Rotavirus Vaccines

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Biology of rotavirus

Rotaviruses are 100 nm, nonenveloped RNA viruses belonging to the family Reoviridae . They were identified in humans in 1973 by Bishop and coworkers who used immune electron microscopy to demonstrate wheel-shaped particles (rota = wheel in Latin) in biopsies of duodenal mucosa from infants with gastroenteritis in Australia ( Fig. 14.1 ). Rotavirus particles contain a triple-layered capsid surrounding a viral genome consisting of 11 segments of double-stranded RNA. These RNA segments code for six structural proteins (VP1–VP4, VP6, and VP7) and six nonstructural proteins (NSP1–NSP6). The VP6 protein comprises the middle layer of the capsid and is the protein to which common immune diagnostics are directed. Eight groups of rotavirus have been described (A–H) based on genetic and antigenic differences in the VP6 protein. Only rotaviruses in groups A, B, and C are known to cause disease in humans, with group A rotaviruses being the principal cause of human disease. The VP7 protein (a glycoprotein, or G-type protein) and VP4 protein (a protease-activated protein, or P-type protein) comprise the outer layer of the capsid. These proteins form the basis of binary classification (G and P types) of rotavirus. To date, >20 G serotypes and >30 P genotypes have been described, and theoretically they could form more than 600 different G/P combinations by segregation. However, globally five G types (G1–4 and G9) and three P types (P[4], P[6], and P[8]) predominate , and five combinations of these common types generally account for more than 90% of circulating viruses: P[8]G1, P[4]G2, P[8]G3, P[8]G4, and P[8]G9.

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Rotavirus disease and treatment

The clinical spectrum of rotavirus infection ranges from subclinical illness or mild, watery diarrhea of limited duration to frequent, profuse diarrhea with vomiting and fever that can result in dehydration with shock, electrolyte imbalance, and death. Rotavirus illness usually begins with acute onset of fever and vomiting, followed 1–2 days later by frequent, watery stools. Up to one-third of children may have a moderate fever (temperature > 102 ^° F or 39 ^° C). Vomiting usually lasts less than 1–2 days and other gastrointestinal symptoms generally self-resolve in 3–7 days. While gastroenteritis is the chief manifestation of rotavirus infection, neurologic features—including benign convulsions, encephalitis/encephalopathy, and cerebellitis—have been described in children with rotavirus gastroenteritis.

The management of acute rotavirus gastroenteritis primarily focuses on the treatment and prevention of dehydration. In most situations the clinician will not be aware at the start of treatment whether the etiologic agent is rotavirus or another pathogen. Initial assessment therefore focuses on determining the degree of dehydration because this will both guide and monitor treatment. It is important that appropriate feeding continue throughout rehydration and maintenance phases of treatment.

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Burden and epidemiology of rotavirus

Rotavirus is the leading etiologic agent of severe childhood gastroenteritis globally, causing an estimated 25 million clinic visits, 2 million hospitalizations, and 180,000–450,000 deaths in children <5 years of age each year ( Fig. 14.2 ). Rotavirus infects nearly all children—in both developed and developing countries—by 3–5 years of age. Neonatal infections occur, but are often asymptomatic or mild, possibly because of protection from antibodies acquired from the mother or from breastfeeding. The incidence of clinical illness peaks among children ages 4–23 months, who are also at greatest risk for severe disease requiring hospitalization. Repeat infections are common (eg, 3 or more rotavirus infections occurred in about 42% of children by 2 years of age in one follow-up study in a cohort of Mexican children ); however, symptoms are milder with each subsequent infection. Therefore, rotavirus infections of adults are usually subclinical or mild, but can be severe, particularly in immunocompromised persons and the elderly.

Rotavirus is the leading cause of hospitalization for gastroenteritis, accounting for 33–49% of hospitalizations for gastroenteritis in countries in different geographic regions and with varying levels of child mortality. However, >90% of global deaths from rotavirus occur in low income countries in sub-Saharan Africa and South Asia, likely because of suboptimal access to health care including basic hydration therapy. In addition, compared with industrialized countries, severe rotavirus gastroenteritis occurs at a younger age in developing countries and coinfections with other enteric pathogens are more common. In temperate climates, rotavirus gastroenteritis shows prominent seasonality, occurring mainly during the fall and winter, with little disease activity during summer months. In tropical countries, rotavirus occurs year-around, although seasonal increases in incidence during the cool, dry months are often seen even in these settings.

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Rationale for rotavirus vaccine development

Vaccines to prevent rotavirus disease have been developed for several reasons. First, because rotavirus infects nearly all children in both industrialized and developing countries early in life, improvements in hygiene and sanitation alone are considered inadequate for prevention. Second, follow-up studies of birth cohorts of infants indicated that, although children can be infected with rotavirus up to 4–5 times in the first 2 years of life, the incidence of severe rotavirus gastroenteritis is reduced with each repeat infection. Therefore, orally administered, live attenuated, rotavirus vaccines have been developed to mimic the effect of natural infection and prevent severe rotavirus disease.