Efficacy, safety and immunogenicity of a human rotavirus vaccine (RIX4414) in Hong Kong children up to three years of age: A randomized, controlled trial

Article (PDF Available)inVaccine 31(18) · March 2013with104 Reads
DOI: 10.1016/j.vaccine.2013.03.001 · Source: PubMed
Abstract
Background: A phase III, double-blind, randomized, controlled trial was conducted in Hong Kong to evaluate the efficacy, safety and immunogenicity of a human rotavirus vaccine, RIX4414 (Rotarix) against severe rotavirus gastroenteritis in children up to three years of age. Methods: Healthy infants aged 6-12 weeks were enrolled between 08-December-2003 and 31-August-2005 and received two oral doses of either RIX4414 vaccine (N=1513) or placebo (N=1512) given 2 months apart. Vaccine efficacy was assessed from two weeks post-Dose 2 until the children were two and three years of age. Anti-rotavirus IgA seroconversion rate was calculated pre-vaccination and 1-2 months post-Dose 2 using ELISA (cut-off=20 U/mL) for 100 infants. Safety was assessed until the children were two years of age; serious adverse events (SAEs) were recorded throughout the study period. Results: In children aged two and three years of life, vaccine efficacy against severe rotavirus gastroenteritis was 95.6% (95% CI: 73.1%-99.9%) and 96.1% (95% CI: 76.5%-99.9%), respectively. The seroconversion rate 1-2 months after the second dose of RIX4414 was 97.5% (95% CI: 86.8%-99.9%). At least one SAE was recorded in 439 and 477 infants who were administered RIX4414 and placebo, respectively (p-value=0.130). Six intussusception cases were reported (RIX4414=4; placebo=2) and none was assessed to be vaccine-related. Conclusion: RIX4414 was efficacious, immunogenic and safe in the prevention of rotavirus gastroenteritis for at least two years post-vaccination in Hong Kong children.

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Vaccine
31 (2013) 2253–
2259
Contents
lists
available
at
SciVerse
ScienceDirect
Vaccine
jou
rn
al
h
om
epa
ge:
www.elsevier.com/locate/vaccine
Efficacy,
safety
and
immunogenicity
of
a
human
rotavirus
vaccine
(RIX4414)
in
Hong
Kong
children
up
to
three
years
of
age:
A
randomized,
controlled
trial
Yu-Lung
Lau
a,1
,
E.
Anthony
S.
Nelson
b,,2
,
Kin-Hung
Poon
c
,
Paul
K.S.
Chan
d
,
Susan
Chiu
a
,
Rita
Sung
b
,
Chi
Wai
Leung
e
,
Daniel
Ng
f
,
Yee
Man
Ma
g
,
Desmond
Chan
h
,
Tsz
Leung
Lee
i
,
Joyce
Tang
j
,
Yat
Wah
Kwan
e
,
Patricia
Ip
h
,
Marco
Ho
i
,
Lai-Wah
Eva
Fung
b
,
Haiwen
Tang
k
,
P.V.
Suryakiran
l
,
Htay
Htay
Han
m
,
Hans
Bock
n
,
Hong
Kong
Rotarix
Study
Group
a
Department
of
Paediatrics
and
Adolescent
Medicine,
The
University
of
Hong
Kong,
Hong
Kong
b
Department
of
Paediatrics,
The
Chinese
University
of
Hong
Kong,
Hong
Kong
c
Department
of
Paediatrics
and
Adolescent
Medicine,
Tuen
Mun
Hospital,
Hong
Kong
d
Department
of
Microbiology,
The
Chinese
University
of
Hong
Kong,
Hong
Kong
e
Department
of
Paediatrics
and
Adolescent
Medicine,
Princess
Margaret
Hospital,
Hong
Kong
f
Department
of
Paediatrics,
Kwong
Wah
Hospital,
Hong
Kong
g
Department
of
Paediatrics
and
Adolescent
Medicine,
Pamela
Youde
Nethersole
Eastern
Hospital,
Hong
Kong
h
Department
of
Paediatrics
and
Adolescent
Medicine,
United
Christian
Hospital,
Hong
Kong
i
Department
of
Paediatrics
and
Adolescent
Medicine,
Queen
Mary
Hospital,
Hong
Kong
j
United
Christian
Nethersole
Community
Health
Service,
Hong
Kong
k
GlaxoSmithKline
Vaccines,
Shanghai,
China
l
GlaxoSmithKline
Pharmaceuticals,
Bangalore,
India
m
GlaxoSmithKline
Vaccines,
King
of
Prussia,
PA,
USA
n
GlaxoSmithKline
Vaccines,
Singapore
a
r
t
i
c
l
e
i
n
f
o
Article
history:
Received
17
October
2012
Received
in
revised
form
27
February
2013
Accepted
1
March
2013
Available online 13 March 2013
Keywords:
Efficacy
Gastroenteritis
Hong
Kong
Intussusception
Rotavirus
Safety
a
b
s
t
r
a
c
t
Background:
A
phase
III,
double-blind,
randomized,
controlled
trial
was
conducted
in
Hong
Kong
to
evaluate
the
efficacy,
safety
and
immunogenicity
of
a
human
rotavirus
vaccine,
RIX4414
(Rotarix
TM
)
against
severe
rotavirus
gastroenteritis
in
children
up
to
three
years
of
age.
Methods:
Healthy
infants
aged
6–12
weeks
were
enrolled
between
08-December-2003
and
31-August-
2005
and
received
two
oral
doses
of
either
RIX4414
vaccine
(N
=
1513)
or
placebo
(N
=
1512)
given
2
months
apart.
Vaccine
efficacy
was
assessed
from
two
weeks
post-Dose
2
until
the
children
were
two
and
three
years
of
age.
Anti-rotavirus
IgA
seroconversion
rate
was
calculated
pre-vaccination
and
1–2
months
post-Dose
2
using
ELISA
(cut-off
=
20
U/mL)
for
100
infants.
Safety
was
assessed
until
the
children
were
two
years
of
age;
serious
adverse
events
(SAEs)
were
recorded
throughout
the
study
period.
Results:
In
children
aged
two
and
three
years
of
life,
vaccine
efficacy
against
severe
rotavirus
gastroenteritis
was
95.6%
(95%
CI:
73.1%–99.9%)
and
96.1%
(95%
CI:
76.5%–99.9%),
respectively.
The
seroconversion
rate
1–2
months
after
the
second
dose
of
RIX4414
was
97.5%
(95%
CI:
86.8%–99.9%).
Abbreviations:
ARSN,
Asian
Rotavirus
Surveillance
Network;
ATP,
According-to-protocol;
CCID
50
,
Cell
culture
infectious
dose;
DTPa,
Diphtheria-tetanus-acellular
pertussis;
DTPw,
Diphtheria-tetanus-whole
cell
pertussis;
ELISA,
Enzyme-linked
immunosorbent
assay;
GMCs,
Geometric
mean
concentrations;
Hib,
Haemophilus
influenzae
type
b;
ICD,
International
Classification
of
Diseases;
IPV,
Inactivated
polio
vaccine;
OPV,
Oral
polio
vaccine;
RT-PCR,
Reverse
transcriptase
polymerase
chain
reaction;
RVGE,
Rotavirus
gastroenteritis;
SAE,
Serious
adverse
event;
U/mL,
Units
per
milliliter;
WHO,
World
Health
Organization.
Corresponding
author
at:
Department
of
Paediatrics,
The
Chinese
University
of
Hong
Kong
Prince
of
Wales
Hospital,
Shatin,
Hong
Kong,
China.
Tel.:
+852
26322861;
fax:
+852
26360020.
E-mail
addresses:
lauylung@hku.hk
(Y.-L.
Lau),
tony-nelson@cuhk.edu.hk
(E.A.S.
Nelson),
pkh978@ha.org.hk
(K.-H.
Poon),
paulkschan@cuhk.edu.hk
(P.K.S.
Chan),
ssschiu@hkucc.hku.hk
(S.
Chiu),
yntzsung@cuhk.edu.hk
(R.
Sung),
leungcw@ha.org.hk
(C.W.
Leung),
dkkng@ha.org.hk
(D.
Ng),
maskmanma@yahoo.com
(Y.M.
Ma),
cw.chan@mail.stpaul.org.hk
(D.
Chan),
leetl@hkucc.hku.hk
(T.L.
Lee),
joycesf.tang@ucn.org.hk
(J.
Tang),
kwanyw1@ha.org.hk
(Y.W.
Kwan),
patipls@gmail.com
(P.
Ip),
a8914760@graduate.hku.hk (M.
Ho),
eva
fung@cuhk.edu.hk
(L.-W.E.
Fung),
haiwen.h.tang@gsk.com
(H.
Tang),
p.v.suryakiran@gsk.com
(P.V.
Suryakiran),
htay.h.han@gsk.com
(H.H.
Han),
halubo@yahoo.com
(H.
Bock).
1
Principal
Investigator,
The
University
of
Hong
Kong.
2
Principal
Investigator,
The
Chinese
University
of
Hong
Kong.
0264-410X/$
see
front
matter ©
2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.vaccine.2013.03.001
2254 Y.-L.
Lau
et
al.
/
Vaccine
31 (2013) 2253–
2259
At
least
one
SAE
was
recorded
in
439
and
477
infants
who
were
administered
RIX4414
and
placebo,
respectively
(p-value
=
0.130).
Six
intussusception
cases
were
reported
(RIX4414
=
4;
placebo
=
2)
and
none
was
assessed
to
be
vaccine-related.
Conclusion:
RIX4414
was
efficacious,
immunogenic
and
safe
in
the
prevention
of
rotavirus
gastroenteritis
for
at
least
two
years
post-vaccination
in
Hong
Kong
children.
© 2013 Elsevier Ltd. All rights reserved.
1.
Introduction
In
2008,
diarrhea
attributable
to
rotavirus
infection
was
estimated
to
have
resulted
in
453,000
deaths
worldwide
(95%
CI:
420,000–494,000)
in
children
aged
less
than
5
years
[1].
An
estimated
41%
(188,000)
of
these
deaths
occurred
in
the
Asian
region
[1].
The
World
Health
Organization
(WHO)
recommends
that
rotavirus
vaccines
should
be
used
in
all
countries,
and
considered
a
priority
especially
in
countries
with
high
rotavirus-
related
mortality
[2].
Rotavirus
is
prevalent
throughout
Asia
and
is
an
important
cause
of
gastroenteritis
requiring
hospitalization
and
medical
care
in
children
aged
less
than
5
years
[3].
Data
derived
through
passive
surveillance
of
rotavirus
underestimated
the
disease
burden
in
Hong
Kong
[4]
and
highlighted
the
need
for
active
rotavirus
surveillance
[5].
The
first
phase
of
the
Asian
Rotavirus
Surveillance
Network
(ARSN)
conducted
across:
China,
Hong
Kong,
Indonesia,
Malaysia,
Myanmar,
South
Korea,
Taiwan,
Thailand
and
Vietnam
between
2001–2003
[3,5],
showed
that
rotavirus
accounted
for
30–55%
of
hospitalization
in
children
aged
less
than
5
years
with
the
lowest
rotavirus-positivity
rate
(30%)
recorded
in
Hong
Kong
[3].
In
2006,
two
new
rotavirus
vaccines,
RIX4414
(Rotarix
TM
;
GlaxoSmithKline,
Belgium)
and
(Rotateq
TM
;
Merck
Vaccines)
became
available
[1].
In
studies
undertaken
in
the
Americas
and
Europe,
both
were
reported
to
be
highly
efficacious
and
were
not
associated
with
any
safety
concerns
in
children
during
the
first
two
years
of
life
[6–9].
This
three-year
study
was
conducted
in
high-income
regions
of
Southeast
and
East
Asia
(Singapore,
Hong
Kong
and
Taiwan)
to
evaluate
the
efficacy,
safety
and
immunogenicity
of
the
RIX4414
vaccine.
The
overall
efficacy
results
have
been
previously
presented
elsewhere
[10,11]
and
this
publication
describes
specific
data
pertaining
to
the
efficacy,
safety
and
immunogenicity
of
RIX4414
vaccine
in
a
pediatric
population
in
Hong
Kong.
2.
Materials
and
methods
2.1.
Study
design
and
infants
This
phase
III,
randomized,
double-blind,
placebo-controlled
study
(NCT00197210)
was
conducted
at
eight
public
hospitals
in
Hong
Kong.
The
study
protocol
and
related
documents
were
approved
by
the
ethics
committee
of
the
individual
study
centers
and
the
study
was
conducted
in
accordance
with
Good
Clinical
Practice
guidelines.
Parents
or
legal
guardians
of
the
participating
infants
provided
written
consent
before
any
study-
related
procedure
was
undertaken.
Healthy
infants
6–12
weeks
of
age
were
equally
randomized
(1:1
blocking
scheme)
to
receive
two
doses
of
either
RIX4414
vaccine/placebo
at
2
and
4
months
of
age.
Participants
received
a
combined
diphtheria-tetanus-
acellular
pertussis
[DTPa],
inactivated
poliovirus
[IPV]
and
Haemophilus
influenzae
type
b
[Hib]
vaccine
(Infanrix
TM
IPV/Hib;
GlaxoSmithKline,
Belgium)
concomitantly
with
the
study
vaccines
according
to
the
local
vaccination
schedules.
Alternatively,
if
requested,
participants
could
receive
diphtheria-tetanus-whole
cell
pertussis
[DTPw],
and
oral
poliovirus
vaccine
[OPV]
at
Maternal
and
Child
Health
Centres
for
routine
vaccination.
According
to
Hong
Kong
government
policy,
infants
received
a
birth
dose
of
Bacillus
Calmette-Guérin,
hepatitis
B
and
OPV
vaccines.
Two
weeks
lapsed
between
the
administration
of
any
OPV
dose
and
the
RIX4414
vaccine/placebo;
the
second
and
third
doses
of
hepatitis
B
vaccines
were
administered
at
1
and
6
months
of
age.
Infants
were
ineligible
to
participate
if
they
had
previously
received
any
investigational
drug/vaccine
30
days
before
the
study,
had
allergy
to
any
of
the
vaccine
components,
or
were
immunosuppressed
or
had
a
history
of
chronic
gastrointestinal
disease.
2.2.
Study
objectives
and
end
points
The
first
co-primary
objective
of
this
study
was
to
evaluate
the
efficacy
of
the
RIX4414
vaccine
against
severe
rotavirus
gastroenteritis
from
two
weeks
after
the
second
vaccine
dose
until
two
years
of
age.
The
second
co-primary
objective
was
to
assess
the
safety
of
the
vaccine
with
regard
to
occurrence
of
definite
intussusception
within
31-days
following
each
vaccine
dose.
2.3.
Vaccine
Each
dose
of
the
lyophilized
formulation
of
RIX4414
(Rotarix
TM
,
GlaxoSmithKline,
Belgium)
vaccine
contained
at
least
10
6.0
median
cell
culture
infectious
dose
(CCID
50
)
of
live,
attenuated
human
G1P[8]
rotavirus.
The
placebo
had
the
same
constituents
and
appearance
as
the
active
vaccine
but
without
the
vaccine
viral
strain.
Both,
the
RIX4414
vaccine
and
placebo
were
reconstituted
in
a
calcium
carbonate
buffer
before
oral
administration.
RIX4414
vaccine
lot
numbers
RVC018A42,
RVC019A43
and
RVC021A44
were
used.
Lot
numbers
DD05A003A,
DD05A003B
and
DD05A003C
were
used
for
the
calcium
carbonate
buffer
and
RVC020A41PL
was
used
for
placebo.
2.4.
Assessment
of
efficacy
The
surveillance
for
gastroenteritis
episodes
started
from
the
first
dose
of
RIX4414
vaccine/placebo
and
continued
until
the
children
were
three
years
of
age.
A
gastroenteritis
episode
was
defined
as
the
occurrence
of
diarrhea
[three
or
more,
looser
than
normal
stools
within
a
day]
with
or
without
vomiting.
If
there
was
an
interval
of
five
or
more
symptom-free
days
between
the
two
gastroenteritis
episodes,
they
were
considered
as
two
different
episodes.
Hospital/medical
facility
surveillance
ensured
that
all
gastroenteritis
cases
requiring
hospitalization
and/or
re-hydration
therapy
(equivalent
to
WHO
plan
B
[oral
re-
hydration
therapy
for
children
with
some
dehydration
in
a
medical
facility]
or
C
[intravenous
re-hydration
for
severe
dehydration
in
a
medical
facility])
[12]
were
recorded.
Study
personnel
accessed
computerized
admission
databases
in
the
study
centers
on
a
daily
basis
to
determine
whether
any
study
participants
had
been
admitted
to
public
hospitals.
In
addition,
study
personnel
contacted
families
by
telephone
at
least
every
month
to
determine
any
admissions
to
private
hospitals.
For
each
qualifying
episode
of
gastroenteritis,
parents/guardians
of
infants
completed
a
gastroenteritis
diary
card
every
day
until
Y.-L.
Lau
et
al.
/
Vaccine
31 (2013) 2253–
2259 2255
two
days
after
the
gastroenteritis
symptoms
had
ceased.
Diarrheal
stool
samples
were
collected
as
soon
as
possible
(within
7
days)
after
hospitalization
for
the
treatment
of
dehydration.
The
severity
of
the
gastroenteritis
episodes
was
assessed
using
a
20-Point
Vesikari
Scale
where
a
score
of
11
was
considered
to
be
severe
[13].
Stool
samples
were
stored
between
20
C
and
70
C
until
transported
to
GlaxoSmithKline
Biologicals
laboratory
where
they
were
analyzed
for
rotavirus
using
enzyme-linked
immunosorbent
assay
(ELISA;
RotaClone
TM
assay,
Meridian
Biosciences,
USA).
Rotavirus-positive
stool
samples
were
subsequently
transported
to
Delft
Diagnostic
Laboratory,
the
Netherlands
(where
they
were
stored
at
4
C)
and
tested
using
reverse
transcriptase
polymerase
chain
reaction
(RT-PCR)
followed
by
reverse
hybridization
to
determine
the
G
and
P
types
[14].
2.5.
Assessment
of
safety
Vaccine
safety
was
assessed
with
respect
to
serious
adverse
events
(SAEs),
intussusception
cases,
hospitalizations
and
deaths
starting
from
Dose
1
until
the
children
were
two
years
of
age.
Although
safety
was
not
an
endpoint
during
the
follow-
up
period
between
Year
2
and
Year
3,
investigators
were
asked
to
report
any
unusual
or
vaccine-related
SAEs
during
this
period.
2.6.
Assessment
of
immunogenicity
Blood
samples
from
a
subset
of
100
infants
were
collected
before
vaccination
and
one
to
two
months
post-Dose
2
of
RIX4414
vaccine/placebo.
All
children
were
invited
to
participate
in
the
immunogenicity
subset,
and
the
first
100
infants
with
parental
consent
had
blood
taken
to
measure
the
serum
anti-rotavirus
IgA
antibody
concentrations
using
an
in-house
ELISA
[15];
cut-off
was
20
Units
per
milliliter
(U/mL).
2.7.
Statistical
analyses
All
statistical
analyses
were
performed
using
SAS
8.2
(SAS
Institute
Inc.,
USA)
and
95%
Confidence
Interval
(CI)
was
calculated
using
Proc
StatXact-5
(Cytel
Software
Corporation,
USA).
The
details
of
the
sample
size
calculation
have
been
previously
presented
[10,11].
Primary
vaccine
efficacy
analysis
was
performed
from
two
weeks
post-Dose
2
until
two
years
of
age.
Secondary
vaccine
efficacy
analysis
was
performed
from
two
weeks
post-Dose
2
until
three
years
of
age.
Both
vaccine
efficacy
analyses
were
performed
on
the
according-to-protocol
(ATP)
efficacy
cohort
with
95%
CI.
The
ATP
efficacy
cohort
included
infants
who
had
received
two
doses
of
RIX4414
vaccine/placebo,
who
had
entered
the
efficacy
follow-up
period
and
who
had
no
rotavirus
other
than
the
vaccine
strain
in
their
gastroenteritis
stool
samples.
Estimates
of
vaccine
efficacy
against
severe
rotavirus
gastroenteritis
caused
by
wild-type
rotavirus,
against
rotavirus
gastroenteritis
requiring
hospitalization
and
against
all-cause
severe
gastroenteritis
were
calculated
during
the
period
starting
from
two
weeks
post-Dose
2
until
two
and
three
years
of
age,
respectively.
One
to
two
months
post-Dose
2
of
RIX4414
vaccine/placebo,
the
anti-rotavirus
IgA
antibody
seroconversion
rate
(anti-rotavirus
IgA
antibody
concentration
20
U/mL
in
infants
previously
seronegative)
and
corresponding
geometric
mean
concentrations
(GMCs)
were
measured
with
95%
CI
estimated.
3.
Results
3.1.
Demography
A
total
of
3025
infants
(RIX4414
=
1513;
placebo
=
1512)
were
enrolled
in
Hong
Kong
between
08-December-2003
and
31-
August-2005
and
were
followed
until
three
years
of
age
for
vaccine
efficacy.
The
ATP
cohort
for
efficacy
at
the
two-
and
three-year
follow-up
periods
included
2993
infants.
The
reasons
for
excluding
subjects
from
the
analyses
are
presented
in
Fig.
1.
There
was
no
difference
between
the
treatment
groups
with
respect
to
age,
gender
and
race.
The
mean
age
of
infants
was
11.6
weeks
(standard
deviation
[SD]:
2.37)
at
Dose
1
and
17.8
weeks
(SD:
1.53)
at
Dose
2
of
RIX4414/placebo.
According
to
Hong
Kong’s
routine
immunization
schedule,
the
majority
of
infants
(99.8%)
in
the
RIX4414
and
placebo
groups
received
a
birth
dose
of
OPV
before
Dose
1
of
RIX4414
vaccine/placebo.
Only
one
infant
received
OPV
between
Doses
1
and
2
of
the
RIX4414
vaccine.
All
other
infants
in
the
RIX4414
and
placebo
groups
received
DTPa-IPV-Hib
concomitantly
with
both
doses
of
RIX4414
vaccine/placebo.
3.2.
Vaccine
efficacy
Vaccine
efficacy
for
severe
rotavirus
gastroenteritis
was
95.6%
(95%
CI:
73.1%–99.9%)
up
until
two
years
of
age
(Table
1).
Vaccine
efficacy
against
rotavirus
gastroenteritis
requiring
hospitalization
was
91.3%
(95%
CI:
64.7%–99.0%)
while
vaccine
efficacy
against
gastroenteritis
due
to
any
etiology
requiring
hospitalization
was
36.8%
(95%
CI:
12.5%–54.6%)
in
the
first
two
years
of
life
(Table
1).
Similar
efficacy
results
were
obtained
during
the
follow-up
period
until
three
years
of
age
(Table
1).
The
cumulative
incidence
of
severe
rotavirus
gastroenteritis
during
the
first
two
years
of
life
was
0.1%
(1/1494)
among
RIX4414
recipients
and
1.5%
(23/1499)
among
placebo
recipients;
the
difference
was
statistically
significant
(p-value
<
0.001).
Similar
results
for
cumulative
incidence
during
the
first
three
years
of
life
are
shown
in
(Table
1).
The
RV
types
isolated
during
severe
rotavirus
gastroenteritis
episodes
up
until
three
years
of
age
were
wild-type
G1P[8]
(placebo
=
10),
G3P[8]
(RIX4414
=
1;
placebo
=
11)
and
G9P[8]
(placebo
=
3).
3.3.
Safety
No
case
of
intussusception
was
reported
within
the
31-days
following
each
vaccine
dose.
Six
cases
of
intussusception
were
reported
in
the
follow-up
period
until
two
years
of
age;
four
cases
in
the
RIX4414
group
and
two
cases
in
the
placebo
group.
All
these
cases
occurred
between
2
and
19
months
after
the
second
dose
of
RIX4414
vaccine/placebo.
Five
of
the
children
(RIX4414
=
3;
placebo
=
2)
underwent
surgery
(laparotomy)
and
one
in
the
RIX4414
group
underwent
an
air
enema
procedure
for
the
reduction
of
intussusception.
No
case
was
considered
by
the
investigator
to
be
vaccine-related
and
all
the
infants
recovered
within
two
months
(range:
2–37
days).
No
further
case
of
intussusception
was
reported
during
the
Year
3
follow-up
period.
No
death
was
reported
throughout
the
study.
In
the
follow-up
period
from
Dose
1
until
two
years
of
age,
at
least
one
SAE
was
recorded
in
439
infants
in
the
RIX4414
group
and
477
infants
in
the
placebo
group
(p-value
=
0.130)
(data
not
shown).
Based
on
the
discharge
diagnosis
International
Classification
of
Diseases
(ICD)
codes,
gastroenteritis-related
symptoms
that
required
hospitalization
at
least
once
were
recorded
in
119
RIX4414
infants
and
147
infants
in
the
placebo
group
(Table
2).
2256 Y.-L.
Lau
et
al.
/
Vaccine
31 (2013) 2253–
2259
Table
1
Efficacy
of
RIX4414
from
two
weeks
post-Dose
2
until
two
and
three
years
of
age
(ATP
cohort
for
efficacy).
Gastroenteritis
type
RIX4414
Placebo
Vaccine
efficacy
%
(95%
CI)
p-value
d
N
a
n
b
%
b
(95%
CI)
c
N
a
n
b
%
b
(95%
CI)
c
Severe
rotavirus
gastroenteritis
from
two
weeks
post-Dose
2
until
three
years
of
age
1494
1
0.1
(0.0–0.4)
1499
26
1.7
(1.1–2.5)
96.1
(76.5–99.9)
<0.001
Severe
rotavirus
gastroenteritis
from
two
weeks
post-Dose
2
until
two
years
of
age
1494
1
0.1
(0.0–0.4)
1499
23
1.5
(1.0–2.3)
95.6
(73.1–99.9)
<0.001
Severe
rotavirus
gastroenteritis
from
two
weeks
post-Dose
2
until
Year
1
1494 0 0.0
(0.0–0.2) 1499 8 0.5
(0.2–1.0)
100.0
(41.2–100.0)
0.008
Severe
rotavirus
gastroenteritis
from
Year
1–Year
2
1494
1
0.1
(0.0–0.4)
1498
15
1.0
(0.6–1.6)
93.3
(56.6–99.8)
<0.001
Severe
rotavirus
gastroenteritis
from
Year
2–Year
3
1461
0
0.0
(0.0–0.3)
1464
3
0.2
(0.0–0.6)
100.0
(<0.0–100.0)
0.250
Severe
rotavirus
gastroenteritis
from
two
weeks
post-Dose
2
until
three
years
of
age
G1
1494
0
0.0
(0.0–0.2)
1499
11
0.7
(0.4–1.3)
100.0
(60.0–100.0)
<0.001
G3
e
,
f
1494 1 0.1
(0.0–0.4) 1499 13 0.9
(0.5–1.5)
92.3
(48.6–99.8)
0.002
G9
1494
0
0.0
(0.0–0.2)
1499
4
0.3
(0.1–0.7)
100.0
(<0.0–100.0)
0.125
Hospitalization
due
to
rotavirus
gastroenteritis
from
two
weeks
post-Dose
2
until
three
years
of
age
1494
2
0.1
(0.0–0.5)
1499
27
1.8
(1.2–2.6)
92.6
(70.4–99.1)
<0.001
Hospitalization
due
to
rotavirus
gastroenteritis
from
two
weeks
post-Dose
2
until
two
years
of
age
1494
2
0.1
(0.0–0.5)
1499
23
1.5
(1.0–2.3)
91.3
(64.7–99.0)
<0.001
Hospitalization
due
to
rotavirus
gastroenteritis
from
two
weeks
post-Dose
2
until
Year
1
1494
0
0.0
(0.0–0.2)
1499
8
0.5
(0.2–1.0)
100.0
(41.2–100.0)
0.008
Hospitalization
due
to
rotavirus
gastroenteritis
from
Year
1-Year
2
1494
2
0.1
(0.0–0.5)
1498
15
1.0
(0.6–1.6)
86.6
(42.5–98.5)
0.002
Hospitalization
due
to
rotavirus
gastroenteritis
from
Year
2–Year
3
1461
0
0.0
(0.0–0.3)
1464
4
0.3
(0.1–0.7)
100.0
(<0.0–100.0)
0.125
Hospitalization
due
to
gastroenteritis
of
any
cause
from
two
weeks
post-Dose
2
until
three
years
of
age
1494
83
5.6
(4.4–6.8)
1499
119
*
7.9
(6.6–9.4)
30.0
(6.6–47.8)
0.011
Hospitalization
due
to
gastroenteritis
of
any
cause
from
two
weeks
post-Dose
2
until
two
years
of
age
1494
63
4.2
(3.3–5.4)
1499
100
*
6.7
(5.5–8.1)
36.8
(12.5–54.6)
0.004
Hospitalization
due
to
gastroenteritis
of
any
cause
from
two
weeks
post-Dose
2
until
Year
1
1494
21
1.4
(0.9–2.1)
1499
44
2.9
(2.1–3.9)
52.1
(17.7–73.0)
0.005
Hospitalization
due
to
gastroenteritis
of
any
cause
from
Year
1–Year
2
1494
42
2.8
(2.0–3.8)
1498
59
3.9
(3.0–5.1)
28.6
(-7.8–53.1)
0.105
Hospitalization
due
to
gastroenteritis
of
any
cause
from
Year
2–Year
3
1461
20
1.4
(0.8–2.1)
1464
21
1.4
(0.9–2.2)
4.6
(<0.0–50.9)
1.000
a
N
=
number
of
infants
included
in
each
group.
b
n/%
=
number/percentage
of
infants
recording
at
least
one
severe
rotavirus
gastroenteritis
episode/rotavirus
gastroenteritis
requiring
hospitalization
or
severe
gastroenteritis
regardless
of
any
cause
in
each
group.
c
95%
CI
=
95%
confidence
interval.
d
p-value
=
two-sided
Fisher’s
exact
test
(significant
level
of
˛
=
0.05).
e
One
infant
from
the
placebo
group
counted
in
G1
and
G3
categories
since
both
RV
strains
were
isolated.
f
One
infant
from
the
placebo
group
counted
in
G3
and
G9
categories
since
both
RV
strains
were
isolated.
*
Number
of
hospitalizations
did
not
represent
the
sum
of
hospitalizations
from
the
individual
years
because
a
subject
might
have
reported
a
gastroenteritis
episode
requiring
hospitalization
in
each
year;
however,
only
the
first
gastroenteritis
episode
requiring
hospitalization
was
considered
in
the
combined
year
follow-up.
Y.-L.
Lau
et
al.
/
Vaccine
31 (2013) 2253–
2259 2257
Tot
al enro
lled inf
ants (Tot
al
vaccinat
ed cohort)
(N = 3
025)
RIX4414 group (N = 1
513)
Placebo g
roup (N = 1
512)
ATP cohort for
efficacy from
2 weeks post-Dose 2 up to
one
years of age
(N = 1
494)
ATP cohort for
efficacy from
2 weeks post-Dose 2 up to
one
years of age
(N = 1
499)
Protoco
l forbidden vaccine
administered = 2
Randomi
zation code
bro
ken
*=
6
At least one study vaccine not
administered = 11
Protoco
l forbidden vaccine
administered = 2
Randomi
zation code
bro
ken
*=
3
At least one
study vaccine not
administered = 7
Rotavi
rus
posi
tiv
e (other
than
vaccine strain)
from Dose 1 till 2
weeks post-Dose 2 = 1
ATP cohort for
efficacy from
Year 1 to Year 2
(N = 1
494)
ATP cohort for
efficacy from
Year 1 to Year 2
(N = 1
498)
Subjects who
did n
ot enter into the
surveillanc
e peri
od
of th
e second
efficacy follow-up p
eriod = 0
Subjects who
did n
ot enter into the
surveillanc
e peri
od
of th
e second
efficacy follow-up p
eriod = 1
Subjects who
did n
ot enter into the
surveillanc
e peri
od
of th
e third
efficacy follow-up p
eriod = 33
Subjects who
did n
ot enter into the
surveill
anc
e peri
od
of th
e third
efficacy follow-up p
eriod = 34
ATP cohort for
efficacy from
Year 2 to Year 3
(N = 1
461)
ATP cohort for
efficacy from
Year 2 to Year 3
(N = 1
464)
Fig.
1.
CONSORT
flowchart.
Footnotes:
*
The
randomization
code
was
broken
for
the
following
reasons:
Kawasaki
disease
(RIX4414
=
2;
Placebo
=
2);
Non-fatal
SAEs—Constipation
(Placebo
=
1),
anorexia
(RIX4414
=
1),
poor
weight
gain
(RIX4414
=
1),
rash
(RIX4414
=
1)
and
gastroenteritis
(RIX4414
=
1).
Table
2
Gastroenteritis-related
serious
adverse
events
recorded
from
Dose
1
up
to
two
years
of
age.
RIX4414
N
a
=
1513
Placebo
N
a
=
1512
Difference
(RIX4414
minus
Placebo)
p-value
n
b
per
10,000
(95%
CI)
c
n
b
per
10,000
(95%
CI)
Value
(95%
CI)
Diarrhea
2
13.2
(1.6–47.7)
3
19.8
(4.1–57.9)
6.6
(46.4
to
30.3)
0.654
Hemorrhagic
diarrhea
1
6.6
(0.2–36.8)
0
0.0
(0.0–24.4)
6.6
(18.7
to
37.3)
0.317
Enteritis
3
19.8
(4.1–57.8)
2
13.2
(1.6–47.7)
6.6
(30.3
to
46.3)
0.655
Frequent
bowel
movements
1
6.6
(0.2–36.8)
0
0.0
(0.0–24.4)
6.6
(18.7
to
37.3)
0.317
Infectious
diarrhea
1
6.6
(0.2–36.8)
0
0.0
(24.4–6.6)
6.6
(18.7
to
37.3)
0.317
Campylobacter
intestinal
infection
0
0.0
(0.0–24.4)
2
13.2
(1.6–47.7)
13.2
(48.1
to
12.1)
0.157
Salmonella
gastroenteritis
19
125.6
(75.8–195.4)
25
165.3
(107.3–243.1)
39.8
(130
to
47.5)
0.361
Shigella
gastroenteritis
1
6.6
(0.2–36.8)
0
0.0
(0.0–24.4)
6.6
(18.7
to
37.3)
0.317
Bacterial
gastroenteritis
(unspecified)
2
13.2
(1.6–47.7)
0
0.0
(0.0–24.4)
13.2
(12.1–48.1)
0.157
Caliciviral
gastroenteritis
6
39.7
(14.6–86.1)
7
46.3
(18.6–95.2)
6.6
(60.3
to
45.5)
0.780
Norwalk
virus
1
6.6
(0.2–36.8)
0
0.0
(0.0–24.4)
6.6
(18.7
to
37.3)
0.317
Viral
gastroenteritis
(unspecified)
3
19.8
(4.1–57.8)
7
46.3
(18.6–95.2)
26.5
(77.7
to
17.4)
0.205
Dehydration 1
6.6
(0.2–36.8)
3
19.8
(4.1–57.9)
13.2
(52.3
to
19.2)
0.317
Food
poisoning
0
0.0
(0.0–24.4)
1
6.6
(0.2–36.8)
6.6
(37.4
to
18.7)
0.317
Gastritis
7
46.3
(18.6–95.1)
9
59.5
(27.3–112.7)
13.3
(71.9
to
42.9)
0.615
Vomiting
2
13.2
(1.6–47.7)
2
13.2
(1.6–47.7)
0.0
(36.2
to
36.2)
0.999
Miscellaneous
gastrointestinal
symptoms
70
462.7
(362.4–581.0)
90
595.2
(481.3–726.6)
133
(295–27.2)
0.103
At
least
one
symptom 119
147
a
N
=
number
of
subjects
having
received
at
least
one
dose.
b
n
=
number
of
subjects
reporting
at
least
once
the
specified
SAE.
c
95%
CI
=
95%
confidence
interval.
Note:
The
gastroenteritis-related
symptoms
reported
at
least
once
were
based
on
discharge
diagnosis
ICD
codes.
2258 Y.-L.
Lau
et
al.
/
Vaccine
31 (2013) 2253–
2259
Eight
vaccine-related
SAEs,
all
occurring
after
the
first
vaccine
dose,
were
recorded
(six
in
the
RIX4414
group
and
two
in
the
placebo
group).
They
comprised
rash
(RIX4414
=
1),
gastroenteritis
(RIX4414
=
3;
placebo
=
1),
constipation
(placebo
=
1),
anorexia
(RIX4414
=
1)
and
poor
weight
gain
with
frequent
bowel
movement
(RIX4414
=
1).
All
infants,
except
the
one
with
constipation,
were
hospitalized
for
these
SAEs
and
all
recovered.
3.4.
Immunogenicity
One
to
two
months
post-Dose
2,
the
anti-rotavirus
IgA
antibody
seroconversion
rate
in
the
subset
of
100
infants
was
97.5%
(95%
CI:
86.8%–99.9%)
in
the
RIX4414
group,
with
a
GMC
of
314.6
U/mL
(95%
CI:
215.1–460.1).
None
of
the
infants
in
the
placebo
group
seroconverted
for
anti-rotavirus
IgA
antibodies
and
the
GMCs
in
this
group
were
below
20
U/mL.
4.
Discussion
This
was
the
first
study
to
report
detailed
efficacy,
safety
and
immunogenicity
data
for
the
RIX4414
vaccine
specifically
in
children
from
Hong
Kong.
Further
data
on
rotavirus
and
all-cause
gastroenteritis
may
be
useful
in
making
informed
decisions
on
the
use
of
rotavirus
vaccination
in
this
setting.
The
results
established
that
the
RIX4414
vaccine
provided
high
and
sustained
protection
against
severe
rotavirus
gastroenteritis
caused
by
wild-type
rotavirus
strains
particularly
during
the
first
two
years
of
life
(vaccine
efficacy
=
95.6%).
Although
possible
protection
was
observed
during
the
third
year
(vaccine
efficacy
=
96.1%),
the
group
difference
did
not
reach
statistical
significance.
The
efficacy
of
the
RIX4414
shown
in
this
study
was
comparable
to
that
observed
in
two-year
efficacy
studies
conducted
in
Latin
America
(vaccine
efficacy
=
80.5%
[95%
CI:
71.3%–87.1%])
and
Europe
(vaccine
efficacy
=
90.4%
[95%
CI:
85.1%–94.1%])
[8,9].
RIX4414
vaccine
had
an
acceptable
safety
profile.
As
anticipated,
the
number
of
infants
who
reported
gastroenteritis-related
symptoms
at
least
once
in
the
placebo
group
(n
=
147)
was
higher
than
that
in
the
RIX4414
group
(n
=
119).
There
were
no
clinical
or
statistical
differences
between
the
groups
from
Dose
1
up
to
three
years
of
age
with
respect
to
gastroenteritis
symptoms
or
etiologies
(Table
2)
except
for
rotavirus
gastroenteritis,
which
was
significantly
lower
in
the
vaccine
group
(Table
1).
Additionally,
none
of
the
six
intussusception
cases
(RIX4414
=
4;
placebo
=
2)
reported
here
were
vaccine-related.
The
vaccine’s
immunogenicity
was
demonstrated
by
the
high
anti-rotavirus
IgA
seroconversion
rate
(97.5%)
in
the
subset
of
100
infants
one
to
two
months
post-
Dose
2.
The
fact
that
no
seroconversion
was
found
in
the
placebo
group
when
tested
between
approximately
4
and
6
months
of
age
indicated
that
natural
rotavirus
infection
in
early
infancy
was
quite
uncommon
in
Hong
Kong.
Consistent
with
a
previous
report
from
Hong
Kong,
G1
and
G3
were
the
most
prevalent
circulating
rotavirus
strains
followed
by
G9
in
children
[3].
However,
unlike
previously,
we
did
not
observe
the
circulating
G2
rotavirus
strain
in
this
study
[3].
RIX4414
demonstrated
efficacy
against
the
three
circulating
rotavirus
strains
(92.3–100%).
ARSN
data
for
Hong
Kong
reported
that
approximately
one-third
of
all
diarrhea-related
hospital
admissions
were
due
to
rotavirus
[5],
with
significant
health
care
and
societal
costs
[16].
An
economic
evaluation
using
a
Markov
model
and
2002
cost
assumptions
estimated
that
the
introduction
of
routine
rotavirus
vaccination
at
a
cost
of
US$40–$92
per
course
could
be
potentially
cost-saving
from
a
government
perspective
alone
[17].
In
this
study,
the
percentage
of
hospitalization
due
to
severe
rotavirus
gastroenteritis
in
the
first
three
years
of
life
was
1.7%
(26/1499
or
1
in
58)
in
the
placebo
recipients
and
0.1%
(1/1494)
in
the
RIX4414
recipients.
In
contrast,
the
previous
ARSN
surveillance
data
estimated
a
2.4%
(1
in
41)
cumulative
risk
of
a
rotavirus-associated
admission
by
three
years
of
age
and
4.2%
(1
in
24)
by
five
years
of
age
[5].
The
present
data
could
reduce
previous
estimates
of
the
potential
economic
benefit
of
vaccination
[17],
although,
the
previous
economic
evaluation
did
not
take
into
account
vaccine
efficacy
against
hospitalization
due
to
diarrhea
of
any
etiology
(30%
in
the
first
three
years
of
life,
preventing
2.3
admissions
per
100
children
vaccinated
or
1
in
43).
It
is
also
possible
that
vaccination
could
prevent
nosocomial
infections
[18].
Furthermore,
vaccinating
infants
against
rotavirus
provides
indirect
protection
to
unvaccinated
older
children
and
adults
through
reduced
transmission
of
the
virus
in
the
community
resulting
in
fewer
infections
in
the
population
[19].
This
amplifies
the
economic
benefit
of
rotavirus
vaccination
by
reducing
rotavirus-related
hospitalization
costs
in
older
age
groups
who
are
ineligible
for
rotavirus
vaccination
[19,20].
This
study
had
some
limitations.
First,
while
it
was
possible
to
routinely
capture
all
admissions
to
public
hospitals
via
a
computerized
system
in
this
trial,
admissions
to
private
hospitals
might
have
been
missed
or
notified
late.
Although
such
cases
should
have
been
recorded
in
the
diary
cards
maintained
by
parents,
the
retrospectively
obtained
information
could
be
less
complete
and
stool
samples
might
not
have
been
collected.
This
limitation
could
contribute
to
the
apparent
low
rotavirus
admission
rates
and
vaccine
efficacy
against
all-cause
diarrhea.
Second,
this
study
was
not
powered
to
draw
more
definitive
conclusions
on
the
potential
benefits
of
introducing
rotavirus
vaccines
in
Hong
Kong.
Nevertheless,
substantial
reductions
in
rotavirus-
associated
hospitalization
rates
have
been
observed
following
universal
rotavirus
vaccination
in
both
developed
countries
(Australia
[20,21],
Austria
[22],
Belgium
[23,24],
United
States
[25])
and
developing
countries
(Brazil
[26,27],
El
Salvador
[28,29],
Mexico
[30],
Nicaragua
[31],
Panama
[32]).
In
addition,
Brazil
and
Mexico
have
witnessed
reductions
in
all-cause
mortality
from
gastroenteritis
following
the
introduction
of
rotavirus
vaccination
[27,33,34].
Third,
although
there
were
multiple
comparisons
(without
adjustment)
of
SAEs,
calculated
p-values
less
than
0.05
were
used
to
highlight
potential
differences
which
would
require
further
attention.
Therefore,
statistically
significant
findings
should
be
interpreted
with
caution
and
clinical
significance
must
be
considered.
5.
Conclusion
The
study
provided
specific
data
about
rotavirus
vaccination
in
Hong
Kong
that
could
help
public
health
officials
with
their
consideration
of
universal
rotavirus
vaccination.
There
were
no
safety
concerns
or
cases
of
vaccine-related
intussusception
in
this
study.
Two
oral
doses
of
RIX4414
administered
concomitantly
with
routine
childhood
vaccines
offered
high
and
sustained
protection
against
severe
rotavirus
gastroenteritis
caused
by
circulating
rotavirus
strains
and
against
all-cause
gastroenteritis
in
Hong
Kong
children
during
their
first
two
years
of
life
and
possibly
extending
to
their
third
year.
Acknowledgements
The
authors
would
thank
G.
Subramanyam,
A.
Ravishankar
and
A.
Pal
for
providing
medical
writing
assistance,
R.
Tien,
M.T.
Lim
and
V.
Wascotte
(GlaxoSmithKline
Vaccines)
for
editorial
assistance
and
manuscript
coordination.
We
gratefully
acknowledge
the
investigators,
clinicians,
study
nurses
and
other
staff
members
for
contributing
in
to
this
study
in
particular:
P.P.W.
Lee,
J.L.F.
Lo,
W.H.S.
Wong
(Queen
Mary
Y.-L.
Lau
et
al.
/
Vaccine
31 (2013) 2253–
2259 2259
Hospital,
Hong
Kong),
K.
Chang
and
K.S.
Tong
(Tuen
Mun
Hospital,
Hong
Kong),
J.S.H.
Chan,
K.S.
Ip
and
W.K.
Lee
(Pamela
Youde
Nethersole
Eastern
Hospital,
Hong
Kong),
K.L.E.
Hon,
M.C.
Yam,
K.L.
Cheung,
H.M.
Cheung,
H.S.
Lam,
F.Y.
Chan,
T.W.
Leung,
W.L.
Kwok,
I.M.T.
Chu
(Prince
of
Wales
Hospital,
Hong
Kong),
T.F.
Tong,
B.
Pau
(Kwong
Wah
Hospital,
Hong
Kong),
H.K.
Hui,
C.W.
Leung,
(United
Christian
Hospital,
Hong
Kong),
I
Chan
(United
Christian
Nethersole
Community
Health
Service,
Hong
Kong),
W.W.S.
Lau
(Chief
Research
Nurse)
and
team,
W.
Wong
(IT)
and
team.
Contributors:
All
named
authors
have
contributed
in
the
design/acquisition
of
data
or
analysis
and
interpretation
of
data.
They
have
provided
substantial
intellectual
and
scientific
input
in
the
development
of
this
manuscript.
All
authors
were
involved
in
critically
reviewing
the
content
and
revising
the
manuscript.
P.V.
Suryakiran
also
provided
statistical
input
for
the
manuscript.
Conflict
of
interest:
Yu-Lung
Lau
declares
to
have
received
travel
support
from
GlaxoSmithKline
group
of
companies
for
attending
scientific
meetings.
E.
Anthony
S
Nelson
declares
to
have
participated
in
other
vaccine
studies
funded
by
GlaxoSmithKline
group
of
companies
and
to
have
received
honoraria,
travel
support
and
consultancy
fees
from
GlaxoSmithKline
group
of
companies.
Paul
Chan
has
participated
in
vaccine
studies
funded
by
GlaxoSmithKline
group
of
companies
and
received
honoraria
and
travel
support
from
GlaxoSmithKline
group
of
companies
for
attending
scientific
meetings.
Daniel
Ng
declares
to
have
received
sponsorship
from
GlaxoSmithKline
group
of
companies
to
attend
a
chest
conference
in
Vancouver,
Canada
in
Oct
2010.
Haiwen
Tang,
P.V.
Suryakiran,
Htay
Htay
Han
and
Hans
Bock
are/were
employees
of
GlaxoSmithKline
group
of
companies
at
the
time
of
the
study
and
manuscript
preparation.
Htay
Htay
Han
declares
to
have
stock
options
in
GlaxoSmithKline
group
of
companies.
The
other
authors
declare
to
have
no
conflict
of
interests.
Funding:
GlaxoSmithKline
Biologicals
SA
was
the
funding
source
and
was
involved
in
all
stages
of
the
study
conduct
and
analysis.
GlaxoSmithKline
Biologicals
SA
also
took
charge
of
all
costs
associated
with
the
development
and
the
publishing
of
the
present
manuscript.
Trademark:
Rotarix
is
a
trademark
of
the
GlaxoSmithKline
group
of
companies.
Rotateq
is
a
registered
trademark
of
Merck
&
Co.,
USA.
Infanrix
is
a
registered
trademark
of
the
GlaxoSmithKline
group
of
companies.
Clinical
trial
registration:
ClinicalTrials.gov
Identifier:
NCT00197210;
E-track
444563/029
References
[1] Tate
JE,
Burton
AH,
Boschi-Pinto
C,
Steele
AD,
Duque
J,
Parashar
UD,
et
al.
2008
estimate
of
worldwide
rotavirus-associated
mortality
in
children
younger
than
5
years
before
the
introduction
of
universal
rotavirus
vaccination
programmes:
a
systematic
review
and
meta-analysis.
Lancet
Infect
Dis
2012;12(2):136–41.
[2]
Rotavirus
vaccines,
WHO
position
paper
January,
2013.
Wkly
Epidemiol
Rec
2013;88(5):49–64.
[3]
Nelson
EA,
Bresee
JS,
Parashar
UD,
Widdowson
MA,
Glass
RI,
Asian
Rotavirus
SN.
Rotavirus
epidemiology:
the
Asian
Rotavirus
Surveillance
Network.
Vaccine
2008;26(26):3192–6.
[4]
Nelson
EA,
Tam
JS,
Yu
LM,
Glass
RI,
Parashar
UD,
Fok
TF.
Surveillance
of
childhood
diarrhoeal
disease
in
Hong
Kong,
using
standardized
hospital
discharge
data.
Epidemiol
Infect
2004;132(4):619–26.
[5]
Nelson
EA,
Tam
JS,
Bresee
JS,
Poon
KH,
Ng
CH,
Ip
KS,
et
al.
Estimates
of
rotavirus
disease
burden
in
Hong
Kong:
hospital-based
surveillance.
J
Infect
Dis
2005;192(Suppl.
1):S71–9.
[6]
Ruiz-Palacios
GM,
Perez-Schael
I,
Velazquez
FR,
Abate
H,
Breuer
T,
Clemens
SC,
Cheuvart
B,
Espinoza
F,
et
al.
Safety
and
efficacy
of
an
attenuated
vaccine
against
severe
rotavirus
gastroenteritis.
N
Engl
J
Med
2006;354(1):11–22.
[7]
Vesikari
T,
Matson
DO,
Dennehy
P,
Van
Damme
P,
Santosham
M,
Rodriguez
Z,
et
al.
Safety
and
efficacy
of
a
pentavalent
human-bovine
(WC3)
reassortant
rotavirus
vaccine.
N
Engl
J
Med
2006;354(1):23–33.
[8]
Vesikari
T,
Karvonen
A,
Prymula
R,
Schuster
V,
Tejedor
JC,
Cohen
R,
et
al.
Efficacy
of
human
rotavirus
vaccine
against
rotavirus
gastroenteritis
during
the
first
2
years
of
life
in
European
infants:
randomised,
double-blind
controlled
study.
Lancet
2007;370(9601):1757–63.
[9]
Linhares
AC,
Velazquez
FR,
Perez-Schael
I,
Sáez-Llorens
X,
Abate
H,
Espinoza
F,
López
P,
et
al.
Efficacy
and
safety
of
an
oral
live
attenuated
human
rotavirus
vaccine
against
rotavirus
gastroenteritis
during
the
first
2
years
of
life
in
Latin
American
infants:
a
randomised,
double-blind,
placebo-controlled
phase
III
study.
Lancet
2008;371(9619):1181–9.
[10]
Phua
KB,
Lim
FS,
Lau
YL,
Nelson
EA,
Huang
LM,
Quak
SH,
et
al.
Safety
and
efficacy
of
human
rotavirus
vaccine
during
the
first
2
years
of
life
in
Asian
infants:
randomised,
double-blind,
controlled
study.
Vaccine
2009;27(43):5936–41.
[11]
Phua
KB,
Lim
FS,
Lau
YL,
Nelson
EA,
Huang
LM,
Quak
SH,
et
al.
Rotavirus
vaccine
RIX4414
efficacy
sustained
during
the
third
year
of
life:
A
randomized
clinical
trial
in
an
Asian
population.
Vaccine
2012;30(30):4552–7.
[12] World
Health
Organization.
The
treatment
of
diarrhoea:
a
manual
for
physicians
and
other
senior
health
workers.
http://www.searo.who.int/
LinkFiles/CAH
Publications manual physicians.pdf;
2005.
[Accessed
14.11.12].
[13] Ruuska
T,
Vesikari
T.
Rotavirus
disease
in
Finnish
children:
use
of
numerical
scores
for
clinical
severity
of
diarrhoeal
episodes.
S
Scand
J
Infect
Dis
1990;22(3):259–67.
[14]
van
Doorn
LJ,
Kleter
B,
Hoefnagel
E,
Stainier
I,
Poliszczak
A,
Colau
B,
et
al.
Detection
and
genotyping
of
human
rotavirus
VP4
and
VP7
genes
by
reverse
transcriptase
PCR
and
reverse
hybridization.
J
Clin
Microbiol
2009;47(9):2704–12.
[15] Ward
RL,
Bernstein
DI,
Shukla
R,
Young
EC,
Sherwood
JR,
McNeal
MM,
et
al.
Effects
of
antibody
to
rotavirus
on
protection
of
adults
challenged
with
a
human
rotavirus.
J
Infect
Dis
1989;159(1):79–88.
[16]
Nelson
EA,
Tam
JS,
Yu
LM,
Ng
YC,
Bresee
JS,
Poon
KH,
et
al.
Hospital-based
study
of
the
economic
burden
associated
with
rotavirus
diarrhea
in
Hong
Kong.
J
Infect
Dis
2005;192(Suppl.
1):S64–70.
[17] Ho
AM,
Nelson
EA,
Walker
DG.
Rotavirus
vaccination
for
Hong
Kong
children:
an
economic
evaluation
from
the
Hong
Kong
Government
perspective.
Arch
Dis
Child
2008;93(1):52–8.
[18]
Macartney
KK,
Porwal
M,
Dalton
D,
Cripps
T,
Maldigri
T,
Isaacs
D,
et
al.
Decline
in
rotavirus
hospitalisations
following
introduction
of
Australia’s
national
rotavirus
immunisation
programme.
J
Paediatr
Child
Health
2011;47(5):266–70.
[19]
Lopman
BA,
Curns
AT,
Yen
C,
et
al.
Infant
rotavirus
vaccination
may
provide
indirect
protection
to
older
children
and
adults
in
the
United
States.
J
Infect
Dis
2011;204(7):980–6.
[20]
Buttery
JP,
Lambert
SB,
Grimwood
K,
et
al.
Reduction
in
rotavirus-
associated
acute
gastroenteritis
following
introduction
of
rotavirus
vaccine
into
Australia’s
National
Childhood
vaccine
schedule.
Pediatr
Infect
Dis
J
2011;30(Suppl.
1):S25–9.
[21]
Field
EJ,
Vally
H,
Grimwood
K,
Lambert
SB.
Pentavalent
rotavirus
vaccine
and
prevention
of
gastroenteritis
hospitalizations
in
Australia.
Pediatrics
2010;126(3):e506–12.
[22] Paulke-Korinek
M,
Rendi-Wagner
P,
Kundi
M,
Kronik
R,
Kollaritsch
H.
Universal
mass
vaccination
against
rotavirus
gastroenteritis:
impact
on
hospitalization
rates
in
austrian
children.
Pediatr
Infect
Dis
J
2010;29(4):319–23.
[23] Hanquet
G,
Ducoffre
G,
Vergison
A,
Neels
P,
Sabbe
M,
Van
Damme
P,
et
al.
Impact
of
rotavirus
vaccination
on
laboratory
confirmed
cases
in
Belgium.
Vaccine
2011;29(29–30):4698–703.
[24]
Raes
M,
Strens
D,
Vergison
A,
Verghote
M,
Standaert
B.
Reduction
in
pediatric
rotavirus-related
hospitalizations
after
universal
rotavirus
vaccination
in
Belgium.
Pediatr
Infect
Dis
J
2011;30(7):e120–5.
[25]
Tate
JE,
Mutuc
JD,
Panozzo
CA,
Payne
DC,
Cortese
MM,
Cortes
JE,
et
al.
Sustained
decline
in
rotavirus
detections
in
the
United
States
following
the
introduction
of
rotavirus
vaccine
in
2006.
Pediatr
Infect
Dis
J
2011;30(Suppl.
1):
S30–4.
[26]
Gurgel
RQ,
Ilozue
C,
Correia
JB,
Centenari
C,
Oliveira
SMT,
Cuevas
LE.
Impact
of
rotavirus
vaccination
on
diarrhoea
mortality
and
hospital
admissions
in
Brazil.
Trop
Med
Int
Health
2011;16(9):1180–4.
[27]
do
Carmo
GMI,
Yen
C,
Cortes
J,
et
al.
Decline
in
diarrhea
mortality
and
admissions
after
routine
childhood
rotavirus
immunization
in
Brazil:
a
time-
series
analysis.
PLoS
Med
2011;8(4):e1001024.
[28] Yen
C,
Armero
Guardado
JA,
Alberto
P,
Rodriguez
Araujo
DS,
Mena
C,
Cuellar
E,
et
al.
Decline
in
rotavirus
hospitalizations
and
health
care
visits
for
childhood
diarrhea
following
rotavirus
vaccination
in
El
Salvador.
Pediatr
Infect
Dis
J
2011;30(Suppl.
1):S6–10.
[29]
de
Palma
O,
Cruz
L,
Ramos
H,
de
Baires
A,
Villatoro
N,
Pastor
D,
et
al.
Effectiveness
of
rotavirus
vaccination
against
childhood
diarrhoea
in
El
Salvador:
case-control
study.
BMJ
2010;340:c2825.
[30]
Quintanar-Solares
M,
Yen
C,
Richardson
V,
Esparza-Aguilar
M,
Parashar
UD,
Patel
MM.
Impact
of
rotavirus
vaccination
on
diarrhea-related
hospitalizations
among
children
<5
years
of
age
in
Mexico.
Pediatr
Infect
Dis
J
2011;30(Suppl.
1):S11–5.
[31]
Patel
M,
Pedreira
C,
de
Oliveira
LH,
Tate
J,
Orozco
M,
Mercado
J,
et
al.
Association
between
pentavalent
rotavirus
vaccine
and
severe
rotavirus
diarrhea
among
children
in
Nicaragua.
JAMA
2009;301(21):2243–51.
[32]
Molto
Y,
Cortes
JE,
de
Oliveira
LH,
Mike
A,
Solis
I,
Suman
O,
et
al.
Reduction
of
diarrhea-associated
hospitalizations
among
children
aged
<5
Years
in
Panama
following
the
introduction
of
rotavirus
vaccine.
Pediatr
Infect
Dis
J
2011;30(Suppl.
1):S16–20.
[33]
Richardson
V,
Parashar
U,
Patel
M.
Childhood
diarrhea
deaths
after
rotavirus
vaccination
in
Mexico.
N
Engl
J
Med
2011;365(8):772–3.
[34] Lanzieri
TM,
Linhares
AC,
Costa
I,
Kolhe
DA,
Cunha
MH,
Ortega-Barria
E,
et
al.
Impact
of
rotavirus
vaccination
on
childhood
deaths
from
diarrhea
in
Brazil.
Int
J
Infect
Dis
2011;15(3):e206–10.
  • [Show abstract] [Hide abstract] ABSTRACT: Rotaviruses (RV) are the leading cause of gastroenteritis in infants and children worldwide and are associated with high mortality predominately in low-income settings. The virus is classified into G and P serotypes and further into P genotypes based on differences in the surface-exposed proteins VP7 and VP4, respectively. Infection results in a variable level of protection from subsequent reinfection and disease. This protection is predominantly homotypic in some settings, whereas broader heterotypic protection is reported in other cohorts. Two antigenically distinct oral RV vaccines are licensed and are being rolled out widely, including in resource-poor setting, with funding provided by the GAVI alliance. First is a monovalent vaccine derived from a live-attenuated human RV strain, whereas the second is a pentavalent bovine-human reassortment vaccine. Both vaccines are highly efficacious in high-income settings, but greatly reduced levels of protection are reported in low-income countries. Here, the current challenges facing mucosal immunologists and vaccinologists aiming to define immunological correlates and to understand the variable levels of protection conferred by these vaccines in humans is considered. Such understanding is critical to maximize the public health impact of the current vaccines and also to the development of the next generation of RV vaccines, which are needed.Mucosal Immunology advance online publication 3 December 2014; doi:10.1038/mi.2014.114; published online 3 December 2014.
    Full-text · Article · Dec 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Rotaviruses remain the major cause of childhood diarrheal disease worldwide and of diarrheal deaths of infants and children in developing countries. The huge burden of childhood rotavirus-related diarrhea in the world continues to drive the remarkable pace of vaccine development. Data sources: Research articles were searched using terms "rotavirus" and "rotavirus vaccine" in MEDLINE and PubMed. Articles not published in the English language, articles without abstracts, and opinion articles were excluded from the review. After preliminary screening, all articles were reviewed and synthesized to provide an overview of current vaccines and vaccination programs. Results: In this review of the global rotavirus vaccines and vaccination programs, the principles of rotavirus vaccine development and the efficacy of the currently licensed vaccines from both developed and developing countries were summarized. Conclusions: Rotavirus is a common cause of diarrhea in children in both developed and developing countries. Rotavirus vaccination is a cost-effective measure to prevent rotavirus diarrhea.
    Full-text · Article · Oct 2015
  • [Show abstract] [Hide abstract] ABSTRACT: This study evaluated the immunogenicity of the human rotavirus (RV) vaccine (RIX4414) when co-administered with routine childhood vaccines in Chinese infants (NCT01171963). Healthy infants aged 6–16 weeks received 2 doses of either RIX4414 or placebo according to a 0, 1-month schedule. Infants received routine diphtheria-tetanus-acellular pertussis (DTPa) and oral poliovirus (OPV) vaccines either separately from or concomitantly with RIX4414/placebo (separate and co-administration cohorts, respectively). Anti-RV IgA seroconversion rates (one month post-dose-2) and seropositivity rates (at one year of age) were measured using ELISA. Immune responses against the DTPa and OPV antigens were measured one month post-DTPa dose-3 in the co-administration cohort. Solicited local and general symptoms were recorded for 8-days post-vaccination (total cohort). The according-to-protocol immunogenicity population included 511 infants in the separate cohort and 275 in the co-administration cohort. One month post-RIX4414 dose-2, anti-RV IgA seroconversion rates were 74.7% (95% confidence interval [CI]: 68.9–79.9) and 64.2% (95% CI: 55.4–72.3) in the separate and co-administration cohorts; seropositivity rates at one year of age were 71.5% (95% CI: 65.5–77.1) and 50.0% (95% CI: 40.9–59.1), respectively. One month post-DTPa dose-3, all infants in the co-administration cohort were seroprotected against diphtheria and tetanus, and seropositive for pertussis toxoid, pertactin and filamentous haemaglutinin. Two months post-OPV dose-3, seroprotection rates against anti-poliovirus types 1, 2 and 3 were >99% in the co-administration cohort. Reactogenicity profiles were similar in both cohorts. RIX4414 was immunogenic and well-tolerated in Chinese infants and did not appear to interfere with the immunogenicity and reactogenicity of co-administered routine childhood vaccines.
    Full-text · Article · Mar 2016
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