paper about constraints in antigenic mutation

[gsgs]

The entire PDF is available for free at the link. Worth a skim at least... interesting theory.

The Generation of Influenza Outbreaks by a network of host immune responses against a limited set of antigenic types

Abstract:

It is commonly believed that influenza epidemics arise through the
incremental accumulation of viral mutations, culminating in a novel
antigenic type that is able to escape host immunity. Successive
epidemic strains therefore become increasingly antigenically distant
from a founding strain. Here, we present an alternative explanation
where, because of functional constraints on the defining epitopes,
the virus population is characterized by a limited set of antigenic
types, all of which may be continuously generated by mutation from
preexisting strains and other processes. Under these circumstances,
influenza outbreaks arise as a consequence of host immune selection
in a manner that is independent of the mode and tempo of viral
mutation. By contrast with existing paradigms, antigenic distance
between epidemic strains does not necessarily accumulate with time
in our model, and it is the changing profile of host population
immunity that creates the conditions for the emergence of the next
influenza strain rather than the mutational capabilities of the virus.

http://www.pnas.org/cgi/reprint/0702154104v1



I printed it, but this is hard for me to read and understand.
Takes hours.I don't like the language.

Let me just look at the abstract for now.
How big is that "limited set of antigenic types" ? approximately.
Independant of the mode and tempo of viral mutation ?
They must mean it differently than it sounds.
Does antigenic distance accumulate or not ? We should see
it in the databases.
Leter they distinguish epidemics and pandemics, assuming
pandemics happen by reassortment and epidemics by
antigenic mutations.

 

[Mamabird]

Re: paper about constraints in antigenic mutation

A particularly interesting point made in the paper is the following:

"...a phylogeny estimated from full-length HA gene
sequences will accurately represent the shared ancestry among
the sampled sequences but not necessarily their antigenic
relationships."

Therefore, while we all like to review and discuss phylogenic trees as these viruses change over time, and perhaps reflect on the ancestral spread of the bug across the country, the antigenic distance between the root of these trees and the tips of any of their branches may not be large.

It goes to the point that just because a gene segment of a viral strain may substantially change over time, does not mean that this virus is any better at causing an epidemic/pandamic or more or less virulent. It really depends on which portions of the segment are changing and whether or not such portions have pandemic importance. We just need to have a better understanding of which positions in the HA receptor binding domain are really significant for example, and how they relate to other segment changes. I suspect they may be different for the various subtypes, and may also be host dependent.

In any event, this paper appears to warrant additional study and open minded consideration.

 

[gsgs]

Re: paper about constraints in antigenic mutation

there should be a program to quickly and easily display the
antigenic distance of two HA-sequences.
And then we can build antigenic phylo-trees just as we build HA-phylo-trees.

...where is it ?

 

[aardvark]

Re: paper about constraints in antigenic mutation

There is very limited published information on H5 epitopes. Various computer programs can be used to try to predict epitopes based on genetic and amino acid sequence data, but the results are typically inconsistent and unreliable. Most influenza virus epitope mapping has been done on H3 strains, and there is very little published research correlating known H3 epitopes with specific H5 strains. In any case, the point raised in this thread is a critical one -- namely, the comparative analysis of genetic sequence data for phylogenetic purposes is all well and good, but says little to nothing about the antigenic properties of a particular isolate. For those of us interested in identifying and working with neutralizing antibodies, this is a very tangible and persistent obstacle.

 

[kent nickell]

Re: paper about constraints in antigenic mutation

This is an interesting article... Among other things it talks about the limited antigenic variability of the HA molecule such as H5 and that these changes may occur from interaction with pre-existing types rather than random mutations. They mention good cross-protection in ferrets against H5N1 if they have been previously immunized with H5N3 or mice previously immunized with H5N2. And they mention that this gives hope that the effects of a newly emergent pandemic H5N1 strain may be mitigated by vaccination even if the vaccine strain is not antigenically identical to the pandemic strain...

 

[gsgs]

Re: paper about constraints in antigenic mutation

just yesterday, I read this paper about protection against H5N1 from
normal seasonal vaccine or immunity acquired by H1N1:

http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0040059

and was wondering, whether the protection could come
from HA rather than NA ?!?


from fluwikie:

N1-protection
thanks, very interesting. I hadn't seen that paper yet.
I may have written earlier that the N1s from seasonal vaccine and H5N1
are probably too much different to induce cross-immunity.
Well, it worked pretty well in mice and 8 out of 38 humans
indicated some (low) protection against H5N1.
And it was humoral, B-cell, IG? life-long lasting protection in the mice.
This is surprising to me, since the N1s were only 80% similar,
it should be examined which epitopes could be identical.
And NA only confers reduced immunity as compared with HA, about 1/3.
And seasonal vaccine only reduces absenteism by only 1 hour per year
or such and was even recommended to be discontinued by some scientists.
However 8 from 38 is only 21% and protection was assumed to be low.
Now, what can we expect with a better matching N1 or
even with a H5 vaccine ???
And there is also the factor of possible T-cell protection.
Well, infection from 1918 first wave almost halfed the
risk to die from 2nd wave - and that was a very well matching
and a real infection, not only vaccine so it seems we shouldn't
expect too much from vaccine.
1968 pandemic was H3N2, very good match in NA with previous H2N2,
still a pandemic, although maybe less virulent due to the match.


http://www.newfluwiki2.com/showDiary.do?diaryId=241

I probably saw it
but forgot most of it. Well worth a reread.
As for your question of reduced virulence due to H1-immunity,
the authors of that paper think, that virulence-reduction could
go so far that the cases weren't even detected.
But with 8/38 and only low protection there shouldn't be too many.
They should have examined the blood of H5N1-victims
as they did examine the serum of human volunteers on page
0269 bottom right.


epitopes
larger regions of identity in the N1s of
Vietnam/1203,HK/213 and Caledonia/20 are:
106-154 (49)
174-187 (14)
190-213 (24)
290-310 (21)
314-328 (15)
352-364 (13)
370-381 (12)
394-426 (33)
436-453 (18)
456-471 (16)
none of the known epitopes from IEDB do match

protection from HA ?
wait, couldn't the protection in the paper result from
the H1 of the PR/8/34 strain ?
That's H1 vs. H5, so pretty much different, but HA is better than NA.
OK, the same calculation as above for regions of identity gives:
20-30 (11)
348-362 (15)
376-385 (10)
440-449 (10)
451-467 (17)
482-508 (27)
557-571 (15)
again no matches with the epitopes from the IEDB database.
Also, it seems that the antigenic sites are more at the beginning of HA,
I'm not sure.