Rotavirus disease and its prevention Marc-Alain Widdowson, Joseph S. Bresee, Jon R. Gentsch and Roger I. Glass Purpose of review Correspondence to Marc-Alain Widdowson, Viral Gastroenteritis Section, MS G04, Respiratory and Enteric Viruses Branch, National Center for Infectious Diseases, Rotavirus infection is the foremost cause of severe Centers for Disease Control and Prevention, 1600 Clifton Road NE, Atlanta,GA gastroenteritis of young children worldwide. Efforts to 30333, USA develop safe and effective vaccines resulted in licensure Tel: 404 639 4688; fax: 404 639 4960; e-mail: [email protected] of the first live oral vaccine, tetravalent, rhesus-based Current Opinion in Gastroenterology 2005, 21:26–31 rotavirus vaccine (RRV-TV), which was incorporated into Abbreviations the US immunization schedule in 1998. Less than 1 year ICD International Classification of Disease later, however, the vaccine was withdrawn when reports of RRV-TV rhesus rotavirus tetravalent cases of intussusception were linked to recent VP viral protein vaccination. This setback created significant hurdles as © 2004 Lippincott Williams & Wilkins well as new opportunities for the development of the next 0267-1379 generation of rotavirus vaccines. This review focuses on Introduction new information related to the clinical presentation and Rotavirus infection remains the most common cause of pathogenesis of rotavirus infection, the associated global severe, dehydrating gastroenteritis among children disease burden, and the ongoing efforts to develop and worldwide. Almost every child in the world, in both de- introduce the next generation of rotavirus vaccines for veloped and developing countries, will be infected with widespread use. rotavirus in the first 5 years of life. Globally, approxi- Recent findings mately 500,000 children die every year from rotavirus Recent studies have confirmed that rotavirus infection is gastroenteritis, with the vast majority of these deaths not confined only to the gut but can have extraintestinal occurring in the poorest countries. In developed nations, manifestations, including viremia. Estimates of the global rotavirus infection rarely results in death but remains the disease burden of rotavirus diarrhea have been refined most common cause of hospitalizations for acute gastro- and suggest that mortality has not declined, and that enteritis in children and leads to major medical and so- among hospitalized cases of diarrhea, the fraction cietal costs. associated with rotavirus has increased in many countries. In the United States, the estimated number of In 1998, the first vaccine against rotavirus, tetravalent, hospitalizations attributed to rotavirus has increased. rhesus-based rotavirus vaccine (RRV-TV), was approved Debate continues about the magnitude of the attributable by the US Food and Drug Administration and recom- risk of the association between RRV-TV and mended for inclusion in the 1999 US schedule for rou- intussusception. Several new rotavirus vaccines are in late tine childhood immunizations. In July 1999, this vaccine stages of development. One vaccine was licensed in was withdrawn in the United States following reports Mexico in 2004 and a second has completed clinical trials of cases of intussusception among recently vaccinated in the United States and Europe and may be licensed children. within 2 to 3 years. Since 1999, several important developments have im- Summary proved our understanding of the natural history of rotavirus The tremendous burden of rotavirus diarrhea among infection and of intussusception, as well as the disease children all over the world continues to drive the burden of rotavirus-associated gastroenteritis. Moreover, remarkable pace of vaccine development and the variety of efforts to develop other vaccines have been stimulated approaches to creating rotavirus vaccines. by the withdrawal of RRV-TV, and at least two vaccines are now in the final stages of clinical trials. Keywords rotavirus, vaccine, disease burden, intussusception Pathogenesis Rotavirus infects the mature absorptive enterocytes in the proximal two thirds of the ileum, and is thought to Curr Opin Gastroenterol 21:26–31. © 2004 Lippincott Williams & Wilkins. cause diarrhea by several mechanisms. First, virus-associ- ated cell death, with subsequent sloughing of the villus epithelium and proliferation of the secretory crypt cells, Viral Gastroenteritis Section, Respiratory and Enteric Viruses Branch, National results in reduced absorptive capacity of the gut, leading Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA to fluid and electrolyte loss into the lumen. Epithelial 26 Rotavirus disease and prevention Widdowson et al.27 Table 1. Rotavirus vaccines Concept Status Reassortant vaccines Rotateq Pentavalent bovine–human reassortants with G1, Phase III G2, G3, G4, P[1a] types Rotashield Tetravalent rhesus–human reassortants with G1, Licensed in United States (1998) but withdrawn G2, G3, G4 types from market in 1999 Human-bovine (United Kingdom) Quadrivalent bovine–human reassortants with Phase II G1, G2, G3, G4 types Monovalent vaccines Rotarix Human strain P[8]G1 Licensed in Mexico, Dominican Republic, and Kuwait; phase III elsewhere LLR Lamb strain P[12]G10 Licensed in China (2001) Neonatal strain vaccines RV3 Neonatal strain P[6]G3 Phase II I-321 Neonatal strain P[11]G9 Phase I Modified from Glass et al. [51]. dysfunction also leads to reduced expression of certain declined appreciably in the same time frame [7•]. The digestive enzymes such as sucrase and isomaltase, and reasons for this decline in mortality and not incidence the osmotic pull of accumulated sugars in the small in- remain poorly delineated although increased measles testine further exacerbates fluid loss. In addition, a non- vaccination and better access to oral rehydration therapy structural protein (NSP4) expressed by rotavirus is cannot be ruled out. Estimates of mortality caused by thought to trigger an intracellular Ca++-dependent sig- rotavirus diarrhea appear to have declined along with naling pathway, which leads to an increased membrane those of overall diarrheal mortality; the most recent glob- permeability to electrolytes. Lastly, rotavirus seems to al estimate is of 352,000 to 592,000 deaths (median 440 activate the secretormotor neurons of the enteric nervous 000) attributable to rotavirus [8•]. However, this recent system that stimulate secretion of fluids and solutes, an estimate relies on multiplying overall diarrheal mortality effect recently found to be mediated via vasoactive in- data from a variety of different countries by the propor- testinal peptide [1]. tion of hospitalizations for severe diarrhea attributed to rotavirus reported in studies in the 1990s, which in de- Rotavirus infection has traditionally been thought to be veloping countries averages at about 22 to 25%. In the limited to the gastrointestinal tract, but several recent past few years, evidence suggests that the proportion case reports have challenged this paradigm. Evidence of of hospitalizations attributable to rotavirus in poorer rotavirus RNA has been found by polymerase chain re- countries may actually be much higher [9•,10,11], and action in the cerebrospinal fluid of rotavirus-infected therefore that the estimated number of deaths caused by children who have seizures [2] and in liver and kidney rotavirus infection may have been substantially underes- sections of immunocompromised children [3]. A recent timated. study used reverse transcriptase polymerase chain reac- tion, immunohistochemistry, and in situ hybridization to In developed countries, studies have focused on assess- detect rotavirus in a variety of internal organs of two ing the burden of hospitalizations due to rotavirus. The children who died with severe rotavirus-associated vom- risk of hospitalization with rotavirus diarrhea among chil- iting and diarrhea and who also had neurologic disease dren under 5 years of age in the United States has been [4•]. One elegant study used a commercial enzyme im- estimated to be 1 in 73, or about 55,000 hospitalizations munoassay test designed to detect rotavirus antigen in annually in studies reliant upon hospital discharge Inter- stool but applied it to serum and found that 22 of 33 national Classification of Disease (ICD) codes for diar- immunocompetent children with confirmed rotavirus rhea [12]. Since 1993, rotavirus-specific ICD 9 and ICD gastroenteritis had rotavirus antigenemia, providing evi- 10 codes have been introduced, but since rotavirus is not dence that rotavirus may commonly escape the gastroin- routinely detected, these codes are underused and will testinal tract [5••]. The clinical significance of these severely underestimate the number of hospitalizations findings remains unclear but is under active investiga- attributable to rotavirus diarrhea. A study among hospi- tion. talized children in New York State in the period 1993 to 2000 found that 8.7% of all diarrhea-associated illnesses Rotavirus disease burden were coded for rotavirus; however, 54% of hospitals The Institute of Medicine estimated in 1985 that rota- never used the new code, while 12% of hospitals coded virus is associated with 9 million cases of severe diarrhea rotavirus in more than 30% of diarrheal episodes [13•]. globally and 870,000 deaths [6]. In the past two decades, Specific rotavirus codes, however, were found in this however, successive studies have documented a sus- study to be highly predictive of rotavirus disease;