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Evidence of Herd Immunity and Sustained Impact of Rotavirus Vaccination on the Reduction of Rotavirus-Related Medical Encounters Among Infants from 2006 through 2011 in the United States

Mast, T. Christopher MSc, PhD*; Wang, Florence T. ScD; Su, Sue MS; Seeger, John D. PharmD, DrPH†‡

Author Information
The Pediatric Infectious Disease Journal: June 2015 - Volume 34 - Issue 6 - p 615-620
doi: 10.1097/INF.0000000000000702

Abstract

Rotavirus (RV) is the leading cause of severe acute gastroenteritis (AGE) in infants and young children. Globally, an estimated 453,000 deaths were caused by RV in 2008.1 Although the risk of death is greater in developing nations, the risk of RV infection is similar across all economic levels and geographic regions.2

RV causes substantial morbidity in the US2 and places a significant burden on the health care system.3 RV gastroenteritis (RGE) is responsible for more than 55,000–117,000 hospitalizations, 205,000–272,000 emergency department (ED) visits, more than 400,000 physician office visits and 20–60 deaths annually. In the US, the annual economic burden from RV in the prevaccine era was more than $1 billion in direct and indirect costs.4

Vaccination has long been recognized as the only way to prevent RV morbidity and mortality. On February 3, 2006, the US Food and Drug Administration approved a pentavalent human-bovine (WC3 strain) reassortant RV vaccine (RVV) [pentavalent RV vaccine (RV5); RotaTeq, Merck & Co., Inc., Whitehouse Station, NJ]. RV5 contains 5 bovine-human reassortant rotaviruses with G1, G2, G3, G4 and P[8] human surface antigens and is administered as a 3-dose series at ages 2, 4 and 6 months. In April 2008, the Food and Drug Administration approved a monovalent RVV (RV1; Rotarix, GlaxoSmithKline, Research Triangle Park, NC). RV1 contains a single attenuated strain of G1P[8], the most prevalent serotype globally, and is administered as a 2-dose series at ages 2 and 4 months. The safety and efficacy of RVV have been demonstrated in clinical trials5–7 as well as in postlicensure studies.8–15

In the US, routine RV vaccination has been recommended by the Advisory Committee on Immunization Practices (ACIP), American Academy of Pediatrics and American Academy of Family Physicians. RV5 was recommended for routine infant immunization by the ACIP in August 2006. RV1 was recommended for routine infant immunization by the ACIP in April 2008.

In 2009, the first year for which national RVV coverage data are available in the US, RVV coverage among children aged 19–35 months was 44%. Since then, RVV coverage has increased to 59% in 201016 and to nearly 70% in 2012.17 Because RVV administered within the first year of life, these data reflect infant vaccine coverage approximately 2 years before the survey date; nevertheless, the data show the rapid uptake of RVV in the US. Extensive evidence from multiple studies has demonstrated the substantial impact of RV5 on RV disease burden in the 2007–2008 RV season in the US, the first season for which RV5 was expected to demonstrate an impact on public health, as well as sustained reductions in RGE or AGE requiring an ED visit or inpatient admission since RVV.8,9,12,18–22

The objective of the analysis was to confirm a sustained reduction in the incidence of RGE and AGE following the introduction of RVV. To that end, we analyzed RV-related medical insurance claims to compare the incidence of RGE and AGE between an RV-vaccinated cohort and a non─RV-vaccinated cohort and to compare the incidence of RGE and AGE among infants in the pre-RVV and post-RVV era.

METHODS

Data Source

Data were derived from the Optum Research Database (ORD), which includes data from electronically captured provider, facility and pharmacy claims of a large health insurer in the US. The ORD has been used by the authors for previous research on RVV safety and effectiveness.8,13 The data are geographically diverse and represent a national sample of the US privately insured population. Over the period of the study, the ORD included data for approximately 3–4% of US annual birth cohorts. There was no active enrollment or active follow-up of children from the database, and no data were directly collected from parents or infants. The study was approved by the Privacy Board of the New England Institutional Review Board.

Study Population

All infants born from January 1, 2002 through July 31, 2011, who were enrolled in the health plan within 1 month of birth, were eligible for study inclusion. Each infant was followed from the receipt of a first administration of RVV or diphtheria, tetanus, and acellular pertussis (DTaP) vaccine through the earlier of either insurance plan disenrollment, 1 year of age or end of the study (July 31, 2011). The study included data from all available states, including infants from states with universal RV vaccination programs. Although these programs pay for the cost of the vaccine, providers still bill the insurers for the vaccine administration fee. Thus, such administrations are captured by the data system through the presence of procedure codes.

Identification of RVV and DTaP Vaccinations

All infants included in the study had received either a RVV or DTaP vaccine. Vaccination status was determined by Current Procedural Terminology (CPT) codes or National Drug Codes (NDC) on health insurance claims for RV1 (CPT 90681; NDC 58160-0805-01, 58160-0805-11 and 58160-0854-52); RV5 (CPT 90680; NDC 00006-4047-20, 00006-4047-31 or 00006-4047-41) or DTaP (CPT 90698, 90700, 90721 or 90723). Infants receiving both an RVV and DTaP were included in the RVV cohort, but those vaccinated with DTaP (and not RVV) were included in the DTaP cohort.

DTaP recipients were selected as comparators because the recommended ages for receiving the DTaP vaccination series (ages 2, 4 and 6 months) correspond to the recommended ages for receiving either RV vaccination series. An infant was considered RV-vaccinated upon receipt of first RVV dose. Infants who received a DTaP vaccine without a concomitant RVV were considered DTaP-vaccinated until receipt of an RVV, after which these infants were considered RVV-vaccinated and censored from the DTaP cohort.

Identification of Outcomes

For each vaccine type (RVV or DTaP), the dates of the first vaccine-associated claims determined the vaccination status of each infant. Among all vaccinated infants, identification of RGE or AGE was restricted to the period following vaccination. Gastroenteritis events were identified using well-described method for RV surveillance31 by utilizing International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) codes associated with a hospitalization, ED visit or outpatient visit: RGE [008.61] and AGE [001–005 excluding 003.2, 006–007 excluding 006.2–006.6, 008.0–008.8 (including RGE), 009.0–009.3 and 558.9]. The claims-based date of service served as a proxy for the diagnosis date.

Statistical Analysis

We summarized baseline demographic data for the infants in the study. To describe potential differential resource utilization between the 2 cohorts, the prevalence of healthcare claims for otitis media and dermatitis, proxies for infantile healthcare utilization unrelated to RV, identified from birth through the receipt of the corresponding vaccine dose among the RVV cohort was compared with that of the DTaP cohort.

Temporal trends in RV vaccination coverage were assessed by calculating the percentage of infants vaccinated with an RVV by calendar month. Longitudinal, seasonal RV patterns in the period before (July 1, 2002–February 2, 2006) and after (February 3, 2006–July 31, 2011) RVV availability were determined by plotting the count and monthly incidence (per 100,000 infants) of all RGE claims for the referent DTaP-vaccine cohort (n = 131,529) and for the RVV cohort (n = 140,952), overall and stratified by age (<2 months, 2–7 months and >7 months). All analyses were conducted using SAS version 9.2 (SAS Institute Inc., Cary, NC).

RESULTS

Demographic and baseline characteristics for infants born from January 1, 2002 through July 31, 2011 are summarized in Table 1. Of the vaccinated infants in the study population who were enrolled in the health plan in the first year of life, 140,952 were in the RVV cohort, and 131,529 were in the DTaP cohort. The geographic distribution of the RVV cohort and the DTaP cohorts was similar, with approximately 50% of the infants residing in the south of the US. On average, the infants were included in the study cohorts at age 2 months, corresponding with the age of first RVV or DTaP administration. The median enrollment time was 8 months in both cohorts, and approximately one-quarter of infants in both cohorts were followed up to age 10–12 months. As would be expected, the size of the RV5 cohort (relative to the DTaP cohort) increased over time, corresponding to the uptake of RVV. The rates of otitis media and atopic dermatitis were similar between RVV and DTaP cohorts (≤3% in either cohort), although the period of assessment was somewhat short.

TABLE 1
TABLE 1:
Baseline Characteristics of Infants Born January 1, 2002–July 31, 2011, Optum Research Database

More than 91% of RVV administered were RV5. By July 2007, the RV5 vaccination coverage rate among enrolled infants aged 2–7 months who were eligible to receive RVV was approximately 35%; by July 2008, the RV vaccination coverage rate was 45% and 53% by July 2009.

The impact of RV vaccination in reducing RGE-related medical claims is evident based on the pattern of claims for RV-vaccinated infants compared with DTaP-vaccinated infants (Fig. 1). In the pre-RVV period of 2002–2006, the rate of RGE was observed only among the DTaP-vaccinated infants. Note that the lower RGE rate in 2002 compared with that of subsequent years (Fig. 1A) reflects the younger age distribution of the study population in that year; as the study began accruing newborns in 2002, the majority of infants at risk in 2002 were under age 7 months (Fig. 1B). Following the introduction of the RV5 vaccine in 2006, the incidence of RGE-related claims in infants <1 year of age was dramatically lower for RV-vaccinated infants compared with non–RV-vaccinated infants (RVV cohort vs. DTaP cohort, Fig. 1A). The mean seasonal peak incidence of RV medical encounters in the cohort of RV-vaccinated-infants in the 2007–2011 period was 96% lower than incidence among the cohort of DTaP-vaccinated infants in the pre-RVV period 2002–2006 (6 vs. 151 per 100,000 infants) and 95% lower than incidence among the concurrent cohort of non–RV-vaccinated DTaP recipients (6 vs. 110 per 100,000 infants).

FIGURE 1
FIGURE 1:
RGE incidence (per 100,000) of rotavirus gastroenteritis (RGE), by month, for infants born January 1, 2002, through July 31, 2011 before and after RVV introduction in a large insured US population. Incidence (per 100,000) of RGE by month for infants born from January 1, 2002 through July 31, 2011. (A) Incidence of RGE for all infants in the RVV and DTaP-vaccine cohorts <1 year of age. Incidence of RGE for infants in the RV-vaccine and DTaP-vaccine cohorts (B) 2–7 months of age and (C) >7 months of age.

Similar patterns of reduced RGE incidence following the introduction of the RV5 vaccine were also apparent when the analysis is stratified by age (Fig. 1B and C). The highest monthly incidence of RV medical encounters in the 2007–2011 period was among non–RV-vaccinated infants aged >7 months in 2011 (298 per 100,000) (Fig. 1C).

The mean seasonal peak incidence of RGE claims among the non–RV-vaccinated infants (ie, the DTaP-vaccinated cohort) dropped in all age groups beginning with the 2007–2008 RV season (Fig. 2) but rose again in the 2011 season among the children aged >7 months. During the 2007—2011 period, the incidence of AGE-related medical claims among the non–RV-vaccinated cohort dropped substantially compared with previous RV seasons and was similar to the incidence of AGE among the RV vaccinated cohort (Fig. 3). The timing of this substantial drop in AGE-related claims coincides with the timing of an RVV coverage rate of 35% for eligible infants 2–7 months of age in 2007.

FIGURE 2
FIGURE 2:
RGE incidence in DTaP-vaccinated (non–RV-vaccinated) infants <1 year old in a large insured US population, overall and age-specific rates. Incidence (per 100,000) of RGE by month for infants born from January 1, 2002 through July 31, 2011 in the ORD.
FIGURE 3
FIGURE 3:
AGE incidence (per 100,000) by month in DTaP-vaccinated (non–RV-vaccinated) infants <1 year old before and after RVV introduction in a large insured US population and AGE incidence for all infants in the RV-vaccine cohort <1 year of age. Infants in the DTaP-vaccine cohort were those born from January 1, 2002 to July 31, 2011 and enrolled within first year of life in the ORD and who had not been vaccinated against RV.

DISCUSSION

Our health insurance database analysis provides evidence of a substantial and sustained reduction in seasonal RV activity following the introduction of RVV in the US. The mean seasonal peak incidence of RV medical encounters for RV-vaccinated infants in the 2007–2011 period was 95% lower than the peak incidence for non–RV-vaccinated infants in the same time period and 96% lower than the peak incidence for non–RV-vaccinated infants in the pre-RVV period (2002–2006). Our analysis also reveals evidence of indirect protection against RV following the introduction of RVV.

The annual pattern of RV-related health care utilization reported in this study is generally similar to that reported in other national studies.10,23 The mean peak incidence of RGE-related and AGE-related combined hospital, ED and outpatient encounters in our database population for the 2009–2010 season was substantially reduced compared with all RV seasons from 2002–2003 through 2008–2009. The highest incidence of RV-related medical encounters in our database population during the 2007–2011 period (peaking in 2011) was among non–RV-vaccinated infants >7 months of age. Previous studies have demonstrated the postlicensure effectiveness and impact of RV vaccination by comparing the incidence of RV-coded and all-cause AGE incidence rates among RV-vaccinated versus RV-unvaccinated (but eligible) cohorts in national datasets.8,10 Additionally, studies also show an overall decline in RV medical encounters in the postvaccine era; however, these depictions do not usually account for vaccination status of the underlying populations.10,24 This study among infants was able to provide gastroenteritis incidence by RVV vaccination status and demonstrates that, in the cohort of children in this study, most of the RGE and AGE events can be attributed to infants who were not RV-vaccinated (see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C92).

Following RVV introduction, the incidence of AGE in the non–RV-vaccinated infants was substantially lower than the incidence of AGE in the pre-RVV era. Both the similar pattern of AGE incidence in the RV-vaccinated and non–RV-vaccinated infants in our database and the substantial reduction in AGE incidence among non–RV-vaccinated infants compared with the pre-RVV era suggest the indirect benefits that a national RV vaccination program may have on unvaccinated infants (eg, herd protection). Cortese et al19 reported that the reduction in the number of gastroenteritis-associated visits among children <5 years of age in hospital and office settings during the 2007–2008 RV season exceeded the reduction that could be explained by direct protection via RV vaccination alone. Since then, the effects of indirect protection from pediatric RV vaccination have been reported for older children and adults.25,26 More recently, a study of US claims data found evidence that the US infant RV vaccination program provided additional, indirect protection against moderate-to-severe RGE in some household members of vaccinated children.34

Similar trends of sustained RV reduction following the introduction of RVV have been reported based on National Respiratory and Enteric Virus Surveillance System data. The 2007–2008 and 2008–2009 RV seasons were shorter, later and characterized by substantially fewer positive RV test results compared with median data for 2000–2006.27 The threshold for the start of the 2009–2010 RV season was not met in most regions of the United States.27 Compared with the pre-RVV era, the duration of the 2010–2011 RV season was 8 weeks shorter, and the threshold for the start of the 2011–2012 RV season was never met nationally.28

Our data provide more evidence to support other observations of an indirect effect of RVV programs. However, as expected, there continue to be small peaks of RGE incidence among the unvaccinated children. From a public health perspective, it may be helpful to understand whether there are identifiable at-risk populations that may benefit from specific interventions to improve RVV coverage. As RVV coverage rates continue to increase, active vaccination against RV as well as indirect benefits (in unvaccinated children and adults) may further reduce the burden of RV disease on the United States health care system. Significant reductions in AGE-associated and RGE-associated health care costs have been reported following the introduction of RVV.8,10 Kilgore et al29 reported an annual reduction of $187 million in total medical costs associated with RGE-related hospitalizations and ED visits following implementation of routine RV vaccination. Of note, economic benefits of RV vaccination also arise from the herd immunity effect—reduced health care usage among unvaccinated older children and young adults (5–24 years of age) may account for up to 15% of averted hospitalizations and 20% of averted direct medical costs that have been attributed to the RV vaccination program in the United States.30

The use of medical claims data for health care research is associated with certain limitations. Laboratory confirmation of RGE diagnosis was not available for this study, although it has been reported that 98% of patients with a RGE diagnosis code were RV-positive.31 Furthermore, testing practices among clinicians for RV-vaccinated versus unvaccinated infants are not known. Diagnosis codes used for capturing AGE included diarrhea of both determined and undetermined causes; however, it has been estimated that in children <5 years, 56–70% of AGE cases during winter months (January through May) are attributable to RV.32 In addition, because RV is not routinely tested for in clinical practice, absolute rates of RGE using ICD-9 codes are likely to underestimate the actual rates of RGE33; however, rates of RGE identified using ICD-9 codes are likely to accurately reflect rate trends over time. Nevertheless, the use of a large national insurance database provides a large sample size for evaluation of the impact of RV vaccination, and thus the rates of overall gastroenteritis (Fig. 3) tend to show a more robust pattern of the impact of RVV because much of the annual AGE diagnosis are attributable to RV.

In summary, although our study has a number of limitations, our data are consistent with other studies that have assessed the indirect effects of RVV. Our analysis of a national medical claims database indicates a sustained and substantial decrease in the typical seasonal RV medical claims pattern following the introduction of RVV in the US in 2006. The reduction in RV-related medical claims among a non–RV-vaccinated cohort of infants compared with the pre-RVV era suggests that the RV vaccination program in the US conferred a herd protective effect. However, continued small peaks in seasonal RV medical claims may be attributable to children who have not been vaccinated against RV disease. Overall, the results of this study demonstrate that RV vaccination has been associated with a marked reduction in RGE health care encounters via both the direct impact of vaccination and the indirect herd protection.

ACKNOWLEDGMENTS

The authors acknowledge Dana L. Randall, MS, PharmD, of Arbor Communications, Inc., Ann Arbor, MI, for manuscript preparation and editorial assistance on behalf of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ.

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Keywords:

acute gastroenteritis; herd immunity; rotavirus; rotavirus gastroenteritis; rotavirus vaccine

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