Conquering rotavirus: from discovery to global vaccine implementation.

Rotavirus, the commonest cause of severe dehydrating gastroenteritis world-wide, was discovered less than 50 years ago. It causes about 450,000 deaths per year in children <5 years of age and hospitalises millions more. Rotavirus vaccines have been shown to have a major impact on hospital admissions due to rotavirus gastroenteritis and all-cause gastroenteritis and reduce mortality in developing countries. In Australia, there has been a 71% decrease in rotavirus hospitalisations in children 0-5 years of age. From the discovery of rotavirus as the major causative agent for severe gastroenteritis, through vaccine development and vaccine post-marketing surveillance activities, Australian scientists and clinicians have played a significant role in the global effort to reduce the burden of rotavirus infection.

Discovery of rotavirus: Implications for child health.

For centuries, acute diarrhea has been a major worldwide cause of death in young children, and until 1973, no infectious agents could be identified in about 80% of patients admitted to hospital with severe dehydrating diarrhea. In 1973 Ruth Bishop, Geoffrey Davidson, Ian Holmes, and Brian Ruck identified abundant particles of a 'new' virus (rotavirus) in the cytoplasm of mature epithelial cells lining duodenal villi and in feces, from such children admitted to the Royal Children's Hospital, Melbourne. Rotaviruses have now been shown to cause 40-50% of severe acute diarrhea in young children worldwide in both developing and developed countries, and > 600 000 young children die annually from rotavirus disease, predominantly in South-East Asia and sub-Saharan Africa. Longitudinal surveillance studies following primary infection in young children have shown that rotavirus reinfections are common. However the immune response that develops after primary infection is protective against severe symptoms on reinfection. This observation became the basis for development of live oral rotavirus vaccines. Two safe and effective vaccines are now licensed in 100 countries and in use in 17 countries (including Australia). Rotarix (GSK) is a single attenuated human rotavirus, representative of the most common serotype identified worldwide (G1P[8]). RotaTeq (Merck) is a pentavalent mixture of naturally attenuated bovine/human rotavirus reassortants representing G1, G2, G3, G4, and P(8) serotypes. Preliminary surveillance of the numbers of children requiring hospitalization for severe diarrhea, in USA, Brazil, and Australia, after introduction of these vaccines, encourages the hope that rotavirus infection need no longer be a threat to young children worldwide.

Rotavirus vaccines: is the second time the charm?

The rotavirus vaccines that have been evaluated in clinical trials thus far have all been live, attenuated strains delivered orally to mimic natural infections. Early vaccine candidates were animal strains that are naturally attenuated for humans. Due to the lack of consistent protection, these were reassorted with human rotaviruses to create multivalent vaccines with neutralization proteins of the circulating human strains. One of these multivalent candidates, RotaShield, was launched in the US but withdrawn due to association with intussusception. Another vaccine, Rotateq, is expected to be launched by 2006. Human rotaviruses have also been developed as candidate vaccines and Rotarix, which is attenuated by passage in cell culture, has been launched in Mexico and may soon be available worldwide.