THE ROTAVIRUS VACCINE STORY

P Heaton, J Sadoff, M Dallas, J Heyse, D Margolskee

Merck Research Laboratories, USA

Background: The public health impact of rotavirus disease worldwide has triggered the development of several vaccine candidates. In 1998, a rhesus rotavirus tetravalent vaccine (RRV-TV) was licensed in the United States. This vaccine is no longer recommended for use in the US because of data describing an increased incidence of intussusception in vaccinated children, particularly within the first 2 weeks after the first dose of a 3-dose regimen. Intussusception is an uncommon form of bowel obstruction (incidence 50/100,000 infant years among children <2 years old) in which the intestine telescopes on itself. It is potentially fatal, but outcomes are favorable if treated promptly.

Objective: To show that Merck’s investigational rotavirus vaccine is efficacious and safe with respect to intussusception in healthy infants.

Study Design: A trial has been designed which combines: a relatively large sample size, continuous monitoring by a Data Safety Monitoring Board during predefined time points following vaccination in relation to predefined safety boundaries, and group sequential design. Extensive simulations have been performed to ensure the study design provides power for stopping the trial early if the Merck investigational rotavirus vaccine is associated with an increased risk of intussusception similar to that of RRV-TV.

Conclusions: This design combined with education about intussusception and active monitoring of each child in the trial minimizes risk to the participants. If no safety boundaries are crossed, the trial reaches completion and satisfies the primary safety hypothesis; the study will show that the vaccine was generally well tolerated and clinically acceptable with respect to intussusception.