Intussusception and Rotavirus Vaccine

A licensed rotavirus vaccine became available in North America on August 31, 1998. The Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) subsequently recommended its routine use for vaccination of healthy infants (Pediatrics 1998;102:1483-91 ; JAMA 1999;281:601-3 ). In prelicensure studies this tetravalent rhesus rotavirus-based reassortant vaccine (RRV-TV), developed by the National Institutes of Health and then by Wyeth-Lederle (RotaShield), was highly effective in preventing severe gastroenteritis due to rotavirus (Pediatrics 1996;97:7-13 ). In these initial studies intussusception was noted in five infants among the 10,054 vaccine recipients, but this rate did not differ significantly from controls or from observed background rates in several populations (Pediatr Infect Dis J 1998;17:924-5 ). Nevertheless, postlicensure surveillance for this and other potential adverse events was recommended by the ACIP. By June 1999, 13 cases of intussusception were reported to the Vaccine Adverse Events Reporting System (VAERS) after an estimated 1.5 million doses of the vaccine had been given. About 10 to 16 cases of intussusception among infants would be expected by chance. The disconcerting feature was that a number of cases occurred during the first week after vaccine administration. On June 14, 1999 the AAP issued the following interim recommendations: Clinicians temporarily should suspend administration of rotavirus vaccine to unimmunized and partially immunized children, pending the collection and critical evaluation of additional information. Parents or guardians of children who have received RRV-TV within a period of approximately 3 weeks should be advised to promptly contact their physician if signs or symptoms compatible with intussusception develop. All cases of intussusception that occur after administration of RRV-TV should be reported to VAERS (1-800-822-7967; www.fda.gov/cber/vaers/report.htm). It should be emphasized that these data are preliminary, are very limited, and must be interpreted with caution. The U.S. Centers for Disease Control and Prevention (CDC) is further investigating this issue via three mechanisms: 1) VAERS, 2) a postlicensure study of adverse events in Northern California (Kaiser-Permanente Medical Care Program), where 20,000 vaccinated infants are under active surveillance, and 3) active case finding in 15 states. What is one to make of these events? If the association is shown not to be one of cause and effect (it is hard to disprove rare events), then the previous ACIP/AAP recommendations could be reinstituted, because the case for universal rotavirus vaccination has been well established. If it appears that there is a causal link, that will be a very disappointing outcome in the long process of developing an effective oral rotavirus vaccine. If the rhesus rotavirus-based vaccine is rejected on these grounds, might a bovine rotavirus-based vaccine also come under suspicion? Bovine reassortant vaccines may be equally efficacious and less reactogenic, at least in terms of fever. Whether they would also prove less likely to predispose to intussusception would need to be established. Human strain-based vaccines also might be less likely to cause intussusception because there is no definite association of community (human) rotavirus infection and intussusception (in contrast to adenovirus infection). For developed countries, if intussusception is proven to be a side effect, such a complication would require full reassessment of whether rotavirus vaccine should be used. For developing countries, where mortality remains high after rotavirus infection, difficult judgments would need to be made about relative mortality rates-clearly a disincentive in addition to the current high price of the vaccine. These reports of intussusception will stimulate more vigorous activity in the development of non-living rotavirus vaccines, including particle, vector, and DNA candidates, but unfortunately, it is likely to be several years before they become available. Graeme Barnes, MD, FRACP Department of Gastroenterology and Clinical Nutrition; Royal Children's Hospital, Melbourne, Australia