Zoonotic H9N2 Avian Influenza Further Destabilises H1N1 Pandemic Genetics

Is the H1N1 Pandemic Influenza Reservoir Stable?

If you enjoy counting, even measuring by observation, please continue reading.

But you must realize that the iota, the jot and even the title, will be considered of value in this forthcoming exercise. Some in the science community appear to find the process of discovery by observation just too tedious.  If you are of that mindset, please direct your attention to any of the many “Science for Hire” venues where illogical, but comforting, summations are drawn from cleverly manipulated data streams.  Science sells today. But we sometimes speculate that science is becoming just another sell-out, an industry pursuing profit over knowledge?

On the other hand, if careful examination, even hard work, is part of your daily lab book, you'll find evidence in this discussion to introspect.

Leading public health officials continue even today to indicate that the pandemic virus is unchanged.  Keep that statement in mind as you read this analysis of heavy change activity in the pandemic reservoir, watching closely for the recent branching into genetic areas matching H9N2.

Also keep in mind that even single changes have demonstrated substantial importance.

Ongoing worldwide studies duplicated by independent, geographically dispersed laboratories, including the labs of those noted public health officials, indicate that a single polymorphism may produce a significant outcome within a Pandemic Influenza reservoir. Numerous accounts of important revisions are on record across a vast geography. The HA gene segment provides suitable examples for this discussion. 225G has produced a Vaccine Escape event in LvivN6, an elevated Case Fatality Rate and a substantial number of severe outcomes. Individual changes from 157 to 159 have also demonstrated “low reactor” status and registered as Vaccine Escape events.  When 230I entered the H5N1 Gharbiyah cluster in Egypt, the resultant Case Fatality Rate became 80% for that strain, a substantial increase from the accepted H5N1 CFR.

Three separate single genetic changes are well characterised in leading to various forms of Anti-Viral resistance. TamiFlu Resistance (TmX) has now dispersed widely in a pattern following the rapid spread of resistance in seasonal influenza via the same Single Nucleotide Polymorphism coding for 275Y on the Neuraminidase. Emergent and attractant H1N1 strains (Triple Reassortments again) co-circulating alongside the pandemic reservoir also carry 275Y. H5N1 inclusions increase in the pandemic reservoir with a continuous flow. The PB2 627K is confirmed as leading to increased replication speed in humans and has recently been documented in a second pandemic sequence. As we have maintained from the beginning of this pandemic, TamiFlu Resistance and 627K are foregone conclusions according to our calculations.

Our team noted an increase in Avian inclusions and recently predicted HA 230I for ΣPF11. The polymorphism was documented last week in Wisconsin (US) on a background that does not deter transmission. The geographic area has a notable increase in cross-linked activity. The individual sample, A/Wisconsin/629-D00337,  is primed for spread with 2 additional HA markers, 275A (TX, NM, CA and Sweden) and 377K (aggressively emerging). The NA carries 220K, a marker found on one cross-linked sequence from the Ukraine and across a wide US geographic pattern from December 2009 to the most recent 2010 sequences (North Carolina, New Hampshire, Wisconsin and Nebraska). The H6N1 Avian reservoir conserves 220K on the NA of 6 samples. We consider the Wisconsin0337 sample to be an excellent candidate as a universal donor of sorts due to limited polymorphisms, FlightPath intersecting location and the fact that each revision is currently an emergent change. 

A second variant of 230I has been recorded from southern China with A/Guangdong/2282.  Though the underlying 230I nucleotide coding and the overall background is different from the Wisconsin0337 sequence, Guangdong2282 remarkably carries the extremely rare 275A, a permutation found in less than ten samples within this pandemic reservoir.  Guangdong2282 displays a highly polymorphic HA with 131P, 202A, 230I, 244I and 275A.  All but 131P are rare. 202A is only found on one other human pandemic sequence, a 2010 TamiFlu Resistant case from Mexico.  Two of the four NA changes match 1918 (53I, syn315G) with potential H5N1 involvement on one other.  Convergence of numerous rare polymorphisms, including potential acquisitions from H5N1, H6N1, H9N2 and 1918, informs us that the viral reservoir is amply supplied for variation and is adamant about exercising fresh patterns.

H9N2, a "bird flu" serotype, has been recently evaluated for human pandemic potential.  By all appearances, the present H9N2 reservoir is not becoming a pandemic virus, but is very much influencing the genetic acquisition cycle of the currently circulating PF11 pandemic virus (pH1N1).  Which is worse, another species-jumping serotype entering the fray or a combinational virus with genetics from multiple pandemic potential reservoirs appending onto the current partially-adapted virus?  In either case, the Hydra Effect appears to be operating in full force.

Given this information, obvious questions begin to form. If one genetic change may potentiate variant clinical outcomes, drug resistance or Vaccine Escape, what is the potential for multiple changes producing a variant outcome? And if a single genetic change and/or multiple changes are capable of producing large changes in behaviour, should we, in turn, have a very high and accurate level of surveillance on this reservoir? And what should we do with that important information? Should our public health officials speak from a platform of candor and accuracy when carrying out the responsibilities of their trusted positions?

Let’s investigate now if the viral reservoir is, in fact, unchanged?

Approximately 86% of the Hemagglutinin positions between 186 and 244, including antigenic areas of the RBD, are on record as polymorphic. Only 8 positions in that range are stable.  Many positions rate multiple changes. The list presented today is certainly not comprehensive. For the sake of brevity, only one section is discussed from one gene segment (HA) covering just 59 amino acid positions. The extensive variation in that short range is documented in the trailing data. Tracking these revisions against various baselines has informed our studies over the past year.

The positional summary may perhaps be instructive for those who hold the belief that the pandemic reservoir is stable. This report may provide reversing guidance for those who make public statements to the effect that pandemic H1N1 is not changing. Although their multiple motivations to transmit these types of false “Feel Good” statements are somewhat discernable, the citizen requires the full story, the truth, to make informed decisions.

Those making these statements do, in fact, understand Primary Logic and Basic Science; they do know that for a vaccine to be considered widely useful, the viral reservoir must be cooperative and unchanging. They also know that this reservoir is vastly changed.  However, their jobs depend on providing a social message with a stated solution. Knowing that the vaccine is not useful against this present changed virus, they must by now realise that they have lost their stated solution.  The traditional public health strategy in these solution-less situations is obfuscation.  Re-education on basic fact, re-definition of truth, has now become the chief tenet, their tool of choice, to bridge that failure to solve. 

Science solves . . . crafting a clever press release is not an act of science.

The official repetition of the “All Clear” social messaging campaign cannot reverse the weight of the actual data. The presently circulating virus is hereby documented in this report as changed and changing. No amount of repetition invoking the “unchanged” myth, that mystical “Feel Good” chant, can conjure an environment that miraculously creates a stable viral reservoir or that alters the ongoing genetic acquisition cycle.

However, that ongoing strategy of repetition is apparently very effective in managing the perception and manipulating the belief of the unsuspecting public.  Sleight of hand is always discovered on careful observation . . . but will this reliance on myth be discovered soon enough?

Observe.

The viral reservoir backing this present H1N1 pandemic is far from stable and is actively acquiring new genetics. Current data does not indicate an immediate direction toward stability.

As is the nature with an IDRREAV, the positions reported here will not necessarily be the most important amino acid positions in the future. The reservoir will evade immunity and escape vaccine by heavily self-revising in the near future at key locations between 131 and 182 (emphasis at 155 to 177). Variation will occur with lower penetration at the head of the HA and from 272 downstream approximately 55 positions. Potential is very high that 22I will achieve density in one or more sub-clades. Expect 100N to spread and penetrate initially on sub-clades without the 22I appearances. South American polymorphisms from their fatal mid-pandemic strains of 2009 will recycle into the United States and other Northern Hemisphere nations with substantial thrust in the coming 90 days. Acceleration of the Avian based cross-linking will continue in the Western world.

Bear in mind also that a solid portion of the changes documented in this current list will become fixed even as additional donations are accumulated. The zoonotic movement from birds into human PF11 sequences is earnestly progressing in the most recent 45 days of available data. Several polymorphisms, HA and NA, from the recent 2010 Georgia hospitalization resurgence may have originated in Avian Influenza samples.

Expect continued acquisition from Avian H5N1, H6N1 and H1N1, and also watch the acceleration from one particularly new Avian donor serotype. H9N2 demonstrated a human jump in late 2008 and has very recently become fully engaged in ΣPF11 genetics with a well-defined etching on the newest cross-linked sequences. The reservoir flux will also be influenced by Swine H1N2 and H1N1 (emphasis on 3 certain emergent strains).

Is the Pandemic Influenza Reservoir Stable?

You decide . . .

186S synonymous (TCc) Russia61, BZSP53823_2009_08_01_f,
. . . . BadenWurttemberg8_2010, TexasJMS387_2009_12_08,
. . . . KO_Daegu1873_2009_12_16_TmX,
. . . . H9N2 (cCc, cac)
186P (cCT) CalifVRDL7, UkraineChernihiv857, Ankara17
186F (TtT) Ankara26
187T synonymous (ACc) Berlin164, S5, 1918, H9N2
187A (gCT) TexasJMS405_2009, TexasJMS406_2009,
. . . . H5 (gaT)
188T (AcT) swThaiCURA75_2010_01,
. . . . H6N1 dkHK202_1977, dkKOS17_2003,
. . . . H7N7 extensive including human fatality
188S synonymous (AGc) NY6943_xL
188N SC16, SC31, NY3502, ME15, CatS1187, Milan433, Kaifu4142,
. . . . Japan, Bilthoven4360903023,
. . . . swHK_NS1809_2009_12_03 (189T), swHK_NS1810_2009_12_03
. . . . S5, H5
188I Growing in US on cross-linked background (4), BZSP53823 (186S),
. . . . H1N1 (1943, 46, 51)
189V Sydney2503, Texas46172731,
. . . . Sask, H6N1 mallMaryland887_2002
189S Wisc1434
189T Extensive in US incl NY7020 (77N), on cross-linkage (4) incl NY6943_xL,
. . . . Ontario328474
. . . . swHK_NS1809_2009_12_03 (188N)
. . . . H5N1 2009, H6N1, H9N2 2008
189A synonymous (GCc), Georgia01_2010, Georgia 2010 (+5), swOR4060
190D synonymous (GAt) Nebraska02_2010, Milan326, UkraineZakarpatska830,
. . . . AfghanN09833_2009_08
. . . . 1918, H1N1 (1943, 51)
190Y SwedenMalmoe1_2010_01_01, H6N1 (tTG)
191R Chengdu18 (131P), GuangdongSWL28
192H GuangdongSWL28
192Q synonymous (CAg) RomaISS50, Nebraska01_2010, H1N1 (1943, 46)
193S synonymous (AGc) SC18, US 2010 (4), Milan294, Japan,
. . . . AfghanN10765_2009_09
. . . . H3N8 AGc aplatBelgium12827_2007,
. . . . H6N1 AGc chkTaiwan0706_2003,
. . . . H9N2 Aac dkViet2009,
. . . . H11Nx Aac dkViet2009
193G (gGT) AR08, Cal_SDINS04
. . . . H5N1 (gGg), H3N8 (gaT, gac, gaa), H11 (gac, gat)
193N (AaT) Washington72, H3N8, H6N1, H9N2, H11
193R (cGT) catItaly304678_1_2009_12_17_f, Origin Unknown
194I NC38E3, VA27, SC18, Bangladesh3009, StPete59, StPete99
194L synonymous (CTa) Japan4081, tn
. . . . H9N2 2008 (tTa), H6N1 chkTaiwan1205_2001 (CTa)
194L synonymous (CTt) TexasJMS385_2009, EgyptN11640_2009_10
. . . . H9N2 dkVietnamOIE2327_2009
196Q synonymous (CAa) Wisc (3), Moldova (3), Malaysia (2), Milan326,
. . . . Pavia (6), Ankara18, NordrheinWestfalen106, swOR4060
197T Malaysia4039
198A synonymous (GCc) KO_Seoul1870_2009_12_18_TmX
198V Malaysia5283, Malaysia9117
199N GuangdongSWL28, Milan80, Milan83, S9, S7, M7, Sask, H5 (aCT),
. . . . H1N1 (1943, 46, 51) (aCT)
199D synonymous (GAc) swine Illinois, H5, H9N2
200A synonymous (GCc) swOR4060, S5
200T (aCA) FL31, RomaniaTimis2018, Australia (6), Asia (13), 
. . . . MilanUSHR1, Bilthoven4360901004,
. . . . ShizuokaC247_2009_11_08, H5, KO_Seoul1785_2009_11_TmX,
. . . . KuwaitN12991_2009_08_24
. . . . tkDeutsche, swDeutsche,
. . . . H9N2
200S (tCA) NY1999_2010_01_18, NY0461, NY6945, NY5276,
. . . . NC57, SC46, WiscD0780, WiscS1338,  NJ11, DC_INS31,
. . . . cheetahCA30954
. . . . H11 Avian tCt ext, tCc ext including dkViet2009
201H (cAT) Wisc1140, Darwin2140,
. . . . H3N8 (cAa, cga), H7N7 (cta, ctg)
202A (GcT) MXinDRE797 2010 TmX (280A, syn321L, 324I), IA14, KY25,
. . . . HK34360, Guangdong2282 (230I, 275A),
. . . . Bilthoven4310901550 (89G), Bilthoven4360903104 (89G),
. . . . H9N2 (AcA, AcG)
202V synonymous (GTc) YAMAGATA778, YAMAGATA803, swIllinois,
. . . . H1N1 (1943, 46, 51)
204V synonymous (GTa) PA31, SHIZUOKA1573, 1918, S7
204V synonymous (GTa) TexasJMS367_2009_11_12, PA31,
. . . . AfghanN10767_2009_09, AfghanN10974_2009_09,
. . . . KuwaitN13111_2009_09_23,
. . . . Shizuoka1573, Niedersachsen34, RheinlandPfalz86,
. . . . 1918, S9, S7, M7, Sask,
. . . . H9N2 Israel 2009, H9N2 Iran 2008
205E (GaG) BadenWurttemberg8_2010, ShizuokaC247_2009_11_08
. . . . Alabama03_2010_03_01 mix,
. . . . H11 (Gat), H7N7 (Gaa), H7N7 dkVictoria1976 (GaG)
205G synonymous (GGa) Texas76C2, AfghanN09836_2009_08, Wisc (4),
. . . . tkDeutsche, swDeutsche,
. . . . S5, H3N8 (tCa), H9N2 (GCa), H6N1 (GGa), H7N7 (GGa)
206A CatS1161
206T Extensive
207S synonymous (TCg) California01_2010
208K US, UK, Canada, HK, MX, Italy (2), Australia (12), Asia (3),
. . . . BahrainN11890_2009_10, BahrainN11892_2009_10,
. . . . swOR4060
208S Australia43, Australia45, H6N1
208G NY6292
208T Norway3440
208R synonymous (AGg) TexasJMS385_2009
209D NorthDakota15
210G (gGC) Bilthoven4360903119 (225E)
210S synonymous (AGt) Bogota0466N, Malaysia9131, H9N2 (Aat)
210N Texas76C2, H1N1 (1943, 46, 51)
211K synonymous MXinDRE50617 (225G)
211R swOR4060_2009_12_31, 1918, H1N1 (1943, 46, 51)
212R swOR4060_2009_12_31, 1918, H1N1 (1943, 46, 51)
212E Vlad01 (225G), Argentina8574_41, IN21, HI30, Malaysia4039
212N ME15
212T Anadyr177_F (225G), CA07X179, CA07X181
212K synonymous (AAa) NY1999_2010_01_18, NY0461, TexasJMS404_2009,
. . . . AfghanN11216_2009_10_16
213L TX15, Iowa04_2010, H5
213F synonymous (TTt) NY3230_2010_01_25 (100N, 159K), StPete99 (225E),
. . . . Sachsen156
214E Kurgan01, Moldova (3), swOR4060_2009_12_31
214N ENG92960012, SHIZUOKA1514, Hessen48
214Q Wisc0936 (237L)
214K synonymous (AAa) CalifVRDL81 (100N, 135I), San DiegoINS101_2009, NM13,
. . . . CatS1937, ENG620, China22811, S5,
. . . . H9N2
215P synonymous (CCa) NY2372_2010_01_20 (233H), San DiegoINS101_2009,
. . . . SC33, Eng616, GuangdongyunchengSWL51, BZ_Bahia15525_42M_f (RRT),
. . . . Kuwait (4), swHK_2299_2009_10_22, swHK_NS1583_2009_10_22
215P synonymous (CCt) NY_WC37RG, MO02, Eng256
216E synonymous (GAg) BadenWurttemberg490_xL, Hamburg14_xL,
. . . . Thuringen189_xL, Thuringen227_xL, Bilthoven4360903109, 
. . . . Moldova (4), Belarus, Bosnia (3, 225G), Indiana,
. . . . tn, H9N2 (GTg)
218A synonymous (GCg) Belarus, GhanaN12987_2009_10, H9N2 (GGg), H6N1
218A synonymous (GCt) Nebraska02_2010
218E Texas77 (159S, syn173G, 275A, 377K, 454I)
218S (tCA) Georgia07_2010 mix
218T Hiroshima201 (225G), KuwaitN12991_2009_08_24
218V (GTa) GuangdongyunchengSWL51, Malaysia (2 mix wt)
218V (GTc) swIll02930, 2931, 2932, 2937 (2009-12-29, 30)
219I synonymous (ATt) Calif_SDINS35, CalifVRDL84 (35I), NY6939 (35I),
. . . . Ancona451_f, Lyon2490,
. . . . RheinlandPfalz81, Berlin210, BadenWurttemberg511,
. . . . H5 (Act), H6N1 (gct, gat)
219T (AcA) Wisc0134 (225E), Ontario315107 (225E), RomaISS223,
. . . . Korea3623_2009_11_09 (131P, 226R, 280A), swOR4060_2009_12_31
220R synonymous (AGg) Mexico476, Malaysia9451, H6N1
223V synonymous (GTa) Utah59, H1N1 (1943, 46, 51),
. . . . H6N1 mallSweden30_2005
223M CA33
224K SC18_VxX, Melbourne1_1946
224M NY5186
225D synonymous (GAc) swHK_NS1809_2009_12_03, swHK_NS1810_2009_12_03
225N BZ_SP53838, Ukraine mix wt, Victoria2125, Malaysia8860
. . . . EgyptN14648_2009_11, et al
225E Extensive on multiple backgrounds, incl Kuwait, Ghana and Egypt
225G LvivN6_VxX with syn413K, UkDnip273 (GgT mix wt),
. . . . YaroslavlIIV196_2009_12_04_f  (89G & 4 silent H5N1 changes)
. . . . NY7216 (148F),
. . . . H1N1 (1943, 46, 51), H9N2, H6N1
225G (Gga) RomaISS1897 & 1941, EgyptVacsera138,
. . . . EgyptN14644_2009_11_01, ex225E all with 300S, H6N1
225E+226R Russia (3), GermanyBY74, swMX4
226R Alabama01_2010, Trabzon01 (Turkey), GermanyMVHGW4_2009_12,
. . . . Korea3623_2009_11_09 (131P, 280A), catItaly304678_2_2009_12_17_f, et al
227A swOR4060_2009_12_31, NJ11_1976_X53A, 1918,
. . . . H1N1 (1943, 46, 51)
227V RomaISS50
227G Utah20 with wt mix
229R synonymous (AGg) swMX04 (225G, 226R), H6N1
230I Wisc0337_2009_12_15 (275A), Guangdong2282 (131P, 202A, 275A),
. . . . H1N1 (1943, 46, 51), H5 Gharbiyah 80% CFR, H9N2, H6N1
230V (gTG) TexasJMS369_2009
231D Ankara05, OSAKA2143, H9N2 2008, H6N1
231N synonymous (AAt) NY3230_2010_01_25 (100N, 159K), CalifVRDL36
231K Wisc0853, Wisc1915, Wisc2337
232Y synonymous (TAc) NY7216 (148F, 225G), TexasJMS386_2009,
. . . . Florida30, PuertoRico51,
. . . . S9, S7, M7, Sask,
. . . . H9N2, H5, H6N1
233Y synonymous (TAt) AthensINS85, Hiroshima645, H9N2 2008, H6N1
233H (cAC) NC Duke TmX cluster (5, mix, 225G, 225N), NY2372_2010_01_20,
. . . . AZ17 & Australia6, swHK_189_2010_01_07
235A CatNS7632, CalifVRDL55
235I Wisc2489
236L synonymous (CTg) Wisc0099, H9N2 (gTg)
236V Eng93120020, ENG645, H9N2, H6N1
237I Delaware02_2010, Cal_SDINS69, England (2), Russia (4), Asia (2)
237L Wisc0936 (214Q), 1918, H1N1 (1943, 46, 51),
. . . . tn, H5, H9N2, H6N1
237V synonymous (GTg) Pennsylvania31, KuwaitN13111_2009_09_23,
. . . . AfghanN10767_2009_09, AfghanN10974_2009_09,
. . . . H9N2 (TTg), M7 (CTg)
238D Kaliningrad01 (225E+226R), tn
238K (aAG) Wisc2485 (225E), DjiboutiN13142_2009_12_08, Spain (2),
. . . . OrenburgIIV13_2010_03_02_xL_f (225G), China,
. . . . swOR4060,
. . . . Iowa_1943, H5, H9N2 2008, H6N1
238E synonymous (GAa) Extensive Wisc2424, EgyptN14648_2009_11,
. . . . SC01_2010, MN01_2010,
. . . . H9N2 (aAa), H6N1 (aAa)
239P synonymous (CCt) ENG621, NY6939, swOR4060_2009_12_31
239P synonymous (CCa) Ancona508PG, Russia180, Australia60, ME01_2010, tn,
. . . . H9N2, H6N1
240G synonymous (GGg) DC_INS24, H9N2, H6N1 (GGg), S9, S7, M7, Sask
240G synonymous (GGc) Wisc0636, H9N2 (GGc)
240E (GaA) Brandenburg34
241D synonymous (GAt) CatS1943, tn
241G NH17, ENG93040048
241E China22811, H9N2 (CAa, CAg), H6N1 (GAa, GAg)
242K synonymous (AAg) swOR4060_2009_12_31
244I ThaiCU_H9, Guangdong2282 (131P, 202A, 230I, 275A), Shiga1,
. . . . Ancona02, Stockholm29,
. . . . Alabama03_2010, H1N1 (1946, 51), S9, S7, M7, Sask
244T synonymous (ACt) CatS1935, CatS2120

The truth is in the sequences.

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