Diarrheal Diseases Control Program: Rotavirus Diarrhea

Rotavirus was first detected in humans in Melbourne, Australia, in 1973, by thin-section electron microscope examination of duodenal biopsies obtained from children with acute diarrhea. Shortly thereafter, rotavirus was found in Australia, Canada, the United Kingdom, and the United States by electron microscope examination of diarrheal stool specimens. The virus has since emerged as the single most important cause of diarrhea in infants and young children admitted to hospitals for treatment of gastroenteritis. The present state of knowledge in the field of rotavirus diarrhea was reviewed in depth at the second meeting of the Scientific Working Group on Viral Diarrheas, and priority areas for future research were outlined (1).

Although there have been numerous studies in both tropical and temperate countries on the monthly and annual frequency of rotavirus infection in children admitted to hospitals, a need still exists for long-term, community-based studies of the incidence and prevalence of the infection. These should include longitudinal surveys of titers of rotavirus antibody in sera from selected cohorts of children in developing countries. The incidence and clinical severity of concurrent infections with rotavirus and other enteric pathogens also requires further study.

More research is needed on the factors that influence the survival of rotaviruses in the environment, both in the community at large and within closed communities, such as hospital wards, day-care centers, and nursing homes. The relative importance of water, food, air, and fomites as vehicles in the spread of rotavirus infection needs to be determined.

The exact antigenic structure of rotavirus is still unclear, and at present, investigators disagree about which polypeptides are incorporated in the virion and which are non-structural. The precise disposition of the polypeptides in the virion is, therefore, important, and much research is already in progress in this area; work on monoclonal antibodies and further biochemical studies will probably help considerably to clarify the position.

The availability of new techniques for the direct isolation of rotavirus from clinical material has stimulated research relating to the structure and classification of the antigen and diagnosis of rotavirus infection. Further attention is needed for: 1) development of methods for rapid identification of rotavirus subgroups and serotypes; 2) adoption of an agreed-upon nomenclature or numbering system for the classification of rotavirus subgroups and serotypes; 3) rotavirus from clinical material has stimulated research relating to the structure and classification of the antigen and diagnosis of rotavirus infection. Further attention is needed for: 1) development of methods for rapid identification of rotavirus subgroups and serotypes; 2) adoption of an agreed-upon nomenclature or numbering system for the classification of rotavirus subgroups and serotypes; 3) adoption of an agreed-upon system, possibly similar to that used for influenza virus and poliovirus, for the registration of tissue-culture-adapted rotavirus isolates in each country or region; 4) further development of monoclonal antibodies for the diagnosis of rotavirus.

The development of a rotavirus vaccine deserves high priority. In developing such a vaccine, it would be helpful to have an understanding of the mechanisms by which immunity to rotaviral illness is achieved. To date, studies in calves, piglets, and lambs have demonstrated the importance of intestinal rotarviral antibody in preventing or attenuating illness. In specially pertinent studies in lambs, rotavirus antibody administered by the alimentary route was effective in inducing resistance to rotavirus challenge by the same route, whereas circulating antibody alone was not characteristically protective. There have been very few studies, however, of the mechanisms of immunity to rotavirus illness in humans.

A major obstacle to vaccine development has been the inability to propagate human rotaviruses efficiently in cell cultures; thus, it has not been possible to produce enough human rotavirus antigen for vaccine development studies. However, important advances have been made in this area, and several human rotavirus strains have now been successfully cultivated in cynomolgus monkey kidney cell cultures. It may now be possible to develop attentuated mutants by various methods, such as cell culture passage, cold adapatation, chemical mutagenesis, and reassortment.

Another strategy being pursued is the use of a calf rotavirus to immunize humans, in an effort to evoke protective antibodies without causing illness. The promise of this type of approach has been demonstrated 1) in calves inoculated in utero with bovine rotavirus; they were significantly protected against challenge with human rotavirus on the day of, or one day after, birth, and 2) in piglets infected with bovine rotavirus and later challenged with human rotavirus; they shed virus for substantially fewer days than control animals.

A number of research groups are seeking to apply recombinant deoxyribonucleic acid methods to the characterization of rotavirus genome segments. This approach is seen as a promising means both of obtaining basic information on the nature of rotavirus genes and of producing rotavirus proteins that could be of value in vaccine development.

Another approach to the prevention of rotavirus illness involves the administration of high-titer rotavirus antibody by the alimentary route. Various animals studies have demonstrated the feasibility of this passive immunization approach for a defined period. In one study in humans, 4- to 9-day-old, breast-fed infants had substantially fewer rotavirus infections than those who were not breast fed. In another study, antibodies and/or trypsin inhibitors present in human milk were found to be associated with protection of neonates against rotavirus infection in the first 5 days of life. These findings could be important, but they require confirmation.

With the passive immunization approach, it might be feasible to immunize pregnant mothers with inactive or live rotavirus vaccine in an attempt to stimulate high levels of antibody in breast milk. It might also be feasible, in selected circumstances, to produce high-titre homologous antibody (or heterologous antibody, if found safe), or to prepare suitably treated human immune serum globulin, and add such antibody to the infant's diet for a defined period. Reported by WHO Weekly Epidemiological Record 1983;58:165-6.

Reference

1. World Health Organization. Report of the second meeting of the Scientific Working Group on Viral Diarrhea: microbiology, epidemiology, immunology, and vaccine development. World Health Organization unpublished document, WHO/CDD/VID/82.3, 1982.

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