Effectiveness of Pentavalent Rotavirus Vaccine Under Conditions of Routine Use in Rwanda
Effectiveness of Pentavalent Rotavirus Vaccine Under Conditions of Routine Use in Rwanda
Jacqueline E. Tate 2 3
Fidele Ngabo 1 2
Philippe Donnen 1 2
Maurice Gatera 0 2
Jeannine Uwimana 2 6
Celse Rugambwa 2 5
Jason M. Mwenda 2 4
Umesh D. Parashar 2 3
0 Rwanda Biomedical Center
1 Universite Libre de Bruxelles, Ecole de Santé Publique , Brussels , Belgium
2 MS-A34 , Atlanta, GA 30333 , USA
3 Centers for Disease Control and Prevention , Atlanta , Georgia
4 World Health Organization , Regional Office for Africa, Brazzaville , Republic of Congo
5 World Health Organization , Rwanda Office, Kigali
6 University Teaching Hospital
Background. Rotavirus vaccine efficacy is lower in low-income countries than in high-income countries. Rwanda was one of the first low-income countries in sub-Saharan Africa to introduce rotavirus vaccine into its national immunization program. We sought to evaluate rotavirus vaccine effectiveness (VE) in this setting. Methods. VE was assessed using a case-control design. Cases and test-negative controls were children who presented with a diarrheal illness to 1 of 8 sentinel district hospitals and 10 associated health centers and had a stool specimen that tested positive (cases) or negative (controls) for rotavirus by enzyme immunoassay. Due to high vaccine coverage almost immediately after vaccine introduction, the analysis was restricted to children 7-18 weeks of age at time of rotavirus vaccine introduction. VE was calculated as (1 - odds ratio) × 100, where the odds ratio was the adjusted odds ratio for the rotavirus vaccination rate among case-patients compared with controls. Results. Forty-eight rotavirus-positive and 152 rotavirus-negative children were enrolled. Rotavirus-positive children were significantly less likely to have received rotavirus vaccine (33/44 [73%] unvaccinated) compared with rotavirus-negative children (81/ 136 [59%] unvaccinated) (P = .002). A full 3-dose series was 75% (95% confidence interval [CI], 31%-91%) effective against rotavirus gastroenteritis requiring hospitalization or a health center visit and was 65% (95% CI, −80% to 93%) in children 6-11 months of age and 81% (95% CI, 25%-95%) in children ≥12 months of age. Conclusions. Rotavirus vaccine is effective in preventing rotavirus disease in Rwandan children who began their rotavirus vaccine series from 7 to 18 weeks of age. Protection from vaccination was sustained after the first year of life.
In May 2012, Rwanda became the first country in sub-Saharan
Africa to introduce the pentavalent rotavirus vaccine (RV5),
RotaTeq (Merck & Co) into its routine immunization program
with 3 doses recommended at 6, 10, and 14 weeks of age. A
clinical trial of RV5 in 3 low-income countries in sub-Saharan
Africa found modest efficacy of 64% against severe rotavirus
disease that was similar to the efficacy of 61% observed in a
clinical trial conducted in 2 sub-Saharan African countries with the
monovalent rotavirus vaccine (RV1), Rotarix
(GlaxoSmithKline), the other rotavirus vaccine currently available on global
]. The efficacy of 61%–64% in sub-Saharan Africa
was lower than the efficacy of 85%–98% observed in clinical
trials in developed countries [
]. Although it is not fully
understood, lower efficacy in low-income settings has been
hypothesized to be due to a variety of reasons including higher
levels of comorbidities and coinfections, environmental
enteropathy, interference by high titers of maternal antibodies,
coadministration with oral polio vaccine, and malnutrition.
However, given the substantial rotavirus disease burden in
low-income countries, the World Health Organization
recommends the use of rotavirus vaccine in all countries globally and
particularly in those countries with high child mortality due to
]. As Rwanda was one of the first low-income
countries in sub-Saharan Africa to introduce rotavirus vaccine
into its national immunization program, we sought to evaluate
the effectiveness of RV5 under conditions of routine use, which
may differ considerably than the ideal conditions in a clinical
trial, in Rwanda.
Rotavirus vaccine effectiveness (VE) was assessed using a
casecontrol design. Cases and controls were identified through an
ongoing active surveillance platform. Eight sentinel district
hospitals and 10 associated health centers located throughout the
country conducted active surveillance for rotavirus diarrhea
from September 2012 to May 2015 using the World Health
Organization generic protocol [
]. Because rotavirus vaccine
coverage among children ≤6 weeks of age at the time of vaccine
introduction reached >95% almost immediately after vaccine
introduction and continued at this level throughout the period
of our evaluation, VE could not be assessed in this age cohort.
Therefore, we restricted our analysis to children who were 7–18
weeks of age at the time of vaccine introduction. These children
had not yet completed their complete infant immunization
series at the time of rotavirus vaccine introduction, with doses
recommended at 6, 10, and 14 weeks of age, and thus visited
vaccination clinics during the initial weeks of rotavirus vaccine
rollout. Coverage among children in this 7- to 18-week of age
window was variable and allowed VE to be assessed.
Cases were defined as children born between 15 January 2012
and 15 April 2012 (ie, were 7–18 weeks of age when rotavirus
vaccine was introduced in May 2012) who presented with a
diarrheal illness to a participating surveillance health facility and
had a stool specimen that tested positive for rotavirus by
enzyme immunoassay (EIA). A diarrheal illness was defined as
the occurrence of ≥3 episodes of diarrhea (stools of a less
formed character than usual) within a 24-hour period, <7
days prior to enrollment. “Test-negative” controls were defined
as children born between 15 January 2012 and 15 April 2012
who presented with a diarrheal illness to a participating
surveillance facility and had a stool specimen that tested negative for
rotavirus by EIA.
Clinical and sociodemographic information were collected
from the clinical evaluation of the child and through interview
of the parent or guardian. Vaccination data were collected from
the child’s vaccination card. If the card was unavailable during
the child’s hospital stay, the health facility where the child was
reported to be vaccinated was visited by project staff and the
vaccination data were abstracted from clinic records.
Photocopies of the vaccine card were retained. A dose of rotavirus vaccine
was considered relevant if it was administered at least 14 days
prior to the child’s admission date.
A whole stool specimen (approximately 5 mL) was obtained
from enrolled children during the acute illness. All attempts
were made to obtain a stool specimen within 48 hours of
hospital admission to avoid the detection of nosocomial infection.
Stool specimens were refrigerated at 2°C–8°C until tested for
rotavirus antigen using a commercially available EIA (ProSpecT,
Oxoid, United Kingdom) at the University Teaching Hospital
laboratory in Kigali by trained staff.
Bivariate analyses were conducted to assess differences in
sociodemographic and clinical characteristics of cases and
controls using the χ2 test for categorical variables and the
Wilcoxon rank-sum test for continuous variables. VE was
calculated using the following formula: VE = (1 – odds ratio) ×
100, where the odds ratio is the adjusted odds ratio for the
rotavirus vaccination rate among case-patients compared with
controls. The odds ratio was calculated using unconditional
logistic regression. Age at enrollment was included in the model
a priori to account for possible waning immunity. Potential
confounders identified in bivariate analyses were included in
the initial model and retained if their removal from the
model changed the odds ratio for the primary outcome by
>10%. Only children with card-confirmed vaccination status
were included in the analyses. The primary analysis included
all verified reports of vaccine status for children who had
received a full vaccine series vs no doses of the vaccine.
This evaluation was reviewed and approved by the Rwanda
National Ethics Committee and received a public health
nonresearch determination from the Centers for Disease Control and
A total of 200 children born between 15 January 2012 and 15
April 2012 were enrolled in the surveillance program between
September 2012 and May 2015. Of these, 48 (24%) tested
positive for rotavirus by EIA. Stool specimens were collected within
2 days of admission for 93% of children. Rotavirus-positive
children were significantly older (median age: 15.5 months) than
children who were rotavirus negative (median age: 10 months)
(P < .001). There were no other significant differences in
sociodemographic factors between rotavirus-positive and
rotavirusnegative children (Table 1). Rotavirus-positive children were
more likely to have a higher number of vomiting episodes, sunken
eyes, an abnormal thirst status, and lower skin turgor than
children who tested negative for rotavirus (Table 2).
The proportion of children with confirmed vaccination status
either by vaccine card or clinic record was similar between
rotavirus-positive children (94%) and rotavirus-negative children
(90%) (P = .65). Rotavirus-positive children were significantly
less likely to have received rotavirus vaccine (73% unvaccinated)
compared with rotavirus-negative children (59% unvaccinated)
(P = .002; Table 3). The age at vaccination was similar among
rotavirus-positive and -negative children with doses 1, 2, and
3 given at 10.5 weeks, 15 weeks, and 18 weeks of age,
respectively, in rotavirus-positive children and 11 weeks, 15 weeks, and 19
weeks of age, respectively, in rotavirus-negative children. No
differences were observed in the vaccination status for
rotavirus-positive and -negative children with respect to the other
infant immunizations including pentavalent vaccine, oral polio
vaccine, and pneumococcal vaccine. Rotavirus-positive children
were more likely to have received measles vaccine than
rotavirus-negative children, but rotavirus-positive children were
significantly older than rotavirus-negative children and this
difference was not statistically significant after adjusting for
age (P = .96).
Among all enrolled children, a full 3-dose series of RV5 was
75% (95% confidence interval [CI], 31%–91%) effective against
rotavirus gastroenteritis requiring hospitalization or a health
center visit (Table 4). RV5 was 80% (95% CI, 28%–94%)
effective against rotavirus disease requiring hospitalization. Vaccine
effectiveness was 65% (95% CI, −80% to 93%) in children 6–11
months of age and 81% (95% CI, 25%–95%) in children ≥12
months of age.
Data are presented as No. (%).
Abbreviations: IV, intravenous; ORT, oral rehydration therapy.
a Fever based on parental report.
(n = 152)
A full course of rotavirus vaccine was 80% effective against
rotavirus disease requiring hospitalization among Rwandan
children who began their rotavirus vaccine series between 7 and 18
weeks of age. Protection from vaccination was sustained after
the first year of life. The high observed VE is consistent with
the declines of 61%–70% in rotavirus hospitalizations and
17%–49% in all-cause diarrhea hospitalizations observed in
the first 2 years following rotavirus vaccine introduction in
The population included in this evaluation was unique in
several aspects. First, due to rapid uptake of the vaccine
among age-eligible children in Rwanda, we were unable to
evaluate rotavirus VE among children vaccinated on the
recommended schedule of 6, 10, and 14 weeks of age. Instead, we
evaluated VE among children who were >6 weeks of age at
time of rotavirus vaccine introduction but who were still visiting
vaccine clinics to receive their routine infant immunizations
during the time of initial rotavirus vaccine rollout. Only some
of these children began the rotavirus vaccine series, albeit on
a slightly delayed schedule, with median ages at vaccination
of 11, 15, and 19 weeks for the 3 doses, respectively. Given
the limited time period during which children were completing
their primary vaccine series, we had a somewhat limited sample
size for our analysis. Second, given the timing of vaccine
introduction and the seasonality of rotavirus disease, these children
were beginning the rotavirus vaccine series just prior to or at the
beginning of the rotavirus season.
Reasons for lower effectiveness of oral rotavirus vaccines in
developing compared with developed countries are not fully
understood and likely multifaceted, but interference by high titers
of maternal antibodies has been suggested as one factor that
may influence an infant’s response to the vaccine [
cohort of infants included in this evaluation were born
immediately prior to the start of the season, when passively acquired
antibodies transferred from mother to child either
transplacentally or through breastfeeding are likely to be at their lowest
level. Furthermore, these infants were a median of 5 weeks
older than the recommended age for vaccination when they
began the series, providing further time for maternal antibodies
to wane. Thus, our VE estimate may be higher than that in the
age-eligible population that received the vaccine on the
recommended schedule. However, given the large declines that were
observed in rotavirus and all-cause diarrhea hospitalizations
following vaccine introduction [
], the vaccine is likely effective
in the age-eligible population as well.
Rotavirus vaccine is effective in preventing rotavirus disease
in children in Rwanda. Further understanding of the factors
influencing effectiveness of oral rotavirus vaccines, particularly
with regard to the age and timing of vaccination, is needed.
Continued surveillance is also important to document the
long-term impact of rotavirus vaccine on the burden of
rotavirus disease in Rwanda.
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.
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.
Financial support. This evaluation was funded by Gavi, the Vaccine
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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