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Rotavirus Vaccine Withdrawn from Use
Reports of bowel blockages, known as intussusception, among small numbers of children who received the orally administered vaccine known as RotaShield, led Wyeth Lederle Vaccines, a division of American Home Products Corp., the manufacturer of this quadrivalent product, to withdraw it from the market last October. That decision came barely a year after officials at the U.S. Food and Drug Administration (FDA) licensed the vaccine, which then appeared to offer a promising means of controlling the severe diarrhea and other complications, including many deaths, that rotavirus causes at a high frequency among newborn and very young children throughout the world (ASM News, October 1999, p. 671; January 1999, p. 7).
In August 1998, FDA licensed RotaShield for general use in U.S. children in a move that recognized a 25-year period of basic research that led to discovery of the rotavirus and of basic and applied research to develop and evaluate the vaccine. A series of three clinical trials indicated that the vaccine is highly effective in protecting children against severe diarrheal bouts caused by this virus, which infects virtually all children at least once and typically several times before they reach the age of five.
In the United States, infections caused by this 70-nM, wheel-shaped virus lead to perhaps 500,000 physician visits and 50,000 hospitalizations annually, according to estimates from the Centers for Disease Control and Prevention (CDC) in Atlanta, Ga. Its effects are more severe in developing nations, where rotavirus infections cause a high number of cases of severe diarrhea and are responsible for an estimated 600,000 deaths each year.
Rotavirus infections follow a seasonal pattern in temperate zones, peaking during those months when cooler temperatures dominate. Several rotavirus serotypes circulate in human populations, but four of them appear more frequently than the others. Successive infections tend to become milder than the initial bout with this virus. For such reasons, developers sought to produce a live, attenuated vaccine, reasoning that infections would be difficult if not impossible to prevent, but natural infections that occurred following vaccination would be less likely to cause severe symptoms.
Despite initial enthusiasm for the licensed vaccine, U.S. public health officials in mid-1999 recommended suspending its use temporarily and, by October of last year, urged a more permanent halt in response to concerns raised by the intussusception reports. Sharing those concerns, Wyeth Lederle withdrew the product from the market in October and requested that all vaccine doses be returned, noting that the ``use of RotaShield should not be resumed during the upcoming rotavirus season.'' CDC officials are continuing to investigate the connection between intussusception and rotavirus vaccine use.
Although there is ``no known cause'' for intussusception, investigators point to several ``possible mechanisms'' for how it may occur following use of the vaccine, including enlargement of lymphoid tissue (Peyer's patches) along the gastrointestinal (GI) tract that might lead them to invaginate and become blocked, according to Albert Kapikian from the National Institute for Allergy and Infectious Diseases (NIAID) in Bethesda, Md., who has been studying rotaviruses for several decades and was involved in developing the vaccine.
By now there are several reports describing a possible connection between that GI complication and vaccine use. Although the samples are small from a statistical standpoint, making those interim reports potentially misleading and far from conclusive, their ``consistency raises strong concerns,'' Kapikian says. ``Many important questions remain to be answered.''
For instance, intussusception was not a statistically significant complication spotted during the three prelicensure clinical trials. Moreover, in some trials, when this complication showed up at all, it did so following administration of the second or third dose of the vaccine, rather than after the first as occurred in the adverse event reports that came in after the vaccine was licensed. ``My favorite question is `what's the overall attributable risk?''' Kapikian says. If that risk proves low enough, health officials in some developing countries might decide that it is worth incurring the risk of this rare complication while avoiding the far higher, often deadly risk of young children incurring rotavirus disease.
Jeffrey L. Fox
Jeffrey L. Fox is the ASM News Current Topics and Features editor.
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