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Lack of Nonspecific Protection Against All-Cause Nonrotavirus Gastroenteritis by Vaccination with Orally Administered Rotavirus Vaccine

Grant, Lindsay; Watt, James; Moulton, Lawrence; Weatherholtz, Robert; Reid, Raymond; Santosham, Mathuram; O’Brien, Katherine

Journal of Pediatric Gastroenterology and Nutrition: June 2013 - Volume 56 - Issue 6 - p 635–640
doi: 10.1097/MPG.0b013e318287c5cc
Original Articles: Gastroenterology

Objectives: Acute gastroenteritis (AGE) is recognized as a global, common threat to child survival, especially in developing countries. Rotavirus, in particular, has been implicated as a leading cause of severe AGE; however, there are numerous other pathogens that also cause AGE. Several studies have demonstrated that oral vaccination against rotavirus has generated the unanticipated benefit of protecting against AGE caused by nonrotavirus pathogens.

Methods: Safety and efficacy of the pentavalent bovine-human reassortant rotavirus vaccine were studied in multiple populations, including children of the Navajo and White Mountain Apache tribes in the southwestern United States. Stool specimens were collected from children with AGE and tested for rotavirus using an enzyme immunoassay. Analyses were conducted to detect the presence or absence of a vaccine effect on incidence, severity, and duration of AGE in which rotavirus was not detected.

Results: The majority of AGE (N = 558: 472 nonrotavirus vs 86 rotavirus) occurred between August 2002 and March 2004 among children ranging from ages 4 to 23 months. The incidence of nonrotavirus AGE was similar by vaccine groups with an incidence rate ratio of 1.07 (incidence rate ratio = vaccinated/unvaccinated, 95% confidence interval 0.89–1.29). The hazards of first, second, third, or any AGE in which rotavirus was not detected differed little by vaccination status (P > 0.05). Duration of symptoms and severity of nonrotavirus AGE were similar by vaccine group.

Conclusions: There was no vaccine effect on frequency or severity of nonrotavirus AGE.

Supplemental Digital Content is available in the text

Department of International Health, Johns Hopkins Bloomberg School of Public Health, Center for American Indian Health, Baltimore, MD.

Address correspondence and reprint requests to Dr Lindsay Grant, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Center for American Indian Health, 621 N Washington St, Baltimore, MD 21205 (e-mail:

Received 8 February, 2012

Accepted 14 January, 2013

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (

The study was supported by Merck & Co, Inc.

The opinions expressed in this paper are those of the authors and do not necessarily reflect the views of the Indian Health Service.

M.S. has served on a scientific advisory committee for Merck & Co and GlaxoSmithKline. The other authors report no conflicts of interest.

Acute gastroenteritis (AGE) was recognized by the United Nations Children's Fund and the World Health Organization as the second leading cause of death among children younger than 5 years worldwide, accounting for an estimated 1.5 million deaths each year (1). A majority of these deaths occur in the developing world, of which 80% are in Africa and south Asia and are primarily the result of malnutrition and the lack of safe drinking water, sanitation, and hygiene. Rotavirus is consistently identified as the most frequent cause of severe AGE among children, whereas norovirus is a significant cause of AGE among all ages (2–4). Other common enteric viruses include astrovirus, enteric adenovirus, and sapovirus (5–8). Viruses are the most common cause of AGE in developed countries. In developing countries, advances in sanitation and improvements in water quality are associated with a reduction in the proportion of AGE caused by bacteria and an increase in the proportion of AGE associated with enteric viruses (9,10). Antigen-based and nucleic acid detection methods have increased the detection of enteric viruses.

Vaccines to protect against AGE caused by rotavirus, Salmonella typhi, Vibrio cholerae serogroups O1 and O139 are available, whereas new vaccines against several bacterial enteric pathogens, including Escherichia coli, Shigella, and Campylobacter jejuni, are under development (11). Orally administered rotavirus, S typhi, and V cholerae vaccines are highly protective against AGE, but protection by rotavirus vaccine appears to be diminished in some developing countries during the second year of life, whereas S typhi and V cholerae vaccines induce long-lasting immunity (12–18). Oral vaccination is thought to generate the optimal immune response against enteric pathogens because the oral route of vaccine administration mimics that of natural infection (19). The 2 available rotavirus vaccines, RotaTeq and Rotarix, are both administered orally and contain vaccine-type virus particles that are morphologically identical to wild-type rotavirus (20,21). The vaccine-type virus is expected to interact with the host immune system to induce a protective mucosal immune response through the same mechanisms that would combat a naturally occurring rotavirus infection.

RotaTeq is a live, pentavalent bovine-human reassortant vaccine (PRV) that is composed of 5 bovine-human strains. Each vaccine strain consists of the full bovine genome (genotype G6P[5]) and a human gene segment representing a capsid protein for serotypes G1–G4 or P[8]. The Wistar Calf-3 strain that is used in the vaccine was isolated from a calf with diarrhea and adapted for growth in cell culture (22). The vaccine is administered at 6.7 × 107 to 12.4 × 107 infectious units per dose and induces a serotype-specific serum-neutralizing antibody response among vaccinated individuals (12). Vaccination prevented 74% (95% confidence interval [CI] 66.8–79.9) of G1–G4 rotavirus gastroenteritis during the first rotavirus season after vaccination and 98% of severe rotavirus gastroenteritis (95% CI 88.3–100) (12).

Rotarix was developed from an attenuated human rotavirus G1 serotype strain (89–12). The strain was chosen for use in vaccine development because it provided both homotypic and heterotypic protection against subsequent rotavirus disease. The strain was further attenuated by 26 serial passages in African green monkey kidney cells and 7 passages in another African green monkey kidney cell line (23). Immunization generated an IgA antibody response detected in both serum and stool when vaccine was administered at 105 plaque-forming units (24). Vaccination with Rotarix prevented 90.4% (95% CI 85.1–94.1) and 84.7% (95% CI 71.7–92.4) of severe rotavirus episodes among European and Latin American children, respectively (25,26).

The rhesus-human reassortant tetravalent rotavirus vaccine (RRV-TV) was designed using a similar strategy as PRV. Vaccination with RRV-TV prevented 66% of any rotavirus AGE and unexpectedly induced nonspecific protection against AGE by reducing the duration and severity of AGE caused by other common enteric viruses, enteric adenovirus, and sapovirus (27–30). A similar result was observed for a live, attenuated bovine rotavirus vaccine, RIT 4237, in which 66% (95% CI 29–84) of AGE was prevented regardless of etiology (31).

Prevention of AGE is especially important among children who have nutritional deficits because of an increased risk of death. Approximately 60% of diarrhea deaths among children with low weight-for-age can be attributed to malnutrition (32). Repeated bouts of diarrhea that result in loss of nutrients are known to perpetuate the infection–malnutrition cycle. Reducing the duration and severity of AGE, particularly caused by pathogens that affect the absorptive function or the epithelial integrity of the small intestine, could decrease the probability of death among children with poor anthropometric indicators. The purpose of the analysis described here is to determine whether vaccination with PRV in the Navajo and White Mountain Apache (N/WMA) population generated a protective effect against nonrotavirus AGE by reducing the frequency, duration, or severity of cases.

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Sample Collection

The pentavalent human-bovine reassortant rotavirus vaccine, licensed as RotaTeq (Merck & Co, Whitehouse Station, NJ) in 2006, underwent safety and efficacy testing in a multicenter trial that included 2 sites based in the United States, the Navajo and Fort Apache Reservations. N/WMA children 6 to 12 weeks of age were enrolled in the trial and randomized to receive 3 doses of PRV or placebo, with intervals of 28 to 70 days between doses. In the event of an AGE, parents or caregivers of study participants recorded clinical symptoms and collected 2 stool specimens 24 hours apart immediately after symptom onset. Stools were collected using containers provided by study personnel and kept frozen inside the family home until the next study visit. Specimens were transported on ice and stored at −70°C until processed. Rotavirus AGE was defined by ≥3 watery or looser-than-normal stools within a 24-hour period and/or forceful vomiting plus detection of rotavirus by an antigen capture enzyme immunoassay (EIA) in a stool specimen that was collected within 14 days of symptom onset.

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Laboratory Analyses

Laboratory analyses of stool specimens were performed according to the original trial protocol. Twenty percent stool suspensions were made and tested by EIA for rotavirus detection of the intermediate capsid structural protein, VP6 (33). The lower limit of detection of the assay is 107 to 108 viral particles per milliliter. A sample was classified as rotavirus positive by EIA using 2 criteria: an optical density of ≥0.31 and an optical density at least 1.63 times that of the negative control.

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Study Design

Per-protocol (PP) recipients received 3 vaccine or placebo doses with a minimum of 28 days between doses. PP subjects entered analyses and became at risk for a nonrotavirus AGE 14 days following administration of the third dose. Any AGE with either a positive or nondeterminable EIA result for rotavirus was excluded. Subjects were not at risk for another AGE until 14 days after symptom onset to discriminate between episodes.

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Statistical Analyses

Analyses were restricted to PP children and entered analysis on or after August 1, 2002. Season of analysis origin was represented by AGE (October 2002–April 2003 and October 2003–February 2004) and non-AGE seasons (August 2002–September 2002 and May 2003–September 2003). Season strata were defined according to historical data on AGE occurrence (34,35). The analysis timeline was set to zero at 14 days after the third dose of study vaccine. Age at analysis origin was represented by a continuous variable because the range of ages was narrow (4–7 months).

Incidence of nonrotavirus AGE occurring at least 14 days after dose 3 was calculated among PP subjects. Child-months were determined by subtracting the date of vaccine dose 3 administration plus 14 days from the date of censoring and dividing the result by 30.44 (the average number of days in a calendar month) to obtain the number of months contributed by each child to follow-up. Based on the available person-time in the placebo and vaccine groups (approximately 3200 child-months per group), the study was powered at 80% to detect a 25% difference in nonrotavirus AGE rates.

Kaplan-Meier curves were generated to visualize the probability of nonrotavirus AGE-free survival by groups and compared using the log-rank test. The average survival time (ie, restricted mean survival time) was estimated using the exponential distribution and included all survival times except for the maximum.

Smoothed hazard estimates were graphed from the cumulative hazard curve by applying a Gaussian kernel function. Cox proportional hazards models with Efron method for handling tied failure times were used to examine the time from 14 days postvaccine dose 3 to the first, second, third, and any nonrotavirus AGE. The analysis timeline is the same for time to second or third episode analyses, in which subjects enter analysis at 14 days after the third vaccine dose but are required to experience a first (or second) episode before entering. Subjects could experience >1 AGE during the course of “any” nonrotavirus AGE analysis using calendar time from analysis origin to any AGE as the timeline of analyses. Within-subject correlations are accounted for in Cox models by using a robust estimate of variance to adjust for clustering. Violations of the proportional hazard assumption were assessed by a link test and examination of Schoenfeld residuals (36).

Hazard ratios were adjusted for confounding by age and season at 14 days after vaccine dose 3 and for tribal affiliation. Age in months at 14 days postdose 3 was modeled as a fixed, continuous variable because there was little variation across the study population in age at this time. Season of analysis origin was treated as a fixed, categorical variable that represented entrance into survival analyses during AGE and non-AGE seasons. This allowed for 3 waves of origin seasons to enter into analyses and for comparison by these seasons to determine whether vaccination during the AGE season had any effect on protection against nonrotavirus AGE. Interactions between covariates and/or analysis time were evaluated. Subjects were censored from analysis when the respective AGE occurs according to the analysis being performed or upon loss to follow-up/censoring.

Severity scores for nonrotavirus AGE were calculated following the 24-point scoring scale developed by Clark et al, in which a numerical value of 1, 2, or 3 is assigned to clinical characteristics of an AGE, which are then summed together to obtain the final score (37). Scores of 9 to 16 and 17 to 24 are associated with moderate and severe disease, respectively. Median severity scores and values for each clinical characteristic contributing to this score were compared by vaccine group using the Mann-Whitney U test. Distribution trends were compared using a nonparametric test for trend across ordered pairs, which is an extension of the Wilcoxon rank-sum test (or Mann-Whitney U test). Statistical significance was achieved when P < 0.05. Statistical analyses were conducted using STATA 10.0 (StataCorp, College Station, TX).

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Human Subjects

Parents or caregivers of children who were enrolled in the vaccine trial provided informed consent. Institutional review boards at Johns Hopkins Bloomberg School of Public Health, Centers for Disease Control and Prevention, the Navajo Nation, and the Phoenix Area Indian Health Service approved the study.

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There were 1008 Navajo and WMA children enrolled in the trial. Five hundred twelve were randomized to the group that received PRV and 496 were randomized to the placebo group. Of these, 1003 children received the first vaccine dose, 888 received 2 doses, and 825 received 3 doses. Protocol violators included 232 children who were dosed earlier than 28 days since the previous dose and 2 children who were randomized to receive placebo, but received PRV or a mixed regimen of PRV and placebo. The remaining 769 PP subjects were eligible to enter the analysis with dates of enrollment extending from August 1, 2002 to January 14, 2004. Of these subjects, 393 PRV recipients and 376 placebo recipients experienced 267 (N = 247 nonrotavirus, N = 20 rotavirus) and 291 (N = 225 nonrotavirus, N = 66 rotavirus) AGE episodes, respectively. The mean age of children included in this analysis was 5.25 months (range 3.7–7.9). The majority of subjects entered analyses from October 2002 to September 2003 (70%). A majority of nonrotavirus AGE occurred from October 2002 to January 2004 (online-only Fig. 1, seasonality of nonrotavirus AGE during the months of the PRV vaccine trial that occurred among the Navajo and WMA populations).

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Incidence of Nonrotavirus AGE

The overall incidence of nonrotavirus AGE was 70.9/1000 child-months (Table 1) and did not vary by vaccine group (P = 0.44). The incidence of nonrotavirus AGE was higher among children 4 to 11 months of age (103.4/1000 child-months) compared with 12 to 23 (27.5/1000 child-months; P < 0.001). During the first time period, the incidence of nonrotavirus AGE was 2 to 3 times higher compared with the 2 successive time periods of May 2003 to September 2003 and October 2003 to February 2004. WMA children experienced >3 times the rate of nonrotavirus AGE compared with Navajo children (P < 0.001).



During an AGE season (October 2002–April 2003 and October 2003–February 2004), the incidence of nonrotavirus AGE was the same among the PRV and placebo groups (P = 0.17, Table 2). Conversely, during a non-AGE season (May 2003–September 2003), the nonrotavirus AGE incidence was 17% lower among the vaccine group (P = 0.35), but neither of these comparisons was significant. Comparing seasons by vaccine group confirmed that nonrotavirus AGE is significantly higher in AGE seasons for both PRV (incidence rate ratio 2.14, P < 0.001) and placebo recipients (incidence rate ratio 1.54, P = 0.003).



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Probability of Nonrotavirus AGE

The average follow-up time ranged from 258.7 days for PRV to 264.7 days for placebo recipients. The probability of remaining free of nonrotavirus AGE for a first, second, third, and any nonrotavirus AGE was similar by vaccine group (P = 0.62, 0.99, 0.51, and 0.48, respectively). WMA children were more likely to experience the first nonrotavirus AGE and to experience this nonrotavirus AGE significantly closer to the analysis origin compared with Navajo children (35 vs 131 days, P < 0.001). The estimated mean survival time to the first nonrotavirus AGE was no different for the placebo group (341.1 days, 95% CI 316.3–366.0) compared with the PRV group (347.9 days, 95% CI 321.4–374.4). A similar trend was observed for the second and third nonrotavirus AGE.

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Time to Nonrotavirus AGE Analysis

The hazard of nonrotavirus AGE decreased substantially over follow-up with nearly identical hazard functions for both vaccine and placebo. Regardless of nonrotavirus AGE number and adjustment for confounding covariates, the effect of vaccine remained constant over time with no difference in the risk of nonrotavirus AGE by vaccine group (Table 3). Additional analyses explored the presence of a vaccine effect on nonrotavirus AGE after 1 vaccine dose; however, an effect was not detected for the first or any nonrotavirus AGE occurring after the first dose (first AGE: hazard ratio 1.05, 95% CI 0.87–1.26; any AGE: hazard ratio 1.04, 95% CI 0.92–1.17).



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Impact of Vaccination on Severity of Nonrotavirus AGE

The severity ranged from scores of 1 to 20, with more than half of nonrotavirus AGE characterized as mild (online-only Fig. 2, distribution of severity scores of nonrotavirus AGE in placebo and PRV groups). There were no nonrotavirus AGEs with a severity score >20. The severity score distributions were similar for placebo and PRV nonrotavirus AGE (P = 0.85). A similar percentage of placebo (64%) or PRV recipients (59%) experienced mild nonrotavirus AGE (P = 0.3). The median values that describe the clinical characteristics of nonrotavirus AGE were similar for PRV and placebo recipients (Table 4).



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The quest to develop a safe and efficacious rotavirus vaccine has resulted in numerous clinical trials representing various developmental and scientific approaches. In 2006, PRV was licensed in the United States, followed by the monovalent live, attenuated vaccine in 2008. Although both vaccines have proven to be highly efficacious against rotavirus AGE, orally administered rotavirus vaccines also have been described as providing nonspecific protection against AGE of all etiologies. A review of multiple rotavirus vaccine trials in Finland calculated a mean vaccine efficacy against all-cause severe AGE of 73% (95% CI 54–84) (39). Furthermore, a virus-specific effect of the rhesus-human reassortant rotavirus vaccine was observed for AGE associated with detection of enteric adenovirus; however, these effects were not significant for astrovirus or calicivirus AGE (28–30,40). For enteric adenovirus AGE, the RRV-TV vaccine significantly shortened AGE duration (P = 0.008) and lessened AGE severity (P = 0.07). A protective effect was not observed for a subsequent analysis of the monovalent human rotavirus vaccine on the occurrence of norovirus gastroenteritis (41).

The purpose of this analysis was to determine whether vaccination with PRV could provide protection against nonrotavirus AGE. With the hypothesis that rotavirus vaccination could delay nonrotavirus AGE, survival analyses compared the time to first, sceond, third, and any nonrotavirus AGE, but there was no difference in the timing of nonrotavirus AGE by vaccine group. To compare with vaccine efficacy analyses done for RRV-TV, the incidence of nonrotavirus AGE was calculated, but a decrease in the incidence of AGE among the vaccine group was not observed. Overall, there was no evidence that vaccination with PRV had any effect on incidence, delay, duration, or severity of nonrotavirus AGE in the study population.

The severity-scoring scheme in the present study made it possible to assign AGE a score ranging from 1 to 24. A majority of nonrotavirus AGE in this population was characterized as mild (score ≤7). Therefore, attenuation of AGE severity by vaccination may be undetectable. When analyses were restricted to moderate and severe AGE, a vaccine effect was still not present, even though previous studies observed a substantial vaccine effect for these severity categories (39). The severe AGE that was susceptible to the vaccine effect observed in other rotavirus vaccine trials could come from a population with different severe AGE epidemiology.

In multiple rotavirus vaccine trials, monovalent live, attenuated, and human-animal reassortant vaccines have performed well in high-income countries such as the United States and those in Europe and Latin America, but efficacy against rotavirus AGE has been relatively poor in low-income settings, including the Navajo Reservation (12,13,42–46). The mechanism of this diminished protection is not understood; however, many hypotheses exist and include differences in host and environmental factors, malnutrition, and infection pressure (47). The lack of a vaccine effect in N/WMA children compared with those from Finland could be attributed to differences in vaccine immunogenicity by income setting; however, PRV efficacy against any rotavirus AGE among N/WMA children (77.1% [95% CI 59.8–87.6]) was comparable with efficacy estimates from the entire trial population (74% [95% CI 66.8–79.9]) (12,48).

Studies that examined the effect of rotavirus vaccine on nonrotavirus AGE included rhesus- or bovine-derived vaccines. PRV is a bovine-human reassortant made from the Wistar Calf-3 bovine strain, whereas RIT 4237 is a live, attenuated vaccine made using bovine strain NCDV. The type of vaccine (eg, live, attenuated vs reassortant) could affect vaccine immunogenicity and the generation of a vaccine effect. Conducting an analysis in Finland to evaluate the presence or absence of a vaccine effect by PRV would be of interest because a vaccine effect was previously observed for RIT 4237, and RRV vaccines would be in that population.

An etiology study among placebo recipients was conducted using the AGE stools collected during the PRV trial to understand the contribution of other enteric viruses as causes of AGE, including enteric adenovirus, astrovirus, norovirus, and sapovirus. The distributions of enteric viruses associated with AGE were similar between children participating in the RRV-TV vaccine trial in Finland and the PRV trial in N/WMA (49). A virus-specific analysis of N/WMA data may correlate with vaccine effect results from the Finnish analysis and be useful in understanding the mechanism and specificity behind nonspecific protection (50); however, because pathogen distributions, vaccine immunogenicity, and laboratory assays for rotavirus detection can vary geographically, comparison of results between populations and extrapolation of the presence or degree of vaccine effects could be unreliable.

Further exploration of the mechanism by which this nonspecific vaccine effect is conferred could provide clues to which pathogens would be most affected and the populations that could benefit most from orally administered vaccines, such as those in developing country settings. Regardless of the additional benefit of nonspecific vaccine effects, orally administered vaccines are a valuable strategy for reducing AGE and have led to substantial reductions in rotavirus disease.

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The authors express their deep gratitude to the children and their parents or caregivers from the Navajo and White Mountain Apache tribes who participated in the PRV vaccine trial. We thank the Center for American Indian Health nurses and research program assistants for their conduct of the rotavirus vaccine trial. The authors also thank Michele L. Coia, Donna M. Hyatt, Michael J. Dallas, and Max Ciarlet (Merck & Co) for contributing to the understanding of the database, understanding how the analyses in the original clinical trial were performed, and/or critically reviewing the manuscript. The trial could not have taken place without the guidance and input from the institutional review boards of the Navajo Nation, the Phoenix Area IHS, and the Johns Hopkins Bloomberg School of Public Health.

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    acute gastroenteritis; rotavirus; rotavirus vaccine; vaccine effect

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