Rotavirus Vaccine and Intussusception

VACCINE R E C 0 M M E " S : CHALLENGES AND CONTROVERSIES

0891-5520/01 $15.00

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ROTAVIRUS VACCINE AND INTUSSUSCEPTION Where Do We Go From Here? Penelope H. Dennehy, MD, and Joseph S. Bresee, MD

Rotavirus is the most common cause of severe diarrhea worldwide. Rotavirus illness ranges from mild, watery diarrhea of limited duration to severe, dehydrating diarrhea with vomiting and fever, resulting in death.30*33,69 Virtually all children become infected in the first 3 to 5 years of life, but severe diarrhea and dehydration occur primarily among children 3 to 35 months of age.30r49,78 Rotavirus is estimated to be responsible for 20%of diarrheal deaths and 6% of all diarrheal episodes worldwide.= In a review in 1986, the Institute of Medicine estimated that each year rotavirus causes diarrheal illness in 130 million children under 5 years of age worldwide, of whom 18 million develop moderate or severe dehydration, and an estimated 600,000 to 873,000 die.36 In addition, rotavirus causes a substantial disease burden for children in the United States, accounting for 20 to 40 deaths annually;" and approximately 50,000 hospitalizations due to severe diarrhea and dehydration.%Rotavirus is responsible for as many as 50% of pediatric admissions to hospitals because of diarrhea and 20% to 25%of cases of pediatric diarrhea in outpatient clinics.8,49, 69 During peak rotavirus season, the virus can be the cause of over 75% of inpatient pediatric admissions for gastrointestinal illness.8, 49, 69 Rotavirus gastroenteritis

From the Division of Pediatric Infectious Diseases, Rhode Island Hospital, Providence, Rhode Island (PHD), and the Viral Gastroenteritis Section, Respiratory and Enteric Viruses Branch, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia (JSB). ~~

INFECTIOUS DISEASE CLINICS OF NORTH AMERICA VOLUME 15 NUMBER 1 * MARCH 2001

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predominantly affects young children. In the United States, 72% of rotavirus hospitalizations occur during the first 2 years of life, and 90% occur by age 3 years.58 THE VIRUS

Rotaviruses, a genus in the family Reoviridae, are 70-nm nonenveloped RNA viruses. The viral particle is composed of three concentric shells that enclose 11 segments of double-stranded RNA (Fig. 1).The outermost layer contains two structural proteins: VP7, the glycoprotein (G protein), and VP4, the protease-cleaved protein (P protein). These two proteins define the serotype of the virus and are considered critical to vaccine development because they are targets for neutralizing antibodies that can provide p r o t e c t i ~ n A . ~ typing ~ system has been developed to specify each protein. Currently, 14 VP7 (G) serotypes and 20 VP4 (P) genotypes have been described. Three P types (lA, lB, and 2) and five G types (1, 2, 3, 4, and 9) are associated with most human rotavirus Strains are designated generally by their G serotype specificity (e.g., Gl), and it has been shown that different strains predominate in regions throughout the world. The development of successful rotavirus vaccines may require inclusion of all the major P or G types causing disease in a specific region. In addition to human rotavirus strains, strains of rotavirus that are antigenically distinguishable are found in many species of mammals. Rotaviruses are shed in high concentrations in the stools of infected children and are transmitted by the fecal-oral route, both through close person-to-person contact and through fomites.1° Rotaviruses also might be transmitted by other modes, such as respiratory droplets.” NATURAL PROTECTION

Although children can be infected with rotavirus several times during their lives, initial infection after age 3 months is most likely to cause severe diarrhea and dehydrati0n.2~- 78 Neonates infected by 2 weeks of age are protected against relatively severe disease, but not against reinfe~tion.~ Similarly, after a first natural infection, infants and young children are protected against subsequent symptomatic disease regardless of whether the first infection was symptomatic or asymptomatic. After a single natural infection, 40% of children are protected against any subsequent infection with rotavirus, 75% are protected against diarrhea caused by a subsequent rotavirus infection, and 88% are protected against severe rotavirus diarrhea.78Second, third, and fourth infections confer progressively greater protection. The immune correlates of protection from rotavirus infection and disease are not completely understood. Both serum and mucosal antibodies probably are associated with protection from disease. VP4 and

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Figure 1. A three-dimensional structure of a rotavirus particle. Individual proteins are localized in different protein shells of the virus. Outer capsid proteins VP4 and VP7 are neutralization antigens that induce neutralizing antibody. The protein that makes up the intermediate protein shell, VP6, is the subgroup antigen and is the protein detected in diagnostic immunoassays. (From Estes MK: J Infect Dis 174(suppl 1): S39, 1996; with permission.)

Figure 2. The production of RRV-TV. Single gene reassortant vaccines (RV-serotype 1, RV serotype 2, RV serotype 4) are developed by incorporating the human VP7 genes of the three human rotavirus G types (S1, S2, and S4) into a parent rhesus rotavirus strain (Rhesus S3). The three reassortants for G1, G2, and G4 were then combined with the parent rhesus strain (RV serotype 3) to create RRV-TV with specificity for each of four common serotypes. (From MPE Communications, Inc., with permission.)

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VP7 were found to be independently capable of evoking antibodies that neutralize virus infectivity in vitro and protect against rotavirus challenge in vivo. In vaccine studies, however, correlation between serum antibody and protection has been poor.%The first infection with rotavirus elicits a predominantly homotypic, serum-neutralizing antibody response to the virus, and subsequent infections elicit a broader, heterotypic High concentrations of virus-specific IgA in fecal specimens at the time of reinfection have been correlated with mild disease or asymptomatic infection.5O For many children, however, the quantity of virus-specific IgA produced at the intestinal mucosal surface declines to undetectable concentrations within 1 year of natural infection.=

GOALS FOR A ROTAVIRUS VACCINE

A realistic goal for a rotavirus vaccine is to duplicate the degree of protection against disease that follows natural infection. Therefore, vaccine program objectives include the prevention of moderate to severe disease but not necessarily of mild disease associated with rotavirus. An effective rotavirus vaccine clearly will decrease the number of children admitted to the hospital with dehydration or seen in emergency departments, but also should decrease the burden on the practicing primary care practitioner, as evidenced by a decline in office visits or telephone calls. By reducing the disease burden, particularly of severe dehydrating gastroenteritis, the costs of a rotavirus vaccination program should be more than offset by societal savings, both in a reduction in direct medical costs and in reduced lost time from work of parents with sick Finally, effective rotavirus vaccines are most needed in developing countries where mortality associated with rotavirus is high.

VACCINE STRATEGIES

The strategies used to construct current rotavirus vaccines are different from those employed for any currently licensed vaccine. These strategies take advantage of the fact that rotaviruses infect the young of virtually all mammalian species; however, replication and disease induction are usually species specific. Research to develop a safe, effective rotavirus vaccine began in the mid-l970s, when investigators demonstrated that previous infection with animal rotavirus strains protected laboratory animals from experimental infection with human rotaviruses.86During the past two decades, three types of rotavirus vaccines have been evaluated.

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Monovalent Animal Strain Vaccines

The first attempts to develop rotavirus vaccines were based on the Jennerian approach, which used live animal strains that were attenuated naturally for humans. Researchers thought that these strains, when given orally, would mimic the immune response to natural infection and would protect children against disease. Four monovalent vaccines were developed and tested in human trials: two serotype G6 bovine strains (RIT 4237 and WC3), a serotype G3 rhesus rotavirus strain (RRV), and a serotype G10 lamb strain (LLR).9,53 The first field trial of rotavirus vaccine was conducted in 1983 in Finland, using the RIT 4237 strain. In this trial, one or two doses prevented 80% to 88% of severe rotavirus diarrhea in Finnish children.79, so, Subsequent trials in The GambiaMand Peru,"Ahowever, demonstrated low efficacy (33%and 40%, respectively), and trials among Rwandamz6and in the United States among Native Americans71demonstrated no protection. Because of the lack of efficacy in some trials, development of the RIT 4237 vaccine was halted. Clark et al. developed a less-attenuated bovine vaccine, WC3, in hopes of improving efficacy, and the vaccine was tested in four field trials. In two trials, qn efficacy of 50% to 76% was demonstrated against all rotavirus diarrhea and 100% against severe diarrhea.l6,I7Again, however, two additional trials, one in the United States5 and one in the Central African demonstrated no efficacy. The experience with rhesus rotavirus vaccine strain MMU18006 (RRV), developed by Kapikian et al, was similar. The efficacy of RRV in eight field trials in the United States, Scandinavia, and Venezuela varied from 0 to 66% for any rotavirus diarrhea and from 0 to 90% for severe disease.15,31, 48, 60, 65, 66, 71, 8z The highest efficacy occurred in a trial in Venezuela, where the circulating strain, G3, was the same serotype as the RRVm This finding suggested that a multivalent vaccine that provided serotype-specific immunity against all common human rotavirus strains might be more effective. Multivalent Human-Animal Reassortant Vaccines

The monovalent animal rotavirus vaccine approach was abandoned because of the inconsistent capacity of these vaccines to induce protection against disease. The next generation of rotavirus vaccines consisted of reassortant vaccines composed of human and animal strains. This strategy took advantage of the fact that when two different rotavirus strains infect the same cell at the same time, their gene segments can reassort. Reassortant viruses contain some genes from the animal rotavirus parent and some genes from the human rotavirus parent. The challenge to researchers in rotavirus vaccine development was to determine which genes from the human rotavirus were associated with protective immune responses. Both VP4 and VP7 were thought to be important in

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protection; therefore, human-animal reassortant rotaviruses for use as vaccines include either human VP7 or VP4 genes to provide protective immune responses. Multivalent vaccine candidates were first developed in 1985 by 51 Single-gene reassortant vacKapikian et a1 using gene reassortment.40* cines were developed that incorporated the human VP7 genes of the three common rotavirus G types (Gl, G2 and G4) into a parent rhesus rotavirus strain (Fig. 2). The three reassortants for G1, G2, and G4 then were combined with the parent rhesus strain to create a tetravalent vaccine (RRV-TV) with specificity for each of four common serotypes. These human-animal reassortant rotaviruses possessed the attenuated virulence characteristics of the animal strain and included the human VP7 genes associated with protective immune responses. Similar multivalent vaccines were constructed using a bovine parent strain. Human-bovine reassortant vaccines were developed at the Wistar Institute using bovine rotavirus WC3 as donor strain and containing human P type 1A or G types 1, 2, and 3.18 A quadrivalent vaccine consisting of bovine strains (WC-QV) that contain three different human G type proteins (Gl, G2, G3) and one human P-type protein (P1A) was tested in an efficacy trial of a three-dose regimen in the United States (Table 1).The incidence of fever, irritability, and vomiting was no different from that seen for the placebo recipients, but mild diarrhea was more prevalent among infants receiving the first dose of vaccine than among those given Protection induced by immunization was 67% against all rotavirus diarrhea and 69% against severe rotavirus disease.19 A second human-bovine reassortant vaccine was developed using bovine rotavirus strain UK as the donor strain. Reassortants whose VP7 gene is derived from human rotavirus strains D, DS-1, P, or ST3, which represent VP7 serotypes 1,2,3, and 4,respectively, and whose remaining genes are derived from bovine rotavirus strain UK also have been generated.51,52 Studies evaluating the safety and immunogenicity in adults, children, and infants of each reassortant demonstrated that these vaccines were well tolerated and immunogenic.2oAdditional studies of a candidate vaccine containing these four strains are under way. Human Rotavirus Vaccine Strains

Neonatal strains initially were explored as vaccine candidates because they appeared to be naturally attenuated and a natural-history study had shown that asymptomatically infected neonates subsequently had a reduced frequency and severity of rotavirus diarrhea.7Strain M37, a serotype G1 human rotavirus isolated from an asymptomatic newborn infant, provided no protection against G1 strains in a small efficacy study in Finland.*l Further efficacy studies with this vaccine candidate have not been pursued. A live, oral human rotavirus vaccine, 89-12, a G1 strain attenuated

3 3 3 3 3 2

Countrv (ReO

United Statesm Finland* Venezuela" United Statesn United StatesI6,I* United States4

Vaccine

RRV-TV

WC-QV 89-12

Number of Doses 4 4 4 4 3.5 1

x 105

x 107

x 105

x 105 x 105 x 105

Dose 398/385 1127/1146 1112/1095 357/348 206/199 108/107

Number Enrolled VaccinePlacebo

-

10-26 wk

5-25 wk 3-5 mo 8-18 wk 6 2 4 wk

Age of Vaccines

-

G1

G1, G3 G1, G2 G1 G3

Circulating Strains

Table 1. SUMMARY OF EFFICACY TRIALS OF CURRENTLY LICENSED VACCINES OR VACCINES IN DEVELOPMENT

49 68 48 50 67 89

80 91 88 69 69 78-100

Severe Disease

Vaccine Efficacy All RV Disease

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& BRESEE

by multiple passage, was developed by Bernstein et al.'j In a recently completed, randomized, placebo-controlled, double-blinded multicenter trial with US children given two doses, vaccine efficacy was 8970, the highest reported for any rotavirus vaccine (see Table l).4Low-grade fever after the first dose was found in 19% of vaccinees and was the only side effect observed. An immune response to vaccine was detected in 94% of vaccinees. Of potential concern in the use of a live, attenuated human rotavirus as a vaccine is the possibility that, like poliovirus, this vaccine strain will revert to a virulent form during replication in the infected infant or following spread to human contacts. A second live attenuated human rotavirus vaccine candidate, RV3, has been developed by Bishop et al. and has been found to be safe and well tolerated in healthy volunteers.2 Further efficacy studies of this vaccine candidate are planned.

TETRAVALENT RHESUS ROTAVIRUS VACCINE In August 1998, RRV-TV, as 4 X lo5 plaque-forming units (pfu) per dose (Rotashield), was licensed by the Food and Drug Administration (FDA), and recommended by the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians for routine vaccination of healthy infants at ages 2, 4, and 6 months as part of their regular childhood immunizations.', l3 Rotashield was the first and remains the only rotavirus vaccine yet to be licensed. This vaccine incorporates RRV (G3 serotype specificity) with three reassortants: DxRRV (serotype Gl), DS-lxRRV (serotype G2), and ST3xRRV (serotype G4). Licensure and subsequent recommendation of this vaccine was based on the disease burden associated with rotavirus in the United States, the proven efficacy and safety of the vaccine in prelicensure trials, and the predicted favorable cost-effectiveness of a rotavirus vaccination program. Efficacy

Before licensure, seven large efficacy trials were conducted using RRV-TV at two dosages, three at lo4 pfu of each strain and four at a tenfold higher dose (the dose at which the vaccine was subsequently 37, 45* 46, 72 In all trials, three doses of vaccine were given to li~ensed).~, optimize the immune response to all of the component antigens. Like trials studying the earlier vaccines, the first three trials using a low-lose RRV-TV vaccine yielded variable results. A multicenter trial in the United States3demonstrated an efficacy of 57%, while trials in and Brazil%found little or no efficacy. The data from the Peruvian and Brazilian studies, however, have been reevaluated recently using the same scoring system for disease severity used in later trials.47The reanalyzed data showed that, in the Peruvian study, one dose of vaccine

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yielded 64% protection against pure cases of moderate to severe rotaviru5 disease (i.e., those in which no other enteropathogen was found). In Brazil, a trend in preventing "all" and "pure" moderate to severe cases of rotavirus diarrhea (44% and 45%, respectively) occurred, and the vaccine was 75% protective against pure severe rotavirus diarrhea. The efficacy of RRV-TV at the higher dose was evaluated in four field trials, two in the United States64, and one each in Venezuelab1and Finland37(see Table 1).The findings of all four studies were similar; the vaccine demonstrated 48% to 68% efficacy against any rotavirus diarrhea, 38% to 91% against moderate disease, and 70% to 100% efficacy against severe diarrhea. The studies demonstrated a 50% to 100% efficacy in preventing doctor visits for evaluation and treatment of rotavirus diarrhea. The vaccine was also effective in reducing the duration of rotavirus diarrhea. The trial in Finland demonstrated 100% efficacy in preventing rotavirus hospitalizations and protection from nosocomially acquired rotavirus diarrhea in vaccinated children. In extended followup in the study in Fmland, protection against severe disease persisted through three rotavirus seasons.38The vaccine was effective in preventing 64, 72 infections with both serotupe G1 and nonserotype G1 viru~es.3~, The vaccine has been demonstrated to have consistently high efficacy when tested in both developed and developing countries. In addition, with the reanalysis of the data from the low-dose South American trials, the efficacy found in all seven trials is remarkably consistent, despite variability in study setting. Safety

RRV-TV was administered to almost 7000 infants 6 to 28 weeks of age in clinical trials.13 Overall, a statistically significant excess of both low-grade fever (over 38°C) and high fever (over 39°C) was seen following the first dose of vaccine compared with placebo. Fevers usually occurred 3 to 5 days after administration of vaccine, were low grade, and occurred in fewer than 25% of recipients. Decreased appetite, irritability, and decreased activity also were reported following the first dose of vaccine in some trials; these symptoms were associated closely with fever.39A statistically significant excess of low-grade fever (over 38°C) also was noted after the second dose of RRV-TV. No increase in any symptoms was noted after the third dose of RRV-TV. vaccinated children had a signifiIn the efficacy study in cantly increased rate of diarrhea after the first dose of vaccine compared with placebo recipients; diarrhea also was associated with fever.39No significant differences in vomiting were demonstrated between vaccinees and placebo recipients. RRV-TV and lntussusception

Intussusception is a bowel obstruction in which one segment of bowel becomes enfolded within another segment. It is most common

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among young children, especially infants 4 to 10 months of age.” In prelicensure vaccine trials, five cases of intussusception occurred among 10,054 vaccine recipients. A further analysis found that the rate of intussusception among vaccine recipients was not significantly different from the rate of intussusception among placebo recipients in the same tria1s.g In addition, the absence of a seasonal increase in intussusception in the general population, as might be expected with a disease associated with natural rotavirus infection, provided ecologic evidence against an association with vaccine. Even so, three of the five cases occurred among vaccinated children within 6 to 7 days of receiving rotavirus vaccine. The ACIP noted that the association of rotavirus vaccination and inhssusception appeared to be temporal rather than causal, but postlicensure surveillance was needed for these and other rare adverse events that might occur after ~accinati0n.l~ On the basis of these data, intussusception was included as a potential adverse reaction on the package insert, and the Vaccine Adverse Event Reporting System (VAERS) was monitored closely for reports of the disease. Following licensure, from September 1, 1998 to July 7, 1999, 15 cases of intussusception among infants who had received RRV-TV were reported to VAERS.12 Of these, 13 (87%) developed intussusception following the first dose of the three-dose RRV-TV series, and 12 (80%) of 15 developed symptoms within 1 week of receiving any dose of RRVTV. Intussusception was confirmed radiographically in all 15 patients. Eight infants required surgical reduction, and one required resection of 18 cm of distal ileum and proximal colon. Histopathologic examination of the distal ileum showed lymphoid hyperplasia and ischemic necrosis. All infants recovered. The median age of patients was 3 months (range: 2 to 11 months). Estimates of the incidence of intussusception before the licensure of rotavirus vaccine range from 0.39 to 0.74 per 1000 person-years among children younger than 12 months.12The background rate of intussusception among infants under 12 months of age was 0.39 per 1000 personyears in four large health maintenance organizations on the West Coast (Vaccine Safety Datalink [VSD]) during the period 1991 to 1997 (CDC, unpublished data). Slightly higher background rates were reported previously using hospital discharge data from New York State (1991 to 1995, 0.5 per 1000) and Northern California Kaiser Permanente (1995 to 1996, 0.74 per 1000); the latter is a subset of the VSD data cited above. In the VSD sites, the incidence was highest (0.4 to 0.8 per 1000) among infants 4 to 10 months of age, with lower rates among younger infants (0.06 to 0.07 per 1000 among those 2 months of age, and 0.3 per 1000 among those 3 months of age). A similar pattern was found in the New York State hospital discharge data, although slightly higher rates were reported for most age groups. Using background rates for intussusception from the VSD sites and New York State hospital discharge data and assuming that 1.5 million doses of RRV-TV had been administered, 10 to 16 cases of intussusception among vaccine recipients within 1 week of vaccination would be

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expected to occur by chance alone; 12 of the 15 cases developed intussusception within 1 week of receiving RRV-TV.12Although the number of reported cases of intussusception with onset within 1 week of receipt of vaccine was in the range expected, because reporting to VAERS of adverse events following vaccination is incomplete,7O the actual number of cases of intussusception among recipients of RRV-TV was thought to be greater than that reported. In response to the VAERS reports, a preliminary analysis of data from an ongoing postlicensure study at Northern California Kaiser Permanente (NCKP) was performed.12 Cases of intussusception occurring from December 1, 1998 to June 10, 1999, were identified among infants age 2 to 11 months at NCKP by review of hospital discharge diagnoses, admitting diagnoses for the records for which discharge summaries were not yet complete, and computerized records of all barium enemas performed on children less than 1 year old. Relative risks were ageadjusted because of differences in the ages of vaccinated and unvaccinated infants, and p values were calculated by Poisson regression. At NCKP, 16,627 doses of RRV-TV were administered to 9802 infants from December 1,1998 to June 10,1999. Nine cases of intussusception among infants were identified hith onset during that same period, all of which were confirmed radiographically or surgically. Three were among vaccinated children, with intervals of 3,15, and 58 days following vaccination. The rate of intussusception among never-vaccinated children was 45 per 100,000 infant-years, and among children who had received RRV-TV the rate was 125 per 100,000 infant-years (age-adjusted relative risk [RR] = 1.9, 95% CI = 0.5-7.7, p = 0.39). The rate among children who had received RRV-TV during the preceding 3 weeks was 219 per 100,000 infant-years (age-adjusted RR = 3.7,95% CI = 0.7-19, p = 0.12). Among children who had received RRV-TV during the previous week, the rate was 314 per 100,000 infant-years (age-adjusted RR = 5.7, 95% CI = 0.7-50, p = 0.11). In addition, preliminary data on intussusception from Minnesota were analyzed.12Intussusception cases were identified among infants 30 days to 11 months old who were born after April 1, 1998, and were hospitalized with radiographically or surgically confirmed intussusception with onset during the period from November 1, 1998 to June 30, 1999. During this period, 62,916 doses of vaccine were distributed. Eighteen cases of intussusception were identified, five of which were among infants who had received RRV-TV. Vaccinated children had a median age of 4 months (range: 3 to 5 months), and unvaccinated children had a median age of 7 months (range: 5 to 9 months). Four of the five RRVTV recipients with intussusception required surgical reduction, and 5 of 13 unvaccinated children required surgical reduction. Intussusception occurred after receipt of dose one (two children), dose two (two children), and dose three (one child). The five RRV-TV recipients developed intussusception within 2 weeks of receipt of vaccine (range: 6 to 14 days). Assuming 85% of RRV-TV doses distributed in Minnesota were administered, the observed rate of intussusception within 1 week of receipt of RRV-TV was 292 per 100,000 infant-years.

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Preliminary data from Minnesota and from NCKP both suggested an increased risk for intussusception following receipt of RRV-TV, and the observed rates of intussusception among recently vaccinated children were similar in both studies. The number of cases of intussusception among vaccinated children was small at both NCKP and in Minnesota, however, and neither study had adequate power to establish a statistically significant difference in incidence of intussusception among vaccinated and unvaccinated children. In July 1999, CDC recommended that health-care providers and parents postpone use of RRV-TV for infants, at least until November 1999, when additional data from the case-control study would be available.'* Also at that time, the manufacturer, in consultation with the FDA, voluntarily ceased further distribution of the vaccine. Several studies are under way to define and quantify the association. A multistate case-control study of cases of intussusception occurring between November 1, 1998 and June 30, 1999 in the 19 states with the highest reported vaccine distribution was begun in June 1999. Preliminary results of the case-control study show a significantly elevated risk A cohort study in 10 during the 7 to 14 days fellowing va~cination.~~ health maintenance organizations (HMOs) with automated databases for case finding and vaccine status also has been initiated. On October 22, 1999, the ACIP, after a review of scientific data from several sources, including preliminary data from both the managed care cohort and the multistate case-control studies, concluded that intussusception occurs with significantly increased frequency in the first 1 to 2 weeks after vaccination with RRV-TV, particularly following the first dose.I4 The ACIP and the AAP withdrew their recommendations for vaccination of infants in the United States with RRV-TV, and the manufacturer withdrew the vaccine from the market.I4 ROTAVIRUS VACCINE: CURRENT ISSUES

Several questions remain concerning the association between this rotavirus vaccine and intussusception. The answers will be of great importance for the development and acceptance of the next generation of rotavirus vaccines. What Is the Mechanism for the Association Between RRV-TV and Intussusception?

Several hypotheses have been suggested to explain the link between RRV-TV and intussusception. Possibly, intussusception might be associated with a variety of enteric infections, or more specifically with wild-type rotavirus infections. That is, the association may not be RRVTV-specific, but a general phenomenon of infections of the gastrointestinal tract, possibly leading to a common pathway of lymphoid hypertro-

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phy as the proximate cause of intussusception. In this hypothesis, the association between RRV-TV and intussusception reflects the shift in the age distribution of intussusception, as RRV-TV infection replaces naturally occurring rotavirus infection as an important inciting event. A second hypothesis is that virulence of RRV differs from that of the wildtype human rotaviruses, and the association with intussusception is, therefore, an RRV-TV-specific phenomenon. Evidence to support these hypothesesis are presented subsequently.

Does Natural Rotavirus Infection Cause Intussusception?

The first hypothesis would be supported by data showing an association between naturally acquired rotavirus gastroenteritis and intussusception. Although it *is biologically plausible that rotavirus infection could cause hypertrophy of intestinal lymphoid tissue leading to intussusception (and enlarged mesenteric lymph nodes have been noted in children who have died with rotavirus gastroenteritis'l), an association between infection with wild-type rotavirus and intussusception has not been well documented. As noted previously, the marked wintertime peaks associated with rotavirus disease in the United States are not seen in hospitalizations for intussu~ception,6~ as might be expected if wildtype rotavirus infection were an important cause. Similarly, in the VSD sites, intussusception rates were highest in spring and early summer (CDC, unpublished data), whereas diarrhea-associated hospitalizations and emergency room visits (many that are due to rotavirus) peaked in November through February in the California sites and January through April in the northwestern Although wild-type rotavirus infection might account for some cases of intussusception, these data do not support a major role. Rotavirus infection has been reported among young children with intussusception." 5a, 56 In 1978, Konno et a1 reported detecting rotavirus by electron microscopy in stools of 11 of 30 Japanese infants and young children with intussusception, and suggested that rotavirus might be associated with intussuscepti~n.~~ A prospective study of 64 French children with intussusception found that six had antibody rises to rotavirus; however, four had a concomitant adenovirus infection and a fifth case likely represented nosocomial rotavirus infection in a child hospitalized for intussu~ception.~~ Finally, in a study from Australia, Mulcahy et a1 found evidence of rotavirus infection in only 2 of 24 children with intussusception surveyed prospectively.54These investigators also failed to demonstrate the seasonal variation in the occurrence of intussusception that was seen for rotavirus infection. Although the evidence available does not indicate that rotavirus infection acquired naturally represents a major risk factor for intussusception, few data exist and the data that are available are ecologic or

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uncontrolled. This question remains an important one, and studies are being planned to address this question using better designs. Is the RRV Strain Important in Intussusception?

RRV has several properties that could play a role in the development of intussusception, although none is currently implicated. Of the four rotavirus strains in RRV-TV, RRV is shed in the largest quantities after the first dose, suggesting that it is the strain most likely to cause fever and perhaps most likely to give rise to lymphoid hyperplasia leading to intussusception after the first dose.s5 RRV also causes diarrhea across species, and therefore it might not be fully attenuated.63Extra-intestinal spread causing hepatitis was observed in mice with severe combined immunodeficiency (SCID) mice and in sucklings of one strain of inbred mice given RRV, suggesting that the virus retains virulence when introduced into other species.77 Is lntussusception Likely to Occur with Other Candidate Rotavirus Vaccihes?

Because the etiology of intussusception associated with RRV-TV is not known, it is not clear whether other candidate oral rotavirus vaccines also will cause intussusception. Several possibilities exist depending on the possible reasons for intussusception with RRV-TV. If the intensity of replication in the gastrointestinal tract is correlated with intussusception, then bovine reassortant vaccines that replicate relatively poorly in the gastrointestinal tract may result in less intussusception compared with the attenuated human vaccine strain, 89-12, and RRV which replicate better. If natural infection is related to intussusception (i.e., if the risk is not strain specific), then any candidate vaccines also could cause intussusception. If the association with intussusception is unique to RRV, then other vaccines may not have problems. Further studies are necessary to determine the risk of intussusception for the other oral candidate vaccines. How Can Other Candidate Rotavirus Vaccines Be Evaluated Safely?

Given the estimated rate of one case of intussusception per 5000 doses of RRV-TV,55safety studies of new rotavirus vaccines will have to be large to exclude the possibility of intussusception with reasonable certainty. In addition, the balance of risks and benefits will differ between the developed and developing worlds. In the United States, new rotavirus vaccine trials could be exceedingly difficult to carry out, owing to public concern about vaccine safety and the recent withdrawal of RRV-W. The risks of causing an uncommon, but serious, adverse event

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with vaccine for a disease accounting for only 20 deaths per year may not be justified, especially because early diagnosis and treatment of severe dehydration from diarrhea are readily available. These concerns may not be applicable in developing countries, where the burden of disease is substantially higher and the risks and benefits of rotavirus vaccination are likely to be different. Currently, the World Health Organization (WHO) has suspended all rotavirus vaccine trials in developing countries pending the results of the investigations of the association of intussusception with RRV-TV. Should the RRV-TV Vaccine Be Used in the Developing World?

The worldwide burden of rotavirus disease remains substantial, and RRV-TV might be useful in reducing morbidity and mortality associated with childhood diarrhea if introduced into immunization programs in developing countries. Several reasons exist to adopt RRV-TV immunization of infants as the primary public health intervention to prevent rotavirus disease in the less-developed countries. First, similar rates of illness among children in industrialized and less-developed countries indicate that clean water supplies and good hygiene have not decreased the incidence of rotavirus diarrhea in developed countries, and therefore further improvements in water or hygiene are unlikely to have a substan35, 59,69,74, 78 Second, the magnitude of the impact caused by tial impa~t.2~. rotavirus on childhood health in many countries, and the probable substantial delay in development of new rotavirus vaccine, favor proceeding with the use of RRV-TV. The decision by developing countries regarding the possible use of RRV-TV, however, is a complicated one. The benefits of RRV-TV to the developing world have not been clearly defined in the efficacy trials completed thus far. Although high efficacy was observed in Venezuela, several factors, such as younger age at infection, potentially larger inoculum of infection, presence of unusual strains of rotavirus, interference by other enteropathogens, and poorer nutritional status of children, could adversely affect the efficacy of rotavirus vaccine in developing countries. Similarly, the risk of intussusception in developing countries is largely unknown and is likely to differ from that in the United States. Each country will need to make its own assessment of the costs, risks, and benefits of using RRV-TV. Further studies of the performance of RRV-TV in the developing world are necessary to define the expected benefits and risks of a vaccination program. References 1. American Academy of Pediatrics Committee on Infectious Diseases: Prevention of

rotavirus disease: Guidelines for use of rotavirus vaccine. Pediatrics 102(6):1483-1491, 1998

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Address reprint requests to Penelope H. Dennehy, MD Division of Pediatric Infectious Diseases Rhode Island Hospital 593 Eddy Street Providence, RI 02903 e-mail [email protected]