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Summary of neuraminidase amino acid substitutions associated with reduced inhibition by neuraminidase inhibitors (NAI)* Susceptibility assessed by NA inhibition assays (IC50 fold change vs. wild type [NAI susceptible virus])b Laninamivir Oseltamivir Zanamivir Peramivir Source of viruses/ Selection withc Type/Subtype Comments Amino acid substitutiona N2 numberinga A(H1N1)pdm09 E119G E119V D199G I223K 119 119 198 222 NI (3) RI (60) RI (17) RI (12-39) HRI (832) HRI (571) NI (6) NI (5-6) RI (51) RI (25) NI (2) NI (1-4) ?d ? ? ? I223R 222 RI (28-45) RI (10-12) ? ? I223V S247N 222 246 NI (6) NI (4-8) NI (2) NI (2-5) NI (2) NI (1) ? ? H275Y 274 HRI (221-1637) NI (1-6) RI/HRI (50-751) NI (1-2) Clin/Ose; Sur; In vitro N295S 294 HRI (208) NI (3) RI (12) ? RG (52) (29) (5, 12, 22, 32, 39, 45, 46, 48, 50, 60) (52) D199N+H275Y 198+274 HRI (318-744) NI (2-3) HRI (108) ? Clin/Ose (20, 50) I223K+H275Y I223R+H275Y I223V+H275Y S247N+H275Y 222+274 222+274 222+274 246+274 HRI (>10822) HRI (>9100) HRI (1733) HRI (5880) RI (11) RI (27-22) NI (2) NI (5) HRI (5343) HRI (>7500) HRI (1331) HRI (334) RI (11) RI (17) ? ? Sur; In vitro Clin/Ose; RG Clin/Ose; RG Sur (46) (43, 46, 51) (10, 52) (29) Q313R+I427T 313+427 RI (10-43) NI/RI (3-20) NI (4) ? Sur (22, 25) E119V 119 RI/HRI (15/1727) HRI (136/2144) HRI (5050) ? RG (1, 11) Q136K 136 NI (1) RI/HRI (36-327) RI (75-80) ? Sur (27, 49) Y155H 155 HRI (123) HRI (555) ? ? Sur (41) I223M I223V S247G H275Y R293K 222 222 246 274 292 NI (8) NI (3) NI (5) HRI (321-2597) NI (1) NI (1) NI (2) NI (1) NI (1-2) RI (18 NI (1) NI (1) ? HRI (111-1095) ? ? ? ? ? ? RG; In vitro/Zan RG; In vitro/Zan Sur Sur; RG RG (26) (26) (55) (11, 22, 40, 55) (11) Some IC50s were given for mixed virus populations; to be assessed using recombinant NA Only I427T affects IC50?- to be assessed using recombinant NA A(H1N1) Host cell- selected in both studies; not found in clinical specimens This result is virus specific Last updated 21 October 2016 RG RG RG Sur Clin/No; Clin/Ose/Zan; RG RG Sur Reference (52) (52) (52) (43) (17, 51, 63) Page 1 of 9 Type/Subtype Comments Both changes were host cellselected Q136K was host cell-selected D151E/N was host cell-selected D151G was host cell-selected Q136K+D151N were host cellselected Susceptibility assessed by NA inhibition assays (IC50 fold change vs. wild type [NAI susceptible virus])b Laninamivir Oseltamivir Zanamivir Peramivir Source of viruses/ Selection withc Reference ? ? ? ? ? ? ? ? RG RG RG RG RG RG RG RG (1, 11) (11) (11) (11) (11) (11) (11) (11) RI (18) ? Sur (49) RI (15) HRI (1805) ? Sur (49) HRI (231-799) NI (1-3) RI/HRI (80-718) ? Sur (49) 151+274 HRI (1189) RI (14) HRI (1161) ? Sur (49) I223M+H275Y I223V+H275Y I223V+N295S R293K+H275Y N295S+H275Y S334N+H275Y I117V+N295S+H275Y I117M+N295S+H275Y 222+274 222+274 222+294 292+274 294+274 336+274 117+294+274 117+294+274 HRI (1943) HRI (584/971) RI (97) HRI (207) HRI (108) HRI (415) HRI (336) HRI (121) NI (1) NI (1/2) NI (2) NI (1) NI (1) NI (1) RI (12) RI (11) HRI (400) HRI (893) ? ? ? ? ? ? ? ? ? ? ? ? ? ? RG; In vitro/Zan RG; In vitro/Zan RG RG RG RG RG RG (26) (11, 26) (11) (11) (11) (11) (11) (11) Q136K+D151N+H275Y 136+151+274 HRI (356) NI (4) HRI (23 00) ? Sur (49) I223V+N295S+H275Y 222+294+274 HRI (300) RI (13) ? ? RG (11) V96A I97V E99A E99G Q116L V129A D179G I203M I203V 116 117 119 119 136 149 198 222 222 RI (11-18) NI (5) RI (35) NI (3-4) RI (26) NI (4) RI (32) RI (36) NI (7) RI (10-63) NI (4) HRI (1254) HRI (1345-1485) HRI (350) NI (8) RI (44) NI (1) NI (1) NI (4) ? ? RI/HRI (12-164) ? ? NI (4) NI (1) NI (1) ? ? ? ? ? ? ? ? ? Sur RG; Sur RG RG; In vitro/Zan In vivo/Zan Sur RG; In vitro/Zan RG; In vitro/Zan RG; In vitro/Zan (6, 31) (33, 37) (33) (26) (30) (42) (26) (26) (26) Amino acid substitutiona N2 numberinga N295S I117V+E119V I117M+E119V I117V+H275Y I117M+H275Y I117V+N295S I117M+N295S E119V+ H275Y 294 117+119 117+119 117+274 117+274 117+294 117+294 119+274 RI/HRI (40/197) NI (7) RI (20) HRI (683) HRI (395) RI (60) RI (52) RI (21) NI (1/5) HRI (391) HRI (181) NI (1) NI (1) NI (1) NI (4) HRI (132) RI (12) ? ? ? ? ? ? ? Q136K+D151E 136+151 NI (1) RI (25) Q136K+H275Y 136+274 HRI (198) D151E/N+H275Y 151+274 D151G+H275Y A(H5N1) Last updated 21 October 2016 Page 2 of 9 Type/Subtype Comments Susceptibility assessed by NA inhibition assays (IC50 fold change vs. wild type [NAI susceptible virus])b Laninamivir Oseltamivir Zanamivir Peramivir Amino acid substitutiona N2 numberinga S227N 246 RI (24) NI (2) ? ? H255Y 274 HRI (911-2502) NI (1-3) HRI (108-533) NI (6) N275S I97V+I294V I203M+H255Y I203V+H255Y K130N+I203L+S227N 294 117+314 222+274 222+274 150+222+246 RI/HRI (12-138) RI (16) HRI (8024) HRI (1925) RI (77) NI/RI (2-27) NI (1) NI (3) NI (2) NI (1) NI/RI/HRI (3-130) NI (1) HRI (3340) HRI (2106) ? ? ? ? ? ? E119D E119I 119 119 NI (2) HRI (208) RI (32) RI (17) NI (2) NI (3) ? ? E119V 119 RI/HRI (18-2057) NI (1-7) NI (1-3) NI (3-4) Q136K 136 NI (1-7) RI/HRI (30-132) ? D151E D151V/D I222L R224K Del 245-248e E276D 151 151 222 224 245-248 276 RI (11) NI (8) NI (9) HRI (>4000) HRI (157-175) RI (15) NI (2) HRI (164) NI (2) RI (>50) NI (3) HRI (160) R292K 292 HRI (>10000) N294S R371K 294 371 E119V+T148I Source of viruses/ Selection withc Sur Sur; Clin/Ose; RG; In vitro/Zan Clin/Ose; RG Sur RG; In vitro/Zan RG; In vitro/Zan Sur Reference (6) (26, 33, 38, 44) (14, 33, 38) (31) (26) (26) (6) RG Clin/Ose; In vitro Sur; Clin/Ose; In vitro; RG (67) (47) (1, 34, 40, 47, 56, 61, 62, 67) ? Sur (13, 48) ? ? ? ? NI (1) ? ? ? ? ? ? ? NI/RI/HRI (3-134) RI/HRI (14-719) ? HRI (300-1879) RI (45) NI (8) RI (15) NI (1) ? ? ? RG Sur RG RG Clin/Ose RG Clin/Ose; In vitro/Zan; RG Clin/Ose; RG RG (66) (55) (53) (66) (2) (66) (1, 8, 36, 55, 62, 65-67) (1, 36) (66) 119+148 HRI (>6000) HRI (>800) HRI (>110) HRI (>250) Sur; In vitro; RG (61) E119V+I222L E119V+I222V 119+222 119+222 HRI (1571) HRI (293-2286) RI (5) NI (2) ? NI (7) ? ? RG Clin/Ose (53) (4, 56) A(H3N2)v S245N S247P S245N+S247P 245 247 245+247 NI (1) RI (42) RI (25-40) NI (1) HRI (266) HI/HRI (66-235) NI (1) NI (2) NI (1-2) NI (1) NI (9) NI (7-9) Sur; RG Sur; RG Sur; RG (58) (58) (48, 58) A(H7N9) R289K 292 HRI (>4600) RI (11-64) HRI (405-997) RI (15-33) In vitro; RG (23, 57) B E105K 110 NI (4-8) RI (15-42) HRI (213-436) NI/RI (3-12) Clin/No; RG (19) A(H3N2) Host cell-selected, not found in clinical specimens T148I was host cell-selected Last updated 21 October 2016 Page 3 of 9 Type/Subtype Comments CDC: IC50s for a mixed virus population reported a Susceptibility assessed by NA inhibition assays (IC50 fold change vs. wild type [NAI susceptible virus])b Laninamivir Oseltamivir Zanamivir Peramivir Source of viruses/ Selection withc Amino acid substitutiona N2 numberinga E117A E117A or D E117G E117V Q138R P139S G140R 119 119 119 119 140 141 142 RI/HRI (3171) HRI (>300) RI (31) HRI (300) NI (1) RI (10) RI (9) RI/HRI (12538) HRI (>560) RI/HRI (33-560) NI (2) RI (15) RI (25) RI (30) HRI (13780) HRI (>1598) HRI (>1598) HRI (531) RI (41) HRI (322) HRI (321) ? ? ? ? RI (7) RI (6) RI (9) R150K 152 HRI (100-252) NI/RI/HRI (5-1000) HRI (214-400) ? D197E 198 RI (12-26) NI (3-7) RI (16-18) ? D197N 198 NI/RI (4-10) NI/RI (3-17) NI (5) ? D197Y 198 RI/HRI (15/57) RI (14) HRI (168) ? Sur; RG RG In vitro; RG RG Sur; In vitro Sur; In vitro Sur; In vitro Clin; Clin/Zan; RG; Sur Clin/No; Sur; RG Clin/No; Clin/Ose; Sur Sur; RG A200A/T 201 RI (5-8) RI (5-7) ? ? Sur (48) I221L 222 HRI (70-121) RI (7-13) ? ? Clin/Ose I221T 222 NI/RI (5-8) NI (2-4) RI (15-43) NI (<3) Clin/No; Sur; RG I221V/I A245T H273Y R292K N294S K360E R374K A395E G407S D432G G140R+N144K Y142H+G145R 222 246 274 292 294 358-359f 371 390 402 429 142+146 144+147 NI (3-6) RI (24) NI/RI (2-12) HRI (>300) RI (17-61) NI (2) HRI (101/407) RI (5) NI (4) NI (1) NI (6) RI (5) NI (1) RI (39) NI (1) RI (29) NI (1-4) NI (2) RI/HRI (29/145) NI (1) NI (7) NI (1) RI (10) NI (4) NI (4-8) RI (5) RI/HRI (15-110) HRI (502) RI (31) HRI (165) HRI (352) RI (5) ? RI (41) HRI (257) HRI (487) ? NI (3) ? ? ? NI (<3) ? NI (<3) ? NI (<3) ? NI (<3) Sur Sur Sur; RG RG Clin/No; RG Sur Sur; RG Sur Clin/Ose; Sur Sur Sur Sur (15) (24, 39, 41, 64){Burnham, 2014 #6313 (59) (39) (7, 50, 55) (35) (7, 9) (39) (7, 55) (39) (24) (39) (50) (39) Reference (7, 54) (35) (3, 35) (35) (18) (18) (18) (21, 35, 40, 59, 66) (7, 28, 41) (24, 34, 40, 55) (7, 16) Numbering is based on an alignment of neuraminidases from: A/Brisbane/59/2007 [H1N1], A/California/7/2009 [H1N1pdm09], A/turkey/Turkey/1/2005 [H5N1], A/Singapore/1/57 [H2N2], A/Perth/16/2009 [H3N2, A/Hong Kong/1074/97 [H9N2], A/Anhui/1/2013 [H7N9], A/Jiangxi-Donghu/346/2013 [H10N8], B/Brisbane/60/2008 [B/Vic lineage], B/Bangladesh/3333/2007 [B/Yam lineage]. Last updated 21 October 2016 Page 4 of 9 b Assessed by NA inhibition assays chemiluminescent (NA-Star), fluorescent (MUNANA), and/or colorimetric (fetuin). NAI phenotype is shown according to the referenced studies: NI, normal inhibition; RI, reduced inhibition; HRI, highly reduced inhibition as defined in - World Health Organization. Meetings of the WHO working group on surveillance of influenza antiviral susceptibility – Geneva, November 2011 and June 2012. Wkly Epidemiol Rec. 2012 Sep 28;87(39):369-74. c Source: Sur, surveillance studies; Clin, clinical detection; RG, reverse genetics; In vitro, cell-culture studies; In vivo, animal studies. Drug use: No, no NAI used; Ose, oseltamivir; Zan, zanamivir. d ? indicates that the NAI(s) indicated were not studied. e Del indicated deletion of the three amino acids indicated. f Precise N2 numbering cannot be given as the influenza B NA carries an insertion in the alignment compared to the H3N2 NA. * Substitutions table developed by the WHO GISRS antiviral susceptibility expert working group (AVWG). 2014. 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