New Rotavirus Vaccines Safe and Effective in Large Clinical Trials

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The January 5 issue of The New England Journal of Medicine carries reports of 2 large clinical trials of promising new oral vaccines for rotavirus, the leading recognized cause of diarrhea-related illness and death among infants and young children. Every year, rotavirus is associated with 25 million clinic visits, 2 million hospitalizations, and more than 600,000 deaths worldwide among children younger than 5 years of age. Development of a safe and effective rotavirus vaccine has become a high priority, particularly but not exclusively in developing countries, where the burden of disease is highest. A tetravalent rhesus–human reassortant vaccine was withdrawn from the market due to an association with intussusception, prolapse of a portion of the intestine within another immediately adjacent portion of intestine. Thus, ruling out such a risk has become critical for the licensure and universal use of any new rotavirus vaccine.

The new vaccines, Rotateq from Merck and Rotarix from GlaxoSmithKline, are both live oral vaccines intended to be given to infants at the same time as their immunizations for diphtheria, pertussis, and tetanus, but they differ in their approaches, strains, and formulations. Rotarix is a monovalent vaccine derived from the most common human rotavirus strain, G1P[8], that has been attenuated by serial passage and is administered in 2 oral doses 1 to 2 months apart. Rotateq is a pentavalent vaccine based on a bovine strain, WC3, that contains 5 human–bovine reassortant viruses. WC3 is naturally attenuated for humans but is not broadly cross-protective, so each reassortant virus contains a single gene encoding a major outer capsid protein from the most common human serotypes. The bovine virus grows less well in the human intestine, so the aggregate titer required to immunize a child is greater. In addition, the vaccine strains are infrequently shed in the stool, and 3 oral doses are required, with at least a month between doses.

The Rotarix study involved more than 63,000 healthy infants from 11 Latin American countries and Finland. Two oral doses of the live attenuated G1P[8] HRV vaccine were found “highly efficacious in protecting infants against severe rotavirus gastroenteritis.” The authors with the Human Rotavirus Vaccine Study Group stated that the doses “significantly reduced the rate of severe gastroenteritis from any cause, and were not associated with an increased risk of intussusception. For this randomized, double-blind, placebo-controlled, phase 3 trial, investigators from Argentina, Brazil, Chile, Colombia, the Dominican Republic, Honduras, Mexico, Nicaragua, Panama, Peru, Venezuela, and Finland recruited and enrolled infants 6 to 13 weeks old at public pediatric clinics or hospitals. The infants were randomly assigned to receive 2 oral doses of either the HRV vaccine or placebo–the first dose at approximately 2 months and the second at 4 months of age. After the administration of the second dose, the overall cohort was followed for a median duration of 100 days after the first dose for the assessment of any adverse events, including the occurrence of intussusception (the safety cohort, evaluated at visit 3), and a subgroup of infants was followed for 9 to 10 months for the assessment of efficacy (the efficacy cohort, evaluated at visit 4).

According to the authors, vaccine efficacy against severe rotavirus gastroenteritis and against rotavirus-associated hospitalization was 85% (P < .001 for the comparison with placebo) and reached 100% against more severe rotavirus gastroenteritis. Hospitalization for diarrhea of any cause was reduced by 42%. During the 31-day window after each dose, 6 vaccine recipients and 7 placebo recipients had definite intussusception, the authors say.

In the Rotateq trial, conducted by the Rotavirus Efficacy and Safety Trial (REST) Study Team, healthy infants approximately 6 to 12 weeks old were randomly assigned to receive 3 oral doses of live pentavalent human–bovine (WC3 strain) reassortant rotavirus vaccine containing human serotypes G1, G2, G3, G4, and P[8] or placebo at 4–10-week intervals in a blinded fashion. Active surveillance was used to identify subjects with serious adverse and other events. The 34,035 infants in the vaccine group and 34,003 in the placebo group were monitored for serious adverse events. Intussusception occurred in 12 vaccine recipients and 15 placebo recipients within 1 year after the first dose including 6 vaccine recipients and 5 placebo recipients within 42 days after any dose (relative risk, 1.6; 95% confidence interval, 0.4 to 6.4). “The vaccine reduced hospitalizations and emergency department visits related to G1–G4 rotavirus gastroenteritis occurring 14 or more days after the third dose by 94.5% (95% confidence interval, 91.2% to 96.6%),” the authors state. “In a nested substudy, efficacy against any G1–G4 rotavirus gastroenteritis through the first full rotavirus season after vaccination was 74.0% (95% confidence interval, 66.8% to 79.9%); efficacy against severe gastroenteritis was 98.0% (95% confidence interval, 88.3% to 100%). The vaccine reduced clinic visits for G1–G4 rotavirus gastroenteritis by 86.0% (95% confidence interval, 73.9% to 92.5%).” The report concludes that the vaccine “was efficacious in preventing rotavirus gastroenteritis, decreasing severe disease and health care contacts. The risk of intussusception was similar in vaccine and placebo recipients.”

In an editorial in the Journal, Drs Roger I. Glass and Umesh D. Parashar of the Centers for Disease Control and Prevention note that despite their differences, “both vaccines demonstrate an impressive efficacy profile. The slight differences in observed efficacy against severe rotavirus disease (85% for Rotarix and 98% for Rotateq) might well be explained by differences in the classification of disease severity and the populations studied.” They note that “GlaxoSmithKline conducted its trials primarily among infants of poor and middle-income families in Latin America, whereas the Merck vaccine was tested in the United States and Finland.” In addition, Glass and Parashar also note that the magnitude of the reduction in hospitalizations for diarrhea of any cause, “a decrease that was greater than expected given the number of diagnosed cases of rotavirus” was a “particularly exciting finding of great importance to public health and to the economic burden of disease.”

For further details, see: The New England Journal of Medicine 2006;354:11–22, 23–33, and 75–77.