October 2010 Sequences from Thailand Increase Genetic Diversity with 232H

The Mahidol University in Bangkok deposited a group of 6 pH1N1 HA sequences at GenBank on 2010-11-22. The samples were all taken last month, October 2010, and produced partial sequences.

ThaiSN_0116_2010_10 deploys a rare polymorphism at aa163 that may be related to our discussion of change at that position in April of this year.  Only New Zealand reports another instance of 163T.  Each 163T-bearing sequence is recent indicating potential emergent behaviour at this key amino acid position.  A second Thai sequence, ThaiSN_0112_2010_10, corroborates another novel amino acid revision (found only in Cuba).  232H, just downstream of the recent critical RBD revisions to 230I, increases the genetic diversity of the ΣPF11 reservoir.  The post-pandemic H1N1 virus appears to be as unstable as during the early pandemic.

Previously, we have detailed this genetic diversity and Vaccine Escape tendencies within this viral reservoir.  100% of the Hemagglutinin positions between 186 and 248, including antigenic areas of the Receptor Binding Domain (RBD/RBS), are on record as polymorphic.  No position in that range is stable.  Many positions rate multiple changes.   Protein revision is documented at 58 of the 63 positions (92%), engaging a wide potential for antibody resistance (natural Immune Escape and Vaccine Escape).

The related 232H-bearing Cuban sequence is from 2010 and mirrors directly and via domaining the emerging post-pandemic sub-clade recently profiled.

. . . . ThaiSN_0116_2010_10 (
. . . . . . . . HA truncated before aa119,
. . . . . . . . 163T [NZChristchurch16_2010_07_12],
. . . . . . . . syn177L,
. . . . . . . . 188T,
. . . . . . . . 200T,
. . . . . . . . HA truncated after aa237)

. . . . ThaiSN_0112_2010_10 (
. . . . . . . . HA truncated before aa103,
. . . . . . . . 137T,
. . . . . . . . 186P,
. . . . . . . . 232H [CubaHabana7374_2010_01],
. . . . . . . . HA truncated after aa239)

Supporting Sequences

. . . . NZChristchurch16_2010_07_12 (
. . . . . . . . #4H,
. . . . . . . . syn44L,
. . . . . . . . 97N,
. . . . . . . . syn106E,
. . . . . . . . 128D,
. . . . . . . . 163T,
. . . . . . . . 225N,
. . . . . . . . 253A,
. . . . . . . . syn362S,
. . . . . . . . 377K)

. . . . CubaHabana7374_2010_01 (
. . . . . . . . HA truncated before aa05,
. . . . . . . . 28P,
. . . . . . . . syn32S,
. . . . . . . . 33G,
. . . . . . . . 165N,
. . . . . . . . 232H,
. . . . . . . . 275I,
. . . . . . . . syn287G,
. . . . . . . . syn305K,
. . . . . . . . syn346G,
. . . . . . . . 421M,
. . . . . . . . 432W,
. . . . . . . . 444Y,
. . . . . . . . HA truncated after aa535)

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225Y from Finland Increases Depth of Genetic Diversity within Critical Receptor Binding Site

Last Updated 2010-12-11

The National Institute for Health and Welfare of Finland deposited a group of 133 HA sequences at GenBank on 2010-11-13. The amino acid range of position 225 is extended by the mixed peaks found on an unidentified age / gender sampled on 2009-11-28, Finland649_2009_11_28. Though 225E is the most common change at the position within this geography, this particular infection attempted immune escape by revising to a Tyrosine at 225.  This inflection point sample was taken at a peak of the pandemic practically one year ago and was not published until November 2010.

. . . . Finland649_2009_11_28 (
. . . . . . . . syn49G [MyanmarJPS020_2010_07_07
. . . . . . . . . . . . . . . . . . . . plus 8 in 2010,
. . . . . . . . . . . . . . India8910_2010-05-08
. . . . . . . . . . . . . . . . . . . . with 188T,
. . . . . . . . . . . . . . SingaporeKK081_2010_02_12,
. . . . . . . . . . . . . . TexasJMS411_2010_01_25
. . . . . . . . . . . . . . . . . . . . plus 2 in late 2009,
. . . . . . . . . . . . . . Virginia01_2010_01-21,
. . . . . . . . . . . . . . Hawaii01_2010_01-03,
. . . . . . . . . . . . . . Hawaii02_2010_01-02,
. . . . . . . . . . . . . . England935_2009_12,
. . . . . . . . . . . . . . Yakutsk_EAV_2009_11_18,
. . . . . . . . . . . . . . swIowa44837_1_2009_11_08_xL
. . . . . . . . . . . . . . . . . . . . with 225N, 230I,
. . . . . . . . . . . . . . CaliforniaVRDL71_2009_08_28,
. . . . . . . . . . . . . . WiscS0435_2009,
. . . . . . . . . . . . . . HK01_2009_04_30, et al],
. . . . . . . . syn216E,
. . . . . . . . 225Y mix wt (kAT),
. . . . . . . . 324I,
. . . . . . . . syn413K)

Another trace supporting this Finnish deposit showed a mix at 225 equating to 225G and wild type. Note the consecutive numbering of the 225Y sample to the 225G sample and the similarity of the two sequences.  Of the 5 morphic positions, they share 4 and have matching revision values at 3 of those 5.

. . . . Finland648_2009_11_19 (
. . . . . . . . 129Q,
. . . . . . . . syn216E,
. . . . . . . . 225G mix wt,
. . . . . . . . 324I,
. . . . . . . . syn413K)

Previously, we have detailed the genetic diversity and Vaccine Escape tendencies within this viral reservoir.  100% of the Hemagglutinin positions between 186 and 248, including antigenic areas of the Receptor Binding Domain (RBD/RBS), are on record as polymorphic.  No position in that range is stable. 

Many positions rate multiple changes with position 225 increasing by the novel Tyrosine with the Finnish deposit.   Protein revision is documented at 58 of the 63 positions (92%), engaging a wide potential for antibody resistance (natural Immune Escape and Vaccine Escape).  Specifically, the range from 220 to 226 shows deep diversity, driving sequences that are laboratory confirmed as Low Reactors (Vaccine Escape).  With the critical position 225 depth chart now moving into double digits at 10 values within this reservoir, ample consideration must be given to the rapid acquisition feature on display.

Amino Acid Position 225 Variation in ΣPF11

• 225D (GAt) wt
• 225D synonymous (GAc)
• 225A
• 225E (GAa)
• 225E (GAg)
• 225E (GAa) plus 226R
• 225G (Gga) from 225E
• 225G (GgT)
• 225N
• 225V
• 225Y

Supporting Sequences

. . . . Yakutsk_EAV_2009_11_18 (
. . . . . . . . syn49G,
. . . . . . . . syn164L [1918],
. . . . . . . . 206S [Yaro_CHMV_2009_11_10_f (224K & 225G)],
. . . . . . . . 286N [H3N8],
. . . . . . . . . . . [Yaro_CHMV],
. . . . . . . . 296H [Yaro_CHMV],
. . . . . . . . syn348V [Yaro_CHMV,
. . . . . . . . . . . . . . . IndiaPune10604_2009_09,
. . . . . . . . . . . . . . . BZ_SaoPaulo53823_2009_08_01_f,
. . . . . . . . . . . . . . . Eng662_2009_08],
. . . . . . . . syn429L (TTa) [H3N8 Avian, 1918, WSN33, S5, M7],
. . . . . . . . syn448L [S9],
. . . . . . . . . . . . . [Yaro_CHMV],
. . . . . . . . syn490P [S5, tn],
. . . . . . . . . . . . . [Yaro_CHMV],
. . . . . . . . syn511T [Yaro_CHMV],
. . . . . . . . syn542S [H2, H5, H9N2],
. . . . . . . . . . . . . [Yaro_CHMV])

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300S with 225E Arises in 6 Year Old Nagasaki Boy during Late August in Japan

Nobuyuki Kobayashi Graduate School of Biomedical Sciences at Nagasaki University deposited 29 HA sequences today at GenBank from July, August and September 2009.  These 29 sequences join 3 previous Nagasaki samples for our geographic evaluation.  206T is found on 75% of the area specimens (24 of 32) and is not included in the polymorphism count. 57 total polymorphisms within the HA antigen are spread across 8 residue positions. 

2 revisions found only on the Nagasaki backgrounds within ΣPF11 are now conserved.  

• 124I is found on 75% of the area specimens (24 of 32 )
• 307S is found on 78% of the area specimens (25 of 32 )

Also notable is the first recorded emergence in Japan of 300S.  All 300S sequences on file travel with 225E and 206T.  A/Nagasaki/HA-44 sampled on 2009-08-20 from a 6 year old boy becomes #8 in this rare combination.  Half with this combination were sampled from US residents, 2 from Italy and 1 from Spain. Nagasaki/HA-44 is most similar to A/California/25 (1700/1701) and the TamiFlu Resistant A/Hong Kong/2369 (1699/1701) that was sampled from a traveler originating in San Francisco, California.  Nagasaki/HA-44 demonstrates a significant series of amino acid changes:  206T, 225E, 300S, 447K.

HA Amino Acid Codings to 3 Novel Polymorphisms and 5 Rare Signals

•    40N
•  124I
•  225E
•  300S
•  307S
•  447K
•  513V
•  549K

40N
Nagasaki/HA-10
Nagasaki/HA-17
A/Santiago/2968 (2009-06-26 from 8F) is the singular ΣPF11 peer.
Progenitors may include:
A/red-winged tinamou/Argentina/MP1/2008 (H1N1)
H1N1 Human 2007, 2008, 2009
H1N1 Avian
H1N2 Avian

124I
All Nagasaki except:
Nagasaki/HA-4
Nagasaki/HA-6
Nagasaki/HA-9
Nagasaki/HA-10
Nagasaki/HA-17
Nagasaki/HA-25
Nagasaki/HA-44
Nagasaki/NU-1
Unique to Nagasaki within ΣPF11.
Progenitors may include:
A/goose/Hong Kong/8/1976(H1N1)
A/chicken/Hong Kong/14/1976(H1N1)

225E
Nagasaki/HA-44.
Presently velocitised within recent ΣPF11.
A/Sapporo/1 (2009-06-11) is the singular ΣPF11 peer in Japan.

300S
Nagasaki/HA-44.
Rare to ΣPF11.
Progenitors may include:
H1N1 Swine
H1N1 Avian

307S
All Nagasaki except:
Nagasaki/HA-4
Nagasaki/HA-6
Nagasaki/HA-9
Nagasaki/HA-26
Nagasaki/HA-29
Nagasaki/HA-44
Nagasaki/NU-1
Unique to Nagasaki within ΣPF11.
Progenitor unknown.

447K
Nagasaki/HA-44.
A/Mexico City/70 and A/Italy/132 are the lone ΣPF11 peers.
Progenitor unknown.

513V
Nagasaki/HA-41.
A/Nanjing/1 (2009-06-18) is the singular ΣPF11 peer.
Progenitors may include:
H1N1 Human 2007, 2008, 2009
H1N1 Avian
H1N1 Swine
H1N2 Swine
1918

549K
Nagasaki/HA-10
Nagasaki/HA-14
Novel to ΣPF11.
Progenitor unknown.

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225E Trend Continues in Spain Through October 2009

The Hospital Clinic of Barcelona, Spain continued a strong professional showing this evening by depositing 41 sequences at GenBank covering the month of October 2009, including 14 HA and NA segments.  The Spanish officials and medical community must be highly commended for continuing to provide research data of the highest calibre and timeliness during this early stage of the pandemic. 

The velocity of change at amino acid residue 225 in the Receptor Binding Domain from October in Spain parallels our report from yesterday on August and September.  These samples are contemporary, dating from 2009-10-05 to several in the third week of October (up to 2009-10-22).  6 of 14 specimens (43%) demonstrate 225E paired with 206T.  As of this accumulation, Spain shows 37 instances of 225E with no 206S and 3 instances of 225G with 206T. 

Additional unique faces also enter  ΣPF11 with the Hospital Clinic's October sequences.  26 total polymorphisms within the antigens, HA and NA, spread across 13 amino acid positions generates branching on the Spanish tree in directions that may be suggestive of critical human fitness paths occurring throughout the world. 

Of particular interest is the potential cluster:

• A/Catalonia/S1515, HA, NA, MP, sampled on 2009-10-13, 14F
• A/Catalonia/S1554, HA, NA, MP, sampled on 2009-10-20, 1F

The CatS1515 and CatS1554 are identical on the HA and MP segments. The HA segments carry the very odd 377K most recently found in Avian H8N4. But the NA segments don't match and they vary in an unusual pattern. The earlier case carries a novel introduction to the pandemic on the NA at T483C coding for a synonymous 161C. The SNP from the earlier case, CatS1515, either did not transmit to the later case or did transmit and then was recombined back to wild type from a dual infection in the 1 year old host, CatS1554.

Clinical information would be very useful in this matter.  We are compelled by this Spanish cluster because a very striking HA homology has been circulating in North America since early August.  The H8N4 strains may have donated 377K to the H5N1 along the flightpath with a surveillance lag not yet chronicling the event.

HA Amino Acid Codings to 3 Novel Polymorphisms and 8 Rare Signals

•    35I
•   71G
•   88L
•   89N
•  100N
•  142T
•  225E
•  298V
•  373H
•  504N

35I
CatS1533, CatS1547.
Rare to ΣPF11.
Found in 10 other sequences including recent TamiFlu-Resistant US sequence, A/Texas/47.
Progenitors may include:
H5N1 Avian
H5N1 Human

71G
CatS1478, CatS1587.
CatS1436 and NY80 are the lone ΣPF11 peers.

88L
CatS1533.
Novel to ΣPF11.

89N
CatS1589.
Novel to ΣPF11.

100N
CatS1589.
Rare to ΣPF11.
Found in A/Sao Paulo/55312 and Argentina7953 from the INEI/CII Influenza Virus Sequencing Site.
Progenitors may include:
H1N1 Swine 2009
H1N2 Swine

142T
CatS1574.
CatS1411 is the singular ΣPF11 peer.

225E
CatS1478, CatS1479, CatS1490, CatS1545, CatS1587, CatS1592.
Presently velocitised within recent ΣPF11.

298V
CatS1478, CatS1479, CatS1587.
Unique to Catalonia within ΣPF11.
CatNS2001, CatNS2008, CatS1237, CatS1248, CatS1286, CatS1369, CatS1436.

373H
CatS1525, CatS1589.
Unique to Catalonia within ΣPF11.
CatS1285, CatS1353.

377K
CatS1515, CatS1554.
Novel to ΣPF11.
Progenitors may include:
H8N4 Avian
H6N1 Avian

504N
CatS1525, CatS1589.
A/Gifu-C/67 is the singular ΣPF11 peer.
Progenitors may include:
H1N1 Avian
H1N2 Swine

Neuraminidase Triple Combination
106I, 248D, 286S
All October sequences.

The Neuraminidase displays strong homology with exception in only three sequences.

NA Amino Acid Codings to 2 Novel Polymorphisms

•  161C (synonymous T483C)
•  442I

syn161C
CatS1515.
Identical in HA and MP segments to CatS1554.
Novel to ΣPF11.
Progenitors unknown, but adjacent residue 162 is highly active in:
H5N1 Human
H5N1 Avian
H1N1 Human
H1N1 Avian
H3N2 Human

442I
CatS1525, CatS1589.
Novel to ΣPF11.
Progenitors may include:
H5N1 Human
H5N1 Avian
H1N1 Swine
WSN33

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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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225G in Receptor Binding Domain Traveled to China without Vaccine Pairing of 206S

The expected Hydra Effect on Hemagglutinin patterns are being validated with the latest sequence deposits.  Multiple antigenic heads continue to arise within single geographic areas while the march from Southern Hemisphere winter strains (May-July 2009) into the Northern Hemisphere ΣPF11 lays distinct markers.

Two sequences today from China carry the Receptor Binding Domain polymorphism coding for 225G similar to the fatal cases during the South American winter.  These sequences represent the first movement of 225G into China and the second into Asia after Hiroshima201, although we have observed 225E in one instance, Changsha78.

This incursion of 225G makes Zhejiang Province one of very few geographic locales to represent both vaccine RBD polymorphisms as 226R was demonstrated mid-summer in A/Zhejiang/DTID-ZJU01/2009.

Let's examine the new Yiwu HA segments for this analysis:

• A/Zhejiang-Yiwu/11/2009     
• A/Zhejiang/DTID-ZJU02/2009  

These two Zhejiang province cases were sampled in September making the sequences contemporary for evaluation of the genetic acquisition cycle pertinent to North America today.  Each case continues the recent affinity of 206T with 225G.  Nine of fourteen instances of 225G on record within ΣPF11 are paired with 206T and only one isolated sequence after April has 206S in the pairing. You will note that the live vaccine is based on an early finding in Texas and Mexico (Texas05 pairing of 206S / 225G).  The current sequences continue to demonstrate a directional movement away from those four early Texas and Mexican strains from April. 

The Yiwu11 case, 41F, is specifically noted as having "severe symptoms".  Confidence is increased that these sequences are valid due to independent verification.  The two sequences were managed from separate labs though the hosts were apparently from the same city, Yiwu, and suffered during the same time frame.

Each of the two HA sequences represent a novel introduction into ΣPF11.   Yiwu11's closest GenBank match is 1758 of 1774 nucleotides and ZJU02's closest match is Yiwu11.  The two sequences are an exact nucleotide match (1759/1759) at all alignable positions (sequence truncation at Yiwu11 head and ZJU02 tail), potentially representing perfect transmission in Asia of 225G.  The Catalonia sequences from Spain in early August initiated the first and only previously recorded perfect segment transmission of a 206T / 225G pairing.  The Brasil deaths share amino acid homology, but varied at a silent SNP coding for Lysine at residue 222 (222K). 

If a cluster is in effect with these two sequences, then we may be observing a foundational, well-passaged, human-fit strain in the Northern Hemisphere heralding Pandemic 2.0 Influenza.    Only time will tell.

A correlation is also emerging in consideration of geography and population ethnicity with nine of the fourteen 225G cases in areas with a substantial Hispanic population. The ethnic profiles of the individual cases are not identified. Yiwu is a burgeoning commodities trading area with a substantial immigrant population including import/export workers from South America.  If we note that NY and Georgia have Hispanic populations, then only Hiroshima remains as a potential non-Hispanic area.  At any rate, the correlation of 225G to areas with Hispanic human genotypes bears scrutiny for pathogen-host interaction at the genetic level. 

Recall that other human-fit genetic advances are recorded in the Zhejiang Province recently.  Of minor note, the Neuraminidase segments of Yiwu11 and ZJU02 are also novel to the reservoir though the amino acid levels match widely.  A third base SNP that merits attention has now spanned from the original introduction in A/Netherlands/602 to ZJU02, A408G coding at residue 136 for a synonymous Glutamine (136Q).  Movement at this amino acid position is implicated in Relenza resistence (136K), though the synonymous change from the Netherlands and Zhejiang is not accorded trait enhancement in the literature.

This advancing Antigenic Diversity and movement of 225G separated from the 206S into a highly populated country prior to winter should generate a call for wider surveillance and more rapid deposition of sequences.

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HA 263D Observed in Russia, Thailand and Japan

A/Tomsk/01, deposited in late July 2009, introduced the pandemic to 263D on Segment 4 (HA).

Since that novel introduction, four additional specimens have been deposited matching the Tomsk01 nucleotide sequence coding for 263D, spreading the geographical and time range.

• A/Thailand/CU-H9/2009      collected on 2009-06-17
• A/Thailand/CU-H276/2009   collected in 2009-07
• A/Thailand/CU-B938/2009   collected in 2009-08
• A/Wakayama/57/2009        collected on 2009-07-13

A/Thailand/271/2005 (H1N1) is a potential progenitor for this SNP and other recent pandemic acquisitions.

These sequences carry additional HA polymorphisms including 244I on ThaiCU-H9 matching Ancona02 and 405T on ThaiCU-H276 matching TorontoT5362.

You've noticed from our discussions that this HA domain has activity occurring in many parts of the world.  Residue 263 continues to rank as a primary watch position within ΣPF11 for our team.

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