Download NAI - World Health Organization

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.
Last updated 21 October 2016
Page 5 of 9
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