After only a little more than a year on the market, the first rotavirus vaccine (RotaShield, Wyeth Lederle Vaccines) was withdrawn after reports of intussusception occurred following receipt of the vaccine. Wyeth pulled the product from the market and requested all doses be returned. The Advisory Committee on Immunization Practices (ACIP) soon followed with a recommendation that RotaShield no longer be used under any circumstance.
The Food and Drug Administration (FDA) has yet to take action regarding the vaccine's license, but continues to evaluate data as it becomes available, according to William Egan, PhD, acting director of the Center for Biologics Evaluation and Research at the FDA.
The events surrounding rotavirus vaccine during 1999 were chosen as one of the top 10 stories of the year by the Infectious Diseases in Children editorial advisory board.
Reports of intussusception linked to rotavirus vaccine began surfacing in July through the Vaccine Adverse Events Reporting System (VAERS) and prompted federal health agencies to call for a suspension in use of the vaccine until further notice.
Further data was presented during the October ACIP meeting, during which the committee unanimously voted to rescind its recommendation regarding the use of rotavirus vaccine. The vote was based on an overwhelming amount of data that indicated a strong association between rotavirus vaccine and bowel obstruction among some infants during the first one to two weeks following vaccination.
As of late November, a total of 102 confirmed and presumptive cases of intussusception following receipt of rotavirus vaccine were reported to VAERS. Lynn Zanardi, MD, National Immunization Program (NIP) at CDC, told Infectious Diseases in Children that 57 of those cases had onset within seven days of receipt of the vaccine.
"One hundred two cases of intussusception is the total number of reports received. However, many of these occurred weeks or months following vaccination. It is unlikely that these are associated with vaccination," she said. "Those cases of intussusception occurring within one week are more likely to be related. There is a baseline rate of intussusception in infants; therefore, some cases of intussusception will have occurred following vaccination just by chance."
Of the 57 cases, 29 underwent surgery; seven required bowel resection. One fatal case was reported in a 5-month-old, according to John Livengood, MD, director of the Epidemiology and Surveillance Division, NIP.
At the ACIP meeting, Livengood also presented data from a population-based cohort study of intussusception and rotavirus vaccination. The data were collected from the Vaccine Safety Datalink (VSD), including four HMOs consisting of 2% of the U.S. population, which was also linked with computerized vaccination, medical visits and covariates records. Additional results are still pending.
The preliminary results of the population-based cohort study suggested that rotavirus vaccine is associated with elevated risk of intussusception, with the greatest risk between three and seven days after vaccination.
The case definition of intussusception was defined as intussusception that occurred in a child age 1-11 months (born between Dec. 2, 1997-June 15, 1999). The cases had to have occurred between Dec. 1, 1998 and July 16, 1999, and were diagnosed by radiological procedure (barium or air contrast with barium enema), or directly at the time of surgery or at autopsy.
Case-series and case-control analyses based on a 19-state investigation of intussusception in recipients of rotavirus vaccine was also conducted with the NIP and local and state health departments.
The case series data indicated an overall risk of intussusception was increased by 60% after rotavirus vaccination among cases ever vaccinated, compared with cases who were never vaccinated (P<0.0003). For dose one, the risk of intussusception was increased 19-fold in the first three to seven days after vaccination and almost fourfold (3.6) in the eight to 14 days after vaccination (P<0.0002).
Similar results occurred with the interim results of the case-control analysis. These data indicate that the risk of intussusception is increased by 80% after rotavirus vaccination in an ever vs. never comparison. For dose one, the risk of intussusception increased 25-fold in the first three to seven days following vaccination and 7.1-fold in eight to 14 days after vaccination. For dose two, the risk of intussusception increase 13.4-fold in three to seven days after rotavirus vaccination.
While the ACIP recommendation stated that RotaShield no longer be routinely given to children, the statement also stressed the clinical impact of rotavirus disease and encouraged future research toward the development of new rotavirus vaccines, said ACIP member Paul Offit, MD, chief of the section of infectious diseases, Children's Hospital of Philadelphia. "There remains a need for a safe and effective rotavirus vaccine," he said.
According to Larry K. Pickering, MD, editor of the American Academy of Pediatrics' 2000 Red Book and director of the Center for Pediatric Research, Norfolk, Va., studies must now be conducted to monitor the continuing effect of rotavirus as a cause of disease in infants and children, since the wild-type strains will continue to infect children.
"We must also continue to evaluate methods to prevent infection and disease," said Pickering, a member of the Infectious Diseases in Children editorial board.
The reports of intussusception were not a complete surprise. In rotavirus vaccine prelicensure studies, five cases were reported among 10,054 children who received various formulations of rotavirus vaccine; one case occurred in 4,633 controls. It was, therefore, listed in the package insert as a potential adverse event.
However, an association could not be established that these cases were due to rotavirus vaccine, or whether they occurred following receipt of rotavirus vaccine by chance alone. The prelicensure studies are almost always too small to definitely determine anything about rare events. "In reality, it would have been very difficult to be certain about this in studies of reasonable size in the prelicensure period," said Melinda Wharton, MD, chief of the Child Vaccine Preventable Disease Branch at the NIP, when the vaccine was first suspended.
Intussusception is an obstruction of the bowel that occurs when the bowel folds in on itself. It is most common among young children. Some cases seem to occur in association with viral infections or structured abnormalities such as polyps, but most cases have not been linked to an identified cause. The usual site of obstruction is where the small bowel joins the large bowel, but it may occur at other sites. With treatment, most patients fully recover.
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