Rotavirus vaccine withdrawal in the United States: The role of postmarketing surveillance
n August 31, 1998, Rotashield (Wyeth Laboratories, Marietta, Pennsylvania) was licensed by the United States Food and Drug Administration for oral administration to infants at two, four and six months of age in the United States. This product is a live, attenuated rhesus rotavirus- based tetravalent vaccine (RRV-TV). Each dose of vaccine contains 1X105 plaque forming units of each of four strains: one is a rhesus rotavirus strain with human serotype 3 specificity, and the three other strains are single gene human-rhesus reassortants that contain the human gene for serotype 1, 2 and 4 antigens, respectively, along with other genes from the parent rhesus rotavirus strain. Shortly following licensure of the vaccine in the United States, the Advisory Committee on Immunization Practices (ACIP) recommended routine im-munization with three oral doses of RRV-TV for infants at age two, four and six months of age for the prevention of rotavirus disease in the United States. The rationale for recommending use of the vaccine was the following.
• The rate of illness due to rotavirus among children in the United States is quite high.
• Although the implementation of oral rehydration programs to prevent dehydration has reduced to a great extent mortality due to diarrhea-associated disease in the United States, rotavirus continues to cause significant morbidity particularly in terms of hospitalizations.
• Trials of RRV-TV vaccine in the United States, Finland and Venezuela showed efficacy rates of approximately 80% for the prevention of severe disease and of 48% to 68% against all rotavirus induced diarrheal episodes.
• Prelicensure clinical trials data suggested that the vaccine was quite safe. Excess fever, decreased appetite, irritability and decreased activity were reported after the first dose of the vaccine. Only one study suggested an increased rate of diarrhea after the first dose of vaccine compared with placebo recipients. There was no statistically significant difference between vaccinees and placebo recipients in the rate of intussusception (five of 10,000 recipients of any reassortant vaccine versus one of 4632 placebo recipients).
The American Academy of Pediatrics also recommended RRV-TV for use in infants two, four and six months of age for prevention of rotavirus disease. However, it stated that “routine implementation of this recommendation will require reconciliation of related economic issues”.
From September 1, 1998 to July 7, 1999, 15 cases of intus-susception among infants who had received RRV-TV were re-ported to the Vaccine Adverse Event Reporting System (VAERS) (12). Of the 15 infants, 11 developed intussusception following the first of the three dose series and 12 developed the symptoms within one week of receiving any dose of RRV-TV. Intussusception was confirmed radiographically in all 15 patients. Eight infants required surgical reduction, and one required resection of 18 cm of the distal ileum and proximal colon. Histopathological examination of the distal ileum indicated a lymphoid hyperplasia and ischemic necrosis. All infants recovered. The median age of the patients was three months, and reports were received from seven states. Based on prevaccine data on the incidence of intussusception in the United States and based on vaccine distribution data, 14.7 cases of intussusception were to be expected within one week of receipt of rotavirus vaccine due to temporal association without causation. However, in light of under-reporting of vaccine-associated adverse effects, these data suggested an increased risk of intussusception following rotavirus vaccination. In addition, surveillance data from the Northern California Kaiser Permanente Health Maintenance Organization and from the states of Tennessee and Minnesota also showed a trend towards the increased risk of intussusception following receipt of rotavirus vaccine. Although none of these findings were found to be conclusive, the consistency of the findings from the three data sources raised strong concerns. Based on these concerns, the Centers for Disease Control and Prevention (Atlanta, Georgia) recommended postponing administration of RRV-TV to children scheduled to receive the vaccine at least until November 1999. The manufacturer in consultation with the Food and Drug Administration voluntarily ceased further distribution of the vaccine.
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