pick up of these cases via human surveillance is the exception that proves the rule. We were able to pick it up because we saw it caused disease in humans and shortly thereafter that it was transmissible. We can’t do either of those things with swine surveillance yet. What is notifiable is disease in humans because that is evidence that humans can get the disease, the first requirement of a zoonosis.

  12. #12 Lavendr
    June 12, 2009

    First signs now of community level transmission in NZ rather than linked to international travel.
    http://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=10578236&ref=rss

    I must confess I’m getting nervous now about my young asthmatic daughter.

  13. #13 Dylan
    June 13, 2009

    I agree with Revere, here. We do not have, nor would we have found, the index case, or a fully articulated, and acknowledged “patient zero” swine, here (or even a “patient zero” herd, for that matter). Nor do we have an inarguably authentic “Patient Zero” human identified either. Unless I have somehow missed something, in the course of the continuing conversation that was first generated in this area in late April.

    As long as a pathogen remains confined to one species of animal reservoir, I do not see how you can predict, with any measurable degree of scientific confidence, that it will soon mutate into a form that can readily infect a host population of an entirely different genetic configuration. If I remember correctly, we have 144 different combinations of avian HN configurations. The vast majority of them have never been encountered in the human population. They leave us alone. Far too exotic? Or the swine population, either, for that matter. The proper combination that allows for the precise alignment of all essential elements to accomplish the necessary shift must be one hell of an utterly improbable crap shoot. We just witnessed one. And I don’t think that anyone, yet, has even the foggiest idea of exactly how it all came about. I suppose that our “Patient Zero” is certainly out there, somewhere. But nobody has identified him. Or her. Or it. As far as I know, at least. And if we can’t manage it in this case, then it seems entirely likely that we would have no greater prospect of success with any future, similar event. Give the current state of both our knowledge, and our technology; as I believe Revere correctly points out.

    We humans are on an eight lane highway, crowded with bumper-to-bumper pathogens, all changing lanes at 80 mph; occasionally, one inevitably runs us over. Did anyone get the license number of that pathogen…before the crash?

  14. #14 Peer
    June 13, 2009

    Dear Revere,

    Surveillance is never about predicting a disease. It’s about being prepared to deal with an emerging diseases. In the case of bird flu – as soon as humans were infected systematic surveillance was conducted in poultry throughout Hong Kong and southern China.

    In the case of swine flu, we’ve collectively missed the boat in being prepared. Swine surveillance would inform us what was the diversity of viruses with pandemic potential currently circulating in swine. A question we still have no answer for. Are there additional influenza variants in swine that may have pandemic potential?

    Even though the authors never claim that surveillance would have predicted this pandemic, there were plenty of people calling for systematic surveillance of influenza in swine and they were ignored.

    All said, I do genuinely enjoy this blog. And this post is another example of fantastic reporting.

  15. #15 K
    June 13, 2009

    Peer, the large swine factories are under siege by disease, most not human transmittable (hopefully). They do not want to air their dirty laundry for various reasons and they will therefore fight tooth and nail to keep testing out.

    They are now in the desperate mode of breeding high health (they hope) pigs and creating vaccines instead of changing how they raise the pigs. In the end no doubt they would have been better off without the huge pig factories but they lacked the foresight to peer into the future and see their “efficiency” as dangerous since it was so profitable in the present. Common defect of our economic system.

    http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/54200.htm
    Here is one of them “Postweaning multisystemic wasting syndrome (PMWS) of swine was identified in western Canada in 1991; however, retrospective studies from several countries indicate PMWS was present in the previous decade. PMWS is distributed worldwide and most swine-producing countries report variable prevalence of the disease. The primary manifestations are poor growth rate, ill thrift, and/or wasting. PMWS often occurs after weaning in pigs 4-14 wk old. The disease can also be seen in older pigs, particularly finishing pigs that weigh 45-70 kg. Morbidity is typically 5-20% among cohorts in the nursery or finishing stages. Mortality in swine that show signs of PMWS often is >50%. In addition to death loss, PMWS in finishing pigs may prevent, or substantially delay, affected pigs from reaching market weight, which can result in economic loss for the producer.”

  16. #16 Peer
    June 13, 2009

    K,

    You may be right, you may be wrong. The problem I see is that no one actually knows what potential human diseases exist in swine hosts.

    The swine industry are doing the surveillance. And, as far as the industry people are concerned, as long as swine flu is not a major disease in pigs, they don’t care. And, as long as they don’t look for it, it doesn’t exist.

    All you heard for weeks was that swine flu was not in pigs therefore it shouldn’t be called swine flu. They managed to successfully petition the US gov’t and the WHO to change the name of the virus to something entirely uninformative. One thing you can say about this virus and is confirmed from the Nature, Science and NEJM papers is that this is a swine origin virus.

  17. #17 Mathfizz
    June 13, 2009

    A week or so ago I looked at some graphs, contained or referenced in one of Revere’s posts, of US confirmed flu /or maybe it was hospital admissions for ILI, I can’t remember. And today I haven’t been able to find the earlier post with the graphs. But graphs at CDC’s FluView (a page referenced by Revere in a June 3 post) look similar to the ones I remember.

    The graphs showed hospital admissions (or whatever) by week of flu season for the last 4 years or so. In my experience (40 years, often looking for interesting features in (mainly physical) data) I was suspicious of what looked like a hint of a relatively sharp upturn around weeks 3-5 of 2009 in what otherwise was a very mild season. This seemed to convert a mild season into an average season by the end of March. While I commented on it to my colleagues, I didn’t post here because the data wasn’t good enough to be strongly suggesting any early undiagnosed novel swine flu in the US from mid January. (And perhaps this is really unlikely, because of the surveillance systems here?) But I’ve decided to post given the findings of this paper “the authors suggest the species jump (to us) may have happened somewhere around the first of the year or perhaps a few months earlier”.

    And if I seem vague, it’s because I’m 10 hours jet-lagged from just flying from Sydney to Newark.