Prospects for development of a rotavirus vaccine against rotavirus diarrhea in infants and young children

Abstract

Major advances have been made in elucidating the etiologic agents of severe infantile diarrhea, and it is clear that rotaviruses are the single most important etiologic agents. Progress in the development of rotavirus vaccine candidates has also moved swiftly with the "Jennerian" approach, in which a related live, attenuated rotavirus strain from a nonhuman host is used as the immunizing antigen. If this strategy is not effective against all rotavirus serotypes, reassortant rotaviruses hold great promise for the development of a multivalent vaccine. Field trials with the "Jennerian" approach vaccines are under way, and phase 1 trials with the reassortants have been initiated.

PIP: In 1972, the 27-nm Norwalk virus associated with epidemic viral gastroenteritis in older children and adults was discovered, and in 1973, the detection of the 70-nm human rotavirus associated with acute gastroenteritis in infants and young children followed. They are responsible for 35-50% of severe diarrhea in children under 2. In a Bangladesh study, rotaviruses were the most frequent pathogens in children under 2 with diarrheal illnesses. 4 epidemiologically important human rotavirus serotypes have been identified. After inoculation in utero with bovine rotavirus (NCDV), calves were protected against disease following challenge at birth with human rotavirus type 1. The human rotavirus vaccine, RIT 4237, is derived from the cold-adapted bovine rotavirus NCDV (Lincoln) strain. A single oral dose of the vaccine provided a protection rate of 88% against rotavirus diarrhea in 178 Finnish infants 8-11 months of age. An 82% protection rate was observed in 331 Finnish infants 6-12 months of age following 2 oral doses. The rhesus rotavirus strain MMU 18006 as a candidate rotavirus vaccine was safe and antigenic after oral administration in adult volunteers, children, and infants. The rhesus rotavirus vaccine induced significant febrile reactions in 64% and watery stools in 20% of 608 month old Finnish infants; and it was more antigenic than the RIT 4237 vaccine. Neither adult volunteers became ill during recent phase 1 trials in Baltimore with 2 rotaviruses: the D (human rotavirus serotype 1) x RRV (rhesus rotavirus) reassortant. Similar studies were carried out with a DS-1 x RRV reassortant in 2 volunteers with high levels of prechallenge plaque-reduction neutralization (PRN) antibody to this reassortant. Neither volunteer became ill. Later 14 volunteers with little prechallenge PRN serum antibody to this reassortant were given the reassortant; none developed diarrheal illness. Each of the 4 rotavirus serotypes has been isolated from newborns with asymptomatic infections 1 strain recovered from asymptomatic neonates within the first 14 days of life induced significant protection against serious rotavirus disease for up to 3 years. Attenuation of virulent human rotavirus strain might also be achieved by cold adaptation.