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Risk of intussusception after monovalent rotavirus vaccine (Rotavac) in Indian infants: A self-controlled case series analysis

  • The INCLEN Trust International, New Delhi

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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 monovalent 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 vaccination 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 during 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 analysis of 52 children.
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Risk of intussusception after monovalent rotavirus vaccine (Rotavac) in
Indian infants: A self-controlled case series analysis
Manoja Kumar Das
, The INCLEN Intussusception Surveillance Network Study Group
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
Rotavirus vaccine
Vaccine safety
Self-controlled case-series
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
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
, 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
, RV1; GlaxoSmithKline Biolog-
icals and RotaTeq
, 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
0264-410X/Ó2020 The Author(s). Published by Elsevier Ltd.
This is an open access article under the CC BY license (
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
); RV5,
Pentavalent rotavirus vaccine (Rotateq
); 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:,
Vaccine xxx (xxxx) xxx
Contents lists available at ScienceDirect
journal homepage:
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,
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
RV1-116E; Bharat Biotech and Rotasill
, RV5; Serum. Institute of
India) have undergone efficacy trials in India and remaining two
and RotaTeq
) 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
in March 2016
and Rotasill
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
or Rotateq
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
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
) 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
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
) 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
) 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%
IS cases (n) Relative incidence (RI with 95%
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
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
)[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
) 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
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.
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
[1] ROTA Council. Global Introduction Status [Internet]. 2020 [cited 2020 May 30].
Available from:
[2] 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:S11–5.
[3] Pendleton A, Galic M, Clarke C, Ng SP, Ledesma E, Ramakrishnan G, et al.
Impact of rotavirus vaccination in Australian children below 5 years of age: a
database study. Hum Vaccines Immunother 2013;9(8):1617–25.
M.K. Das Vaccine xxx (xxxx) xxx
[4] Burnett E, Jonesteller CL, Tate JE, Yen C, Parashar UD. Global impact of rotavirus
vaccination on childhood hospitalizations and mortality from diarrhea. J Infect
Dis 2017;215(11):1666–72.
[5] Jonesteller CL, Burnett E, Yen C, Tate JE, Parashar UD. Effectiveness of rotavirus
vaccination: a systematic review of the first decade of global postlicensure
data, 2006–2016. Clin Infect Dis 2017;65(5):840–50.
[6] Murphy TV, Gargiullo PM, Massoudi MS, Nelson DB, Jumaan AO, Okoro CA,
et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J
Med 2001;344(8):564–72.
[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] Ruiz-Palacios GM, Pérez-Schael I, Velázquez FR, Abate H, Breuer T, Clemens SC,
et al. Safety and efficacy of an attenuated vaccine against severe rotavirus
gastroenteritis. N Engl J Med 2006;354(1):11–22.
[9] Patel MM, López-Collada VR, Bulhões MM, De Oliveira LH, Márquez AB,
Flannery B, et al. Intussusception risk and health benefits of rotavirus
vaccination in Mexico and Brazil. N Engl J Med 2011;364(24):2283–92.
[10] Velázquez FR, Colindres RE, Grajales C, Hernández MT, Mercadillo MG, Torres
FJ, et al. Postmarketing surveillance of intussusception following mass
introduction of the attenuated human rotavirus vaccine in Mexico. Pediatr
Infect Dis J 2012;31(7):736–44.
[11] Carlin JB, Macartney KK, Lee KJ, Quinn HE, Buttery J, Lopert R, et al.
Intussusception risk and disease prevention associated with rotavirus
vaccines in australia’s national immunization program. Clin Infect Dis
[12] Yih WK, Lieu TA, Kulldorff M, Martin D, McMahill-Walraven CN, Platt R, et al.
Intussusception risk after rotavirus vaccination in U.S. Infants. N Engl J Med
[13] Weintraub ES, Baggs J, Duffy J, Vellozzi C, Belongia EA, Irving S, et al. Risk of
intussusception after monovalent rotavirus vaccination. N Engl J Med
[14] Stowe J, Andrews N, Ladhani S, Miller E. The risk of intussusception following
monovalent rotavirus vaccination in England: a self-controlled case-series
evaluation. Vaccine 2016;34(32):3684–9.
[15] Yen C, Tate JE, Hyde TB, Cortese MM, Lopman BA, Jiang B, et al. Rotavirus
vaccines: current status and future considerations. Hum Vaccines Immunother
[16] Jiang J, Jiang B, Parashar U, Nguyen T, Bines J, Patel MM. Childhood
intussusception: a literature review. Cameron DW, editor. PLoS ONE. 2013;8
[17] Jehangir S, John J, Rajkumar S, Mani B, Srinivasan R, Kang G. Intussusception in
southern India: comparison of retrospective analysis and active surveillance.
Vaccine 2014;32:A99–A103.
[18] Bhandari N, Rongsen-Chandola T, Bavdekar A, John J, Antony K, Taneja S, et al.
Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian
infants: a randomised, double-blind, placebo-controlled trial. The Lancet
[19] Kulkarni PS, Desai S, Tewari T, Kawade A, Goyal N, Garg BS, et al. A
randomized Phase III clinical trial to assess the efficacy of a bovine-human
reassortant pentavalent rotavirus vaccine in Indian infants. Vaccine
[20] Press Informationn Beureau. Shri J P Nadda launches Rotavirus vaccine as part
of Universal Immunization Programme; terms it a ‘‘historic moment”.
[Internet]. Ministry of Health & Family Welfare Government of India; 2016
[cited 2019 Jan 10]. Available from:
[21] Das M, Arora N, Bonhoeffer J, Zuber P, Maure C. Intussusception in young
children: protocol for multisite hospital sentinel surveillance in India. Methods
Protoc 2018;1(2):11.
[22] Bines JE, Kohl KS, Forster J, Zanardi LR, Davis RL, Hansen J, et al. Acute
intussusception in infants and children as an adverse event following
immunization: case definition and guidelines of data collection, analysis,
and presentation. Vaccine 2004;22(5–6):569–74.
[23] Tate JE, Mwenda JM, Armah G, Jani B, Omore R, Ademe A, et al. Evaluation of
intussusception after monovalent rotavirus vaccination in Africa. N Engl J Med
[24] Whitaker HJ, Paddy Farrington C, Spiessens B, Musonda P. Tutorial in
biostatistics: the self-controlled case series method. Stat Med 2006;25
[25] Whitaker HJ, Hocine MN, Farrington CP. The methodology of self-controlled
case series studies. Stat Methods Med Res 2009;18(1):7–26.
[26] Yung C-F, Chan SP, Soh S, Tan A, Thoon KC. Intussusception and monovalent
rotavirus vaccination in Singapore: self-controlled case series and risk-benefit
study. J Pediatr 2015;167(1):163–168.e1.
[27] Pérez-Vilar S, Díez-Domingo J, Puig-Barberà J, Gil-Prieto R, Romio S.
Intussusception following rotavirus vaccination in the Valencia Region,
Spain. Hum Vaccines Immunother 2015;11(7):1848–52.
[28] Groome MJ, Tate JE, Arnold M, Chitnis M, Cox S, de Vos C, et al. Evaluation of
intussusception after oral monovalent rotavirus vaccination in South Africa.
Clin Infect Dis 2020;70(8):1606–12.
[29] Leino T, Ollgren J, Strömberg N, Elonsalo U. Evaluation of the intussusception
risk after pentavalent rotavirus vaccination in Finnish infants. Kirk M, editor.
PLOS ONE. 2016;11(3):e0144812.
[30] Farrington CP, Whitaker HJ, Hocine MN. Case series analysis for censored,
perturbed, or curtailed post-event exposures. Biostatistics 2008;10(1):3–16.
[31] Musonda P, Paddy Farrington C, Whitaker HJ. Sample sizes for self-controlled
case series studies. Stat Med 2006;25(15):2618–31.
[32] WHO and Unicef. India: WHO and UNICEF estimates of immunization
coverage: 2019 revision [Internet]. World Health Organization; 2020 [cited
2020 Aug 12]. Available from:
[33] Patel M, Shane AL, Parashar UD, Jiang B, Gentsch JR, Glass RI. Oral rotavirus
vaccines: how well will they work where they are needed most? J Infect Dis
[34] Srinivasan R, Girish Kumar CP, Naaraayan SA, Jehangir S, Thangaraj JWV,
Venkatasubramanian S, et al. Intussusception hospitalizations before rotavirus
vaccine introduction: retrospective data from two referral hospitals in Tamil
Nadu, India. Vaccine 2018;36(51):7820–5.
[35] Gupta M, Kanojia R, Singha R, Tripathy JP, Mahajan K, Saxena A, et al.
Intussusception rate among under-five-children before introduction of
rotavirus vaccine in North India. J Trop Pediatr 2018;64(4):326–35.
[36] Singh JV, Kamath V, Shetty R, Kumar V, Prasad R, Saluja T, et al. Retrospective
surveillance for intussusception in children aged less than five years at two
tertiary care centers in India. Vaccine 2014;32:A95–8.
[37] Steele AD, De Vos B, Tumbo J, Reynders J, Scholtz F, Bos P, et al. Co-
administration study in South African infants of a live-attenuated oral human
rotavirus vaccine (RIX4414) and poliovirus vaccines. Vaccine 2010;28
[38] Emperador DM, Velasquez DE, Estivariz CF, Lopman B, Jiang B, Parashar U, et al.
Interference of monovalent, bivalent, and trivalent oral poliovirus vaccines on
monovalent rotavirus vaccine immunogenicity in rural Bangladesh. Clin Infect
Dis 2016;62(2):150–6.
[39] Ramani S, Mamani N, Villena R, Bandyopadhyay AS, Gast C, Sato A, et al.
Rotavirus serum IgA immune response in children receiving rotarix
coadministered with bOPV or IPV. Pediatr Infect Dis J 2016;35(10):1137–9.
[40] Carvalho MF, Gill D. Rotavirus vaccine efficacy: current status and areas for
improvement. Hum Vaccines Immunother 2019;15(6):1237–50.
[41] Parker EP, Ramani S, Lopman BA, Church JA, Iturriza-Gómara M, Prendergast
AJ, et al. Causes of impaired oral vaccine efficacy in developing countries.
Future Microbiol 2018;13(1):97–118.
[42] Bhandari N, Antony K, Balraj V, Rongsen-Chandola T, Kumar T, Sinha B, et al.
Assessment of risk of intussusception after pilot rollout of rotavirus vaccine in
the Indian public health system. Vaccine 2020;38(33):5241–8.
M.K. Das Vaccine xxx (xxxx) xxx
... RV vaccination has been associated with an increased risk of intestinal intussusception in selected geographies, primarily high-and middle-income countries [31][32][33]. An increase in Intus-susception risk was not observed during ROTAVAC Ò Phase 3 trials [60,61] nor during post-introduction surveillance [62,63]. In addition, a modeling analysis comparing the risk of intussusception with the reduction of mortality provided by RV vaccination in 135 lower-and middle-income countries found that vaccination showed a significantly positive benefit-risk profile [64]. ...
Full-text available
Background Rotavirus infection remains an important cause of morbidity and mortality in children. The introduction of vaccination programs in more than 100 countries has contributed to a decrease in hospitalizations and mortality. This study investigates the epidemiological impact of the rotavirus vaccine ROTAVAC® in the Palestinian Territories, the first country to switch from ROTARIX® to this new vaccine. Methods Clinical surveillance data was collected from children younger than 5 attending outpatient clinics throughout Gaza with diarrhea between 2015 and 2020. The incidence of all-cause diarrhea was assessed using an interrupted time-series approach. Rotavirus prevalence was determined at the Caritas Baby Hospital in the West Bank using ELISA on stool specimen of children younger than 5 with diarrhea. Genotyping was performed on 325 randomly selected rotavirus-positive samples from January 2015 through December 2020 using multiplex PCR analysis. Results Average monthly diarrhea cases dropped by 16.7% annually from introduction of rotavirus vaccination in May 2016 to the beginning of the SARS-CoV-2 epidemic in March 2020 for a total of 53%. Case count declines were maintained after the switch to ROTAVAC® in October 2018. Rotavirus positivity in stool samples declined by 67.1% over the same period without change following the switch to ROTAVAC®. The distribution of predominant genotypes in rotavirus-positive stool samples changed from a pre-vaccination G1P [8] to G9P[8] and G12P[8] during the ROTARIX® period and G2P[4] after the introduction of ROTAVAC®. Conclusion ROTAVAC® has shown epidemiological impact on par with ROTARIX® after its introduction to the national immunization schedule in the Palestinian Territories. A molecular genotype shift from a pre-vaccination predominance of G1P[8] to a current predominance of G2P[4] requires more long-term surveillance.
Background: A low-level risk of intussusception following rotavirus vaccination has been observed in some settings and may vary by vaccine type. We examined the association between RotaTeq vaccination and intussusception in low-income settings in a pooled analysis from five African countries that introduced RotaTeq into their national immunization program. Methods: Active surveillance was conducted in 20 sentinel sites to identify intussusception cases. A standard case report form was completed for each enrolled child and vaccination status was determined by review of the child's vaccination card or clinic record. The pseudo-likelihood adaptation of self-controlled case-series method was used to assess the association between RotaTeq administration and intussusception in the 1-7, 8-21, and 1-21 day periods after each vaccine dose in infants 28 to 245 days of age. Results: Data from 318 infants with confirmed rotavirus vaccination status were analyzed. No clustering of cases occurred in any of the risk windows after any of the vaccine doses. Compared to the background risk of naturally occurring intussusception, no increased risk was observed after dose 1 in the 1-7 day (relative incidence=2.71, 95% confidence interval (CI)=0.47-8.03) or the 8-21 day window (relative incidence=0.77, 95%CI=0.0-2.69). Similarly, no increased risk of intussusception was observed in any risk window after dose 2 or dose 3. Conclusions: RotaTeq vaccination was not associated with an increased risk of intussusception in this pooled analysis from five African countries. This finding mirrors what was reported in similar analyses with other rotavirus vaccines in low-income settings and highlights need for vaccine-specific and setting-specific risk monitoring.
Full-text available
Background Intussusception is a prevalent pediatric issue causing acute abdominal pain, with potential links to rotavirus vaccines. The variety of these vaccines has grown in recent years. This meta-analysis study aims to evaluate the impact of various rotavirus vaccines on intussusception incidence. Methods We executed a thorough search across databases like PubMed, Cochrane Library, Embase, and Web of Science, leading to the selection of 15 credible randomized controlled trials (RCTs) that encompass various types of rotavirus vaccines. From each study, we extracted essential details such as vaccine types and intussusception occurrences. We assessed the risk of bias using the Cochrane Collaboration's tool, conducted statistical analysis with R (version 4.2.3), determined relative risk (RR) using a random effects model, and performed a subgroup analysis for vaccines of differing brands and types. Results We included 15 randomized controlled studies from various countries. While intussusception incidence differed between vaccinated and control groups, this difference was not statistically significant. The overall risk ratio (RR), calculated using a random effects model, was 0.81, with a 95% confidence interval of [0.53, 1.23]. This crossing 1 shows that vaccination didn't notably change disease risk. Additionally, the 0% group heterogeneity suggests consistency across studies, strengthening our conclusions. Subgroup analysis for different vaccine brands and types (RV1 (Rotarix, Rotavac, RV3-BB), RV3 (LLR3), RV5 (RotasiiL, RotaTeq), and RV6) showed no significant variation in intussusception incidence. Despite variations in RR among subgroups, these differences were not statistically significant ( P > 0.05). Conclusions Our study indicates that rotavirus vaccination does not significantly increase the incidence of intussusception. Despite varying impacts across different vaccine brands and types, these variations are insignificant. Given the substantial benefits outweighing the risks, promoting the use of newly developed rotavirus vaccines remains highly valuable. Systematic Review Registration , Identifier CRD42023425279.
Full-text available
Although vaccines are one of the most rigorously tested biological products, the safety concerns persist globally. The vaccine safety concerns linked to measles, pentavalent and human papillomavirus (HPV) vaccines have affected the vaccine coverage significantly in past. While surveillance of adverse events following immunization (AEFI) is part of the national immunization program mandate, it suffers from challenges and biases related to reporting, completeness, and quality. Some conditions of concern, termed as adverse events of special interest (AESI) following vaccination, mandated specialised studies to prove/disprove the association. The AEFIs/AESIs are usually caused by one of the four pathophysiologic mechanisms, but for several AEFIs/AESIs, the exact pathophysiology remains elusive. For the causality assessment of AEFIs, a systematic process with checklists and algorithm are followed to classify into one of the four causal association categories. While the causal association primarily banks on epidemiological observations for several AEFIs, the emerging evidences indicate roles of underlying genetic, gender, age and other pro-inflammatory risk factors for AEFIs and AESIs. The emerging evidences suggest role of antigenic mimicry, autoantibody(ies) and underlying genetic susceptibility for the AEFIs/AESIs. The uncertainty about the frequency, profile, interval, and severity of AEFIs/AESIs and variations across the population, ambiguity about the exact pathophysiology mechanism, absence of definite markers, suggest a possible black box effect of the vaccines. Unless these unanswered questions concerning the AEFIs/AESIs are addressed appropriately and communicated to the stakeholders (professionals, care providers, beneficiaries, general public and media), the anti-vaccine movement shall keep challenging the vaccine and vaccination program.
Live-attenuated rotavirus vaccine has shown low protection in underdeveloped or developing countries. However, the inactivated rotavirus vaccine may have the potential to overcome some of these challenges. In the present study, the immunogenicity and protective efficacy of a bivalent inactivated rotavirus vaccine by parenteral administration were elevated in a neonatal rhesus monkey model. A bivalent inactivated rotavirus vaccine containing G1P[8] (ZTR-68 strain) and G9P[8] (ZTR-18 strain) was administered to pregnant rhesus monkeys twice at an interval of 14 days. Neutralizing antibodies against RV strains ZTR-68, ZTR-18, SA11, WA, UK, and Gottfried emerged in pregnant rhesus monkeys and were transplacentally transmitted to the offspring. In the vaccine group, clinical symptoms of diarrhea, viral load in the gut tissue and histopathological changes were significantly reduced in the neonatal rhesus monkeys following oral challenge with the SA11 strain.
Background: There is limited comprehensive evaluation of the methodology and reporting quality of observational studies of vaccine safety. Methods: Databases including Medline, Embase, Web of Science, Scopus, and Chinese databases were searched from inception to 31 May 2021. All observational studies regarding vaccine safety using an SCCS design were selected. Information regarding methodological elements were extracted. In addition, reporting quality was assessed using the REporting of studies Conducted using Observational Routinely collected health Data statement for PharmacoEpidemiology (RECORD-PE). Results: : Of the 105 studies identified, administrative databases were the main data source for vaccination records and adverse events following immunization (AEFI). Twenty-eight articles (27%) used multiple designs to verify the association, and the results obtained with the SCCS design were robust. The top three AEFI studied were intussusception, Guillain-Barré syndrome, and convulsions. Only 21 studies (20%) reported the approach for case validation by chart review. The healthy vaccinee effect was considered by 51 studies (49%), with 16 of them (31%) using extended SCCS models to alleviate this effect. Overall, the reporting quality of included studies could be improved. Conclusions: Administrative databases were the main data source for vaccination records and adverse events following immunization. Case validation, the validity of assumptions for standard SCCS, and quality of reporting should be given more importance in future research projects.
Full-text available
This supplement contains the findings from intussusception surveillance conducted in 9 countries. These articles provide information on the age distribution of intussusception in the first year of life with cases peaking at 4-6 months of age, highlight the high proportion of cases in most, but not all, countries that undergo surgery and often require bowel resection for the treatment of intussusception, and show the variability of treatment outcomes in different countries. These data will be important for improving diagnosis and treatment of intussusception in young children in sub-Saharan Africa.
Introduction Rotavirus is the primary cause of severe acute gastroenteritis among children under the age of five globally, leading to 128,500 to 215,000 vaccine-preventable deaths annually. There are six licensed oral, live-attenuated rotavirus vaccines, including four vaccines pre-qualified for global use by WHO, and two country-specific vaccines. Successful expansion of rotavirus vaccines into national immunization programs worldwide has led to a 59% decrease in rotavirus hospitalizations and 36% decrease in diarrhea deaths due to rotavirus in vaccine-introducing countries. Areas covered This review describes the current rotavirus vaccines in use, global coverage, vaccine efficacy from clinical trials, and vaccine effectiveness and impact from post-licensure evaluations. Vaccine safety, particularly as it relates to the risk of intussusception, is also summarized. Additionally, an overview of candidate vaccines in the pipeline is provided. Expert opinion Considerable evidence over the past decade has demonstrated high effectiveness (80-90%) of rotavirus vaccines at preventing severe rotavirus disease in high-income countries, although the effectiveness has been lower (40-70%) in low-to-middle-income countries. Surveillance and research should continue to explore modifiable factors that influence vaccine effectiveness, strengthen data to better evaluate newer rotavirus vaccines, and aid in the development of future vaccines that can overcome the limitations of current vaccines.
Full-text available
Rotavirus is a major cause of severe pediatric diarrhea worldwide. In 2006, two live, oral rotavirus vaccines, Rotarix and RotaTeq, were licensed for use in infants and were rapidly adopted in many high- and middle-income settings where efficacy had been demonstrated in clinical trials. Following completion of additional successful trials in low-income settings, the World Health Organization (WHO) recommended rotavirus vaccination for all infants globally in 2009. In 2018, two new rotavirus vaccines, Rotasiil and Rotavac, were prequalified by WHO, further expanding global availability. As of March 2021, rotavirus vaccines have been introduced nationally in 106 countries. Since introduction, rotavirus vaccines have demonstrated effectiveness against severe disease and mortality, even among age groups not eligible for vaccination. Cross-genotypic protection has also been demonstrated, and the favorable benefit-risk profile of these vaccines continues to be confirmed via post-marketing surveillance. Ongoing research seeks to better understand reasons for the lower effectiveness observed in lower-resource settings, and to use these findings to optimize vaccine strategies worldwide.
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Relative risk (RR) is a preferred measure for investigating associations in clinical and epidemiological studies with dichotomous outcomes. However, if the outcome of interest is rare, it frequently occurs that no events are observed in one of the comparison groups. In this case, many of the standard methods used to obtain confidence intervals (CIs) for the RRs are not feasible, even in studies with strong statistical evidence of an association. Different strategies for solving this challenge have been suggested in the literature. This paper, which uses both mathematical arguments and statistical simulations, aims to present, compare, and discuss the different statistical approaches to obtain CIs for RRs in the case of no events in one of the comparison groups. Moreover, we compare these frequentist methods with Bayesian approaches to determine credibility intervals (CrIs) for the RRs. Our results indicate that most of the suggested approaches can be used to obtain CIs (or CrIs) for RRs in the case of no events, although one-sided intervals obtained by methods based on deliberate, probabilistic considerations should be preferred over ad hoc methods. In addition, we demonstrate that Bayesian approaches can be used to obtain CrIs in these situations. Thus, it is possible to obtain statistical inference for the RR, even in studies with no events in one of the comparison groups, and CIs for the RRs should always be provided. However, it is important to note that the obtained intervals are sensitive to the method chosen in the case of small sample sizes.
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Background Pre-licensure trials of ROTAVAC® were not adequately powered to assess risk of intussusception, a rare adverse event associated with other rotavirus vaccines in some settings. We examined the risk of intussusception after ROTAVAC® vaccination among Indian infants during pilot rollout of the vaccine in the public health system in three states - Himachal Pradesh, Maharashtra and Tamil Nadu. Methods Passive surveillance for intussusception was set up in 35 sentinel health facilities covering 26.3 million population in the three states under monitoring of an Interministerial-Interagency Steering Committee. Clinical and immunization data were collected by independent teams. An expert committee blinded to vaccination status, classified intussusception cases using Brighton criteria. The self-controlled case-series method was used to estimate risk of intussusception (Brighton Level 1) after ROTAVAC® vaccination. Results 151 intussusception cases were included in the analysis. The relative incidence (incidence during the risk period compared to the control period) 1–21 days after doses 1 and 2 combined was 1.56 (95% CI, 0.0–5.28) and that for three doses combined was 1.88 (95% CI, 0.76–4.30). Attributable risk 1–21 days after doses 1 and 2 combined was 0.11 (95% CI, 0.0–0.25) and that for 3 doses combined was 0.42 (95% CI, 0.0–0.70) per 100,000 doses. Conclusions No increased risk of intussusception within 21 days of receipt of the first two doses combined or all 3 doses combined of ROTAVAC® was detected.
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Background: Post-licensure studies have shown an association between rotavirus vaccination and intussusception. We assessed the risk of intussusception associated with Rotarix® (RV1) administration, at six and 14 weeks of age, in an upper-middle income country, South Africa. Methods: Active prospective surveillance for intussusception was conducted in eight hospitals from September 2013-December 2017. Retrospective case enrolment was done at one hospital from July 2012-August 2013. Demographic characteristics, symptom onset and rotavirus vaccine status were ascertained. Using the self-controlled case-series method, we estimated age-adjusted incidence-rate ratios within 1-7, 8-21, and 1-21 days of rotavirus vaccination in children aged 28-275 days at onset of symptoms. In addition, age-matched controls were enrolled for a subset of cases (n=169), and a secondary analysis performed. Results: There were 346 cases included in the case-series analysis. Post-dose one, there were zero intussusception cases within 1-7 days, and five cases within 8-21 days of vaccination. Post-dose two, 15 cases occurred within 1-7 days, and 18 cases within 8-21 days of vaccination. There was no increased risk of intussusception 1-7 days after dose one (no cases observed) or dose two (relative incidence (RI): 1·71; 95% confidence interval (CI) 0·83-3·01). Similarly, there was no increased risk 8-21 days after the first (RI: 4·01; 95% CI 0·87-10·56) or second dose (RI: 0·96; 95% CI 0·52-1·60). Results were similar for the case-control analysis. Conclusions: The risk of intussusception in the 21 days after the first or second dose of RV1 was not higher than the background risk among South Africa infants.
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The difference noted in Rotavirus vaccine efficiency between high and low income countries correlates with the lack of universal access to clean water and higher standards of hygiene. Overcoming these obstacles will require great investment and also time, therefore more effective vaccines should be developed to meet the needs of those who would benefit the most from them. Increasing our current knowledge of mucosal immunity, response to Rotavirus infection and its modulation by circadian rhythms could point at actionable pathways to improve vaccination efficacy, especially in the case of individuals affected by environmental enteropathy. Also, a better understanding and validation of Rotavirus entry factors as well as the systematic monitoring of dominant strains could assist in tailoring vaccines to individual’s needs. Another aspect that could improve vaccine efficiency is targeting to M cells, for which new ligands could potentially be sought. Finally, alternative mucosal adjuvants and vaccine expression, storage and delivery systems could have a positive impact in the outcome of Rotavirus vaccination.
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Background Postlicensure evaluations have identified an association between rotavirus vaccination and intussusception in several high- and middle-income countries. We assessed the association between monovalent human rotavirus vaccine and intussusception in lower-income sub-Saharan African countries. Methods Using active surveillance, we enrolled patients from seven countries (Ethiopia, Ghana, Kenya, Malawi, Tanzania, Zambia, and Zimbabwe) who had intussusception that met international (Brighton Collaboration level 1) criteria. Rotavirus vaccination status was confirmed by review of the vaccine card or clinic records. The risk of intussusception within 1 to 7 days and 8 to 21 days after vaccination among infants 28 to 245 days of age was assessed by means of the self-controlled case-series method. Results Data on 717 infants who had intussusception and confirmed vaccination status were analyzed. One case occurred in the 1 to 7 days after dose 1, and 6 cases occurred in the 8 to 21 days after dose 1. Five cases and 16 cases occurred in the 1 to 7 days and 8 to 21 days, respectively, after dose 2. The risk of intussusception in the 1 to 7 days after dose 1 was not higher than the background risk of intussusception (relative incidence [i.e., the incidence during the risk window vs. all other times], 0.25; 95% confidence interval [CI], <0.001 to 1.16); findings were similar for the 1 to 7 days after dose 2 (relative incidence, 0.76; 95% CI, 0.16 to 1.87). In addition, the risk of intussusception in the 8 to 21 days or 1 to 21 days after either dose was not found to be higher than the background risk. Conclusions The risk of intussusception after administration of monovalent human rotavirus vaccine was not higher than the background risk of intussusception in seven lower-income sub-Saharan African countries. (Funded by the GAVI Alliance through the CDC Foundation.)
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India has recently introduced a rotavirus vaccine under a universal immunization program. There is limited information on intussusception, an adverse event, following immunization in children from India. We are conducting sentinel surveillance for intussusception in children aged under two years at 19 hospitals. The sentinel sites' selection followed a multistage process. The surveillance combines retrospective surveillance for 69 months and prospective surveillance for 18 months. The suspected intussusception cases shall be reviewed for capturing confirmed cases and detailed data collection and classification according to Brighton Collaboration criteria. Data shall be analysed to describe epidemiology, trends, regional and seasonal variations, clinical profiles, management modalities, and outcomes of intussusception. The combination of prospective and retrospective surveillance shall be informative about the trend of intussusception over the last seven years in India. At four sites where rotavirus vaccines have been introduced, the change in intussusception trends shall be documented. The potential association with rotavirus vaccines and other vaccines shall be assessed using case-control and self-controlled case series methodology. Results are forthcoming. The results shall support the national vaccine safety surveillance effort by providing baseline estimates of intussusception for continued monitoring. The surveillance protocol and site selection processes shall inform similar vaccine-safety surveillance in India and other developing countries.
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Oral vaccines are less immunogenic when given to infants in low-income compared with high-income countries, limiting their potential public health impact. Here, we review factors that might contribute to this phenomenon, including transplacental antibodies, breastfeeding, histo blood group antigens, enteric pathogens, malnutrition, microbiota dysbiosis and environmental enteropathy. We highlight several clear risk factors for vaccine failure, such as the inhibitory effect of enteroviruses on oral poliovirus vaccine. We also highlight the ambiguous and at times contradictory nature of the available evidence, which undoubtedly reflects the complex and interconnected nature of the factors involved. Mechanisms responsible for diminished immunogenicity may be specific to each oral vaccine. Interventions aiming to improve vaccine performance may need to reflect the diversity of these mechanisms.
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Background: The indigenous oral rotavirus vaccine Rotavac® was introduced into the public immunization system in India in 2016 and will be expanded in phases. This data will describe the epidemiology of intussusception in India in absence of rotavirus vaccination and will help in setting up or designing a safety monitoring system. Methods: Medical records of intussusception cases between 2013 and 2016 in two major referral hospitals in Tamil Nadu, India were reviewed, and data on clinical presentation and management and outcome were collated. Results: A total of 284 cases of intussusception were diagnosed and managed at the two centers of which 280/284 could be classified as level 1 by the Brighton criteria. Median age at presentation was 8 months (Inter Quartile Range, IQR 6-17.2) with a male to female ratio of 2.1:1. Over half (57.7%) required surgical intervention while the rest underwent non-surgical or conservative management. Conclusions: Retrospective data from referral hospitals is sufficient to classify cases of intussusception by the Brighton criteria. These baseline data will be useful for monitoring when rotavirus vaccination is introduced.
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Rotavirus is the most common cause of moderate-to-severe infant diarrhoea in developing countries, resulting in enormous morbidity, mortality, and economic burden. A bovine-human reassortant pentavalent rotavirus vaccine (BRV-PV) targeting the globally most common strains was developed in India and tested in a randomized, double-blind, placebo-controlled end-point driven Phase III efficacy clinical trial implemented at six sites across India. Infants 6 to 8weeks of age were randomized (1:1) to receive three oral doses of BRV-PV or placebo at 6, 10, and 14weeks of age along with routine vaccines. Home visit surveillance was conducted to detect severe rotavirus gastroenteritis (SRVGE) and safety outcomes until the children reached two years of age. A total of 3749 infants received BRV-PV while 3751 received placebo. At the time of the primary end-point (when the minimum number of cases needed for analysis were accrued) the vaccine efficacy against SRVGE was 36% (95% CI 11.7, 53.6, p=0.0067) in the per protocol (PP) analysis, and 41.9% (95% CI 21.1, 57.3, p=0.0005) in the intent to treat (ITT) analysis. Vaccine efficacy over the entire follow-up period (until children reached two years of age) was 39.5% (95% CI 26.7, 50, p<0.0001) in the PP analysis and 38.8% (95% CI, 26.4, 49, p<0.0001) in the ITT analysis. Vaccine efficacy against the very severe rotavirus cases (VSRVGE, Vesikari score≥16) was 60.5% (95% CI 17.7, 81, p=0.0131) at the time of the primary analysis and 54.7% (95% CI 29.7, 70.8, p=0.0004) for the complete follow-period in the PP population. The incidence of solicited, unsolicited, and serious adverse events were similar in both the vaccine and placebo groups. Likewise, the number of intussusceptions and deaths were similar between both groups. Thus, BRV-PV is an effective, well tolerated and safe vaccine in Indian infants. (Trial registration: Clinical Trials.Gov [NCT 02133690] and Clinical Trial Registry of India [CTRI/2013/05/003667]).
Background: Baseline data on intussusception are needed to compare the intussusception rates following introduction of rotavirus vaccine. Methods: A hospital-based bidirectional surveillance (retrospective from 2009 to 2012; and prospective from 2013 to 2015) was set up in a tertiary care hospital in Chandigarh, India, to enrol children <5 years of age admitted with intussusception as per Brighton's classification, to estimate the hospital admission rate. Incidence of intussusception among infants and children <5 years of age was also estimated. Results: A total of 277 intussusception cases (96 retrospective; 181 prospective) were reported. Majority of cases were males (69.7%) and infants (72%). Median age at diagnosis was 10 months (interquartile range 6-12 months). Nearly 62% cases were treated surgically and 33% radiologically. Incidence was estimated to be 20/100 000 infants, and 5/100 000 children <5 years of age per year, in Chandigarh. Conclusion: Intussusception surveillance system provided background hospital admission and incidence rate before rotavirus vaccine introduction in North India.
Two rotavirus vaccines, Rotarix (RV1) and RotaTeq (RV5), were licensed for global use in 2006. A systematic review of 48 peer-reviewed articles with post-licensure data from 24 countries showed a median RV1 vaccine effectiveness (VE) of 84%, 75%, and 57% in low, medium, and high child mortality countries, respectively, and RV5 VE of 90% in low and 45% in high child mortality countries. A partial vaccine series provided considerable protection, but not to the same level as a full series. VE tended to decline in the second year of life, particularly in medium and high mortality settings, and tended to be greater against more severe rotavirus disease. Post-licensure data from countries across geographic regions and with different child mortality levels demonstrate that under routine use, both RV1 and RV5 are effective against rotavirus disease, supporting the WHO recommendation that all countries introduce rotavirus vaccine into their national immunization program.