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Ref-5 Cma.j.issn.0366-6999.2010.13.012
Ref-5 Cma.j.issn.0366-6999.2010.13.012
nes
e Medi
cal
Jour
nal
201o:
123(13)
:1679—1684 1679
Ori
ginal
art
icl
e
1
D
~ ynam i
■
c cI
l
an2e
i 0In
m 0t
J
1
ne
r-source
neUt
●
ral
1
l●
●
Zl
n2
ant
Jl
●
1
Dodi
1■
es
agai
■
nst
・
ent
erovi
rus
7
1 and
coxsacki
evi
rus
A
1
6 i
n i
nfant
s
MAO
Qun—
ying,LI
AO
Xue—
yan,
YU
Xiang,LI
Na
n,ZHU
Feng—
cai
,ZENG
Ying,LI
ANG
Zheng—
lun,
LI
Feng—
xiang,W AN G
Jun-zhi
,LU
Feng—
min
and
ZH U AN G
Hui
Ke
ywor
ds:hu
man
ent
erovi
rus
71;hu
a n
m coxs
acki
evi
rusA1
6;mat
ern
all
y—ac
qui
redi
mmuni
ty;han
d,f
ootandmout
h di
seas
e
Back
gr ound Enter
ovi
rus
71(EV71)and coxsacki
evir
us
A1 6(
Cox A1
6)are maj
or
causat
i
ve
agent
s f
or
han d,foot
and
mout
h diseas
e( HFMD).St
udi
es j
ndic
ate
that
the f
requent
HFMD out
breaks
r
esul
t
in
a
few hundr
eds c
hil
dren’s
dealh i
n
Chi
na
in r
ecent
year
s.The
vacci
ne
and ot
her
resear
ch
for
HFM D need
to be
devel
oped ur
gent
ly.The
aim s
of
our
st
udy
wer
e:t
o expl
ore dynam i
c devel
opment
of
mot
her
-sour
ce neut
ral
i
zing ant
ibodi
es agai
nst
EV71
and Cox
A1
6 i
n i
nfant
s
f
rom Ji
angsu Pr
ovi
nce, Chi
na, and t
o pr
ovi
de t
he f
undament
al dat
a f
or f
urt
her
est
abl
i
shi
ng of
cor
respondi
ng
i
mm uni
zat
ion
cour
se.
Methods Per
ipher
al
blood
sam pl
es
wer
e col
lect
ed
from 1
33
of
par
tur
ient
women
once
imm edi
atel
y bef
ore
del
i
ver
y and
t
hei
r i
nfant
s at
two and seven m ont
hs of
age.Met
hod of
m i
cro-
dose cyt
opat
hogeni
c efect
was used t
o measur
e
neut
ral
izi
ng
ant
ibodi
es
agai
nst
EV71
and
Cox
A1
6.r
espect
ivel
y.
Resul
ts Ser
oposi
t
ive
rat
es
of
ant
i-
EV71
an
d ant
i—
Cox
A1
6 i
n pr
enat
al women
wer
e 79-
7% (
1
O6/
1
33)and
92.
5%
(
1
23/
1
33)
,res
pec
tivel
y;geome
tri
c mean
ti
ter
s(GM1
_s)wer
e 29.
0 and
61.
9;75.
9% (
1
01门33)pr
enat
al
women
wer
e bot
h
posi
ti
ve i
n ant
i—EV71
and ant
i—
Cox A1
6:ser
oposi
ti
ve r
ates of
ant
i-EV71
and ant
i.Cox A1
6 wer
e 25.
6% (
34/1
33)and
38.
3% (51/1
33)i n
infants a
t two months
of age;GMT s
were 12.
3 and 18.0,respecti
vel
y.GMTs of
ant
i.EV71 were
si
gni
fi
cant
l
y higher
for
infant
s at
seven
mon t
hs(82.6)compared
wit
h t
hat
at wo
t mont hs(P<O.
05),
showing i
nfants
had
i
nappar
entl
y i
nfect
ed
by
EV71 duri
ng wo
t to
seven mont
hs.Alt
hough onl
y one
ofspring(0.
75%)at se
ven mon t
hs was
f
ound havi
ng ant
i-Cox A1
6 t
ransf
ered f
rom mat
ernal
,thi
s obser
vat
ion suggest
ed no mat
ernal
ant
ibody may r
emai
n i
n
i
nfant
s at
seven mont
hs.
Concl
usi
ons The pr
eval
ence
of
EV71
and
Cox
A1
6 wer
e r
elat
ivel
y hi
gh i
n Ji
angsu
Pr
ovi
nce.Bi
val
ent
vacci
ne
agai
nst
bot
h EV71
and
Cox
A1
6 shoul
d be devel
oped.and t
he
ideal
ti
me
poi
nt
for
pr
ime i
mm uni
zat
ion
for
inf
ant
s i
s ar
ound
2—5
mont
hs
of
age.
Chi
n MedJ201o:
123f
13)
:1679.
1684
71(
EV71)and
coxs
acki
evi
rus
A16(
Cox i
n t
he popul
ati
on,Cox A 16 has
al
so recei
ved i
ncreasi
ng
ong t
o ent
erovi
rus
and ow n si
mil
ar at
tent
ions.
vi
rus
par
ticl
e i
s 24—30 am,no envel
ope,
(
+)S
SRNA
vius
r es
,four
types
of
vi
us
r pa
rti
cle
pr
ote
ins
Speci
fic mat
ernal
neut
ral
izi
ng ant
ibody ca
n prot
ect
(VP1 一
re4)t o
for
m pent
amer
,si
xty
pent
ame
rs
for
m vi
us
r i
nfants
agai
nst
pat
hogen at
tack.
“ 。As 90% pat
ient
s of
par
ticle ca
psid.
’
EV71 and Cox A16 a
re major
HFM D ar e bet
ween 1-3 year s age.
and fat al
ity rat
e
causat
ive agent
s f
or hand, f
o ot
and mout
h di
sease i
ncreas
es wi t
h the l
ower age of infa
n ts.
’ 。 appropriat
e
(
HFM D). Except
HFM D, EV7
1 al
so caused asept
ic
meni
ngi
tis, brai
n st
em encephal
iis, acut
t e f
lacci
d
DOI:10.
3760/cma.
j.
issn.
0366—6999.
201
0.13.01
2
pa
ral
ysi
s,r
espi
rat
ory t
rac
t i
nfect
ion
and nyoc
rdi
a ti
s 2nd
Divi
sion
of
vira
1 Vacci
nes(Mao Q Liao
XY and
Lin g
a ZL)
.
whi
ch
have
been r
epor
ted
in
Eur
ope.
厶 Japan.
Tai
wan of Depar
tment
of
Biol
ogi
cal
Cont
rol(
Li Fx
and
Wang
JZ).Nat
iona
l
Chi
na,
M al
ays
ia。and Si
ngapor
e. I
n t
erm of Cox A 16.
I
nst
itut
e f
or Cont
rol
of
Phar
maceut
ica
l and Bi
ologi
cal
Pr
oduc ̄.
Be ̄
ji
ng l
00050.Chi
na
al
though
most
of
h e pat
t ients
show sl
ight
si
gns,wi
th key
De
par
tme
nt of
Vacci
ne Resea
rch,Hua
la
n Bi
ologi
ca
l Engi
neer
ing
f
eat
tires
such as
fever
and ski
n rash or herpes on ha
n d,
I
nc.
,Xi
nxi
n g,He
a nan
453003,Chi
na(
Yu
X n d
a Li
N)
f
oOd.oral;
appr
oxi
mat
ely 6% of cases
were report
ed J
in gs
a u Pr
ovi
nci
l Cent
a er f
or Di
sea
se Prevent
ion and Cont
rol
,
havi
ng ser
iOUS
compl
icat
ion mani
fes
tat
ions.
A l
arge Na
nii
ng,Ji
n gsu
a 210009.Ch
ina(
Zhu
FC)
Depa
rtment
of Vacc
ine
Resea
rch,Shenzhen Ka
n gt
ai Bi
ologi
ca
l
out
break of H ⅥD due t o EV7 1 infect
ion occurred in
Pr
oduct
s Co.
,Lt
d.Shenz
hen,Gua
n gdong
5
1
8057,Ch
ina(
Zeng
Y)
Tai
wan of
Chi na i
n 1998.a tot
al of 129 106 cases were
Peki
ng Univer
sit
y Hea
lth Sci
ence Ce
nte
r,Be
iji
ng 1
001
91
,Cl
1i
na
report
ed,i
ncl
udi
ng 78 deat
h s.
In recent
years.H ⅥD (LuFM a
n dZhuan gH、
has become as
one of t
he most
impor
tant
infect
ious
Correspondence
to:Dr.LI
ANG Zheng—
lun.2nd Divi
sion of Vira
l
di
seas
e among chi
ldren i
n t
he mai
nland of Ch
i na.
”’
“ Vaccines.Nat
iona
l Ins
it
t ut
e f
or
the
Cont
rol of
Phar
ma ceutica
l and
Therefor
e,pr
ophyl
act
ic vacci
ne
has s
ubsequent
ly
brought
Bi
olog
ica
l
ro
P duc
ts,Bei
ji
ng
10005
0,Ch
ina(
Tel
:86
—10—
6709
535
7.
Fax:86—10—67095357.Email
:lzlun@ya hoo.com)
great
at
tent
ions t
o agai
nst
HF]
ⅥD. Consi
der
ing t
h e The st
udy was supposed
by a grant
fr
om Natura
l Key
ro
P ject
s of
co-
-
infect
ion and cr
oss.
.
preval
ence of
EV71
and
Cox A 16 China(No.2008B 69B01) .
prot
ect infants, but
also avoid adverse effects
f rom ant
i.EV7l
an d a
nti
—Cox A 16.
“,1
/5
bl
ood sampl
es wer
e
matem al
anti
body 力, Us.under
stn di
a ng
the s
eroprevalence.
di
lut
ed
rom l:
f 8 rat
io.i
nact
ive t
h e
ser
u m on 56。C f
or 30
as
wel
l as
the dynami
c change of mat
er
n al
neut
ral
izi
ng i nut
m es. St
art
ing f
rom 1:
8 t
O 1:
2048 s
erial
di
lut
ions.
ant
ibodys
for
EV7
1 f
ant
i EV7 l
1
and
Cox A 1
6(ant
i—Cox i xed
m the di
lut
ed ser
u m wi
th 100 TCⅡ)
n EV71a
n d
Cox
A16)a mong
chi
ldr
en.ar
e of
antecede
ntl
y i
mport
ance f
or A
1
6 equal
ly,t
hen added t
hem i
nto a 96.
i cr
m o pl
ate on
t
he development
of
pr
event
ive i
mmuni
zat
ion st
rategy t
o 37。C f
o r 2 hours.f
inal
ly added RD cel
1 sus
pens
ion
contro1
EV7 l
and/or Cox A l
6 infect
ion.However,the f
l×l
0 ce
lls
/m1
).Set
cel
l c
ont
rol
。ser
um
cont
rol
and
vir
us
dynami c devel
opm ent of m at
em al
ant
i—EV7
1 and cont
rol
on
each
plat
e,al
so
set
vi
us
r
backdr
ops(
if
res
ult
of
ant
i.Cox A
1
6 ant
ibody rem ai
ns l
argel
y unknown.In t
his
bac
kdr
ops
was
32-320
TCI
D5dwel
1.t
he
tes
t was
suc
ces
s)
prospect
ive designed,
long—ter
m followed—up study,
in each
test
and put
them i
nto CO,i ncubator
on 35。C or
f
healt
hy prenatal
wom en and t
heir i
nfants’
serum 7 days,observed t
he cyt
opathogeni
c effect
by m
i croscopy,
ant
i.EV7
l and ant
i—Cox A
1
6 neut
ral
izi
ng ant
ibody were def
ined neut
ral
izi
ng t
iters
as i
nhi
bit
ion of 50%
measured,the
dynam
i c development
of
m ater
nal
anti
body cVt
Opat
hogeni
c eff
ect
.Thi
s met
hod had been pr
evi
ous
ly
was analyzed.To t
he best of our
knowledge.t
his study measur
ed
by r
eference serum s
Of
EV71
an d Cox
A 16.no
was
the f
irst
report
on t
he dynami
c devel
opment
of cross—
react
ion found.Neutralizi
ng ant
ibodies f
o r EV7 1
m at
ernal ant
i.Cox
A 1
6 neut
ral
izi
ng a
nt i
body i
n neonat
es and Cox A 1
6 were de1
5ned positi
ve,i
f neutr
ali
zi ng t
iter
and infants.Our study provi
des t
h e evi
dence for
the was
equal
and
great
er
than 1:
8 di
lut
ions.
est
abl
ishment
of
pr
imary
immuni
zat
ion
time
poi
nt.
Stat
isti
ca
l anal
ysi
s
M ETHoDS
The ser
oposi
tive rat
es of ant
ibodies were compar
ed by
c
hi—
squa
re t
est
.The
ge
ome
tic
r mea
n t
ite
rs(
GMTs
1 of
Subj
eet
s and
sampl
es anti
bodies
were anal yzed with SPSS 10. 0 sof
tware
Thi
s st
udy empl
oyed cohort
st
udy.Bet
ween Sept
ember
package.For m e st
ati
stical
analysi
s of GM Ts.t
h e dat
a
2007 and July 2009, 1
62 par
tur
ient women and t hei
r
wer
e t
rans
or
f m ed us
ing t
he Logl0 of
h e or
t igi
nal
val
ues,
neonat
es were enroll
ed from t
hree hospi
tals
in Ji
angsu
c
his
transf
ormat
ion i
s ef
fect
ive i
n st
abi
lizi
ng t
h e
Provi
nce.Blood samples
were coll
ected f
rom neonates
at
di
spersi
on and m akes
the vari
ances
independent
of t
he
2.7 mont
hs of age.Am ong 1
62
prenatal women and 1
63
means.f
f t
iter
s of neut
ral
izi
ng ant
ibody were negat
ive,
neonat
es,148 neonat
es were f
oll
owed up at
2 m ont
hs of
t
hen assumed t
he t
iter
was
1:
4 f
or cal
cul
ati
on.Then.a
age and l
35 neonates
at
7 months of age.Fi
nal
ly.t
he
Pa
ired t
-tes
t was
per
for
m ed.P <0.
05 was
consi
dered
blood of I
33 Pair
s of part
ur
ient women and their
s
tat
ist
ical
ly s
igni
icant
f .
of
fspf
ing at
2 and 7 mont
hs wer
e col
lect
ed.These 1
33
pairs
of blood samples
were measur
ed or
f
EV7
1 and
Cox
RESU1 S
A 1
6 neutr
alizi
ng ant
ibodi
es det
erminat
ion.
Seroposi
tive
rate and GM Ts of
anti.EV71 j
n bl
ood
The st
u dy protocol
was appr
oved by Local Ethics
sam pl
es
of prenatal wom en
and infa
n t
s
Comm i
ttee,prenatal
women an d guardi
ans
of i
nfants
As
shown i
n 1’
abl
e 1.s
eroposi
tive rat
e of
nt
a i
—EV7
1 was
si
gned
the
infor
m ed
consent
s.Dur
ing
h e
t st
u dy
per
iod,no
cl
ini
cal
si
gn
of
HFM D
in
coho ̄ i
nfa
n ts
was
observed.
79.
7% f
106/
133)i
n pr
enat
al
women
and
25.
6% (
34/
133)
i
n i
nfant
s at
2 m ont
hs of
age.GM Ts of a
nti—
EV71
in
pr
enat
al wom en was
29.
0 a
n d
in i
nfant
s at
2 mont
hs was
Cel
ls
and
viI
ns
strai
ns
l2_
3:GM Ts of i
nfant
s at
7 mont hs
was signiicant
f ly
Rhabdomyos
arc
oma
ce
lls(
RD ce
lls
)we
re c
ult
ured
in
i
ncrease t
o 82.
6.Amongl9 infants
at 7 months of age
M EM sol
uti
on (GIBC0L, USA) whi
ch added 1
0%
who wer
e pos
iti
ve f
or ant
i.EV7
1. 1
7 i
nfant
s’ant
ibody
Newbovi
ne cal
f senl
m (
GIBC0L),2 mo1
/L L—
glut
amine
ti
ter j
ncreased o ur_
f fold t
h an t
h at
at
2 months
of
age.a
n d
(
GIBCOL1
. 1
00 I U/
ml peni
cill
in and str
eptomyc
in
2 i nfant
s tit
er i ncreased from 0 to f our fol
d. W i
th
(
GIBCOL)
.EV7
l/
Fuyang/
m01/2008 (C4 genotype
)and
Cox A 16/
G.1Of
kindl
y provi
ded
by
Kunm
i ng I
nst
itut
e of det
ermi
nat
ion cr
iteri
a of
inappa
r ent
inf
ect
ion
as
ant
ibody
t
iter i
ncr
easi
ng four
fol
d and above t
han bef
ore. t
he
Me
dica
l Bi
ology,Chi
nes
e Acade
my
of
Medi
cal
Sci
ence)
wer
e adapt
ed t
o growt
h i
n RD cel
ls.Vi
rus
tit
er was 10 i
nappa
rent
inf
ect
ion r
ate
was
12.
8% f
17/
133)dur
ing a
and 1
0 一 TCID5
0/m1.respect
ivel
y.Befo re using,EV7 l per
iod bet
ween 2 t
o 7 m ont
hs of
age.Dur
ing f
oll
ow—
up
and Cox A 1
6 were measured by reference serum of per
iod,none of t
he 17 i
nfant
s who were i
napparent
ly
anti
—EV71 a
n d a
nti.Cox A 16 and PCR.The vi
us
r st
rain infected showed any cli
nical
si
gns of
HFM D :continuous
used f
or ver
ificat
ion was cul ur
t ed i
n RD cell
s an d des cent of ser
um a
nt ibody was not f
o und i
n any inf
ant
enl
arged。f
reezi
ng and t
hawi
ng 3 t
imes
to r
elease t
he (
Tabl
e 2
.
vi
rus
。the
n ce
ntif
r uge
d(200
xg 1
0 i nut
m es)at
low
spe
ed
t
o get
ri
d of cel
l debr
is,package t
h e s
upem at
ant
and Di
stri
buti
on
of
ant
i.EV71
in
Pairs
of
blood
sam pl
es
st
ored
in
reezer
f approxi
mat
ely—70。C.
col
lect
ed
from
prenat
al
wom en
and
infant
s
For fur
ther anal
ysi
s t
he rel
ati
onshi
p of
ant
ibody t
iters
Determi
nati
on
m et
hod
of
ant
i-EV71
and
ant
i-C0x
A 16 bet
ween prenat
al women and
h ei
t r ofspr
ing,i
nfa
nts
at
2
neutral
izing antibody mOnt
hs Of age wer
e al
lOcat
ed tO four
grOups
by GM Ts
Using m
i cro—dose cyt
opat
hogeni
c ef
fect
to measur
e l
evel
0f ant
i EV7l
of mei
r mOt
hers:negat
ive gr
oup Of
Tabl
e 1.Dynami
c devel
opment
of
ser
opos
iti
ve
rat
e a
nd
GM Ts
of
neu ̄ i
zing
nt
a i
bodi
es
from
133
pai
rs
of
blood
sampl
es
of
prena
tal
women
n d
a neonat
es
Ser
oposi
tive r
ate of
anti
.EV7l i
n infa
nts
at
2 mont
hs ol
d w as
obvi
ousl
y l
ow er
tha
n t
llei
r m om ers,
=78 17,P <O.
01.’
Seroposi
tive r
ate
of
nt
a i
—EV 71
in i
nfant
s at
7
mont
hs ol
d w as
obvi
ousl
y I
ow er
tha
n i
nfa
nts at
2 m ont
hs
old a
n d t
hei
r m ot
hers,
=5_
30,P <O.
05:
1
14.
23,尸 <0.
O1.
Seroposi
tive
rat
e of
ant
i Cox
A 16
in i
nfant
s at
2
mont
hs ol
d w as
obvi
ousl
y l
ower
than t
hei
r m ot
l1ers,
=86.1
4,尸 <0.
01.0
Ser
opos
iti
ve r
ate
of
nt
a i
.Cox
A 16
in
inf
n ts
a at
7
m or
tths
ol
d was
obvi
ousl
y l
ower
tha
n i
nfant
s at
2
m ont
hs
old a
n d
thei
r mot
h ers,
-45-
22,P <0.
Ol;
=206.
o4,尸 <O.
01.“
GM Ts
of
nt
a i
.EV 71
in
inf
n ts
a at
2
m ont
hs
old wa
s obvi
ousl
y l
ow er
tha
n t
heir
m ot
hers,P <O
O5.
1GM Ts
of
anti
.EV71
in i
nfn ts
a at
7 mor
tths
ol
d was obvi
ous
ly
higher
than
infa
n ts
at
2 mont
hs ol
d and t
hei
r mother
s.P <O.
05.’’
GM r
rs of
anti
.Cox A16 i
n i
nfa
n ts
at
2
mont
hs
old was
obvi
ousl
y l
ower
than
thei
r m ot
hers
.尸 <O.
O5.
Tabl
e 2.Res
ult
s f
rom
bot
h s
eropos
iti
ve
of
nt
a i
—EV71
n d
a nt
a i
—Cox
A16
in
inf
ant
s at
7
mont
hs
of
age(
pai
rs
of
nt
a i
body)
I
f t
iters
of neut
ral
izi
ng ant
ibody w a
s negat
ive.t
hen a
s sumed t
h e t
iter
w as 1:
4 for
ca
l cul
ati
on.
:Ser
oposi
tive anti
—EV71
in i
nfa
n ts
at
7 m ont
hs ol
d.十:Ser
opos
itive
ant
i—Cox A 16
in
inf
nt
a s
at
7 moi
lt
hs ol
d.
Tabl
e 3.Rel
ati
ons
hip
of
ant
ibody
tit
ers(
ant
i—EV7
1 a
n d
nt
a i
—Cox
A16
in
high,mi
ddl
e n d
a low
group)bet
ween
prenat
al
women
and
t
hei
rinf
nt
a s
ant
i-EV71 (<1:
8),we ak pos
iti
ve group (1:8
一),middl
e 2 m ont
hs of
age and i
n t
hei
r Pai
red m ot
her
,w ere show n
posi
tive
gr
oup(1:32-)and hi
gh posi
tive
group(>1:
128).
i
n Fi
gure.Sor
ted by t
he a
n ti
—EV7
1 l
evel
of mot
hers
by
Si
ze and per
cent
age of
infant
s i
n each group w ere ascending order,mean anti—
EV7 1
GM 1’
s of i
nfants at
2
t
abul
ated
in
Tabl
e 3.
mont hs
age i ncreased from 1:4 tO l:
1 2.
8. anti
—EV7 1
GM Ts
of i
nfa
nts at
2 m ont
hs w er
e di
rect
ly cor
rel
ated
Of
27 m ot
hers
and
thei
r i
nfant
s at
2 m ont
hs of
age w ere wi
th t
hat
of
the m ot
hers.The r
esul
t i
ndi
cat
ed t
hat
fo r
bot
h ser
onegat
ive f
or ant
i.EV7
1. Among 78 i
nfant
s i
nfants
at
2 months.if
mot hers
owned the
hi gher l
evel
of
whose
mothers wer
e in weak
posi
tive
gr oup。6
1(61/
78,
nt
a i—EV7
1.the
tit
ers
of ant
ibody t
ransf
ered from
mothers
78.
2%1 were
se r
onegati
ve f
or nt
a i
—EV71 and 17(17/
78.
i
nto
inf
ant
s wer
e als
o hi
gh.
21.
8%1 were weak posi
tive;among 16 i nfant
s whose
mothers were i
n middle pos
iti
ve group, 8 were Seroposit
ive
rate and
GM rl
1s
of
ant
i.Cox
A 16
in
ser
onegat
ive.7 wer
e wea
k posi
tive and l
was mi
ddl
e prenatal
wom en and i
nfants
pos
iti
ve;am ong 1
2 inf
ants whose mothers
were in high Resul
ts of
m easurement
for
Cox A
1
6 wer
e t
abul
ated i
n
pos
iti
ve,3
were seronegat
ive,6 were
weak pos
iti
ve and 3 Tabl
e 1.Seropos
iti
ve r
ate of ant
i—Cox A16 was
92.
5%
wer
e mi
ddl
e pos
iti
ve.
(1
23/133)in pr
enata
l women,38.
3% ( 51
/133)in i
nfnt
a s
at
2 months of age
and 4.5% (
6/133、in inf
ants
at 7
Correl
ati
on
of
cal
cul
ated
GM 1’
s
of
ant
i—EV7
1 i
n i
nfant
s at
m ont
hs age.
Tabl
e 4.Ser
opos
iti
ve
rat
e of
ant
i—
EV71
and
ant
i—Cox
A16(%)
:Seroposi
tive r
ate
of ant
i—EV71
and ant
i—Cox A 16 i
n i
nfants
at
2 m ont
hs ol
d
we
re
obv
iou
sl
y
lo
wer
t
hn
ath
eir
mot
her
s, ̄=1
10.
24,
P<o
.O1
.
:S
ero
pos
it
iv
e r
at
e
of
nt
a i
--
EV7
1 a
n d a
nti
・-
Cox
A 16
in
inf
ants
at
7 m ont
hs
old
wer
e obvi
ous
ly
lower
ha
t n
be
for
e a
nd t
hei
r
mo
the
rs, ̄=1
48.
05,P <o
.01
;
=
7.7
9,P <
0.0
1,
respect
ively.
<8 1:
8
M ean GM Ts
in pr
enat
al w om en was
61,
9: G M 11
s i
n ant
i EV7】& ant
i.CoxA 】
6 ofmot
hers
i
nfants
at
2 mont
hs of
age was
1
8.0:whi
le t
he mean
Fi
gur
e.Compar
ison of
GM Ts
among neonat
es gi
ven bi
rth
by
GM 11
s Of i
nfant
s at
7 mont
hs of age increased t
o 35.
6
m ot
her
s w ho owned di
fer
ent
level
s of
ant
ibodi
es at
2 m ont
hs
f1、
able 1
1.Among 6 i
nrants
at
7 months
of
age who were ol
d.。
:A nt
i—EV7
1 GM Ts
in i
nfn t
a s w hos
e mot
her
s cam e
from
posit
ive for ant
i.Cox A 1
6. 3 i
nfant
s’ ant
ibody t
iter gr
oup
wi
tll
l:
32一 of a
nti
—EV71
w as
si
gni
icant
f ly hi
gher
than
i
ncreas
ed more t
han four
-fbl
d compari
ng t
o t
hat
at
2 negat
ive group a
n d gr
oup w i
th 1:
8- of
nt
a i—EV71.P <0.
05. :
mol
lths
of age.2 i
nfant
s’ant
i—Cox A
1
6 ant
ibody t
iter Anti—
EV71 GM Ts i
n inr
ant
s whos e mot
h ers
came f
rom group
wih great
t er
than 1:1
28 of
Ant
i—EV7 1
was s
igniica
f ntl
y hi
gher
increased from 0 to f
ourfol
d.The above resul
ts i
ndicat
ed
t
han negat
ive gr
oup a
n d group
wi m 1:8- a
nd gr
oup wi
m l:32_
3 out of 133 had been i
napparent
ly i
nfect
ed by Cox A16,
of
ant
i—EV71.P <0.
05.
:Ant
i—Cox
A16
GM Ts
in i
nfnt
a s
whos
e
bet
ween 2 t
o 7 mont
hs of age.t
he i
nappar
ent
infect
ion m ot
h er
s’ant
i—Cox A 1
6 gr
eat
er t
hal
l 1:
128 was
si
gni
icant
f ly
r
ate of
Cox A1
6 was
2.
3% (
3/133)
.Dur
ing f
oll
ow—
uD hi
gher
tha
n gr
oup
wit
h negat
ive
and 1:
8-and
1:32一of
nt
a i
—Cox
peri
od.t
here
w ere
no cl
ini
cal
si
gns
of
HFM D occured
in A 16.P <0.
05.
∞
g ul
0∞l
1罢 0
t
he above
3 i
nfants
who
were
inappar
ent
ly
inf
ect
ed
by
the
A1
6 was
lower
thf
in t
hat
at
2 mont
h of
age.meanwhi
le.
vi
ms;not
icea
6
bly
,onl
y o
4
ne
inf
a
2
nt
r0.
75%.No:Y120036)
O 8 6
4 2 0
s
howed
a cont
inuous
ti
ter
decl
ine(
T{l
ble
2 .
t
he ant
i—EV7l
ti
ter
of t
his i
nfant
increased fourf
old.
i
ndicaf
ing [he
inapparent
EV7 1
infect
ion of
this
anti—Cox
Di
stri
buti
on
of
ant
i.Cox
A16
in
pai
rs
of
blood
sam pl
es A1
6 rem ai
ned positi
ve in i
nfant.W l
e also noticed that
from
prenat
a1 wom en
and
thei
r i
nfants f
our
fol
d ant
ibody t
iter i
ncreas
e of
bot
h a
nti
.EV7
1 a
n d
The
ant
i.Cox A16
level
of
infants
at
2
mont
hs of
age was
nt
a i
—Cox A l6 i
n 2 i
nfants;t
hey were i
nfect
ed by bot
h
st
rat
ined
by
mot
her’
s serum
ant
ibody t
iti
ers.As
shown i
n EV71
and
Cox
A 16 between 2 t
o 7
mont
hs of
age.whi
ch
1、abl
e 3.10 mot hers
and their
2一
mont h—old infants
were sugges
ted t
he i
nci
dence of
dual
inappar
ent
inf
ect
ion rat
e
seronegat
ive f
o r ant
i.Cox A l6.w hi
le am ong 3 1
infant
s by
EV71
and
CoxA16
was
1.
5% (
2/133)(
11ab1
e 4)
.
whose mot
her
s wer
e i
n weak posi
tive group,l
7(
55%)
DISCUSSION
wer
e s
eronegat
ive
and 1
4(45%、we
re weak pos
iti
ve;
among 57 i
nfant
s whose mot
her
s wer
e mi
ddl
e posi
tive.
HFM D has
been emer
ging as
a
m ost
import
ant
infect
ious
36 (
63%1
wer
e s
eronegat
ive, 1
8 (
32%) wer
e wea
k
posi
tive a
n d 3 f
5% 1
were m
i ddl
e posi
tive;among 35 di
sease among chi
ldren i
n recent
years
in Chi
na.A t
otal
i
nfant
s whose
mot
hers
wer
e hi
gh
posi
tive,1
9(54% )were of
488
955 cases
wer
e r
eport
ed,i
ncl
udi
ng 126 deat
hs i
n
s
eronega
tive,8(
23%)wer
e wea
k pos
iti
ve,7(
20%)wer
e 2008.i
n t
he year af
ter
HFM D was
int
egr
ated i
nto t
he
i ddl
m e posi
tive
and 1
f3%)was
hi
gh
posi
tive.
Nat
ional
Not
iiabl
f e Di
seas
es Repor
ting Syst
em
f
NNDRS1.
A
number
of
evi
dences
have shown
that
the
As
shown
in
Figure.a corr
elat
ion s
im il
ar
to
that
of
GM Ts
causat
ive
pat
hogens
are
EV71
and/
or
Cox
Al
6,Theref
o re.
of nt
a i—EV7 1 bet
ween infant
s at
2 months
ol
d and t
hat
of devel
opi
ng pr
ophyl
act
ic vacci
ne f
or t
he cont
rol
of
thei
r paired mother at
pregnancy was demonstr
ated f
or epi
dem
i c EV71
a
n d/
or Cox A 16 i
nfect
ion i
s i
n
ant
i—Cox A16.乃 e mean ant
i—Cox A 16 GM Ts
of
infant
s i
m m edi
atel
y ur
gent.
at
2 mont
hs of age i
ncr
eased f
rom 1:
4.0 t
0 1:
10.
2.wi
th
t
he i
ncr
eas
e of ant
i.Cox A
1
6 GM Ts
in ser
um of pai
red The EV7
1 vi
rus
st
rai
n used i
n neut
ral
izat
ion t
est
may
m ot
hers
at
pregnancy.
i
nfluence t
he meas
urement
of
neut
ral
izi
ng ant
ibody.Our
r
esul
ts(
unpubl
ishe
d) s
hown
tha
t t
her
e was
si
gni
ic
f ant
Dual
seroposi
tive
of
anti
・-
EV71
and
anti
--
Cox
A16
in di
fference bet
l ween
usi
ng
C4 or
A genot
ype;even i
f t
hey
pai
rs
of
blood
sampl
es col
lected
from prenatal
wom en are bot
h of
C4 subt
ype,di
ferent
resul
ts
may be acqui
red
and
thei
r i
nfant
s by using di
ffer
ent
viu s s
r train.M izut
a et
al
had used si
x
The dual
seroposi
tive rat
e of bot
h ant
i.EV7
l and subtypes Of EV7 1
virus stains t
o measure the ti
cers
Of
a
nti
—Cox
Al6
in
prenat
a1
women
was
75.
9% (
101
/133)
, neut
ra1
izi
ng ant
ibOdi
es i
n bl
OOd s
ampl
es col
1ect
ed f
om
whi
le t
he dual
seropos
iti
ve rat
e i
n i
nfants
at
2
m ont
hs of pOpu1
ati
On, t
he di
虢 r
ence cont
ained i
n f
ouff
0ld.
T0
a
ge
was
12.
1%f
l6/1
33)a
nd
it
dec
reas
ed
to
3.0% (
4/l33)
ens
ure t
he accuracy Of meas
urement
0f neut
mli
zing
i
n i
nfant
s at
7 mont
hs of
age.Among 4
infant
s wi
th
bot
h ant
ibodV, a er pe r
ming of pre.
neut
ral
izat
i0n test
bV
ant
ibodi
es posi
tive at
7 m ont
hs of age, one’
s ant
i—Cox usi
ng di
fl
fer
ent
s
ubt
ype s
trai
ns,
we sel
ect
ed
EV71/
Fuyang/
m01
/2008 and Cox A 16 /G一10 st
rai
n f
or t
ime—
poi
nts
for
immunizat
ion of pol
io, measl
es and
neut
ral
izat
iOn t
est
to m eas
ure ei
ther ant
i—EV 7
l Or
hepat
iti
s A
vir
us vacci
nes.So
expl
oring
the weaken t
rend
ant
i—Cox
A1
6. of
m aternal
ant
ibody f
or
EV 7
1 a
n d
Cox
A 16 wer
e cruci
al
or
f est
abl
ishment
of pr
ime i
m unizat
ion course,and i
t
Res
ult
s fr
om t
his
st
udy show n, seroposi
tive rat
e of
w as
als
o hel
pful
to avoi
d t
he i
nter
rupt
ion of m at
ernal
ant
i—EV7
l i
n Ji
angs
u provi
nce was
79.
7%.whi
ch was
ant
ibody
and
prot
ect
suscept
ibl
e popul
ati
on.
si
gni
icant
f ly hi
gher
than t
he 50% —60% rat
e i
n Tai
w an of
Chi
na and 44% rat
e i
n Si
ngapore.
t
his
suggest
ed It
was
report
ed t
hat
HFM D even
occur
red i
n i
nrant
s aged
higher rat
e of EV7 1 i
nf ecti
on exist
ing in Chinese no m or
e t
han 3 mont
hs,even as young as
4 weeks
ol
d,
populati
on Up t o no there were only a f
ew s
tudies and l
eaded t
o seri
OUS
compl
icat
ions.
。Thi
s st
u dy s
hown
f
ocused on m at
em al
ant
i—EV 7
1 and ant
i.Cox A
1
6 t
hat
seroposi
tive rat
es of
ant
i—EV7
1 and ant
i.Cox A
l
6 i
n
ant
ibody i
n i
nfants.A ccordi
ng to t
he resul
ts cam e f
rom i
nfants at 2 months of
age were signiicant
f l
y lower t
han
EV7
l neut
ral
izi
ng ant
ibody assay i
n a popul
ati
on aged t
he l
evel
i n
prenatal
wom en.Rates of
inapparent
inf
ecti
on
bet
w een 1
and 22 m ont
hs i
n Si
ngapore.t
he m ater
nal
i
n i
nfant
s dur
ing a per
iod bet
ween 2 and 7 mont
hs age
ant
ibody agai
nst
EV7
1 decr
eased rapi
dly i
n i
nfant
s.and wer
e 12.
8% and 2.
3% . res
pect
ivel
y. Consi
der
ing t
hat
becam e negat
ive aft
er one m ont
h age.
I
n cont
rast
,the al
tem at
ive and m
i x i
nfect
ion r
ate were hi
gher i
n t
he
pr
esent
st
udy s
howed t
he t
ransferr
ed EV7
l mater
nal
mai
nland of Chi
na, we recomm end t
hat
the bi
val
ent
a
nti
body
was
hi
ghe
r(25.
6%)
。even
in
inf
ant
s a
t 2
mont
hs vacci
ne whi ch contains EV71 and Cox A16 ant igens
of age. The diference may attibut
r e t
o di
ffer
ent shoul
d be
devel oped t
o prot
ect
chi
ldren f
rom
HFM D ,and
ser
opositive r
ates
an d GM Ts of ant
i.EV 7
1 bet
ween the bas
ed on l
ocal
epi
demi
ology, we suggest
s sel
ect
ion
t
wo count
ies (
r 79.7% vs .44.
O% a nd 29.0 vs.17.
8. bet
ween
2 t
o 5 mont
hs of
age
as
the
prim e
immuni
zat
ion
r
especti
vel
y).No infant
at
7
months
of
age
was
obse
rved t
im epoi
nt.
m at
ernal
ant
i—EV7 a
nti
body out
,w hi
ch was
si
mil
ar
wit
h
t
he 1% resul
ts
of
infant
s at
6 mont
hs of
age i
n Tai
wan
of REFERENCES
China —
1.
Chan
YF
A buBaker
S.Recom bi
nant
hum an
ent
erovi
rus
7
1 i
n
ha
nd,f
oot
n d
a mout
h di
sease
Pa
tient
s.Em e职 I
nfect
Di
s 2004;
Cox
A 1
6 i
s a
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