Re: Would VAX based on current SF strains work if recombined with southern seasonal H1N1?
<meta http-equiv="Content-Type" content="text/html; charset=utf-8"><meta name="ProgId" content="Word.Document"><meta name="Generator" content="Microsoft Word 10"><meta name="Originator" content="Microsoft Word 10"><link rel="File-List" href="file:///D:%5CDOCUME%7E1%5CADMINI%7E1%5CLOCALS%7E1%5CTemp%5Cmsohtml1%5C01%5Cclip_filelist.xml"><o:smarttagtype namespaceuri="urn:schemas-microsoft-com
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urple; text-decoration:underline; text-underline:single;} @page Section1 {size:612.0pt 792.0pt; margin:72.0pt 90.0pt 72.0pt 90.0pt; mso-header-margin:35.4pt; mso-footer-margin:35.4pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> </style><!--[if gte mso 10]> <style> /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman";} </style> <![endif]--> What we know ? or think we know.
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Flu is very variable and rapidly mutates. It can also acquire whole new <st1:stockticker>RNA</st1:stockticker> strands, in the case of dual infection, both between strains and serotypes (Reassortment). Dual infection also allows for the insertion of new borrowed sections of genes (Recombination) and, if Dr. Niman is right, this is a very common occurrence.
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Of the Type A serotypes various strains of H1N1 and H3N2 circulate and cause us a recurring headache as we our antiquated egg based vaccine production system has such a long lead time. The WHO guesses the following season dominant strains in February for the Northern Hemisphere and September for the Southern. They recommend one strain each for H1N1, H3N2 and Type B.
At this point I would like to admit to a crime. I know I have frequently written something along the lines ?flu mutates so rapidly that last year?s vaccine won?t protect you hence the need for an annual flu shot? which is sloppy. It does change rapidly but it is not that the variation in one particular strain has been so great that immunity from catching it last year will not protect you this year, it is more to do with a different strain being in circulation.
We also know that in 1918 an H1N1 strain emerged causing a very nasty pandemic and then became the only circulating serotype. As it adapted to us, and we learnt to cope with it, the virulence dropped and it became our seasonal flu until 1957. A new pandemic (H2N2) completely displaced H1N1 which disappeared in humans. In 1968 H2N2 Reassorted and became H3N2, another pandemic and again a complete replacement. Up until this point each serotype may have split into competing strains but they existed one at a time, however in birds there have always been many co-existing serotypes ? I don?t know why this is. In 1977 H1N1 reappears as a seasonal human flu without either causing a pandemic or displacing H3N2.
Now we have a new player H1N1(2009) a very different strain of an existing serotype. Evolutionary theory says this strain should undergo rapid evolutionary change as it is under severe selection pressure having just emerged in a new host species. While there are many randomly occurring mutations in flu?s genes that we do not know the consequences of, there are also some that we know are important and why. Some are these know to be species specific. As an example you may have seen a discussion in the ?
sequences at genbank? thread regarding the H1N1(2009) not having the E627K on the PB2 gene. The PB2 protein is made up of about 780 amino acids in a chain ? which then folds up into a blob. If you count 627 amino acids along a typical avian PB2 protein you find a Glutamic acid (E or Glu), in a human you are more likely to find a Lysine (K or <st1
lace>Lys</st1
lace>). E627K means that the more normal E has been replaced by K in this strain. The significance of this is that it lowers the temperature at which the virus is optimised to reproduce. Birds have a body temperature of about 41C, humans 37C and the crucial area for initial infection of nose and throat is about 33C. H1N1(2009) has the E (bird like) not the human K and this should make it less efficient at infecting us, however if it does pick up this change it will be strongly selected for and the new variant would rapidly supplant the old. Another important change to watch for would be if it picked up H274Y on the <st1:stockticker>NA</st1:stockticker> protein as this confers resistance to Tamiflu (along with A193T on HA which seems to be involved in fixing the H274Y). If Tamiflu is widely used ? and enormous amounts have been stockpiled ? this would provide very strong selection pressure in favour of this mutation. How likely these are to occur has a lot to do with how important Recombination is because it provides a mechanism for moving polymorphisms from seasonal H1N1 ?where they are the norm ? to H1N1(2009).
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What are the implications of all this?
It is a brave man who tries to predict what is going to happen next.
Will this H1N1 kill off the old H1N1 and H3N2? This might make vaccine selection easier in the future.
Will it die down in the Northern hemisphere and head south for the summer, what about the tropics? Not enough data either historically or on this virus to say. If the reason for seasonality is related to transmission the lack of E627K may mean this is following an unconventional route and is therefore less seasonal.
Will the heavy selection pressure cause it to rapidly drift away form any vaccine seed strains leaving them largely ineffective due to the long lead time? No idea.
What happens when it meets H5N1? I think that will have a lot to do with H5N1?s progression towards starting its own pandemic. There has already been opportunity for it to mingle with the seasonal flu strains. If a full-blown pandemic occurs there will be more chances for dual infection but as the numbers of human H5N1 cases are low then the risk probably does not go up significantly. There are some provisos H5N1 cases do not increase, there are no other species that can act as co-infection host (e.g. pigs, ferrets or even birds). The other factor for both H5N1 and seasonal flu is a whole load of new polymorphisms have been added to the co-infection gene pool possibly adding an important but previously missing ingredient.
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As always my thoughts, no one else to blame and I am a layman not an expert in this field. Discuss.
