Effectiveness of Pentavalent Rotavirus Vaccine Against Severe Disease
OBJECTIVE: To determine the vaccine effectiveness (VE) of complete and partial vaccination with the pentavalent rotavirus vaccine (RV5) in the prevention of rotavirus acute gastroenteritis (AGE) hospitalizations and emergency department visits during the first 3 rotavirus seasons after vaccine introduction.
METHODS: Active, prospective population-based surveillance for AGE and acute respiratory infection (ARIs) in inpatient and emergency department settings provided subjects for a case-control evaluation of VE in 3 US counties from January 2006 through June 2009. Children with laboratory-confirmed rotavirus AGE (cases) were matched according to date of birth and onset of illness to 2 sets of controls: children with rotavirus-negative AGE and children with ARI. The main outcome measure was VE with complete (3 doses) or partial (1 or 2 doses) RV5 vaccination.
RESULTS: Of age-eligible children enrolled, 18% of cases, 54% of AGE controls, and 54% of ARI controls received ≥1 dose of RV5. The VE of RV5 for 1, 2, and 3 doses against all rotavirus genotypes with the use of rotavirus-negative AGE controls was 74% (95% confidence interval [CI]: 37%–90%), 88% (95% CI: 66%–96%), and 87% (95% CI: 71%–94%), respectively, and with the use of ARI controls was 73% (95% CI: 43%–88%), 88% (95% CI: 68%–95%), and 85% (95% CI: 72%–91%), respectively. The overall VE estimates were comparable during the first and second years of life and against AGE caused by different rotavirus strains.
CONCLUSION: RV5 was highly effective in preventing severe rotavirus disease, even after a partial series, with protection persisting throughout the second year of life.
WHAT'S KNOWN ON THIS SUBJECT:
The pentavalent rotavirus vaccine RV5 was licensed and recommended for routine immunization in US infants in 2006. Results of studies performed before licensure demonstrated this vaccine to be highly efficacious against rotavirus-associated hospitalizations and emergency department visits.
WHAT THIS STUDY ADDS:
In this case-control study the effectiveness of RV5 under field conditions was examined. Both full and partial immunization with RV5 were found to be highly effective against rotavirus-associated hospitalizations and emergency department visits, and effectiveness in children persisted during the second year of life.
Rotavirus is the most common cause of severe acute gastroenteritis (AGE) in children worldwide. Before the introduction of rotavirus vaccine in the United States, nearly all children were infected with rotavirus in the first 5 years of life, leading to approximately 55 000 to 70 000 hospitalizations, 205 000 to 272 000 emergency department (ED) visits, and 410 000 physician visits at a cost of $1 billion US in direct medical and societal costs each year.1,–,6 Since February 2006, a 3-dose pentavalent human-bovine reassortant rotavirus vaccine (RV5) (RotaTeq, Merck & Co Inc, Whitehouse Station, NJ) has been recommended for routine use in US infants.7,8 In the large efficacy trial leading to its licensure, RV5 was found to have an efficacy of 74% against G1–G4 rotavirus AGE of any severity and an efficacy of 98% against severe G1–G4 rotavirus AGE during the first full rotavirus season.9 In addition, RV5 reduced office and clinic visits for G1–G4 rotavirus AGE by 86% and had an efficacy of 94.5% against hospitalizations or ED visits attributable to infection by G1–G4 rotavirus strains.9 Despite the demonstrated high efficacy of RV5 against severe rotavirus AGE in clinical trials, there is an ongoing need to assess the effectiveness of RV5 administered as part of routine clinical care. Several factors, including vaccine delivery and storage issues, age at receipt, interval between doses, natural circulating rotavirus genotypes, and inclusion of children who might respond differently to the vaccine, could reduce the vaccine effectiveness (VE) of RV5 when it is delivered under field conditions.10,–,13
Since January 2006, the US Centers for Disease Control and Prevention (CDC) have funded the New Vaccine Surveillance Network (NVSN) to conduct active, population-based surveillance for AGE in 3 US counties.14,15 Within this surveillance framework, we examined the effectiveness of RV5 against rotavirus hospitalizations and ED visits during the first 3 rotavirus seasons after vaccine implementation.
Overall Study Design
Active, prospective, population-based surveillance for AGE and acute respiratory infections (ARIs) in inpatient and ED settings provided subjects for a matched case-control evaluation to measure the effectiveness of RV5.
The NVSN conducted active, prospective, population-based surveillance for hospitalizations and ED visits for treatment of AGE in children aged <4 during 3 rotavirus seasons: December 1, 2006, through June 30, 2007 (2007); December 1, 2007, through June 30, 2008, (2008) and December 1, 2008, through June 30, 2009, (2009).14,15 The surveillance sites included the University of Rochester Medical Center, Cincinnati Children's Hospital Medical Center, and Vanderbilt University Medical Center. Each surveillance site provided care for >95% of hospitalized children in their respective counties. These surveillance sites are hereafter referred to as Rochester, Cincinnati, and Nashville. Institutional review board approvals were obtained from the CDC and from each study site.
Details of NVSN AGE surveillance have been previously described.14,15 In brief, children were enrolled if they were aged 15 days through 47 months, had AGE of ≤10 days' duration, were county residents, and had informed consent provided by a parent or guardian. Children were ineligible if they had diarrhea that their health care provider attributed to noninfectious causes, were known to be immunocompromised, had been previously enrolled for the same AGE episode, were transferred from another hospital, or did not speak English. Children enrolled in the ED who were subsequently admitted were categorized as hospitalized. Surveillance for hospitalized children occurred 5 days each week. In the ED, systematic sampling was performed 2 to 4 days each week for 10 to 12 hours' duration to ensure sampling on different days of the week. Demographic (age, gender, insurance type) and clinical information (vomiting and diarrhea episodes) were collected. Bulk stool samples were obtained within 14 days of the child's visit for AGE symptoms (95% collected within 7 days). Fourteen days was used because it was the same duration allowed for specimen collection as the RV5 efficacy study.9 Specimens were tested at each site by using Rotaclone, a commercial enzyme immunoassay (Meridian Bioscience, Inc, Cincinnati, OH). Rotavirus-positive samples were sent to the CDC for genotype determination by reverse transcription polymerase chain reaction and nucleotide sequencing.16,–,19
During the same time period, the NVSN conducted active, population-based surveillance for ARI.20,–,22 Children eligible for enrollment were aged <5 years, had ARI symptoms, and were residents of the same study counties. Children were excluded if they had fever and neutropenia associated with chemotherapy, had been hospitalized in the previous 4 days, had been transferred from another surveillance hospital, were never discharged from the hospital, or had had symptoms for >14 days.
Parents provided the names of all health care providers from whom their child received immunizations, and documentation of the immunization record for all vaccines was requested. When provider records were not available, information was obtained from state registries. The dates and types of rotavirus vaccine were abstracted.
Rotavirus VE Methods
VE Study Design
A matched case-control design was used to assess the effectiveness of RV5 in preventing rotavirus-associated hospitalizations and ED visits. Vaccine exposure among cases was compared with vaccine exposure among controls. Cases were defined as children who were born on or after April 1, 2006 (eligible for vaccine receipt), were enrolled in NVSN surveillance, and had laboratory-confirmed rotavirus AGE. Two control groups were selected from the NVSN surveillance program and also included children born on or after April 1, 2006. The first control group included children who were hospitalized or seen in the ED with AGE and had rotavirus-negative samples. The second control group included children hospitalized or seen in the ED for ARI. Children enrolled in both ARI and AGE surveillance were excluded as ARI controls.20,–,22 Cases were matched to a variable number of controls (1–5 per case) according to date of birth (±30 days) and symptom-onset date (±30 days). Case and control children had to be at least 52 days old to be included in the study and were excluded if they were missing vaccine information for all vaccines (4 cases and 26 AGE, and 66 ARI controls). Children who had received the monovalent rotavirus vaccine (RV1) (Rotarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) alone (1 case, 6 AGE, and 21 ARI controls) or in combination with RV5 (0 cases, 2 AGE, and 6 ARI controls) were excluded. In Cincinnati, 0.7% of children enrolled in AGE and 9.6% enrolled in ARI surveillance were excluded because of protocol deviations.
VE Statistical Methods
VE was calculated for 1, 2, or 3 doses of RV5 against rotavirus-associated hospitalizations and ED visits combined and caused by any rotavirus genotype. The following formula was used: VE = (1 − odds ratio) × 100, where the odds ratio is a comparison of the vaccination rates among cases and controls.10,–,13 Subanalyses were done to assess VE during the first and second years of life, against hospitalizations or ED visits separately, and according to individual and combined G types.
RV5 doses for each dose were defined as valid if given ≥14 days before the onset of symptoms for the cases and ≥14 days before the enrollment date for the controls; ≥14 days was used to provide sufficient time for an immune response.9 The odds ratio and 95% confidence intervals (CIs) were calculated by use of logistic regression. Potential covariates included: insurance status (private versus public or no insurance); study site (Rochester, Cincinnati or Nashville); and clinical setting (inpatient versus ED). Covariates having a P value of >.20 in bivariate analyses were excluded. Covariates with a P value of ≤.20 were entered into a multivariate model and subject to backward elimination. In the AGE rotavirus-negative control analysis, the P value for insurance status was ≤.20 in the bivariate analyses; however, it was removed during the backward elimination portion of the analysis. In the ARI control group, insurance status, geographic region, and clinical setting were significant in the bivariate analyses. After backward elimination, geographic region was removed and insurance status and clinical setting remained as covariates. Analyses were performed using SAS 9.2 (SAS Institute, Inc, Cary, NC). All tests were 2-sided with a significance level of .05.
Over the 3 seasons, 1660 children were eligible for enrollment in AGE surveillance. After application of inclusion criteria of age ≥ 52 days and exclusion of children who had received RV1, 1174 (70.7%) remained. Of these, 833 (71.0%) provided a stool specimen for testing (Fig 1A). Reasons for nonenrollment included refusal (9.6%), non–English-speaking parent (5.5%), parent unavailable (2%), and other reasons (1.8%).
Overall, there were 184 rotavirus-positive AGE cases with a median age of 13 months (Table 1). Of these children, 51% were boys, 43% were white; 41% were inpatients, and 59% were cared for in the ED. The distribution of the cases varied according to year, with 31% enrolled in 2007, 10% in 2008, and 59% in 2009. Over the study period, 34% of cases were from Rochester, 44% from Cincinnati, and 22% from Nashville. Overall, 18% of cases had received at least 1 dose of RV5. Vaccine coverage (with at least 1 dose of vaccine) increased over the study period from 11% in 2007 to 22% in 2009.
The genotype distribution of the cases according to study year is shown in Appendix 1. Of the 57 rotavirus cases from 2007, 35% were PG1, 32% were PG12 (all from Rochester15), and 14% were PG2. In 2008, Rochester had no rotavirus cases, and the 18 cases from the other 2 sites were all PG1. In 2009, 45% were PG3, 25% were PG9, and 15% were PG2. Overall, 99% of isolates shared genotypes that are included in the RV5 vaccine (G1–G4 and P), and 68% were G1–G4.
Rotavirus-Negative AGE Controls
Of 613 rotavirus-negative AGE control children, 329 were matched to 159 cases (Fig 1A). Of these 159 cases, 50% had 1 control, 21% had 2 controls, and 28% had ≥3 controls. Demographic factors, study site, and clinical setting did not differ significantly between rotavirus-positive cases and rotavirus-negative AGE controls, but vaccine coverage was significantly different (P < .0001) (Table 1). Overall, 54% of AGE controls received at least 1 documented dose of RV5, and coverage increased from 28% in 2007 to 62% in 2008 and 2009.
Over the 3 seasons, 4264 children were eligible and 2867 (67%) were enrolled in ARI surveillance (Fig 1B). Reasons for nonenrollment included refusal (11.8%), non–English-speaking parent (4.2%), parents not available (3.8%), and other reasons (3.3%).
Of 2014 available ARI controls, 675 could be matched to 183 cases. Of these 183 cases, 21% had 1 control, 8% had 2 controls, and 70% had 3 or more controls (Fig 1B). Cases and ARI controls were significantly different with regard to age (P = .0004), insurance status (P < .0001), visit setting (P = .01), study site (P = .01), and vaccine coverage (P < .0001) (Table 1). Overall, 54% of ARI controls had at least 1 documented dose of RV5 and vaccine coverage increased over the study period; 30% in 2007, 52% in 2008, and 65% in 2009.
VE estimates for any genotype are provided for each control group, according to number of vaccine doses, site (hospitalization or ED visit), and year of life in Tables 2 and 3, and according to individual and combined genotypes of rotavirus in Table 4.
Overall VE According to Clinical Settings
Study results that indicate overall VE according to clinical settings are shown in Table 2. Using the rotavirus-negative AGE controls, VE against any genotype causing hospitalization or ED visits for 1, 2, and 3 doses of vaccine was 74% (CI: 37%–90%), 88% (CI: 66%–96%) and 87% (CI: 71%–94%), respectively. Using ARI controls, VE estimates were similar for 1, 2, and 3 doses, 73% (CI: 43%–88%), 88% (CI: 68%–95%), and 85% (CI: 72%–91%), respectively.
The VE against rotavirus hospitalizations alone using AGE controls was 89% (CI: 16%–99%), 89% (CI: −93% to 99%) and 95% (CI: 48%–99%) for 1, 2, and 3 doses, respectively. Using ARI controls, the sample size was insufficient to determine VE for 2 doses, but the VE was 94% (CI: 55%–99%) for 1 dose and 82% (CI: 50%–93%) for 3 doses. VE against ED visits alone using AGE controls was 75% (CI: −64% to 96%), 82% (CI: 31%–95%), and 74% (CI: 16%–92%) for 1, 2, and 3 doses, respectively. Using ARI controls, the VE against ED visits for 1, 2, and 3 doses of vaccine was 45% (CI: −80% to 83%), 81% (CI: 45%–93%) and 88% (CI: 64%–96%), respectively.
VE According to Age
Using the AGE control group, VE for 3 vaccine doses during the first year of life was 86% (CI: 31%–97%), and during the second year of life the VE was 90% (CI: 65%–97%) (Table 3). Similarly, the 3-dose VE using the ARI controls during the first year of life was 84% (CI: 41%–96%) and during the second year of life the VE was 87% (CI: 68%–95%).
The genotype-specific VE for any vaccine dose using both control groups was estimated (Table 4). The VE was highest for G1 with a VE using AGE controls for any dose of 96% (CI: 79%–99%) and using ARI controls of 88% (CI: 60%–97%). The VE was >80% for all other genotype-specific analyses, except for the G2-specific analyses. For the G2 analysis the VE for any dose was 72% (CI: −7% to 92%) using rotavirus-negative AGE controls and 77% (CI: 22%–93%) using ARI controls. Appendix 2 provides detailed genotype-specific VE estimates for 1, 2, and 3 doses of RV5 vs 0 doses when sample size permitted.
Description of Vaccine Failures
Among the 34 children who were rotavirus positive and had received any rotavirus vaccine, 17 had received 3 doses, 7 had received 2 doses, and 10 had received 1 dose. All but 1 of these children had received vaccine doses within the ages and intervals recommended by the US Advisory Committee for Immunization Practices,23 and that child received the first dose of vaccine earlier than the recommended age. For the 17 cases who received 3 doses of vaccine, the median onset of disease was18.1 months (range: 8.1–31.9 months); 7 were inpatients and 10 were seen in the ED. The ranges of the intervals between the first and second and second and third doses were 1.6 to 2.5 and 1.5 to 2.9 months, respectively. The median time from the third dose until the disease-onset date was 11.8 months (range: 1.7–25.8 months). The rotavirus genotypes recovered from cases with vaccine failure were all types included in the RV5 vaccine: PG3 (n = 13), PG9 (n = 9), PG1 (n = 5), PG12 (n = 3), PG2 (n = 1), and PG2 (n = 3).
Our postlicensure estimates of RV5 effectiveness in preventing severe rotavirus gastroenteritis requiring hospitalization and ED visits were comparable to efficacy figures from the large prelicensure clinical trial.9 In the prelicensure study, efficacy against G1–G4 rotavirus hospitalizations and ED visits of 3 doses of RV5 was 94.5% (95% CI: 91.2%–96.6%), whereas we estimated effectiveness to be 91% (95% CI: 73%–97%) using AGE controls and 86% (95% CI: 70%–94%) using ARI controls. Furthermore, we found good protection from less than a full 3-dose series of RV5, with levels of 85% and 81% for 1 dose and 79% and 88% for 2 doses of vaccine, depending on the control group used. Because some children may not receive all 3 recommended vaccine doses, it is reassuring that partial vaccination was effective; however, whether the effectiveness is long-lasting could not be determined in our study.
Our results support those found in 2 other postlicensure VE studies.23,–,25 One study, conducted at a large, urban pediatric ED in Houston over 2 seasons and also using 2 control groups23,24 found an overall 3-dose VE of 83% and 86%, which was similar to our overall 3-dose VE of 74% and 88% in our ED analysis. In our study we were also able to examine effectiveness over 3 study years and to provide estimates of hospitalization and ED visits combined as well as for hospitalization and ED visits separately. Our use of 2 different control groups limited biases for different health care utilization or vaccination patterns among children belonging to different primary care practices across the study sites. Our study was also able to determine genotype-specific VE estimates for most genotypes. In another study examining the impact of 3 doses of RV5 against rotavirus-associated hospitalizations, Wang et al reported 100% VE.25 This study used a large health insurance claim database and identified cases through rotavirus-specific ICD-9-CM coding, and included only children who had received both 3 doses of rotavirus and 3 doses of diphtheria-tetanus-acellular pertussis vaccines. Thus, these differences may have accounted for the higher efficacy seen in their study compared with ours.
Some limitations in our study should be considered. It is possible that some rotavirus cases were misclassified as AGE controls, either because fecal specimen amounts or timing differed or because the enzyme immunoassay, reported to be >95% sensitive, may have failed to detect rotavirus. However, only bulk specimens were collected, and 99% of cases and 96% of controls had stools collected in the first 7 days. Furthermore, we obtained similar effectiveness estimates with the 2 control groups, which suggests that this did not substantially affect our findings. Another limitation was that although significant estimates of RV5 effectiveness were obtained for most analyses, our CIs for effectiveness were wide for some of the subanalyses because of the smaller sample sizes. Another possible limitation was the exclusion of some non–English-speaking subjects; however, this occurred for both cases and controls and therefore should not have introduced bias in our study. Although there was a potential for bias with the exclusion of AGE and ARI subjects for protocol deviations at the Cincinnati site, those who were excluded did not differ significantly from those included with respect to age, race, gender or having insurance (data not shown). Finally, studies of VE always have the potential bias that the propensity to seek medical care differs between cases and controls. In our study this bias could have been introduced if rotavirus immunization was related to the propensity to seek medical care (for example, if cases were collected in the hospital or ED but controls were from a community or office cohort). However, because we included children receiving medical care at the same health care setting as cases and as controls, this bias is unlikely.
RV5 was found to be highly protective in routine use and even partial immunization was effective. Additional monitoring is needed to assess genotype-specific effectiveness, duration of protection from vaccination, and the effectiveness of the newly licensed RV1 vaccine introduced into the US immunization schedule in 200826,27 (Appendixes 1 and 2).
- Accepted April 22, 2011.
- Address correspondence to Mary Allen Staat, MD, MPH, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229. E-mail:
The views in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
FINANCIAL DISCLOSURE: Dr Staat received past research funding from Merck Research Laboratories, Inc, and current funding from GlaxoSmithKline, Inc; and served on the Rotavirus Advisory Board for Merck and Company and GlaxoSmithKline, Inc; Ms Donauer received research funding from GlaxoSmithKline, Inc; Dr Weinberg served on the advisory board for MedImmune and the vaccine speaker's bureaus for Merck, GlaxoSmithKline, and Sanofi Pasteur; and Dr Edwards received research funding from Novartis and Wyeth. The other authors have indicated they have no financial relationships relevant to this article to disclose.
- AGE —
- acute gastroenteritis
- ED —
- emergency department
- CDC —
- Centers for Disease Control and Prevention
- NVSN —
- New Vaccine Surveillance Network
- ARI —
- acute respiratory infection
- VE —
- vaccine effectiveness
- CI —
- confidence interval
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- Copyright © 2011 by the American Academy of Pediatrics