Rotaviruses

Authors: Dorsey M. Bass, M.D., Harry B. Greenberg, M.D.

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Virology

Rotaviruses, of the family Reoviridae, are icosahedral viruses approximately 75 nm in diameter that comprise three protein layers, giving them a distinct wheel-like appearance under the electron microscope. The viral capsid encloses 11 segments of double-stranded RNA, each of which codes for a single viral protein, except for gene 11, which is bicistronic. Five major rotavirus groups (A-E) have been identified on the basis of genetic relatedness and immunologic reactivity of the inner capsid protein VP6. Group A and C rotaviruses can be grown in culture, but no system has been developed for culturing group B viruses.

Epidemiology

Only rotavirus groups A, B, and C have been found to be pathogens in the human population (Table 1). Group A rotaviruses account for 25 to 50% of the infantile diarrheal illnesses found in both the developing and the developed world. In the United States, infections predominate in children between 6 months and 2 years old, while in the developing world, illness is frequently reported in children younger than 6 to 12 months. Maternal antibodies are generally believed to protect neonates from infection, but this protection wanes after the third month. Rotavirus displays a seasonal cycle of infection in temperate climates, with most infections occurring in the winter months. In Washington DC, for example, as many as 60 to 65% of all hospital visits for diarrheal illness in January and February over an 8-year period, were due to rotavirus infection (6). This same pattern of seasonal distribution of infections is not observed in countries within 10° of the equator, where rotavirus infections occur year-round, with a slight increase during the rainy season. Group A viruses are spread predominantly through the fecal-oral route, facilitated by crowding and poor sanitation, which further increase the risks for rotavirus infection in developing countries.

Although less prevalent than group A, the group B and group C viruses are significant pathogens in the human population. Group B rotaviruses were originally identified after and epidemic outbreak of waterborne diarrhea in China in 1982-1983 that affected more than 12,000 adults (31).

Unlike group A viruses, group B viruses produce considerable illness in the adult population, with 85% of infected individuals being over 15 years of age. Group C rotavirus infections occur sporadically and appear to primarily infect older children, between 4 and 7 years of age. Recent preliminary studies have provided conflicting evidence linking group C rotavirus infections with primary biliary atresia of neonates (5, 26).

Clinical Manifestations

Rotaviral illness is characterized by a relatively short incubation period (1-3 days) followed by a symptomatic illness with a 5- to 7-day duration (Table 2). Onset of illness is associated with watery diarrhea, fever, and vomiting, with severe fever (>39°C) and severe diarrhea (>10 times per day) occurring with high frequency. Although diarrheal illness persists through the length of the infection, vomiting and fever usually remit within 2 days after onset. Dehydration is very common in rotavirus illness and is the primary cause of rotavirus-associated mortality in the developing world where access to appropriate rehydration therapy is frequently lacking. Asymptomatic illness is fairly common, especially among neonates and older children and adults.

Laboratory Diagnosis

Rotavirus infection is associated with large quantities of virus shed in the stool, making the virus easy to detect by electron microscopy, enzyme-linked immunosorbent assay (ELISA), or direct visualization of viral genomic RNA in fecal extracts. Double-stranded RNA is highly stable and can be extracted, separated by polyacryamide gel electrophoresis (PAGE), and stained with silver or ethidium bromide. Polymerase chain reaction (PCR) of the genes encoding VP7 and VP4 has been widely used to identify the serotype of the virus present during infection. Solid-phase immunoassays have been particularly useful for identifying the group A rotaviruses, and a number of immunoassay kits are available for rapid identification of subgroup and serotypes of virus in fecal samples. These kits, however, do not detect non-group A viruses. In outbreaks of group B rotaviruses in China, classical RNA visualization and electron microscopy both determined that a rotavirus was present and that the genomic structure differed significantly from that of standard group A viruses (31). Recently, a recombinant protein-based ELISA was developed to detect group B rotavirus, but it is not yet widely available (21). Commercial antigen detection tests for group C rotavirus are also not currently available.

Pathogenesis

In most cases, rotavirus infection is restricted to the villus enterocytes in the small intestine and spreads from the proximal small bowel to the ileum. The histopathology of rotavirus infection in humans has not been extensively studied. Viral destruction of villus tip cells is thought to result in a loss of absorptive capacity for water and sodium, with the resulting imbalance producing characteristic watery diarrhea. Transient deficiencies in intestinal lactase have also been observed after rotavirus infection. Recently, the product of rotavirus gene 10, NSP4, has been implicated as an enterotoxin in murine model and may potentially be responsible for some of the diarrhea occurring during infection (3).

Group B rotavirus displays a slightly different pattern in infection that group A and C viruses. This virus has been found to infect primarily the distal small intestine rather than the proximal small intestine. In addition, group B viruses cause syncytia in the epithelial layer, which can damage large contiguous portions of infected epithelium and may play an additional role in producing diarrheal illness.

SUSCEPTIBILITY IN VITRO AND IN VIVO

Identifying model systems for studying viral gastroenteritis has been a key step in the identification of mechanisms of immunity and has provided systems in which to study potential vaccination or other therapeutic protocols. Development of animal models has been assisted by the fact that many species harbor viruses that are closely related to human agents. This has been crucial, because in most cases, human viruses are restricted in growth in nonhuman species.

Because rotaviruses are ubiquitous in mammalian species, a number of animal rotaviruses have been identified and used to generate models of human group A rotavirus infection. Although studies of rotavirus infection have been conducted in gnotobiotic lambs and calves, extensive study of the immunologic response, including vaccination studies, has been limited to mice, rabbits, and gnotobiotic pigs.

Infection of mice with murine rotaviruses results in a diarrheal illness only when mice are less than 15 days old, but adult mice generate a full range of protective immune responses. Despite the fact that adult mice do not manifest disease, immunologically naïve adult mice do shed murine rotavirus after infection. Protection of adult mice from virus shedding has been used as a model for vaccine induced immunity. Mice are semipermissive for infection by some heterologous (nonmurine) rotaviruses, although disease can only be spread from mouse to mouse when homologous viruses are used. The mouse model has proven useful for studying passive transfer of immunity to pups from immunized dams through serum or milk. The availability of many genetic knockout mice has been key in assisting detailed study of the cellular and antibody-mediated immune response to rotavirus.

Rabbits can be productively infected by homologous rotaviruses up to 1 year of age. Natural infections in the field appear to be associated with diarrhea and classic histopathologic lesions (shortening of villi, mononuclear infiltration, vacuolation). Although rabbits can be infected by heterologous viruses, neutralizing antibody responses are lower than those observed with homologous infection.

Gnotobiotic pigs are the most convenient model for studying disease as well as viral infection. Piglets can be infected with rotaviruses and develop diarrheal illness up to 6 weeks of age, whether porcine or human virus strains are used. Because the disease parameters and immune response in pigs resemble those observed in humans, this model is the only one in which the impact of immunization on disease, as well as viral infection, can be studied. The cost, however, makes it less generally useful than the rabbit and mouse models of infection.

Group B rotaviruses have been identified as causing epidemics of diarrhea in rats and pigs, and both of these animals have been found to be good models of rotavirus illness after inoculation with group B viruses from the homologous species. Experimentally infected animals develop diarrheal disease that can be transmitted, although they shed lower levels of virus than animals infected with group A viruses. Because no culture system exists for group B viruses, these systems are the only ones available for studying and propagating these viruses.

ANTIVIRAL THERAPY

At present, development of chemotherapeutic agents for treating gastrointestinal viruses has made little headway. One major obstacle is the fact that animal models show that a good deal of viral replication occurs prior to the onset of overt symptoms. Although a number of investigations have been carried out in tissue culture models of rotavirus replication, no agents are currently in clinical trials. Ribavirin, a broad-spectrum antiviral, was originally identified as having antirotavirus activity in tissue culture but no measurable effect in the mouse model of rotavirus infection (27, 29). Isoprinosine and a number of other modified nucleoside analogues have shown an ability to prevent viral RNA and protein synthesis in tissue culture, but no experiments in animal models have been reported (19, 20). Flavins, found in tea extracts have also been shown to posses some in vitro anti rotaviral activity (9, 23).

Although rotavirus is sensitive to interferons in vitro (4), neither type 1 nor type 2 interferons seem to be effective in ameliorating disease or viral replication in the murine model (2).

Although experimental, some efforts have been to treat rotaviral illness by passively transferring antibodies. Human serum immunoglobulin administered orally to children with chronic rotavirus infection was able to associate with rotavirus in the gut, resulting in formation of large immune complexes rather than free virus. Antigen shedding was significantly reduced after antibody therapy, although the virus was not eliminated in all cases (13). Enteric administration of antibody has shown some efficacy in normal children. A single dose of human immunoglobulin preparation that had a high titer against rotavirus (1:800-1:3,200) significantly speeded the rate of virus clearance and recovery from diarrhea in children infected with rotavirus (12). However, a similar study showed no significant effect of orally administered immunoglobulin. Bovine immunoglobulin against rotavirus has been produced by hyperimmunizing cattle with human and simian rotaviruses (14). Either the milk of hyperimmunized cattle or serum immunoglobulins resuspended in milk formula significantly reduced the incidence of rotavirus illness in children from 3 to 7 months old when orally administered. Children receiving immunoglobulins had significantly diminished symptoms upon becoming infected, compared with children receiving placebo formula.

An alternative means of producing antirotavirus immunoglobulins is to harvest specific immunoglobulins form the yolks of eggs laid by chickens immunized with rotavirus. Egg yolks contain large quantities of specific immunoglobulin following intramuscular immunization of hens, and the antibody Y stable for long periods of time. Oral dosing of mice and calves with these immunoglobulins significantly reduces overall disease (20, 21). In mice, this protection was directly associated with reduced rotavirus antigen distribution within the intestinal tract, suggesting that replication of the virus has been inhibited. Recent human trials in Bangladesh suggested that such egg yolk preparations may have therapeutic value in human infants as well (17, 18).

Other Therapies

A number of reports have suggested that bacteria may be useful in the treatment of rotavirus-induced gastroenteritis. Feeding two bacterial strains, Bifidobacterium bifidum and Streptococcus thermophilus, to hospitalized infants aged 6 to 24 months reduced the incidence of diarrheal illness and rotavirus shedding, suggesting that some mechanisms of protection from infection was in operation. Feeding another bacterial strain,Lactobacillus casei strain GG, to infected children appears to shorten diarrheal illness, presumably by restoring the microflora of the intestine and reversing intestinal osmotic and chemical imbalances (11, 15). In addition, when administered in the acute diarrheal phase, L casei appears to stimulate the immune response to rotavirus, particularly the production of IgA, and may significantly enhanced protective immunity to subsequent infection (16). A quite recent meta analysis of the use of lactobacillus species for treatment of rotavirus diarrhea suggested a slightly positive effect.

Other therapies which have been studied for rotavirus diarrhea include bismuth subsalycylate which had mild efficacy (30) and a new experimental enkephalase inhibitor which in preliminary studies reduced rotavirus diarrhea by 50% without significant side effects (8). Nonspecific antidiarrheals such as loperimide are not suggested for infants with rotavirus disease.

Because immunotherapy is relatively expensive and the opportunity to treat quite brief, it remains to be seen what the practical utility of these interventions is. Obviously, in the rare cases of chronic rotavirus infection in severely immunocompromised individuals, passive immunotherapy may play a bigger role in treatment.

ADJUNCTIVE THERAPY

Due to the absence of pharmaceutical agents to treat rotavirus and the self-limiting nature of the viral infection of the gastrointestinal tract in most normal individuals, the key therapeutic goal is to prevent severe dehydration leading to electrolyte imbalance, shock, and death. Dehydration and complications arising from dehydration are most prevalent in rotavirus infection and are the major cause of mortality in infected children. Rehydration can be performed orally or, in patients with severe vomiting or in shock, by intravenous fluid administration. For oral rehydration, the WHO recommends a standard oral rehydration solution containing 3.5 g of sodium chloride, 2.5 g of sodium bicarbonate, 1.5 g of potassium chloride, and 20 g of glucose per liter. An alternative formulation that contains less sodium (40-60 vs. 90 meq/L) is available in the United States. Intravenous rehydration can be achieved using standard saline solutions containing glucose and potassium. In addition to rehydration therapy, it is recommended that efforts be made to improve the nutritional condition of the patient, as malnutrition exacerbates symptoms and slows recovery from diarrheal illness. Several studies have shown that refeeding promptly after rehydration leads to quicker resolution of illness.

VACCINES

Because no specific therapies have been developed for rotavirus and because it is endemic throughout the world, major efforts aimed at treating rotavirus diarrhea have focused on developing vaccines to prevent infection. Studies on rotavirus in particular are well advanced because of the existence of animal models, the availability of tissue culture systems to manipulate the virus, and the frequency and severity of the clinical illness in children. It is hoped that the lessons learned in developing an effective rotavirus vaccine will be applicable to developing vaccines for other viral diarrheal agents mentioned elsewhere in this volume.

Replicating Vaccines

Because natural infection with rotavirus does not efficiently protect against repeat infection and mild disease, the goal of vaccination is not to prevent rotavirus infection, but rather to reduce the incidence of severe diarrheal illness during the first 2 years of life. Natural rotavirus infection often provides only partial protection against disease upon subsequent reinfection. Vaccination efforts are currently aimed at group A viruses, as they represent the major cause of severe diarrheal illness. Group A viruses are subdivided into serotypes on the basis of their ability to be neutralized by antibodies to the two major outer capsid proteins, VP4 and VP7 (G serotypes), 8 of which are found in humans. Of these, serotypes G1-G4 represent 80 to 95% of the viruses that are found in the human population, and all four serotypes can be present at any given time and location, although serotype G1 tends to predominate in most parts of the world. In recent years G9 serotypes seem to be emerging as important human pathogens in various regions of the world (). Neutralization studies based on reactivity with VP4 (P serotype) have identified at least 13 distinct P serotypes, but serologic reagents are not as readily available for their identification. While 19 distinct P serotypes have been identified by DNA sequence analysis of VP4 sequences, serotype and genotype do not always correlate directly, and viruses are often characterized by VP4 genotype rather than P serotype.

Studies in animal models of rotavirus infection indicated that the most important correlate of protective immunity was a strong local antibody response, rather than a serum antibody response. To provide the best chance for presenting rotavirus antigens locally, a Jennerian vaccination strategy was proposed. In this strategy, humans would be inoculated with animal viruses that would present antigen to the gut but not be able to replicate sufficiently to induce clinical symptoms. At least three Jennerian vaccine strains have been tested: RIT 4237, a tissue culture-adapted bovine virus (G6); RRV, a virus isolated from a young rhesus monkey (G3); and WC3, a bovine virus displaying a lower degree of attenuation than RIT 4237. In clinical trials, results have been mixed but generally positive. Although RIT 4237 protected 50% of vaccinees in Finland against infection and 80 to 80% against severe illness, it had very little reported efficacy in other areas of the world (Africa, Arizona). The second bovine strain, WC3, was able to protect 100% of children in American trials from severe serotype 1 diarrhea, but efficacy in other countries ranged from 0 to 48%. The efficacy of the WC3 and RIT vaccines did, however, demonstrate that cross-serotypic protective responses could be generated. The RRV strain of virus induced a mild-to-moderate symptomatic temperature elevation in some vaccinees and generated a highly serotype-specific G3 antibody response.

Due to the random circulation of all four human serotypes and assuming that immunity was G serotype-specific, an effective vaccine would need to be able to generate a heterotypic or multiple serotype-specific response to protect against the major human strains. (G1-G4). To address this, a modified Jennerian approach was studied in which the gene coding for the VP7 protein in animal viruses (RRV or WC3) was exchanged (reassorted) with genes from three or four human serotypes. The product of this study was the RRV-tetravalent vaccine (RRV-TV). This vaccine contains a mix of RRV (serotype G3) and RRV reassortants containing G1, G2, or G4 VP7 genes. This vaccine underwent clinical trials in the United States, Finland, and Venezuela. In the United States trials, the tetravalent vaccine sometimes induced a higher incidence of fever after vaccination than a serotype 1 monoreassortant (RRV-S1), although this was not always significant (3, 34). Significant diarrhea and vomiting were not reported, and shedding of the vaccine strain in the stool was detected at a low level. Children receiving RRV-TV displayed a measurable but relatively low type-specific response to serotypes 1 to 4, while RRV-S1 recipients had measurable responses to serotype 1 only. The tetravalent vaccine provided significant protection (65-77%) against disease induced by serotype 3 virus, whereas the monovalent vaccine provided variable protection (0-45%). Thus, although overall protection by the tetravalent vaccine against severe illness caused by all serotypes was only 57%, it provided consistent heterotypic protection that may be necessary for efficacy in areas where serotype prevalence varies. The most significant finding was that RRV-TV vaccination prevented approximately 80% of dehydrating illness associated with gastroenteritis relative to placebo recipients. Further studies in Finland and Venezuela with the RRV-based tetravalent vaccine confirmed its substantial efficacy against moderate-to-severe diarrhea.

The RRV-TV vaccine was licensed in the United States as Rotashield in 1998. By 1999, reports of intussusception associated with the vaccine were noted in a passive reporting system (1). After these cases were publicized, many more cases were reported. Initial epidemiologic investigations estimated a 10 to 50 fold-increased risk of intussusception in the first week after immunization with Rotashield (24). The manufacturer removed the vaccine from the market. Subsequent population based and case-control studies have confirmed the association of intussusception with the administration of Rotashield with the highest risk period being in the first week after the first dose of vaccine. Interestingly, population-based ecological studies failed to find significant increases in the total incidence of intussusception in states with high usage of the vaccine (28). It is now estimated that the risk of intussusception with Rotashield was approximately 1 excess case per 10,000 doses of vaccine administered.

Nonreplicating Vaccines

With the application of molecular biology to the vaccine problem, a number of alternatives to live-attenuated vaccines have been developed. All of these alternative candidates are still experimental and have only been evaluated in animal models of disease.

Subunit Vaccines

Using recombinant viral proteins to induce an antirotavirus immune response has focused on the VP4 and VP7 proteins. Expression of recombinant VP7 on the surface of cells by use of a vaccinia virus construct has resulted in an immunogenic protein that can provide passive protection in suckling mice. VP4 is efficiently expressed in baculovirus, and immunization of mice with recombinant protein can provide lactogenic immunity to virus challenge (22).

Viruslike Particles

Viruslike particles have been generated by simultaneous expression of viral structural proteins in insect cells, and their potential for vaccination tested in animal models (10). Viruslike particles are thought to display outer capsid proteins in more native-like conformations and are stable under a variety of physical conditions. In the mouse-model, vaccination with rotavirus viruslike particles conferred significant protection to viral infection in mice (25).

Encapsulation

A third effort to enhance local immunity is to microencapsulate rotavirus proteins or whole viruses for more effective delivery to mucosal surfaces. Studies in mice have shown that microencapsulated virus is more efficiently absorbed and delivered to gut-associated lymphoid tissue after oral inoculation than free virus, and that the local immune response is greatly enhanced by this mode of presentation (7).

PREVENTION

General Preventive Measures

Vaccination plays an important role in preventing the infant mortality associated with rotavirus diarrhea. Sanitary waste disposal, effective hand washing and hygienic practices are other important measures. Although breastfeeding decreases the severity of rotavirus diarrhea, it does not prevent it.

Hospital Infection Control Measures

The 1996 CDC guidelines recommend contact isolation including private rooms and cohorting of patients if private rooms are not available. Isolation is to be continued during the entire duration of illness. The 1996 CDC guidelines also mandate the use of gloves, proper hand washing and use of gowns if there is a possibility of soiling with infectious material. Patient transport should be done for essential purposes only and daily environmental cleaning is required. The patient care equipment should be dedicated or cleaned between each use. Age <6 y or diapered or incontinent patients need isolation. Empiric precautions are also mandated in patients with diarrhea syndrome, before the diagnosis of rotavirus diarrhea is made. Rotavirus is often resistant to the commonly used chemical disinfectants and antiseptics. However in experimental studies Lysol spray has been effective. Hence disinfection of environmental surfaces with Lysol or other alcohol-containing disinfecting agents might decrease the amount of virus on surfaces in an infected child's room and decrease nosocomial transmission of rotavirus. Since handwashing with plain soap is ineffective and only spreads the virus on the entire surface of the hand, disinfection of hands with 90% ethanol solution along with handwashing or use of waterless handwashing agents containing at least 70% alcohol may help limit rotavirus transmission.

REFERENCES

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Tables

TABLE 1. Epidemiologic Characteristics of Diarrheal Viruses

	Rotavirus	Enteric Adenovirus	Norwalk Virus	Astrovirus
Population affected	Children (A, C) and adults (B)	Children	Children, epidemic illness in adults	Children, elderly patients, adult epidemics, immunocompromised
Transmission	Fecal-oral, water	Fecal-oral	Fecal-oral, water, shellfish	Fecal-oral, water, shellfish
Seasonality	Winter/rainy season	Year-round	Year-round	Winter/rainy season

TABLE 2. Clinical Presentation of Viral Illness

	Rotavirusa	Enteric Adenovirusa	Norwalk Virusb	Astrovirusc
Symtomatic patients studied (N)	168 children	32 children	36 adults	44 children
Diarrhea (%)	98 (21% severe)	97 (22% severe)	66	100
Nausea (%)	NAd	NA	75	71
Vomiting (%)	87	78	44	61
Fever (%)	84 (42% severe)	44 (3 severe)	25	80
Dehydration (%)	55	37	NA	5
Abdominal pain (%)	18	25	75	58
Blood in stools (%)	1	3	NA	7
Mucus in stools (%)	17	19	NA	55
Respiratory (%)	33	19	NA	NA
Durations: Incubation period Diarrhea	1-3 days 5.9 days	7 days 10.8 days	1-2 days 15-55 h	3-4 days 5-6 days