Emergent H7N9 Homology in Fatal Human pH1N1 Case Near Caspian Sea

Sequences discussed in this analysis are variously stored publicly at GenBank and at GISAID. We gratefully acknowledge the authors, originating and submitting laboratories of the sequences from GenBank and from GISAID’s EpiFlu™ Database on which this research is based. A GISAID-generated list is detailed in a linked Excel workbook for completeness in citation.

Publish Date : 2013-09-26
Last Update : 2013-11-04

Geographic Distribution

On 2013-09-25, the Rospotrebnadzor of Moscow, Russia released a set of human pH1N1 sequences without age or gender at GISAID, including 6 Fatal cases. The Neuraminidase segments were not released.

One HA segment sampled in late January 2013 from Astrakhan [map], near the Caspian Sea, [EPI471830] strongly suggests Emergent H7N9 involvement.   This Astrakhan H7N9-related viral Hemagglutinin displays a standard Emergent H7N9 amino at 179V on a pH1N1 Clade2:188T background.  The HA 179V is Novel to pH1N1 after more than 4 years of pH1N1 circulation in humans.  HA 89G, found in the H7N9 reservoir, is co-located on this same pH1N1 sequence.  Polymorphisms at two antigenic amino positions practically adjacent, HA 129Q and HA 131L, provide grist for the Host-Transition mill.

Contemporary sequences from Spain carry homology as well as an unusual change adjacent to these odd aa129 and aa131 positions from the Russian Federation:

• HA 477M SpainCatalonia5925S_29F_2013_02_05
• HA 132S  SpainMurcia164_80F_2013_01_30_s

Furthermore, SpainMurcia164_80F_2013_01_30_s, an In-Patient case, is on a cross-clade background (HA 188T & 189T) and features a polymorphism at aa89 (HA 89N)

HA 219T, also seen in the H7N9 reservoir, is demonstrated in Kazan [map], [EPI471827].

HA 225G continues to inform Fatal pH1N1 cases:

• EPI471832 Volgograd 
• EPI471828 Moscow 

Hemagglutinin Sequences

. . . . RussiaVolgogradCRIE25_2013_02_28_VxX_f (
. . . . . . . . A/Volgograd/CRIE-25/2013

. . . . . . . . GISAID HA EPI471832

. . . . . . . . GISAID Isolate EPI_ISL_146874

. . . . . . . . 22 Polymorphisms (8 Amino and 14 Silent)

. . . . . . . . syn39K (AAa),

. . . . . . . . syn77S (AGt),

. . . . . . . . syn99I (ATa),

. . . . . . . . 100N,

. . . . . . . . syn179L (CTg),

. . . . . . . . 188T,

. . . . . . . . 225G,

. . . . . . . . 237I,

. . . . . . . . syn239P (CCa),

. . . . . . . . 286E,

. . . . . . . . syn308K (AAg),

. . . . . . . . syn333F (TTc),

. . . . . . . . syn338G (GGc),

. . . . . . . . syn372Q (CAa),

. . . . . . . . 377K,

. . . . . . . . syn396V (GTg),

. . . . . . . . syn448L (TTg),

. . . . . . . . 454N,

. . . . . . . . syn461K (AAa),

. . . . . . . . 502K,

. . . . . . . . syn546L (tTg),

. . . . . . . . syn548C (TGc))

. . . . RussiaOrenburgCRIE26_2013_02_13_f (
. . . . . . . . A/Orenburg/CRIE-26/2013

. . . . . . . . GISAID HA EPI471833

. . . . . . . . GISAID Isolate EPI_ISL_146875

. . . . . . . . 23 Polymorphisms (8 Amino and 15 Silent)

. . . . . . . . syn39K (AAa),

. . . . . . . . syn61A (GCa),

. . . . . . . . syn77S (AGt),

. . . . . . . . 100N,

. . . . . . . . 166I,

. . . . . . . . syn179L (CTg),

. . . . . . . . 188T,

. . . . . . . . 237I,

. . . . . . . . syn239P (CCa),

. . . . . . . . 286E,

. . . . . . . . syn308K (AAg),

. . . . . . . . syn333F (TTc),

. . . . . . . . syn338G (GGc),

. . . . . . . . syn372Q (CAa),

. . . . . . . . 377K,

. . . . . . . . syn396V (GTg),

. . . . . . . . syn417G (GGc),

. . . . . . . . syn448L (TTg),

. . . . . . . . 454N,

. . . . . . . . 502K,

. . . . . . . . syn542S (TCc),

. . . . . . . . syn546L (tTg),

. . . . . . . . syn548C (TGc))

. . . . RussiaAstrakhanCRIE18_2013_02_05_f (
. . . . . . . . A/Astrakhan/CRIE-18/2013

. . . . . . . . GISAID HA EPI471831

. . . . . . . . GISAID Isolate EPI_ISL_146873

. . . . . . . . 20 Polymorphisms (8 Amino and 12 Silent)

. . . . . . . . syn39K (AAa),

. . . . . . . . syn77S (AGt),

. . . . . . . . 100N,

. . . . . . . . 166I,

. . . . . . . . syn179L (CTg),

. . . . . . . . 188T,

. . . . . . . . 237I,

. . . . . . . . syn239P (CCa),

. . . . . . . . 286E,

. . . . . . . . syn308K (AAg),

. . . . . . . . syn333F (TTc),

. . . . . . . . syn372Q (CAa),

. . . . . . . . 377K,

. . . . . . . . syn396V (GTg),

. . . . . . . . syn448L (TTg),

. . . . . . . . 454N,

. . . . . . . . 502K,

. . . . . . . . syn542S (TCc),

. . . . . . . . syn546L (tTg),

. . . . . . . . syn548C (TGc))

. . . . RussiaAstrakhanCRIE17_2013_01_28_f (
. . . . . . . . A/Astrakhan/CRIE-17/2013

. . . . . . . . GISAID HA EPI471830

. . . . . . . . GISAID Isolate EPI_ISL_146872

. . . . . . . . 23 Polymorphisms (13 Amino and 10 Silent)

. . . . . . . . syn16T (ACg),

. . . . . . . . 77I [avH1N1],

. . . . . . . . 89G [H7N9 wt],

. . . . . . . . 100N,

. . . . . . . . 129Q,

. . . . . . . . 131L,

. . . . . . . . syn162P (CCt),

. . . . . . . . 179V [pH1N1 Novel],

. . . . . . . . . . . . [Emergent H7N9 wt],

. . . . . . . . 188T,

. . . . . . . . 237I,

. . . . . . . . 286E,

. . . . . . . . syn308K (AAg),

. . . . . . . . syn333F (TTc),

. . . . . . . . syn372Q (CAa),

. . . . . . . . 377K,

. . . . . . . . syn396V (GTg),

. . . . . . . . syn448L (TTg),

. . . . . . . . 454N,

. . . . . . . . 477M [SpainCatalonia5925S_29F_2013_02_05 (PhyloTree)],
. . . . . . . . . . . . [sH1N1],

. . . . . . . . syn497K (AAg),

. . . . . . . . 502K,

. . . . . . . . syn546L (tTg),

. . . . . . . . syn548C (TGc))

. . . . RussiaMoscowOblastCRIE08_2013_01_28_VxX_f (
. . . . . . . . A/Moscow-Oblast/CRIE-08/2013

. . . . . . . . GISAID HA EPI471828

. . . . . . . . GISAID Isolate EPI_ISL_146870

. . . . . . . . 23 Polymorphisms (8 Amino and 15 Silent)

. . . . . . . . syn64I (ATt),

. . . . . . . . syn77S (AGt),

. . . . . . . . 100N,

. . . . . . . . syn111V (GTa),

. . . . . . . . syn141H (CAc),

. . . . . . . . 188T,

. . . . . . . . syn223V (GTa),

. . . . . . . . 225G,

. . . . . . . . 259T,

. . . . . . . . 286E,

. . . . . . . . syn308K (AAg),

. . . . . . . . syn333F (TTc),

. . . . . . . . syn338G (GGc),

. . . . . . . . syn372Q (CAa),

. . . . . . . . 377K,

. . . . . . . . syn396V (GTg),

. . . . . . . . syn402H (CAt),

. . . . . . . . syn448L (TTg),

. . . . . . . . 454N,

. . . . . . . . 502K,

. . . . . . . . syn542S (TCc),

. . . . . . . . syn546L (tTg),

. . . . . . . . syn548C (TGc))

. . . . RussiaAstrakhanCRIE16_2013_01_26_f (
. . . . . . . . A/Astrakhan/CRIE-16/2013

. . . . . . . . GISAID HA EPI471829

. . . . . . . . GISAID Isolate EPI_ISL_146871

. . . . . . . . 20 Polymorphisms (9 Amino and 11 Silent)

. . . . . . . . syn16T (ACg),

. . . . . . . . 77I,

. . . . . . . . 89G,

. . . . . . . . 100N,

. . . . . . . . syn179L (CTg),

. . . . . . . . 188T,

. . . . . . . . 237I,

. . . . . . . . 286E,

. . . . . . . . syn308K (AAg),

. . . . . . . . syn333F (TTc),

. . . . . . . . syn372Q (CAa),

. . . . . . . . 377K,

. . . . . . . . syn396V (GTg),

. . . . . . . . syn448L (TTg),

. . . . . . . . 454N,

. . . . . . . . syn497K (AAg),

. . . . . . . . 502K,

. . . . . . . . syn542S (TCc),

. . . . . . . . syn546L (tTg),

. . . . . . . . syn548C (TGc))

. . . . RussiaKazanCRIE01_2012_12_29 (
. . . . . . . . A/Kazan/CRIE-01/2012

. . . . . . . . GISAID HA EPI471827

. . . . . . . . GISAID Isolate EPI_ISL_146869

. . . . . . . . 21 Polymorphisms (8 Amino and 13 Silent)

. . . . . . . . syn39K (AAa),

. . . . . . . . syn77S (AGt),

. . . . . . . . 100N,

. . . . . . . . syn179L (CTg),

. . . . . . . . 188T,

. . . . . . . . 219T [H7N9],

. . . . . . . . 237I,

. . . . . . . . syn239P (CCa),

. . . . . . . . 286E,

. . . . . . . . syn308K (AAg),

. . . . . . . . syn333F (TTc),

. . . . . . . . syn338G (GGc),

. . . . . . . . syn372Q (CAa),

. . . . . . . . 377K,

. . . . . . . . syn396V (GTg),

. . . . . . . . syn448L (TTg),

. . . . . . . . 454N,

. . . . . . . . 502K,

. . . . . . . . syn542S (TCc),

. . . . . . . . syn546L (tTg),

. . . . . . . . syn548C (TGc))

This analysis catalysed with ingenuity from 2 lead Professors of Group10 at Ion₂₀₃.  We never cease to find inspiration in your halls of instruction.

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pH1N1 Influenza Hemagglutinin Segments elucidated at 2013-09-26-00_39_36_150170  by GeneWurx see.PolyDetector v0, Copyright 2007-2013.

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Potential Catalyst for Pandemic 2.0 Emerges in Italy during July

During the Summer of 2009, an unsuspecting twelve year old boy in Veneto, Italy may have become the host of an influenza strain that is now setting the Pandemic 2.0 stage.

The Northern Italian region of Veneto has a population nearing 5 million and hosts 60 million tourists each year with many passing through the canals of the capital, Venice.  The Laguna Veneta is the largest wetland in the Mediterrean (340mi² / 550km²) and the delta serves a wide range of migratory bird species. 

The University of Padova lab deposited 24 Neuraminidase (N1) sequences today from Italy sampled during July 2009 (Pandemic 1.5) bringing the total number of Italian NA segments on file to 26.  Antigenic diversity is observed in the Italian sequences, several with novel introductions, but the point variations are not our primary interest in this very important deposit. 

One sequence from the Padova lab signals the first recorded instance of a key transition for this pandemic.  The NA Triple Combination may mark an axis or inflection point for PF11.  A/Italy/134, from a student (12M) in Veneto, demonstrates a match to Seasonal Influenza in a permutation of 3 key markers that we have anticipated as a potential catalyst to Pandemic 2.0. 

A Balkan emergence had generated the highest probability in our research with the Italian peninsula and bounding northern states ranking as "Very Probable".  Few sequences have been made available to evaluate the Balkan states during this pandemic, so we cannot determine if the recombinations occurred in that area as well as in Italy.  Emergence was expected within a 250 mile radius (400km) of a significant body of water, particularly the Adriatic Sea, the Black Sea or the western boundary of the Caspian Sea.  Of course, we may be searching for our keys under the streetlamp.  So little surveillance is surfaced at this point that rough estimates are the maximum any lab may produce.

In Italy134, this coalescing set of 3 human-fit markers, predicted by our research in mid-May, emerged during the summer, recombined as expected onto the swine N1 background.  As you may observe from the positional study, this sequence may have required two or more in situ polymorphisms from consensus within this geography to gain these genetics.  In the estimation of our research team, random mutation is a less than stellar explanation.  Human-fit Seasonal Influenza and ΣPF11 now have much more in common as ΣPF11 moves into tighter conformation potentially gaining trait enhancements.

Neuraminidase Triple Combination
106I, 248N, 286G : Italy134
106I, 248N, 286G : Seasonal Influenza 2005, 2006, 2007, 2008, 2009
106I, 248N, 286G : H5N1 (Avian, Human), H1N1 (Avian, Swine)
106I, 248N, 286G : 1918 Brevig Mission

This July sequence lays additional groundwork for attractant donations from candidates in previously observed donor serotypes. 

Few Italian points of comparison are available prior to this large NA deposit.  Of the two, NA Italy05 is unremarkable for this study and NA Italy127 is quite remarkable due to temporal and geographic proximity, as you will see in the Italian permutation discussion.  We also note that the Hemagglutinin segments so prolifically available from Italy demonstrate exceptional variance (20 major polymorphisms from 34 Sequences). These Hemagglutinin amino acid revisions include, but are not limited to, 137T, 199N, 200T, 219T, 225E (4), 244I, 261G (2), 277E, 296H (4) and 300S (2).  NA variance is correlated with HA variance in ΣPF11. 

Antigenic Diversity, even within the sparse 26 Italian NA sequences is observable if only upon reviewing the four permutations of the Neuraminidase Triple Combination.

106I, 248N, 286G : Italy134 from Veneto, sampled 2009-07
106I, 248N, 286S  : Italy127 from Veneto, sampled 2009-06-17, 256L (H3N2, H5N1 Avian)
106I, 248D, 286S  : 23 Sequences, including Italy05 from May 2009
106V, 248N, 286S : Italy149

Italy134 is most similar at the protein (468/469) and nucleotide (1407/1410) levels to two different groups of sequences: the NA 286G bearing group from Canada (5 of 6 Sequences) and the Asian group (with Louisiana03) carrying the rare PF11 dual combination of 106I and 248N (20 sequences).  The Russian Almati01 and Ekaterinburg01 round out the set with the 106I/248N pairing, but vary at an additional amino acid from Italy134.  Only 24 sequences at GenBank carry the PF11 amino acid homology between 106I and 248N.

Until PF11_Ω is achieved, Influenza Flux will continue to vary the virulence and transmute the transmissibility at individual geographies. Future scrutiny of the NA permutations discussed here is merited.  Bear in mind that the current reservoir, even with this instance of tighter human coupling, remains hobbled by transitional genetics.  Fitness determination of this Seasonal NA Triple Combination on the swine N1 background of PF11 remains to be determined at such time as sequences are surfaced.

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