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Assessment of Postlicensure Safety of Rotavirus Vaccines, with Emphasis on Intussusception

  1. Julie E. Bines1,2,3,
  2. Manish Patel4 and
  3. Umesh Parashar4
  1. 1Department of Paediatrics, University of Melbourne,
  2. 2Royal Children’s Hospital, and
  3. 3Murdoch Childrens Research Institute, Melbourne, Australia; and
  4. 4Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
  1. Reprints or correspondence: Prof. Julie E. Bines, Dept. of Paediatrics, The University of Melbourne, Flemington Rd., Parkville 3052, Victoria, Australia (julie.bines{at}rch.org.au)
 
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Abstract

The global implementation of rotavirus vaccines will result in a major step toward limiting the disease burden of rotavirus infection. However, as history has shown with the experience of Rotashield (Wyeth Lederle Vaccines), the introduction of a new vaccine should occur in parallel with a postmarketing surveillance strategy to detect any unexpected or rare adverse events. Two new rotavirus vaccines (Rotarix [GSK Biologicals] and RotaTeq [Merck]) have been found to be safe and effective in large clinical trials involving >60,000 infants in the Americas and Europe. However, given that intussusception is an extremely rare event, some risk could be detected as the vaccine is administered to a larger number of infants. In response to a recommendation of the World Health Organization Global Advisory Committee for Vaccine Safety, a standardized approach to the postmarketing surveillance of rotavirus vaccine safety has been developed. We review the principal safety issues requiring further evaluation in postlicensure use of rotavirus vaccines. For intussusception, we also discuss challenges and approaches to monitoring

The first oral rotavirus vaccine (Rotashield; Wyeth Lederle Vaccines) was licensed in the United States in October 1998, heralding a major step toward the reduction in severe rotavirus disease [1–3]. However, 9 months later, the Rotashield immunization program was suspended because of an unexpected association with intussusception [4, 5]. In October 1999, the US Advisory Committee on Immunization Practices [4, 6] withdrew its recommendation for Rotashield, and the manufacturer voluntarily withdrew the vaccine from the US market. The abrupt demise of Rotashield delayed the introduction of potentially lifesaving rotavirus vaccines for children in the developing world. Clinical trials of new rotavirus vaccines were now required to demonstrate safety for an adverse event occurring in <1 in 10,000–32,000 vaccine recipients. Two new rotavirus vaccines (Rotarix [GSK Biologicals] and RotaTeq [Merck]) have been found to be safe and effective in large clinical trials of >60,000 infants in the Americas and Europe [7, 8]. These vaccines have been licensed in >80 countries and have been introduced into the routine infant immunization schedule in several countries of the Americas and Europe and in Australia. However, given that intussusception is an extremely rare event, some risk could be detected as the vaccine is administered to a larger number of infants after licensure. We review the principal safety issues requiring further evaluation in postlicensure use of rotavirus vaccines. For intussusception, we also discuss challenges and approaches to monitoring

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Intussusception

What Is Intussusception?

Intussusception is the invagination of a segment of the intestine within a more distal segment. It is the most common cause of bowel obstruction in infants, usually occurring between 4 and 10 months of age [9]. In most infants, the intussusception involves the ileum invaginating through the ileocaecal valve into the caecum. As the bowel intussuscepts, it pulls along its blood supply. If the intussusception is not relieved, the vascular supply of the bowel may be compromised, resulting in intestinal ischemia and possibly perforation. Untreated intussusception may be fatal

Clinical Features and Diagnosis

The clinical presentation of infants with intussusception reflects the underlying pathophysiology. Intestinal obstruction causes abdominal pain, vomiting, and abdominal distension. Obstruction to the venous or arterial supply of the effected intestine results in rectal bleeding, sometimes described as “red currant jelly” stool. An abdominal mass, representing the intussusception, may be palpated on clinical examination. The diagnosis of intussusception is confirmed by the demonstration of intestinal invagination during surgery, air- or liquid-contrast enema, or ultrasound examination (Figure 1). Because transient invaginations are observed during dynamic procedures, such as ultrasound or endoscopy, the diagnosis of intussusception requires an assessment of the extent of invagination and evidence of obstruction or failure of spontaneous resolution. With recognition that access to radiological facilities may be limited in some regions, a clinical case definition for the diagnosis of acute intussusception in infants and children was developed by the Brighton Collaboration [10]. This definition provides a clinical approach to diagnosis of intussusception that is suitable for use in a range of health care settings and has been validated in developed and developing countries [11]. Uncomplicated intussusception is treated by air-contrast or hydrostatic enema under radiological or ultrasound guidance or by surgery. Treatment practices appear to vary by region; surgical treatment percentages range from 12% to 88% in large studies worldwide (Table 1). Approximately 10% of infants require intestinal resection as a result of intestine ischemia or perforation [9]

Figure 1
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Figure 1

Air-contrast enema showing the apex of an ileocolic intussusception at the hepatic flexure of the colon

Figure 2
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Figure 2

Intussusception hospitalization rates per 100,000 infants aged <12 months, by week of age, United States, 1993–2004. Reproduced with permission from Pediatrics Vol. 121, Pages e1125–32, Copyright © 2008 by the AAP

Table 1
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Table 1

Literature Review of Population-Based Studies Examining National or Regional Rates of Hospitalization for Intussusception among Children Aged <12 Months

Epidemiology

Despite being an important cause of intestinal obstruction in infants, intussusception is relatively uncommon. The incidence is reported to be <100 cases per 100,000 infants aged <1 year in most developed countries, and a consistent but unexplained decrease in the number of cases has been observed over the past decade [18, 20, 24, 25]. The incidence of intussusception varies among global regions (Table 1). A slightly higher incidence is reported in the United Kingdom, Australia, Hong Kong, Taiwan, and Denmark (66–88.2 cases per 100,000 infants aged <1 year) [17, 19, 26–29], and a slightly lower incidence is reported in Panama, Venezuela, Switzerland, and some states in the United States (30–38.1 cases per 100,000 infants aged <1 year). The incidence of intussusception in Vietnam is reported to be >300 cases per 100,000 infants, 9-fold higher than that reported among infants in the United States [13]. It is not known whether genetic, cultural, dietary, or environmental factors may place infants in some regions at a higher risk for development of intussusception. Interestingly, no microbiological, dietary or environmental risk factors explained the marked difference in incidence of intussusception in a parallel case-controlled study involving infants in Vietnam and Australia [13]

The incidence of intussusception varies substantially by age during the first 6 months of life. The expected intussusception hospitalization rate among US infants is low from birth to age 8 weeks (2–5 hospitalizations per 100,000 infants) but increases almost 10-fold during the next 2 months, peaking at age 26–29 weeks (62 hospitalizations per 100,000 infants) before decreasing again by age 1 year (∼26 hospitalizations per 100,000 infants) (Figure 2) [24]. Interesting differences in age-specific incidence were observed by race/ethnicity. For infants who were aged <16 weeks, intussusception rates did not vary meaningfully by race/ethnicity. This was in sharp contrast to the group aged 21–44 weeks, in which non-Hispanic white infants had substantially lower rates of intussusception, compared with non-Hispanic black infants and Hispanic infants

Etiology

In older children and adults, intussusception is frequently associated with a pathological “lead point,” such as a polyp or tumor. In contrast, the cause of intussusception in the majority of infants is not known [9]. The presence of mesenteric lymphadenitis observed in association with intussusception has led to the search for a possible infectious agent. A wide range of viruses, bacteria, and parasites have been identified in patients with intussusception [9]. The development of intussusception in infants who received Rotashield raised the question of whether wild-type rotavirus infection was associated with intussusception [30]. Wild-type rotavirus has variably been identified in stool samples from patients with intussusception (incidence range, 3%–49%) [13, 31–33], and changes in the thickness and characteristics of the intestinal wall have been detected on ultrasound in infants with acute rotavirus infection [34]. However, controlled studies do not suggest a significant association between wild-type rotavirus infection and intussusception [13, 35]. On the other hand, adenovirus was identified in the stool samples from more than one-third of infants with intussusception in a case-controlled study involving Vietnamese and Australian infants with intussusception [13]. Interestingly, the predominant adenovirus detected in infants with intussusception was serotype C, a respiratory adenovirus [36]. Adenovirus has also been identified in the mesenteric lymph nodes of patients with intussusception, consistent with the hypothesis that a mesenteric lymphoid tissue reaction in response to an infection, such as infection with adenovirus, may affect mucosal thickness or function of the distal small intestine, contributing to the development of intussusception [37, 38]

Intussusception and Rotashield Vaccine

In prelicensure trials, 5 of 10,054 Rotashield vaccine recipients (∼0.5 per 1000) developed intussusception, compared with 1 of 4633 control individuals (∼0.2 per 1000) [39]. Three of the 5 cases of intussusception occurred in the week after vaccination. However, the rate of intussusception was not statistically different in the vaccine recipients, compared with control individuals, and the cases occurred after receipt of the second and third doses of vaccine, at an age when the background rate of intussusception is increasing rapidly. Rotashield was licensed, but the package insert included intussusception as a potential adverse event

Initial data presented to the US Advisory Committee on Immunization Practices in October 1999 estimated the population-attributable risk of intussusception following Rotashield vaccination to be 1 in 2500–3300 (relative risk, 1.6–1.8 in the first year of life), or an additional 1200–1600 cases per year of intussusception if the Rotashield immunization program was fully implemented [5, 6]. The risk estimate was reduced to 1 in 4670–9474 after analysis of case-series and case-control studies [5, 40]. However, no increase in intussusception-related hospitalizations were noted in ecological studies, and it has been suggested that the risk may have been as low as 1 in 32,000 vaccinees [40, 41]

Although the magnitude of risk of intussusception following Rotashield vaccination remains controversial, the temporal relationship between the receipt of the vaccine and the development of intussusception in affected infants is acknowledged. Cases of intussusception clustered at 3–14 days following vaccination with the first dose of the vaccine (odds ratio, 21.7) [5]. Some have suggested that the age of the infant at the time of administration of the first dose of Rotashield appeared to influence the risk of intussusception [42, 43]. Of cases of intussusception reported following Rotashield vaccination, 80% occurred in infants who received dose 1 at age >3 months, whereas only 38% of the first doses had been given to this age group [43]. However, firm conclusions about an age-dependent risk could not be made, because of the sparse data for certain age groups [42, 44, 45]. After reviewing all the available evidence, the World Health Organization (WHO) Global Advisory Committee on Vaccine Safety concluded that the risk for Rotashield-associated intussusception was high in infants vaccinated after age 60 days and that insufficient evidence was available to conclude that the use of Rotashield at age <60 days was associated with a lower risk. The Global Advisory Committee on Vaccine Safety noted, however, that the possibility of an age-dependent risk for intussusception should be taken into account in assessment of future rotavirus vaccines. In part on the basis of these considerations, the currently licensed rotavirus vaccines have developed clear recommendations, restricting the administration of the first dose of vaccine to infants aged >6 weeks and <12 weeks (RotaTeq) and infants aged >6 weeks and ⩽20 weeks (Rotarix)

The pathophysiological mechanism for the association between Rotashield and intussusception is not well understood. Early clinical trials suggested that Rotashield was reactogenic with fever, irritability, and decreased appetite and activity, which were reported in a higher proportion of infants who received vaccine, compared with control infants who did not receive vaccine [46]. This was attributed to a reaction to the rhesus component of the vaccine. Subsequent analysis of adverse events reported during the period of Rotashield availability suggested that fever, bloody stool, diarrhea, abdominal pain, and dehydration were part of a spectrum of gastrointestinal illness related to vaccination [47, 48]

Intussusception and New Rotavirus Vaccines

After the withdrawal of Rotashield, the future development of rotavirus vaccine hinged on the answer to the question: Was intussusception an adverse event specifically related to Rotashield, or would intussusception also occur following administration of other rotavirus vaccines? Although Rotashield and the new Rotarix and RotaTeq are all live attenuated rotavirus vaccines, their intrinsic biological characteristics and reactogenicity profiles are quite different. Rotashield and RotaTeq are both multivalent human-animal rotavirus reassortant vaccines; Rotashield is based on a rhesus rotavirus strain, and RotaTeq is based on a bovine rotavirus strain. Rotarix is a monovalent, attenuated human rotavirus strain–based vaccine. In prelicensure trials, neither RotaTeq nor Rotarix was observed to be particularly reactogenic, especially when compared for rates of fever, vomiting, and diarrhea that were reported among infants who received Rotashield. Furthermore, the Rotashield vaccine strain replicated well in the infant gut and was shed in >80% of vaccine recipients after the first dose. In contrast, RotaTeq replicates poorly and is shed in only ∼10% of first-dose recipients. With Rotarix, shedding by enzyme-linked immunosorbent assay (ELISA) occurs in ∼50% of infants after dose 1 in the first 2 weeks after vaccination, and live virus can be detected in approximately one-half of the infants who demonstrate shedding by ELISA

Despite these biological differences between the different rotavirus vaccine strains, it was not possible to determine the risk of intussusception with each vaccine on theoretical considerations alone. Both vaccines have been required to assess safety in large clinical trials involving >60,000 infants, powered to assess an intussusception risk of a magnitude similar to that seen for Rotashield [49, 50]. No significant association between receipt of vaccine and intussusception was identified in these large clinical trials. Rotarix and RotaTeq have been licensed in >80 countries

Rationale for Postlicensure Monitoring for Intussusception

Although prelicensure trials did not demonstrate an association of the new rotavirus vaccines with intussusception, efforts to monitor safety postlicensure must continue for several reasons. First, even though each of the clinical trials evaluated a large number of infants, they were powered only to exclude a risk of intussusception similar in magnitude to that of Rotashield (eg, the RotaTeq trial was powered to exclude a risk of >10-fold during the 42-day period after vaccination) [51]. To evaluate a risk of smaller magnitude with any specific dose of vaccine will require careful follow-up of hundreds of thousands of infants during routine vaccine use. Second, the incidence and epidemiology of intussusception varies across different geographical settings, and the safety of rotavirus vaccines in different regions and across a wide range of health care settings has not yet been demonstrated. Finally, in the clinical trials, both vaccines were administered according to a very strict vaccination schedule, with the first dose given at age 6–14 weeks. The incidence of intussusception varies substantially during the first 6 months of life, and the safety of these vaccines when given outside the administration schedule examined in the clinical trials has not been evaluated

Goals and Approaches for Postlicensure Monitoring for Intussusception

The WHO Global Advisory Committee on Vaccine Safety has recommended a standardized approach to postmarketing surveillance in countries planning to introduce and implement rotavirus vaccines [52]. In response to this recommendation, the document Post-marketing Surveillance of Rotavirus Vaccine Safety was developed by the WHO [53]. This document provides guidelines for routine postmarketing surveillance to assess the safety of rotavirus vaccines and can be adapted at the country level, according to existing surveillance systems, health care infrastructure, and resources [54]. A key goal is to enhance the quality of safety data at a regional level so that the safety of rotavirus vaccines can be established and compared across regions

Surveillance systems require clear case definitions to assist in the identification and reporting of potential adverse events. The Brighton Collaboration has developed a number of standardized case definitions for the detection of vaccination-related adverse events and to assist in the comparability of data collected from different surveillance systems [55]. Ideally the baseline incidence of intussusception should be known for sites prior to the introduction of rotavirus vaccines. A generic protocol from the WHO has been developed to assist in the defining the epidemiology and baseline incidence of intussusception in countries where these data do not currently exist [56]

Passive surveillanceThe association between Rotashield vaccine and intussusception was first detected by a passive surveillance system, the US Vaccine Adverse Events Reporting System [57]. Such passive surveillance systems aim to detect a “signal” (ie, when the number of reported events exceed the number expected to occur by chance) of an association with an adverse event. Interpretation of data on intussusception from passive reporting systems requires data on 3 key parameters: (1) completeness of reporting of intussusception events after vaccination, (2) background rates of natural intussusception, and (3) number of rotavirus vaccine doses administered. The completeness of reporting of adverse events tends to be highest for events occurring soon after vaccination (eg, 1–2 weeks). This may result in an apparent clustering of events close to vaccination that may not necessarily indicate a signal or a true association with vaccination. Intussusception provides specific challenges in the interpretation of passive surveillance data. Baseline expected intussusception rates are known to vary up to 10-fold by week of age during the first 6 months of life. This is also the time when rotavirus vaccines are administered. Therefore, intussusception rates among vaccine recipients should be stratified according to age (ideally by week of age) to allow comparison with expected intussusception rates among the unvaccinated population of that age. Finally, calculation of the intussusception rate among vaccine recipients requires the estimation of the number of doses of vaccine administered in the target population. Unfortunately, often data are available only on the number of doses sold by the manufacturer, and the reporting completeness of adverse events to passive surveillance systems is not known. In this scenario, sensitivity analyses incorporating various assumptions for these parameters should be conducted to allow interpretation of passive surveillance data. However, even with these techniques, passive surveillance has limitations, and investigation of a signal generated by passive surveillance requires more-sophisticated methods

Active surveillance and epidemiological studiesActive surveillance of intussusception cases with verification of diagnoses through review of clinical features and with diagnostic evaluation of potential cases remains the reference standard for detection of intussusception cases. Once intussusception cases are identified through active surveillance, the association with rotavirus vaccination can be assessed through various methods

In traditional cohort-based evaluations, the rate of intussusception among vaccinated infants is compared with the rate among unvaccinated infants during specific time periods after vaccination. To adjust for potential differences in characteristics of vaccinated and unvaccinated children, multivariate analyses can be conducted to include potential confounders (eg, age, socioeconomic status, and feeding practices). Because intussusception is uncommon, follow-up data on large numbers of children are needed to assess a low level of risk. Generally, such data are available only through large administrative data sets that capture information on vaccination and medical outcomes for an enrolled population, such as the US Vaccine Safety Datalink

If platforms such as the Vaccine Safety Datalink and the substantive resources needed to establish a cohort study are not available, the risk of intussusception could be assessed using case-control or case-series methodology. Indeed, when the passive Vaccine Adverse Events Reporting System identified a signal of a possible association between Rotashield and intussusception, a nationwide case-control study was conducted to confirm this association. Both case control and case series are case-based methods that begin with identification of children with intussusception, as opposed to cohort methods, in which vaccinated and unvaccinated children are followed up over time to determine whether they develop intussusception. A key advantage of the case-based methods is that a smaller sample size is required to identify an association, compared with a traditional cohort-based study. However, case-control studies are particularly challenging because of the importance in identifying appropriate controls and their vaccination status. If the controls are not representative of the source population from which the cases arise, the study may be prone to bias

In the absence of an existing database platform or the resources needed to conduct a cohort study and to avoid the potential biases of case-control study that result from the choice of controls, the relatively novel self-controlled case-series (SCCS) method could be used. The SCCS relies only on identification of intussusception cases, and no controls are needed. An important caveat is that the surveillance system used to identify intussusception cases for the SCCS analysis should not preferentially identify cases on the basis of vaccination status. Thus, data from passive surveillance systems for monitoring adverse events cannot be used, because they are likely to be biased toward cases occurring shortly after vaccination. To assess risk with vaccination, the incidence of intussusception in the “risk” windows close to vaccination (eg, 0–7 days or 0–21 days after vaccination) is compared with the incidence in “control” windows. Because incidence is compared for different time periods after vaccination for the same case, the SCCS approach automatically controls for fixed individual-level confounders (eg, socioeconomic status and race/ethnicity) that might affect risk assessment. Furthermore, because no controls are needed, several potential biases in selection of controls are avoided, and fewer subjects need to be studied, which reduces the resources required

Three key issues in assessment of the risk of intussusception by the SCCS method deserve special attention. First, because the background rate of intussusception varies substantially during the first few months of life, it is important to adjust for the difference in background rates for the “risk” and “control” periods for each case. Therefore, data on the relative incidence of intussusception among unvaccinated children at the same ages are required. Second, data from clinical trials of the Rotarix vaccine suggest the possibility of a reduced rate of intussusception among vaccinated infants, compared with placebo recipients, when they were followed up for a period of 1 year after vaccination [58]. If vaccine alters the overall risk of developing intussusception in the first year of life, then the fundamental assumption of the SCCS method (ie, that the incidence in the “control” period is unchanged from baseline in the absence of vaccination) would be violated, and a falsely elevated risk estimate could be derived. Until additional data are obtained, a second approach, such as the case-control or the cohort approach, should support the SCCS method. Finally, in light of the public awareness of intussusception as a potential association with a rotavirus vaccine, there may be a “diagnostic bias” in which there is increased vigilance in diagnosis and treatment of intussusception soon after vaccination (eg, within 7 days), compared with the current practice for unvaccinated children. This phenomenon might falsely increase risk in the windows of time closest to vaccination and would call for cautious interpretation of elevated risks of smaller magnitude (eg, relative risk of 2–4) during these windows

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Other Potential Safety Issues

Extraintestinal spread of rotavirus infectionWild-type rotavirus infection is not confined to the gut. Rotavirus has been identified in lymph nodes, liver, lung, myocardium, and the central nervous system of patients with acute rotavirus gastroenteritis [59]. Noninfectious rotavirus proteins (antigens) and infectious particles have been identified in serum samples from a large proportion of children hospitalized with severe gastroenteritis [59–61]. In one study, 22 of 33 children with acute gastroenteritis who had rotavirus detected in stool samples also had rotavirus antigen detected in their serum samples [60]. Rotavirus double-stranded RNA was detected by reverse-transcriptase polymerase chain reaction in 3 of the 6 antigen-positive serum samples, suggesting that infectious particles may also be present in the serum of patients with acute rotavirus gastroenteritis [59, 60, 62]. The transmission of rotavirus infection via serum of a rotavirus-infected animal has been demonstrated in gnotobiotic piglets [63]. The ability of a rotavirus to be associated with antigenemia or viremia may vary with specific characteristics of the rotavirus. G1 rotavirus strains appear to have a unique tropism for blood [64]. No data on viremia after vaccination have been reported

Central nervous system infection, including seizures, meningitis, and encephalitis, have been reported following wild-type rotavirus infection [65–70]. The same rotavirus strain was identified in paired faecal and cerebrospinal fluid samples obtained from children presenting with acute gastroenteritis, meningitis, and seizures [71]. However, these reports are rare and are likely to be associated with high rates of viral shedding or with specific serotypes, such as G1 [70, 71]. To date, there have been no reports of central nervous system disease associated with rotavirus vaccines

Concerns regarding other potential rare adverse events following rotavirus vaccination have been raised; however, these can be investigated further only by large-scale phase IV clinical trials or with postmarketing surveillance after vaccine implementation. In the phase III trial of the Rotarix vaccine, an excess of pneumonia-related deaths were observed in vaccine recipients (16 vaccine vs 6 placebo recipients) [7]. It is difficult to interpret this unexpected finding, because it was not consistent across studies and there was no significant difference in other potential pneumonia-related outcomes such as hospitalization or in pneumonia-related deaths in the 31 days immediately following vaccination. In response to a small number of reports of Kawasaki disease following vaccination with RotaTeq, the US Food and Drug Administration amended the product information for the United States to capture any cases. However, a causal relationship between RotaTeq and Kawasaki disease has not been established [72]. Because rotavirus contains peptide sequences similar to T cell epitopes in the islet autoantigens glutamic acid decarboxylase and tyrosine phosphatase, there have been concerns that acute rotavirus infection may trigger or exacerbate islet cell autoimmunity, leading to the development of diabetes in genetically susceptible children [73]. However, conflicting results from studies investigating this hypothesis have been presented, and it is considered more likely that the development of type 1 diabetes results from a complex series of environmental and genetic factors [73–75]. The risk of celiac disease is reported to be higher in children with a history of repeated rotavirus infection in infancy and early childhood. It has been suggested that the disturbance in intestinal permeability associated with rotavirus infection may facilitate the deamination of cereal proteins into more immunogenic epitopes, resulting in celiac disease in genetically susceptible individuals [76]. Postmarketing surveillance is likely to be an effective method for further investigation of a potential association between vaccination and these rare but not confirmed observations linked with wild-type rotavirus infection

Furthermore, to understand fully the risks and benefits of vaccination, it is of value also to understand the long-term risk of these adverse events beyond the risk window after vaccination that is being monitored (ie, >30 days after vaccination). If natural rotavirus infection is associated with conditions such as seizures, celiac disease, or diabetes, then vaccination could conceivably protect against these conditions, and evidence of such protection would help interpret the full risk profile and health benefits of the vaccines

Shedding and transmission of vaccine virus strainsThe potential of vaccine strains to infect human intestinal cells and to shed the vaccine virus in the stool varies according to the specific characteristics of the vaccine strain [77]. The Rotarix vaccine is a monovalent vaccine derived from the human rotavirus strain G1P[8]. It replicates well within the intestine, and live virus can be detected in >25% of patients after only 1 dose of vaccine [78]. RotaTeq vaccine is a pentavalent human-bovine reassortant vaccine that does not replicate well in the human intestine and is shed infrequently (incidence of virus in stool, <10%) in the stool [78]. As a result, higher aggregate vaccine titers are required to achieve protection. Because both Rotarix and Rotateq are live attenuated vaccines, the safety of these vaccines for immunocompromised patients or for immunodeficient household contacts requires consideration. Unfortunately, there are no clinical data to confirm the safety of rotavirus vaccines for patients with immunodeficiency. However, available evidence does not indicate that wild-type rotavirus infection is more severe in HIV-infected infants than in HIV-uninfected infants, suggesting that the risk from attenuated vaccine virus may be minimal, if any [79]. Studies addressing the safety of rotavirus vaccines for infants with HIV infection are currently in progress and will further guide immunization recommendations

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Conclusions

The global implementation of rotavirus vaccines will result in a major step toward limiting the disease burden of rotavirus infection. However, as history has shown with the experience of Rotashield, the introduction of a new vaccine should occur in parallel with a postmarketing surveillance strategy to detect any unexpected or rare adverse events not identified prelicensure. Despite the large clinical trials that each involved >60,000 infants and the growing experience after implementation of rotavirus vaccines in some countries, the safety of rotavirus vaccines should be further evaluated outside the clinical trial setting in a range of health care environments. In response to a recommendation of the WHO Global Advisory Committee on Vaccine Safety, a standardized approach to the postmarketing surveillance of rotavirus vaccine safety has been developed

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Footnotes

  • ↵Potential conflicts of interest: none reported

  • ↵Financial support: none reported

  • ↵Supplement sponsorship: This article was published as part of a supplement entitled “Global Rotavirus Surveillance: Preparing for the Introduction of Rotavirus Vaccines,” which was prepared as a project of the Rotavirus Vaccine Program, a partnership between PATH, the World Health Organization, and the US Centers for Disease Control and Prevention, and was funded in full or in part by the GAVI Alliance

  • ↵The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention

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