Sometimes, scientists manage to be in the right place at the right time. For example, a group from Lawrence Livermore National Laboratory submitted a paper1 early in January, and it just turned up in pre-publication form. When they submitted it I really doubt they expected to have it appear in the midst of a new influenza pandemic, even though that’s exactly what they were trying to predict.
What they are actually trying to predict is exactly what the CDC and WHO are now looking at. If you have the genome sequence of an influenza virus, can you predict how dangerous it’s going to be? Can it infect humans? Will it be mild, or highly virulent?
The answer is probably “Not so much,” but the question is an excellent and very relevant one. In fact (as far as I know), there’s not a lot understood about how genome sequences correlate with an influenza strain’s ability to infect and cause disease. So that puts public health essentially in a reactive role, waiting to see what the virus does and then going back to look at the sequences involved. It would be nice to have some kind of prediction, where we could see that the virus is moving toward a more or less dangerous capability.
What the authors of this paper did is gather flu sequences from high- and -low-mortality strains and from pandemic and non-pandemic strains, and then ask what amino acids they had in common.
They found 34 markers of specificity and virulence. They then asked how likely it is for all 34 danger markers to arise in a single strain of influenza, pointing out that:
While marker re-emergence in a single strain does not predict pandemic potential, their presence could highlight unexpected evolutionary events in circulating strains that warrant closer scrutiny.2 … The high mortality rate markers appeared in a wide variety of avian strains but the recent avian to human strain crossovers lacked most of the human strain specific markers. Human persistent strains retained human specific markers (by definition) but lacked most of the high mortality rate markers. Swine strains fell in the middle, carrying both high mortality rate and host specificity markers but with no single strain containing all 34 markers. 1
In other words, swine influenza strains look as if they have the potential to either infect humans and cause a pandemic, or to cause high mortality in humans, but not both (without a lot of mutation or recombination). So that kind of matches what we’re seeing in the present outbreak.
I haven’t looked at the present outbreak to see which of these markers the new H1N1 has — it’s going to be a lot of work to match them up because of the way they’re presenting the data, unfortunately. In any case, they emphasize that their markers are not absolutely predictive, especially the high-mortality markers:
Finding that classification accuracy for high mortality rate strains is lower than the host type classification weakens support for the notion of a single essential common set of high mortality rate markers.
(It’s those high-mortality markers that we’d be most interested in with the present H1N1 strain, because it’s obvious that the virus has already become fairly comfortable with humans, so the specificity markers are unnecessary.)
- Allen, J., Gardner, S., Vitalis, E., & Slezak, T. (2009). Conserved amino acid markers from past influenza pandemic strains BMC Microbiology, 9 (1) DOI: 10.1186/1471-2180-9-77[↩][↩]
- This is exactly the scenario we’re in now, monitoring the present outbreak.[↩]
Long time reader, first commenter:
We have just finished a first analysis of swine flu sequences from a different perspective: What level of immune memory is expected based on sequence conservation of T- and B-cell epitopes found in seasonal flu strains. The analysis is available from http://iedb.zendesk.com/forums/45499/entries/35037. In short, we believe there could be substantial pre-existing T-cell immunity to swine flu, definitely more than humoral immunity.
I view our analysis to be complementary to the full genome sequence approach as performed in the article you discuss. Critical comments are welcome.
Hi, Bjoern. Thanks for the pointer, very nice work. I tried something similar but was too lazy to work through the recent strains and so forth (and the new IEDB still isn’t allowing custom results pages, which makes new analysis hard — though I have most of it in a local database).
My main comment — which you know already, of course, but for the record — is that CTL epitopes are so poorly studied that those in the database vastly under-represent the real T cell responses, so your conclusion that CTL epitopes cross-react is likely very conservative. The large number of matches for H5N1 epitopes, almost all coming from Schumacher’s 2006 paper, illustrates that (assuming those are real epitopes) — I find 44 perfect epitope matches between the new H1N1 and A/Viet Nam/1194/2004(H5N1), and the vast majority of those are probably conserved between recently-circulating strains as well, but just aren’t in the database.
I agree that our results are likely to underestimate the total number of T cell epitopes. That’s why we have tried to focus on the relative degree with which T cell epitopes are conserved compared to B cell epitopes, which should be accurate even if we don’t have the total number.
do you guys support GISAID-secrecy ?
When can I expect more updates on your blog entry? I am doing research for my school paper, thanks!
My blog: American Rag Clothing
If it was possible to predict precisely what the impact of an influenza virus on humans would be, it would have a huge impact on how these diseases are treated. However, a lot of things have happened since this paper had been delivered. We now know that the predictions of a pandemic with high mortality for both the swine flue and bird flue were wrong, so scientists still have to do a lot of research to be more accurate in predicting. All in all, we as ordinary inhabitants of this planet are thankful for the time-consuming work being done by researchers.
I’m with ‘American Rag’ on this one, when can I expect updates on your blog entry? ;)
For some strange reason, all the comments I leave on this post seem to get removed… by Akismet?
Help a brother out :D