Global, Regional, and National Estimates of Rotavirus Mortality in Children <5 Years of Age, 2000–2013
Global, Regional, and National Estimates of Rotavirus Mortality in Children <5 Years of Age, 2000-2013
Jacqueline E. Tate 2 3
Anthony H. Burton 1 2
Cynthia Boschi-Pinto 0 1 2
Umesh D. Parashar 2 3
for the World Health Organization-Coordinated Global Rotavirus Surveillance Network 2
0 Universidade Federal Fluminense , Rio de Janeiro , Brazil
1 World Health Organization , Geneva , Switzerland
2 ters for Disease Control and Prevention , 1600 Clifton Rd, NE MS-A34, Atlanta, GA 30329-4018 Clinical Infectious Diseases
3 Centers for Disease Control and Prevention , Atlanta , Georgia
Background. Rotavirus vaccine is recommended for routine use in all countries globally. To facilitate decision making on rotavirus vaccine adoption by countries, help donors prioritize investments in health interventions, and monitor vaccine impact, we estimated rotavirus mortality for children <5 years of age from 2000 to 2013. Methods. We searched PubMed using the keyword “rotavirus” to identify studies that met each of the following criteria: data collection midpoint in year 1998 or later, study period of a 12-month increment, and detection of rotavirus infection by enzyme immunoassay in at least 100 children <5 years of age who were hospitalized with diarrhea and systematically enrolled through active surveillance. We also included data from countries that participated in the World Health Organization (WHO)-coordinated rotavirus surveillance network between 2008 and 2013 that met these criteria. To predict the proportion of diarrhea due to rotavirus, we constructed a multiple linear regression model. To determine the number of rotavirus deaths in children <5 years of age from 2000 to 2013, we multiplied annual, country-specific estimates of the proportion of diarrhea due to rotavirus from the regression model by the annual number of WHO-estimated child deaths caused by diarrhea in each country. Results. Globally, we estimated that the number of rotavirus deaths in children <5 years of age declined from 528 000 (range, 465 000-591 000) in 2000 to 215 000 (range, 197 000-233 000) in 2013. The predicted annual rotavirus detection rate from these studies declined slightly over time from 42.5% (95% confidence interval [CI], 37.4%-47.5%) in 2000 to 37.3% (95% CI, 34.2%40.5%) in 2013 globally. In 2013, an estimated 47 100 rotavirus deaths occurred in India, 22% of all rotavirus deaths that occurred globally. Four countries (India, Nigeria, Pakistan, and Democratic Republic of Congo) accounted for approximately half (49%) of all estimated rotavirus deaths in 2013. Discussion. While rotavirus vaccine had been introduced in >60 countries worldwide by the end of 2013, the majority of countries using rotavirus vaccine during the review period were low-mortality countries and the impact of rotavirus vaccine on global estimates of rotavirus mortality has been limited. Continued monitoring of rotavirus mortality rates and deaths through rotavirus surveillance will aid in monitoring the impact of vaccination.
Rotavirus is the most common cause of severe diarrhea among
children <5 years of age globally. Since 2006, 2 rotavirus
vaccines (RotaTeq, Merck & Co and Rotarix, GSK Biologicals)
have been licensed in >100 countries worldwide [
]. In 2009,
the World Health Organization (WHO) recommended that all
countries, and particularly those countries with high diarrhea
mortality rates in children, introduce rotavirus vaccines into
their national immunization programs . By the end of 2014,
>70 countries had introduced rotavirus vaccine into their
routine immunization programs for children.
Several countries that have implemented routine childhood
vaccination against rotavirus have documented a tremendous
impact on severe diarrhea and rotavirus disease requiring
]. Additionally, some countries, including
Mexico, Brazil, and Panama, have documented substantial
decreases of 22%–50% in diarrhea mortality among children
<5 years of age following vaccine introduction [
rotavirus vaccine implementation in settings of high child
mortality in Africa and Asia is just beginning to occur, and the real
lifesaving potential of vaccination has yet to be realized. To facilitate
decision making on rotavirus vaccine adoption by countries and to
help donors prioritize investments in health interventions,
upto-date estimates of childhood mortality from rotavirus are
needed. Furthermore, baseline estimates of rotavirus mortality
are required to measure the impact of vaccination.
The latest WHO estimate of 453 000 rotavirus deaths in
children globally was derived using data on overall childhood
mortality from diarrhea in the year 2008 and applying the then-available
surveillance data on rotavirus detection rates in children
hospitalized with diarrhea [
]. Availability of new data and the use of
new methods have resulted in several updated estimates of
diarrhea mortality among children in recent years [
]. In 2010,
diarrhea mortality was estimated at 1.24 million deaths among
children <5 years of age in 2008. In 2013, this estimate was
updated to 752 000 diarrheal deaths among children <5 years of
age in 2008, a 39% decline from the previous 2008 estimate in
]. Additionally, the WHO’s Global Network for
Rotavirus Surveillance has expanded since its inception in 2008
and includes data from many countries where rotavirus burden
data were not previously available [
Our objective was to derive updated estimates of rotavirus
mortality for children <5 years of age for the period 2000–
2013 using updated estimates of diarrhea mortality,
hospitalbased studies, and surveillance data on rotavirus disease burden,
and incorporating the impact of rotavirus vaccine use in early
Search Strategy and Selection Criteria
To determine the proportion of diarrhea deaths attributable to
rotavirus, we used the same literature search and selection
criteria as those used for previous WHO rotavirus mortality
]. We searched PubMed using the keyword
“rotavirus” as the primary search term to identify rotavirus
surveillance studies published from January 1998 through
December 2014 that met our inclusion criteria. To be included
in the analysis, a study had to meet each of the following criteria:
a data collection midpoint in the year 1998 or later, study period
of a 12-month increment (to account for possible seasonality in
rotavirus disease), and detection of rotavirus infection by enzyme
immunoassay (EIA) in at least 100 children <5 years of age who
were hospitalized with diarrhea and systematically enrolled
through active surveillance. We also included data from countries
that participated in the WHO-coordinated rotavirus surveillance
network between 2008 and 2013 that met the above-mentioned
]. For studies that included data from several
countries and/or several sites within a country, we entered each
country and site into our database as separate data points, where
possible. Similarly, for sites that had multiple years of surveillance
data, we separately entered the data from each year into our
database, when possible. Eligible studies were identified and the
data abstracted by a single author (J. E. T.) and reviewed by a
second author (U. D. P.). For each study that satisfied our inclusion
criteria, we abstracted the start and end dates of the study period,
the country in which the study was conducted, the number of
fecal specimens tested, the number of rotavirus-positive results,
and the proportion of positive results.
To predict the proportion of diarrhea deaths due to rotavirus,
we constructed a multiple linear regression model with the
midpoint of the study period, the under-5 child mortality estimate
during the midpoint of the study period for the country where
the study was conducted, the region where the country is
located, and an indicator as to whether the study was conducted
before or after rotavirus vaccine introduction into the country’s
national immunization program as the independent variables.
The country-/year-specific under-5 mortality estimates were
from the United Nations (UN) Inter-agency Group for Child
Mortality Estimation [
]. Countries were classified into regions
using the current UN Millennium Development Goals regional
]. A study was considered as conducted during the
post–vaccine introduction period if the midpoint of the data
collection period was at least 1 full year after the year of national
vaccine introduction and vaccine coverage among children <1
year of age was ≥60%. For example, if a country introduced
rotavirus vaccine in 2008, it would be classified as post–vaccine
introduction starting in 2010 if vaccine coverage was ≥60%
and pre–vaccine introduction otherwise. Vaccine coverage
estimates were obtained from the 2013 WHO/United Nations
Children’s Fund national immunization coverage data [
To determine the number of deaths due to rotavirus in
children <5 years of age from 2000 to 2013, we multiplied annual,
country-specific estimates of the proportion of diarrhea due to
rotavirus by the annual number of WHO-estimated child deaths
caused by diarrhea in each country [
]. We then summed up
these estimates to obtain the annual regional and global estimates
of the number of deaths due to rotavirus in children <5 years of
age. To calculate annual rotavirus-specific mortality rates per
100 000 children <5 years of age from 2000 to 2013, we used as
denominator the 2012 revision of the UN Population Division
estimates for the population aged <5 years [
Trends in Rotavirus Mortality From 2000 to 2013
Specimens from 448 139 children <5 years of age hospitalized for
diarrhea were tested for rotavirus by EIA from surveillance studies
in 90 countries that met our inclusion criteria, including 269 968
specimens from 121 published articles from 74 countries and
229 527 specimens from 175 WHO-supported surveillance sites
in 61 countries (Figure 1). The predicted annual rotavirus
detection rate from these studies declined slightly over time from 42.5%
(95% confidence interval [CI], 37.4%–47.5%) in 2000 to 37.3%
(95% CI, 34.2%–40.5%) in 2013 globally (Table 1). The rotavirus
detection rate also declined slightly over the study period in all of
the regions except Latin America, where the detection rate began
to decline more sharply in 2008, and Northern Africa and
developed countries, where the detection rates began to decline more
sharply in 2012 (Figure 2B). The highest predicted rotavirus
detection rates were in Southeast Asia (50.7%–54.6%) and the lowest
rates were in Latin America (26.1%–35.5%).
Globally, we estimated that the number of rotavirus deaths in
children <5 years of age declined from 528 000 (range, 465 000–
591 000) in 2000 to 215 000 (range, 197 000–233 000) in 2013
(Figure 2A). The largest number of rotavirus deaths occurred
in sub-Saharan Africa, where the number ranged from
250 000 (range, 217 000–282 000) deaths in 2000 to 121 000
(range, 111 000–131 000) deaths in 2013. Rotavirus deaths
decreased at a slower rate in sub-Saharan Africa than in the
other regions, resulting in an increasing proportion of all
rotavirus deaths occurring in this region from 47.3% in 2000 to
56.3% in 2013. More than 90% of rotavirus deaths occurred
in countries eligible for Gavi support [
]. From 2000 to
2013, the largest number of rotavirus deaths occurred in India.
Country and Regional Distribution of Deaths in 2013
In 2013, an estimated 47 100 rotavirus deaths occurred in
India, 22% of all deaths due to rotavirus that occurred globally
that year. Four countries (India, Nigeria, Pakistan, and
Democratic Republic of Congo) accounted for approximately half
(49%) of all rotavirus deaths in 2013, and 10 countries (India,
Nigeria, Pakistan, Democratic Republic of Congo, Angola,
Ethiopia, Afghanistan, Chad, Niger, and Kenya) accounted
for almost two-thirds of all deaths (65%) in 2013 (Figures 3
and 4A). In 2013, the highest rate of rotavirus mortality
occurred in Angola (240 per 100 000 children <5 years of
age). By 2013, all 10 of the countries with a mortality rate
>100 per 100 000 children were located in sub-Saharan Africa
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We estimated that 37% of the 578 000 diarrheal deaths in
children <5 years of age in 2013 were due to rotavirus, resulting in
215 000 rotavirus deaths in this age group. The proportion of
diarrheal deaths due to rotavirus decreased only slightly from
43% to 37% over the 14-year study period from 2000 to 2013.
However, because the estimated number of diarrheal deaths
declined by more than half during this time period, the number
of rotavirus deaths decreased from 528 000 to 215 000. More
than 90% of rotavirus deaths in 2013 occurred in 72 low-income
and low-middle-income countries eligible for support for
rotavirus vaccine procurement from Gavi, the Vaccine Alliance. The
majority (56%) of rotavirus deaths occurred in countries of
sub-Saharan Africa, the region that also accounted for all 10
countries in 2013 with rotavirus mortality rates >100 per
100 000. Given its large population size, India had the largest
number of estimated rotavirus deaths for a given country,
singularly accounting for more than one-fifth of global rotavirus
deaths in 2013. With the implementation of rotavirus vaccines
beginning in 2012 in several sub-Saharan African countries, and
the licensure of a low-cost, locally manufactured rotavirus
vaccine in India in early 2014 [
], the impact of vaccination on
childhood mortality from rotavirus may soon be more fully
Comparison of the current figures with our own previously
published estimates of rotavirus mortality for the year 2004
and 2008 derived using the same methods is difficult [
largely because of changes in methods and data sources for
estimating the overall envelope of diarrhea mortality that we used to
derive rotavirus mortality figures over the years . For example,
we previously estimated 453 000 rotavirus deaths in 2008, based
on the 2010 WHO estimate of 1.2 million diarrheal deaths in
children <5 years of age in 2008 [
]. In this analysis, we now
estimate 296 000 rotavirus deaths in 2008, based on the updated
2013 WHO estimate of 752 000 diarrheal deaths in children <5
years of age in 2008. However, the proportion of diarrhea deaths
due to rotavirus in 2008 was similar for the previous (37%) and
current (39%) analyses. The figures presented in this report thus
represent the most updated and consistent comparison of trends
in diarrhea and rotavirus mortality over the period 2000–2013.
Our estimates of 265 000 (range, 244 000–286 000) rotavirus
deaths in 2010, 248 000 (range, 228 000–267 000) rotavirus deaths
in 2011, and 215 000 (range, 197 000–233 000) rotavirus deaths in
2013 are somewhat higher than other contemporary estimates of
173 000 (uncertainty range, 133 100–284 400) rotavirus deaths in
2010 by Lozano et al, 192 700 (uncertainty range, 133 100–
284 400) rotavirus deaths in 2011 by Fischer Walker et al,
197 000 (uncertainty range, 110 000–295 000) rotavirus deaths
in 2011 by Lanata et al, and 122 000 (uncertainty range,
97 000–152 000) in 2013 by the Global Burden of Disease
(GBD) Study in 2013 [
] (Table 2). This disparity is
largely related to differences in data sources and analytic assumptions
for the various studies. For the overall envelope of diarrhea
mortality used to estimate rotavirus deaths, we used estimates based
on the 2013 Child Health Epidemiology Reference Group
(CHERG) diarrhea mortality estimates, whereas Fischer Walker
et al and Lanata et al used the 2011 CHERG diarrhea mortality
estimates, and Lozano et al and GBD 2013 used their own GBD
estimates for diarrhea mortality for the years 2010 and 2013,
respectively. The large differences in overall diarrhea mortality
envelopes have a substantial impact on rotavirus mortality estimates
among various studies.
Another key difference is that the studies of Fischer Walker
et al, Lanata et al, and Lozano et al adjusted lower their etiologic
fraction of hospitalized diarrhea attributable to rotavirus to
account for factors such as mixed infections with other diarrheal
pathogens and possible detection of rotavirus in asymptomatically
infected children [
11, 13, 25
]. We did not make such adjustments
because the recently completed Global Enteric Disease
Multicenter Study (GEMS), one of the most comprehensive and
up-to-date evaluations of the etiology of childhood diarrheal
illness conducted in 4 African and 3 Asian countries, found that
nearly all children infected with rotavirus were symptomatic
with moderate-to-severe diarrhea [
] and that approximately
90% of cases with moderate-to-severe diarrhea with rotavirus
detected by EIA in the stool were attributable to rotavirus.
Other studies have also shown that rotavirus is infrequently
detected by EIA in stools from healthy children [
]. Thus, we
assumed that the detection of rotavirus by EIA in children
hospitalized with diarrhea was causally related to illness. Although
we may be overestimating rotavirus deaths by approximately
10% for not making any adjustments for mixed or
asymptomatic infections, laboratory testing by EIA may not detect
rotavirus in some children infected by this pathogen if specimens are
obtained late in illness or are of insufficient quantity; the
resulting underestimation of rotavirus burden may offset, in part or
fully, any overestimation from not accounting for coinfection
with other pathogens.
Additionally, the GBD 2013 study with the lowest estimate
of 122 000 rotavirus deaths in 2013 used the most distinctive
counterfactual approach to estimate pathogen-specific diarrhea
mortality, incorporating GEMS data into their estimates by
calculating etiologic-specific population attributable fractions
using the relative risk of pathogens for diarrhea together with
the prevalence of the pathogen in patients. Additionally, as
GEMS data were only available for 4 African and 3 Asian
countries, these attributable fractions had to be extrapolated to all
countries globally. Of note, using this counterfactual approach,
41.5% of all childhood diarrhea deaths were of unidentified
etiology. Without a more detailed examination of the various
analytic approaches, which is beyond the scope of our study,
a proper comparison of our estimates with other studies is
The large declines in diarrhea mortality over the past decade
are likely largely related to general improvements in sanitation
and hygiene; however, the impact of these interventions is not
likely consistent across pathogens and, in particular, may have
less of an impact against pathogens such as rotavirus that are
more frequently transmitted person-to-person rather than
through contaminated food and water. Thus, the decline in
diarrhea mortality may occur equally across all pathogens. This
hypothesis is supported by data from a literature review showing
that rotavirus caused approximately 22% (range, 17%–28%) of
childhood diarrhea hospitalizations in studies published between
1986 and 1999, whereas for studies published from 2000 to 2004,
this proportion increased to 39% (range, 29%–45%) [
18, 24, 29
In addition, data from the United States and Mexico showed that
as diarrhea-related childhood deaths decreased dramatically in
both countries in the latter part of the 20th century, the decline
was greatest during the summer months when diarrheal diseases
caused by bacteria are more prevalent [
]. Finally, an analysis
of longitudinal surveillance data from Dhaka Hospital in
Bangladesh showed that the proportion of diarrhea attributable to
rotavirus nearly doubled during 2002–2004 compared with
1993–1995 (42% vs 22%; P < .001) . Thus, an additional
factor that may affect the variability of rotavirus mortality estimates
from various studies is the time period for which the rotavirus
literature was examined. While we limited studies included in
our analysis to those with a midpoint of data collection as
1998–2014 to assess contemporary trends, Lanata et al reviewed
studies from 1990 to 2011, Fischer Walker et al reviewed studies
from 1980 to 2010, and GBD 2013 reviewed studies with data
from 1975 to 2013 as well as administrative databases of hospital
discharges that rely on coding rather than specimen testing to
An additional and unique strength of our approach was that
we incorporated rotavirus vaccine use and coverage thresholds
into our models. Latin America was the only region that had
any appreciable vaccine use during our study period. Rotavirus
vaccine introduction began in 2006 with 5 countries in Latin
America introducing vaccine into their national immunization
programs. By the end of 2011, the last year that rotavirus
vaccine could have been introduced to be classified as a
vaccineusing country in our analysis, 15 countries that comprised
84% of the region’s under-5 population had included rotavirus
vaccine in their national immunization programs. Prior
to vaccine introduction in the region (2000–2006), the
proportion of diarrhea due to rotavirus was 34%–36%. By 2008, the
proportion of diarrhea due to rotavirus began to decline and
was 26% in 2013. Similarly, the proportion of diarrhea due to
rotavirus began to decline in 2012 in developed countries and
in countries in Northern Africa where 34% and 18% of the
population in these regions, respectively, lived in a country where
rotavirus vaccine was available in the national immunization
program. Less than 10% of the population had access to
rotavirus vaccines in all other regions. Documenting this early decline
in Latin America and more recently in developed countries and
Northern Africa, but not in other regions where vaccine was not
used, provides further reassurance regarding the validity of our
Our estimates have some limitations. Like other studies, we
used the proportion of rotavirus hospitalizations among
allcause diarrhea hospitalizations as a proxy for the contribution
of rotavirus to all-cause diarrhea deaths, as laboratory
confirmation of causes of diarrheal deaths, particularly those deaths that
occur in the community, is rare. However, we do require
specimens to be collected through active surveillance meeting a set of
strict, standardized criteria for enrollment and testing of
specimens and exclude studies using administrative coding or passive
surveillance to limit incomplete identification of rotavirus.
Countries that have published rotavirus surveillance data or that
participated in the WHO-coordinated rotavirus surveillance
network may be systematically different in their approach to
treatment and care of children with diarrheal disease than
countries without such data and thus could influence the proportion
of diarrheal hospitalizations due to rotavirus. However, we
included data from 774 data points from 90 countries, so we
capture a wide variety of study settings in this analysis. Similarly,
within countries with such data, hospitals that conduct rotavirus
surveillance may not reflect the healthcare-seeking behavior or
management that is generalizable at the national level. Also, for
our regression model, we used national-level, rather than
sitespecific, covariates for child mortality and vaccine coverage.
While there was some variation in methods in the studies we
reviewed (eg, timing of stool specimen collection), and although
the number of studies in each region that met the selection
criteria varied, we sought to minimize bias by using a standard set of
criteria to identify published reports and also applied these same
criteria to the network of sentinel hospital-based surveillance
sites maintained by WHO that collects data using a standard
protocol. Together, these studies provided data from 90 countries
representing 86% of the worldwide under-5 population.
While rotavirus vaccine had been introduced into >50
countries worldwide by the end of 2013, the majority of countries
currently using rotavirus vaccines are low-mortality countries,
so the impact of vaccine use on global estimates of rotavirus
mortality has been limited. However, rotavirus vaccines have
been shown to have an impact on all-cause diarrhea mortality.
Mexico introduced rotavirus vaccines in 2007, and by 2008 had
documented a 41% decline in all-cause diarrheal deaths in
children <1 year of age [
]. These declines in diarrhea mortality
were seen in older age groups in subsequent years and have
been sustained through 2011 [
]. Similar declines in
diarrhea mortality have been seen in Brazil and Panama [
These declines are consistent with our estimates of the
proportion of diarrhea due to rotavirus before vaccine was
implemented, which further validates our findings. As rotavirus vaccine
use becomes more widespread, particularly in high-mortality
countries, the impact on global mortality rates could be
dramatic. Continued monitoring of rotavirus mortality rates and
deaths through rotavirus surveillance will aid in monitoring
the impact of vaccination. Further understanding of the
differences between the currently available estimates of rotavirus
mortality also remains a priority to ensure that obtained
estimates of vaccine impact are accurate.
WHO-coordinated Global Rotavirus Surveillance Network authors.
World Health Organization: Mary Agocs and Fatima Serhan; Pan American
Health Organization (WHO/AMRO): Lucia de Oliveira; World Health
Organization Regional Office for Africa (WHO/AFRO): Jason M. Mwenda and
Richard Mihigo; World Health Organization Southeast Asia Regional Office
(WHO/SEARO): Pushpa Ranjan Wijesinghe and Nihal Abeysinghe; World
Health Organization Western Pacific Regional Office (WHO/WPRO):
Kimberley Fox and Fem Paladin.
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) or the decisions or policies of the
World Health Organization. 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.
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. A. H. B. and C. B.-P. are staff members
of the World Health Organization. All other authors report no potential
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.
1. Vesikari T , Matson DO , Dennehy P , et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine . N Engl J Med 2006 ; 354 : 23 - 33 .
2. Ruiz-Palacios GM , Perez-Schael I , Velazquez FR , et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis . N Engl J Med 2006 ; 354 : 11 - 22 .
3. Rotavirus vaccines: an update . Wkly Epidemiol Rec 2009 ; 84 : 533 - 40 .
4. Patel MM , Glass R , Desai R , Tate JE , Parashar UD . Fulfilling the promise of rotavirus vaccines: how far have we come since licensure? Lancet Infect Dis 2012 ; 12 : 561 - 70 .
5. Richardson V , Hernandez-Pichardo J , Quintanar-Solares M , et al. Effect of rotavirus vaccination on death from childhood diarrhea in Mexico . N Engl J Med 2010 ; 362 : 299 - 305 .
6. do Carmo GM , Yen C , Cortes J , et al. Decline in diarrhea mortality and admissions after routine childhood rotavirus immunization in Brazil: a time-series analysis . PLoS Med 2011 ; 8 : e1001024 .
7. Lanzieri TM , Linhares AC , Costa I , et al. Impact of rotavirus vaccination on childhood deaths from diarrhea in Brazil . Int J Infect Dis 2011 ; 15 : e206 - 10 .
8. Bayard V , DeAntonio R , Contreras R , et al. Impact of rotavirus vaccination on childhood gastroenteritis-related mortality and hospital discharges in Panama . Int J Infect Dis 2012 ; 16 : e94 - 8 .
9. Tate JE , Burton AH , Boschi-Pinto C , et al. 2008 estimate of worldwide rotavirusassociated mortality in children younger than 5 years before the introduction of universal rotavirus vaccination programmes: a systematic review and meta-analysis . Lancet Infect Dis 2012 ; 12 : 136 - 41 .
10. Liu L , Johnson HL , Cousens S , et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000 . Lancet 2012 ; 379 : 2151 - 61 .
11. Lozano R , Naghavi M , Foreman K , et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010 . Lancet 2012 ; 380 : 2095 - 128 .
12. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013 . Lancet 2015 ; 385 : 117 - 71 .
13. Fischer Walker CL , Rudan I , Liu L , et al. Global burden of childhood pneumonia and diarrhoea . Lancet 2013 ; 381 : 1405 - 16 .
14. Black RE , Cousens S , Johnson HL , et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis . Lancet 2010 ; 375 : 1969 - 87 .
15. World Health Organization. Child cause of death estimates 2000-2013 . Available at: http://www.who.int/entity/healthinfo/global_burden_disease/childCOD_ estimates_ 2000 _ 2013 .xls? ua=1. Accessed 12 January 2015 .
16. Agocs MM , Serhan F , Yen C , et al. WHO global rotavirus surveillance network: a strategic review of the first 5 years, 2008 - 2012 . MMWR Morb Mortal Wkly Rep 2014 ; 63 : 634 - 7 .
17. World Health Organization. Rotavirus Laboratory network . Available at: http:// www.who.int/immunization/monitoring_surveillance/burden/laboratory/Rota virus/en/. Accessed 26 August 2014 .
18. Parashar UD , Burton A , Lanata C , et al. Global mortality associated with rotavirus disease among children in 2004 . J Infect Dis 2009 ; 200 ( suppl 1 ): S9 - 15 .
19. United Nations Statistics Division. Millennium Development Indicators: World and regional groupings . Available at: http://mdgs.un.org/unsd/mdg/Host.aspx? Content=Data/RegionalGroupings.htm. Accessed 12 January 2015 .
20. World Health Organization / United Nations Children's Fund. WHO UNICEF review of national immunization coverage . Available at: http://apps.who.int/ immunization_monitoring/globalsummary/wucoveragecountrylist.html. Accessed 12 January 2015 .
21. United Nations Department of Economic and Social Affairs. World population prospects: 2012 revision . Available at: http://esa.un.org/unpd/wpp/Excel-Data/ population.htm. Accessed 12 January 2015 .
22. Gavi , the Vaccine Alliance. Countries eligible for support . Available at: http://www. gavialliance.org/support/apply/countries -eligible-for-support/ . Accessed 13 February 2014 .
23. Bhandari N , Rongsen-Chandola T , Bavdekar A , et al; India Rotavirus Vaccine Group. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial . Lancet 2014 ; 383 : 2136 - 43 .
24. Parashar UD , Hummelman EG , Bresee JS , Miller MA , Glass RI . Global illness and deaths caused by rotavirus disease in children . Emerg Infect Dis 2003 ; 9 : 565 - 72 .
25. Lanata CF , Fischer-Walker CL , Olascoaga AC , et al. Global causes of diarrheal disease mortality in children <5 years of age: a systematic review . PLoS One 2013 ; 8 : e72788 .
26. Kotloff KL , Nataro JP , Blackwelder WC , et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study . Lancet 2013 ; 382 : 209 - 22 .
27. Phillips G , Lopman B , Tam CC , Iturriza-Gomara M , Brown D , Gray J . Diagnosing rotavirus A associated IID: using ELISA to identify a cut-off for real time RT-PCR . J Clin Virol 2009 ; 44 : 242 - 5 .
28. Tate JE , Mijatovic-Rustempasic S , Tam KI , et al. Comparison of 2 assays for diagnosing rotavirus and evaluating vaccine effectiveness in children with gastroenteritis . Emerg Infect Dis 2013 ; 19 : 1245 - 52 .
29. Institute of Medicine. The prospects of immunizing against rotavirus. New vaccine development: diseases of importance in developing countries . Washington, DC: National Academy Press, 1986 : D13 -1 -D- 2.
30. Kilgore PE , Holman RC , Clarke MJ , Glass RI . Trends of diarrheal disease-associated mortality in US children, 1968 through 1991 . JAMA 1995 ; 274 : 1143 - 8 .
31. Villa S , Guiscafre H , Martinez H , Munoz O , Gutierrez G . Seasonal diarrhoeal mortality among Mexican children . Bull World Health Organ 1999 ; 77 : 375 - 80 .
32. Tanaka G , Faruque AS , Luby SP , Malek MA , Glass RI , Parashar UD . Deaths from rotavirus disease in Bangladeshi children: estimates from hospital-based surveillance . Pediatr Infect Dis J 2007 ; 26 : 1014 - 8 .
33. Gastanaduy PA , Sanchez-Uribe E , Esparza-Aguilar M , et al. Effect of rotavirus vaccine on diarrhea mortality in different socioeconomic regions of Mexico . Pediatrics 2013 ; 131 : e1115 - 20 .
34. Richardson V , Parashar U , Patel M. Childhood diarrhea deaths after rotavirus vaccination in Mexico . N Engl J Med 2011 ; 365 : 772 - 3 .