2009-11-30

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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2009-11-28

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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2009-11-27

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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2009-11-26

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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2009-11-25

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)

277N
Rare to ΣPF11 with 8 sequences including Argentina7937 and Bogota0466N.
Lorestan1599
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

syn350G
Novel to ΣPF11.
Lorestan1599
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.

syn465N
NY3205 is the singular ΣPF11 instance.
Ghom1550
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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2009-11-24

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:

Ukraine
Norway
Sweden
Finland

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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2009-11-23

Hong Kong reports 225G in Fully Recovered 1 Year Old Male from July at Prince of Wales Hospital

225G is not new. 

The public perception of 225G and the media linkage to hemorrhagic pneumonia is new. 

These Hydra Effect viral backgrounds carrying 225G within ΣPF11 are, in fact, very dangerous strains for what they are doing now and, more importantly, for where they are going . . . no question exists about that risk tendency.  The only question is why hasn't the science community driven the clinical linkages to the forefront before this week?  Fatal outcomes have been documented on record since July in multiple cases from Brasil.

Prince of Wales Hospital in Hong Kong, notable for their handling of the SARS epidemic and additional limited waves in the following years, has released data today concerning the very popular polymorphism, 225G.  A one year old male child presented on July 25 and was reported to have exhibited symptoms as early as July 22.  The report indicates a discharge 3 days after admittance with recovery. 

One week of illness.  One important discussion point for those characterising 225G as essentially a high morbidity polymorphism. 

We certainly do not impeach the idea of higher morbidity.  Biasing any induction solely on singular reports like this Hong Kong case is errant logic, but the evidence does suggest that patience and some exertion may be required to accurately surmise the effector mechanisms of PF11 with and without the pairing of 206T and 225G.  Proceeding with a data basis will slowly build the well-supported pyramidal steps required to undertake a capstone solution against this genetically simple, yet clinically complex disease.

We expect to see another half dozen of the major research areas also report 225G, not because the change is new, but because they’ve had the reins lightened, the leash lengthened, on this particular revision and are now encouraged to report this popular news item. This polymorphism, 225G, is seeded around the world.

225G is not as wide or as deeply penetrating as 225E.  Our team expected and predicted this Hydra Effect with multiple, human-fit strains on diverse genetic backgrounds that would co-circulate in an emerging pandemic due to Influenza Flux during the pre-PF11Ω phases.  An enterprising question might be, “How many Hydra strains will co-circulate in each phase?” 

Numerous sub-species are spreading according to the genetic databases, including TamiFlu Resistant and epitope variant strains.  The lead US public health agency reports again this week an instance of a low reactor against the antisera.  Additionally, silent spread may be expected due to the wide geography of consistent SNP genetics.  The present stock explanation of spontaneous random "mutation" will soon be replaced with more rigourous descriptions based on patterns found in factual data.

The epidemiology of this virus did not suddenly change, just the perception.  The only thing that has changed in the last few days is that the leading public health agencies have allowed public reporting of the 225G revision.  This particular popular 225G with commensurate background of 206T has been in active circulation since May after emerging in April, vectored from both New York and Georgia, and is on record with documented fatal cases since July

Nothing new there.

Why are the offical public health agencies raising awareness only now?  While we do applaud the release of information and the present focus on matching clinicals to the sequences, we also caution against obverse speculation.  A primary topic of concern is Cytokinic Dysregulation.  Reliance on inspecific terms like "Cytokine Storm" in the media will only continue to misinform the public on a process that is far less understood than the lead investigators would like to admit.

All of which returns us to the basic categories:
  • What we do know?
  • What we don't know?
What we do know?

Now that matched clinical data is available, however limited, a potential correlation is being drawn on lung tropism. The standing bench studies, including the Palese and JKT team collaboration in 2006, detailing variant tropism based on differential HA reception at α2-3 and α2-6-linked sialic acids evaluated correlative to residue 225 lend evidence to the concept of deep lung involvement though the experiments were conducted by varying permutations of residues 190 and 225 on 1918 variants.  Whereas, we stand in 2009 with quite different genetics that require cross-validation prior to citation with applicability to PF11.

Tissue type targets are compelling studies and this particular superarray protocol may prove even more useful on PF11 than 1918 samples.  We note that though 1918 and PF11 now share 190D and 225G, that all 1918 public sequences show 206S206T continues to emerge and conserve regionally in PF11.  All 225G bearing strains after April show 206T, except the July CatNS1706 and the undated Vladivostok01.

Reproducing the glycan microarray procedure with the contemporary and ideal dataset including Brasil and Catalonia may bring a tigher focus onto today's issues.  We couldn't ask for a more balanced set of control factors with Catalonia offering sequences less than one week apart demonstrating both important pairings: 206S/225G and 206T/225G . . . a bench review made to order.

We also do know that a proper immune response, that is a timely and regulated innate immune response, is not occurring in certain of these patients. When the n +1 generations of the virus progeny begin to lyse the host cells, that failure of innate immune function to have responded early leads to an undetected and massive viral load due to the rapid replication trait of PF11. The cell detritus and the density of moving viral particles elicit a host-driven, limited “self-destruct” series of events because the multiple levels of early detection parameters have been bypassed leaving the core essentially defenseless.

What we don’t know?

Much of what we need to know today about Cytokinic Regulation is yet to be studied. 

The systems of feedback loops are extensive with individual effectors often having multiple functions, in some cases, opposing functions.  So please bear in mind that we are looking into an instantaneously self-modifying system that not only self-revises the systemic parameters, but recruits and removes players in the middle of the game and then encourages them to change sides without even changing jerseys.  And to top the difficulties, Heisenberg applies.  Tighten down the screws to look at one molecule and his best friend will no longer stand anywhere near him, though they were conversing with verve before we attempted to measure.

That disclaimer in place, you may still note important aspects of proper cell-to-cell signaling systems from the following discussion as you keep in mind that the presentation is highly compressed for educational purposes.

Though Cytokinic Dysregulation is occurring in most cases at some level of interchange, the 225G and 225E strains may potentially interfere at a more profound level with the early innate response by amplifying the PF11 conserved effect of the NS1 paired Glutamates at residues 96 & 97 that suppresses the IFN synthesis instantiation cycle by binding TRIM25, an early catalyst to RIG-I ubiquination.  Influenza bench researchers don’t know exactly where the failure is occurring or at which combination of cell-to-cell signalers in PF11 or the PF11 225G strains.  Until those identification studies are designed, undertaken and reproduced, discussion at this point is stark hypothesis based frequently on the speaker’s sheer lack of present research content mastery. Apparently, saying “I don’t know?” and then returning to the bench to design and gather a proper foundation of data is a skill rarely encouraged in our “Science for Hire” era.

Our team is unimpressed that the wider science community, with such broad analytical skills and exceptional equipment, relies on pseudo-explanation, this cloud of diversion, by invoking the “Cytokine Storm” phrase.  More than 20 well-characterised and 100 identified distinct molecular signal functions are at work in the early immune response, including cytokines, but not limited to that class of communicators.  Tagging a term for PR purposes is much simpler than tagging a molecule for tracking, but you received your instruments because you can think, not for your ability to improvise inventive talk.

Think.

Eighty billion dollars in research should arrive at a better answer with higher specificity and actionability than the blanket “Cytokine Storm” tome.  Data and procedure discover Facts.  Anything less is purely Public Relations.

Our team continues to hold an opinion that we first described in 2006 concerning Cytokinic Dysregulation and the NS1 protein of Influenza.  Succinctly, the viral ability to suspend innate immunity for up to two days post-infection, as characterised by Mount Sinai this year, prevents the early and required pro-inflammatory Cytokinic Response to viral detection.  That blunting, taken in conjunction with detailed studies around adaptive immunity, may result not only in failure to clear the virus from some patients in a timely fashion, but also in failure to produce a useful quantity and competence of memory T-cells and Ab.  The early failure to clear a rapidly replicating virus like H5N1 or PF11 results in a frank trauma to the immune system when the first generations of viral progeny lyse their host cells after being undetected and flood the tissues with virii and toxic cell detritus.  That disorderly surge of human and viral proteins en masse activates a late and cascading pro-inflammatory response that frequently fails to down-regulate properly.

This explanation is contrary to "pop" science reports that a normal and robust immune response over-generates cytokines and attacks self indiscriminately.  We hold that, by the time the virus has lysed thousands of cells and released millions of virii, that most adjacent tissue areas are "fair game" for immune response due to toxic cell detritus and viral travel.  That flooding of antigen and waste matter, widespread and instantaneous to the immune system, may further interact with some virally induced derangement of the alternative pathway of complement and generate the intensive up-regulation of signaling, pro-inflammation cascades and the resultant tissue damage described in the clinicals as DIC, DAH and ARDS.

Ergo, the findings of massive tissue damage on necropsy is the result of a failed early innate immune response, not a normal robust response.  A normal, properly up- and down-regulated robust innate response clears infection in more than 90% of various infections (viral, fungal and bacterial) and proceeds to generate Ab in short order via the adaptive arm of immunity.

When viral hosting cells properly detect intrusion, flag themselves for apoptosis (cell death) and are then assisted by cytotoxic T-cells, the injection of fragmentins via perforin "tubes" induces an endogenous apoptotic program literally cutting DNA into 200 base multimers (fragments) and eventually condensing chromatin.  That organised molecular result is far less inflammatory and far more useful for antigen identification than the disorderly outcome of a virally "exploded" cell.  Now you can see why proper genetic expression during each phase of this programmed cell death guarantees a lower pathology than the chaotic and toxic outcome of lytic host cell destruction resulting from viral NS1-induced, delayed genetic expression. 

A confluence of PF11 traits (failed early detection, multi-tropism and rapid replication) against the host-pathogen interface may force a limited "self-destruct" in the host upon eventual detection in an attempt to save the organism.  That limited "self-destruct" is not the desired outcome of a normal and robust immune response, but occurs due to a failure of the immune system to detect and respond early in the process.

Timing matters. 

Individual viral genetics and individual host immune genetic expression are primary effectors that must no longer be discounted under the clouds of some nebulous "Cytokine Storm" or Mysterious Mutation.

May we see the sequences paired with the clinicals?



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2009-11-22

TamiFlu Resistance #13 from Italy: Novel with Swine Inclusion plus 4 Rare PF11 Amendments

The thirteenth TamiFlu Resistant specimen with a publicly available sequence, A/Pavia/21, was deposited Friday at GenBank with only Segment 6 (NA).  The sample is contemporary and was taken 2009-11-16 on a nasal swab from a host with no gender or age identification in Pavia, a city of 71,000  in the Lombardy region of north central Italy.  This Neuraminidase is remarkable due to the number and range of polymorphisms though the sequence is truncated 35 bases from the end.

The NA of Pavia21 is novel at the amino acid and the nucleotide level with no peer within ΣPF11, nor in the TamiFlu Resistant subset.  The 5 polymorphisms on this sequence, if acquired via recombination, require a wide set of donors or more likely coincident recombination and adaptation events.  Inclusions are noted that previously appear on Swine H1N1 (recent and 1931), Avian H1N1, Seasonal H1N1, Avian H5N1, Avian H6N1, Avian H10N1, Avian H11N1 and on very small and diverse sets of European PF11 sequences. 

Three of the polymorphisms are silent.  No combination of any 2 of the 5 signals seems to appear on documented public sequences.  None of the signals other than 275Y appear on any previous PF11 TamiFlu-Resistant sequence.

NA Amino Acid Codings to 1 Novel Polymorphism and 4 Rare Signals
  • syn70S
  • 275Y
  • 332K
  • syn360G
  • syn398E

syn70S
encoded from C210T, AGc->AGt 
A/Catalonia/NS675 (2009-06-08) is the singular ΣPF11 peer.

332K
Novel to ΣPF11.
Progenitors may include:
H5N1 Avian Asia 2005, 2006, 2007, 2008
H6N1 Avian Europe 2005
H1N1 Swine 1977, 2002
H1N1 Seasonal 2007 (230I)
NCsw36883 (212E)
HKswNS1659
Iowa human swine worker 2005 H1N1 (IA/CEID23/2005)

syn360G
encoded from G1080A, GGg->GGa 
Rare to ΣPF11 with 4 French instances in early pandemic.
Paris2590
Paris2591 (HA:225E)
Paris2592
Paris2604
Progenitors may include:
H1N1 Human North America 2007, Middle East 2006, 2007
H1N1 Avian North America 2006, 2007, 2008
H1N1 Avian Asia 2006
H1N1 Swine North America 1931, 2003, 2004, 2005, 2006
H1N1 Swine US 1931 
H1N1 Swine Asia 1993, 2001, Europe 2001
H5N1 Avian North America 2005
H6N1 Avian North America 2007, Asia 2006
H10N1 Avian North America 2007
H11N1 Avian North America 2002

syn398E
encoded from G1194A, GAg->GAa 
Rare to ΣPF11 with 7 instances.
Italy160 (July from Veneto)
Spain with 5 sequences as recently as 2009-10-28
Canada (May)
Progenitors unknown; however, a 12 residue span in this area, including residue 398, revises for WSN33 and H5N1 Human.

On Pavia21 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

The following permutations are now represented on the thirteen 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

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 Pavia21 heavily leverages position 248 toward Aspartate (D) with 9 specimens versus 4 with Asparagine (N). No TamiFlu Resistant specimen on file displays 286G as yet.

Pavia21 is the most hypermorphic TamiFlu-Resistant PF11 strain seen since the oddities from the immuno-compromised patients in Washington.  Four changes other than H275Y is unusual in a single sequence. 

We are quite impressed with the Influenza reservoir's ability to recycle data between serotypes without reassortment.  Unless this sample were exposed to low level radiation during incubation, a series of accumulative recombinations have occurred over a very short time period or a triple co-infection enlisted all variants to build Pavia21 within a single host using an adaptation event to smooth the topping. 

The most probable explanation is an accumulation of recombinations across the hypermorphic Catalonia region then exporting data to Italy via wild birds with a single co-incident adaptation event within the eventual host.  Additionally, our team would not be at all surprised to find 225E on the HA of this patient's virus if the data is eventually published.

At any measure, another new background is now carrying TamiFlu Resistance in a central flyway for Influenza's primary transportation vector, wild birds.


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2009-11-20

225G New to Norway and Ukraine; Worldwide Evaluation Concerning Range and Co-Circulation with 225E

“… viruses with a similar mutation had been detected in several other countries, including Brazil, China, Japan, Mexico, Ukraine and the United States. "No links between the small number of patients infected with the mutated virus have been found and the mutation does not appear to spread," ...”

If the official statement in today’s Washington Post is accurate concerning the circulating geography of the Norway polymorphism associated with several fatalities, then the only probable selection is 225G. Evaluating the meta-data of available published and partially public sequences, no other SNP of interest corresponds to the range stipulated.

The positive statement indicating low transmissibility of 225G, however, is not supportable at this time by solid evidence due to lack of surveillance using the proper tools and testing protocols.  The statement is perhaps intended to assuage rather than inform.

Countries with Probable * or Confirmed 225G

While 225G is probable or confirmed with very limited depth in 12 countries, our team is more concerned about the extensive range of 225E at the moment, documented with considerable penetration in at least 21 countries, including island nations and prominent international tourism hotspots.  At any measure, the 225E circulating range is wider and deeper than 225G though the two overlap geography in at least 6 countries.  Linked SNPs of interest appear to be more involved, as 225E demonstrates several clear acquisition paths that are not apparent with 225G.

Though the clinical attributions are not presently noted as a corollary to fatal cases like 225G, the accompanying changes and multiple backgrounds onto which the Glutamate at 225 (225E) is found may eventually provide a substantially more capable viral strain and most certainly is providing co-circulating sub-species of high interest alongside the 225G.

225G does, of course, merit scrutiny due to patterning with 230I on H1N1 Seasonal 2008 and 2009 sequences. If the range of 225G continues to smoulder, an attractant effect may draw 230I due to co-infection in areas that continue to have Seasonal H1N1 strains in circulation.  The very high level of bird involvement in transporting genetics across serotypes may provide proximity, attraction and opportunity for H5N1 as a donor candidate for 230I due to verified H5N1 ranges at geographic inflection points for PF11.  The world may not yet be seeing this permutation (225G & 230I) because the shortened infection to expiration timing also provides less time for viral recombination.

This 1918 and Avian SNP travels with H1N1 and H5N1 Avian polymorphisms indicating potential wild bird transport vectors.  In a human host, the Avian modifications may find advantage at certain tissue types due to body core proximity providing basal temperature increases and may drive replication behaviour.  The human lung may be precisely the correct temperature to promote rapid replication, more efficient binding or improved cleavage capability. 

Influenza Flux will eventually find the appropriate or optimal combination of genetics to achieve stasis, but until that stasis of PF11is achieved, these sub-species will continue to be quite dangerous, demonstrating varying levels of Cytokinic Dysregulation according the host-pathogen interplay and the viral strain's capacity for temporarily suspending early catalysts to the innate immune response, including suppression of RIG-I ubiquination as the viral NS1 protein binds TRIM25 ultimately leading to reduced intra-cellular synthesis of Type I IFN.  The timing and the level of RIG-I ubiquination suppression, thus interferon synthesis blocking, may eventually be found as the primary effector of host pathology from this IDRREAV, PF11.  We feel that the evidence is well structured toward timing as an effector equal in importance to the level of inactivation / suppression. 

225G gets the virus situated in the lung tissue and NS1 blocks the innate response.  Add back the rapid replication at a multiplier over the speed of a Seasonal Influenza strain and you find an overwhelming viral load before any cell has signalled for assistance.  When millions of viral particles erupt in a concentrated area from the lysed cells, the detritus alone drives an surging cascade of inflammatory cytokines.  A slow response creates deadly risk.  Then the body must take into account the travelling circus of sub-species that waste no time returning to their hard work of re-engineering the next cell for a viral production line.

As the data on 225G cases are released, including the sequences, presentation and progression, testing protocols, sampling protocols, prognoses, sequencing lab procedures and epidemiology, a higher level of interpretation may be made concerning these polymorphisms based on facts, rather than speculation.

A present 225G sequence set of less than 25 instances within ΣPF11 and those few having little to no associated clinicals does not provide a stable foundation at this time for determination of emergent characteristics such as rate of transmissibility, probability of co-infection with wildtype or spontaneous revision from wt due to tropism upon attaining deep lung infection.

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