Effectiveness of Monovalent and Pentavalent Rotavirus Vaccines in Guatemala
Effectiveness of Monovalent and Pentavalent Rotavirus Vaccines in Guatemala
Paul A. Gastañaduy 1 2 3
Ingrid Contreras-Roldán 0 2
Chris Bernart 0 2
Beatriz López 0 2
Stephen R. Benoit 2 5
Marvin Xuya 0 2
Fredy Muñoz 0 2
Rishi Desai 1 2 3
Osbourne Quaye 1 2 4
Ka Ian Tam 1 2
Diana K. Evans-Bowen 1 2
Umesh D. Parashar 2 3
Manish Patel 2 3
John P. McCracken 0 2
0 Center for Health Studies, Universidad del Valle de Guatemala
1 National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention , Atlanta , Georgia
2 tion and Respiratory Diseases, Centers for Disease Control and Prevention , 1600 Clifton Rd NE, MS A-34, Atlanta, GA 30333
3 Epidemic Intelligence Service
4 West African Center for Cell Biology of Infectious Pathogens, Department of Biochemistry, Cell and Molecular Biology, University of Ghana , Legon
5 International Emerging Infections Program, Centers for Disease Control and Prevention , Guatemala City
Background. Concerns remain about lower effectiveness and waning immunity of rotavirus vaccines in resource-poor populations. We assessed vaccine effectiveness against rotavirus in Guatemala, where both the monovalent (RV1; 2-dose series) and pentavalent (RV5; 3-dose series) vaccines were introduced in 2010. Methods. A case-control evaluation was conducted in 4 hospitals from January 2012 to August 2013. Vaccine status was compared between case patients (children with laboratory-confirmed rotavirus diarrhea) and 2 sets of controls: nondiarrhea “hospital” controls (matched by birth date and site) and nonrotavirus “test-negative” diarrhea controls (adjusted for age, birth month/year, and site). Vaccine effectiveness ([1 - odds ratio of vaccination] × 100%) was computed using logistic regression models. Results. We evaluated 213 case patients, 657 hospital controls, and 334 test-negative controls. Effectiveness of 2-3 doses of a rotavirus vaccine against rotavirus requiring emergency department visit or hospitalization was 74% (95% confidence interval [CI], 58%-84%) with hospital controls, and 52% (95% CI, 26%-69%) with test-negative controls. Using hospital controls, no significant difference in effectiveness was observed between infants 6-11 months (74% [95% CI, 18%-92%]) and children ≥12 months of age (71% [95% CI, 44%-85%]) (P = .85), nor between complete courses of RV1 (63% [95% CI, 23%-82%]) and RV5 (69% [95% CI, 29%87%]) (P = .96). An uncommon G12P strain, partially heterotypic to strains in both vaccines, was identified in 89% of cases. Conclusions. RV1 and RV5 were similarly effective against severe rotavirus diarrhea caused by a heterotypic strain in Guatemala. This supports broader implementation of rotavirus vaccination in low-income countries where >90% global deaths from rotavirus occur.
To help control the large burden of childhood deaths and
hospitalizations associated with rotavirus disease, the World Health
Organization (WHO) recommends all infants receive 1 of 2 live
oral rotavirus vaccines, a monovalent human vaccine (Rotarix
[RV1], GlaxoSmithKline Biologicals, Rixensart, Belgium), or a
pentavalent bovine-derived vaccine (RotaTeq [RV5], Merck
and Co, Whitehouse Station, New Jersey) [
]. Although both
vaccines were found to perform well in prelicensure studies in
middle- and high-income countries, where efficacy ranged from
77% to 98% [
], the efficacy of these vaccines was lower
(18%–64%) in low-income settings of Africa and Asia [
The lower efficacy in low-income populations may be related
to host and environmental factors (eg, enteric coinfections,
concurrent oral polio vaccine administration, micronutrient
malnutrition, transplacental maternal antibodies, and human
immunodeficiency virus infection) that could impede initial
immune responses and adversely affect vaccine performance
]. Accordingly, evaluating vaccine effectiveness (VE)
under routine conditions in resource-limited settings remains
a public health priority.
Although >25 middle- and high-income countries have
adopted rotavirus vaccines for routine childhood
immunization, and several of these countries have documented large
declines in rotavirus disease burden, fewer low-income countries
are currently using rotavirus vaccines [
]. As a result, there are
limited data on the field performance of these vaccines in
developing countries, and WHO has emphasized the need for
additional VE data from these settings [
]. In addition, previous field
assessments in low-income settings in Latin America [
well as recent clinical trials in Africa and Asia [
], have shown
a decline in protection in children aged >1 year, suggesting
waning immunity in resource-limited settings. Moreover, given the
differences in strain makeup between RV1 and RV5, and the
constant evolution of new strains in resource-poor settings
], measuring RV1 and RV5 effectiveness during
contemporaneous use in the same population is important. In
particular, no previous evaluations have assessed the performance of
both vaccines during concurrent use in a lower middle-income
We conducted a case-control study to assess the effectiveness
of both RV1 and RV5 during contemporaneous use against
rotavirus diarrhea requiring emergency department (ED) care
or hospitalization in Guatemala.
Guatemala is a lower middle-income country in Central
America with a gross national income (GNI) per capita of $3070
annually and an annual birth cohort of approximately 298 154 live
births (http://data.worldbank.org/). In February 2010, Guatemala’s
Ministry of Health (Ministerio de Salud Publica de Guatemala
[MSPAS]) introduced RV5 into its routine immunization
program, with 3 doses recommended at ages 2, 4, and 6 months.
In July 2010, the MSPAS began to vaccinate with RV1 instead
of RV5, with 2 doses recommended at ages 2 and 4 months.
From 1 January 2012 to 30 August 2013, we conducted active
hospital-based diarrhea surveillance in the pediatric ED and
wards of 4 national hospitals in Guatemala (2 urban hospitals
in the capital, Guatemala City, and 1 rural hospital each in
Cuilapa and Quetzaltenango).
Participants: Case Patients and Controls
A case patient was defined as a child visiting the ED and/or
hospitalized for laboratory-confirmed rotavirus diarrhea and who
was age-eligible to receive rotavirus vaccination (born after 1
June 2009). Vaccine effectiveness was assessed using 2 groups
of controls: children hospitalized for a condition unrelated to
diarrhea (ie, “hospital” controls), and children with
rotavirusnegative diarrhea (ie, “test-negative” controls). After a case
patient was identified, up to 3 hospital controls matched to the
case patient’s date of birth (±30 days) were sequentially enrolled
during the study period in the same hospital. Test-negative
controls were those children who were enrolled during surveillance
for diarrhea but that tested negative for rotavirus.
After written informed consent, parents or guardians of case
patients and controls were interviewed face to face for
information on demographics, socioeconomic factors, birth weight,
history of breastfeeding, and the child’s medical history. For both
case patients and test-negative controls, data on clinical
characteristics, treatment, and the illness course were also collected
from the medical record and the hospital staff providing care.
Rotavirus vaccination status was confirmed by review of
vaccination cards if available from the parents during enrollment
(88%), or from logbooks at the clinic where the child was
reportedly vaccinated (12%). Case patients and controls were
considered vaccinated with the corresponding number of doses (eg,
1, 2, or 3) if the most recent dose was administered ≥14 days
before the date of presentation. If available, the type of vaccine
(RV1 or RV5) was abstracted from the vaccination card or clinic
Specimen Collection, Storage, and Laboratory Testing
Bulk stool specimens were collected from children presenting
with diarrhea within 48 hours of the hospital visit. In the 2
urban hospitals in Guatemala City, specimens were stored at
2°C–8°C prior to biweekly or weekly transfer to the Universidad
del Valle de Guatemala, where testing for rotavirus antigen
using a commercially available enzyme immunoassay (EIA)
kit (ProSpecT Rotavirus Microplate Assay, Oxoid, United
Kingdom) was performed. For Culiapa and Quetzaltenango, EIA
rotavirus antigen testing was performed in-hospital. Specimens
were stored frozen at −70°C and shipped to the Centers for
Disease Control and Prevention (Atlanta, Georgia), where
rotavirus-positive specimens were genotyped to determine the
infecting strain, using methods previously described [
Sample Size and Data Analysis
Using a precision-based approach, we estimated that a total of
170 case patients would be needed to compute a VE of 60% with
confidence limit width of 30%, using a matched design with a
hospital control-to-case ratio of 3:1 and vaccine coverage of 50%.
The main objective of this study was to estimate the
effectiveness of rotavirus vaccination against rotavirus-associated ED
visit or hospitalization. Primary analyses assessed the
effectiveness of a full series of RV1 (2 doses), a full series of RV5 (3
doses), or 2–3 doses of a rotavirus vaccine (either RV1, RV5,
or unrecorded vaccine type), compared with no dose. To
identify potential confounders or biases for the association between
rotavirus vaccination and subsequent rotavirus diarrhea, we
conducted bivariate analyses to assess for differences in
characteristics and indicators of socioeconomic status between case
patients and the 2 control groups. Differences in categorical data
were assessed using χ2 tests; continuous variables were assessed
with the Wilcoxon rank-sum test. We then compared the
proportion vaccinated among case patients and controls. VE was
calculated using only data from children with confirmed vaccination,
ensuring use of accurately ascertained vaccination status.
Two separate logistic regression models were constructed to
calculate the odds ratios with 95% confidence intervals (CIs) of
rotavirus vaccination in case patients vs each of the control
groups. For hospital controls, conditional logistic regression
models were used to account for matching by date of birth and
site (hospital). For test-negative controls, unconditional logistic
regression models that adjusted for age (in months), birth
month/year, and hospital were used. Adjusting for time of birth
and hospital in the base models is important because it controls
for potential confounding due to variation in vaccination
coverage from month to month and by geographic location. We also
assessed for additional confounding by including in the model
variables with a P value ≤.20 in the bivariate analyses.
Hierarchical backward elimination approach was used to select the
covariates in the final model, retaining variables significant at P < .05.
Subgroup analyses were conducted using the same approach
to assess (1) protection from receipt of 1 dose of a rotavirus
vaccine; (2) protection from receipt of 1 or more doses of a
rotavirus vaccine (intention-to-vaccinate analysis); (3)
strainspecific protection (against the predominant rotavirus
genotype); (4) duration of protection after vaccination, by measuring
effectiveness among children 6–11 months of age compared to
those aged ≥12 months (here an interaction term was included
between age and vaccine receipt in the regression models); and
(5) for a potential gradient in protection against illness of
varying severity, using a previously described 20-point clinical
severity score (Vesikari scale) [
]; illnesses with scores ≥11
were classified as severe and illnesses with scores ≥15 were
classified as very severe. To assess for a difference in effectiveness
between RV1 and RV5, regression models were repeated
limiting analyses to case patients and controls who had received
either RV1 or RV5 and including a term for vaccine type in
VE was calculated as (1 – odds ratio) × 100%. Statistical
significance was designated as a P value <.05. Analyses were
performed using SAS statistical software (version 9.3).
A total of 261 case patients, 769 hospital controls, and 387
testnegative controls were enrolled. Of the 261 case patients,
221 (85%) received intravenous rehydration, 111 (43%) were
hospitalized for a median duration of 2 days, and 1 died. The
age distribution of case patients was as follows: 33 (13%) were
<6 months, 90 (34%) were 6–11 months, 116 (44%) were 12–23
months, and 22 (8%) were ≥24 months of age.
Vaccine status was confirmed for 85% (1204/1417) of
participants. There were no differences in demographic or
socioeconomic variables among children with confirmed and nonconfirmed
vaccination (P > .06 for all), except for the number of children
in the home (2 [range, 1–40] vs 2 [range, 1–6], respectively;
P = .008). No significant difference in confirmation of
vaccination status was noted among case patients (82% [213/261]),
hospital controls (85% [657/769]), or test-negative controls
(86% [334/387]) (P = .23).
Compared to hospital controls, case patients were more likely
to be younger at presentation, more likely to be male, and less
likely to have a chronic underlying illness (Table 1). Compared
to test-negative controls, case patients were older and less likely
to have a chronic underlying illness.
Overall, among case patients, hospital controls, and
testnegative controls, respectively, 39% (84/213), 22% (145/657),
and 22% (73/334) were unvaccinated, and 61% (129/213),
78% (512/657), and 78% (261/334) received 1 dose or more.
Among 709 children who received 2–3 doses, information on
rotavirus vaccine type (RV1 or RV5) was available for 430 (61%),
including 60 case patients, 253 hospital controls, and 117
testnegative controls; 71% (306/430) received RV1 and 29% (124/
430) received RV5. Among children with information on
vaccine type, no mixed series were identified, and <1% (1/430) of
completed series were given incorrectly (on 1 occasion, 3 RV1
doses were administered). Doses of RV5 were administered
between February 2010 and March 2013, whereas doses of RV1
were administered between July 2010 and May 2013.
Effectiveness of 2–3 doses of a rotavirus vaccine against
rotavirus diarrhea requiring an ED visit or hospitalization was 74%
(95% CI, 58%–84%) in the analysis with hospital controls, and
52% (95% CI, 26%–69%) in the analysis with test-negative
controls (Table 2). One dose of a rotavirus vaccine also provided
significant protection of 59% (95% CI, 26%–78%) with hospital
controls, and 60% (95% CI, 27%–78%) with test-negative
controls. In the intention-to-vaccinate analysis, effectiveness of 1 or
more doses was 64% (95% CI, 45%–77%) with hospital controls,
and 55% (95% CI, 31%–71%) with test-negative controls. A
complete 2-dose course of RV1 and a complete 3-dose course
of RV5, respectively, were 63% (95% CI, 23%–82%) and 69%
(95% CI, 29%–87%) effective using hospital controls, and 51%
(95% CI, 15%–71%) and 43% (95% CI, −18% to 72%) effective
using test-negative controls. We did not find a significant
difference in effectiveness between the 2 types of vaccine using either
hospital controls (P = .96) or test-negative controls (P = .61).
Among 145 case patients with complete clinical information
on rotavirus severity, 15 (10%) were classified as mild to
moderate (Vesikari score ≤10), 90 (62%) as severe (Vesikari score
≥11 and <15), and 40 (28%) as very severe (Vesikari score
≥15). Protection was similar against the 2 levels of disease
severity we evaluated. With hospital controls, 2–3 doses of a
rotavirus vaccine provided protection of 73% (95% CI, 50%–86%)
against rotavirus diarrhea with severity score ≥11 and 76%
(95% CI, 18%–93%) against severity score ≥15 (Table 3).
No significant differences in effectiveness of 2–3 doses of a
rotavirus vaccine against a rotavirus ED visit or hospitalization
were observed between children 6–11 months of age compared
with children ≥12 months of age: 74% (95% CI, 18%–92%) vs
71% (95% CI, 44%–85%) using hospital controls (P = .85), and
73% (95% CI, 35%–89%) vs 53% (95% CI, 12%–75%) using
test-negative controls (P = .76) (Table 3).
Strain characterization was conducted for 99% (258/261) of
rotavirus-positive specimens. Among these, G12P[
] was the
predominant strain, detected in 89% (229/258) of the samples.
] is partially heterotypic to both vaccines (ie, the G
component is not among the strains contained in the vaccines). G2P
] was detected in 5% (14/258) of samples; the remaining 6%
were sparsely detected strains (G3P[
mixed infections. Two- or 3-dose VE specific against G12P[
alone was 74% (95% CI, 55%–85%) with hospital controls, and
54% (95% CI, 28%–71%) with test-negative controls (Table 3).
Effectiveness of RV1 and RV5 against rotavirus caused by G12P
] was 62% (95% CI, 14%–83%) and 73% (95% CI, 24%–90%)
using hospital controls, and 55% (95% CI, 21%–74%) and 39%
(95% CI, −30% to 71%) using test-negative controls, respectively.
During routine programmatic use in a lower middle-income
country, we demonstrate that 2–3 doses of a rotavirus
vaccine was approximately 50%–70% effective against
rotavirusassociated ED visits or hospitalizations. In the context of earlier
postlicensure evaluations in Latin America, this estimate is what
we would expect for Guatemala, based on the gradient of
effectiveness by socioeconomic status of the population. A full series
of RotaTeq provided 44% protection against severe rotavirus
disease in Nicaragua (GNI $1866), and effectiveness of Rotarix
was 69%–77% in Bolivia (GNI $2280), 76% in El Salvador (GNI
$3730), and 85% in Brazil (GNI $12 160) [
]. The finding
of similar effectiveness of RotaTeq and Rotarix in Guatemala
supports the notion that differences in host and environmental
factors are the likely cause of the heterogeneity in vaccine
performance. Importantly, demonstration of a protective effect in
this and other resource-limited settings is encouraging, as it is in
these populations with high baseline rates of severe rotavirus
outcomes where these vaccines offer their greatest life-saving
This is the first postlicensure assessment of the performance
of both rotavirus vaccines during concurrent use in a
developing country. Using hospital controls, we showed that 2 doses
of RV1 and 3 doses of RV5 were similarly effective against
rotavirus disease requiring an ED visit or hospitalization, with
VE estimates of 63% (95% CI, 23%–82%) and 69% (95% CI,
29%–87%), respectively. Our evaluation was not powered to
measure differences in effectiveness between the 2 vaccines
and, thus, prudent interpretation is warranted. However, 3
previous field effectiveness evaluations in 2 high-income countries
where concomitant use of both vaccines has been evaluated
] also did not find any evidence of a difference in
effectiveness between RV1 and RV5. Moreover, because almost 90%
of strains were of the G12 genotype, we were able to estimate
effectiveness for RV1 and RV5 against this emerging genotype
(62% [95% CI, 14%–83%] and 73% [95% CI, 24%–90%],
respectively). A previous study had demonstrated a protective
effect against G12 strains for RV5 only, and in a high-income
]. Our findings contribute to accumulating evidence
showing that both vaccines appear to provide good protection
against a wide range of homotypic and heterotypic rotavirus
strains, as shown in both clinical trials and postlicensure
2–7, 11, 12, 21
Our study provides evidence for considerable protection
(approximately 60%) against severe rotavirus diarrhea from 1 dose
of rotavirus vaccine among children in Guatemala. This
shortperiod protection, before completion of a full schedule, is
particularly reassuring for low-income countries, where a substantial
proportion of rotavirus hospitalizations and deaths occurs
among infants aged <6 months [
], and where many
infants may not return to complete their vaccination series. We
also note sustained protection through the second year of life,
the age period within which most rotavirus hospitalizations
occur in developing countries [
]. Conversely, a larger
study in Nicaragua [
], the poorest setting in which the
field performance of RV5 has been evaluated, as well as clinical
trials of both RV1 and RV5 in Africa [
], have demonstrated
an approximate 2- to 3-fold decline in protection after the first
year of life. In addition, studies in poor populations in Brazil
and Australia suggest that effectiveness against fully heterotypic
strains may decline more rapidly than protective immunity
against homotypic strains. Thus, it is in the most impoverished
regions, where factors that impair initial immune responses to
vaccines and strain diversity are more prominent, that waning
immunity may become most apparent. This warrants additional
monitoring of rotavirus disease incidence among older children,
and consideration of other interventions in resource-limited
A few limitations should be considered. We cannot be certain
that our controls ideally represent the distribution of
vaccination histories in the source population of case patients.
Confounding bias was likely decreased by matching and
adjustments for age and site, and the similarity in measures of
socioeconomic status between case patients and controls was
reassuring. Because not all families bring the child’s
immunization card to the hospital in Guatemala, we were able to obtain
vaccination records for only about 85% of participants, and
children with unknown vaccination (no card or clinic logbook
available) were excluded from the analyses. However, there were
no differences in confirmation between case patients and
controls, and characteristics and indicators of socioeconomic status
did not differ significantly between children with confirmed and
nonconfirmed vaccination, and so their respective rates of
vaccination are expected to be similar. Finally, although significant
estimates of RV1 and RV5 effectiveness were obtained with
hospital controls, approximately 40% of case patients and controls
who had received 2–3 doses lacked documentation of vaccine
type, and thus our CIs were wide and nonsignificant for RV5
using test-negative controls. Neither subgroup analyses
(duration of protection, partial vaccination, gradient by severity)
for each of the vaccine types were possible due to a small sample
In summary, rotavirus vaccination provided substantial
protection against severe rotavirus diarrhea in a lower
middleincome country setting in Latin America. We found good and
similar protection from complete courses of both RV1 and RV5.
Considerable protection was also conferred by 1 dose of vaccine,
vaccine effect was sustained among children ≥1 year of age, and
effectiveness was confirmed against a strain partially heterotypic
to both vaccines. Our findings reinforce WHO
recommendations for continued implementation of rotavirus vaccination
in low-income countries, where >90% of the annual deaths
from rotavirus occur.
Acknowledgments. We thank Cesar Racancoj, Aleida Roldan, Mathew
Esona, Rashi Gautam, Slavica Mijatovic-Rustempasic, and Michael Bowen
for their laboratory support, and Kimberly Pringle for help in ascertainment
of vaccination status at immunization clinics. We also thank all the members
of the research team in Guatemala involved in the enrollment of the
participants for this evaluation, as well as the Guatemala Ministry of Health and
the staff at participating hospitals for their cooperation.
Disclaimer. This work was funded by the Centers for Disease Control
and Prevention (CDC), Department of Health and Human Services, but the
final document was submitted at the sole discretion of the authors. The
findings and conclusions in this report are those of the authors and do not
necessarily represent the official position of the CDC. The views expressed by
the authors do not necessarily reflect the views of PATH, the CDC
Foundation, the Bill and Melinda Gates Foundation, or GAVI, the Vaccine Alliance.
Financial support. This work was supported by the CDC (cooperative
agreement number UO1 GH000028-02).
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 interests. 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.
1. Rotavirus vaccines: an update . Wkly Epidemiol Rec 2009 ; 84 : 533 - 40 .
2. Linhares AC , Velazquez FR , Perez-Schael I , et al. Efficacy and safety of an oral live attenuated human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in Latin American infants: a randomised, double-blind, placebo-controlled phase III study . Lancet 2008 ; 371 : 1181 - 9 .
3. 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 .
4. 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 .
5. Armah GE , Sow SO , Breiman RF , et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in subSaharan Africa: a randomised, double-blind, placebo-controlled trial . Lancet 2010 ; 376 : 606 - 14 .
6. Madhi SA , Cunliffe NA , Steele D , et al. Effect of human rotavirus vaccine on severe diarrhea in African infants . N Engl J Med 2010 ; 362 : 289 - 98 .
7. Zaman K , Dang DA , Victor JC , et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial . Lancet 2010 ; 376 : 615 - 23 .
8. Jiang V , Jiang B , Tate J , Parashar UD , Patel MM . Performance of rotavirus vaccines in developed and developing countries . Hum Vaccin 2010 ; 6 : 532 - 42 .
9. Patel M , Shane AL , Parashar UD , Jiang B , Gentsch JR , Glass RI . Oral rotavirus vaccines: how well will they work where they are needed most ? J Infect Dis 2009 ; 200 ( suppl 1 ): S39 - 48 .
10. 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 .
11. de Palma O , Cruz L , Ramos H , et al. Effectiveness of rotavirus vaccination against childhood diarrhoea in El Salvador: case-control study . BMJ 2010 ; 340 : c2825 .
12. Patel M , Pedreira C , De Oliveira LH , et al. Association between pentavalent rotavirus vaccine and severe rotavirus diarrhea among children in Nicaragua . JAMA 2009 ; 301 : 2243 - 51 .
13. Glass RI , Parashar U , Patel M , Gentsch J , Jiang B . Rotavirus vaccines: successes and challenges . J Infect 2014 ; 68 ( suppl 1 ): S9 - 18 .
14. Banyai K , Laszlo B , Duque J , et al. Systematic review of regional and temporal trends in global rotavirus strain diversity in the pre rotavirus vaccine era: insights for understanding the impact of rotavirus vaccination programs . Vaccine 2012 ; 30 ( suppl 1 ): A122 - 30 .
15. Hull JJ , Teel EN , Kerin TK , et al. United States rotavirus strain surveillance from 2005 to 2008: genotype prevalence before and after vaccine introduction . Pediatr Infect Dis J 2011 ; 30 ( 1 suppl):S42-7.
16. Ruuska T , Vesikari T. Rotavirus disease in Finnish children: use of numerical scores for clinical severity of diarrhoeal episodes . Scand J Infect Dis 1990 ; 22 : 259 - 67 .
17. Desai R , Oliveira LH , Parashar UD , Lopman B , Tate JE , Patel MM . Reduction in morbidity and mortality from childhood diarrhoeal disease after species A rotavirus vaccine introduction in Latin America-a review . Mem Inst Oswaldo Cruz 2011 ; 106 : 907 - 11 .
18. Castilla J , Beristain X , Martinez-Artola V , et al. Effectiveness of rotavirus vaccines in preventing cases and hospitalizations due to rotavirus gastroenteritis in Navarre, Spain . Vaccine 2012 ; 30 : 539 - 43 .
19. Payne DC , Boom JA , Staat MA , et al. Effectiveness of pentavalent and monovalent rotavirus vaccines in concurrent use among US children <5 years of age, 2009 - 2011 . Clin Infect Dis 2013 ; 57 : 13 - 20 .
20. Cortese MM , Immergluck LC , Held M , et al. Effectiveness of monovalent and pentavalent rotavirus vaccine . Pediatrics 2013 ; 132 : e25 - 33 .
21. Vesikari T , Karvonen A , Prymula R , et al. Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study . Lancet 2007 ; 370 : 1757 - 63 .
22. Bresee JS , Hummelman E , Nelson EA , Glass RI . Rotavirus in Asia: the value of surveillance for informing decisions about the introduction of new vaccines . J Infect Dis 2005 ; 192 ( suppl 1 ): S1 - 5 .
23. 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 .
24. Cunliffe NA , Kilgore PE , Bresee JS , et al. Epidemiology of rotavirus diarrhoea in Africa: a review to assess the need for rotavirus immunization . Bull World Health Organ 1998 ; 76 : 525 - 37 .
25. Patel M , Pedreira C , De Oliveira LH , et al. Duration of protection of pentavalent rotavirus vaccination in Nicaragua . Pediatrics 2012 ; 130 : e365 - 72 .
26. Cunliffe NA , Witte D , Ngwira BM , et al. Efficacy of human rotavirus vaccine against severe gastroenteritis in Malawian children in the first two years of life: a randomized, double-blind, placebo controlled trial . Vaccine 2012 ; 30 ( suppl 1 ): A36 - 43 .
27. Patel M , Glass RI , Jiang B , Santosham M , Lopman B , Parashar U. A systematic review of anti-rotavirus serum IgA antibody titer as a potential correlate of rotavirus vaccine efficacy . J Infect Dis 2013 ; 208 : 284 - 94 .