Future looks bright for next generation of rotavirus vaccines

December 2006

This year saw two new vaccines against rotavirus in development, and although the Merck and GlaxoSmithKline rotavirus vaccines are made differently, they both had similar safety and efficacy profiles.

“We have two good rotavirus vaccines now,” said Harry Greenberg, MD, Stanford University School of Medicine. “Both appear to be safe, both appear to be highly efficacious. One is given as two doses; the other is given as three doses. One of the vaccines may have somewhat more efficacy against one of the strains, but in total efficacy they are the same.”

Second generation

The second-generation rotavirus vaccines are based on the same technology as the first rotavirus vaccine (RotaShield, Wyeth), according to Greenberg. Like the first vaccine, Merck’s rotavirus vaccine (RotaTeq) uses the generian approach to make a reassortant. In this case, the vaccine was made from a bovine virus for attenuation. Merck also added another serotype not included in the original vaccine. The four common G types plus the common P type genes are included in the Merck product.

RotaTeq, like other rotavirus vaccines, appears to work best for severe cases rather than mild disease. The vaccine provided nearly 100% protection and appeared to work against many serotypes.

“Serologically, there is no good correlation between the type-specific immune response to the various components to the vaccine and the very high efficacy seen,” Greenberg said.

Because the new vaccine was developed after the intussusception cases, “the hurdle for safety testing put forth by the public and the FDA was high,” Greenberg said.

“Both new rotavirus vaccines have really been tested at a new level of safety compared with all the old vaccines we’ve studied,” Greenberg said.

Merck studied the vaccine’s safety in 70,000 infants. Thirteen cases of intussusception occurred in the treatment group vs. 19 cases in the placebo group of the randomized, double-blind, placebo-controlled Rotavirus Efficacy and Safety Trial (REST). The cases appeared during the long-term follow-up but not during the short-term follow-up.

“An advantage is the high level of safety assurance,” said Greenberg. “A disadvantage is that maybe it can’t be sold to anyone in the developing world that needs it.”

GlaxoSmithKline also developed a rotavirus vaccine (Rotarix) that is more similar to RotaShield. This vaccine is made from a human rotavirus isolate, in contrast to Merck’s bovine virus.

More than 63,000 children participated in the RotaRix clinical trials. The safety and intussusception rates were similar to those of RotaTeq. Intussusception occurred more frequently in the placebo group (n=16) than the vaccine group (n=9) in the first 100 days post-vaccination. The rates at one-year post-vaccination were four for the vaccine group and 14 for the placebo group.

“This almost looks like the vaccine had a protective effect against intussusception, which probably is the case, in my opinion,” said Greenberg.

The GSK efficacy rates vary slightly regarding serotypes. The G2 viruses have a lower protective efficacy, but according to Greenberg, data is emerging that indicates the vaccine protects against serotypes not included in the vaccine.

Another difference is that the GSK vaccine is given in two doses and the Merck vaccine is given in three doses.

What about intussusception?

The cause of intussusception is unknown. According to Greenberg, it peaks at about 6 months of age but is rare in very young children. In fact, CDC data for the original vaccine showed little evidence of an association with intussusception among infants older than 60 days but younger than 70 days who received the vaccine.

“There was very little, if any, association with intussusception in the youngest children who received the vaccine. Most of the intussusception occurred in the older children who got the vaccine, as you might expect, because intussusception occurs more commonly in [that age group],” said Greenberg.

Disease burden

Rotavirus is a burden on the U.S. population with 55,000 to 70,000 hospitalizations occurring annually, along with large numbers of outpatient services according to Greenberg. However, the developing world bears the greatest burden. Rotavirus is one of the largest causes of mortality; about 500,000 children die each year from rotavirus infection. This occurs despite a decrease in other causes of diarrhea.

Several promising third-generation rotavirus vaccines are in development, including a bovine strain and a human neonatal strain that may benefit the developing world, according to Greenberg.

For more information:

• Greenberg H. Session 141G. Presented at the 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. Sept 27-30, 2006. San Francisco.