Contents:
Introduction
Disease
Vaccines
Issues
Additional
Links
| Diarrhea is certainly not a glamorous disease,
but it is a serious killer. An estimated 2.4-3.3 million children ages 5 and under die from severe dehydrating diarrhea each year.(1) Twenty percent of these deaths are the result of a 70 nm icosahedral virus called rotavirus. Consequently, rotavirus is the single most important cause of severe dehydrating diarrhea worldwide. (2) |
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Virus and Immune Response
Rotavirus is composed of 11 segments of double
stranded RNA, each of which encodes a structural or non-structural protein,
surrounded by 3 shells. The outer shell contains two distinct structural
proteins; each of these proteins has specific antigenic determinants, elicits
serotype specific neutralizing antibodies, and induces serotype specific
protective immune response. (3)
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Epidemiology
Most children have encountered rotavirus by 2-3 years of age and all children acquire antibodies by 3-5 years.(5) In developing countries children encounter rotavirus early in lifeóa review of rotavirus in Africa for instance found that 81% of hospitalizations for rotavirus occurred in the first year of life and 38% of cases occurred before 6 months of age. In contrast, because of the distinct seasonality of rotavirus in temperate climates, children from industrialized countries experience rotavirus related disease at a later age. (6)
In the first 3 months of life infections are asymptomatic, and although this observation has not been fully explained it may be due to protection given by maternal antibody. After 3 months most infections are mild, but about 1 in 50 are characterized by severe fever, diarrhea, and vomiting, which can be serious enough to result in fatal dehydrating gastroenteritis. This dehydration is associated with a loss of sodium and chloride in the stools and a compensated metabolic acidosis. (7)
A number of studies have suggested that infection with group A rotaviruses causes serotype specific immunity. For various reasons, researchers have prioritized the development of a recombinant attentuated viral vaccine. (7)
One reassortment vaccine, consisting of simian x human rotavirus, contains a single human gene (VP7) and the remaining 10 genes from rhesus rotavirus vaccine (RRV). This tetravalent rhesus-based vaccine went through safety, immunogenicity, and efficacy trials in 7 locations, including one trial in Venezuela (7). Results of these trials suggested that this vaccine could be useful in both industrialized and developing countries. In August 1998 it was licensed in the United States by the Food and Drug Administration. These results were the exciting culmination of years of research. (8)
Soon after the vaccine was put on the market, the Vaccine Adverse Event Reporting System (VAERS) started receiving reports of intussusception in children who had recently received the rotavirus vaccine. Intussusception is a rare type of bowel obstruction that occurs when the bowel folds in on itself. As of July 7, 1999 VAERS had received 15 reports of intussusception, out of the approximately 1.5 million infants who had received the vaccine since August 1998. (9) Because this appears to be a higher rate of intussusception then seen in unvaccinated children, the vaccine was temporarily suspended. Data from an ongoing case-control study on intussusception following rotavirus infection will be available soon. (9)
For additional information, look to this page:
http://www.aap.org/policy/re9938.html
Several features of rotavirus epidemiology
have made the need for a vaccine particularly clear. Because
of the observation that children throughout the world are infected early
in life, even in countries with modernized sewage and sanitation facilities,
vaccines are being developed as the primary public health strategy.(10)
In addition, while extensive efforts to distribute oral rehydration therapy
worldwide have certainly reduced global diarrhea mortality, the continuing
toll of 1600-2400 diarrhea deaths per day suggest that a safe, economical
and efficacious vaccine would be preferable.(11)
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Characteristics of the epidemiology of rotavirus worldwide will need to be considered in the process of vaccine development. Fecal specimens from children in developed countries show a single virus strain from one of the four common serotypes found globallyóspecifically P(8)G1, P(8)G3, P(4)G2, and P(8)G4.(12) In contrast in developing countries the rate of mixed infections of at least two strains can be 30% and viruses can include uncommon geographically specific serotypes. For instance, the G5 strain is prevalent in Brazil, while the G9 strain is common in India. (12) Diversity of strains could be important for vaccine development. For instance reassortment vaccines were engineered to contain the prevalent G strains on the assumption that serotype immunity confers the best protection. This could mean that these vaccines are less effective in developing countries where unusual strains are prevalent. (13)
In temperate climates rotavirus has a distinct winter seasonality which contrasts the year round exposure observed in tropical climates. A child born in a temperate climate directly after the rotavirus season will not encounter the virus for almost a full year. In the tropics, however, a child could be exposed any day of the year. Therefore, in developing countries an effective immunization program will require earlier and higher levels of coverage then developed countries. The vaccines most useful worldwide would be safe and effective in very young children. (14)
*Economics of Vaccine Development and Program Implementation
www.rotavirus.com
www.cdc.gov/ncidod/dvrd/nrevss/rotfeat.htm