Rotavirus: epidemiology and disease burden

Estimates of diarrhea disease burden have changed over the past 30 years. In 1979, WHO estimated that one episode of illness was caused by a gastrointestinal infection per person per year. Gastroenteritis caused about 5 to 10 million deaths per year in all age groups. It was, according to WHO’s estimates, a more common illness than malaria, measles, schistosomiasis and whooping cough.

Improvements in sanitation measures have changed the seasonality of gastroenteritis in many parts of the world. In the early 1900s, some developed countries came to recognize a winter peak of vomiting illnesses. Before — as is still the case in many underdeveloped parts of the world — the predominant season for gastroenteritis was the wet, hot summer months.

David O. Matson

Most gastroenteritis that occurs in summer is due to infection with bacteria and parasites. When drinking water quality improved and sewage was handled properly, the summer peak markedly reduced. A winter virus peak was evident, with rotavirus being the most common serious pathogen.

In Mexico, the summer disease was still predominant in 1985, but a few years later, winter disease predominated after the country implemented a nationwide program to improve water and sewage handling.

Global estimates

The major health issues associated with gastroenteritis are diarrhea and vomiting, which can lead to dehydration and metabolic changes that are reflected in the blood, such as high or low sodium concentrations. If dehydration is not treated, then children are at risk of death.

Using an annual birth cohort of 124 million children worldwide, a 2006 study estimated that 1.6 million deaths were caused by diarrhea among the 620 million children younger than age 5. About 611,000 of the deaths (40%) were due to serious rotavirus disease; 5% of all deaths in children younger than 5 years old worldwide are caused by rotavirus.

The deaths are not equally distributed, however. Data from 2003 indicate a concentration of rotavirus deaths in the Indian subcontinent, where 30% of all rotavirus deaths occur. A significant number of rotavirus deaths also occur in Africa and China. According to the 2003 data, there were 20,000 rotavirus-related deaths in Brazil and 12,000 in Mexico.

U.S. estimated disease burden

Between 1968 and 1991, the United States had an 80% reduction in gastroenteritis-associated mortality in children. Approximately 2.7 million children younger than age 5 experience symptomatic episodes of rotavirus gastroenteritis that include vomiting and diarrhea. Only a fraction of those symptomatic episodes need medical attention. Although rotavirus is rarely fatal in the United States, it is a major cause of severe dehydration and hospitalization.

One in 10 children in the United States (approximately 410,000 children per year) visit a doctor for rotavirus gastroenteritis during the first five years of life. Each year, approximately 55,000 to 70,000 children visit the emergency department or are hospitalized for dehydration and/or other sequelae of rotavirus, and about 20 to 60 of these children die of rotavirus gastroenteritis. The actual number of rotavirus deaths and the number of hospitalizations and emergency department visits likely are underreported because the estimates come from counting discharge codes. Rotavirus accounted for about 7% to 10% of all hospitalizations of children, before mass immunization with rotavirus vaccines was implemented.

A birth cohort study monitored infants from the first week of life to age 2 years. The study provided evidence about protective immunity of natural rotavirus infection.

Data showed that by 24 months, 96% of the children had had a first rotavirus infection. Two-thirds had had a second rotavirus infection, and 40% a third rotavirus infection. Some children had four or five rotavirus infections during the first two years of life. One infection yielded 87% protection against subsequent serious rotavirus disease. Two infections were 100% protective against subsequent serious disease. These results provided a benchmark against which rotavirus vaccines could be measured.

Rotavirus structure and types

Rotavirus is one of three virus pathogens, including influenza and Colorado tick fever, in which the genome is segmented. When two rotaviruses infect the same cell, they can reassort the segments. Co-infections by rotaviruses are not infrequent.

The VP4 and VP7 proteins on the surface of the rotavirus induce protective immunity. These proteins are neutralization antigens; an antibody to either can block infectivity of the virus.

There are many different serotypes of these proteins in rotavirus. The VP7 protein is the G serotype, and the VP4 protein is the P serotype. In the overall worldwide distribution of G and P rotavirus serotypes, the most common G serotype is G1, which makes up about two-thirds of all strains.

G2 accounts for 13% and G4 for 12% of infections. The G9 serotype is also notable because it is increasing in prevalence wherever it has been reported. The G9 serotype accounted for nearly 100% of infections in northern Portugal two years ago. Other emerging G serotypes are G6 and G12.

P serotypes differ as well. Most strains circulating are P1A[8]. The P1B[4] serotype accounts for 15% of circulating P types and usually occurs in combination with G2 in children.

Similarities with influenza viruses

Rotavirus has several similarities to the influenza virus: Both have a segmented genome that facilitates novel antigenic combinations; both have two neutralization antigens, one of which is a hemagglutinin, that have multiple antigenic types; and both have a winter peak of illness and are highly contagious. Also both rotavirus and influenza virus can infect animals, and the animal strains are infectious in humans.

A susceptible child placed in a room with another child who is excreting rotavirus may be infected with rotavirus in 20 minutes. By comparison, exposure for measles infection occurs in minutes, and exposure for tuberculosis infection is usually weeks.

Rotavirus vaccines

Two vaccines for rotavirus are available — a pentavalent vaccine and a monovalent vaccine. Pivotal trial results for the two vaccines are comparable.

The pentavalent vaccine follows the classic strategy of vaccines, which matches the immunogen to the composition of strains in the community, a matching of the serotype diversity to which susceptible persons will be exposed. This vaccine contains the most common serotype antigens among circulating rotavirus strains — five human-bovine rotavirus reassortants.

In a trial with the pentavalent vaccine, which included 70,301 healthy infants aged 6 to 12 weeks, there was a 96% reduction in hospitalizations, a 93% reduction in emergency department visits, an 86% reduction in non-urgent health care visits, and an 87% reduction of parental workdays missed.

The monovalent vaccine relies on data from epidemiologic and serologic studies showing that a single immunogen may be all that is necessary to protect against serious rotavirus disease. This vaccine contains only one G serotype and a P protein in a virus that comes from a human source. The vaccine strain shares neutralizing epitopes with most strains of G1, G3, G4 and G9 serotypes because of the shared P[8] antigen of VP4.

In a study with the monovalent vaccine that included 63,255 healthy infants aged 2 to 4 months, there was an 85% reduction in rotavirus hospitalizations.

The vaccines have good safety and efficacy profiles, but they differ in antigenic composition. The complexity of circulating rotaviruses raises the question whether the differences in composition will result in different impacts on circulating rotavirus types.

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