A Preliminary Assessment of Rotavirus Vaccine Effectiveness in Zambia
A Preliminary Assessment of Rotavirus Vaccine Effectiveness in Zambia
Correspondence: L. K. Beres 1 4
Johns Hopkins Bloomberg School of Public Health 1 4
N Wolfe St 1 4
Baltimore 1 4
(). Clinical Infectious Diseases® 1 4
0 Division of Viral Diseases, Centers for Disease Control and Prevention , Atlanta , Georgia
1 The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions , e-mail
2 Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland
3 Centre for Infectious Disease Research in Zambia , Lusaka
4 Laura K. Beres
5 University of North Carolina School of Medicine , Chapel Hill
Background. Diarrhea is the third leading cause of child death in Zambia. Up to one-third of diarrhea cases resulting in hospitalization and/or death are caused by vaccine-preventable rotavirus. In January 2012, Zambia initiated a pilot introduction of the Rotarix live, oral rotavirus vaccine in all public health facilities in Lusaka Province. Methods. Between July 2012 and October 2013, we conducted a case-control study at 6 public sector sites to estimate rotavirus vaccine effectiveness (VE) in age-eligible children presenting with diarrhea. We computed the odds of having received at least 1 dose of Rotarix among children whose stool was positive for rotavirus antigen (cases) and children whose stool was negative (controls). We adjusted the resulting odds ratio (OR) for patient age, calendar month of presentation, and clinical site, and expressed VE as (1 - adjusted OR) × 100. Results. A total of 91 rotavirus-positive cases and 298 rotavirus-negative controls who had under-5 card-confirmed vaccination status and were ≥6 months of age were included in the case-control analysis. Among rotavirus-positive children who were ageeligible to be vaccinated, 20% were hospitalized. Against rotavirus diarrhea of all severity, the adjusted 2-dose VE was 26% (95% confidence interval [CI], −30% to 58%) among children ≥6 months of age. VE against hospitalized children ≥6 months of age was 56% (95% CI, −34% to 86%). Conclusions. We observed a higher point estimate for VE against increased severity of illness compared with milder disease, but were not powered to detect a low level of VE against milder disease.
Globally, an estimated 751 000 deaths in children <5 years of
age were caused by diarrhea in 2010, making it the second
leading cause of death in children <5 years of age [
accounts for 46% of the world’s child diarrheal deaths but only
13% of its population [
]. Rotavirus infection caused
approximately 37% of diarrhea-attributable deaths worldwide in 2008
]. Diarrhea is the third leading cause of child death in Zambia.
In 2009, Zambia reported an annual diarrheal burden of 10
million episodes among its 2.4 million children <5 years of age,
reflecting an average of >2 episodes per child per year [
]. Up to
one-third of diarrhea cases resulting in hospitalization and/or
death are caused by vaccine-preventable rotavirus [
Research from other countries, particularly in Latin America
and several African countries including South Africa and Malawi,
has shown the promise of the rotavirus vaccine in reducing child
deaths attributable to rotavirus, incident severe gastroenteritis,
and related hospital admission [
In January 2012 the Zambian government, in partnership with
the Centre for Infectious Disease Research in Zambia (CIDRZ)
and Ark, initiated a 2-year, pilot introduction of the Rotarix
live, oral rotavirus vaccine in all public health facilities in Lusaka
Province. Details of this program rollout are available elsewhere
]. In November 2013, following this sucessful pilot, Zambia
became the 17th Gavi-eligible country to introduce the vaccine
nationally. The recommended schedule for Rotarix in Zambia
aligned with the standard Expanded Programme on
Immunization (EPI) visits with 2 doses recommended at 6 and 10 weeks of
age, but allowing the first dose to be administered between 6 and
20 weeks of age. The pentavalent diphtheria-tetanus-pertussis
(DTP), Haemophilus influenzae type b (Hib), and hepatitis B
(HepB) vaccine has been a part of Zambia’s EPI since 2005,
with the first 2 doses recommended at 6 and 10 weeks of age,
making it a good comparator for vaccine uptake.
As part of a larger evaluation of diarrhea-related child illness in
Lusaka and Ndola, Zambia, we conducted a case-control study to
evaluate the effectiveness of the rotavirus vaccine in this
population. Here we present vaccine effectiveness (VE) findings from the
regional pilot vaccine introduction in Lusaka Province, Zambia.
This study was conducted between July 2012 and October 2013 at
6 sentinel, public health facilities in Lusaka Province, which were
included in the pilot vaccine rollout. Three facilities were in
Lusaka District, the most densely populated, urban district in
Zambia, and 1 additional facility was in each of the 3 remaining
districts—Kafue, Chongwe, and Luangwa—which contain a
lower-density, more rural population. Facilities were purposively
selected. We selected facilities with inpatient departments,
sufficient under-5 patient volume, space to support study activities,
and geographical consistency with the pilot vaccine rollout.
Screening, Enrollment, and Study Procedures
The study team conducted active surveillance for children
presenting with diarrhea at each of the study sites. A child was
considered eligible if they met the following criteria: age 0–59
months; admitted to the inpatient department or under care in
the outpatient department at the time of screening; and caregiver
verbal confirmation of child presenting with diarrhea (defined as
the passing of ≥3 abnormally loose stools in the past 24 hours).
Additionally, children were determined to be eligible if there was
an indication of potentially severe diarrhea by confirmation of at
least 1 of the following symptoms assessed through physical
examination by the study nurse or verbal confirmation by the
caregiver: sunken eyes, loss of normal skin turgor, intravenous
rehydration prescribed/administered, blood in stool, and
hospitalization for diarrhea or dysentery. Study nurses targeted
enrollment of younger children, attempting to enroll approximately
two-thirds of the sample from children <24 months of age.
As part of the larger evaluation of diarrheal disease, caregivers
who voluntarily consented to participate completed a 3-part
assessment: part 1 immediately upon enrollment, targeted to occur
as soon as possible after the child entered care; part 2 at the child’s
discharge from health services (same day if an outpatient); and
part 3 thirty days after enrollment. Part 1 data utilized for the
VE evaluation included individual and household demographics
(eg, age, sex, caregiver education level, family size), maternal
health status, the child’s symptoms, history and treatment of
the current illness, and child health background. The child’s
vaccination history and growth trajectory were recorded from the
under-5 card (child health record). If the under-5 card was
unavailable, verbal confirmation of vaccination status was requested
from the caregiver. The child’s health status during the study
assessment was documented based on a combination of health
facility record review for the current visit and a clinical examination
of the child by the study nurse. A stool sample was collected for
laboratory assessment. Part 2 included a review of the child’s
health status and treatment received while in care. Part 3
determined child vital status at 30 days after enrollment.
A combination of parts 1 and 2 provided the 7 components
required for assessment of the child’s disease severity using a
Vesikari score (diarrheal stool and vomiting frequency and duration
based on caregiver report, treatment based on admission status,
temperature, and dehydration based on clinical assessment) [
Stool specimens were refrigerated and transported from the
study sites to the CIDRZ laboratory. They were tested for
rotavirus antigen by enzyme immunoassay (EIA) using a
monoclonal antibody solid phase sandwich. The Meridian
Rotaclone EIA kit for the detection of rotavirus antigen in fecal
samples (catalog number 696004) was used for the analysis.
The study was approved by research ethics authorities at the
Zambian Ministry of Health, the University of Zambia, the
University of Alabama at Birmingham, and the University of North
Carolina at Chapel Hill.
Vaccine Effectiveness Analysis
Children who presented with moderate to severe diarrhea and
who were age-eligible to have received rotavirus vaccine and had
under-5 card-confirmed vaccination records were included in the
VE analysis. Children whose stool specimen tested positive for
rotavirus by EIA were classified as cases, whereas those with
EIAnegative results were controls. A child was considered age-eligible
for the vaccine if the rotavirus vaccine was available in the child’s
health facility when the child was 6 weeks of age. A child was
considered vaccinated if she or he received a minimum of 1 dose of
vaccine at least 14 days before presentation to the study site.
Data Processing and Analysis
Study data were collected on paper forms by trained research
nurses stationed at the study clinic sites, who conducted quality
control on the data they collected. Centrally, the data were again
checked for quality by the study Quality Control Nurse and
investigators before they were entered onto a database constructed
in SQL 2008 and Access 2010. Severity of rotavirus diarrhea was
classified using the 20-point Vesikari scoring system. EIA
results were entered by a laboratory technician into a separate
database that was merged with other study data using the
participant’s study-assigned unique identification number.
Sociodemographic and clinical characteristics of cases and
controls were compared using χ2 analyses for categorical variables.
For continuous variables, medians were compared using the
Wilcoxon rank-sum test. We reviewed age at vaccination, rotavirus
vaccine coverage by rotavirus result, and rotavirus vaccine uptake
compared to pentavalent vaccine (DTP-Hib-HepB) uptake.
We used unconditional logistic regression, controlling for
month and year of birth, month and year of admission, and
clinical site to calculate the adjusted odds ratio (aOR) for
rotavirus vaccination compared to no vaccination. To account for
residual confounding related to age given the small sample
size, we restricted our results to children aged ≥6 months. VE
was expressed as (1 – aOR) × 100.
Presentation of Rotavirus Diarrhea
Among all 1506 children <5 years of age enrolled in the study in
Lusaka, rotavirus detection between July 2012 and October
2013 showed 2 peaks, 1 around October (a hot, dry month
a Statistically significant at the .05 level.
b No. of children with nonmissing data on household food expenditure: 93 for rotavirus positive and 258 for rotavirus negative; No. of children with nonmissing data on household nonfood
expenditure: 82 for rotavirus positive and 227 for rotavirus negative.
before the rainy season) and 1 in June (a cool, dry month after
the rainy season) (Figure 1).
Vaccine Effectiveness Analysis Sample
We excluded 904 children enrolled in diarrhea surveillance
from the VE analysis, of whom 885 (98%) were excluded
because they were age-ineligible to receive vaccine either
because they were enrolled in the study prior to vaccine rollout
at their district or were too old to receive the vaccine. A total
of 125 rotavirus-positive cases and 404 rotavirus-negative
controls that had under-5 card-confirmed vaccination status were
included in the case-control analysis (Figure 2).
a Statistically significant at the .05 level.
Characteristics of Cases and Controls
Cases and controls were similar in age, sex, chronic disease
prevalence, and household demographics. The rotavirus
cases were more often brought in by a caregiver other than
their mother and reported higher median expenditure on
food and nonfood items in the child’s household 30 days
prior to the child’s presentation at the health facility
Compared to antigen-negative children, those who were
rotavirus positive had more severe diarrhea (including a greater
duration and maximum number of diarrhea episodes), were more
likely to have vomiting and for a longer duration, were in worse
clinical condition on arrival at the facility, and had a higher
Vesikari score compared to controls (Table 2). Only 20% of cases
and controls were hospitalized.
Vaccine Coverage and Age Appropriateness
Vaccine coverage among cases and controls was high, at 70% for
at least 1 dose and 58% for 2 doses of rotavirus vaccine.
Although cases had lower pentavalent vaccine coverage, there
were no significant differences between cases and controls for
rotavirus vaccine coverage (Table 3).
Rotavirus vaccination timing was consistent with
recommended schedules, compared to pentavalent vaccine administration
(Figure 3). The median age at rotavirus and pentavalent vaccine
administration was 6 weeks for dose 1 and 11 weeks for dose
2. Among children vaccinated against rotavirus, 79% received
their first dose within 2 weeks of the recommended age for
vaccination and 64% received their second dose within 2 weeks of
the recommended age. Among children receiving pentavalent
vaccine, 84% and 71% received their first and second doses,
respectively, within 2 weeks of the recommended age.
Vaccine Effectiveness, Children Aged ≥6 Months
Against rotavirus diarrhea of all severity, the adjusted 2-dose VE
among children ≥6 months of age was 26% (95% confidence
interval [CI], −30% to 58%). Against rotavirus diarrhea that
required hospitalization, it was 56% (95% CI, −34% to 86%).
VE against very severe rotavirus (Vesikari ≥15) for children
with 2 doses was 48% (95% CI, −163% to 90%) (Table 4).
Our study is the first report on rotavirus VE in Zambia, in the
context of a regional pilot project. We observed a higher point
estimate for VE among children with more severe illness
compared with children with milder illness, consistent with what
has been reported elsewhere [
]. For children ≥6 months
of age who were hospitalized, we observed 57% effectiveness
with at least 1 dose of vaccine.
Among age-eligible children, more children received the
pentavalent vaccine, to which the rotavirus vaccine timing was
synchronized, than the rotavirus vaccine. This likely represents the
challenges that the health system experienced in supply and
training of staff to support new vaccine rollout, even with the
dedicated support accompanying the pilot [
]. This suggests
that additional research on ways to limit missed opportunities
for rotavirus vaccine administration would be useful as
rotavirus becomes part of the routine immunization program of
additional countries. It is unclear, however, why cases have lower
pentavalent coverage than controls.
Interestingly, although the study was conducted in a period
just over 1 calendar year, our results confirm the typical trend
on the seasonality of rotavirus disease as has been reported
elsewhere; 1 peak in the cool dry seasons (May–July) and a second,
but smaller peak in the hot dry season (September–
]. Future research characterizing trends in
under-5 diarrhea seasonality may demonstrate shifts based on
vaccination effects and the impact of other etiologic agents of
The overall trend of VE, with an aOR ranging from 17% to 60%
for at least 1 dose, is consistent with other studies from developing
14, 15, 18
]. These findings support prior reports of the
relatively lower VE of live oral vaccines in low- to middle-income
countries such as Zambia, compared with more developed
]. Effective public health efforts to reduce diarrhea
must continue to emphasize the importance of other preventive
practices alongside vaccination to minimize cases.
The study is limited by its small sample size of severe
rotavirus cases and its high vaccination coverage. Only 20% of the
children enrolled through the outpatient surveillance required
hospitalized care in our study. Rotavirus is the most common
cause of severe gastroenteritis in young children and accounts
for a higher proportion of cases among children hospitalized
for acute gastroenteritis than among children requiring
outpatient care. Furthermore, rotavirus vaccines are more effective in
preventing severe disease than mild disease. Whereas 23% of
all diarrhea cases in the study were severe and 4% very severe,
the study also included mild diarrhea. Thus, given the high
proportion of children receiving outpatient care enrolled in our
study, we were not powered to detect a low-level VE against
Data are presented as No. (%) unless otherwise specified.
Abbreviations: CI, confidence interval; ref, reference; VE, vaccine effectiveness.
a Protection conferred 14 days after vaccine receipt.
b Adjusted for month and year of admission, month and year of birth, and clinic.
c All controls included in analysis.
mild disease. All children in the study were aged ≤21 months,
with a median age of 8 months, so we were also not able to
assess waning immunity in this population.
In conclusion, we found that rotavirus vaccine may provide
better protection against severe disease compared with milder
disease, which is consistent with other research conducted in
the region, but there is need for a more robust evaluation to
ascertain a definitive estimate of rotavirus VE in Zambia.
Acknowledgments. We acknowledge the contributions of Annika
Kruuner, Pauline Musumali, Carolyn Bolton, Karen Foo, Emma Chyapeni,
Muyangana Mwanamuke, Mwinga Mwendalubi, Lombe Silwizya, Andrew
Westfall, Kabwe Kapasa, and Lauren Beach. We especially acknowledge
the support and contributions of the Zambian Ministry of Mother and
Child Health, the Zambian Ministry of Health, the Lusaka District Health
Management Team, In-Charge Officers and staff at the study sites, the
ACADEMIC lab, the ACADEMIIC study research team, and participants. We
acknowledge GlaxoSmithKline Biologicals (Belgium) for the kind donation
of Rotarix vaccines.
Author contributions. M. B. G., J. S. A. S., and R. C. designed the
study. L. N., M. B. G., and L. K. B. contributed to primary data collection.
B. C. and M. B. G. contributed to the required laboratory analysis. J. E. T.
and U. D. P. contributed to study oversight and interim data analysis.
J. E. T. conducted the final data analysis. R. C. drafted the initial manuscript.
L. K. B. wrote substantive manuscript revisions. All authors edited the
manuscript with substantive contributions.
Disclaimer. The findings and conclusions of 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 Bill & Melinda
Gates Foundation and by Ark.
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. L. K. B., L. N., B. C., M. B. G., and
J. S. A. S. were supported by the Bill & Melinda Gates Foundation. Travel
to work on the study for J. E. T. and U. D. P. was supported by the Bill &
Melinda Gates Foundation. C. R. and R. C. were supported by Ark. 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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