Rotavirus (RV) is the leading cause of severe acute gastroenteritis (AGE) among young children worldwide, accounting for approximately 23 million outpatient visits, 2.3 million hospitalizations and almost half a million deaths annually among children <5 years of age.1–3 Before 2007, RV infection accounted for an estimated 25–43% of all AGE hospitalizations among children <5 years of age in Taiwan, with many RV hospitalizations occurring by the age of 3 years.4–6 To help mitigate this significant disease burden, in August 2006, the Department of Health in Taiwan licensed 2 orally administered, live, attenuated RV vaccines—Rotarix (GSK Biologicals, Rixensart, Belgium) and RotaTeq (Merck & Co., Inc., PA). Rotarix is a monovalent vaccine given to infants in Taiwan in 2 doses at ages 2 and 4 months; RotaTeq is a pentavalent vaccine given to infants in Taiwan in 3 doses at ages 2, 4 and 6 months. Prelicensure clinical trials of both vaccines conducted in various middle- and high-income countries, including Taiwan, demonstrated vaccine efficacy of 85–98% against severe RV AGE.7–9 However, both vaccines are available only on the private market and have not yet been recommended for routine use in Taiwanese infants.
Because the performance of vaccines in real world settings may differ from that in clinical trial settings, post-licensure evaluation of vaccine performance is crucial for monitoring and sustaining vaccination programs. Vaccine effectiveness (VE) studies from Latin America, the United States and Europe have demonstrated effectiveness of Rotarix and RotaTeq comparable with that seen in the prelicensure clinical trials.10–14 However, no studies have been published regarding VE in Asian countries that are currently using these vaccines in the private sector. Data from such studies could help these countries weigh the benefits of RV vaccine introduction into national immunization programs. In addition, the simultaneous introduction of Rotarix and RotaTeq in Taiwan provides a unique opportunity to assess the field performance of both RV vaccines in the same population. Our objective was to examine VE of both Rotarix and RotaTeq against severe RV AGE resulting in hospitalization among children in Taiwan.
Hospital-based Surveillance System
In 2004, the Taiwan Centers for Disease Control (CDC) established a sentinel surveillance system for RV AGE at 3 hospitals located in the northern, middle and southern regions of Taiwan: the Chang Gung Memorial Hospital, Linkou Branch, the Changhua Christian Hospital and the Chang Gung Memorial Hospital, Kaohsiung Branch, respectively. At each hospital, active surveillance for AGE (defined as ≥3 episodes of vomiting and/or loose stools and/or bloody/mucoid stools in a 24-hour period and with onset <14 days before hospitalization) among children <5 years of age is conducted year-round. Bulk stool specimens of cases are collected within 48 hours of admission and are tested by each hospital-based laboratory for RV by an enzyme immunosorbant assay (EIA; RIDASCREEN Rotavirus, RBiopharm AG, Germany). All specimens (both positive and negative specimens) are then sent to the Viral Enteric and Emerging Diseases Laboratory at the Taiwan CDC for confirmatory testing and further strain characterization of EIA-positive specimens by real-time reverse-transcription polymerase chain reaction (RT-PCR) and nucleotide sequencing.6,15
Matched Case-control Study
From May 2009 through April 2011, a case-control assessment of Rotarix and RotaTeq VE against severe RV gastroenteritis resulting in hospitalization was conducted at all 3 sentinel surveillance sites in collaboration with the Taiwan CDC and the Taiwan National Health Research Institutes (NHRI). This study was approved by the Institutional Review Board at all surveillance sites and by the Taiwan CDC and Taiwan NHRI. Informed consent was obtained from parents or guardians of all participants before enrollment. Case-patients were defined as children aged 8–35 months hospitalized with laboratory-confirmed RV AGE. Children 8 months of age and older were selected for enrollment to ensure that all children had reached the maximum age limit for RV vaccine administration to limit confounding by age. Case-patients were matched with 2 groups of controls. One group included children who were born within 1 month of the case-patient’s date of birth and hospitalized with RV-negative AGE. A second group included children who were born within 1 month of the case-patient’s date of birth and seen for medical care for illnesses unrelated to diarrhea in either the outpatient or inpatient setting at the same sentinel hospitals. Age matching within 1 month of the date of birth was performed to control for changing vaccine coverage over time. Information on demographics, socioeconomic indicators (ie, maternal education, number of family members in the household, family income), birth history, duration of breastfeeding, history of breastfeeding within the week before hospitalization and clinical symptoms were obtained through interview of a parent or guardian. RV vaccination history and vaccine type were confirmed through vaccination card or hospital record review. Given our sample size of children enrolled through sentinel surveillance for RV AGE and assuming an estimated vaccine coverage of 50%, this study was powered adequately to detect a VE of ≥60%.
Case-patients and controls were considered vaccinated if the vaccination date was ≥14 days before the case-patient’s date of hospital admission. Differences in characteristics between case-patients and controls were separately assessed using t-tests for ages, Wilcoxon rank-sum tests for the number of family members and duration of breastfeeding and χ2 tests for categorical variables.
Exact conditional logistic regression was used to estimate an odds ratio of vaccination in case-patients compared with their matched controls. This method was used because no cases had received a full 3-dose series of RotaTeq, which would result in a zero-cell situation leading to estimates with wide confidence intervals (CIs). Thus, exact conditional inference was applied for the unstable model, regardless of other confounders; only 1 predictor of RV vaccine type at 5 levels (1-dose Rotarix, 2-dose Rotarix, 1- or 2-dose RotaTeq, 3-dose RotaTeq and unvaccinated) was used in the final model.
VE of RV vaccine against laboratory-confirmed RV AGE resulting in hospitalization was calculated as (1 − odds ratio of vaccination) × 100%. Statistical significance was designated as a 2-tailed P-value of <0.05. Sensitivity analyses were performed to determine the impact of excluded controls without vaccination history on VE estimates. The 127 controls missing vaccination history were included in 3 models under the following assumptions: (1) all were unvaccinated; (2) all were fully vaccinated with Rotarix; and (3) all were fully vaccinated with RotaTeq. All analyses were performed using SAS statistical software (version 9·1, SAS Institute, Cary, NC).
Over the 2-year surveillance period, 1280 children 8–35 months of age hospitalized with AGE were enrolled at the 3 surveillance sentinel sites (Fig. 1); 184 (14%) tested positive for RV by EIA and were enrolled as cases. The remaining 1096 RV-negative AGE patients were enrolled as controls. Additionally, 1183 non-AGE patients were enrolled as another group of controls. The 184 case-patients were then matched with 943 RV-negative AGE controls at a ratio of up to 6 controls for each case and 997 non-AGE controls at a ratio of up to 6 controls for each case. One hundred twenty-seven controls with missing vaccination information were excluded (vaccination information was available for all case-patients). Thus, 184 case-patients, 904 RV-negative AGE controls and 909 non-AGE controls were included in the final analysis.
Case-patients significantly differed from RV-negative controls and from non-AGE controls by age, likely due to the variable number of controls per case (Table 1). The average age for case-patients was 20.5 months compared with 18.2 and 19 months for the RV-negative and non-AGE controls, respectively. Case-patients also significantly differed from both types of controls by season of enrollment; 39.1% of case-patients were enrolled during the winter season (ie, December through February), while 20.4% and 19.4% of RV-negative and non-AGE controls were enrolled, respectively. Additionally, 47.5% of mothers of case-patients had a college degree or higher compared with 63% of mothers of non-AGE controls.
RT-PCR and nucleotide sequencing of RV strains from positive stool specimens demonstrated a predominance of G1P RV in 127/184 (69%) of specimens (Fig. 2); G2P RV accounted for 23/184 (12.5%). Three of 184 (1.6%) specimens were confirmed to be EIA positive, but were untypeable by RT-PCR and nucleotide sequencing.
A 2-dose series of Rotarix had been given to 1.6% of case-patients versus 14.9% and 18.9% of RV-negative and non-AGE controls who had not received RotaTeq, respectively (P < 0.0001; Table 1). Estimated VE of a full 2-dose Rotarix series against RV gastroenteritis resulting in hospitalization was 90.4% (95% CI: 70.3%, 98.1%) and 92.5% (95% CI: 77.1%, 98.5%) with RV-negative and non-AGE controls, respectively (Table 2). VE was 91.6% (95% CI: 74.6%, 98.3%) when the control groups were combined. VE against G1P RV hospitalization was 94.5% (95% CI: 65.7%, 99.9%), 95% (95% CI: 70.5%, 99.9%) and 94.6% (95% CI: 68.8%, 99.9%) with RV-negative, non-AGE and combined controls, respectively.
A 3-dose series of RotaTeq had been given to 0% of case-patients versus 10.6% and 12% of RV-negative and non-AGE controls, respectively (P < 0.0001; Table 1). Estimated VE of a full 3-dose series against RV gastroenteritis resulting in hospitalization was 96.8% (95% CI: 82.3%, 100%) and 97.1% (95% CI: 84%, 100%) with RV-negative and non-AGE controls, respectively. VE was 97% (95% CI: 83.5%, 100%) when the control groups were combined (Table 2). VE against G1P RV hospitalization was 94.2% (95% CI: 67.6%, 100%), 93.8% (95% CI: 65.3%, 100%) and 94.3% (95% CI: 68.5%, 100%) with RV-negative, non-AGE and combined controls, respectively.
For sensitivity analyses conducted to determine the impact of excluding 127 controls without vaccination history, VE estimates for both vaccines either increased or decreased slightly, while CIs remained within the same range. VE point estimate ranges with RV-negative, non-AGE and combined controls for each model were as follows: (1) 127 controls unvaccinated: 89.8–91.7% for Rotarix and 96.7–96.8% for RotaTeq; (2) 127 controls fully vaccinated with Rotarix: 90.4–92.5% for Rotarix and 97.9–98.5% for RotaTeq; (3) 127 control fully vaccinated with RotaTeq: 92.8–95.3% for Rotarix and 96.9–97.1% for RotaTeq.
To our knowledge, this is one of a very few, head-to-head comparisons of the field effectiveness of both RV vaccines in one country and the only one conducted in an Asian country. Our analysis demonstrates that both RV vaccines provide greater than 90% protection against severe RV gastroenteritis hospitalization among infants in Taiwan. While the point estimates of effectiveness of the full series of Rotarix and RotaTeq differed by about ~8%, the substantial overlap in the CIs precludes any distinction between the 2 vaccines. In addition, the 14% RV detection rate among children 8–35 months of age in this study is much lower than the ~25–40% RV detection rate seen in studies conducted before RV vaccine introduction in Taiwan.4,6 This lower detection rate likely reflects partial coverage with RV vaccines that have >90% effectiveness against severe RV gastroenteritis.
Although the 3 sentinel surveillance hospitals serve families from a range of socioeconomic backgrounds, including those with low to high incomes, our findings are comparable with vaccine efficacy estimates from clinical trials and VE estimates from studies conducted in other high-income countries. In clinical trials conducted in the Europe and Asia, Rotarix vaccine efficacy against severe RV AGE was 90–96%7,16,17; in the United States and Europe, RotaTeq vaccine efficacy was 94–98%.9,17,18 Rotarix VE has been estimated to be 75–97% in Spain,13,19 while RotaTeq VE has been estimated to be 81–95% in Spain and the United States.10,13,19–21 Of note, the only other published VE studies comparing the simultaneous introduction of both Rotarix and RotaTeq were conducted in Spain.13,19
This study has some limitations. First, not all children who presented with RV-negative AGE or for non-AGE visits were included in the final analysis due to lack of vaccination history confirmation, and not all children enrolled as controls were matched to a case-patient by date of birth within 1 month. Any potential difference between these children and those included in the final analysis may have affected our VE estimates. An analysis of potential differences between excluded versus included children in each control group indicate no major differences in demographic characteristics, except that the relative distribution of hospital location differed between excluded and included non-AGE controls. There were no significant differences in age, sex, prematurity, mother’s education, season of enrollment or number of family members between excluded and included controls (data not shown). Also, given the comparable VE estimates among the 2 control groups and the comparable VE estimates seen in the sensitivity analysis including the excluded controls, the exclusion of these children likely was not a major factor. Second, case-patients differed from controls by season of enrollment. The fact that a greater proportion of case-patients were enrolled during the winter season compared with children enrolled as controls is likely a reflection of the seasonality of RV disease in Taiwan. Also, case-patients and RV-negative AGE controls differed from non-AGE controls by maternal educational background. Mothers of non-AGE controls tended to report a college education or higher more frequently than mothers of case-patients and RV-negative AGE controls. The reasons for this are unclear, but could reflect a better understanding of how to manage AGE at home among mothers with higher educational backgrounds. Third, enrollment was limited to 3 surveillance sites in 3 major cities, so results may not be generalizable to the entire country. Finally, G1P RV accounted for many RV-positive cases. Therefore, we were unable to assess VE against additional strains.
This post-licensure study has demonstrated that both currently licensed RV vaccines provide excellent protection against severe RV gastroenteritis hospitalization among Taiwanese infants, similar to that seen in prelicensure clinical trials and postmarketing evaluations in other high- and middle-income countries. Currently in the private sector in Taiwan, a complete 2-dose course of Rotarix costs approximately US$172 and a full 3-dose course of RotaTeq costs approximately US$200, costs too high to allow some parents to vaccinate their children against RV disease, as likely reflected by the RV vaccination coverage of ~24–28% among our study controls. The addition of RV vaccination into Taiwan’s National Immunization Program has the potential to result in greater RV vaccine coverage through publically funded vaccination. This in turn would lead to the prevention of a substantial number of AGE hospitalizations among children <3 years of age.
Our findings provide compelling evidence of the potential benefits of RV vaccination among infants, and they should help inform policymakers in Taiwan and other similar Asian countries when deciding whether to include RV vaccination into their national immunization programs.
We would like to thank Ms. Ching-Yi Wu (National Health Research Institutes, Taiwan) for assistance in performing RV RT-PCR testing; Ms. Shiau-Mei Tsai (Changhua Christian Hospital, Taiwan), the Chang Gung Memorial Hospital Team (Taoyuan, Taiwan) and the Kaohsiung Chang Gung Memorial Hospital Team (Kaohsiung, Taiwan) for collecting the stool samples and confirming the vaccination history and Dr. Jon Gentsch and Dr. Baoming Jiang for their technical advice on RV specimen testing.
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gastroenteritis; rotavirus; rotavirus vaccine; vaccine effectiveness