TamiFlu Resistance on 50% of Deposit from Japan with HA Cross-Segment Correlation

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 spreadsheet for completeness in citation.

Last Update
2011-09-27

On 2011-09-26, the National Institute for Infectious Disease of Japan published 4 pH1N1 sequences at GISAID.  These sequences were sampled from patients in Japan from January to April 2011 covering the second half of the Northern Hemisphere 2010-2011 season.  No gender, age or clinical outcomes are specified.  All HA sequences relate to Clade 2 (188T) and are HA fragments.  Two of the four NA segments (50%) demonstrate genetic TamiFlu Resistance, one at NA 275 and the latest at NA 247.

A pattern is developing among Clade 1 (189T) and Clade 2 (188T) of genetic revision in the potential Immune Escape domains of HA aa122 to aa124 and aa163 to aa173. JapanAomori39_2011_04_09_TmX247 demonstrates revision in both areas with the rare HA 122M in a mixture with wild type and a rare HA 166T also in a mixture with wild type. JapanKawasaki122_2011_02_14_TmX275 falls onto a numerically significant Clade 2 (188T) background and adds the Vaccine Escape HA 158E in a mixture with wild type to a novel HA 169N.  Three of the four sequences show at least one polymorphism in the HA aa154 to aa169 range totaling four polymorphisms (154I, 158E, 166T, 169N).

The advantage of a larger public database allows surfacing of cross-segment signals related to TamiFlu Resistance.  HA 166T on JapanAomori39_2011_04_09_TmX247 becomes an investigational candidate.  Only 7 sequences occur in the GISAID database bearing HA 166T.  The United States West Coast (statistically significant Asian population) displays 2 of these sequences while Asia claims the remaining 5 of the rare HA 166T signals.  Japan is represented on 3 of the Asian sequences.  100% of those 3 HA 166T-bearing sequences from Japan are genetically TamiFlu Resistant via NA 247N or 275Y.  Those 3 HA gene segments are genetically distinct as well, demonstrating the ability of HA 166T to manifest across TamiFlu Resistant sequences with variant HA backgrounds.

The 4 Japanese HA fragments in this current deposit carry only 64% of a full HA, yet have generated an average of 8.5 polymorphisms (normed to ~13 for a full HA deposit).  Data from Clade 2 (188T) continue to show significant genetic diversity and an ongoing ease of novel genetic acquisition.

. . . . JapanAomori39_2011_04_09_TmX247 (
. . . . . . . . GISAID HA EPI336876
. . . . . . . . 9 Polymorphisms (4 Amino and 5 Silent)
. . . . . . . . syn10Y (TAc),
. . . . . . . . syn23L (tTA) mix wt,
. . . . . . . . syn34N (AAt),
. . . . . . . . 122M mix wt [Rare to pH1N1],
. . . . . . . . syn131S (TCa),
. . . . . . . . 146G,
. . . . . . . . 166T mix wt [Rare to pH1N1],
. . . . . . . . 188T,
. . . . . . . . syn338G (GGc),
. . . . . . . . HA Truncated after aa348)

. . . . JapanAomori39_2011_04_09_TmX247 (
. . . . . . . . GISAID NA EPI336875
. . . . . . . . 10 Polymorphisms (6 Amino and 4 Silent)
. . . . . . . . 44S,
. . . . . . . . syn140L (CTg),
. . . . . . . . syn240T (ACc),
. . . . . . . . 241I,
. . . . . . . . 247N mix wt,
. . . . . . . . 284N mix wt,
. . . . . . . . syn304V (GTa),
. . . . . . . . 369K,
. . . . . . . . syn377P (CCa),
. . . . . . . . 466I)

. . . . JapanKawasaki122_2011_02_14_TmX275 (
. . . . . . . . GISAID HA EPI336870
. . . . . . . . 9 Polymorphisms (6 Amino and 3 Silent)
. . . . . . . . syn10Y (TAc),
. . . . . . . . syn34N (AAt),
. . . . . . . . 146G,
. . . . . . . . 158E mix wt,
. . . . . . . . 169N [Novel to pH1N1],
. . . . . . . . 188T,
. . . . . . . . 200T,
. . . . . . . . 330K,
. . . . . . . . syn338G (GGc),
. . . . . . . . HA Truncated after aa348)

. . . . JapanKawasaki122_2011_02_14_TmX275 (
. . . . . . . . GISAID NA EPI336869
. . . . . . . . 8 Polymorphisms (5 Amino and 3 Silent)
. . . . . . . . 44S,
. . . . . . . . syn240T (ACc),
. . . . . . . . 241I,
. . . . . . . . 275Y,
. . . . . . . . syn304V (GTa),
. . . . . . . . 369K,
. . . . . . . . syn377P (CCa),
. . . . . . . . 465S mix wt)

. . . . JapanFukuoka40_2011_02_02 (
. . . . . . . . GISAID HA EPI336874
. . . . . . . . 8 Polymorphisms (4 Amino and 4 Silent)
. . . . . . . . syn34N (AAt),
. . . . . . . . 143STOP mix wt,
. . . . . . . . 188T,
. . . . . . . . syn190D (GAt),
. . . . . . . . 200T,
. . . . . . . . syn296Q (CAa),
. . . . . . . . 324A,
. . . . . . . . syn338G (GGc),
. . . . . . . . HA Truncated after aa348)

. . . . JapanFukuoka40_2011_02_02 (
. . . . . . . . GISAID NA EPI336873
. . . . . . . . 9 Polymorphisms (6 Amino and 3 Silent)
. . . . . . . . syn28N (AAt),
. . . . . . . . 44S,
. . . . . . . . 74L mix wt,
. . . . . . . . 178S mix wt,
. . . . . . . . syn240T (ACc),
. . . . . . . . 241I,
. . . . . . . . 369K,
. . . . . . . . syn377P (CCa),
. . . . . . . . 415M)

. . . . JapanFukuoka35_2011_01_18 (
. . . . . . . . GISAID HA EPI336872
. . . . . . . . 8 Polymorphisms (5 Amino and 3 Silent)
. . . . . . . . syn34N (AAt),
. . . . . . . . 72T,
. . . . . . . . 154I,
. . . . . . . . 188T,
. . . . . . . . 200T,
. . . . . . . . 218E mix wt,
. . . . . . . . syn296Q (CAa),
. . . . . . . . syn338G (GGc),
. . . . . . . . HA Truncated after aa348)

. . . . JapanFukuoka35_2011_01_18 (
. . . . . . . . GISAID NA EPI336871
. . . . . . . . 10 Polymorphisms (7 Amino and 3 Silent)
. . . . . . . . syn28N (AAt),
. . . . . . . . 44S,
. . . . . . . . 94I mix wt,
. . . . . . . . 161Y mix wt,
. . . . . . . . syn240T (ACc),
. . . . . . . . 241I,
. . . . . . . . 369K,
. . . . . . . . syn377P (CCa),
. . . . . . . . 414E mix wt,
. . . . . . . . 415M)

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