Real-World Effectiveness of Pentavalent Rotavirus Vaccine Among Bedouin and Jewish Children in Southern Israel
Real-World Effectiveness of Pentavalent Rotavirus Vaccine Among Bedouin and Jewish Children in Southern Israel
Eyal Leshem 1 2 3
Noga Givon-Lavi 0 2
Jacqueline E. Tate 1 2
David Greenberg 0 2
Umesh D. Parashar 1 2
Ron Dagan () 0 2
0 Pediatric Infectious Diseases Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev and Soroka University Medical Center , Beer- Sheva , Israel
1 Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention , Atlanta , Georgia
2 Center , PO Box 151, Beer-Sheva 84101 , Israel
3 Internal Medicine C, Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University , Israel
Background. Pentavalent rotavirus vaccine (RV5) was introduced into the Israeli National Immunization Program in January 2011. We determined RV5 vaccine effectiveness (VE) in southern Israel, a region characterized by 2 distinct populations: Bedouins living in a low- to middle-income, semirural setting, and Jews living in a high-income, urban setting. Methods. We enrolled vaccine-eligible children who visited the emergency department (ED) or were hospitalized due to acute gastroenteritis (AGE) during the first 3 rotavirus seasons after RV5 vaccine introduction (2011-2013). Fecal specimens were tested for rotavirus by enzyme immunoassay and genotyped. Vaccination among laboratory-confirmed rotavirus cases was compared with rotavirus-negative AGE controls. Regression models were used to calculate VE estimates by age, clinical setting, and ethnicity. Results. Of 515 enrolled patients, 359 (70%) were Bedouin. Overall, 185 (36%) patients were rotavirus positive; 79 of 119 (66%) were G1P genotype. The adjusted VE for a full 3-dose course of RV5 against ED visit or hospitalization was 63% (95% confidence interval [CI], 38%-78%). RV5 provided G1P genotype-specific effectiveness of 78% (95% CI, 58%-88%). By age, RV5 VE was 64% (95% CI, 21%-84%) and 71% (95% CI, 39%-86%) among children aged 6-11 months and 12-23 months, respectively. By clinical setting, RV5 VE was 59% (95% CI, 23%-78%) against hospitalization, and 67% (95% CI, 11%-88%) against ED visit. The adjusted VE of a full RV5 course among Bedouin children was 62% (95% CI, 29%-79%). Conclusions. RV5 significantly protected against rotavirus-associated ED visits and hospitalizations in a diverse population of vaccine-eligible children living in southern Israel.
Worldwide, rotavirus is a leading cause of severe childhood
diarrhea and accounts for approximately one-third of diarrheal
deaths in this age group [
]. The World Health Organization has
recommended immunization of all children with a rotavirus
vaccine, and 2 live attenuated vaccines have been approved for global
use: RotaTeq (RV5; Merck, Whitehouse Station, New Jersey) is a
pentavalent human-bovine reassortant vaccine, and Rotarix
(RV1; GlaxoSmithKline Biologicals, Rixensart, Belgium) is a
monovalent vaccine derived from an attenuated human strain.
In clinical trials conducted in high-income countries, RV5
efficacy in prevention of rotavirus-associated emergency
department (ED) visits and hospitalizations reached 95% [
lower RV5 efficacy of 39%–48% was reported in similar trials
performed in low-income settings [
]. In routine use, RV5
vaccine effectiveness (VE) in high-income countries ranged
from 84% to 92% [
], whereas in low- to middle-income
settings, based on 2 studies conducted in Nicaragua, RV5 VE
ranged between 46% and 87% [
Prior to rotavirus vaccine introduction in Israel, rotavirus
gastroenteritis was the leading cause of diarrhea-associated
]. In 2007, both rotavirus vaccines were licensed
for use in Israel, and since 1 January 2011, RV5 vaccine is offered
free of charge in the Israeli National Immunization Program
(NIP). The vaccine 3-dose course is recommended at ages 2, 4,
and 6 months and is provided at community health clinics.
Individual child vaccination records are documented at the time of
vaccination. Following rotavirus vaccine introduction into the
Israeli NIP, rotavirus-associated hospitalization rates substantially
The introduction of RV5 in Israel, coupled with a unique
setting in southern Israel where 2 distinct populations (Jewish and
Bedouin children) live, allowed us to assess RV5 VE under routine
use across demographic and income settings. Our main objective
was to evaluate RV5 VE in preventing rotavirus-associated ED
visits and hospitalizations through case-control methodology.
Secondary objectives were to describe age, dose, ethnicity, and
Study Setting and Participants
Two distinct populations inhabit southern Israel: The Jewish
population is primarily a higher-income, urban population, in
contrast to the Bedouin population, which is primarily of low to
middle income, transitioning from a seminomadic rural lifestyle
to semiurban settings. The Bedouin population is further
characterized by lower socioeconomic status, lower educational
attainment, and crowded living conditions of extended families
compared with the Jewish population. While parity rates are
lower in the Jewish populations, birth cohorts of both
populations in southern Israel are similar in size. During the study
years, the populations aged <2 and <5 years of southern Israel
were approximately 30 000 and 72 000 children, respectively
]. The respective populations for the entire country were
approximately 300 000 and 730 000 children. Both Jewish and
Bedouin communities have complete free access to full
ambulatory and emergency medical services. Nearly all (about 95%)
children born at the Soroka University Medical Center
(SUMC) in southern Israel also receive all hospital services,
including ED services and hospitalization, at SUMC.
Study Design and Conduct
Our data were collected during a prospective, population-based
acute gastroenteritis (AGE) surveillance study conducted at
SUMC from April 2006 through March 2013. Study staff
located at the pediatric ED identified all age-eligible children daily,
year round (including weekends and holy days), from 8 AM to 9
PM. Eligible children were those who met all of the following
criteria: (1) aged <5 years; (2) presented to the ED with AGE,
defined as ≥3 liquid or semiliquid stools per 24 hours or forceful
vomiting (excluding posttussive vomiting) lasting <7 days; and
(3) residing in southern Israel. An analysis of rotavirus vaccine
impact based on these data was published previously [
study was approved by the SUMC institutional review board
and the Israel Ministry of Health‘s Ethics Committee.
Children who visited the ED due to AGE were offered study
participation. After written parental consent was granted, a
standardized questionnaire was administered by the study
staff to the parent/guardian that queried demographics (age,
sex, and ethnic group), symptoms, and household
socioeconomic information. Medical information including severity
and duration of symptoms, treatment, and duration of ED
stay or hospitalization were recorded from patients’ medical
records. Rotavirus vaccination status and the dates and number of
RV5 doses were obtained from the vaccination register at the
child community health clinic. Clinical severity was calculated
according to Clark score [
]. Any visit to the ED due to AGE
was defined as an ED visit; a hospitalization was defined as an
admission (hospital stay) lasting ≥24 hours.
A bulk stool sample was obtained from the diaper or directly
from the child within 48 hours of admission. If the stool was
soaked into the diaper lining, an 11 cm2 stool-impregnated
piece was cut from the internal section of the diaper. All samples
were sent to the Pediatric Infectious Disease Unit Research
Laboratory, where a 20% stool suspension in Earle’s balanced salt
solution + Ca++ was made and stored at −70°C. The presence
of rotavirus antigen (VP6) was detected using the IDEIA
rotavirus enzyme-linked immunosorbent assay kit (DakoCytomation
Ltd, Cambridgeshire, United Kingdom). Samples that were
rotavirus positive were genotyped using reverse transcription
polymerase chain reaction [
RV5 VE assessment was restricted to vaccine eligible children
enrolled during the first 3 rotavirus seasons after RV5 vaccines were
introduced into the Israeli NIP. Eligible children were those who
met all of the following criteria: (1) aged ≥6 months, (2) eligible
to have received at least 1 RV5 dose ≥14 days before presentation
(born on or after 1 October 2010), and (3) visited the ED or were
hospitalized during the first 3 post–vaccine introduction seasons
(1 January 2011–31 March 2011; 1 November 2011–31 March
2012; and 1 November 2012–31 March 2013).
Cases were children hospitalized or visiting the ED with AGE
symptoms whose fecal sample tested positive for rotavirus. The
control group was children with AGE whose fecal specimens
tested negative for rotavirus (“rotavirus-negative AGE controls”).
Death (1 mo from ED visit)
Received ORS before
admission, % yes
Received IV fluids during hospital stay, % yes
Rotavirus Cases (n = 185) 0 132 (71)
Ages at diarrhea onset and at each vaccine administration were
calculated. For VE analysis, an RV5 dose was counted if it had
been administered ≥14 days before the date of diarrhea onset.
RV5 VE was calculated as (1 – odds ratio) × 100%. Odds ratios
for having received 1 or more RV5 doses for rotavirus case
subjects compared with rotavirus-negative AGE controls were
calculated by logistic regression, controlling for age and Clark
score >16 (categorical). Overall VE was calculated for children
aged 6–11 and 12–23 months; children aged <6 months were
excluded and sample size for children aged >23 months was
insufficient. Subanalyses were planned a priori to assess VE by age
(stratified analysis), clinical severity (ED visit vs hospitalization
and Clark score), rotavirus genotype, and ethnicity.
During 1 January 2011–31 March 2013, 515 children met the
eligibility criteria for inclusion in the RV5 VE analyses (Table 1); of
these, 185 (36%) were rotavirus cases and 330 (74%) were
rotavirus-negative AGE controls. Among 119 rotavirus cases with known
genotype, 79 (66%) were G1P[
] genotype, 38 (32%) were G3P[
1 (1%) was G1P[undetermined], and 1 (1%) was G4P[
Most children included in the study (359/515 [70%]) were
Bedouin; the mean patient age was 12 months, and 284 (55%)
were males (Table 1). The proportion of Bedouin children was
similar among rotavirus cases and rotavirus-negative controls,
as were the proportion of male patients and the mean ages in
the 2 patient groups. The number of household children,
number of household children visiting a preschool, and the number
of persons per household bedroom were all significantly higher
in the rotavirus case group. Other demographic characteristics
were similar between the groups.
Over the study period, 344 (67%) patients were hospitalized
and 177 (34%) presented with a Clark score >16 (Table 2).
Rotavirus cases were characterized by a significantly higher
hospitalization rate and Clark score, reflecting more severe clinical
presentation compared with rotavirus-negative AGE controls.
None of the patients died.
RV5 Vaccine Effectiveness
Overall, the adjusted VE for a full 3-dose course of RV5 against
ED visit or hospitalization was 63% (95% confidence interval
[CI], 38%–78%; Table 3). Similar adjusted VE of 64% (95%
CI, 40%–78%) and 65% (95% CI, 42%–79%) was demonstrated
for receiving ≥1 dose or ≥2 doses, respectively. Among children
infected with G1P[
] genotype, the adjusted RV5 VE of 3 doses
was 78% (95% CI, 58%–88%).
By age, the VE of a complete 3-dose course of RV5 among
infants aged 6–11 months was 64% (95% CI, 21%–84%)
compared with 71% (95% CI, 39%–86%) for children aged 12–23
months (Table 4). Among infants aged 6–11 months, and
children aged 12–23 months, the adjusted VE for ≥1 dose was 62%
(95% CI, 10%–82%) and 74% (95% CI, 46%–87%), respectively.
For ≥2 doses, the adjusted RV5 VE among children aged 6–11
months and children aged 12–23 months was 64% (95% CI,
23%–83%) and 74% (95% CI, 46%–87%), respectively.
When assessing VE by clinical setting, a complete RV5
course offered 59% (95% CI, 23%–78%) protection against
hospitalization and 67% (95% CI, 11%–88%) effectiveness against
ED visits (Supplementary Table 1). We attempted to determine
VE among the most severe cases defined by Clark score >16;
however, the sample size was too small for statistically
significant results (data not shown).
Bedouin children comprised of the majority of children
enrolled in the effectiveness evaluation. The adjusted VE of a full
3-dose course of RV5 among Bedouin children in southern
Israel was 62% (95% CI, 29%–79%) (Table 5). A full 3-dose
course of RV5 provided 79% VE (95% CI, 55%–91%) against
] rotavirus gastroenteritis among Bedouins (data not
shown). The small sample size of the Jewish children group
included in this evaluation did not allow for a VE analysis in this
We conducted a real-world assessment of RV5 VE in a
demographically diverse population inhabiting southern Israel. We
found that the overall RV5 VE against ED visits and
hospitalizations was 63% (95% CI, 38%–78%). Most patients enrolled in
our evaluation belong to the indigenous Bedouin community,
characterized by low- to middle-income settings, high parity
rates, and rural or periurban living conditions. RV5 VE
among Bedouin children was 62% (95% CI, 29%–79%).
Field trials and postlicensure evaluations have consistently
shown an association between VE and the level of economic
development in the studied population. RV5 vaccine efficacy
reached 95% in a clinical trial conducted in 11 high-income
countries in Europe and the Americas, compared with a
lower efficacy range (39%–48%) demonstrated in trials
performed in Africa and Asia [
]. Postlicensure evaluations
reaffirmed this observation: In high-income countries, RV5 VE
ranged between 84% and 92%, whereas in low- to
middleincome settings, VE ranged between 46% and 87% [
however, other than these 2 evaluations conducted after RV5
was introduced in Nicaragua, literature on RV5 VE in these
settings is scarce.
VE among Bedouin children is of particular interest. Our
study is the first to describe RV5 VE in a crowded multiparous
Bedouin population in the Middle East. Few studies have
described the VE of rotavirus vaccines among indigenous
population living in high-income countries. In Australia, RV1
rotavirus vaccine was shown to be less effective in protecting
aboriginal populations compared with VE in high-income
]. Our results suggest that although RV5 VE
among Bedouin children (62%) was lower than VE demonstrated
among children living in high-income settings in other countries
(84%–92%), in the Bedouin population RV5 VE was comparable
or higher than that observed in low- to middle-income settings
(46%–87%). We did not observe waning of VE during the second
year in the general study population or among Bedouin children.
Prior to RV5 introduction into the Israel NIP, Bedouin infants
had higher acute gastroenteritis hospitalization rates compared
with Jewish children. The introduction of RV5 into the NIP
was followed by a rapid vaccine uptake among both Jewish and
Bedouin populations in southern Israel, resulting in a marked
reduction in the incidences of rotavirus-associated hospitalizations
during both the first and second years of life [
among Bedouin children, rate declines were of lower magnitude
than among Jewish children in both the first and second years of
life. Furthermore, for children aged 2–4 years, no impact was
observed among the Bedouin children during the first 3 years post–
vaccine introduction, whereas among the Jewish children a 45%
decrease was observed in this age group, suggesting, at least in
part, herd protection. Our current findings support the
association of RV5 introduction in 2011 with the observed reduction in
rotavirus-associated hospital visit rates [
]. We speculate that
the lower impact observed among Bedouin children might be
associated with a slightly lower vaccine uptake compared with
Jewish children. The higher crowding resulting in early exposure
to rotavirus, coupled with potential interference of rotavirus
vaccine take, may also have played a role. Due to sample size,
we could not compare RV5 VE between Bedouin and Jewish
children, which could potentially clarify this question.
Our study has several limitations. Low sample size, possibly
associated with rapid increase in vaccine coverage rates among
eligible children, did not allow for a comparison of RV5
effectiveness between Jewish and Bedouin children, VE assessment
in children with higher Clark score, or VE assessment for
genotypes other than G1P[
]. For the homotypic G1P[
VE against ED visits and hospitalizations reached 78% for
children vaccinated with 3 doses. It is unclear if the vaccine is less
effective against other strains. A recent meta-analysis suggests
that RV5 is as effective against partially and fully heterotypic
]. Continued efforts to assess RV5 VE against
genotypes other than G1P[
] are recommended. It is important to
stress that in this study, the calculated VE was against
rotavirus-associated ED visits and hospitalizations, presumed to be
more severe than rotavirus episodes associated with community
clinic visits or those not requiring medical care. Increasing VE
of RV5 was previously associated with more severe disease;
however, we could not confirm this by assessing VE among
children with a higher Clark score due to the low number of severe
In conclusion, RV5 is effective in preventing ED visits and
hospitalizations among children living in southern Israel. RV5
was highly effective in preventing disease caused by the G1P[
genotype. Due to small sample size, we could not evaluate VE
against other genotypes or compare VE in Jewish children vs
Bedouin children; however, VE among Bedouin children was
comparable or higher than that observed in children living in
other low- to middle-income settings. RV5 VE among Bedouin
children may serve to promote rotavirus vaccine integration
into NIPs of other countries with similar population and living
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 Bart A. van der Beek for his contribution
to the manuscript.
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. The Pediatric Infectious Diseases Unit at Soroka
University Medical Center received funding from Merck Sharpe &
Dohme (MSD) to conduct this study.
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. D. G. has served as a consultant and
received honoraria from MSD. N. G.-L., D. G., and R. D. received a grant from
MSD. 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. 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 .
2. 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 .
3. 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 .
4. 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 .
5. Cortese MM , Immergluck LC , Held M , et al. Effectiveness of monovalent and pentavalent rotavirus vaccine . Pediatrics 2013 ; 132 : e25 - 33 .
6. 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 .
7. Staat MA , Payne DC , Donauer S , et al. Effectiveness of pentavalent rotavirus vaccine against severe disease . Pediatrics 2011 ; 128 : e267 - 75 .
8. Vesikari T , Uhari M , Renko M , et al. Impact and effectiveness of RotaTeq(R) vaccine based on 3 years of surveillance following introduction of a rotavirus immunization program in Finland . Pediatr Infect Dis J 2013 ; 32 : 1365 - 73 .
9. Mast TC , Khawaja S , Espinoza F , et al. Case-control study of the effectiveness of vaccination with pentavalent rotavirus vaccine in Nicaragua . Pediatr Infect Dis J 2011 ; 30 : e209 - 15 .
10. 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 .
11. Givon-Lavi N , Ben-Shimol S , Cohen R , Greenberg D , Dagan R . Rapid impact of rotavirus vaccine introduction to the National Immunization plan in southern Israel: comparison between 2 distinct populations . Vaccine 2015 ; 33 : 1934 - 40 .
12. Dagan R , Bar-David Y , Sarov B , et al. Rotavirus diarrhea in Jewish and Bedouin children in the Negev region of Israel: epidemiology, clinical aspects and possible role of malnutrition in severity of illness . Pediatr Infect Dis J 1990 ; 9 : 314 - 21 .
13. Israel Central Bureau of Statistics. Population by district, sub-district and religion . Available at: http://www1.cbs.gov.il/reader/shnaton/shnatone_new.htm? CYear= 2010 &Vol= 61 & CSubject=2 . Accessed 21 May 2014 .
14. Givon-Lavi N , Greenberg D , Dagan R . Comparison between two severity scoring scales commonly used in the evaluation of rotavirus gastroenteritis in children . Vaccine 2008 ; 26 : 5798 - 801 .
15. Gouvea V , Glass RI , Woods P , et al. Polymerase chain reaction amplification and typing of rotavirus nucleic acid from stool specimens . J Clin Microbiol 1990 ; 28 : 276 - 82 .
16. Snelling TL , Andrews RM , Kirkwood CD , Culvenor S , Carapetis JR . Case-control evaluation of the effectiveness of the G1P human rotavirus vaccine during an outbreak of rotavirus G2P infection in central Australia . Clin Infect Dis 2011 ; 52 : 191 - 9 .
17. Snelling TL , Schultz R , Graham J , et al. Rotavirus and the indigenous children of the Australian outback: monovalent vaccine effective in a high-burden setting . Clin Infect Dis 2009 ; 49 : 428 - 31 .
18. Leshem E , Lopman B , Glass R , et al. Distribution of rotavirus strains and strainspecific effectiveness of the rotavirus vaccine after its introduction: a systematic review and meta-analysis . Lancet Infect Dis 2014 ; 14 : 847 - 56 .