Dagan/Rota/2012
Ron Dagan, Noga Givon Lavi The Pediatric Infectious Disease Unit
Soroka University Medical Center
Ben-Gurion University
Beer-Sheva, Israel
Early Effectiveness of the National
Immunization Plan with RV5 on
Pediatric Emergency Room Visits
and Hospitalizations in Southern
Israel
Dagan/Rota/2012
This study was sponsored by MSD
My trip to this meeting was partially sponsored by MSD
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Burden of Rotavirus Gastroenteritis on Pediatric ER Visits and Hospitalization in
Southern Israel - a Population-Based Study
(IsraRota Study)
Beer-Sheva
• ~15,000 annual births
• ~50% Jewish children and ~50%
Bedouin children
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Methods
• A prospective study since April 1st 2006, still on-going
• All PER visits and hospitalizations of children <5 yrs caused by LRI, URI and GE are recorded daily
• All children <5 yrs with vomiting/diarrhea* are offered participation upon presentation daily (a study person is present at the PER 364/365 d/year 08:00 AM – 09:00 PM)
• Stool/diaper specimens are tested for rotavirus by ELISA**
• RVGE is defined by positive ELISA
• All rotavirus (+) stools are being tested by RT-PCR to determine serotype***
• Complex extrapolation for the missing specimens (next slide)….
* ≥watery or looser-than normal stool within a 24h period and/or forceful vomiting
** IDEIATM rotavirus ELISA kit, DakoCytomation
*** Institute for Medical Research, Katholieke Universiteit of Leuven, Leuven, Belgium
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Month 2006 2007 2008
Mo
nth
ly n
um
ber
of
ch
ild
ren
Monthly Figures for the 1
st 2 Yrs of the Study:
All PER Visits (including Hospitalizations) <5 Yrs
105
208
268 263
193 192
233
359
350
164
131 104 113
196
180
142
200
241 232
379
318
174
139 154
6 5 9 11
4 12
37
132
152
34 8
3 0 0 0 4 10
13
44
126 115
46
18 17
0
50
100
150
200
250
300
350
400
4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3
Suitable Enrolled All Samples Rota Pos
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Monthly Figures for the 1st
2 Years of the Study:
All Pediatric ER Visits + Hospitalizations), Children <5 Yrs
Extrapolation was done by each ethnic group, and separately for hospitalization and for PER
outpatient visits
Month
0
50
100
150
200
250
300
350
400
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Cumulative Age-specific Incidence of Hospital Use (PER and
Hospitalization) for RVGE in Southern Israel
Before Implementation of Any Rotavirus Vaccine
16.2
34.9 36.3
26.4
38.7 39.5
0
5
10
15
20
25
30
35
40
45
<12 m 12-23m 24-59m
Jewish Children Bedouin children
Cu
mu
lati
ve
In
cid
en
ce
of
RV
GE
pe
r 1
,00
0 p
op
ula
tio
n
6.3
12.5 13.4
16.2
23.1 23.7
0
5
10
15
20
25
30
<12 m 12-23m 24-59m
9.9
22.1 22.6
10.3
15.7 15.8
0
5
10
15
20
25
30
<12 m 12-23m 24-59m
Overall incidence – hospital use
In hospital
ER - outpatients
P<0.001 in all points P<0.001
P<0.001 in all points
Dagan/Rota2012 Slides prepared by Ron Dagan MD
The Risk to Visit Pediatric ER or to be Hospitalized because of
Rotavirus GE for Jewish and Bedouin Children*
* Using the conservative extrapolation
Event Before Age 2 yrs
Jewish chi ldren Bedouin children
Pediatric Emergency
Room visits (outpatient and in-patients events)
1:29 1:26
Hospitalization 1:78 1:43
Dagan/Rota2012 Slides prepared by Ron Dagan MD
RVGE as Proportions of All Yearly Outpatient Pediatric ER Visits
and Hospitalizations Children <2 Years,
Southern Israel*
•Using the conservative extrapolation
Annual
contribution of
RVGE
Outpatients Inpatients
Jewish
children
Bedouin
children
Jewish
children
Bedouin
children
Rota (+)/all patients 337/12,553 220/8320 197/4240 324/5956
% of all patients 2.7% 2.6% 4.6% 5.4%
The denominator is all Pediatric Emergency Room outpatient visits
and all hospitalizations for each ethnic group
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Effect of Vaccination on Epidemiology
• Pre-NIP – Both RV1 and RV5 were licensed in Israel in 2007
– Both vaccines were subsidized since mid 2008 by the various HMOs in
Israel • Cost ~US$ 100 for the course
• Reimbursement ~50% for complimentary health insurance
• Different use by different socio-economic classes
• NIP – In January 2011, RV5 was introduced to the National Immunization Plan to
all children born since Nov 2010
• Vaccine uptake….(next slide)
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Rota Vaccine Status
All Children Age 8-11 Months
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100% ≥1 dose ≥2 doses 3 doses*
07-09
2009
10-12
2009
01-03
2010
04-06
2010
07-09
2010
10-12
2010
01-03
2011 04-06
2011
07-09
2011
10-12
2011
01-03
2012
04-06
2012
All
children 62 67 70 60 61 86 80 59 73 65 66 60
Initiation of NIP
1/1/11
* Since before NIP both RV1 and
RV5 were used, we considered for
the pre-NIP period 2 doses of RV1
as equivalent to 3 doses RV5 for
the purpose of dosing
measurement
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Rota Vaccine Status
Jewish Children Age 8-11 Months
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100% ≥1 dose ≥2 doses 3 doses*
07-09
2009
10-12
2009
01-03
2010
04-06
2010
07-09
2010
10-12
2010
01-03
2011 04-06
2011
07-09
2011
10-12
2011
01-03
2012
04-06
2012
Jewish
children 33 29 34 24 32 47 41 29 34 27 32 19
Initiation of NIP
1/1/11
* Since before NIP both RV1 and
RV5 were used, we considered for
the pre-NIP period 2 doses of RV1
as equivalent to 3 doses RV5 for
the purpose of dosing
measurement
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Rota Vaccine Status
Bedouin Children Age 8-11 Months
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100% ≥1 dose ≥2 doses 3 doses*
07-09
2009
10-12
2009
01-03
2010
04-06
2010
07-09
2010
10-12
2010
01-03
2011 04-06
2011
07-09
2011
10-12
2011
01-03
2012
04-06
2012
Bedouin
children 29 38 36 36 29 39 39 30 39 38 34 41
Initiation of NIP
1/1/11
* Since before NIP both RV1 and
RV5 were used, we considered for
the pre-NIP period 2 doses of RV1
as equivalent to 3 doses RV5 for
the purpose of dosing
measurement
Dagan/Rota2012 Slides prepared by Ron Dagan MD
0
50
100
150
200
250
Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar
2006-2007
2007-2008
2008-2009
2009-2010
2010-2011
2011-2012
2009-2010 extrapolated
2012-2013
Remark: Due to technical issues (“week 53” in 2011, the report of week 1 2012 is an additive of “week 53”, 2011 and week 1, 2012
Yearl
y c
um
ula
tive n
um
ber
of
cases
Week number
Yearly Cumulative Number of Rota-positive Samples,
<12 Months
0
10
20
30
40
50
60
70
80
90
Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar
2006-2007
2007-2008
2008-2009
2009-2010
2010-2011
2011-2012
2009-2010 extrapolated
2012-2013
Bedouin Children Jewish Children
Dagan/Rota2012 Slides prepared by Ron Dagan MD
0
20
40
60
80
100
120
Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar
2006-2007
2007-2008
2008-2009
2009-2010
2010-2011
2011-2012
2009-2010 extrapolated
2012-2013
Remark: Due to technical issues (“week 53” in 2011, the report of week 1 2012 is an additive of “week 53”, 2011 and week 1, 2012
Week number
Yearly Cumulative Number of Rota-positive Samples,
12-23 Months
0
10
20
30
40
50
60
70
80
90
Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar
2006-2007
2007-2008
2008-2009
2009-2010
2010-2011
2011-2012
2009-2010 extrapolated
2012-2013
Bedouin Children Jewish Children
Yearl
y c
um
ula
tive n
um
ber
of
ca
se
s
Dagan/Rota2012 Slides prepared by Ron Dagan MD
0
2
4
6
8
10
12
14
16
18
20
Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar
2006-2007
2007-2008
2008-2009
2009-2010
2010-2011
2011-2012
2009-2010 extrapolated
2012-2013
Remark: Due to technical issues (“week 53” in 2011, the report of week 1 2012 is an additive of “week 53”, 2011 and week 1, 2012
Week number
Yearly Cumulative Number of Rota-positive Samples,
24-59 Months
0
5
10
15
20
25
30
35
Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar
2006-2007
2007-2008
2008-2009
2009-2010
2010-2011
2011-2012
2009-2010 extrapolated
2012-2013
Bedouin Children Jewish Children
Yearl
y c
um
ula
tive n
um
ber
of
ca
se
s
Dagan/Rota2012 Slides prepared by Ron Dagan MD
RVGE Age-specific Incidence (PER + Hospitalization ) in
Southern Israel
Incid
en
ce o
f R
VG
E p
er
1,0
00 p
op
ula
tio
n
Apr 06 - Mar 08 Apr 08 - Mar 11 Apr 11 - Mar 12
16.2
26.4
10.3
27.3
3.0
8.1
0
5
10
15
20
25
30
35
Jewish children Bedouin children
1st
year of life
P<0.001
P<0.001
P<0.001
* *
* P<0.001
Jewish vs.
Bedouin children
P<0.001 -81%
-70%
18.7
12.3 13.3 14.8
5.7
9.9
0
5
10
15
20
25
30
35
Jewish children Bedouin children
2nd
year of life
P<0.001
P<0.001
P<0.001
** **
** P=0.110
Jewish vs.
Bedouin children
P<0.001 -70%
-27%
1.4 0.7 1.5 0.9 0.9 0.6 0
5
10
15
20
25
30
35
Jewish children Bedouin children
3rd
– 5th
years of life
P=0.019
P<0.066
-36%
Dagan/Rota2012 Slides prepared by Ron Dagan MD
RVGE as Proportions of All Yearly Outpatient Pediatric ER
Visits and Hospitalizations
Children <2 Years in Southern Israel*
Pro
po
rtio
n o
f all o
utp
ati
en
t E
R v
isit
s
Apr 06 - Mar 08 Apr 08 - Mar 11 Apr 11 - Mar 12
2.7 2.6
1.5 2.1
0.5
1.2
0
1
2
3
4
5
6
7
8
Jewish children Bedouin children
Outpatients
ER visits
* *
P<0.001
*P<0.001
Jewish vs.
Bedouin children
•Using the conservative extrapolation
P<0.001
P<0.001
P<0.001
P<0.001
P<0.001
4.6
5.4 5.0
7.3
2.4
3.5
0
1
2
3
4
5
6
7
8
Jewish children Bedouin children
Inpatients
P<0.001
** **
**P=0.023
Jewish vs.
Bedouin children
P<0.001
P<0.001
Pro
po
rtio
n o
f all h
osp
italizati
on
s
-81%
-54%
-48%
-45%
Dagan/Rota/2012
Case-control
study
Nov 1st 2011 through March 31st 2012
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Determination of Cases and Controls
• Initial selection
– All patients <24m that visited the PER from November 1st 2011 through March 31st 2012
with ≥3 diarrhea stools in last 24h (but <7 days) – both hospitalized and non-hospitalized
– Stool samples obtained and tested for Rota
– Information on vaccination recorded (through active surveillance)
• Cases: were children with stool sample positive for Rota (EILSA)
• Controls: were children with negative Rota ELISA stool
• Selection of children for inclusion in the analysis by age-windows
was according to vaccination status in the controls (≥1 dose, ≥2
doses, 3 doses)*
* No interval between dose or after doses was required to be included
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Selection of Age Windows for the Analysis
(according to distribution among controls)
Nu
mb
er
of
co
ntr
ols
Age (weeks)
≥1 doses
≥2 doses
3 doses
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Effectiveness Analysis
• Odds ratios for RVGE in vaccinated vs. non-vaccinated children in
each vaccine status (≥1 dose, ≥2 doses, 3 doses) and their 95% CIs,
were calculated
• Effectiveness was defined as (1.0 –OR) x 100
• Analysis was conducted
– Separately
• Jewish vs. Bedouin children (adjusted for age and hospitalization)
• Hospitalized vs. non hospitalized children (adjusted for age and ethnic group)
– Jointly all children (adjusted for age, ethnic group and hospitalization)
– Jointly for scoring (adjusted for age and ethnic group)
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Effectiveness of RV5 Against RVGE Visits
62.4 60.3 64.4
0
10
20
30
40
50
60
70
80
90
≥1 ≥2 3
*Adjusted for age, ethnic group and hospitalization
Number of doses
Eff
ecti
ven
ess (
95%
CI)
9-69
weeks old
18-69
weeks old
28-69
weeks old
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Effectiveness of RV5 Against RVGE Visits
Children 9-69 Weeks Old*
75.3 78.8
54.3
0
10
20
30
40
50
60
70
80
90
100
≥1 ≥2 3
*Adjusted for age and hospitalization
57.4 57.4
68.7
0
10
20
30
40
50
60
70
80
90
100
≥1 ≥2 3
P=0.009
P=0.004
Two-sample test for binomial proportions (Normal-Theory test)
Number of doses
Eff
ecti
ven
ess (
95%
CI)
Jewish children Bedouin children
9-69
weeks old
18-69
weeks old
28-69
weeks old
9-69
weeks old
18-69
weeks old
28-69
weeks old
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Effectiveness of ≥1 RV5 Dose Against RVGE Visits
Children 9-69 Weeks Old*
*Adjusted for age and ethnic group
40.8
86.1
0
10
20
30
40
50
60
70
80
90
100
9-16 (n=91) >16 (n=78)
23.1
80.1
0
10
20
30
40
50
60
70
80
90
100
11-15 (n=43) 16-20 (n=113)
Two-sample test for binomial proportions (Normal-Theory test)
P<0.001 P<0.001
Eff
ecti
ven
ess (
95%
CI)
Clarck score Vesikari score
There were too few cases scored <9 and <11 in the Clarck and Vesikari scores, respectively to be analyzed
Dagan/Rota2012 Slides prepared by Ron Dagan MD
Conclusions
• Pre-vaccine RVGE was common in both Jewish and Bedouin populations in
southern Israel, and was responsible for high rate of ER visits and hospitalization
in children <2 yrs
• The Bedouin population, with similarities to developing populations, had a higher
rate of hospitalization
• Partial introduction of RV vaccines to the Jewish but not to the Bedouin
population pre-NIP, created inequity in reduction of disease
• Introduction of RV5 to the NIP in January 2011 resulted within 1 year in a 81% and
70% reduction of hospital use because of RVGE during 1st year of life in the
Jewish and Bedouin populations, respectively; the respective figures during 2nd
year of life were 70% and 27%
• The reduction in incidence was associated with the relative reduction of RVGE
burden compared to other diagnoses, despite the introduction of PCV7/13
vaccines in 2009
• The overall effectiveness after ≥2 doses was 60% (79% and 57% for Jewish and
Bedouin children, respectively)
• Effectiveness for severe disease was high (86% - Clarck score >16; 80% Vesikari
score >15)