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Risk of intussusception after monovalent rotavirus vaccine (Rotavac) in
Indian infants: A self-controlled case series analysis
Manoja Kumar Das
a,
⇑
, The INCLEN Intussusception Surveillance Network Study Group
a
The INCLEN Trust International, F1/5, Okhla Industrial Area, Phase 1, New Delhi 110020, India
article info
Article history:
Received 24 June 2020
Received in revised form 1 September 2020
Accepted 3 September 2020
Available online xxxx
Keywords:
Intussusception
Rotavirus vaccine
Vaccine safety
Self-controlled case-series
Rotavac
Infant
India
abstract
Background: An association between rotavirus vaccination and intussusception has been documented in
post-licensure studies in some countries. We evaluated the risk of intussusception associated with mono-
valent rotavirus vaccine (Rotavac) administered at 6, 10 and 14 weeks of age in India.
Methods: Active prospective surveillance for intussusception was conducted at 22 hospitals across 16
states from April 2016 through September 2017. Data on demography, clinical features and vaccination
were documented. Age-adjusted relative incidence for 1–7, 8–21, and 1–21 days after rotavirus vaccina-
tion in children aged 28–364 days at intussusception onset was estimated using the self-controlled case-
series (SCCS) method. Only Brighton Collaboration level 1 cases were included.
Results: Out of 670 children aged 2–23 months with intussusception, 311 (46.4%) children were aged 28–
364 days with confirmed vaccination status. Out of these, 52 intussusception cases with confirmed
receipt of RVV were included in the SCCS analysis. No intussusception case was observed within 21 days
of dose 1. Only one case occurred during 8–21 days after the dose 2. Post-dose 3, two cases in 1–7 days
and 7 cases during 8–21 days period were observed. There was no increased risk of intussusception dur-
ing 1–7 days after the doses 1 and 2 (zero cases observed) or dose 3 (relative incidence [RI], 1.71 [95%
confidence interval {CI} 0.0–5.11]). Similarly, no increased risk during 8–21 days after the dose 1 (zero
cases observed), dose 2 (RI, 0.71 [95% CI, 0.0–3.28]) or dose 3 (RI, 2.52 [95% CI, 0.78–5.61]). The results
were similar for 1–21 day periods after the doses separately or pooled.
Conclusions: The risk of intussusception during the first 21 days after any dose of rotavirus vaccine
(Rotavac) was not higher among the Indian infants than the background risk, based on limited SCCS anal-
ysis of 52 children.
Ó2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
1. Introduction
To prevent diarrhoea related deaths, 107 countries (103 nation-
ally and 4 sub-nationally) have introduced rotavirus vaccine (RVV)
into their national immunization program (NIP) as of April 2020
[1]. The impact of RVV on the illness episodes, hospitalisations
and deaths due to rotavirus and all-cause diarrhoeas has been doc-
umented from post-licensure studies from various countries [2–5].
Following the increased risk of intussusception documented
with the first licensed rotavirus vaccine (RotaShield
TM
, Wyeth-
Lederle Laboratories) [6] and its withdrawal, all the clinical trials
of RVV captured intussusception as an adverse event. No increased
risk of intussusception was observed in large scale multicountry
clinical trials of two RVVs (Rotarix
TM
, RV1; GlaxoSmithKline Biolog-
icals and RotaTeq
TM
, RV5; Merck & Co, Inc) [7,8]. However, several
postlicensure studies have identified some increased risk of intus-
susception during 1–7 days after the first (relative risk, RR: 5.3–
9.9) and second (RR: 1.3–2.8) doses of these two RVVs in different
countries (Mexico, Brazil, Australia, the United Kingdom, and the
United States) [9–11,13,14]. Notably, the impact of RVV on morbid-
ity and mortality outweigh the risk of intussusception and associ-
ated mortality [15].
Intussusception incidence varies widely across the countries
[16]. In India, information on incidence of intussusception is lim-
ited and it varies from 17.7 (Delhi, North India) to 254 (Vellore,
South India) cases per 100,000 child-years [17]. Although the exact
https://doi.org/10.1016/j.vaccine.2020.09.019
0264-410X/Ó2020 The Author(s). Published by Elsevier Ltd.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Abbreviations: CRF, Case record form; CAC, Case Adjudication Committee; CI,
Confidence interval; ICD, International Classification of Diseases; IQR, Interquartile
range; LMIC, Low and middle income countries; MIC, Middle income countries; NIP,
National immunization programmes; SCCS, Self-controlled case series; RI, Relative
incidence; RR, Relative risk; RV1, Monovalent rotavirus vaccine (Rotarix
TM
); RV5,
Pentavalent rotavirus vaccine (Rotateq
TM
); RVV, Rotavirus vaccine; TAG, Technical
Advisory Group; WHO, World Health Organization.
⇑
Corresponding author at: The INCLEN Trust International, F1/5, Okhla Industrial
Area, Phase 1, New Delhi 110020, India.
E-mail addresses: manoj@inclentrust.org,drmanojkdas@gmail.com.
Vaccine xxx (xxxx) xxx
Contents lists available at ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Please cite this article as: M. K. Das, Risk of intussusception after monovalent rotavirus vaccine (Rotavac) in Indian infants: A self-controlled case series
analysis, Vaccine, https://doi.org/10.1016/j.vaccine.2020.09.019
causes of the variation in intussusception rate remain unknown,
ethnicity, dietary pattern, breastfeeding practices, gut microbial
environment, and vertical transmission of rotavirus antibodies
have been proposed as the possible risk factors [16].
Out of the four RVVs licensed in India, two Indian (Rotavac
TM
,
RV1-116E; Bharat Biotech and Rotasill
TM
, RV5; Serum. Institute of
India) have undergone efficacy trials in India and remaining two
(Rotarix
TM
and RotaTeq
TM
) were licensed based on evidence from
other countries. Clinical trials of the Indian-manufactured rota-
virus vaccines enrolled 6799–7500 infants each and had inade-
quate sample size for documenting the risk of intussusception
[18,19]. Under the NIP, India introduced Rotavac
TM
in March 2016
and Rotasill
TM
in April 2018 in different states in a phased manner
[20]. All four licensed vaccines are being used in private sector. In
view of the variable risks of intussusception after RVV doses across
the countries, it is necessary to generate evidence from the Indian
context to sustain confidence of the professionals and public on the
vaccine and program.
As part of the vaccine safety surveillance linked to RVV intro-
duction in India, a nationally representative sentinel surveillance
network was established. We used the self-controlled case series
(SCCS) method to evaluate the risk of intussusception following
Rotavac vaccination in Indian infants.
2. Methods
2.1. Study area and participating hospitals
This active prospective surveillance was conducted during April
2016 to September 2017 at 23 tertiary care hospitals across 20
cities and 17 states in India representing different regions. The list
and location of these hospitals are given in Supplementary Fig-
ure SF1. These hospitals were selected through a systematic pro-
cess and the study protocol has been published earlier [21].
2.2. Case recruitment and data collection
Children aged >1 month and <24 months admitted to these hos-
pitals were screened to identify the suspected cases (any of these
diagnoses: intussusception, intestinal obstruction- acute or suba-
cute, acute abdomen, pain abdomen, abdominal distension, and
blood in stool with vomiting). These suspected cases tracked for
final diagnosis and confirmed intussusception cases meeting the
Brighton collaboration level 1 criteria for diagnostic certainty were
recruited. The cases were recruited irrespective of the immuniza-
tion exposure and data availability. For the recruited cases, data
on clinical features, investigations, treatment, outcome, and
socio-demography were obtained from the hospital records and
parent interview. Immunization data were collected from the
immunization cards and a copy of which was obtained, whenever
possible. An independent Case Adjudication Committee (CAC),
with a paediatrician, paediatric surgeon, and radiologist as mem-
bers, reviewed the documents to assign the diagnostic certainty
levels, according to Brighton Collaboration criteria [22]. Indepen-
dently the suspected and intussusception cases were verified from
the medical records using diagnoses and/or International Classifi-
cation of Diseases (ICD) codes (ICD-9/10, codes listed in Supple-
mentary Table ST1), to identify any missed cases.
2.3. Statistical analysis
We used the SCCS method to estimate the age-adjusted relative
incidence of intussusception for the periods 1–7, 8–21 and
1–21 days after each dose of the RVV among the children aged
28–364 days at onset of symptoms (primary analysis). In the SCCS
method, each case acts as its own control and the frequency of the
outcome (intussusception) that occurred in the exposure periods
after vaccination is compared with the frequency in the unexposed
period [23,24]. As no external controls are used, this method auto-
matically controls for time-invariant confounding [25]. The SCCS
has been used in several studies investigating the risk of intussus-
ception with RVV vaccine [9–11,14,23,26–29] with the pseudo-
likelihood method [30]. We limited the analysis to the first occur-
rences of intussusception that met the level-1 Brighton collabora-
tion criteria and children aged 28–364 days at the onset of
symptoms, considering the minimum and maximum ages at which
RVV could be given in India. Days 22 days after the RVV dose till
364 days of age were considered as the control period. Onset of
first compatible symptom was considered the date of intussuscep-
tion onset. Cases with confirmed vaccine exposure information
were included in analysis and those without vaccination card were
excluded. The relative incidence (RI) for each case was calculated
comparing the incidence of intussusception within the risk win-
dow with the incidence in all other observation widows using con-
ditional Poisson regression. Because the background incidence of
intussusception varies substantially by age in the first year of life,
age was controlled using 14-day intervals in the model and confi-
dence intervals (CIs) were derived by bootstrapping with 1000 iter-
ations and all cases were included. Sensitivity analysis was done
considering the admission date as the date of intussusception
onset. Pvalues < 0.05 were considered to be statistically significant
and all reported Pvalues are two-sided. Statistical analysis was
performed using STATA version 15.0 (StataCorp LLC, Texas, USA).
2.4. Sample size
To detect a relative incidence of 1.75 within 1–7 days of after
any of the 3 RVV doses with 80% power and 95% confidence level,
the sample size needed was 220 using the signed root likelihood
ratio [31].
2.5. Ethical issues
Informed written consent was obtained for all the eligible cases
from parent or legal guardian before recruitment and data collec-
tion. Confidentiality in data handling was maintained. The study
protocol was reviewed and approved by all the institute ethics
committees of participating institutes.
3. Results
A total of 670 children aged >1 month and <24 months with
intussusception were recruited at these study sites. Among these,
420 (62.7%) children were aged 28–364 days. Out of the infants,
86.4% (364/420) had vaccine exposure information and 80.5%
(338/420) had the first episode of intussusception. The 27 (4%)
children who resolved with conservative management (i.e. no radi-
ologic or surgical intervention) were excluded. The 19 (2.8%) chil-
dren who received either Rotarix
TM
or Rotateq
TM
were also excluded.
Thus data for 311 children (52 with and 259 without RVV) were
analysed. The Fig. 1 shows the selection of cases for SCCS analysis.
There were no significant differences in the age at onset of
symptoms, gender and interval between the onset and hospitalisa-
tion between the cases included in analysis and excluded (Supple-
mentary Table ST2). The median age of cases was 28 weeks
(interquartile range [IQR], 22–35 weeks) and 68.2% were boys
(Supplementary Table ST2). Vomiting (78.8%), blood in stool
(71.1%), excessive crying (62.4%) and abdominal pain (49.8%) were
the commonest presenting features (Supplementary Table ST3).
The median interval between onset of symptoms and hospitaliza-
M.K. Das Vaccine xxx (xxxx) xxx
2
tion was 3-days (IQR, 2–6 days). Overall, RVV was received by 52
(16.7%) cases including three doses by 43, two doses by 5 and
one dose by 4 cases. Among the 53 cases recruited from the five
sites from states in Phase-1 RVV national introduction, 34
(64.1%) received RVV-1. Out of the 258 children recruited from
the 15 sites in the states without RVV in the NIP, 18 (7%) received
RVV-1. The median ages at intussusception were comparable for
the children who received RVV (26.5 weeks; IQR 19.5–32.5 weeks)
and who did not receive (28 weeks; IQR 22–36 weeks) (Supple-
mentary Table ST5). The median ages of vaccination in children
with and without RVV were comparable; dose 1 (with RVV: med-
ian age 7.1 weeks, IQR 6.6–8.8 weeks and without RVV: median
age 7 weeks, IQR 6.6–8.4 weeks), dose 2 (with RVV: median age
12 weeks, IQR 11.3–13.8 weeks and without RVV: median age
12.3 weeks, IQR 11.3–14.1 weeks) and dose 3 (with RVV: median
age 16.6 weeks, IQR 15.7–18.3 weeks and without RVV: median
age 17.1 weeks, IQR 16–19.1 weeks). The Fig. 2 shows the ages at
vaccination for the children with RVV and the ages of vaccination
for children without RVV is given as Supplementary Figure SF2.
There was no significant difference in the characteristics between
the children who did or didn’t receive RVV (Supplementary
Table ST5).
After the first RVV dose, no case of intussusception was
observed during the 1–7 days and 8–21 days risk periods
(Fig. 3A). After the second RVV dose, no case of intussusception
during the 1–7 days and one case during 8–21 days risk periods
were observed (Fig. 3B). After the third RVV dose, two cases of
intussusception during the 1–7 days and seven cases during 8–
21 days risk periods were observed (Fig. 3C). One case occurred
on day zero after RVV dose 3.
Table 1 shows the RI estimates using the date of symptom
onset (primary analysis) and date of admission (sensitivity analy-
sis) for intussusception in different risk periods (1–7 days or 8–
21 days or 1–21 days) after the RVV doses compared to the back-
ground risk. There was no increased risk of intussusception dur-
ing 1–7 days after the first and second doses (no cases
observed) or third dose (relative incidence, RI, 1.03; 95% CI 0–
5.11) of RVV. Similarly, no increased risk of intussusception was
observed during 8–21 risk period after the first dose (no case
observed), second dose (RI 0.71; 95% CI 0–3.28) and third dose
(RI 2.52; 95% CI 0.78–5.61) of RVV. There was no increased risk
of intussusception observed for any RVV dose at pooled level
for 1–7, 8–21 and 1–21 days risk periods.
4. Discussion
This study was conducted at 20 sites as part of the vaccine
safety surveillance linked to rotavirus vaccine introduction. Out
of the 20 sites, five sites were in the states where the RVV was
introduced in Phase-1 of the national introduction. According to
the WHO and UNICEF estimates of immunization coverage using
the administrative report for 2017, the RVV (Rotavac
TM
) coverage
in these Phase-1 states was 69% [32]. The RVV coverage (64.1%)
among the study subjects from the study sites in Phase-1 states
was comparable to the administrative coverage data. Out of the
258 children recruited from other 15 sites (from the states without
Fig. 1. Flow of case selection for the self-controlled case series analysis. Note: RVV:
Rotavirus vaccine.
Fig. 2. The age at rotavirus vaccination and occurrence of intussusception during the first year. Note: The ages at rotavirus vaccination given in weeks as median with
interquartile range (IQR); RVV-1: Rotavirus vaccine first dose; RVV-2: Rotavirus vaccine second dose; RVV-3: Rotavirus vaccine third dose.
M.K. Das Vaccine xxx (xxxx) xxx
3
RVV in the NIP), 18 (7%) children received RVV. We did not observe
an increased risk of intussusception after any of the doses of the
monovalent 116E RVV (Rotavac
TM
) in Indian infants. No clustering
of the intussusception cases in either 1–7 days or 8–21 days or
1–21 days risk windows after any RVV doses was observed. How-
ever, the study was under powered due to the low number of
intussusception cases having received RVV (n = 52).
Our results are comparable to the reports of intussusception
after RV1 (Rotarix
TM
) vaccination in several African countries
(Ethiopia, Ghana, Kenya, Malawi, Tanzania, Zambia, Zimbabwe
and South Africa), where no increased risk of intussusception after
any dose of RV1 were observed [23,28]. However, increased risks of
intussusception were documented in the 1–7 days following dose
2 of RV1 in Brazil (IR 2.6; 95% CI 1.3–5.2; OR 1.9; 95% CI 1.1–3.4)
and after dose 2 (IR 5.3; 95% CI 3.0–9.3 and OR 5.8; 95% CI 2.6–
13) and dose 1 (IR 6.49; 95% CI 4.17–10.09) in Mexico [9,10]. Sim-
ilarly, increased risks of intussusception were documented in high
income countries, United States (first dose, RR 7–8.8; second dose,
RR 1.8–8.1), United Kingdom (first dose, RR 13.8; second dose, RR
2.2), and Australia (first dose, RR 6.8; second dose, RR 2.8) in the
1–7 day period with RV1 vaccine [11-14]. Increased risks of intus-
susception were documented in high income countries in United
Fig. 3. The number of intussusception cases in the first 60 days after rotavirus vaccine dose 1 (3A), dose 2 (3B) and dose 3 (3C). Note: RVV-1: Rotavirus vaccine first dose; RVV-2:
Rotavirus vaccine second dose; RVV-3: Rotavirus vaccine third dose.
Table 1
Relative incidence of intussusception in the risk periods after the rotavirus vaccine in Indian infants.
Dose Risk period Primary analysis*Sensitivity analysis
**
IS cases (n) Relative incidence (RI with 95%
CI)
@
IS cases (n) Relative incidence (RI with 95%
CI)
@
1–7 days 0 0.00 0.00 0.00 0 0.00 0.00 0.00
Dose-1 8–21 days 0 0.00 0.00 0.00 0 0.00 0.00 0.00
1–21 days 0 0.00 0.00 0.00 0 0.00 0.00 0.00
Dose-2 1–7 days 0 0.00 0.00 0.00 0 0.00 0.00 0.00
8–21 days 1 0.71 0.00 3.28 1 0.74 0.00 3.66
1–21 days 1 0.50 0.00 2.37 1 0.52 0.00 2.59
Dose-3 1–7 days 2 1.71 0.00 5.11 3 2.56 0.00 6.92
8–21 days 7 2.52 0.78 5.61 6 2.11 0.61 4.72
1–21 days 9 2.23 0.81 4.58 9 2.20 0.88 4.41
All 3-doses 1–7 days 2 1.03 0.00 3.14 3 1.61 0.00 4.43
8–21 days 8 1.65 0.61 3.49 7 1.46 0.51 3.15
1–21 days 10 1.48 0.67 3.02 10 1.50 0.70 2.92
Notes: Among children aged 28–364 days; Risk period is number of days prior to the reference date; IS: Intussusception; RI: Relative Incidence.
*
Using the symptom onset date for calculating the risk periods.
**
Using the admission date as onset of intussusception for calculating the risk periods.
@
95% confidence intervals bootstrapped with 1000 iterations.
M.K. Das Vaccine xxx (xxxx) xxx
4
States (first dose, RR 2.6–9.1; second dose, RR 1.8; third dose, RR
1.2–2.2), Finland (first dose, IRR 2) and Australia (first dose, RR
9.9; second dose, RR 2.8) in the 1–7 day period with RV5 vaccine
(Rotateq
TM
)[11–13,29]. In Singapore (first dose, RR 8.3; second
dose, RR 3.0)and Spain (first dose, RR 4.7; second dose, RR 1.6) also
the intussusception risk was higher where both RV1 and RV5 were
used [26,27]. The RV1 doses are administered at 2 and 3 or
4 months schedule. The RV5 doses are administered at 2, 4 and 5
or 6 months schedule.
Although the exact reasons of increased risk of intussusception
with RVV in some countries but not in others are not clear, some
possible factors like age at vaccination, coadministration of oral
polio vaccine (OPV), gut replication of RVV virus, intestinal micro-
biota environment, breastfeeding and dietary patterns, maternal
antibody transfer and ethnicity may be considered [33]. In this
study, the median age of the intussusception cases is 28 weeks
(IQR, 22–35 weeks), which is comparable to the reports for Indian
infants without RVV exposure [34–36]. In this study no case was
observed before 6 weeks, one case before 10 weeks and 11 cases
before 14 weeks of ages. This observation is similar to that from
African countries [23,28]. The median or peak ages of intussuscep-
tion in children from the countries with increased risk were also
comparable to the Indian and African children. It was interesting
to note that the countries following 6 and 10 weeks (African coun-
tries) and 6, 10 and 14 weeks (India) schedules have no or lower
risk of intussusception [23,28]. But the countries following 2 and
3 months or 2 and 4 months schedules for RV1 and 2, 3 and
5 months or 2, 4 and 6 months schedules for RV5 had higher risk
of intussusception [9–14,26–29]. Risk of intussusception was high-
est in 1–7 days after the first dose or either RV1 or RV5. In this
study, we observed one case on day-zero of RVV dose-3. Apart from
the schedule, while no increased risk of intussusception was
observed in the low and middle income countries (LMICs) from
Africa and India, the middle income countries (MICs) from Latin
America and developed countries from North America, Europe
and Australia had increased risks of intussusception. So, the earlier
age of administration of first RVV dose may have lower risk of
intussusception, when the background occurrence is low. The
RVV administered at 10–14 weeks schedule was observed to have
higher seroconverion compared to 6–10 weeks schedule [37].In
India and the African countries OPV is coadministered with RVV.
In this study, 47 children received RVV and OPV simultaneously.
The co-administration of RVV and OPV was observed to have lower
rotavirus seroconversion in South Africa, Bangladesh and Chile
infants [37–39]. The lower seroconversion may be due to sub-
optimal RVV virus replication in the intestine.
Lower efficacy (49.7–64.5%) in clinical trials and effectiveness
(18–69%) of the RVVs have been observed in LMICs from Africa,
Latin America and Asia compared to the middle and high
income countries [5,40]. The lower immune responses to the
RVVs may be due to lower replication of the RVV viruses in
the intestine of infants in LMICs, which is reflected in lower
fecal shedding [33]. The lower replication of RVV viruses may
be dependent on the intestinal microbiota and other competing
microbes of the infants in these LMICs [33,41]. The intestinal
replication of virus may be influenced by the breastfeeding pat-
tern, immunoglobulin and non-specific antibodies content in the
breastmilk, dietary pattern, environmental sanitation and nutri-
tional status of the infants [33,41]. Apart from these the mater-
nal infection with rotavirus and vertical transfer to infants may
also affect the vaccine virus replication, and thereby the
immunogenicity and risk of intussusception [33,41]. The varia-
tion in the intussusception rates across the different regions
globally may also be due to genetic and/or ethnic risk factors
[16,41]. With these possible factors influencing the intussuscep-
tion risk after RVV, the subnational variations of the risks in
India should also be explored, considering the wide variation
in the dietary, sociocultural practices, sanitation and environ-
mental risk factors.
Our study had some limitations. First, the number of children
who received RVV was small and is underpowered to observe sig-
nificant risk of intussusception. However, we did not observe any
case of intussusception during 1–7 days after the first and second
doses of RVV, which was reassuring. There were two cases of
intussusception (ages 18.2 and 25.3 weeks) during 1–7 days after
third dose of RVV, which overlaps with the age of natural occur-
rence of intussusception in infants, even without RVV. The obser-
vations are similar to a recent report from India on
intussusception after Rotavac, where out of 104 intussusception
cases, none occurred during 1–7 days after RVV1 and RVV2 while
one case occurred during 1–7 days after RVV3. The relative inci-
dences of intussusception during 1–21 days after RVV1 and
RVV2 (RI: 1.56; 95% CI: 0.0–5.28) and any RVV dose (RI: 1.51;
95% CI: 0.58–3.23). The findings from our study are comparable
to observations from this report [41,42]. Second, only cases from
selected hospitals were included and no definite catchment area
or population base could be ascertained to derive the incidence
rate. Third, all the children with intussusception were recruited
at the sites irrespective of the immunization exposure status. Sev-
eral of the infants were from outside the city and their parents
were not carrying the vaccine cards with them. We surveillance
team tried to collect the vaccination information to their best.
The vaccine exposure information was available for 78.4% of
infants, which corroborates with the immunization coverage sta-
tus of infants in India and there was no significant difference in
the age distribution between the infants who were included in
analysis and those who were not. The key parameters for the vac-
cinated and unvaccinated infants appeared similar. We had study
sites across 17 states of India and had mix of public and private
hospitals and we believe that the findings are generalizable to
other areas of India.
In conclusion, this SCCS analysis did not observe any increased
risk of intussusception in the 1–7 and 8–21 days periods after the
any dose of the oral monovalent 116E RVV (Rotavac
TM
) among
Indian infants compared to the background risk. This observation
is similar to the risks observed among African infants following
oral RV1 administration from post-licensure studies [23,28].
Although no increased risk of intussusception with the RVV in
Indian infants is encouraging, continued documentation over
longer period and sub-national risk assessment should also be con-
sidered. Such evidence will also be useful for other counties in the
region and globally considering use of these RVVs for preventing
diarrhoea morbidity and deaths.
5. Consent for publication
Not applicable.
6. Availability of data and materials
All data is available with the investigators and can be provided
by the corresponding author upon reasonable request.
7. Disclosure statement
None. There is no financial interest or benefit for the authors
arisen from this project or its direct application.
M.K. Das Vaccine xxx (xxxx) xxx
5
8. Funding xxx
This project was supported by the Bill and Melinda Gates Foun-
dation, USA to The INCLEN Trust International (grant number
OPP1116433). The funder or its representative had no role in the
design of the study and collection, analysis, and interpretation of
data and writing the manuscript.
9. Authors’ contributions xxx
MKD and NKA conceptualised the framework for the study pro-
tocol, training, data analysis and interpretation. All TAG members
provided input for finalisation of the study protocol and provided
quality assurance oversight. All site investigators supervised the
data collection at respective study site institutes. BG and AS coor-
dinated the data collection and collation. MKD, RR, JET and BG
analysed the data. MKD and RR wrote the first draft of the manu-
script. JET and UP reviewed and revised the manuscript. All authors
reviewed, provided critical input and approved the final version.
10. Disclaimer
The content represents the views of the authors alone and do
not necessarily represent the official positions of their organiza-
tions, World Health Organization or Ministry of Health and Family
Welfare, Government of India or the US Centers for Disease Control
and Prevention or Bill and Melinda Gates Foundation.
CRediT authorship contribution statement
Manoja Kumar Das and Narendra Kumar Arora: Study con-
ceptualisation, study design, protocol development, training, data
analysis, interpretation, manuscript preparation.
Bini Gupta and Apoorva Sharan: Study coordination, monitor-
ing, data cleaning, data analysis.
Ramesh Poluru, Jacqueline E. Tate and Umesh D. Parashar:
Protocol development, data analysis and manuscript preparation.
Mahesh K. Aggarwal, Pradeep Haldar, Patrick L F Zuber, Jan
Bonhoeffer, Arindam Ray and Christine G. Maure: Protocol
development, quality assurance and monitoring.
Ashish Wakhlu, Bhadresh R Vyas, Javeed Iqbal Bhat, Jayanta
K. Goswami, John Mathai, Kameswari K., Lalit Bharadia, Lalit
Sankhe, Ajayakumar M.K., Neelam Mohan, Pradeep K. Jena,
Rachita Sarangi, Rashmi Shad, Sanjib K. Debbarma, Shyamala
J., Simmi K. Ratan, Suman Sarkar, Vijayendra Kumar, Anand P.
Dubey, Atul Gupta, Cenita J. Sam, Gowhar Nazir Mufti, Harsh Tri-
vedi, Jimmy Shad, Kaushik Lahiri, Krishnaswamy R., Meera
Luthra, Narendra Behera, Padmalatha P., Rajamani G., Rakesh
Kumar, Ruchirendu Sarkar, Santosh Kumar A., Subrat Kumar
Sahoo, Sunil K. Ghosh, Sushant Mane, Arun Kumar Dash, Bashir
Ahmad Charoo, Bikasha Bihary Tripathy, Rajendra Prasad G.,
Harish Kumar S., Jothilakshmi K., Nihar Ranjan Sarkar, Pavai
Arunachalam, Satya Sundar G. Mohapatra, and Saurabh Garge:
Participant recruitment and data collection.
All authors reviewed, provided critical input and approved the
final version. The content represents the views of the authors alone
and do not necessarily represent the official positions.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
We acknowledge the support from Ministry of Health and Health
Welfare, Government of India for undertaking the study. We are
thankful to the institute and hospital administration and the clin-
icians who supported and facilitate undertaking the study.
We highly value the technical guidance and inputs provided by
the members of Technical Advisory Group: Satinder Aneja, Anju
Seth and Archana Puri, Lady Hardinge Medical College, New Delhi;
Ashok Patwari, Hamdard Institute of Medical Sciences & Research,
New Delhi; Yogesh Kumar Sarin, Maulana Azad Medical College,
New Delhi; Rakesh Aggarwal, Anshu Srivastava and Ujjal Poddar,
Sanjay Gandhi Postgraduate Institute of Medical Sciences, Luc-
know; Malathi Satyasekharan, Kanchi Kamakoti Chailds Trust
Hospital, Chennai; Raju Sharma and Nirupam Madan, All India
Institute of Medical Sciences, New Delhi; Jyoti Joshi and Deepak
Polpakara, Immunization Technical Support Unit; Ministry of
Health & Family Welfare, New Delhi; Naveen Thacker, , Gandhi-
gram; and Rashmi Arora, , Ansari Nagar, New Delhi.
We acknowledge the contribution of the research staffs at The
INCLEN Trust International:
Harshpreet Kaur, Janvi Chaubey, Mrimmaya Das, Shweta
Sharma and Vaibhav Jain.
We highly appreciate the efforts made by the research staffs at
the study sites: Aarezo Bashir and Rafia; Sher-e-Kashmir Institute
of Medical Sciences, Srinagar, Jammu & Kashmir; Prabha Shankar,
Medanta-The Medicity Hospital, Gurgaon, Haryana; Anju Sharma;
Maulana Azad Medical College, New Delhi; Anita Singh and Shub-
hanshu Srivastava, King George Medical University, Lucknow, Uttar
Pradesh; Hemant Meena, Choithram Hospital, Indore, Madhya Pra-
desh; Pankaj Kumar and Shashi Kant; Indira Gandhi Institute of
Medical Sciences, Patna, Bihar; Goutam Benia, IMS & Medical Col-
lege & Hospital, Bhubaneshwar, Odisha; Prasntajyoti Mohanty, SVP
Post Graduate Institute of Paediatrics, Cuttack, Odisha; Angshuman
Chatterjee, Institute of Postgraduate Medical Education and
Research & SSKM Hospital, Kolkata, West Bengal; S. Yamuna,
Andhra Medical College, Vishakhapatnam, Andhra Pradesh; Sri-
nidhi Sudan, Apollo Hospitals, Hyderabad, Telengana; Rajesh Fran-
cis, Apollo Hospitals, Chennai, Tamil Nadu; T. Easter Chandru,
Institute of Medical Sciences, Masonic Hospital, Coimbatore Medi-
cal College and GKNM Hospital, Coimbatore, Tamil Nadu; Deepthy
R, Julie and Anju Shivkumar, Government Medical College & SAT
Hospital, Thiruvananthapuram, Kerala; Archit Vaidya, Grant Medi-
cal College & JJ Hospital, Mumbai, Maharashtra; Nimesh Chouksey,
MP Shah Government Medical College, Jamnagar, Gujarat; Nidhi
Singh, Fortis Escorts Hospital, Jaipur, Rajasthan; Mrinmoy Gohain,
Gauhati Medical College, Guwahati, Assam; Arpita Bhattachrjee,
Saugat Ghosh and Tanusmita Debnath, Agartala Government Med-
ical College, Agartala, Tripura.
Appendix A. Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.vaccine.2020.09.019.
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