Epidemiology of rotavirus in young children

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Rotaviruses are ubiquitous in nature, infecting virtually all young children by the second or third year of life resulting in the high burden of disease and morbidity in both developed and developing countries [7, 18]. However, it is clear that differences exist in the epidemiology and the distribution of rotavirus strains between developing countries and industrialized countries. Following a WHO recommendation for specific standardized studies in Africa and Asia on the epidemiology of rotavirus and strain surveillance [19], a more systematic investigation was utilized to examine rotavirus infection in developing countries. Regional rotavirus networks have been established and have contributed significantly to our current knowledge [10, 20]. Differences in the epidemiology of rotavirus infection between developing countries and industrialized countries do exist, and may have some consequences for vaccine strategies (Tab. 1).

First, the primary rotavirus infection, which is usually the most serious episode, tends to occur earlier in infants in these regions. For instance, in many countries in Africa and Asia, almost three-quarters of infants will acquire their primary rotavirus infection before their first birthday [9, 10, 20-24]. Typically, symptomatic rotavirus infection occurs most frequently in children between 3 and about 18 months of age, resulting in mild to severe acute watery diarrhea with a subsequent loss of fluids and electrolytes [18, 25]. Neonatal infections are generally asymptomatic, perhaps due to protection conferred by passively acquired maternal antibodies or an immature intestinal epithelial system [26, 27], or by viral characteristics [28]. Finally, re-infections in older children and adults are common but tend to be sub-

Table 1. Implications for rotavirus vaccine defined by the differences in the epidemiology of rotavirus infection between developing countries and developed countries (adapted from [7])

Epidemiology

Developed Developing Implications for country country vaccine trials

Age of first infection

- Percent infected by 12 months

- Median age of infection

Seasonality

Case fatality

Mixed infection with other enteropathogens

Multiple virus serotypes

Vaccine must be given earlier.

12-18 month 6-12 months Potential interference of maternal antibody with vaccine take.

Winter peak Low

Uncommon

One major type circulating

All year round

High Common

More than one type circulating

Year round exposure to infants, earlier age of acquisition. Need for earlier vaccination.

Outcomes and measurements in vaccine trial design.

May limit vaccine take, and affect diarrhea outcomes of trial design. Necessitate additional vaccine doses. Vaccine efficacy may be challenged in trial design. Vaccine candidates may need different formulations clinical and probably reflect the natural immunity offered by the primary infection.

Secondly, rotavirus infections exhibit a seasonal pattern in temperate countries, where most rotavirus infections occur during the winter [18]. However, in tropical countries and in most developing countries, rotavirus tends to occur year round, although with some increased activity during the cooler months of the year [9, 10, 20-24, 29].

Thirdly, many of the children in developing countries have additional factors, such as malnutrition, concomitant infections and co-morbidity, and potentially multiple enteric pathogens, which may all exacerbate the subsequent disease consequences with rotavirus infection.

What have natural history studies shown?

Natural rotavirus infection has been shown to be highly protective against subsequent infection associated with disease, although not against reinfection. Early studies showed that neonatal rotavirus infection, although asymptomatic, conferred protection against subsequent severe rotavirus diarrhea, although re-infection was common [26, 30].

Furthermore, longitudinal natural history studies following infants from birth to approximately 2 years of age in Mexico and Guinea Bissau, have confirmed that a primary rotavirus infection, whether associated with symptomatic or asymptomatic infection, confers significant protection against disease associated with subsequent re-infection [22, 31]. In Mexican infants, the primary rotavirus infection conferred 77% protection against all symptomatic rotavirus infection and 87% against serious rotavirus diarrhea [31]. This phenomenon has been seen in several other studies and stimulated the concept that a live, orally administered rotavirus vaccine would confer protective efficacy against severe rotavirus disease.

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