Temporal Association of Rotavirus Vaccine Introduction and Reduction in All-Cause Childhood Diarrheal Hospitalizations in South Africa
Temporal Association of Rotavirus Vaccine Introduction and Reduction in All-Cause Childhood Diarrheal Hospitalizations in South Africa
Michelle J. Groome () 0 1 2 3
Elizabeth R. Zell 2 6
Fatima Solomon 1 2 3
Susan Nzenze 1 2 3
Umesh D. Parashar 2 5
Alane Izu 1 2 3
Shabir A. Madhi 1 2 3 4
0 School of Public Health, Faculty of Health Sciences, University of the Witwatersrand , Johannesburg , South Africa
1 Department of Science and Technology/National Research Foundation, Vaccine Preventable Diseases
2 ogens Research Unit; DST/NRF, Vaccine Preventable Diseases , New Nurses Residence, 11th Floor West Wing , Chris Hani Baragwanath Academic Hospital , Soweto 2013 , South Africa Clinical Infectious Diseases
3 Medical Research Council, Respiratory and Meningeal Pathogens Research Unit
4 National Institute for Communicable Diseases, National Health Laboratory Service , Sandringham , South Africa
5 Division of Viral Diseases, Centers for Disease Control and Prevention , Atlanta , Georgia
6 Stat-Epi Associates Inc , West Palm Beach, Florida
Background. The public health impact of rotavirus vaccination in African settings with a high human immunodeficiency virus (HIV) infection prevalence is yet to be established. We evaluated trends in all-cause diarrheal hospitalizations in Soweto, Johannesburg, before and after the introduction of rotavirus vaccine into South Africa's national immunization program in August 2009. Methods. Hospitalizations in children <5 years of age with a diagnosis of diarrhea, defined by International Classification of Diseases, Tenth Revision codes A00-A05, A06.0-A06.3, A06.9, A07.0-A07.2, A07.9, and A08-A09, were identified at the Chris Hani Baragwanath Academic Hospital from 1 January 2006 to 31 December 2014. The median annual prevaccine (2006−2008) hospitalization incidence was compared to that of the vaccine era (2010−2014), and stratified by age group and HIV infection status. Results. Incidence reductions ( per 1000 population) were greatest in children aged <12 months: 54.4 in the prevaccine era vs 30.0, 23.6, 20.0, 18.8, and 18.9 in the postvaccine years 2010-2014, respectively (a 44.9%-65.4% reduction). Lower incidence reductions (39.8%-49.4%) were observed among children aged 12-24 months from the second year post-vaccine introduction onward. Reductions were observed in both HIV-infected and HIV-uninfected children. There was a change in the seasonal pattern of diarrheal hospitalizations post-vaccine introduction, with flattening of the autumn-winter peaks seen in the prevaccine years. Conclusions. An accelerated and sustained decline in all-cause diarrheal hospitalizations, temporally associated with rotavirus vaccine introduction, was observed in children <2 years of age. However, the impact of other interventions such as improved sanitation and changes in HIV management cannot be discounted.
Rotavirus is the leading cause of diarrhea among children <5
years of age, accounting for approximately 27% of all severe
diarrhea episodes worldwide in 2011. Rotavirus vaccines have the
potential to reduce diarrheal morbidity and mortality, especially
in Africa where almost half of the global rotavirus deaths occur
]. Following demonstration of high vaccine efficacy of
Rotarix (GlaxoSmithKline Biologicals, Rixensart, Belgium)
and RotaTeq (Merck Vaccines, Whitehouse Station, New
Jersey) in prelicensure clinical trials in Latin America, Europe,
and the United States, introduction of rotavirus vaccines into
national immunization programs resulted in a substantial
decrease in diarrhea-related hospitalizations and deaths in these
]. Lower vaccine efficacy was, however, observed
in clinical trials in low- to middle-income countries in Africa,
and there are limited data evaluating the impact of rotavirus
vaccines on the burden of diarrheal hospitalizations in African
The effectiveness of rotavirus vaccines in Malawi and South
Africa has been evaluated by case-control studies, but these
studies were not able to fully address the public health impact
of this intervention [
]. Sentinel surveillance in children
aged <5 years in South Africa showed that diarrheal
hospitalizations decreased by about a third in 2010 and 2011 compared
to 2009, the year of vaccine introduction . A study from
Ghana reported a 52%–59% reduction in all-cause diarrhea
hospitalizations in children aged <5 years in the year following
rotavirus vaccine introduction compared with the immediate
prevaccination year [
]. These studies were, however, limited
to the first 2 years postintroduction and did not specifically
assess reductions in diarrhea hospitalizations in human
immunodeficiency virus (HIV)–infected children, who are at 5-fold
greater risk of diarrheal hospitalization compared with
HIVuninfected children [
We investigated the impact of routine infant rotavirus
vaccination on all-cause diarrheal hospitalizations by comparing the
incidence before (2006−2008) and after (2010−2014) vaccine
introduction among HIV-infected and HIV-uninfected children
<5 years of age in Soweto, South Africa.
The Chris Hani Baragwanath Academic Hospital was the only
public hospital serving the urban community of Soweto,
Johannesburg, South Africa, among whom <10% had private
medical insurance. As a result, the majority of children who required
hospitalization were admitted to this hospital, where care was
provided free of charge to children <5 years of age. The prevalence of
HIV infection among mothers attending antenatal clinics in the
Gauteng province remained steady at 30% since 2006; however,
due to improvement in the prevention of mother-to-child
transmission of HIV, the HIV prevalence among children aged
<5 years decreased from 5.0% in 2006 to 3.8% by 2013 [
Access to antiretroviral therapy (ART) has improved since its
introduction into the public sector in 2004, with the estimated
coverage in HIV-infected children requiring treatment being
54% in 2009 and 63% in 2012 [
]. Rotarix was introduced
into the national immunization program on 1 August 2009,
and is provided at no cost at primary healthcare facilities. Two
doses are recommended at 6 and 14 weeks of age, and children
received trivalent oral polio vaccine (OPV-Merieux; Sanofi
Pasteur, Lyon, France) concurrent with rotavirus vaccine at the
6-week immunization visit. District health information systems
estimates of coverage rates for the second dose of rotavirus
vaccine increased from 67% in 2010 to 96% in 2011 .
Children presenting with diarrhea either came directly from the
community or were referred from community clinics. Decisions
regarding hospitalization, investigations, and treatment were at
the discretion of the attending physicians. Patient discharge
diagnoses were obtained from a discharge summary completed by
the attending physician on discharge/death of the child or the
ward admission registry. A study physician coded the discharge
diagnoses using the International Classification of Diseases,
Tenth Revision (ICD-10). HIV infection status was obtained
from HIV test results recorded in the discharge summary,
ward registry, or from the hospital laboratory. Children ≥9
months of age were considered to be HIV infected if either
the HIV enzyme-linked immunosorbent assay (ELISA) or
HIV polymerase chain reaction (PCR) test was positive; and
HIV uninfected if HIV ELISA or HIV PCR test was negative.
Children aged <9 months were considered to be HIV-infected
if the HIV PCR test was positive and HIV uninfected if the HIV
ELISA or HIV PCR test was negative. If a child was hospitalized
more than once, results of any HIV test performed during these
hospitalizations were used to assign HIV status to that child.
All-cause diarrheal hospitalizations were defined by the
following ICD-10 diagnosis codes: A00–A05, A06.0–A06.3, A06.9,
A07.0–A07.2, A07.9, and A08–A09. Children <5 years of age
hospitalized with a primary or secondary diagnosis of diarrhea
from 1 January 2006 to 31 December 2014 were included in this
study. Any hospitalizations with a codiagnosis of nosocomial
infection (ICD-10 code Y95) or occurring within 14 days of
the discharge date of a previous admission in the same child
were excluded. All data were anonymized for personal
identifiers of patients.
Monthly counts of all-cause diarrheal hospitalizations were
plotted against time for age groups 0–11, 12–23, and 24–59
months for the period 2006–2014. A general strike of hospital
staff occurred during a 3-week period in June 2007, resulting in
only 1 pediatric ward remaining functional during this time. We
adjusted for the resulting decrease in hospitalizations by
calculating the ratio of hospitalizations, by age group, in June
compared to May in 2006 and 2008, and multiplying the number of
hospitalizations in May 2007 by this factor. Annual incidence of
all-cause diarrheal hospitalizations ( per 1000 population) was
estimated using the annual number of children hospitalized
for diarrhea in the numerator and the midyear population
estimate in the denominator. Population denominators for Soweto
(subdistrict D and G, Johannesburg) were obtained from
Statistics South Africa, and HIV prevalence was estimated from
projections of the Actuarial Society of South Africa’s 2008 AIDS
and Demographical model [
]. The median annual incidence
during the prevaccine years 2006–2008 was compared to the
incidence in the vaccine era (2010–2014), and stratified by age group
and HIV status. Children who were not tested for HIV infection
were assumed to be HIV uninfected, on the assumption that
physicians were less inclined to test for HIV in the absence of
clinical stigmata. We assessed the incidence of hospitalization
for bronchiolitis (ICD-10 codes J21.0, J21.1, J21.8, J21.9), for
which there were no preventive intervention strategies
implemented over the same period, to determine whether there were any
changes in hospital admission practices. Confidence intervals for
incidence estimates were calculated using the Poisson distribution.
Approval for the study was obtained from Human Research
Ethics Committee (HREC approval number: M110528) of the
University of the Witwatersrand. There was a waiver of consent
for this observational study.
Trends in Diarrheal Hospitalizations
A total of 16 800 diarrheal hospitalizations occurred in children
aged <5 years from 1 January 2006 to 31 December 2014. There
was a downward trend in the number of diarrheal
hospitalizations after rotavirus vaccine introduction, especially in children
aged 0–11 months (Figure 1). Before rotavirus vaccine
introduction, 68.6% of diarrheal hospitalizations occurred in children
0–11 months, 20.9% in those 12–23 months, and 10.5% in
those 24–59 months of age, compared to the vaccine era where
58.8%, 24.3%, and 16.9% of hospitalizations occurred in the
respective age groups (P < .001). During the prevaccine period
there were distinct annual peaks in the number of diarrheal
hospitalizations during the autumn and early winter months
of March–May in children aged <24 months, albeit this varied
in magnitude and timing from year to year. In contrast, the
peaks in diarrheal hospitalizations during the vaccine era were
less pronounced and had a bimodal pattern.
Annual Diarrheal Hospitalization Rates
The estimated annual incidence ( per 1000 population) of
diarrheal hospitalizations among children aged <5 years decreased
from 14.7 (median 2006–2008) to 9.7 in 2010—a 33.8%
reduction (Table 1). Significant incidence reductions of 47.6%–56.6%
(7.0–8.3 per 1000) were maintained through the following 4
years (2011–2014). Reductions were most pronounced in
children 0–11 months and were evident from the first year post–
vaccine introduction (incidence reduction, 24.4 per 1000;
44.9% in 2010 compared to the prevaccine era; Table 1). Further
reduction was seen in 2011, the second postvaccine year (30.8
per 1000 [55.6%]), compared with prevaccine years, and
reductions of 63.2%–65.2% (34.4–35.5 per 1000) were maintained
during 2012–2014 in this age group. Among children aged
12–23 months, there was a marginal reduction in
hospitalization incidence in the first year post–vaccine introduction, and
reductions of 39.8%–49.4% were observed during the
subsequent 4 years. Hospitalization incidence among children aged
24–59 months remained relatively constant with minimal
reductions in the vaccine era compared to prevaccine years
(Table 1). In contrast to the vaccine-era declines in diarrheal
hospitalizations, the incidence of bronchiolitis hospitalizations
remained relatively constant throughout the observation period
HIV-Infected and HIV-Uninfected Children
Of the total diarrheal hospitalizations, 1743 (10.4%) occurred in
children diagnosed with HIV infection. The prevalence of HIV
infection among children aged <5 years hospitalized for
diarrhea decreased from 14.1% in 2006 to 5.3% in 2014. Overall,
only 50% of children were tested for HIV infection, which
varied by age group (older children were less likely to be tested) and
year of hospitalization (increased testing in the latter years; data
Among children assumed to be HIV uninfected, significant
declines in diarrheal hospitalization incidence in the vaccine era
compared with prevaccine years, ranging from 23.2 to 32.8 per
1000 (45.8%–64.9%), were observed in those aged 0–11 months
(Figure 2; Supplementary Table 1). In children aged 12–23
months, reductions of 36.5%–49.5% were observed from the
second year post–vaccine introduction onward. There were
minimal or no incidence reductions in children aged 24–59 months.
The hospitalization incidence among HIV-infected children
aged 0–11 months decreased by 102.0 per 1000 (77%) in 2014
compared to the prevaccine years, with reductions ranging from
21.8% to 70.8% during 2010–2013 (Figure 3; Supplementary
Table 2). In children aged 12–23 months, reductions in
diarrheal hospitalizations in the vaccine era ranged from 45.0% to
64.8% (16.9–24.4 per 1000). There were significant reductions
(41.6%–56.7%) in incidence in HIV-infected children aged
24–59 months in most postvaccine years.
The introduction of an oral live attenuated rotavirus vaccine
into the South African national immunization program was
temporally associated with a 34% to 57% decrease in the overall
incidence of all-cause diarrheal hospitalizations in children
a Incidence in vaccine-era years 2010, 2011, 2012, 2013, and 2014, respectively, compared with median incidence in the prevaccine years 2006–2008. A negative value indicates a reduction in
incidence; a positive value indicates an increase in incidence.
b Confidence interval.
c A negative percentage change indicates a reduction in incidence; a positive percentage change indicates an increase in incidence.
d Median hospitalization incidence 2006–2008.
aged <5 years in the urban setting of Soweto, Johannesburg.
Reductions were greatest among children aged <12 months and
maintained over a 5-year period post–vaccine introduction. A
decrease of 45% in incidence was observed in the first year
post–vaccine introduction in this age group, with further
reductions of 57%–65% maintained through the subsequent 4 years.
Among children aged 12–24 months, reductions of 40%–49%
were observed from the second year post–vaccine introduction
and were also maintained over time. These trends were observed
among both HIV-infected and HIV-uninfected children. The
incidence of all-cause diarrheal hospitalizations in the
postvaccine years remained relatively unchanged or changed minimally
among children aged >24 months.
Rotavirus testing was not conducted, either routinely or as
part of a surveillance program, until diarrheal surveillance
was established at Chris Hani Baragwanath Academic Hospital
in May 2009. We could, therefore, not access the impact of
rotavirus vaccine introduction on rotavirus-specific diarrheal
hospitalizations and used all-cause diarrheal hospitalizations
as a proxy. Our findings do, however, support the hypothesis
that the observed decline in all-cause diarrheal hospitalizations
can be attributed partly to the introduction of rotavirus
vaccination into the routine immunization program. The reductions
in incidence that we observed occurred specifically in the age
groups that received the vaccine and were consistent with
increasing vaccine coverage. Children aged <12 months would
have been eligible to receive rotavirus vaccine from August
2009, and a 45% reduction was observed in the first
postvaccination year (2010). As coverage increased to >90% at the end of
2010, consistent reductions of approximately 65% were
observed from 2011 to 2014. Some of the children aged 12–23
months and hospitalized in the latter half of 2010 may have
received rotavirus vaccine, and there is a small incidence
reduction observed in the first postvaccination year, with greater
reductions observed from the second postvaccination year in
this age group. Previous South African studies showed that
rotavirus disease occurred early in life, with 90%–95% of
children hospitalized for severe rotavirus diarrhea being
<18 months of age; hence, we would expect that the major
public health impact of vaccination would be in children aged
<24 months [
]. We did not see any clear evidence of
indirect protection (ie, protection in older unvaccinated children),
as has been observed in some high-income settings [
In our setting, very little rotavirus-associated hospitalization
occurred in children >2 years of age prior to vaccine introduction,
so any indirect protection in this age group would likely be
minimal. Encouragingly, we did not see a shift toward increased
incidence of diarrheal hospitalizations in these older children
There was a change in the epidemiology of diarrheal disease
after rotavirus vaccine introduction. The prevaccine years were
characterized by peaks in diarrheal hospitalizations among
children aged <24 months during the autumn–winter months of
March to May. This seasonal pattern is consistent with what
was known about rotavirus epidemiology in South Africa prior
to vaccine introduction. Although rotavirus disease occurred
year round, increases in rotavirus shedding had been observed
during the cool, drier months, resulting in autumn–winter
peaks in rotavirus-associated hospitalizations [
]. We observed
a diminished peak in all-cause diarrheal hospitalizations during
2010, and these peaks were less pronounced during 2011–2014,
where a bimodal pattern was observed.
The phase 3 clinical trial, which included both HIV-infected
and HIV-uninfected children, demonstrated efficacy of the
rotavirus vaccine against all-cause severe gastroenteritis of 44%
(95% confidence interval, 19%–61%) during the first year of
life, whereas our trend analysis showed reductions of 57%–
65% in children aged <12 months [
]. Although the confidence
intervals do overlap, the point estimates we observed were
higher. A decrease in transmission due to an overall decrease in
circulation of rotavirus in the population could not be accounted
for in the efficacy study design, and may account for the greater
reductions that we observed in children aged <12 months. Our
observed reductions are also greater than estimates of the
reductions in all-cause diarrheal hospitalizations in children <12
months obtained from sentinel surveillance conducted in
South Africa: 38% in the first and 43% in the second year
after vaccine introduction [
]. However, these data were
based on comparison with prevaccine estimates from 2009,
the year of vaccine introduction, with no data available prior
to vaccine introduction, and analyses were also limited to the
months of May–December.
The oral rotavirus vaccine has been shown to be safe and
immunogenic in HIV-infected children, but vaccine efficacy
against diarrhea has never been specifically assessed in this
]. The rotavirus vaccine effectiveness study conducted
in South Africa observed similar effectiveness in HIV-exposed
but uninfected and HIV-unexposed children, but was not able
to assess effectiveness specifically among HIV-infected children
]. To our knowledge, this is the first study to show the impact
of rotavirus vaccine introduction on diarrheal hospitalizations
in HIV-infected children. The reductions we observed may
have been confounded by interventions other than rotavirus
vaccine introduction, most notably the expanded use of ART.
During the study period there was increased uptake of ART
among HIV-infected children as well as several changes in the
South African guidelines for ART use. In 2010 and 2013 the
HIV management guidelines were revised to include initiation
of ART in all children <12 months and <5 years of age,
respectively, irrespective of immunological status [
monitoring of ART access and usage in South Africa is challenging,
with changes in reporting practices, lack of data on age of
patients, changes in treatment guidelines leading to changes in
the denominator for estimation of treatment coverage, and
debate over the best measures to use to assess coverage. It is thus
difficult to tease out the specific impact of ART vs rotavirus
vaccine among these children, and it is likely that both
interventions contributed to the reduced diarrheal hospitalizations
observed in HIV-infected children.
An ecological study such as this has inherent limitations,
including the ability to attribute causality. We used all-cause
diarrheal hospitalizations as a proxy for rotavirus-associated
hospitalizations, but without pathogen-specific testing it is
difficult to definitively conclude on a causal relationship between
rotavirus vaccine introduction and reductions in diarrheal
hospitalizations. We cannot exclude other possible reasons for the
decline in diarrheal hospitalizations such as changes in the
socioeconomic factors in the population or variability in the
natural occurrence of rotavirus or other enteric pathogens, most
notably norovirus and bacteria. Furthermore, vaccine coverage
data were not available specifically for the Soweto population,
only on a national level. Comparing census data from 2001
and 2011, respectively, there were improvements in the
proportion of households with access to tap water (84.5% to 91.6%)
and flush toilets (86.5% to. 90.5%), as well as a decrease in
the average household size (3.1 to 2.9) in the Johannesburg
region, although no subdistrict-level or year-on-year data were
]. One would assume that changes in sanitation
would improve consistently over the years, leading to a steadier
decline in annual diarrheal hospitalizations, rather than the
more accelerated decline that we observed in the vaccine era.
Our incidence calculations relied on population estimates
that are based on census data (2001 and 2011) with
extrapolation to other years, and this may have led to under- or
overestimation of the incidence. HIV prevalence was determined
using the Actuarial Society of South Africa model with
extrapolation of provincial estimates to the Soweto population, which
may also have influenced our incidence calculations. Our
assumption that children without a documented HIV status
were HIV uninfected may have underestimated the disease
burden among HIV-infected children. We believe, however, that
this assumption likely approximates the true prevalence of
HIV among diarrheal hospitalizations in that clinicians
generally only tested children they suspected of being HIV infected.
An HIV-infected child would most likely have had >1
hospitalization, prompting HIV testing, and if a child tested positive on
a subsequent admission, we assumed that the child would have
been positive on all admissions. Last, our study was restricted to
1 urban community in South Africa and may not be
generalizable to other African settings.
Although the impact of other interventions such as
improvement in socioeconomic conditions and changes in HIV
management cannot be discounted, the accelerated decline in all-cause
diarrheal hospitalizations after rotavirus vaccine introduction
and the observed changes in diarrheal epidemiology are
suggestive of a significant public health impact of rotavirus vaccine
introduction in an African setting with a high prevalence of
Supplementary materials are available at http://cid.oxfordjournals.org.
Consisting of data provided by the author to benefit the reader, the posted
materials are not copyedited and are the sole responsibility of the author, so
questions or comments should be addressed to the author.
Acknowledgments. We thank the Department of Paediatrics, Chris
Hani Baragwanath Academic Hospital, for assistance with collection of
Author contributions. Conception and design of the study: M. J. G.,
U. D. P., S. A. M. Acquisition of data: M. J. G., F. S., S. N. Analysis of
data: M. J. G., E. R. Z., A. I. Interpretation of data: M. J. G., E. R. Z.,
U. D. P., S. A. M. Drafting of article: M. J. G. Critically revising drafts of
article: M. J. G., E. R. Z., F. S., S. N., U. D. P., A. I., S. A. M. Final approval
of submitted version: M. J. G., E. R. Z., F. S., S. N., U. D. P., A. I., S. A. M. The
corresponding author had full access to all the data in the study and had
final responsibility for the decision to submit for publication.
Disclaimer. The funding source had no role in the writing of the
manuscript or the decision to submit it for publication. The views expressed by
the authors do not necessarily reflect the views of PATH, the Centers for
Disease Control and Prevention (CDC), the Bill and Melinda Gates
Foundation, or GAVI, the Vaccine Alliance. The authors have not been paid to
write this article by a pharmaceutical company or other agency.
Financial support. Support for this project was provided by PATH
through funding from the GAVI 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. M. J. G. has received grants from Gavi
and personal fees from GlaxoSmithKline and Sanofi Pasteur. F. S. and
S. N. have received grants from Gavi. S. A. M. has received grants from
Gavi (Accelerated Vaccine Introduction Special Studies), GlaxoSmithKline,
Novartis, and BMGF; and personal fees from GlaxoSmithKline, Pfizer, and
Medimmune. 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.
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