Rotavirus vaccines on the horizon offer some hope

SEATTLE – Future rotavirus vaccines may include both bovine and attenuated human rotavirus strains. They are believed to be unlikely to induce intussusception, and should still be effective, according to Paul Offit, MD, who spoke here at the Pediatric Academic Societies meeting.

Offit, of the Children’s Hospital of Philadelphia, at the University of Pennsylvania School of Medicine, said there are two new rotavirus vaccines on the horizon that may make a dent in the tremendous disease burden caused by rotavirus.

In developing countries, rotavirus is a deadly disease, accounting for approximately 660,000 to 800,000 deaths a year from severe dehydration. It is because of the disease burden that a vaccine is needed, Offit said.

Initially, the first rotavirus vaccine, the live, oral tetravalent RotaShield (RRV-TV, Wyeth-Ayerst) vaccine was developed using a simian rotavirus.

The approval of RotaShield in 1998 was based on positive evaluation of efficacy data from five, large clinical efficacy trials conducted in the United States and Europe. Offit said that the vaccine was about 48% to 68% protective against disease. There were some adverse events, including fever, decreased appetite, irritability and decreased activity after the first dose — these events were not observed after the second dose.

Another problem noted before the vaccine was licensed was intussusception. It was noted in five of 10,992 vaccine recipients, and one per 4,633 placebo recipients. According to Offit, this fact was worrisome enough to be included in the package insert.

About one year after the vaccine was licensed, a Morbidity and Mortality Weekly Report noted 15 cases of intussusception, 13 of which had occurred after the first dose and 11 of which had occurred within seven days of the vaccine’s administration.

The CDC suspended use of the vaccine while a case study was performed, and after that study, researchers determined that the relative risk was highest after the first dose, and declined after the second dose. The risk for intussusception was about one case per 10,000 vaccine recipients. Because of the risk of intussusception, the vaccine’s manufacturer pulled the vaccine from shelves and health officials suspended its use.

During the time that RRV-TV was available, approximately 1 million American infants were immunized, and one child died of vaccine-related intussusception. “One could argue the benefits of the vaccine still outweighed its risk,” Offit said. “There would be far fewer hospitalizations and deaths from intussusception than from rotavirus disease.”

Vaccines in the pipeline

The fact that the vaccine has been pulled from shelves left other companies looking for alternative vaccine strategies. So far, most candidate vaccines against rotavirus have been based on live, weakened animal strains of the virus. These animal strains were used at first, in part, because they grew easily in cell cultures. RRV-TV is based on a strain from the rhesus macaque, but Merck has a candidate based on a bovine strain known as WC3 (RotaTeq).

In developing countries, rotavirus is a deadly disease, accounting for approximately 660,000 to 800,000 deaths a year from severe dehydration.

The WC3 vaccine is a liquid, buffered vaccine that has been administered orally on the two-, four-, six-month and two-, three-, four-month schedule in clinical trials. It is a multivalent vaccine with specificity against the four serotypes — G1, G2, G3 and G4, that are responsible for more than 85% of rotavirus gastroenteritis worldwide.

In several placebo-controlled studies done to date, WC3 and its parent vaccines have been generally well tolerated and efficacious. No statistically significant increase in the incidences of fever, irritability, vomiting, or diarrhea has been observed in vaccine as compared with placebo recipients. For example, in a study of 439 infants, 15.7% of vaccine recipients vs. 14.1% of placebo recipients had fever during the two-week period after dose 1. The proportion of patients who shed vaccine in stools is low, ranging from 3.3% to 4.4% during the three to five days after vaccination.

Offit said a completed study of 1,946 infants who were followed for gastroenteritis throughout the rotavirus season after vaccination, suggests that RotaTeq was 68.8% to 76.6% efficacious in preventing any rotavirus disease regardless of severity or serotype. Preliminary immunogenicity results show a three-fold rise in serum neutralizing antibody titer to G1 in 73.3% to 86.2% of vaccinees, and a three-fold rise in rotavirus-specific serum IgA in >90% of vaccinees.

A large study is underway to evaluate the safety of the vaccine with respect to serious adverse experiences such as intussusception. He said no evidence of intussusception associated with the new vaccine has been noted, yet, in 45,000 infants in clinical trials.

Another option for a rotavirus vaccine lies with the attenuated human rotavirus vaccine (RotaRix, GlaxoSmithKline). Offit said this a phase-2 efficacy study of 215 infants had positive results, with approximately 90% of the vaccinated infants protected from rotavirus and a statistical significance at P<0.001. Examination of the safety data revealed only mild transient symptoms including fever in a small number of infants.

For more information:

• Offit P. New rotavirus vaccines: after Rotashield. Topic symposium 5654. Presented at the Pediatric Academic Societies meeting. May 3-6, 2003. Seattle.

• Dr. Offit is a coholder of the patent on bovine-human reassortant rotavirus vaccine currently being developed by Merck.