A Quadrivalent Vaccine

Rotashield is the live attenuated rotavirus vaccine that was approved by the FDA in 1998, but removed from the market only a little more than a year later. The vaccine contained three reassortants, each with a different human gene encoding a specific serotype of VP4 or VP7. The human serotypes G1, G2, and G4 were represented in the vaccine. For the G3 strain, they used the whole rhesus monkey strain, because it was genetically very similar to the human strain. The animal genes attenuated virulence while the human genes evoked virus-specific antibodies.

Flow chart of production of RotaSheild, human rotavirus (HRV) x rhesus rotavirus (RRV)reassortant quadrivalent vaccine with VP7 serotype 1, 2, 3, and 4 specificity. Note that the originial simian VP7 serotype 3 was left unaltered in the vaccine.

Pre-Licensure Trials

Four large-scale efficacy trials were run, and they all found that Rotashield reduced the duration of diarrhea for infected children, and prevented infections with all serotypes. These results looked promising, and the Food and Drug Association (FDA) approved Rotashield for use. See the timeline of events below.

Post-Licensure Intussusception

However, shortly after this approval, cases of intussusception were reported to the Vaccine Adverse Event Reporting System (VAERS), a surveillance system which collects information about possible side effects of licensed vaccines. VAERS is a program of the FDA and CDC. Intussusception is a condition in which one segment of the bowel enfolds within another segment, causing obstruction. This condition was seen in the pre-licensure clinical trials, but in rates no higher than rates in non-vaccinated children. However, after licensure, VAERS recorded 76 cases in total, with 70% of those cases occurring after the first dose of vaccine. Due to this surveillance, the CDC recommended that vaccine use be suspended until further studies could be performed. One study found one case in every 5000 to 9500 vaccinated infants, with the highest risk after the first dose.

A diagram showing a normal and intussuscepted illeo-cecal junction

Removal from the Market

These findings prompted the Advisory Committee on Immunization Practices (ACIP) to withdraw its recommendation of Rotashield. The makers of Rotashield, Wyeth-Ayerst had withdrawn the vaccine from the market a week earlier.

How Could Rotashield^® Cause Intussusception?

The "unique strain" hypothesis posits that the G3 strain, that was a simian rotavirus strain RRV and not a human-rhesus re-assortment strain, could invade the small intestines, possibly leading to intussusception.

The "heterologous host strain" hypothesis is that because cross-species infections are rare, immunization with Rotashield may differ in certain ways with natural infection, and the biological features of the heterologous strains may lead to intussusception.

The "bolus dose" hypothesis states that the critical difference between Rotashield immunization and natural infection is the dose of virus. In natural infections, relatively small numbers of virus are ingested, and they infect the proximal small intestine first. Immunization, on the other hand, administers a large number of viruses, and they may replicate in sites different from those of natural infection.

Finally, the "viral replication" hypothesis focuses on how the peak times of intussusception corresponded to the peak time in virus replication, and speculates that the replication may occur in a manner different from natural infection

Timeline of Events