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By Ilene

Previous series of swine flu updates by me here.

Transmission of Fatal H1N1 D225G/N Accelerates Concerns

Ukraine takes measures to combat swine flu, closes all school - Kiev

Courtesy of Dr. Henry Niman, Recombinomics Commentary, with my comments.

Recently released H1N1 HA sequences have significantly accelerated pandemic concerns.  These sequences have either D225G, D225N, or both and produce a case fatality rate at or near 100% in many countries.... 

My comment: By the 100% fatality rate, Dr. Niman means that they are finding these changes in the tested fatal cases in some countries.  Keep in mind, these are small numbers of cases.  It does not mean that all cases with these changes prove fatal.  It might be more clear to say a large portion of the fatal cases show these changes in the infecting viruses.

[the] transmission and expansion of these fatal sequences in eastern Europe, including Russia have increased concerns, as has the "low reactor" status as determined by Mill Hill for a tested Ukraine sequence.

Some of the earliest sequences with D225G were in the United States last spring and were generally mild.  However, initial cases in the US were generally mild, which may have reflected low  viral loads infecting a naïve population...

My comment: "Low reactors" status means that the virus is not triggering the immune response expected due to changes in the structure of certain viral proteins (here, the influenza hemagglutinin proteins).  Immune responses target specific proteins and the target proteins' structure is critical to the immune response.  Not all changes in a protein will greatly reduce its immunogenicity (ability to stimulate the immune response) but certain changes will.  The change from the wild-type (common) HA protein to the HA protein with the D225G marker appears to have this adverse effect--i.e., the altered viruses will not provoke the stronger immune response generated in response to the wild-type virus and/or the swine flu vaccine.   

These observations are cause for concern, not alarm.  The changes in the H1N1 virus are natural and predictable; Dr. Niman predicted these changes would occur.  

There already was interest in position 225 for a number of reasons.  D225N  was in seasonal H3N2 and linked to the fixing [establishment of widespread] of adamantine resistance (S31N), while D225G was in 1918 and 1919 samples and linked to a change in receptor binding domain specificities which would target subsets of cells in the lung.  In addition, the polymorphism [genetic change] was jumping from one genetic background to another signaling recombination and increased rise that the polymorphisms would continue to jump to new genetic backgrounds [other viruses]

Thus, when reports from Ukraine described a high number of fatal cases associated with lung destruction and a hemorrhagic component, involvement of D225G and D225N was predicted.  However, although WHO had sent a team to Ukraine and had sent representative clinical samples to Mill Hill and CDC, WHO regional labs, they characterized the sequences changes in Ukraine as insignificant...

The association of D225G and D225N was more directly supported by sequences from the United States, Mexico, and Sweden, which identified samples with both D225G and D225N.  Thus, once again two different changes were appended onto the same genetic background at a given location, but the background varied from location to location, supporting recombination.  Moreover, in Mexico there were fatal infections with D225G and D225N.  Both were in San Luis Potosi and collected with a day of each other, supporting transmission.

My comment: Because these genetic changes have been found in multiple places in viruses with divergent genetics, it is highly unlikely that they result from sporadic and random mutations.  Dr. Niman's theory of recombination better explains the phenomenon.

However, although the above data left little doubt that the receptor binding domain (RBD) changes were transmitting and jumping from one genetic background to the other via recombination, the ECDC came out with a report at the end of the year stating that the WHO working hypothesis stated that each of these changes were independent and due to copy errors within each patient, and the RBD changes did not transmit. 

This position had no support from the data.  The changes at position 225 were only found in 1% of sequences, but were in six of six fatal cases in Ukraine.  Similarly, isolates with both changes were found in two patients at the same location at the same time in Mexico.  The WHO working hypothesis was yet another explanation genetic drift by random mutation, even though the existing data offered no support for such a claim.

My comment: It is not likely that the same mutations are occurring randomly over and over again.  It is more likely that these altered genes are circulating among the viral pools, present generally in low levels along with the more prevalent wild-type virus.  Dr. Niman disagrees with the conclusions of the WHO, and other governmental bodies that stick with the theory that the changes are random.   

The sequences released in the past few days further degrade the WHO working hypothesis as well as the linkage of random mutations to genetic drift.  Mill Hill released sequences from Ukraine and Moldova which also had both changes in the same patients. In Ukraine the sequences followed the outbreak, which spread to the east.  Samples from the Kyiv area were from lung and each samples had D225G andD225N.  One sample also had D225A.  This clustering of position 225 changes within individual samples is not easily explained by independent and random events...

Thus, the recent data demonstrates a case fatality rate at or near 100% in multiple countries, with clustering of polymorphisms and patients consistent with transmission and recombination.  Moreover, Mill Hill ran an antigenicity test on one of the Ukraine samples and found it to be a low reactor, raising concerns that changes at position 225 will become more common in the next H1N1 wave, which could have catastrophic consequences, while WHO is trying to construct a defense for its outdated random mutations as an explanation of viral evolution....


Disclosure: none