New rotavirus vaccines close to rollout

Different formulations might have overcome problems with the previous version, but experts warn that it could take a while to rebuild trust and ensure uptake.

By Victoria Stagg Elliott — Posted Feb. 27, 2006

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Most winter days, the hospital emergency department where Paul A. Offit, MD, works as a pediatric infectious disease specialist is filled with 30 to 35 desperately ill infants and small children sickened by rotavirus.

"I'm dealing with the disease every day, and it's the second most common issue in the winter months," said Dr. Offit, chief of the division of infectious diseases at the Children's Hospital of Philadelphia.

But this regular occurrence soon may be a thing of the past. Two vaccines, including one developed in part by Dr. Offit, have demonstrated efficacy and high levels of safety against this virus.

According to two large studies involving tens of thousands of children from around the world, both an attenuated human rotavirus vaccine and a pentavalent human-bovine reassortant vaccine proved to reduce the incidence of disease dramatically without causing any adverse events. The results were published in the New England Journal of Medicine last month.

Action is now being taken in the regulatory and public health arenas to get these vaccines into medical practice. Specifically, on Feb. 3 the Food and Drug Administration approved Rotateq, a human-bovine version of the vaccine manufactured by Merck & Co.

Additionally, GlaxoSmithKline is expected to apply shortly for FDA's nod for its attenuated vaccine, which is already approved in more than a dozen countries around the world. Also, how a rotavirus vaccine should be used is on the February meeting agenda for the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices.

"A recommendation for the immunization is very imminent if everything falls into place," said Dr. Umesh D. Parashar, who co-authored an editorial accompanying the NEJM papers and is a medical epidemiologist in the CDC's Division of Viral and Rickettsial Diseases.

Challenges ahead

Although there has been significant activity to move these vaccines from the research setting to the real world, experts still acknowledge that there will be particular challenges in convincing physicians to offer it and parents to let their children have it.

The last rotavirus vaccine, which was a combination of rhesus and human rotaviruses, was very different from the ones now under consideration. It gained FDA approval in August 1998 but was withdrawn from the market within a year after being linked to an increased risk of intussusception.

That experience now might translate into a lack of trust in the new vaccines and a hesitation among physicians to be the first to administer them.

According to a study of the attitudes of pediatricians and family physicians after the withdrawal of the original vaccine, only 22% of those who responded believed that the prelicensure system worked well enough to determine vaccine safety. Trusting the system was also associated with being an "early adopter." These findings were published in the September 2001 Archives of Pediatrics and Adolescent Medicine. Thus, experts suggest that the uptake for the newer rotavirus vaccine might not be as speedy as with other new immunizations.

"I think physicians will need to be reassured that the vaccine is safe and that the benefits really strongly outweigh the risk," said Heather McPhillips, MD, MPH, lead author on that paper and assistant professor of pediatrics at the University of Washington School of Medicine, Seattle.

The fact that these trials were the largest prelicensure ones ever conducted for a vaccine, involved a total of more than 130,000 children and were designed specifically to address the possibility of intussusception, though, led some experts to hope that the tests might provide more of a belief in safety. In comparison, the previous vaccine was tested in only 11,000 subjects before it was licensed.

"Never before have we asked for such a large trial," said David Bernstein, MD, the director of the division of infectious disease at Cincinnati Children's Hospital Medical Center. He helped develop one version of the vaccine. "That should give a level of faith that the vaccine will not be a problem."

There is also optimism because the withdrawal of the last vaccine was efficient. The study in the Archives found that although trust in the prelicensure system was low, confidence in the monitoring system in the wake of withdrawal was high, at 83%.

"It should be reassuring that it was taken off the market relatively quickly," said Penelope Dennehy, MD, an author on one of the NEJM papers and professor of pediatrics at Brown Medical School in Providence, R.I. "The early warning systems seemed to work."

Those who have been involved with these vaccines also say that the immunization, in addition to protecting against the rotavirus, might have at least one other characteristic that makes it an easier sell: It's not another needlestick. The pentavalent version requires three oral doses at 2, 4 and 6 months of age. The attenuated one requires only two oral doses at 2 and 4 months.

"They're not trying to compete for space on the arm," Dr. Offit said.

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Do the new rotavirus vaccines work?

Objective: Determine the safety and effectiveness of two different rotavirus vaccines.

Methods: One study randomized nearly 70,000 infants to receive three oral doses of a pentavalent human-bovine reassortant rotavirus vaccine or a placebo. The other study randomized more than 60,000 infants to receive either two doses by mouth of a live attenuated version of this vaccine or a placebo.

Results: In the study of the pentavalent vaccine, the adverse event, intussusception, that derailed the last approved rotavirus vaccine occurred in 12 of those who received the vaccine and 15 who received the placebo. The vaccine reduced hospitalizations and emergency department visits caused by rotavirus by nearly 95%. Immunization also reduced the risk of rotavirus-linked gastroenteritis by 74%. The study of the attenuated version found that it reduced rotavirus-related hospitalization by 85% and reduced the risk of severe gastroenteritis by nearly 100%. Hospitalization for diarrhea of any cause was reduced by 42%. Intussusception occurred in six vaccine recipients and seven who received the placebo.

Conclusion: Both vaccines are safe and efficacious.

Source: New England Journal of Medicine, Jan. 5

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External links

"Safety and Efficacy of an Attenuated Vaccine against Severe Rotavirus Gastroenteritis," abstract, New England Journal of Medicine, Jan. 5 (link)

"Safety and Efficacy of a Pentavalent Human-Bovine (WC3) Reassortant Rotavirus Vaccine," abstract, New England Journal of Medicine, Jan. 5 (link)

"The Promise of New Rotavirus Vaccines," extract, New England Journal of Medicine, Jan. 5 (link)

AMA's Roadmaps for Clinical Practice series, "Improving Immunization: Addressing Racial and Ethnic Populations" (link)

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