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A Systematic Review of the Effect of Rotavirus Vaccination on Diarrhea Outcomes Among Children Younger Than 5 Years

Lamberti, Laura M. PhD, MHS; Ashraf, Sania MPH; Walker, Christa L. Fischer PhD, MHS; Black, Robert E. MD, MPH

The Pediatric Infectious Disease Journal: September 2016 - Volume 35 - Issue 9 - p 992–998
doi: 10.1097/INF.0000000000001232
Vaccine Reports
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Background: Rotavirus is the leading cause of vaccine-preventable diarrhea among children under 5 globally. Rotavirus vaccination has been shown to prevent severe rotavirus infections with varying efficacy and effectiveness by region.

Methods: We sought to generate updated region-specific estimates of rotavirus vaccine efficacy and effectiveness. We systematically reviewed published vaccine efficacy and effectiveness studies to assess the region-specific effect of rotavirus vaccination on select diarrheal morbidity and mortality outcomes in children under 5 years of age. We employed meta-analytic methods to generate pooled effect sizes by Millennium Development Goal region.

Results: Rotavirus vaccination was both efficacious and effective in preventing rotavirus diarrhea, severe rotavirus diarrhea and rotavirus hospitalizations among children under 5 across all regions represented by the 48 included studies. Efficacy against severe rotavirus diarrhea ranged from 90.6% [95% confidence interval (CI): 82.3–95.0] in the developed region to 88.4% (95% CI: 67.1–95.9) in Eastern/Southeastern Asia, 79.6% (95% CI: 71.3–85.5) in Latin America and the Caribbean, 50.0% (95% CI: 34.4–61.9) in Southern Asia and 46.1% (95% CI: 29.1–59.1) in sub-Saharan Africa. Region-specific effectiveness followed a similar pattern. There was also evidence of vaccine efficacy against severe diarrhea and diarrheal hospitalizations.

Conclusion: Our findings confirm the protective efficacy and effectiveness of rotavirus vaccination against rotavirus diarrheal outcomes among children under 5 globally.

Supplemental Digital Content is available in the text.

From the Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Accepted for publication April 13, 2016.

This work was funded through the Maternal Child Epidemiology Estimation (MCEE) grant from the Bill & Melinda Gates Foundation.

The authors have no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).

Address for correspondence: Laura M. Lamberti, PhD, MHS, Department of International Health, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205. E-mail: Llamber3@jhu.edu.

Diarrheal disease is a leading cause of childhood morbidity and mortality globally, causing an estimated 0.578 million [95% confidence interval (CI): 0.448–0.750 million] deaths in children under 5 years of age in 2013.1 Rotavirus is the leading cause of vaccine-preventable diarrhea among children under 5 and is associated with approximately 28% of diarrheal deaths.2,Global causes of diarrheal disease mortality in children <5 years of age: a systematic review. PloS One. 2013;8:e72788.','400');" onMouseOut="javascript:ImageWrapperControl_ImageMouseOut();">3 The highest burden of severe disease and deaths due to rotavirus infections occurs in low-income countries, specifically India, Democratic Republic of Congo, Ethiopia, Nigeria and Pakistan.2,4 In countries without rotavirus vaccination, nearly all children become infected with rotavirus during the first few years of life, regardless of hygiene or sanitation facilities or whether they live in high-income or resource-poor settings.5

World Health Organization recommends the inclusion of rotavirus vaccination in all national immunization programs.6 There are 2 licensed oral live attenuated rotavirus vaccines currently available globally: a monovalent human rotavirus vaccine [Rotarix (RV1) GlaxoSmithKline Biologicals, Rixensart, Belgium] and a pentavalent bovine–human reassortant rotavirus vaccine [RotaTeq (RV5), Merck Vaccines, Whitehouse Station, NJ].6 RV1 is administered in 2 oral doses at 6 and 10 weeks of age, and RV5 is administered in 3 oral doses at ages 6, 10 and 14 weeks.6 In addition, the Lanzhou lamb rotavirus vaccine was licensed in 2000 for prevention of group A rotavirus in China and is administered on a 2-dose schedule at ages 2 months to 3 years and 3–5 years.7,8 More recently, a monovalent human–bovine vaccine was developed in India and evaluated for efficacy.9

In 2011, a systematic review of published vaccine efficacy trials and effectiveness studies estimated that rotavirus vaccines reduced severe rotavirus diarrhea by 91% in developed countries, 88% in low-mortality countries in Asia and North Africa, 81% in Latin America and 50% in sub-Saharan Africa.10 A Cochrane review published in 2012 also found that the effect of rotavirus vaccination varied by region, with higher efficacy of both RV1 and RV5 among children <2 years of age in low-mortality compared with high-mortality countries.11 Both studies cite various potential explanations for the reduced effect of rotavirus vaccination in high-mortality countries, including the prevalence of malnutrition, increased rates of severe infectious disease and comorbidities and differences in immune response resulting from the passive immunity conferred by breastfeeding.10,11

In this systematic review, we aimed to expand upon the existing evidence base for the efficacy and effectiveness of rotavirus vaccination against morbidity and mortality among children <5 years of age. Given the previously observed variation across regions,10 we sought to generate updated estimates of the global effect sizes by Millennium Development Goal (MDG) region. To achieve this goal, we expanded upon a previous review of publications before 2011 using newly available data from efficacy and effectiveness studies published from 2011 to 2014.

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METHODS

Search Strategy

We aimed to update our previously published systematic review of studies published before 2011,10 which included data from 11 studies assessing the effect of rotavirus vaccination on diarrheal morbidity and mortality among children under 5.12–22 We employed an identical search strategy to systematically screen literature published between January 2011 and October 2014, the period immediately following that of the original search. There was no overlap in the search dates of the 2 reviews. We searched PubMed, EMBASE, the Cochrane central register for controlled trials and the Global Health Library Global Index and Regional Index using combinations of key search terms: rotavirus, rotavirus vaccine, randomized controlled trials, case-control, efficacy, phase III trials, vaccine effectiveness and impact and program evaluation. In an effort to identify relevant studies that had not yet been published, we also reviewed conference abstracts from the 11th International Rotavirus Symposium. All articles from both our previous and current searches were screened for inclusion and exclusion criteria.

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Inclusion and Exclusion Criteria

Two independent reviewers screened titles and subsequently reviewed abstracts for inclusion and exclusion criteria. All randomized controlled trials (RCTs) and observational studies reporting outcomes related to rotavirus diarrhea or diarrhea of unspecified etiology in children <5 years of age were eligible for inclusion. Outcomes of interest included episodes of any severity, severe episodes as indicated by a Vesikari score of ≥11 on a 20-point scale or a Clark score of >16 on a 24-point scale,23,24 hospitalizations and deaths.

We excluded review articles, phase I and II trials, cost-effectiveness studies and editorials. We excluded efficacy trials that failed to report separate effect sizes for the intention-to-treat and per-protocol populations and observational studies only reporting the effectiveness of partial vaccine doses. We did not exclude studies on the basis of age at vaccination. Data from studies that solely focused on specific subpopulations, such as HIV-infected children, in which immune responses are likely to differ from those of the general population, were excluded to ensure the generalizability of the pooled estimates. For analytical purposes, we also excluded studies that did not report the inputs required for meta-analysis (eg, effect size and 95% CI) and did not provide sufficient raw data from which the required inputs could be calculated.

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Data Abstraction

We categorized the included studies by study design and MDG region25; we combined data from Southeastern Asia and Eastern Asia but excluded studies that pooled outcomes across other MDG regions. For each outcome, we abstracted published effect sizes and 95% CIs for vaccine efficacy, vaccine effectiveness and percent reduction of relevant outcomes into standardized abstraction tables. We used Stata 12.0 to compute these figures for studies that did not publish effect estimates but provided adequate raw data to carry out such calculations.26

We recorded estimates of vaccine efficacy and effectiveness from RCTs and observational studies, respectively. Vaccine efficacy was defined as the proportionate reduction in an outcome comparing those randomized to rotavirus vaccination to those receiving placebo.27 In abstracting data for efficacy trials, we used only the per-protocol estimate which assessed the efficacy of vaccination among children receiving all required vaccine/placebo doses. Vaccine effectiveness was defined as the vaccine-attributable reduction in an outcome in an uncontrolled or real-world setting and was assessed by several study designs, including case-control studies and cross-sectional studies using historical controls to compare the presence of an outcome in a population prevaccine and postvaccine implementation.27 For case-control studies reporting stratified analyses of partial and complete doses, we used the estimate of vaccine effectiveness of the full recommended dose. We considered healthy neighborhood children, children with nondiarrheal illness and children with non-Rotavirus diarrhea appropriate control groups but utilized the estimate based on diarrhea-free controls if available. In addition to vaccine effectiveness, we abstracted the percent change in selected outcomes from observational studies utilizing historical controls. We recorded individual and population estimates of vaccine effectiveness from cluster randomized controlled trials (cRCTs), which were categorized separately of other study designs.

For studies reporting both separate and pooled effect sizes over various years and/or age strata, we abstracted the pooled estimate only. For studies reporting only separate effect sizes over various years and/or age strata, we conducted fixed-effects meta-analyses in Stata 12.0 to generate the pooled effect size.26

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Data Analysis

From the abstracted estimates of vaccine efficacy and effectiveness, we calculated relative risk (RR) and odds ratios (OR) and used random effects meta-analysis to generate inverse-variance-weighted pooled estimates across studies. We subsequently converted the pooled effect sizes into vaccine efficacy [100%*(1−RR)] and vaccine effectiveness [100%*(1−OR)]. For observational studies reporting percent reduction, we combined estimates across studies by fitting logistic regression models weighted by inverse variance. All statistical analyses were conducted using Stata 12.0 statistical software.26 We conducted Q-tests to assess heterogeneity across studies.

We assessed the quality of evidence for each pooled outcome using the standards for Child Health Epidemiology Reference Group reviews of child survival interventions.28 Applying these guidelines, we graded the evidence for each effect estimate on a 4-point scale (ie, high, moderate, low, very low) based on an evaluation of the design, limitations, consistency and generalizability of contributing studies. RCTs were automatically granted a score of “high” and downgraded for lack of consistency or major limitations, including failure to blind or conceal allocation. Observational studies were given a score of low and upgraded to moderate if effect sizes were consistent across all studies and regions.

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RESULTS

Systematic Literature Review

We screened 1221 titles and abstracts identified through literature searches (Fig. 1). After removing duplications and searching the resulting titles and abstracts, we reviewed 66 full manuscripts. In addition to the 11 studies included from our previous review,12–22 we identified 37 papers meeting our inclusion/exclusion criteria.9,29–64 Of the 48 studies, there were 22 RCTs reporting vaccine efficacy,9,13–19,30–35,40–44,46,57,62 19 observational studies reporting vaccine effectiveness,12,20,21,36–38,45,47–55,60,rotavirus vaccines in concurrent use among US children <5 years of age, 2009–2011. Clin Infect Dis. 2013;57:13–20.','400');" onMouseOut="javascript:ImageWrapperControl_ImageMouseOut();">61,63 6 observational studies reporting percent reductions22,29,39,56,58,59 and 1 cRCT64 (Fig. 1 and Table 1). By outcome, 44 studies reported rotavirus diarrheal morbidity outcomes, 15 studies reported diarrheal morbidity outcomes and 3 studies reported diarrhea-attributable mortality (Table 1). The majority of included studies were conducted in the MDG developed region (n = 18) and Latin America and the Caribbean (n = 15), followed by sub-Saharan Africa (n = 8), Eastern/Southeastern Asia (n = 5) and Southern Asia (n = 3). Additional data on included studies are provided in the Appendix, Supplemental Digital Content 1, http://links.lww.com/INF/C503.

TABLE 1

TABLE 1

FIGURE 1

FIGURE 1

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The Effect of Rotavirus Vaccination on Rotavirus Diarrhea of Any Severity Among Children Under 5

The efficacy of rotavirus vaccination in preventing rotavirus diarrhea was highest in developed countries (75.9%; 95% CI: 72.4–78.9) followed by sub-Saharan Africa (55.4%; 95% CI: 27.6–72.6) and Southern Asia (34.6%; 95% CI: 21.6–45.3; Table 1; Appendix: Figs. 1, 2, Supplemental Digital Content 1, http://links.lww.com/INF/C503). Rotavirus vaccine effectiveness was 86.8% (95% CI: 60.7–95.6) in developed countries and 29.6% (95% CI: −53.5–67.7) in Latin America and the Caribbean (Table 1; Appendix: Fig. 3, Supplemental Digital Content 1, http://links.lww.com/INF/C503). In one study from the developed region, rotavirus vaccination was attributed with a 61.4% (95% CI: 60.2–62.6) reduction in rotavirus cases (Table 1). A cRCT conducted in Bangladesh reported population effectiveness of 28.4% (95% CI: 11.0–42.4) and total vaccine effectiveness of 39.0% (95% CI: 22.0–52.3) against rotavirus diarrhea of any severity.64

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The Effect of Rotavirus Vaccination on Severe Rotavirus Diarrhea Among Children Under 5

Rotavirus vaccination was most efficacious against severe rotavirus diarrhea in the developed region (90.6%; 95% CI: 82.3–95.0) followed by Eastern/Southeastern Asia (88.4%; 95% CI: 67.1–95.9), Latin America and the Caribbean (79.6%; 95% CI: 71.3–85.5), Southern Asia (50.0%; 95% CI: 34.4–61.9) and sub-Saharan Africa (46.1%; 95% CI: 29.1–59.1; Table 1; Appendix: Figs. 4–8, Supplemental Digital Content 1, http://links.lww.com/INF/C503). In Latin America and the Caribbean, vaccine effectiveness against severe rotavirus was 68.8% (95% CI: 55.8–77.9; Table 1; Appendix: Fig. 9, Supplemental Digital Content 1, http://links.lww.com/INF/C503).

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The Effect of Rotavirus Vaccination on Rotavirus Diarrhea Hospitalizations Among Children Under 5

Vaccine efficacy against rotavirus hospitalizations ranged from 94.3% (95% CI: 72.8–98.8) in the developed region to 57.5% (95% CI: 7.2–80.8) in sub-Saharan Africa, and vaccine effectiveness followed a similar regional pattern (Table 1; Appendix: Figs. 10–14, Supplemental Digital Content 1, http://links.lww.com/INF/C503). In Latin America and the Caribbean, rotavirus vaccination led to a 76.7% (95% CI: 75.6–77.7) decrease in rotavirus hospitalizations.

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The Effect of Rotavirus Vaccination on Diarrhea and Severe Diarrhea Among Children Under 5

In one study conducted in sub-Saharan Africa, the efficacy of rotavirus vaccination was 10.0% (95% CI: −22.3–33.9) against diarrhea. Efficacy against severe diarrhea ranged from 49.6% (95% CI: 39.8–57.8) in the developed region to 15.3% (95% CI: 2.9–26.1) in sub-Saharan Africa (Table 1; Appendix: Figs. 15–16, Supplemental Digital Content 1, http://links.lww.com/INF/C503). In the developed region, vaccine effectiveness was 83.2% (95% CI: 41.7–95.1) against severe diarrhea.

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The Effect of Rotavirus Vaccination on Diarrheal Hospitalizations Among Children Under 5

Rotavirus vaccination was 71.5% (95% CI: 53.4–82.9), 28.9% (95% CI: 16.3–39.6) and 38.5% (95% CI: 29.0–46.7) efficacious against hospitalization for diarrhea in the developed, Eastern/Southeastern Asia and Latin America and Caribbean regions, respectively (Table 1; Appendix: Figs. 17–18, Supplemental Digital Content 1, http://links.lww.com/INF/C503). In the developed region, rotavirus vaccination was 77.7% (95% CI: 40.2–91.7) effective against diarrheal hospitalizations among children under 5 and in Latin America and the Caribbean, rotavirus vaccination resulted in a 41.5% (95% CI: 32.5–50.5) reduction in such hospitalizations (Table 1).

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The Effect of Rotavirus Vaccination on Diarrhea-attributable Mortality Among Children Under 5

In Latin America and the Caribbean, rotavirus vaccination resulted in a 41.2% (95% CI: 39.9–42.4) reduction in the diarrhea mortality rate.

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Quality Assessment

In general, outcome-specific quality was high or moderate for most outcomes (Table 2). Pooled effect estimates were consistent across studies and regions. In terms of directness, included studies assessed interventions generalizable to the intervention of interest but were not representative of all MDG regions because of a dearth of available studies reporting certain outcomes for each region.

TABLE 2

TABLE 2

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DISCUSSION

The results of our systematic review confirm the protective efficacy and effectiveness of rotavirus vaccination against rotavirus and all diarrheal outcomes among children under 5 globally. Rotavirus vaccination was efficacious against severe rotavirus infection in all MDG regions, but efficacy was highest in the developed region followed by East/Southeastern Asia, Latin America and the Caribbean, South Asia and sub-Saharan Africa (Fig. 2), and effectiveness estimates followed a similar regional pattern (Fig. 3). Possible explanations for varying levels of protection include regional differences in gut microbiome, environmental enteropathy, inhibitory maternal antibodies and/or interactions with other viruses in the gut.5 Though the protective effects conferred by rotavirus vaccines are greater in higher income settings, rotavirus vaccination has the potential to avert more severe childhood diarrhea cases and deaths in low-income regions where the incidence of severe rotavirus is highest and adequate diarrhea management is less accessible.6 In Latin America and the Caribbean, the region with the most data from different types of evaluations, the efficacy and effectiveness against severe rotavirus diarrhea were 79.6% and 68.8%, respectively, but there was a 41.2% reduction in the diarrhea-attributable mortality rate, reflecting the predominance of this etiologic agent as a cause of death in the region, which is also true in developed countries. Both the lower etiologic fraction of severe diarrhea for rotavirus in less developed regionsGlobal causes of diarrheal disease mortality in children <5 years of age: a systematic review. PloS One. 2013;8:e72788.','400');" onMouseOut="javascript:ImageWrapperControl_ImageMouseOut();">3 and the lower efficacy of the vaccine in these areas suggest that a smaller percentage of all severe diarrhea and diarrheal deaths would be prevented by routine vaccination.

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

The results of this systematic review are strengthened by consistency across all studies, which contributed to a quality assessment of high or moderate for most outcomes (Table 2). However, there was a dearth of studies reporting the region-specific effectiveness of rotavirus vaccine against severe rotavirus diarrhea and hospitalizations. In addition, the regions of Eastern/Southeastern Asia and Southern Asia were less represented by included studies, and there were only 3 studies reporting an effect on diarrhea-attributable mortality—all of which were conducted in Latin America and the Caribbean where the vaccine is highly efficacious (Tables 1 and 2). Further research assessing the mortality effect of rotavirus vaccination, as well as the overall protective effects in Asia, is thus warranted.

The lack of studies meeting our inclusion criteria also precluded further stratification of our analysis by characteristics of the national immunization program, such as coverage level or vaccine type. All included studies used either RV1 or RV5 with the exception of one Indian study assessing the efficacy of a newly introduced monovalent human-bovine reassortant vaccine (116E) and one Ghanaian study of a rhesus/rhesus-human reassortant tetravalent vaccine (RotaShield, RRV-TV).9,35 As countries increasingly adopt rotavirus vaccine recommendations into their national immunization programs, mounting data should enable future analysis of the relative efficacy and effectiveness of the available vaccine types by region.

As of October 2015, 79 countries have introduced rotavirus vaccines, and this number is expected to grow because of the global recommendation and cofinancing by the World Health Organization for eligible countries through the Gavi Alliance.65 The public health benefits of rotavirus vaccination, which are already being realized in early adopter countries, could have considerable impact in low-income, high-burden countries yet to include the vaccine in their immunization programs. Global efforts should continue to push for the introduction of rotavirus vaccines into every national immunization strategy. These efforts should especially focus on the 2 regions with the highest rotavirus mortality—sub-Saharan Africa, where 22 of 51 countries have yet to begin national rotavirus vaccination programs, and Asia, where there are no early adopters.65

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Keywords:

rotavirus; vaccine; children; global

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