Prospects for Rotavirus Vaccine

ABSTRACT & COMMENTARY

Synopsis: Two recent studies of human-rhesus reassortant rotavirus vaccines have been found to be safe in children and efficacious in preventing severe rotavirus diarrheal illness and dehydration.

Sources: Santosham M, et al. Efficacy and safety of high-dose rhesus-human reassortant rotavirus vaccine in Native American populations. J Pediatr 1997;131:632-638; Perez-Schael I, et al. Efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and young children in Venezuela. N Engl J Med 1997;337:1181-1187.

A rhesus rotavirus tetravalent (serotypes g1-4) vaccine (RRV-TV), a rhesus rotavirus monovalent (serotype 1) vaccine (RRV-S1), and placebo were compared in a randomized, double-blind efficacy study in 1185 American Indian infants 6-24 weeks of age. Vaccine efficacy as measured by seroconversion was 93% for RRV-TV and 88% for RRV-S1. During the first year of surveillance, the estimates of vaccine efficacy for preventing symptomatic rotavirus gastroenteritis were 50% (95% confidence intervals, 26-67%) for RRV-TV and 29% for RRV-S1. The estimates for preventing severe disease were 69% for RRV-TV and 48% for RRV-S1.

A tetravalent rotavirus vaccine given at 2, 3, and 4 months of age was studied in a randomized, double-blind, placebo-controlled trial in 2207 infants in Venezuela. Vaccine efficacy as measured by seroconversion was 80%. The relative protective efficacy against the first rotavirus diarrheal episode was 48%, with a protective efficacy of 75% against severe diarrheal illness complicated by dehydration. The vaccine was also associated with a 49% reduction of fever and a 54% reduction in vomiting. There was 88% protection against severe diarrhea and 75% protection against dehydration, with a 70% reduction in hospital admissions.

COMMENT BY HAL B. JENSON, MD, FAAP

Rotavirus infection is the most common cause of gastroenteritis among children worldwide and a leading cause of morbidity among children younger than 2 years of age. Each year in the United States, rotavirus accounts for an estimated 3.5 million cases of diarrhea, 30-50% of hospitalizations for diarrhea during seasonal peaks, and 20 deaths among children younger than 5 years of age. The timing of rotavirus activity in the United States by geographic location has recently been mapped by the CDC.1 (A dynamic display of rotavirus activity during 1996-1997 can be found at ftp://ftp.cdc.gov/pub/Publications/mmwr/ wk/rota9697.gif on the World Wide Web.) Peak activity occurs first in the Southwest in autumn, with sequential progression toward the Northwest and Northeast, and with the last activity in the Northeast in mid-to-late spring. The time of peak activity in the Pacific Northwest is more variable than other regions, occurring from winter to late spring. The reason for this sequential pattern is unknown but is not explained by sequential introduction of rotavirus or by diffusion of new rotavirus strains.

It is difficult to measure efficacy of rotavirus vaccines because seroconversion and the titer of neutralizing antibodies are poor measures of rotavirus vaccine efficacy. With natural rotavirus infection, it is unusual to have more than one serious episode of diarrheal illness, but symptomatic reinfection is common. The prevention of approximately 50% of symptomatic disease and most of the severe diarrheal illness resulting in dehydration requiring hospitalization is probably as much as can be expected from a rotavirus vaccine. The human-rhesus reassortant rotavirus vaccines are safe. In the two studies, the only statistically significant adverse event was a self-limited febrile response in 18% and 15% of vaccines, compared to fever in 12% and 7% of placebo controls.

The study by Santosham and associates is the third and final planned U.S. efficacy trial of rotavirus vaccine and confirms the findings of the previous two multicenter studies of the safety and efficacy of RRV-TV and RRV-S1 vaccines. The study by Perez-Schael et al demonstrates similar efficacy against rotavirus infection in a developing country. The same rotavirus vaccine, at a slightly lower dose, was not as efficacious in studies in Peru and Brazil. It is difficult to directly compare these studies in developing countries to identify the reasons for these different results. There are concerns that poor underlying nutritional status, greater incidence of fecal contamination of food and water, and a high burden of diarrheal disease from other enteric organisms may adversely affect the efficacy of rotavirus vaccine in developing countries. In addition, the cost of the vaccine and the logistics of providing immunizations remain substantial obstacles for many countries of the world. The RRV-TV is currently under review by the FDA for use among U.S. children. The effectiveness of this vaccine to prevent serious disease, the low incidence of adverse events, and the oral administration compatible with other childhood vaccines at 2, 4, and 6 months of age indicate the appropriateness of universal vaccination of U.S. children with this rotavirus vaccine. A greater challenge is to substantiate the efficacy of the vaccine among children of developing countries and, if efficacious, to also provide the vaccine to the population with the greater need. As pointed out in an accompanying New England Journal of Medicine editorial, the cost of the vaccine (~ $30) will make it prohibitively expensive where it is needed most—in the third world.2 (Dr. Jenson is Chief, Pediatric Infectious Diseases, University of Texas Health Science Center, San Antonio, TX.)

References

1. Centers for Disease Control and Prevention. Laboratory-based surveillance for rotavirus—United States, July 1996-June 1997. MMWR Morb Mortal Wkly Rep 1997;46:1092-1094.

2. Kutch GT, Cash RD. A vaccine against rotavirus— When is too much too much. N Engl J Med 1997;337:1129.

Rotovirus vaccines:

a. prevent all diarrhea and vomiting in subsequent rotovirus infections.

b. reduce the frequency of diarrhea-related hospitalizations.

c. will probably be widely used in third-world countries.

d. must be given parenterally.