Real-World Effectiveness of Pentavalent Rotavirus Vaccine Among Bedouin and Jewish Children in Southern Israel

Clinical Infectious Diseases, Apr 2016

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[8] 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[8] 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.

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Real-World Effectiveness of Pentavalent Rotavirus Vaccine Among Bedouin and Jewish Children in Southern Israel

CID 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[8] 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[8] 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 [ 1 ]. 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% [ 2 ], whereas lower RV5 efficacy of 39%–48% was reported in similar trials performed in low-income settings [ 3, 4 ]. In routine use, RV5 vaccine effectiveness (VE) in high-income countries ranged from 84% to 92% [ 5–8 ], whereas in low- to middle-income settings, based on 2 studies conducted in Nicaragua, RV5 VE ranged between 46% and 87% [ 9, 10 ]. Prior to rotavirus vaccine introduction in Israel, rotavirus gastroenteritis was the leading cause of diarrhea-associated hospitalizations [ 11, 12 ]. 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 dropped [11]. 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 strain-specific VE. METHODS 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 [ 13 ]. 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 [ 11 ]. The 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 [ 14 ]. 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 [ 15 ]. Case Definition 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”). Characteristic 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) Statistical Analysis 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. RESULTS Patient Characteristics 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[ 8 ] genotype, 38 (32%) were G3P[ 8 ], 1 (1%) was G1P[undetermined], and 1 (1%) was G4P[ 8 ]. 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[ 8 ] 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 G1P[ 8 ] 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 population. DISCUSSION 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 [ 2–4 ]. 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% [ 5–10 ]; 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 settings [ 16, 17 ]. 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 [ 11 ]; however, 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 [ 11 ]. 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[ 8 ]. For the homotypic G1P[ 8 ] genotype, 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 strains [ 18 ]. Continued efforts to assess RV5 VE against genotypes other than G1P[ 8 ] 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 cases. 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[ 8 ] 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 conditions. Supplementary Data 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. Notes 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. 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Eyal Leshem, Noga Givon-Lavi, Jacqueline E. Tate, David Greenberg, Umesh D. Parashar, Ron Dagan. Real-World Effectiveness of Pentavalent Rotavirus Vaccine Among Bedouin and Jewish Children in Southern Israel, Clinical Infectious Diseases, 2016, S155-S160, DOI: 10.1093/cid/civ1012