Impact of Rotavirus Vaccination on Hospitalizations and Deaths From Childhood Gastroenteritis in Botswana
Impact of Rotavirus Vaccination on Hospitalizations and Deaths From Childhood Gastroenteritis in Botswana
Leslie A. Enane () 1 2 3
Paul A. Gastañaduy 0 2
David M. Goldfarb 1 2 5 6 7
Jeffrey M. Pernica 1 2 5
Margaret Mokomane 2 4
Banno Moorad 1 2
Lingani Masole 1 2
Jacqueline E. Tate 0 2
Umesh D. Parashar 0 2
Andrew P. Steenhoff 1 2 6 8
0 Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention , Atlanta , Georgia
1 Botswana-UPenn Partnership , Gaborone , Botswana
2 phia , Abramson Research Bldg, Rm 1202, 34th St and Civic Center Blvd, Philadelphia, PA 19104
3 Division of Infectious Diseases, Department of Pediatrics, Children's Hospital of Philadelphia , Pennsylvania
4 National Health Laboratory , Gaborone , Botswana
5 Division of Infectious Disease, Department of Pediatrics, McMaster University , Hamilton, Ontario , Canada
6 Department of Pediatrics, University of Botswana , Gaborone
7 Division of Microbiology, Department of Pathology, University of British Columbia , Vancouver , Canada
8 Division of Infectious Diseases and Section of Global Health, Department of Pediatrics, Children's Hospital of Philadelphia and the University of Pennsylvania , Philadelphia
Background. A monovalent human rotavirus vaccine (RV1) was introduced in Botswana in July 2012. We assessed the impact of RV1 vaccination on childhood gastroenteritis-related hospitalizations and deaths in 2013 and 2014. Methods. We obtained data from registers of 4 hospitals in Botswana on hospitalizations and deaths from gastroenteritis, regardless of cause, among children <5 years of age. Gastroenteritis hospitalizations and deaths during the prevaccine period (January 2009-December 2012) were compared to the postvaccine period (January 2013-December 2014). Vaccine coverage was estimated from data collected through a concurrent vaccine effectiveness study at the same hospitals. Results. By December 2014, coverage with ≥1 dose of RV1 was an estimated 90% among infants <1 year of age and 76% among children 12-23 months of age. In the prevaccine period, the annual median number of gastroenteritis-related hospitalizations in children <5 years of age was 1212, and of gastroenteritis-related deaths in children <2 years of age was 77. In the postvaccine period, gastroenteritis-related hospitalizations decreased by 23% (95% confidence interval [CI], 16%-29%) to 937, and gastroenteritis-related deaths decreased by 22% (95% CI, −9% to 44%) to 60. Declines were most prominent during the rotavirus season (May-October) and among infants <1 year of age, with reductions of 43% (95% CI, 34%-51%) in gastroenteritis hospitalizations and 48% (95% CI, 11%-69%) in gastroenteritis deaths. Conclusions. Following introduction of RV1 into the national immunization program, significant declines in hospitalizations and deaths from gastroenteritis were observed among children in Botswana, suggestive of the beneficial public health impact of rotavirus vaccination.
demonstrated high efficacy against severe rotavirus
gastroenteritis in high- and middle-income countries in the Americas and
Europe (85%–98%), trials in low- and middle-income countries
in Africa and Asia have demonstrated lower efficacy (61%–64%
and 48%, respectively) [6–10]. Despite lower efficacy in
lowresource settings, the benefits of vaccination could be
substantial in countries with a high baseline burden of severe rotavirus
disease. Significant declines in all-cause gastroenteritis
mortality and hospitalizations among children <5 years of age have
been observed following rotavirus vaccine introduction in a
few early-adopter countries with low child mortality [11–15].
The variation in efficacy by national gross domestic product
 underscores the importance of monitoring the impact of
rotavirus vaccination in low-income, high-mortality settings
during routine programmatic use, where vaccine performance
may differ from the optimal conditions of clinical trials.
Botswana is a middle-income African country , although
this distinction belies relatively high child mortality (47 deaths
per 1000 children aged <5 years in 2013) , and high human
immunodeficiency virus prevalence (16.9% of the population
aged ≥6 weeks) . Diarrheal illnesses, including rotavirus
gastroenteritis, cause relatively high morbidity and mortality
in Botswana in comparison with other African countries [20,
21]. In July 2012, the Botswana Ministry of Health introduced
a monovalent rotavirus vaccine (RV1; Rotarix) into its routine
immunization program, recommending a 2-dose series at 2 and
3 months of age. We assessed trends in all-cause gastroenteritis
hospitalizations and deaths among young children admitted to
4 public hospitals in Botswana before and after rotavirus
Study Design and Setting
This was a retrospective study conducted from September 2014
to January 2015 at the pediatric wards of 4 hospitals in Botswana:
Princess Marina Hospital in Gaborone, Nyangabgwe Referral
Hospital in Francistown, Letsholathebe II Hospital in Maun,
and Bobonong Primary Hospital in Bobonong. Princess Marina
Hospital and Nyangabgwe Referral Hospital are the country’s 2
tertiary referral centers, Letsholathebe II Hospital is a district
hospital serving northern Botswana, and Bobonong Primary
Hospital is a small primary hospital. These sites are located in
the northeast and in the capital, where the majority of the
population is located, and were chosen to include a range of
geographic and socioeconomic locales, serving populations with
varying health indicators in Botswana. The Health Research
Development Committee of Botswana and the Human Subjects
Committees of the University of Pennsylvania and McMaster
University approved the study protocol.
Vaccination coverage was estimated from data prospectively
collected in June 2013 to April 2015 through a concurrent
case-control study of vaccine effectiveness against rotavirus
admission conducted at the same study hospitals. Vaccination
rates were calculated among infants 4–11 months of age and
children 12–23 months of age admitted with gastroenteritis
who tested negative for rotavirus (ie, “test-negative” controls).
Vaccination status was determined by review of the children’s
We reviewed pediatric ward admission logbooks from January
2009 to December 2014. We recorded every
gastroenteritisrelated admission among children <5 years of age to the
pediatric wards, noting the patient age and outcome of admission
(discharged home, transferred, or deceased). Admissions were
considered related to gastroenteritis of any cause if the diagnosis
listed in the register was gastroenteritis, acute gastroenteritis,
acute diarrheal disease, gastroenteritis and dehydration,
diarrhea, vomiting, enteritis, gastritis, febrile gastroenteritis, food
poisoning, or dysentery. Cases for which there were additional
diagnoses were included.
We excluded cases with the following listed diagnoses:
chronic gastroenteritis, chronic enteritis, chronic diarrhea, vomiting
secondary to toxic ingestion, or vomiting secondary to ingestion
of wild fruits or plants. We also excluded cases where the patient
age was not recorded (2.0% of gastroenteritis cases recorded at
If the outcome of admission was not recorded in the
admission registers, the outcome was sought through review of daily
rounding books and, if patients were transferred to the intensive
care unit (ICU), the hospital ICU registers. Ward death registers
were reviewed to ensure that all gastroenteritis-related deaths
among children admitted to the pediatric wards had been
ascertained in our review of the admission logbooks. For the months
during which admission registers were not available, numbers
of gastroenteritis admissions and deaths were obtained through
review of medical records data and death registers. Complete
admission data were available for 170 of 192 site-months
(89%) during the prevaccine period and 96 of 96 site-months
(100%) during the postvaccine period. Complete mortality
data were available for 185 of 192 site-months (96%) during
the prevaccine period and 96 of 96 site-months (100%) during
the postvaccine period.
The monthly number of admissions and deaths related to
allcause gastroenteritis were stratified by age group: 0–11 months,
12–23 months, 24–59 months, and all ages (0–59 months).
Incidence rates could not be determined as there were no reliable
data regarding the catchment population of the study hospitals.
To minimize the impact of gaps in admissions and mortality
data on the overall analysis, the totals of median monthly
admissions were used, which effectively imputes data for any
missing months. Medians were determined for each calendar month
during the prevaccine years 2009–2012, and during the
postvaccine years 2013–2014. The year 2012 was included in the
prevaccine period as the vaccine was introduced midyear during
the rotavirus season, and given a gradual uptake in coverage
among eligible infants, a significant impact of the vaccine
during that year would not be expected. Annual numbers were
calculated as a sum of the monthly medians over the calendar year.
Rotavirus season numbers were calculated as a sum of the
monthly medians over the rotavirus season, defined as May to
October based on data from 4 years of ongoing hospital-based
active rotavirus surveillance . We compared the annual
median number of admissions and deaths during the pre- and
postvaccine years, stratified by age group. Because few deaths
(n = 16) occurred in children ≥2 years of age over the entire
study period, the mortality analyses was restricted to children
aged <2 years. We also compared the median numbers of
admissions and deaths, stratified by age, during the prevaccine
rotavirus seasons, first with the postvaccine medians, and then by
each postvaccine year individually. Percentage reductions and
associated 95% confidence intervals (CIs) were calculated
using Poisson regression analyses comparing medians in
and deaths for children <2 years of age during each of the
Washington) and SAS version 9.3 (SAS Institute) software.
Hospitalizations From Ingestions
tion served by the study hospitals over time, we compared
body ingestion. Some common examples included paraffin
inComplete data were available for 150 of 192 site-months
(98%) during the postvaccine period.
Vaccine coverage with at least 1 dose of RV1 during 2013
and 2014 was an estimated 90% (212/235) among infants
75% (176/235) were fully vaccinated with 2 doses, and
from 4 hospitals in Botswana.
In total, 359 gastroenteritis-related deaths occurred among
children <2 years of age during the prevaccine years 2009–2012, 303
(84%) of which occurred among infants, and 218 (61%) of
which occurred during the rotavirus season (May–October).
During the prevaccine baseline period, an annual median of
77 deaths among children <2 years of age were related to
gastroenteritis (Table 1). Total annual gastroenteritis-related deaths in
the prevaccine years for children <2 years of age were 72 in
2009, 84 in 2010, 97 in 2011, and 106 in 2012. In the postvaccine
period, the annual median of deaths among children <2 years of
age decreased to 60 deaths, corresponding to a reduction of 22%
(95% CI, −9% to 44%) from the prevaccine annual median.
This included a 32% (95% CI, 1%–53%) decrease in the annual
median of gastroenteritis deaths among infants <1 year of age.
The reduction in deaths was most prominent during the
Rotavirus Season Gastroenteritis-Related
Prevaccine Postvaccine 1212 937 817 545 272 253
Abbreviation: CI, confidence interval.
Prevaccine Postvaccine 696 464 487 279 154 123
Prevaccine Postvaccine 517 473 331 266 118 131
rotavirus season. During rotavirus season months, a median of
27 deaths occurred among children <2 years of age in the
postvaccine period—a 39% reduction (95% CI, 1%–62%) from the
baseline median number of 44 deaths. Among infants <1 year of
age, a median of 21 deaths occurred during the rotavirus season
in the postvaccine period—a 48% reduction (95% CI, 11%–
69%) from the prevaccine median of 40 deaths.
Assessing the postvaccine rotavirus seasons individually,
reductions in infant deaths were sustained over the 2013 and 2014
rotavirus seasons (Figure 1). The greatest declines in deaths
from gastroenteritis among children <2 years of age in 2013
and 2014 occurred during the rotavirus seasons (Figure 2A).
During the non–rotavirus season months, the number of deaths
was consistent with prevaccine medians.
In total, 4440 gastroenteritis-related hospitalizations occurred
among children <5 years of age during the prevaccine years
2009–2012, 2955 (67%) of which occurred among infants,
and 2650 (60%) of which occurred during the rotavirus season
(May–October). Post–vaccine introduction, 1873
gastroenteritisrelated hospitalizations were recorded in 2013–2014. During the
prevaccine baseline period, an annual median of 1212
hospitalizations related to gastroenteritis occurred among children <5
years of age (Table 2). Total annual gastroenteritis-related
hospitalizations in the prevaccine years for children <5 years of age
were 1025 in 2009, 1241 in 2010, 1084 in 2011, and 1090 in
2012. Annual gastroenteritis-related hospitalizations decreased
by 23% (95% CI, 16%–29%) from the prevaccine annual median
to 937 (904 in 2013 and 969 in 2014) in the postvaccine period,
including a 33% (95% CI, 26%–40%) decrease in gastroenteritis
admissions among infants. The reduction in
gastroenteritisrelated hospitalizations was most prominent during the rotavirus
season. The median number of hospitalizations among children
<5 years of age during rotavirus season months in the prevaccine
period was 696, compared to 464 in the postvaccine period,
corresponding to a 33% reduction (95% CI, 25%–41%) overall, and a
43% reduction (95% CI, 34%–51%) among infants. During
2013–2014, seasonal reductions were less pronounced among
children 12–23 months of age (20% [95% CI, −1% to 37%]),
and were not evident among those aged 24–59 months.
Assessing postvaccine rotavirus seasons individually,
reductions in infant hospitalizations with gastroenteritis were sustained
over the 2013 and 2014 rotavirus seasons (Figure 3). A 27%
decrease in gastroenteritis-related hospitalizations among children
12–23 months of age was noted in 2014, the first full year that
this age group would have been eligible to receive the vaccine.
Among children <2 years of age, peak gastroenteritis
hospitalizations during the rotavirus season months were blunted in 2013
and 2014, compared with the median number of hospitalizations
during the same months in the baseline period (Figure 2B).
Hospitalizations From Ingestions
No declines were noted in pediatric hospitalizations related to
ingestions over the study period. During prevaccine baseline
years, the annual median number of hospitalizations related
to ingestions was 256. In 2013 and 2014, respectively, 322 and
269 admissions related to ingestions occurred.
This is the first study to demonstrate the impact of rotavirus
vaccination on childhood mortality from gastroenteritis in
Africa, where more than half of global rotavirus deaths occur.
In the 2 years following rotavirus vaccine introduction in
Botswana, there was a 22% annual reduction in deaths related
to gastroenteritis among children <2 years of age, and a 48%
reduction in infant deaths related to gastroenteritis during the
rotavirus season at the 4 study hospitals. Over the same period
there was a 23% reduction in annual hospitalizations related
to gastroenteritis among children <5 years of age annually,
and a 43% reduction in infant hospitalizations during the
rotavirus season. The findings outlined here are consistent with
mortality and hospitalization trends documented in
middleincome countries in Latin America after rotavirus vaccine
introduction, where declines in deaths and hospitalizations ranged
from 22% to 38% and 11% to 40%, respectively [11, 13, 14].
As in this study, the decline in diarrhea-related mortality was
sustained over a 2-year period after the introduction of the
rotavirus vaccine. Our study suggests the powerful public health
value of rotavirus vaccination during routine use in a
high-mortality setting, and strongly supports WHO recommendations
for continued rollout of rotavirus vaccines in other African
nations with high burdens of severe rotavirus disease.
While the scope of this study evaluates the declines in
mortality and hospitalizations from all-cause gastroenteritis, several
key findings suggest that the observed reductions may be due to
rotavirus vaccination. First, declines were concentrated during
the rotavirus season months, with the great majority of annual
reductions occurring in May through October, as has been
described in other settings after introduction of rotavirus
vaccination [13–15, 22]. Second, declines in deaths and hospitalizations
were most pronounced among infants, which correlated with
the higher burden of severe rotavirus in this age group ,
as well as with the higher vaccine coverage among infants
during the study period. Last, reductions during rotavirus seasons
in individual years were noted sequentially in age groups as they
became increasingly vaccinated. Initial declines (in 2013) in
hospitalizations and deaths were mainly seen among infants,
the first birth cohort eligible to be vaccinated. By 2014, a decline
of 27% was noted in gastroenteritis hospitalizations among
children aged 12–23 months, when coverage increased among older
Several limitations should be considered. First, there were
gaps in the data available from admission registers. These
were supplemented as completely as possible with hospital
records that should provide comparable data. By analyzing totals
of median monthly admissions, the impact of missing months
on the overall analysis was minimized. Importantly, the trends
observed in this study were seen at all study sites. The most
complete data (96% prevaccine and 100% postvaccine) were
available for the mortality analysis, which demonstrated the
greatest impact of the rotavirus vaccine. Second, underreporting
of deaths due to gastroenteritis was likely, as this study did not
capture child deaths that occurred at home, in the emergency
department, or after direct admission to the ICU. Such
underreporting is unlikely to have changed significantly between the
prevaccine and postvaccine time periods. Third, there is the
possibility of secular variation underlying the declines seen in
hospitalizations and mortality from gastroenteritis, including
improvements in sanitation, changes in hospital referral
patterns, or advances in prehospital or in-hospital care. The
prevaccine yearly total hospitalizations and deaths were stable
and increasing, respectively, suggesting that there was not a
preexisting secular trend prior to implementation of RV1
vaccination. To our knowledge, there were no abrupt changes in
hospital referral patterns or care. Such changes, furthermore,
are unlikely to explain the large reductions in hospitalizations
and mortality observed over a short period of time, which
were concentrated during the rotavirus season and sustained
over 2 years across all sites. We were not able to calculate
incidence rates for this study as no reliable catchment population
data were available. However, we believe that the catchment
population for the study hospitals would have remained
relatively stable over the study period; this is supported by the
finding that hospitalizations for ingestions were stable or increased
over the study.
In summary, marked declines in hospitalizations and deaths
from pediatric gastroenteritis, primarily among infants, were
observed during the first 2 complete rotavirus seasons after
the addition of a monovalent rotavirus vaccine to the childhood
immunization schedule in Botswana. In upcoming years, as the
immunization program matures, the observed impact will likely
extend to older age cohorts in the country. Continued
surveillance is key to fully ascertain the effect of rotavirus vaccination
on the burden of childhood diarrheal illness in Botswana. Our
findings are consistent with a benefit from rotavirus vaccination
in protecting against the most severe and fatal forms of rotavirus
gastroenteritis, and strongly support WHO recommendations
for global rotavirus vaccine use.
Acknowledgments. We thank the patients and staff of Princess Marina
Hospital, Nyangabgwe Referral Hospital, Letsholathebe II Hospital, and
Bobonong Primary Hospital. This work is dedicated to the memory of Dr
Melissa Ketunuti. As a compassionate pediatrician and researcher, she worked
to improve health for vulnerable children in Botswana and around the
world, and she continues to inspire our work.
Author contributions. L. A. E., P. A. G., and J. E. T. performed the data
analysis. All authors participated in the preparation of the manuscript and
agreed to submit the manuscript for publication.
Disclaimer. The findings and conclusions in this report are those of the
authors and do not necessarily represent the official position of the Centers
for Disease Control and Prevention (CDC). The views expressed by the
authors do not necessarily reflect the views of PATH, the CDC Foundation, the
Bill and Melinda Gates Foundation, or GAVI, the Vaccine Alliance.
Financial support. This work was supported by the CDC Foundation.
This publication was made possible through core services and support from
the Penn Center for AIDS Research, a National Institutes of Health–funded
program (grant number P30 AI 045008).
Supplement sponsorship. This article appears as part of the supplement
“Health Benefits of Rotavirus Vaccination in Developing Countries,”
sponsored by PATH and the CDC Foundation through grants from the Bill and
Melinda Gates Foundation and GAVI, the Vaccine Alliance.
Potential conflicts of interest. All authors: No reported conflicts. All
authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the content
of the manuscript have been disclosed.
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