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1
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1
m
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[
5
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[
6
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.
T
h
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o
r
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y
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atic
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ev
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we
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llo
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r
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f
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d
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ep
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tin
g
item
s
f
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r
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tem
at
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ev
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(
PR
I
SMA
)
s
tan
d
ar
d
s
in
f
o
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r
p
h
ases
:
d
atab
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ch
,
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e
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ata
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x
tr
ac
tio
n
,
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d
s
u
m
m
ar
y
.
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u
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ed
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r
c
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f
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licat
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th
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s
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tly
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ated
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ex
tr
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ata
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r
o
m
th
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ticles.
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r
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n
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ted
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e
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s
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ata
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p
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o
r
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s
tem
atic
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iew
(
Fig
u
r
e
1
)
.
Fig
u
r
e
1
.
Prism
a
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lo
wch
a
r
t f
o
r
Nip
ah
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ir
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s
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cien
tific
liter
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9
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2
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Me
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ter
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ed
:
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tatio
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Fo
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th
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ata
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,
we
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x
clu
s
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ep
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elate
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s
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g
e
n
icity
.
wer
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c
u
lled
f
r
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e
d
ata.
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[
2
0
]
.
I
n
m
u
t
a
g
e
n
e
s
i
s
a
n
d
s
t
r
u
c
t
u
r
a
l
a
n
a
l
y
s
i
s
,
G
g
l
y
c
o
p
r
o
t
e
i
n
p
l
a
y
s
a
k
e
y
r
o
l
e
f
o
r
r
e
c
e
p
t
o
r
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i
n
d
i
n
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a
n
d
t
h
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s
a
m
e
t
h
i
n
g
i
s
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o
t
a
p
p
r
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d
i
n
v
i
r
a
l
e
p
h
r
i
n
-
B
2
r
e
c
e
p
t
o
r
[
1
4
]
.
H
o
w
e
v
e
r
,
e
p
h
r
i
n
-
B
2
(
w
h
i
c
h
i
s
c
r
i
t
ic
a
l
o
f
b
i
n
d
i
n
g
N
i
V
)
w
a
s
i
d
e
n
ti
f
i
e
d
b
y
t
h
e
p
e
r
f
o
r
m
a
n
c
e
o
f
a
l
a
n
i
n
e
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s
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a
n
n
i
n
g
m
u
t
a
g
e
n
e
s
is
a
n
a
l
y
s
i
s
[
9
]
.
F
u
r
t
h
e
r
a
n
al
y
s
is
o
f
e
p
h
r
in
-
B
2
,
t
h
e
b
i
n
d
i
n
g
a
f
f
i
n
it
y
o
f
t
h
e
m
u
t
a
n
t
r
e
c
e
p
t
o
r
w
i
t
h
N
iV
-
G
(
r
e
s
p
o
n
s
i
b
l
e
f
o
r
r
a
i
s
i
n
g
t
h
e
t
e
n
d
e
n
c
y
o
f
i
n
f
e
c
ti
o
n
s
)
w
as
i
n
c
r
e
as
e
d
b
y
L
1
2
4
A
ep
h
r
i
n
-
B
2
m
u
t
a
n
t
s
[
2
1
]
.
T
h
e
r
e
f
o
r
e
,
L
1
2
4
A
m
u
t
a
n
t
s
g
a
i
n
e
d
t
h
e
a
b
i
l
it
y
t
o
s
u
p
p
o
r
t
t
h
e
N
i
V
i
n
f
e
c
t
i
o
n
a
n
d
a
r
r
a
n
g
i
n
g
a
n
e
w
t
a
r
g
e
t
ce
l
l
p
l
at
f
o
r
m
[
2
2
]
,
[
2
3
]
.
3
.
2
.
P
a
t
ho
g
enesis
o
f
Nipa
h
v
irus
in h
um
a
ns
No
n
-
s
p
ec
if
ic
f
lu
-
lik
e
s
y
m
p
t
o
m
s
s
u
ch
as
f
ev
e
r
,
h
ea
d
ac
h
e,
d
i
s
o
r
ien
tatio
n
,
m
u
s
cle
s
tiff
n
ess
,
an
d
wate
r
y
s
to
o
l a
r
e
co
m
m
o
n
in
th
e
ea
r
ly
s
tag
es o
f
a
NiV
in
f
ec
tio
n
[
2
3
]
.
I
n
ce
r
tain
o
u
tb
r
ea
k
s
,
m
ild
o
r
s
h
o
w
n
o
s
y
m
p
to
m
s
in
f
ec
tio
n
s
h
av
e
b
ee
n
d
o
cu
m
e
n
t
ed
,
b
u
t
th
e
o
v
er
all
f
r
eq
u
e
n
cy
is
lo
w
an
d
s
ee
m
s
to
b
e
s
tr
ain
d
ep
en
d
a
n
t,
with
th
e
Ma
lay
s
ian
v
ar
ian
t
p
r
o
d
u
ci
n
g
less
s
ev
er
e
d
is
ea
s
e,
a
lo
wer
ca
s
e
m
o
r
tality
r
ate,
an
d
a
g
r
ea
ter
p
r
o
p
o
r
tio
n
o
f
asy
m
p
to
m
atic
in
f
ec
tio
n
s
th
an
th
e
B
an
g
lad
esh
s
tr
ain
[
2
4
]
.
A
n
en
ce
p
h
alitic
co
n
d
itio
n
o
cc
u
r
s
in
ar
o
u
n
d
6
0
%
o
f
p
atien
ts
af
ter
a
n
in
c
u
b
atio
n
p
e
r
io
d
o
f
s
ev
e
n
to
f
o
r
ty
d
ay
s
.
T
h
er
e
is
n
o
in
f
o
r
m
atio
n
o
n
h
o
w
l
o
n
g
it
tak
es
f
o
r
t
h
e
illn
ess
to
p
r
o
ce
ed
f
r
o
m
th
e
o
n
s
et
o
f
s
y
m
p
to
m
s
to
th
e
o
n
s
et
o
f
th
e
en
ce
p
h
alitic
co
n
d
itio
n
.
Ab
o
u
t
a
th
ir
d
o
f
in
d
iv
id
u
als
h
av
e
n
eu
r
o
lo
g
ical
s
y
m
p
to
m
s
s
u
ch
as
m
en
in
g
is
m
u
s
(
in
f
lam
m
atio
n
o
f
th
e
ce
n
tr
al
n
er
v
o
u
s
s
y
s
tem
)
an
d
s
eizu
r
es.
An
in
d
iv
id
u
al’
s
m
en
tal
s
tatu
s
m
ay
d
eter
io
r
ate
in
as
lit
tle
as
s
ev
en
d
ay
s
(
i
n
th
e
ca
s
e
o
f
r
ec
en
t
o
u
tb
r
ea
k
s
in
B
an
g
la
d
esh
)
o
r
a
s
lo
n
g
as
1
6
d
a
y
s
(
in
g
en
er
al)
(
Ma
lay
s
ia
o
u
tb
r
ea
k
)
.
Ab
o
u
t
2
0
-
3
0
% o
f
th
o
s
e
wh
o
h
av
e
s
u
r
v
i
v
ed
NiV
en
ce
p
h
alitis
h
av
e
lo
n
g
-
ter
m
n
e
u
r
o
lo
g
ic
d
y
s
f
u
n
ctio
n
m
ar
k
ed
b
y
s
eizu
r
es
th
at
co
n
tin
u
e
,
ex
h
au
s
tio
n
t
h
at
is
in
ca
p
ac
itati
n
g
,
a
n
d
a
b
er
r
an
t
b
eh
a
v
io
r
.
I
n
ad
d
itio
n
,
a
late
-
o
n
s
et
o
r
r
ec
u
r
r
in
g
n
eu
r
o
lo
g
ical
illn
ess
m
ay
d
ev
elo
p
in
p
eo
p
l
e
with
in
itially
m
o
d
er
ate,
n
o
n
-
en
ce
p
h
alitic
co
n
d
itio
n
.
So
m
e
p
atien
ts
also
h
av
e
ch
r
o
n
ic
r
esp
ir
ato
r
y
d
is
tr
ess
,
an
d
r
esp
ir
ato
r
y
i
n
v
o
lv
e
m
en
t
h
as
b
ee
n
m
o
r
e
p
r
e
v
alen
t
in
th
e
B
an
g
lad
esh
o
u
tb
r
ea
k
s
th
a
n
in
th
e
Ma
lay
s
ian
o
u
tb
r
ea
k
s
[
2
5
]
.
3
.
3
.
T
re
a
t
m
ent
cr
it
er
ia
f
o
r
Nipa
h v
irus
(
NI
V)
infe
ct
io
n
T
h
e
ac
tu
al
th
er
ap
y
f
o
r
Nip
a
h
v
ir
u
s
in
f
ec
tio
n
h
as
n
o
t
y
et
b
ee
n
d
ev
el
o
p
ed
(
d
r
u
g
o
r
v
a
cc
in
atio
n
)
.
Su
p
p
o
r
tiv
e
th
e
r
ap
y
,
wh
ich
in
clu
d
es
en
s
u
r
in
g
e
n
o
u
g
h
r
est,
d
r
in
k
in
g
m
o
r
e
wate
r
,
an
d
s
y
m
p
to
m
atic
m
ain
ten
an
ce
o
f
ac
u
te
en
ce
p
h
alitis
s
y
n
d
r
o
m
e,
is
th
e
p
r
im
a
r
y
tr
ea
tm
en
t
[
2
4
]
.
I
t
is
p
o
s
s
ib
le
to
p
r
ev
en
t
th
e
tr
an
s
m
is
s
io
n
o
f
th
is
v
i
r
u
s
f
r
o
m
in
d
iv
id
u
al
to
in
d
iv
i
d
u
al
b
y
u
s
in
g
g
o
o
d
n
u
r
s
in
g
p
r
o
ce
d
u
r
es.
All
s
u
s
p
ec
ted
Nip
ah
v
ir
u
s
-
in
f
ec
ted
a
n
im
als an
d
h
u
m
an
s
s
h
o
u
ld
b
e
q
u
ar
an
t
in
ed
[
2
6
]
.
I
n
f
ec
ti
o
n
c
o
n
tr
o
l
tech
n
iq
u
es
s
h
o
u
ld
n
o
t
b
e
r
ep
lace
d
b
y
s
p
ec
if
ic
p
h
a
r
m
ac
eu
tical
ap
p
r
o
ac
h
es
[
2
6
]
.
T
h
e
in
ten
s
iv
e
ca
r
e
u
n
it
is
th
e
ap
p
r
o
p
r
iate
s
ettin
g
f
o
r
m
o
n
ito
r
in
g
p
atien
ts
wh
o
a
r
e
v
er
y
u
n
well.
Patien
ts
d
iag
n
o
s
ed
with
s
ev
er
e
p
n
e
u
m
o
n
ia
an
d
ac
u
te
r
es
p
ir
ato
r
y
f
ailu
r
e
ar
e
r
eq
u
ir
ed
to
h
av
e
m
ec
h
an
ical
v
en
tilatio
n
a
d
m
in
is
ter
ed
.
T
h
is
in
cu
b
atio
n
p
h
ase
is
th
o
u
g
h
t
to
last
an
y
wh
er
e
f
r
o
m
t
h
r
ee
to
f
o
u
r
teen
d
ay
s
[
2
7
]
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J Pu
b
lic
Hea
lth
Sci
I
SS
N:
2252
-
8
8
0
6
N
ip
a
h
viru
s
a
s
a
n
eme
r
g
in
g
th
r
ea
t:
mu
ta
tio
n
a
l
d
yn
a
mics
,
p
a
th
o
g
en
esis
,
a
n
d
a
d
v
a
n
ce
s
in
…
(
S
a
d
ia
A
fr
in
)
201
Fev
er
,
h
ea
d
ac
h
e,
d
izzin
ess
,
d
i
s
o
r
ien
tatio
n
,
an
d
v
o
m
itin
g
ar
e
s
o
m
e
o
f
th
e
ea
r
l
y
s
ig
n
s
o
f
an
in
f
ec
tio
n
ca
u
s
e
d
b
y
th
e
Nip
ah
v
ir
u
s
.
N
ec
r
o
s
is
o
f
en
d
o
th
elial
ce
lls
in
th
e
v
ascu
latu
r
e
a
n
d
d
am
ag
e
to
n
eu
r
al
tis
s
u
e
ar
e
two
o
f
th
e
m
an
y
ad
v
er
s
e
ef
f
ec
ts
th
at
m
ay
b
e
ca
u
s
ed
b
y
th
is
v
ir
u
s
.
E
n
d
o
th
elial
ce
lls
in
h
u
m
an
s
ar
e
r
esp
o
n
s
ib
le
f
o
r
v
ascu
lar
p
e
r
m
ea
b
ilit
y
;
th
is
p
r
o
g
r
ess
iv
e
ly
d
am
a
g
es
th
e
ce
ll,
wh
ich
r
esu
lts
in
v
ess
el
leak
ag
e,
a
n
d
th
e
f
in
al
o
u
tco
m
e
is
h
y
p
o
v
o
lem
ic
s
h
o
c
k
.
T
h
e
Nip
ah
v
ir
u
s
ca
u
s
ed
s
ev
er
e
s
y
m
p
to
m
s
s
u
ch
as
en
ce
p
h
alitis
,
co
n
v
u
ls
io
n
s
,
an
d
co
m
a
in
t
h
o
s
e
wh
o
wer
e
in
f
ec
ted
.
Ho
wev
er
,
th
e
ep
i
d
em
ic
in
Ma
lay
s
ia
h
as
b
ee
n
lin
k
ed
to
a
g
r
ea
te
r
n
u
m
b
er
o
f
c
o
m
p
licatio
n
s
,
s
u
c
h
as sep
ticem
ia,
in
test
in
al
h
em
o
r
r
h
ag
e,
an
d
r
en
al
im
p
air
m
en
t
[
2
8
]
.
I
n
th
e
ea
r
ly
s
tag
es
o
f
Nip
ah
v
ir
u
s
in
f
ec
tio
n
s
in
S
in
g
ap
o
r
e
a
n
d
Ma
lay
s
ia,
two
m
ed
icatio
n
s
,
r
ib
av
ir
in
an
d
ac
y
clo
v
ir
(
Fig
u
r
e
2
)
,
wer
e
ad
m
in
is
ter
ed
to
p
atien
ts
.
T
h
e
o
p
en
-
lab
el
r
esear
ch
in
Ma
la
y
s
ia
in
d
icate
d
th
at
r
ib
av
ir
in
r
ed
u
ce
d
m
o
r
tality
b
y
3
6
%
in
p
atien
ts
in
f
ec
ted
with
Nip
ah
v
ir
u
s
en
ce
p
h
alitis
,
with
4
5
o
f
1
4
0
p
atien
ts
(
3
2
%)
in
th
e
r
ib
av
ir
in
g
r
o
u
p
d
y
in
g
a
n
d
2
9
o
f
5
4
(
5
4
%)
p
atien
ts
d
ev
elo
p
in
g
th
eir
s
y
m
p
to
m
s
[
2
8
]
,
[
3
0
]
.
Ser
o
lo
g
y
,
h
is
to
p
ath
o
lo
g
y
,
im
m
u
n
o
h
is
to
ch
e
m
is
tr
y
,
r
ea
l
-
tim
e
p
o
ly
m
e
r
ase
ch
ain
r
ea
ctio
n
(
PC
R
)
,
an
d
v
ir
al
is
o
latio
n
tech
n
iq
u
es
ar
e
all
lab
o
r
ato
r
y
m
eth
o
d
s
f
o
r
d
iag
n
o
s
in
g
Nip
ah
v
ir
u
s
in
f
ec
tio
n
[
2
8
]
.
Fig
u
r
e
2
.
Mo
lec
u
lar
d
o
ck
in
g
r
ep
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esen
tatio
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ly
c
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P
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th
e
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,
h
o
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v
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W
HO
r
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o
m
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ass
a
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ev
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e
am
o
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en
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2
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o
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lts
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with
a
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n
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p
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io
d
o
f
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o
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h
ly
1
0
d
a
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s
[
2
5
]
.
I
t
is
p
o
s
s
ib
le
to
ad
m
in
is
ter
r
ib
a
v
ir
in
o
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ally
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in
ce
it
d
o
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n
o
t
b
in
d
to
p
lasma
p
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o
tei
n
.
R
ib
av
ir
in
'
s
s
id
e
ef
f
ec
ts
in
cl
u
d
e
n
e
u
tr
o
p
en
ia
(
8
0
%
-
4
0
%),
an
em
ia
(
1
1
%
-
3
5
%),
ly
m
p
h
o
c
y
to
p
e
n
ia
(
1
2
%
-
1
4
%),
an
d
th
e
p
o
ten
tial f
o
r
s
u
icid
al
t
h
o
u
g
h
ts
.
Ho
w
ev
er
,
r
i
b
av
ir
i
n
h
as
n
o
t
b
ee
n
s
h
o
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t
o
b
e
te
r
a
to
g
en
ic
in
h
u
m
a
n
s
b
u
t
h
as
b
ee
n
r
e
p
o
r
te
d
to
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e
ter
at
o
g
e
n
ic
in
m
i
ce
a
n
d
r
a
b
b
it
s
(
T
ab
le
2
)
[
2
9
]
-
[
3
9
]
.
R
i
b
av
ir
i
n
h
as
a
l
e
n
g
th
y
h
a
lf
-
li
f
e;
t
h
u
s
,
it
m
u
s
t
b
e
t
a
k
e
n
at
least
s
e
v
e
n
m
o
n
t
h
s
b
ef
o
r
e
p
r
e
g
n
a
n
c
y
t
o
b
e
s
a
f
e
[
3
6
]
.
T
h
e
s
h
o
r
t
-
te
r
m
s
a
f
et
y
p
r
o
f
i
le
o
f
R
i
b
a
v
i
r
i
n
is
im
p
r
ess
i
v
e
,
g
i
v
e
n
its
p
r
o
m
is
i
n
g
i
n
-
v
i
v
o
a
n
d
i
n
-
v
i
tr
o
r
esu
lts
.
Alt
h
o
u
g
h
a
c
o
n
t
r
o
lle
d
s
tu
d
y
is
m
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n
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,
th
e
s
t
at
u
s
is
s
til
l
u
n
r
e
s
o
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e
d
.
W
h
e
n
it
c
o
m
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t
o
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r
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ati
n
g
n
ip
a
h
v
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u
s
i
n
f
ec
t
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,
R
i
b
a
v
i
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i
n
was
r
e
c
o
m
m
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n
d
e
d
wit
h
o
u
t
r
es
er
v
a
ti
o
n
[
2
7
]
.
A
s
t
u
d
y
i
n
a
n
i
m
a
ls
f
o
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n
d
th
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r
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th
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el
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m
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tal
it
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b
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it
d
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o
t
d
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te
r
d
e
m
is
e
.
T
h
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a
n
t
im
ala
r
i
al
m
e
d
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ci
n
al
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t
c
h
l
o
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o
q
u
i
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w
o
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k
s
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v
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r
o
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n
a
m
an
n
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s
im
il
ar
to
r
i
b
a
v
i
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i
n
.
Fo
r
t
h
is
r
ea
s
o
n
,
c
h
l
o
r
o
q
u
i
n
e
an
d
r
i
b
a
v
i
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in
w
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e
test
e
d
i
n
a
g
o
ld
en
h
a
m
s
te
r
m
o
d
e
l
f
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th
e
tr
e
at
m
e
n
t
o
f
Ni
p
a
h
v
ir
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s
i
n
f
ec
t
io
n
[
2
7
]
.
3
.
3
.
1
.
M
o
no
clo
na
l a
ntibo
dy
An
an
tib
o
d
y
th
at
tar
g
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th
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ep
h
r
in
-
B
2
an
d
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in
-
B
3
r
ec
ep
to
r
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wh
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ar
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n
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tr
aliz
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b
y
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tib
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v
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b
in
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with
th
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Hen
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p
av
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G
en
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p
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ly
c
o
p
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Evaluation Warning : The document was created with Spire.PDF for Python.
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b
e
p
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v
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in
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r
r
ets
b
y
th
is
an
tib
o
d
y
[
3
6
]
.
I
n
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r
esear
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,
m
1
0
2
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4
p
r
o
tecte
d
Af
r
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g
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e
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m
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k
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t
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n
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ter
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n
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n
o
f
a
f
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am
o
u
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t (
AGM
)
[
3
7
]
.
T
ab
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2
.
Dr
u
g
s
with
p
o
ten
tial
an
tiv
ir
al
ac
tiv
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D
r
u
g
m
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D
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scri
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Ex
p
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I
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v
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t
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o
(
S
y
r
i
a
n
h
a
m
st
e
r
)
[
2
9
]
R
i
b
a
v
i
r
i
n
G
u
a
n
o
s
i
n
e
a
n
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n
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[
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]
A
c
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G
u
a
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o
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e
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u
e
H
i
st
o
r
i
c
a
l
r
e
v
i
e
w
[
3
1
]
R
e
m
d
e
s
i
v
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r
(
G
S
-
5
7
3
4
)
A
d
e
n
o
s
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n
e
a
n
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l
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u
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I
n
v
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o
(
A
f
r
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g
r
e
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m
o
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k
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)
[
3
2
]
,
[
3
3
]
B
a
l
a
p
i
r
a
v
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(R
1419
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C
y
t
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e
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I
n
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o
[
3
4
]
C
h
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q
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4
-
a
mi
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o
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[
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P
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(
I
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(
C
12
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I
n
t
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I
n
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(
H
a
ms
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)
[
3
6
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H
u
ma
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mA
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4
G
g
l
y
c
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f
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[
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7
]
H
u
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5
B
3
.
1
F
g
l
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[
3
8
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,
[
3
9
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3
.
3
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2
.
F
a
v
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ra
v
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An
R
NA
p
o
ly
m
er
ase
in
h
ib
it
o
r
f
o
r
v
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R
NA.
Fav
ip
ir
av
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is
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tiv
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d
r
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d
esig
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ed
to
k
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Nip
ah
v
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s
in
f
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Sy
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ia
n
h
a
m
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ter
s
m
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b
e
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o
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in
h
i
b
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b
y
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s
e
o
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t
h
e
an
tiv
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f
av
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p
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av
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d
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[
4
0
]
.
I
n
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n
em
e
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g
en
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G
an
d
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m
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ar
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f
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ed
in
I
n
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On
ly
if
th
e
R
T
-
PC
R
t
est is
n
eg
ativ
e
o
n
a
th
r
o
at
s
wa
b
o
r
b
lo
o
d
s
am
p
le
m
ay
th
e
p
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t b
e
d
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ch
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g
ed
.
An
d
it's
n
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clea
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h
o
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g
it
will
la
s
t,
b
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t
we
m
ay
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m
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th
at
it
wi
ll
la
s
t
f
o
r
2
1
d
ay
s
.
Af
ter
th
e
in
f
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tio
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h
as b
ee
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co
n
f
ir
m
ed
,
r
elea
s
ed
p
atien
ts
ar
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en
co
u
r
ag
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t
o
r
em
ain
in
is
o
latio
n
f
o
r
a
m
in
im
u
m
o
f
2
1
d
ay
s
[
2
9
]
.
T
h
e
p
r
im
ar
y
co
m
p
o
n
e
n
t
o
f
t
h
er
ap
y
f
o
r
a
NiV
in
f
ec
tio
n
is
p
alliativ
e
ca
r
e
,
wh
ic
h
m
a
y
i
n
clu
d
e
t
h
e
ad
m
in
is
tr
atio
n
o
f
an
tico
n
v
u
ls
an
ts
,
th
e
ad
m
i
n
is
tr
atio
n
o
f
f
l
u
id
s
,
th
e
tr
ea
tm
e
n
t
o
f
s
ec
o
n
d
ar
y
in
f
ec
tio
n
s
,
an
d
m
ec
h
an
ical
v
en
tila
tio
n
[
2
9
]
.
T
h
er
e
ar
e
p
r
esen
tly
n
o
m
ed
icin
es
th
at
ar
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au
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o
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ized
th
at
ca
n
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e
u
s
ed
in
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u
m
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s
th
at
ar
e
ef
f
ec
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in
tr
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tin
g
NiV
in
f
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tio
n
.
Du
r
i
n
g
th
e
NiV
Ma
lay
s
ia
ep
id
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ic
in
1
9
9
8
-
1
9
9
9
,
th
e
an
tiv
ir
a
l
m
ed
icatio
n
r
ib
av
ir
i
n
was
g
iv
en
to
1
4
0
p
atien
ts
,
wh
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r
e
s
u
lted
in
a
3
6
p
er
ce
n
t
d
ec
r
e
ase
in
d
ea
th
wh
en
co
m
p
ar
ed
t
o
th
e
m
o
r
tality
r
a
te
o
f
5
2
co
n
tr
o
l
p
atien
ts
wh
o
wer
e
n
o
t
tr
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ted
[
2
9
]
.
O
n
th
e
o
th
e
r
h
a
n
d
,
th
e
m
ed
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d
is
tr
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u
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was
n
o
t
d
o
n
e
in
a
r
a
n
d
o
m
way
;
t
h
er
e
is
a
p
o
s
s
ib
ilit
y
th
at
th
e
p
atien
ts
wh
o
wer
e
tr
ea
ted
h
ad
s
u
p
er
io
r
ca
r
e
in
g
en
er
al.
T
h
is
m
ak
es
th
e
r
esu
lt
d
if
f
icu
lt
to
p
r
ed
ict.
Su
b
s
eq
u
e
n
t
an
im
al
ch
allen
g
e
tr
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co
n
d
u
cted
in
h
am
s
ter
s
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th
at
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ib
a
v
ir
in
,
alth
o
u
g
h
it
d
id
n
o
t
p
r
e
v
en
t
m
o
r
tality
af
ter
NiV
in
f
ec
tio
n
,
d
id
p
o
s
tp
o
n
e
th
e
o
n
s
et
o
f
t
h
e
d
is
ea
s
e.
Af
ter
tr
an
s
m
is
s
io
n
o
f
Af
r
ican
Gr
ee
n
Mo
n
k
ey
s
with
th
e
s
im
ilar
ly
r
elate
d
Hen
d
r
a
Vir
u
s
(
HeV
; see
also
Hen
d
r
a
Vir
u
s
)
,
r
esear
ch
er
s
f
o
u
n
d
co
m
p
ar
a
b
le
r
esu
lts
[
6
5
]
.
4.
CURR
E
NT
S
T
A
T
E
O
F
NIP
AH
VIRUS VA
CCIN
E
(
NIV
)
DE
VE
L
O
P
M
E
NT
Un
d
o
u
b
t
ed
ly
,
Ni
p
a
h
v
i
r
u
s
is
an
e
m
e
r
g
in
g
,
u
n
a
p
p
a
r
e
n
t
&
m
il
d
d
is
ea
s
e
,
b
u
t
t
h
e
r
e
is
n
o
a
p
p
r
o
v
e
d
v
a
cc
i
n
e
f
o
r
h
u
m
a
n
s
o
r
an
y
li
v
esto
c
k
.
T
h
e
a
p
p
r
o
ac
h
o
f
th
e
Ni
V
v
a
cc
i
n
e
f
o
c
u
s
e
d
o
n
a
n
t
i
g
e
n
s
t
h
at
a
r
e
d
el
iv
er
e
d
as
s
u
b
u
n
it
v
ac
ci
n
es
o
r
u
s
i
n
g
v
ir
a
l
v
e
ct
o
r
s
(
T
a
b
l
e
3
)
[
4
1
]
-
[
5
5
]
.
N
o
wa
d
a
y
s
,
t
h
e
m
o
s
t
s
t
u
d
ie
d
v
a
cc
in
e
p
a
r
ti
ci
p
a
n
t
is
t
h
e
s
o
l
u
b
le
f
o
r
m
o
f
t
h
e
G
p
r
o
tei
n
th
at
is
h
i
g
h
ly
r
ela
te
d
t
o
th
e
Hi
n
d
a
v
ir
u
s
[
5
6
]
.
B
u
t
c
u
r
r
e
n
tl
y
,
t
h
e
r
e
a
r
e
n
o
d
r
u
g
s
o
r
v
a
cc
in
es
f
o
r
t
h
e
Ni
p
a
h
v
i
r
u
s
R
esea
r
c
h
a
n
d
D
ev
elo
p
m
e
n
t
B
l
u
e
p
r
in
t.
T
h
e
y
a
d
v
is
e
t
r
e
ati
n
g
s
ev
er
e
r
es
p
i
r
at
o
r
y
a
n
d
n
e
u
r
o
lo
g
o
i
c
c
o
m
p
lic
atis
a
x
o
n
s
[
5
7
]
.
A
lt
h
o
u
g
h
N
i
V
is
a
n
i
n
f
e
cti
o
u
s
&
p
at
h
o
g
e
n
i
c
d
is
e
ase
,
t
h
e
r
e
is
n
o
li
ce
n
s
e
d
h
u
m
an
v
a
cc
in
e
;
t
h
e
r
e
is
p
o
te
n
t
p
r
o
o
f
t
h
at
an
ef
f
e
cti
v
e
v
a
cc
in
e
is
f
e
asi
b
le
.
T
h
e
r
ec
en
t
e
v
i
d
e
n
c
e
s
u
g
g
ests
t
h
a
t
th
e
a
v
e
r
ag
e
i
n
c
u
b
ati
o
n
p
e
r
i
o
d
f
o
r
Ni
v
is
a
b
o
v
e
t
h
e
5
-
7
d
ay
s
’
t
h
r
es
h
o
l
d
,
a
n
d
s
o
h
as
a
s
tr
o
n
g
p
o
te
n
ti
al
f
o
r
th
e
d
ev
el
o
p
m
en
t
o
f
a
s
u
c
ce
s
s
f
u
l
v
a
cc
in
e
[
5
8
]
.
Vac
cin
e
d
ev
elo
p
e
d
b
y
Au
r
o
Vac
cin
e
an
d
Pu
b
lic
Hea
lth
Vac
cin
es
is
th
e
f
ir
s
t
in
th
e
wo
r
ld
to
r
ea
ch
clin
ical
tr
ial.
All
R
&
D
ac
tiv
i
ties
f
o
r
NiV
v
ac
cin
es
ar
e
in
th
e
p
r
e
-
clin
ical
s
tag
e
,
h
av
i
n
g
b
ee
n
test
ed
in
th
e
h
am
s
ter
,
f
er
r
et,
an
d
/o
r
AGM
p
r
ec
lin
ical
ch
allen
g
e
m
o
d
els
(
T
ab
le
4
,
s
ee
in
Ap
p
e
n
d
ix
)
[2
]
,
[
3]
,
[
5
9
]
–
[
6
5
]
.
Su
g
g
esti
o
n
b
y
a
n
u
m
b
er
o
f
f
a
cto
r
s
s
u
g
g
est
th
at
d
ev
elo
p
in
g
a
s
af
e
an
d
ef
f
ec
tiv
e
h
u
m
an
p
r
o
p
h
y
lactic
v
ac
cin
e
ag
ain
s
t
NiV
is
s
cien
tific
ally
p
o
s
s
ib
le.
T
h
er
e
is
a
b
r
o
a
d
a
g
r
e
em
en
t
th
at
n
eu
tr
alizin
g
a
n
tib
o
d
ies
co
n
f
e
r
p
r
o
tect
ag
ain
t
NiV
in
f
ec
tio
n
[
6
6
]
.
T
h
e
p
ig
s
s
u
f
f
er
ed
d
u
r
in
g
th
e
Ma
lay
s
ian
o
u
tb
r
ea
k
ca
u
s
ed
b
y
th
e
NiV
v
ir
u
s
.
T
h
e
s
ev
er
ity
o
f
s
y
m
p
to
m
s
o
f
NiV
in
f
ec
tio
n
s
in
p
ig
d
if
f
er
with
a
g
e.
An
ad
ju
v
a
n
ted
Hev
SG
p
r
o
tein
s
u
b
u
n
it
-
b
ased
v
ac
cin
e
h
as
b
ee
n
licen
s
ed
in
Au
s
tr
alia
to
p
r
o
tect
h
o
r
s
es
ag
ain
s
t
Hev
an
d
to
r
ed
u
ce
t
h
e
zo
o
n
o
tic
r
is
k
to
h
u
m
an
s
.
B
u
t
u
n
f
o
r
tu
n
ately
,
th
i
s
v
ac
cin
e
f
ailed
to
tr
ea
t
p
ig
s
f
r
o
m
ex
p
e
r
im
en
tal
ch
allen
g
e
with
NiV
[
6
7
]
.
Am
o
n
g
all
s
tu
d
ies
o
f
v
a
r
io
u
s
an
im
als
,
d
u
r
in
g
in
itial
s
tu
d
ies,
m
i
ce
wer
e
f
o
u
n
d
to
b
e
h
i
g
h
l
y
r
esis
tan
t
to
in
f
ec
tio
n
with
NiV
.
R
ec
en
tly
,
two
m
o
u
s
e
m
o
d
els
wer
e
g
iv
en
f
o
r
th
e
e
x
p
er
im
en
t
[
5
0
]
.
Acc
o
r
d
in
g
to
th
at
ex
p
er
im
en
t
,
it
s
h
o
we
d
th
at
a
g
ed
an
im
als
ar
e
s
u
s
ce
p
tib
le
t
o
NiV
in
f
ec
tio
n
v
ia
th
e
in
tr
a
n
asal
r
o
u
te
.
So
f
a
r
,
v
ac
cin
e
r
esear
ch
h
as
co
n
ce
n
tr
ated
o
n
th
e
v
ir
al
F
an
d
G
en
v
elo
p
e
g
ly
co
p
r
o
tein
s
,
eith
er
p
r
o
d
u
ce
d
in
r
ec
o
m
b
in
a
n
t v
ir
u
s
o
r
s
u
b
u
n
it im
m
u
n
o
g
en
s
,
to
p
r
o
tect
ag
ai
n
s
t th
e
h
en
ip
a
v
ir
u
s
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J Pu
b
lic
Hea
lth
Sci
I
SS
N:
2252
-
8
8
0
6
N
ip
a
h
viru
s
a
s
a
n
eme
r
g
in
g
th
r
ea
t:
mu
ta
tio
n
a
l
d
yn
a
mics
,
p
a
th
o
g
en
esis
,
a
n
d
a
d
v
a
n
ce
s
in
…
(
S
a
d
ia
A
fr
in
)
203
T
h
e
im
m
u
n
o
g
en
HeV
r
ec
o
m
b
in
an
t
s
o
lu
b
le
G
g
ly
co
p
r
o
tein
(
s
G)
h
as
also
b
ee
n
u
s
ed
in
m
an
y
r
esear
ch
s
tu
d
ies
(
HeV
s
G)
.
C
ats
wer
e
a
b
le
to
with
s
tan
d
a
d
ea
d
ly
NiV
ch
allen
g
e
with
n
o
clin
ical
i
n
d
icatio
n
s
,
an
d
th
e
r
esu
lts
in
d
icate
d
th
at
th
is
an
im
al
m
o
d
el
h
a
d
d
ev
el
o
p
ed
a
s
ter
ilizin
g
im
m
u
n
ity
.
R
eiso
late
d
v
ir
u
s
was
f
o
u
n
d
i
n
th
e
b
r
ain
s
o
f
s
ix
ca
ts
th
at
h
ad
r
ec
eiv
ed
th
e
s
ec
o
n
d
g
r
ea
test
d
o
s
es
o
f
v
ac
cin
atio
n
,
o
r
v
ir
al
R
NA
wa
s
f
o
u
n
d
i
n
th
e
b
r
ain
s
o
f
o
n
e
v
ac
cin
ated
c
at.
PHV0
2
is
an
R
v
s
v
v
ec
to
r
v
ac
cin
e
ca
n
d
i
d
ate
ex
p
r
ess
in
g
th
e
Nip
ah
v
ir
u
s
g
l
y
co
p
r
o
t
ein
in
th
e
B
an
g
lad
esh
s
tr
ain
o
f
Nip
ah
v
ir
u
s
v
ac
cin
e
(
PHV0
2
)
.
I
t
is
a
l
iv
e,
atten
u
ated
R
v
s
v
v
ec
to
r
v
ac
cin
e
ca
n
d
id
ate.
I
t
will
also
b
e
u
s
ed
to
f
in
d
th
e
d
ev
elo
p
m
en
t o
f
cr
itical
r
esear
c
h
to
o
ls
,
s
u
ch
as
ass
ay
s
an
d
an
t
ib
o
d
y
s
tan
d
a
r
d
s
,
f
o
r
f
o
r
th
co
m
in
g
Ph
ase
I
I
clin
ical
tr
ials
o
f
Nip
ah
v
ac
cin
atio
n
s
,
wh
ich
ar
e
p
r
esen
tly
ex
p
ec
ted
to
b
eg
in
in
m
id
-
to
-
late
2
0
2
2
.
At
th
is
tim
e,
th
e
f
ield
co
n
s
id
er
s
th
e
f
er
r
et
an
d
AGM
m
o
d
els
to
b
e
th
e
m
o
s
t
ap
p
r
o
p
r
iate
an
im
al
m
o
d
els
f
o
r
r
e
p
r
o
d
u
cin
g
h
en
i
p
av
ir
u
s
in
f
ec
tio
n
a
n
d
illn
ess
,
as
well
as
f
o
r
th
e
ass
ess
m
en
t
o
f
n
o
v
el
an
ti
-
h
en
ip
av
ir
u
s
tr
ea
tm
en
ts
a
n
d
v
a
cc
in
es.
I
n
ea
r
lier
r
esear
ch
,
th
e
au
th
o
r
s
a
n
d
o
th
er
s
,
in
clu
d
i
n
g
o
th
er
s
,
h
a
v
e
p
u
t
th
e
HeV
-
s
G
r
ec
o
m
b
in
an
t
s
u
b
u
n
it
im
m
u
n
o
g
en
th
r
o
u
g
h
its
p
ac
es
as
a
p
o
ten
tial
v
ac
cin
e
ca
n
d
id
ate
in
ca
ts
,
f
er
r
ets,
h
o
r
s
es,
an
d
o
th
er
an
i
m
al
m
o
d
e
ls
o
f
th
e
d
is
ea
s
e
[
6
8
]
.
T
ab
le
3
.
An
im
als test
ed
NiV
v
ac
cin
e
ca
n
d
id
ates
R
e
f
e
r
e
n
c
e
V
a
c
c
i
n
e
d
e
scr
i
p
t
i
o
n
A
n
i
m
a
l
(
s)
i
mm
u
n
i
z
e
d
V
a
c
c
i
n
a
t
i
o
n
r
o
u
t
e
/
R
e
g
i
me
n
/
C
h
a
l
l
e
n
g
e
(
S
t
r
a
i
n
3
)
N
i
V
n
e
u
t
r
a
l
i
z
a
t
i
o
n
t
i
t
e
r
s
(Pre
-
c
h
a
l
l
e
n
g
e
)
2
[
4
1
]
V
a
c
c
i
n
i
a
v
i
r
u
s (V
V
)
v
e
c
t
o
r
e
x
p
r
e
ssi
n
g
N
i
V
G
o
r
F
H
a
mste
r
s
S
C
/
2
v
a
c
c
i
n
a
t
i
o
n
s
1
m
o
n
t
h
a
p
a
r
t
/
c
h
a
l
l
e
n
g
e
3
mo
n
t
h
s
a
f
t
e
r
l
a
s
t
v
a
c
c
i
n
a
t
i
o
n
(
M
)
~
1
:
1
0
–
1
:
2
5
[
4
2
]
C
a
n
a
r
y
p
o
x
v
e
c
t
o
r
(
A
LV
A
C
)
e
x
p
r
e
ss
i
n
g
N
i
V
G
o
r
F
P
i
g
s
I
M
/
2
v
a
c
c
i
n
a
t
i
o
n
s
1
4
d
a
y
s a
p
a
r
t
/
c
h
a
l
l
e
n
g
e
o
n
d
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204
5.
CO
NCLU
SI
O
N
Nip
ah
v
ir
u
s
(
NiV
)
r
em
ain
s
a
s
ig
n
if
ican
t
em
er
g
in
g
zo
o
n
o
t
ic
p
ath
o
g
en
with
s
u
b
s
tan
tial
p
an
d
em
ic
p
o
ten
tial.
Acc
u
m
u
latin
g
ev
i
d
en
ce
s
u
g
g
ests
th
at
NiV
i
s
ca
p
ab
le
o
f
ad
ap
tin
g
to
n
ew
h
o
s
t
s
p
ec
ies
an
d
tr
an
s
m
is
s
io
n
p
ath
way
s
b
ey
o
n
d
its
p
r
im
ar
y
r
eser
v
o
ir
,
P
tero
p
u
s
f
r
u
it
b
ats.
Sin
ce
it
s
in
itial
id
en
tific
atio
n
,
NiV
h
as
d
em
o
n
s
tr
ated
t
h
e
ab
ilit
y
t
o
s
p
r
ea
d
t
o
h
u
m
an
s
th
r
o
u
g
h
c
o
n
tact
with
in
f
ec
ted
an
im
als,
p
ar
ticu
lar
ly
p
i
g
s
,
as
well
as
th
r
o
u
g
h
h
u
m
a
n
-
to
-
h
u
m
an
tr
an
s
m
is
s
io
n
.
R
ep
ea
ted
s
p
illo
v
er
ev
en
ts
an
d
s
u
b
s
eq
u
en
t
h
u
m
a
n
tr
an
s
m
is
s
io
n
m
ay
s
u
b
s
tan
tiall
y
in
cr
ea
s
e
t
h
e
o
v
er
all
d
is
ea
s
e
b
u
r
d
e
n
,
h
ig
h
lig
h
tin
g
t
h
e
im
p
o
r
tan
ce
o
f
co
n
tr
o
llin
g
b
o
th
z
o
o
n
o
tic
an
d
in
ter
p
er
s
o
n
al
tr
an
s
m
is
s
io
n
p
ath
way
s
.
De
s
p
ite
ef
f
o
r
ts
to
r
ed
u
ce
e
x
p
o
s
u
r
e
th
r
o
u
g
h
p
h
y
s
ical
an
d
en
v
ir
o
n
m
en
tal
in
ter
v
e
n
tio
n
s
,
th
e
r
is
k
o
f
NiV
tr
an
s
m
i
s
s
io
n
p
er
s
is
t
s
,
p
ar
ticu
lar
ly
in
r
eg
io
n
s
with
clo
s
e
in
ter
ac
tio
n
s
b
etwe
en
h
u
m
a
n
s
,
liv
esto
ck
,
an
d
wild
life
.
C
u
r
r
en
t
r
esear
ch
d
em
o
n
s
tr
ates
p
r
o
m
is
in
g
p
r
o
g
r
ess
in
v
ac
cin
e
d
e
v
elo
p
m
e
n
t,
with
s
ev
er
al
ca
n
d
id
ate
v
ac
cin
es
s
h
o
win
g
ef
f
icac
y
in
an
im
al
m
o
d
e
ls
s
u
ch
as
h
am
s
ter
s
,
f
er
r
ets,
an
d
Af
r
ican
g
r
ee
n
m
o
n
k
ey
s
.
T
h
ese
m
o
d
els
h
a
v
e
b
ee
n
in
s
tr
u
m
e
n
tal
in
r
ep
licati
n
g
k
e
y
f
ea
tu
r
es
o
f
h
u
m
an
NiV
in
f
ec
tio
n
an
d
p
at
h
o
g
en
esis
.
I
n
ad
d
itio
n
,
a
d
v
an
c
es
in
im
m
u
n
o
lo
g
ical
ass
ay
s
an
d
th
e
id
en
tific
atio
n
o
f
n
eu
tr
alizin
g
an
tib
o
d
ies
ar
e
ex
p
ec
ted
to
s
u
p
p
o
r
t
th
e
estab
lis
h
m
en
t
o
f
co
r
r
elate
s
o
f
p
r
o
tectio
n
,
alth
o
u
g
h
ass
ay
s
tan
d
ar
d
izatio
n
r
em
ain
s
in
its
ea
r
ly
s
tag
es.
Ho
wev
er
,
s
ig
n
if
ican
t
ch
allen
g
es
r
em
ain
in
tr
an
s
latin
g
th
ese
f
in
d
in
g
s
in
to
ef
f
ec
tiv
e
h
u
m
a
n
in
ter
v
en
tio
n
s
.
T
h
er
e
ar
e
cu
r
r
en
tly
n
o
licen
s
ed
v
ac
cin
e
s
o
r
s
p
ec
if
ic
an
tiv
ir
al
th
er
ap
ies
f
o
r
NiV
,
a
n
d
tr
ea
tm
e
n
t
r
em
ain
s
lar
g
ely
s
u
p
p
o
r
tiv
e.
T
h
er
ef
o
r
e,
th
e
d
e
v
elo
p
m
e
n
t o
f
s
af
e
an
d
e
f
f
ec
tiv
e
v
ac
cin
es
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[
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Evaluation Warning : The document was created with Spire.PDF for Python.