225E with Adjacent 226R on Novgorod01 May Signal Instability and Hyper-morphic Behaviour at the Receptor Binding Domain

On 2009-12-30, Russia's Vector labs deposited a novel sequence with dual adjacent HA RBD changes as part of a signal-dense batch of data from 4 additional samples.  All are compelling because each shows a polymorphism at position 225, but A/Novgorod/01/2009 is special and may herald a new phase of maturation within ΣPF11.

Special sequence and special location.  Let's talk about geographic connectedness, location, for one moment before examining the sequence.

Though we cannot be certain which Novgorod is the sample location, we will profile one of the two for connectedness in this initial evaluation.  Nizhny Novgorod, in general, was founded at the confluence of the Volga and Oka rivers and is Russia's fourth largest city with a population of 1.3 million.  The geographic and economic details discussed here are supplied by the Nizhny Novgorod entry from Wikipedia.  This city, that you may recall as "Gorky" (1932-1990), offered an ideal administrative seat for the surrounding oblast.  The Kremlin was built in Nizhny Novgorod between 1508 and 1511. 

Though the area is well-connected via multiple transport hubs including the Trans-Siberian Railway, the city was closed to foreign tourism for most of the Soviet era due to military research and development.  Today direct trains run to many Russian cities and to Beijing.  Airports serve Frankfurt, Germany 3 times per week.  The Ukraine, Belarus and Kazakhstan feature in the top four of import and of export partners for this area.  Additional to the extensive cargo transport, passenger cruise vessels operate on the Volga from this area to various Russian cities including Astrakhan where H5N1 has been active in wild birds and humans.

Information about Veliky Novgorod (Great Novgorod) is also available at Wikipedia.

With those transmission vectors, ingres and egress in mind, let's examine the sequence sampled in Novgorod.

Novgorod01 appears to be the first human sequence in this pandemic to carry the dual adjacent RBD polymorphisms of 225E with 226R.  Though we may expect at some point to see 225G paired with 226R, this 225E+226R combination from Russia is yet another point of data to use in determining randomisation versus patterning.  We personally begin to speculate and revise our opinion that the expressively variant RBD sequences recently from Singapore may perhaps be perfectly valid and not the result of lab error?

Though the analysis is far from complete on this set of lung samples from Russia, a second point of interest does come to the forefront.  Preliminary review shows that A/Abakan/02/2009 demonstrates a mixture at HA amino acid position 246 coding for an alternate 246S, a polymorphism found once in the present pandemic with Auckland04, but more importantly found in sequences of H2N2 (Asian Flu Pandemic of 1957) and H2N8 (Asiatic Flu Pandemic of 1889-1890).  Abakan sits near a very large body of water (Krasnoyarskoye) and is somewhat centered north of Mongolia and east of Kazakhstan, geographically providing a mixing area for wild birds.

Of course, we would be remiss to fail mentioning that 225G is found in 3 of the 5 Vector isolates with 225E in the other 2.

This first reported instance (Novgorod01) of adjacent Receptor Binding Site amino acids on one sequence, 225E plus 226R, may equate to a direction change in ΣPF11 signalling a more persistent hyper-morphic behaviour in the reservoir.  At any rate, the recent reports from Russia demonstrate a geographically widespread incursion of polymorphism at amino acid 225, including 225E, 225N (Orenburg) and 225G, presumably on fatal cases. 

Will we also see 225S emerge in Russia or the surrounding states? 

Is ΣPF11 learning how to become a more deadly pandemic virus from previous pandemics of differing serotypes?  Is the ecosystem of Influenza reservoirs more promiscuous than our level of surveillance (granularity and geography) has led us to believe?

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Utah demonstrates Hypermorphic Behaviour at HA 225

A/Utah/42/2009 either demonstrates a profound series of lab errors or a population of sub-species that is essentially hypermorphic at 225.   The original sample was taken from a 28F on 2009-07-24 who has been confirmed as a fatality.

rrT is the representation of the tri-nucleotide (codon) that encodes the amino acid value(s) found in the mixed peaks of the sequencing trace at amino acid position 225 in Utah42.  "R" is a nucleotide Ambiguity Code that represents a Purine.  The Utah42 HA sequence carries the Purine Ambiguity Code at two adjacent nucleotide positions. 

Adjacent mixed peaks are more than rare within PF11.  We have not witnessed the event previously in any sequence that was not suggestive of lab error . . . until now.  Significant selective pressure would have credence as a driver for this type of multiple mixed peak scenario.  A genetic acquisition event of this type may be considered more probable at an antigenic position like 225 in the Receptor Binding Domain than at non-epitope. 

The Purine group includes Adenine (A) and Guanine (G).  4 permutations are demonstrated in the sample according to the output of the sequencing, not 4 possible values, but 4 actual differing values encoding at position 225.

Permutations of RRT Detected at Amino Acid 225 for Utah42

  • GAT=D
  • GGT=G
  • AAT=N
  • AGT=S

In this single original sample notated as Utah42, sub-species are detected that code for 225G, 225N, 225S and wt 225D.

Questions occur:

  • Hypermorphic
  • Special case indicating viral genetic acquisition direction
  • Anomaly

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Spain Introduces 2 November Sequences with Cross-Segment Pairing from Fatal Cases in the Ukraine

The HA and NA cross segment pairing of silent polymorphisms noted on the four fatal 225G cases from the Ukraine has now been tracked to 29 sequences around the globe on a cumulative study showing a quantifiable density in Spain.

  • HA:syn413K encoded from A1281G, AAa->AAg *
  • NA:syn407V encoded from T1221C, GTt->GTc *
* SNP Matches the 4 fatal flashfire cases

The most recent public database entries at GenBank are from Spain and were sampled in November 2009.
  • HA and NA CatNS7362 TamiFlu Resistant
  • HA and NA CatS1827
This background appears to be fertile ground and receptive to both major polymorphisms of interest today:

  • HA 225G correlated with deep lung damage and one "low reactor" vaccine antisera challenge result
  • NA 275Y conferring TamiFlu Resistance

The depth of this background continues to increase with 2 TamiFlu Resistant strains reported in 2 days.  The persistance of this cross segment correlation may signal a viral genetic acquisition response to widespread TamiFlu usage.  These silent polymorphisms are suggestive of an intermediate stage that is moving in the direction of antiviral resistance and continued Receptor Binding Domain revisions due to antiviral blanketing.

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225E in 5 of 9 HA from Spain during 4 Day Span in Mid-November

GenBank deposits on 2009-12-02 from Spain that were sampled from 2009-11-12 to 2009-11-16 demonstrate a significant percentage of 225E225E is now conserved in Spain.

5 of 9 have 225E

0 of 9 elicited 225G

Japan also adds one 225E sequence with NagasakiHA52 sampled on 2009-10-09.

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TamiFlu Resistant Sequence #14 from Spain in Late November Carries Cross Segment Pair of Markers from the Ukraine

HA and NA CatNS7362 is the most recent official entry into the TamiFlu Resistant list of 14 sequences.  This Spanish sequence sampled 2009-11-26 from a male in Catalonia also becomes the first recorded TamiFlu Resistant strain to participate in the cross segment pairing of HA syn413K and NA syn407V.

The NA of CatNS7362 is novel at the nucleotide level with no peer within ΣPF11.  The NA is an exact nucleotide match to A/Singapore/ON1156 (2009-07-14) and A/Catalonia/S1702 (2009-11-02) except for the SNP encoding the antiviral resistance.  The 7 polymorphisms found on the HA and the NA of this sample indicate a similar hyper-morphic behaviour that we saw with the Italian TamiFlu Resistant sequence, Pavia21.  Three of the polymorphisms are silent.  Inclusions are noted that previously appear on other sequences from Spain, Swine H1N1, Swine H1N2, Avian H1N1, Human H5N1, Avian H5N1 and Avian H6N1

NA Amino Acid Codings to 3 Rare Polymorphisms
  • syn149I
  • 275Y
  • syn407V
encoded from T447C, ATt->ATc 
Rare to ΣPF11 with 2 instances from Spain and 1 from Singapore.

encoded from T1221C, GTt->GTc 
Rare to ΣPF11 with 37 instances, yet common to Spain with 15 and the Ukraine with 9.
Progenitors may include:
H5N1 Human
H5N1 Avian

On CatNS7362 TamiFlu Resistance is indicated in typical PF11 fashion via a Single Nucleotide Polymorphism coding for 275Y on the Neuraminidase. The sequence displays the following NA Quadruple Combination:

106I, 248D, 275Y, 286S

106I is implied for CatNS7362 based on previous patterns as that portion of the sequence is truncated.

The following permutations are now represented on the fourteen PF11 anti-viral resistant sequences:

106V, 248N, 275Y, 286S = WA28, WA29, TX47
106I, 248N, 275Y, 286S = Osaka180
106I, 248D, 275Y, 286S = HK2369, Yamaguchi22, Denmark528, Hunan SWL3, Singapore57, Tokushima2, Iwate3, Quebec147365, Pavia21, CatNS7362

Until the 2009-08-21 deposit of the two Washington sequences, all 275Y TamiFlu-Resistant specimens on PF11 backgrounds were paired with 106I.  We continue to see only 3 of the 13 with 106V.  The addition of CatNS7362 heavily leverages position 248 toward Aspartate (D) with 10 specimens versus 4 with Asparagine (N). No TamiFlu Resistant specimen on file displays 286G as yet.

HA Amino Acid Codings to 2 Novel and 2 Rare Polymorphisms
  • 165N
  • 235A
  • 397D
  • syn413K
CatS1687 is the singular instance within ΣPF11.
Progenitors may include:
H1N1 Swine
H1N2 Swine
H6N1 Avian

Novel to ΣPF11.
Progenitors may include:
H1N2 Swine
H6N1 Avian
  Chukkar (first base SNP required)

Novel to ΣPF11.
Progenitors may include:
H6N1 Avian

encoded from A1281G, AAa->AAg 
Rare to ΣPF11 with 74 instances, yet common to Spain (12), the Ukraine (4), Japan (28) and Norway (9).
Progenitors may include:
H1N1 Avian
  red-winged tinamou/Argentina/MP1/2008

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Sweden Deposits 225G with Alternate Coding Matching and Pre-dating Norway3206-3 with NA Marker Homology

Sweden deposited a sequence today from mid summer that carries indicators worthy of study.

Matches include the rare alternate coding for 225G found in the Norway3206-3 fatality sampled 6 weeks after the Swedish case and the NA syn291V on that same Norwegian sample.  Six weeks appear to be enough time for these changes to travel across borders.  The HA sequences are identical, except for the 140S on Norway3206-3.

The two Scandinavian NA segments show a shared polymorphism at syn291V, a change that is found in 103 GenBank sequences including TamiFlu Resistant HK2369, Almati01, Tomsk01, Poland and with deep penetration through Italy and Catalonia.  The G873A coding for the syn291V is also present in CatNS2001 and CatNS2008.  The NA segment of Norway3206-3 is identical to the Swedish NA.

Only this profiled private Swedish sequence from mid summer, CatNS2001 and CatNS2008 from early August and Norway3206-3 from September carry this variant Glycine coding at amino acid 225 that is seen as T717A, GGt->GGa.  Neither of the cross segment pair, HA syn413K or NA syn407V, appears in the recent Scandinavian samples. 

The Swedish sequence is a nucleotide match with Norway2674 and Norway2690 except for the RBD polymorphism 225E on the Norwegian sequences.  Dialing back the resolution by 1 nucleotide, we find that the Swedish sequence is a 1724/1726 match with 2 more Norway 225E cases, Norway3059 and Norway4023.  Delta is indicated after link to sequence.

2009-07-27  Norway2674  Δ 225E
2009-07-29  Norway2690  Δ 225E
2009-08-11  Norway3059  Δ 225E + 1 nucleotide
2009-10-14  Norway4023  Δ 225E + 1 nucleotide

If we return to the tighter resolution again, we find that the Swedish sequence is a exact nucleotide match except for the two nucleotides coding for 225D on 6 additional sequences from Sweden (1),  Germany (1) and Russia (4).  Delta is indicated after link to sequence.

2009-__-__ Bayern66         Δ 225D
2009-05-21 MoscowIIV01    Δ 225D
2009-05-30 Stockholm33    Δ 225D Traveler from US
2009-06-09 MoscowIIV04    Δ 225D
2009-06-20 MoscowIIV05    Δ 225D
2009-09-22 Russia01          Δ 225D

This particular background is far from isolated.  The homology between these 225D, 225E and 225G sequences raises a very basic question. 

Does some mechanism in the protocol from sample to sequence potentially vary the outcome or block 225G materialisation on the resultant sequence?  We know that lungs are being destroyed across extensive geography, yet few 225G sequences are being produced?  Backing studies lead us to believe that 225G bearing samples will grow well in a receptor environment rich in α2-3-linked sialic acid

MDCK cell lines specialised to overexpress α2-6-linked sialic acid at the expense of α2-3-linkedSA are being employed in Neuraminadase Inhibitor sensitivity testing, demonstrating that these canine cell lines are adaptable in linkedSA expression.  Exactly how sensitive is the culture environment that is being used as a predecessor to sequencing?  How consistent are the protocols and materials between labs?

Does a possibility exist that current MDCK cell lines being used are underexpressing α2-3-linked sialic acid in a manner consistent with the low numbers of resultant 225G sequences that have been published?  Are samples that are originating with 225G not growing well due to a limited ratio of matched receptors?  We specifically enquire here on the cell lines, but obviously all aspects of the growth environment must be inspected for inhibitors to 225G materialisation if the presenting sample sequences are to be accurately elicited. 

Similar rare codings across 4 geographically dispersed sequences for Glycine at HA residue 225 and an NA syn291V occurring in temporal sequence from Sweden in late summer, to Catalonia in early August, and onward to Norway on September 1st beg for any explanation other than "spontaneous" mutation within a pandemic reservoir, ΣPF11, that is actively demonstrating an ability to share data. 

Is 225G transmitting?  Is 225G transmitting in 2 variant forms?  Is 225G now confirmed as Hydra?

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NA 106V and 248D Pairing Reaches US and Russia

A/Chita/01, sampled from human lung in Russia with no identifying host gender or age, becomes the 5th distinct sequence on file for the previously discussed 4th permutation of the NA Dual Combination at amino acid positions 106 and 248.  No HA was published for this sample, but the sample location points to fatality and 225G is suspect.

This PF11 sequence demonstrates 106V and 248D and is distinct from the four previous isolates with this characteristic pair:

2009-04 A/Toronto/3184
2009-04 A/Auckland/4
2009-07 A/Toronto/R8564
2009-05 A/Wisconsin/629-D00487

Chita01 is most similar (1417/1419) to Toronto3184, yet all 5 sequences with this pairing are distinct.  2 silent polymorphisms are found on Chita01, coding for syn257R and syn315G.

The NA Dual Combination of 106V and 248D is now found 5 times within ΣPF11:

2009-04 Canada and New Zealand
2009-05 Wisconsin
2009-07 Canada
2009-xx Russia

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Norway Provides Distinct 225G Coding from Lung in September Male Fatality

 A/Norway/3206-3 HA and NA, sampled on 2009-09-01 from the post-mortem lung of a male fatality imports a new 225G to Norway. 

Only CatNS2001 and CatNS2008 from early August carry this variant Glycine coding at amino acid 225 that is seen as T717A, GGt->GGa.  Neither of the cross segment pair, HA syn413K or NA syn407V, appears in this sample.  Norway3206 carries a second HA polymorphism at 140S, a change found only 3 times within the reservoir, but found elsewhere in 1918 specimens, H5N1 Avian, Seasonal 2007, 2008, 2009 and the red-winged tinamou from 2008.

The Norway NA shows one residue of interest at syn291V, a change that is found in 102 sequences including TamiFlu Resistant HK2369, Almati01, Tomsk01, Poland and with deep penetration through Italy and Catalonia.

Two different codings for Glycine at residue 225 at this early stage of the pandemic demonstrates an ability within ΣPF11 for an individual strain to adapt quickly.

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Ukraine and Spain Cross-Linked HA and NA Silent Changes Circle the Globe

Cross-Linked HA and NA Polymorphisms Correlated with Fatal 225G Cases in the Ukraine and Russia
  • HA:syn413K encoded from A1281G, AAa->AAg
  • NA:syn407V encoded from T1221C, GTt->GTc
 PF11 Sequences Demonstrating Cross Segment Linkage
  • Ukraine LvivN2
  • Ukraine LvivN6
  • Ukraine TernopilN10
  • Ukraine TernopilN11
  • HA and NA Norway2924 with mixture of 225D and 225G *
  • HA and NA Norway3364-2
  • HA and NA CatNS7362 TamiFlu Resistant
  • HA and NA CatS1096
  • HA and NA CatS1162
  • HA and NA CatS1179
  • HA and NA CatS1181
  • HA and NA CatS1267
  • HA and NA CatS1268
  • HA and NA CatS1402
  • HA and NA CatS1501
  • HA and NA CatS1687
  • HA and NA CatS1748
  • HA and NA CatS1751
  • HA and NA CatS1761
  • HA and NA CatS1827
  • HA and NA Guangdong02
  • HA and NA Guangdong05
  • HA and NA SingaporeON1156
  • HA and NA Stockholm31
  • HA and NA Russia14 *
  • HA and NA Russia19 *
  • HA and NA Russia74 *
  • HA and NA Russia165 *
  • HA and NA Russia178 *
  • HA and NA Russia190 *
  • HA and NA Russia191 *
  • HA and NA Omsk02 
  • HA and NA Salekhard01 with 225G, presumptive Fatal outcome *
  • HA and NA NY3702
  • HA and NA NY3715
  • HA and NA NY3828
  • HA and NA RhodeIsland08
  • HA and NA Texas42102708 *
  • HA and NA Texas45072128 *
  • HA and NA Texas45122886 *
  • US Private Sequence TamiFlu Resistant  
41 sequences have encircled the globe as of 2009-12-31 * with high fidelity carrying a cross-segment paired set of background markers matching and potentially contributing to the Ukraine fatal cases.  Two now additionally demonstrate the TamiFlu Resistant 275Y on NA, one from Spain in late November 2009 and one from the US with details stored in a private database. 

Areas covered include Texas (3), the Northeastern United States (4), China (2), Singapore, the Ukraine (4), Russia (9), Norway (2), Sweden and extensive penetration in Spain (one-third of the dual matches, 14 sequences).  This particular background pattern may precurse 225G and mixtures of 225D / 225G.  If LvivN6 is officially confirmed as a vaccine escape event, these cross-segment pairs may be surveilled as potential future effectors of vaccine efficacy failure.

Publication of the remaining Neuraminidase segments for the 33 Norwegian and Japanese specimens bearing HA syn413K would allow a more precise review.  Although 9 of the recent sequences from Norway carry syn413K, none of the 225E strains from Norway have the syn413K.  The patterns are highly suggestive that all of the Norse 225G strains do.  The 2009-12-29 release of the NA for Norway2924 confirmed that previous suggestion.

Every Biological Organism Starts Somewhere 

Though the exact origin is not always single point, nor always precisely definable as to geography and timing, the term, "emergence", is generally employed because scientific enquiry requires determination of those "starts", of the ultimate origin.  The viral reservoirs are simpler to track than most complex organisms, so we do.  A wise sage from China once said that a journey of a thousand miles begins with a single step.  Likewise, the emergence of a new pandemic strain begins with a single strain.  We remind the reader that  ΣPF11 swept the globe in less than 6 weeks.

Even one change in one sample during this stage of zoonotic flux where we stand today in ΣPF11 holds the potential to increase in range and penetration.  That potential should guide a portion of our studies toward the outliers, such as the emerging sub-clades or even the single, novel strain with key changes.  A paired set of cross-segment polymorphisms patterned into a sub-clade including fatal 225G cases and shared across 41 sequences encircling the globe considerably increases the importance of this proposed framework that validates emergence of "minor" sub-clades.

Dogma rarely delivers.  Science may only measure what science will see.  Eyes closed to an uncomfortable pattern or a face turned away from a malanthropic misfit does not dematerialise that misfit or render that pattern any less real.  Though ignoring the outlier is sometimes necessary to gain an average understanding (like a phylogenetic tree), monitoring those outliers for functional differentiation may predict a future state.  Science and ignorance should be mutually exclusive

Measure the data.  Balance the facts.  Build the logic framework around those facts, even when they no longer agree with your present foundation.

Mankind is depending on you.

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Vaccine Failure Event Confirmed in New York Times by UK national medical laboratory

The coordinated work of several individuals at FluTrackers.com concerning the newspaper report being referenced in this article adds a new layer of concern to the story.  Though several avenues have been attempted to confirm exact details of this report published in the New York Times, no identification has occurred of the laboratory or lab representative making the comment.  Attribution on an item of this import is essential.  The quote parallels the testing results and is perfectly admirable as to candor. 

Though exceptional effort has been expended in learning the source and to no avail as yet, we do have a reasonable justification in thinking that the information was not invented by the New York Times author.  The quote remains in the online version of the article as of 2009-12-01-21:00Z.

At any rate, the details of the following interpretation hold, as no substantive data has been changed.  We have removed the lab name from the title of this report and the body because no one there has claimed responsibility for the comment.  The "low reactor" status persists and that challenge would have logically been against antisera from ferrets raised against the vaccine candidate strain.  That's the purpose of the test, to determine level of cross-reactivity or, more simply, vaccine match.  We are appreciative of the transparent reporting of this early vaccine escape event.

Our original interpretation follows with minor edits for clarity and with removal of the lab name until additional attribution occurs from the New York Times or other new source.


Updates reflected on the characterisation sheets from the Ukraine indicate antigenic testing against one of the samples.  Of note was the LvivN6 sample from a fatal case with 225G being reported as exhibiting clear vaccine escape signals with a low reactor status update on the antigenicity profile.  That type of information is important news to the world.  We would have expected a news conference or a press release prior to the status update as confirmation of the database detail, but no public health notice of that type has occurred. 

Today, Donald McNeil of the New York Times is reporting that Britain's national medical laboratory has corroborated the status update of "low reactor" as follows:

"One isolate from Ukraine with the mutation had changed so that swine flu vaccine probably would not protect against it well, Britain’s national medical laboratory reported Friday."

Dr. Henry Niman of Recombinomics is concerned that differing opinions have been offered to the public concerning the importance of the D225G polymorphism.  We share that concern about the lack of consistent reporting.  Moreover, a clear finding is required on antigenicity of the remaining Ukraine sequences with a focus on the remaining three 225G samples.  The sequence of interest, LvivN6, is among the least variant of the 4 fatal cases at the HA amino acid level and shares HA amino acid homology with LvivN2 and TernopilN11.

LvivN6 HA, the "low reactor", is very lightly variant with 1 silent polymorphism common to 3 other Ukraine sequences and 1 amino acid revision, 225G, common to 3 other Ukraine sequences.  LvivN2 HA has accumulated 3 silent polymorphisms, 2 that are not found on other Ukraine sequences, and 1 amino acid revision.  TernopilN10 HA is highly variant with 2 silent polymorphisms and 3 amino acid revisions, 2 that are not found on other Ukraine sequences.  TernopilN11 HA is variant with 3 silent polymorphisms, 1 that is not found on other Ukraine sequences, and 1 amino acid revision.  At the NA, the LvivN6 single SNP impeaches the Neuraminidase segment as an antigen differentiator for this group of sequences due to homology with the remaining three 225G samples. 

In this pandemic era that is unprecedented in most of our lives, science has tools, protocols and reference databases that were not available to the researchers in 1918.   ΣPF11 in these early stages is allowing science a real-time, practically freeze-frame, insight into viral genetic acquisition tracked alongside clinical and bench study data.  The research opportunities to change the direction of this pandemic hang low on the tree, ripe for picking. 

Though we know that outcomes of antisera challenge are not perfectly predictable, a reliable database exists of values from antigenic characterisations including the methods used to attain those values from past seasons of Influenza.  A standing genetic sequence catalog is available from a very large set of individual samples in numerous sub-clades from this reservoir.  While we know that independent labs have reproduced experiments detailing that genetics alone do not entirely correlate with antigen characterisation via antisera cross-reactivity, we also know that aggressively measuring and cross-referencing each minutia in this unprecedented event may crystallise new thinking and build stronger frameworks.

Additional detail such as the list of tested samples and the testing protocols employed will provide necessary background for evaluation.  Were Hemagglutinin (HI) and Neuraminidase (NI) Inhibition studies conducted?  Were both HI and NI observed outcomes ranked as "low reactor" status?  Will the results be reported separately within a reasonable timeframe?  Transparency on the maximum values for "low reactor" ranking, generally between a four-fold to an eight-fold decrease in titers on Hemagglutinin or Neuraminidase Inhibition, will allow a comparison of this vaccine escape event to database entries from past seasons' variation captured for vaccine candidate selection.  Discussion of the actual observed titers that did inhibit, if at all, would perfectly surface the issue.

We would expect a similar finding of "low reactor" on 4 of these sequences if the least variant at NA and HA, LvivN6, showed reduced reaction.  If NIMR has, in fact, officially confirmed this vaccine escape event via the New York Times, their lab books may have notations for 3 other 225G Ukraine sequences in the antisera reactivity panels.

Antigenic diversity, whether due to viral response to human immunity, anti-viral selection pressure or vaccine pressure, is a certainty.  Additional reporting of data that may be on hand would easily clear this issue as to the exact nature of the diversity in circulation today within ΣPF11.

Twenty-six sequences are on record from several temporal and geographic points in the pandemic carrying paired HA and NA cross-segment linkages to these Ukraine fatal cases, including the item, LvivN6, reported and validated as a "low reactor" to the current pandemic vaccine.  Those sequences are seeded throughout major population areas of the world.

Forthright communications on these vaccine escape events is crucial to earning public trust around this ongoing health issue.

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France Follows Suit on Continent with 225G in Fatalities, Including a 225G Case with TamiFlu Resistance

France announces the presence of 225G associated with fatalities and indicates that one of the 225G strains is also TamiFlu Resistant

Less than one week after the first official announcement from Norway, western Europe has a growing coverage of confirmed and probable 225G cases.  As we mentioned on the 23rd of November, many countries will now open their databases concerning this RBD change.  Those databases will confirm not that 225G is spreading, but that 225G was already widely dispersed and is spreading faster than we had previously been led to believe.

A glaring signal is apparent concerning the public's right to information that may protect their health.  Release of important policy-making and family protection information has been blocked as the taxpayer-funded research centers and public health officials continue to withhold even the sparse data from the limited surveillance that has been conducted.

The leading world health agency reports a rise in TamiFlu Resistant sequences to 75 cases, geographically dispersed, while continuing to read the script of "spontaneous mutation, not transmitting" over the increasing set of clustered cases.  All TamiFlu Resistant cases from PF11 have had the same Single Nucleotide Polymorphism coding for 275Y in the Neuraminidase and this French case is expected to follow suit.  Not random and not spontaneous.  We have tracked the details of the 13 available public anti-viral resistant sequences for variation.

225G is now being reported widely as countries increase transparency concerning the antigenic diversity and transmissibility of strains carrying this important Receptor Binding Domain change that has, on lab examination of the 1918 strains, conferred dual receptor specificity for tissue in the upper respiratory system and the deep lung tissue.

Countries with Probable * or Confirmed 225G
This drug resistant strain with antigenic diversity in France, an international travel hub, is one Hydra head that merits deep scrutiny. 

Several questions come to mind concerning the French report considering the paired cross-segment changes on the Norway3364 sample from September, HA syn413K and NA syn407V.  At the instant that research centers are identifying cross-segment linkages, we are now presented with a second set of pairs crossing the same two segments, HA 225G and NA 275Y.

Are the French cases contemporary?  What are the clinical details?   Note also that France published one of the first 225E sequences with Paris2591 from a 23M on 2009-05-01.

225G and 225E strains are co-circulating around the world, in one French case with TamiFlu Resistance, killing hosts quickly by destroying the lungs.  Of deepest interest is the exhibition of clear vaccine escape signals if the low reactor status update of one recent Ukraine 225G, LvivN6, is validated.  Antigenic diversity, whether due to viral response to human immunity, anti-viral selection pressure or vaccine pressure, is a certainty.

ΣPF11 is now officially Hydra.

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The Ukraine, Norway and Spain Share Paired HA and NA Changes

A/Norway/3364-2, sampled 2009-09-08 on a tracheal swab from an adult female, is a very special individual in the team of 9 Norwegian sequences that each demonstrate HA syn413K, an Avian H1N1 SNP found in the most recent 225G sequences from the widely reported fatal cases in the ongoing flashfire that has now over 1.7 million cases with 404 deaths and more than 100,000 hospitalisations.  The synonymous 413K is traveling worldwide, potentially laying landing strips for 225G

What would you think if I told you that syn413K was traveling with another silent companion . . . who lives on a different gene segment?  Norway3364 is the only recent sequence from that country with a published Neuraminidase segment.  And this time, they gave us a very useful one.  Cross segment linking is occurring regularly in ΣPF11 and this sequence provides an opportunity to examine one pair. 

Norway3364 carries HA syn413K and NA syn407V.   This particular version of 407V is widespread in H5N1 and the cross-segment pair is also noted under the virulent serotype.

Cross-Linked HA and NA from Norway to the Ukraine
  • HA:syn413K encoded from A1281G, AAa->AAg *
  • NA:syn407V encoded from T1221C, GTt->GTc *
* SNP Matches the 4 fatal flashfire cases

A limited inspection demonstrates a wide range for this paired set of travelers.  The following list is not comprehensive, but is a representative geographic sample of other sequences that carry the pair.  Any attempt at a comprehensive study will only result in disappointment as you'll find that many sequences with syn413K have no NA to evaluate and many sequences with syn407V have no related HA.  Patterns do not precisely define themselves without data, but the range is impressive even with the limited dataset.

Norway, the Ukraine, Sweden, Spain, Russia, the United States and Singapore are identified in this sequence range.

  • LvivN2
  • LvivN6
  • TernopilN10
  • TernopilN11
  • Norway3364
  • CatS1096
  • CatS1162
  • CatS1181
  • CatS1268
  • CatS1402
  • CatS1501
  • CatS1687
  • CatS1748
  • CatS1751
  • CatS1761
  • SingaporeON1156
  • Stockholm31
  • Omsk02
  • NY3702
  • NY3715
  • NY3828
  • RhodeIsland08
Very few of these sequences share 100% homology, meaning that most of the backgrounds are diverse on which these paired, cross-segment changes, HA syn413K and NA syn407V, are overlaid.  Those overlays onto differing genetic templates each require a precise sub-segment data acquisition at the Hemagglutinin paired with a second precise sub-segment acquisition at the Neuraminidase. 

We have provided 22 examples so that random mutation and / or spontaneous mutation proponents may think before answering the probabilities of these outcomes under those outdated frameworks. 

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Iran Provides Novel HA sequences with South American Markers

The first PF11 sequences from Iran were published at GenBank on 2009-10-13.  Today those three NA segments were joined by the 3 HA segments.  The samples were taken between 2009-07-27 and 2009-07-30.  The Hemagglutinins show 3 different faces and two are unique into ΣPF11 due to silent polymorphisms.
HA Amino Acid Codings to 1 Novel Polymorphism, 1 Singular Signal and 1 Rare Signal

  •  277N
  •  350G (synonymous A1092G)
  •  465N (synonymous C1437T)

Rare to ΣPF11 with 8 sequences including Argentina7937 and Bogota0466N.
Progenitors may include:
Avian H1N1 including red-winged tinamou/Argentina/MP1/2008 H1N1
     with HA 225G, 277N, 286H, 298V / NA 106I, 248N, 286G
Swine H1N1
Avian H6N1
Human H5N1
Avian H5N1

Novel to ΣPF11.
Progenitors may include:
A/Thailand/271/2005 (H1N1) with NA 45K & HA 225G, 261N, 263D, 264P and 270T, also manages to carry the silent NA:A1038G coding for a synonymous Valine at residue 346 on the Neuramindase (346V) of Ghom1550.  This silent change is found across many serotypes and primarily spans Avian and Swine species.  Influenza Flux may be at work.

NY3205 is the singular ΣPF11 instance.
Progenitors may include:
Swine H1N1, including NCsw36883
Swine H1N2
H1N1 2005 Human Iowa swine worker (IA/CEID23/2005)

Numerous donations are seen from similar strains into both HA and NA of these Iranian sequences.  Recycling of genetic acquisitions is suggestive of patterned recombination.

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Norway Sequence with 225G Mixture also Carries syn413K Silent Marker found on the 4 fatal flashfire cases

A/Norway/2924, sampled on 2009-08-10 from a 40F, and reported yesterday to carry a mixture of wt 225D and 225G with the 206T pairing also demonstrates syn413K, an Avian H1N1 SNP found in the most recent 225G sequences from the widely reported fatal cases in the ongoing flashfire that is now nearing 1.7 million cases with 397 deaths and 99,661 hospitalisations.

Norway2924 HA
  • 225G *
  • syn413K encoded from A1281G, AAa->AAg *
  • syn464G encoded from A1434G, GGa->GGg
* SNP Matches the 4 fatal flashfire cases

The silent 413K and 464G are both found on a very special bird from Argentina

ReAssortment is downrated as a 225G transfer mechanism from Norway to the flashfire due to Norway2924 having an additional unmatched silent SNP, A1434G, GGa->GGg, coding for a synonymous Glycine at 464 (syn464G).  This SNP is novel to ΣPF11 and is found widely on Swine H1N1 and H1N2, including most recently on A/swine/Hong Kong/294/2009 (H1N2), and Avian H1N1 in the red-winged tinamou/Argentina/MP1/2008 (HA 225G, 277N, 286H, 298V / NA 106I, 248N, 286G).

225G on 5 sequences (Norway2924 and 4 flashfire specimens) all sharing a rare syn413K on 5 distinctly different backgrounds closes the door on spontaneous and / or random mutation in this dataset.

With the two pillars of genetic acquisition impeached, deduction leads us to Dr. Niman's Recombination theory if we seek an explanation based on data.

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Norway: 1 Mixture of 225D/225G, 5 of 25 have 225E; Spain: 7 of 19 have 225E

225E is becoming fixed.

GenBank Deposits 2009-11-23

Norway: 5 of 25 have 225E
Spain   : 7 of 19 have 225E

A/Norway/2924, sampled on 2009-08-10 from a 40F, is a mixture of wt 225D and 225G after canine cell passage.  The sample also carries the prevalent 206T.

The data collection must begin in earnest after this development.  The first data quality improvement might be to release the sample site and the patient outcome please.

We have no evidence that the cases discussed here are related to the three previously reported instances in Norway of 1 serious illness and 2 fatalities.  Sweden is also today reporting 2 cases of 225G that were serious and treated via ECMO during the summer.  No outcomes noted as yet on Sweden.  Finland reports at midday 1 case of 225G in July.  The list of recent reports extends with the counts actively growing:


Our team expects widespread reporting of 225G in the next few days as the revision is most certainly seeded throughout the world and is probable in any European country with a suitable sample size that is investigating.

The most noticable empty slot should be posted as soon as the pizza finishes on the west side of the Adriatic oven.

Islands like Cyprus, Mauritius, Brac (Croatia), Sicily (Italy), Sardinia (Italy), Majorca (Spain), Ibiza (Spain), Corsica (France), Crete (Greece) and Rhodes (Greece) are attractive examination sites in descending order of potential.  Our team would be amazed if reasonable sampling had occurred on these islands and more than 3 of the 10 failed to demonstrate 225G.  A 50% probability exists in our framework (with a reasonable sample population) that all 10 islands should display at least one case of 225G.

Slovakia, Germany, Iceland, Latvia, Lithuania, Moldova and Bosnia from Europe are candidate areas in order of descending potential. 

Africa displays somewhat equal potential at South Africa, Cameroon and Ghana.

The matter of 225G range and transmissibility may best be settled with full sequence publication.

This post will be updated as corroborationg data is made available.

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