Discovery of rotavirus: Implications for Child health

Transcription

1 doi: /j x REVIEW _ : Implications for Child health Ruth Bishop*, *Murdoch Childrens Research Institute, Royal Children s Hospital, and Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia Key words rotavirus, diarrhoea, aetiology in children, epidemiology, vaccine development. Correspondence Ruth Bishop, Enteric Virus Group, Murdoch Children s Research Institute, Royal Children s Hospital, Melbourne, Vic. 3052, Australia. r.bishop@mcri.edu.au Conflict of interest The author has received funding from GSK and Marck for travel to Conferences to present reviews of rotavirus vaccine research, and for financial support of laboratory research on epidemiology of rotavirus serotypes in Australia; and has been an employee of the Murdoch Childrens Research Institute which is developing a novel rotavirus vaccine. Abstract For centuries, acute diarrhea has been a major worldwide cause of death in young children, and until 1973, no infectious agents could be identified in about 80% of patients admitted to hospital with severe dehydrating diarrhea. In 1973 Ruth Bishop, Geoffrey Davidson, Ian Holmes, and Brian Ruck identified abundant particles of a new virus (rotavirus) in the cytoplasm of mature epithelial cells lining duodenal villi and in feces, from such children admitted to the Royal Children s Hospital, Melbourne. Rotaviruses have now been shown to cause 40 50% of severe acute diarrhea in young children worldwide in both developing and developed countries, and > young children die annually from rotavirus disease, predominantly in South-East Asia and sub-saharan Africa. Longitudinal surveillance studies following primary infection in young children have shown that rotavirus reinfections are common. However the immune response that develops after primary infection is protective against severe symptoms on reinfection. This observation became the basis for development of live oral rotavirus vaccines. Two safe and effective vaccines are now licensed in 100 countries and in use in 17 countries (including Australia). Rotarix (GSK) is a single attenuated human rotavirus, representative of the most common serotype identified worldwide (G1P[8]). RotaTeq (Merck) is a pentavalent mixture of naturally attenuated bovine/human rotavirus reassortants representing G1, G2, G3, G4, and P(8) serotypes. Preliminary surveillance of the numbers of children requiring hospitalization for severe diarrhea, in USA, Brazil, and Australia, after introduction of these vaccines, encourages the hope that rotavirus infection need no longer be a threat to young children worldwide. Introduction Historically, diarrheal disease has been a common cause of ill health and death in young children. For example, approximately 80% of babies admitted to foundling homes in Ireland during the 18th century died from cholera infantum during the first 1 2 years of life. In 1900 the death rate of children aged 6 18 months in New York City was calculated as 5603 per Even as late as March 1942 April 1943, 109 of 216 children admitted to the West Middlesex Hospital, London with severe diarrhea died, without the identification of an enteric pathogen. 1 Despite a slow appreciation of the need to replace fluid and sodium losses, UK deaths from enteritis in young children aged < 15 months still averaged 40 of 70 admissions per week in In the early 1900s, of every 1000 babies born in Victoria died before the age of 12 months. The major cause of this mortality was diarrheal disease, particularly during the hotter months ( summer diarrhea ) (J Bradley and AG Catto-Smith, pers. comm., 2009). The death rate from gastroenteritis in young children had fallen by 1940 to 1.64/1000 live births as a result of many factors; these included education of mothers, increased hygiene in the home, availability of refrigeration and home ice-boxes, proper sewerage disposal, changes in hospital attitudes to admission, and advances in treatment. Etiological studies of gastroenteritis still placed a high emphasis on bacterial causes. Techniques to identify nonbacterial agents (including viruses) were still rudimentary. In 1929, Zahorsky described a winter vomiting disease (hyperemesis hiemsis) occurring mainly in artificially fed infants and young children. 2 He suggested that viral infection could be a cause. In 1943, Light and Hodes produced diarrhea in calves inoculated with fecal filtrates from infants with diarrhea, 3 but these agents could not be adapted to cell culture. Numerous later studies isolated known viruses from feces from patients with or without diarrhea, but none could be implicated as etiologic agents of diarrhea. 4 In 1965, Dr Alan Ferris 5 published a retrospective study of hospital and laboratory records of all patients admitted to Fairfield Hospital, Melbourne, with a diagnosis of primary gastroenteritis. Results were analyzed in relation to the month of admission, age, and occurrence of known enteric pathogens. Most gastroenteritis in summer months could be attributed to infection with Salmonella S81

2 sp. or Shigella sp., but the overall case rate was higher in winter. Further, there was clear evidence of winter epidemic peaks in children under 5 years of age, from whom no enteric pathogens (bacterial or viral) could be identified. Failure to identify a pathogen was recorded for 81% (< 5 months old), 78% (< 2 years), and 76% (< 5 years) of children admitted to Fairfield Hospital from 1962 to There was no evidence of known viral agents in these children. The inability to identify a pathogen was therefore considered to indicate a different (unknown) etiologic agent in winter months. Similar findings of winter epidemics of gastroenteritis with no evident etiologic agents had also been reported in Sydney and in Toronto, Canada. Discovery and importance of rotavirus infections In 1970, Dr Rudge Townley was appointed Director of Gastroenterology at the Royal Children s Hospital (RCH), Melbourne, with the responsibility for care of all children admitted with gastroenteritis. He had improved the rapidity and safety of intestinal biopsies in children. In collaboration with the Biomedical Engineering Department of RCH, the standard Watson pediatric biopsy capsule had been adapted to allow it to be mounted on a cardiac catheter. The capsule could then be manipulated through mouth and stomach into the duodenum of a sedated child within 10 min. This skill transformed the technique of duodenal biopsy in children and had been applied to more than 500 children for diagnosis of celiac disease and other conditions associated with malabsorption in the small intestine. 6 In 1972 a collaborative project began with the aim of identifying the histology and estimating the levels of disaccharidase enzymes in the duodenum in children with acute gastroenteritis. Intestinal contents were aspirated to analyze microbial flora in the upper small intestine. The proposal was discussed widely with other pediatricians, nursing staff, and parents. The consensus was that this could reveal important information about this common, severe, and frightening disease. The results showed severe inflammation in the upper small intestine, associated with villous atrophy equivalent to celiac disease in approximately one-third of patients. 7,8 Stomach and rectum showed only minimal changes. Erobic and anerobic cultures and cell culture did not identify known bacterial or viral enteric pathogens in the majority of children (Table 1). 9 In May 1973, a further collaborative project examined ultrathin sections of duodenal mucosa from children with acute gastroenteritis, using electron microscopy. Abundant viral particles were Table 1 Etiological gastroenteritis in children admitted to Royal Children s Hospital, Melbourne Total admissions Salmonella sp. 39 (7.2%) 40 (10%) Shigella sp. 2 (0.4%) 5 (1%) Pathogenic E. coli 23 (4.3%) 7 (2%) Unknown 475 (88%) 102 (29%) Rotavirus not tested 197 (52%) Enteric adenovirus not tested 27 (7%) identified in the epithelial cells lining the upper villous surface. 10 The virus was identified as being reovirus-like/orbivirus-like, with a close resemblance to viruses already implicated in causation of diarrhea in neonatal mice, 11 and in calves. 12 The virus was shed in particles per milliliter in diarrheal feces and could readily be identified (by electronmicroscopy of negatively stained fecal extracts) as 70-nm particles. 13 In 1972, Kapikian et al. reported visualization of a small (27 nm) particle in fecal extracts from adult volunteers who had ingested fecal filtrates from adults with acute nonbacterial gastroenteritis. 14 This virus, subsequently identified as a calicivirus (Norwalk virus) was clearly different from the virus identified from young children. The 70-nm virus from children was initially referred to by several names, including reovirus-like, orbivirus-like, duovirus, infantile gastroenteritis virus, or a new virus. The wheel-like structure seen by electronmicroscopy eventually led to agreement to accept the name Rotavirus (rota = Latin for wheel). Human rotaviruses were quickly linked to previous descriptions in the literature of identical viruses causing severe diarrhea in newborn mice (EDIM virus), 11 newborn calves (NCDV), 12 and a virus identified from a rectal swab of a healthy monkey (SA11). 15 Rotaviruses have now been shown to be a cause of diarrhea in the young of many mammalian and avian species. 16 The importance of rotavirus as a cause of severe acute diarrhea in young children was established by a year long survey of pathogens identified in children equal to or less than 5 years admitted to the Gastroenteritis ward of the RCH. Rotaviruses were identified in diarrheal feces from 52% of gastroenteritis admissions during (Table 1) and were the cause of 73% of admissions during the peak of winter. 17 One of the important consequences of this study was the successful initiative, spearheaded by Rudge Townley, that removed antibiotic treatment from the Pharmaceutical Benefit List for pediatric gastroenteritis. The results of the RCH survey were quickly confirmed in studies of hospital admissions in Birmingham, UK, Toronto, Canada, and Washington, USA. 16 At the same time, limited surveys showed rotaviruses to be causes of severe diarrhea in young children in Singapore, Papua New Guinea, India, Indonesia, and Japan. A 13-month collaborative study between Yogyakarta, Indonesia, and RCH, Melbourne identified rotaviruses as causing severe diarrhea year round in 37% of young children admitted to hospital in this Indonesian city. The burden of disease was greatest in children < 12 months old. 18 Numerous studies over many years have now confirmed rotavirus as the single most common cause of severe acute dehydrating diarrhea in young children worldwide. 19,20 Rotaviruses are now estimated to be responsible for more than half a million deaths annually in young children worldwide. Mortality associated with rotavirus infection is highest in South-East Asia and sub-saharan Africa. In Australia there are estimated to be rotavirus admissions to hospital each year of children under 5 years of age, emergency department visits, and GP visits. 21 Annual rates of hospital admission of Australian children average 7.5/1000 for children under 5 and 11.6/1000 for children under 2. Rates are 3 5 times higher in young Aboriginal children in the Northern Territory with occasional deaths because of severe diarrhea. 22,23 Aboriginal children spend more than twice as long in hospital because of severity of disease, as well as difficulties with follow-up supervision. S82

3 Other aspects of rotavirus infection In addition to hospitalization for treatment of severe diarrhea, rotavirus is an important cause of diarrhea in children in day care centers, in children attending hospital outpatient clinics and visiting general practitioners Studies of the etiology of gastroenteritis outbreaks in aged care facilities in Melbourne have identified rotavirus infection in 13% (7 of 53 outbreaks). 26 Rotavirus diarrhea also occurs occasionally in children postbone marrow transplant. 27 Nosocomial infections occur frequently in children admitted to hospital for other causes. The prolonged excretion after severe rotavirus diarrhea, 28 and the asymptomatic excretion of rotaviruses by adult attendants in hospital wards, 29 contribute to dissemination of infection. A randomized trial of administration of oral human gammaglobulin to low birth weight infants in intensive care nurseries where rotavirus infection was endemic has been shown to delay or prevent rotavirus excretion. 30 Other aspects of rotavirus research have included the successful demonstration that rehydration of children by mouth or nasogastric tube is a safe and effective treatment for moderately dehydrated children. 31 This change from intravenous to oral rehydration has many benefits, including reducing the need for several days of inpatient treatment. Education of village mothers in the need for oral rehydration of young children after onset of diarrhea has lowered costs of treatment and reduced childhood mortality in developing countries. A previously unsuspected consequence of human rotavirus infection has been the demonstration of rotavirus antigenemia/ viremia during (at least) the acute stages of disease. 32,33 This opens up the need for further clinically based studies to examine systemic effects (if any) of rotavirus infection. Previously, rotavirus infection was shown to be associated with changes in serum aspartate aminotransferase levels 34 and with encephalopathy. 35 Although it has been postulated that rotavirus infection could be implicated in etiology of biliary atresia, there is no evidence to date in humans supporting this association. 36 Studies on the pathogenesis of rotavirus disease implicate an enterotoxin in production of profuse watery diarrhea. This enterotoxin results from release of one of the nonstructural rotavirus proteins, NSP4, into the intestinal lumen and circulation. 37,38 In vitro studies of human rotavirus infection in Caco2 cells shows that the early stages of infection in vitro result in transcytosis of macromolecules from the epithelial cell. 39 Increased understanding of the influences of rotavirus infection on intestinal fluid and electrolyte transport could lead, in time, to effective treatment strategies. Development of rotavirus vaccines The worldwide burden of disease because of rotavirus quickly led to initiatives supported by the World Health Organization (WHO) to develop vaccines to prevent this disease. The vaccine initiative was developed in parallel with initiatives aimed at widespread extension of oral rehydration therapy in developing countries. A need for a rotavirus vaccine was proposed once the importance of rotavirus infection was recognized. Encouragement that a live oral rotavirus given to children in the first few month of life could be effective was supported by longitudinal studies. The first study was Table 2 Development of rotavirus vaccines 1983 RIT Single bovine strain 1986 RRV Single simian strain 1991 TRRV Simian/human reassortant G 1 G 2 G 3 G Withdrawn 1999 Rotarix Single human strain G 1 P(8) 2000 RotaTeq Bovine/human reassortants G 1 G 2 G 3 G 4 P(8) based on recruitment and longitudinal surveillance of babies housed in the Royal Women s Hospital, Melbourne, where rotavirus infection with an unusual strain (RV3) had been shown to be endemic. 40 Infants recruited were kept under clinical and serological surveillance for the first 3 years of life. Infants infected with rotavirus as neonates were not protected from rotavirus reinfection, but were protected from severe symptoms of diarrhea on reinfection. 40 A similar study in Mexican children supported the protective effect of natural rotavirus infection against disease symptoms on reinfection. 41,42 Intensive studies of human and animal rotaviruses adapted to cell culture provided the basis for vaccine design. Rotaviruses possess 11 genes coding for 12 proteins and are composed of three protein layers of six structural proteins. Two structural proteins, VP4 and VP7, form the outer protein layer and stimulate production of neutralizing antibodies in sera and intestinal secretions. 43 Antibodies to both proteins are implicated in protection. Rotaviruses are classified into serotypes based on VP4 and VP7. The existence of cross-protection between serotypes has been demonstrated. 44,45 There are 15 VP7 types (G-types) and 25 VP4 (P-types). Five rotavirus serotypes, G 1 P(8), G 2 P(4), G 3 P(8), G 4 P(8), and G 9 P(9) have been the most common causes of severe disease in children worldwide during the past 35 years. Five candidate vaccines have been extensively trialed since 1983 (Table 2). The strategies adopted were based around use of animal strains, shown to be naturally attenuated for humans, or a human strain representative of the most common serotype found worldwide, and attenuated by multiple in vitro passages. Single animal strains (RIT, RRV) were shown to have limited protection against the range of human serotypes, so the strategy of combining human/animal reassortant strains was adopted. Longitudinal studies had shown that single human strains were capable of protecting against a range of human serotypes. 40,42,44 The tetravalent TRRV vaccine was shown to be highly effective and was licensed and used widely in the USA. However it was withdrawn after post-licensing surveillance showed an association with development of intussusception. 46 Two oral live attenuated rotavirus vaccines, Rotarix (GSK), containing a single attenuated human rotavirus of serotype G 1 P(8), and RotaTeq (Merck), containing 5 bovine/human reassortant viruses G 1,G 2,G 3,G 4, and P(8) have been shown (in extensive placebo-controlled trials) to be safe and to have efficacies of 70% against rotavirus gastroenteritis of any severity. Their efficacies against severe rotavirus gastroenteritis have ranged from % in clinical trials in many countries. 47,48 At the end of 2008, these vaccines had been licensed in more than 100 countries, but in routine use in only 17 countries. Endorsement of worldwide use of rotavirus vaccines has recently been announced by the WHO Strategic Advisory Group of S83

4 Table 3 Other live oral rotavirus vaccines Human neonatal strains RV 3 Australia G 3 P(6) 116E India G 9 P(11) Animal/human reassortant strains UK Bovine G 1 G 2 G 3 G 4 P(8) P(4) Optimal G 5 G 8 G 9 G 10 Experts (SAGE) on Immunization. The decision was made after SAGE considered results from rotavirus vaccine trials in South Africa and Malawi together with post-licensing monitoring data from Nicaragua and El Salvador. Based on the evidence of high vaccine efficacy against severe disease and reduction in mortality, SAGE recommended the inclusion of rotavirus vaccination of infants into all national immunization programs. The vaccines are considered to be safe and intussusception risks similar to that of Rotashield can be ruled out. Rotavirus vaccines can be co-administered with oral poliovirus vaccine (OPV). A study in South Africa has shown that Rotarix given to HIV-positive children was well tolerated, immunogenic and did not affect the clinical status of the HIV infection. At present the first dose of Rotarix or RotaTeq should be given when the infant is aged 6 weeks to 15 weeks. This age restriction will be reviewed after collection of further data. These vaccines have been shown to be a cost-effective intervention in all countries studied to date. Both are licensed for use in Australia where the burden of rotavirus illness, and the likely cost-effectiveness have been assessed Currently, Rotarix is used to vaccinate all infants born in Northern Territory, NSW, ACT, Tasmania, and Western Australia. RotaTeq is given to infants in Victoria, Queensland, and South Australia. SAGE has recommended that sentinel surveillance should continue to monitor vaccine impact, possible adverse events (including intussusception), and the emergence of new serotypes with the potential to evade vaccine-stimulated immunity. Rotarix relies on cross-protection to protect against non-g 1 P (8) rotaviruses. It is possible that it will be less effective against G 2 P (4) viruses. However, it replicates well in the gut and may stimulate a wide range of (currently not identified) protective antibodies. In time, RotaTeq might offer reduced protection against VP4 and VP7 serotypes not included in the vaccine. Emergence of currently rare serotypes and/or reassortants between human and animal rotaviruses could limit the long-term effectiveness of either vaccine. Other barriers to take of live oral vaccines may emerge that could interfere with effective protection in developing countries, as has been observed with oral poliovirus, cholera, and typhoid vaccines. These barriers include high levels of rotavirus antibodies in breast milk. Changes in vaccine formulation, scheduling, and development of parenteral vaccines could mitigate or avoid some of these problems. Development of other vaccine strategies is proceeding (Table 3); this includes trials of a live oral candidate vaccine 53,54 that seems suitable to be administered to neonates. Most research now concentrates on worldwide studies of epidemiology of rotavirus serotypes, the changing balance between strains and emergence of new strains, together with development of second generation vaccines and studies of rotavirus vaccine costeffectiveness. Success of the two current vaccines should not deter comprehensive strategies to control diarrheal diseases, including improvements in hygiene and sanitation, zinc supplementation, and community-based administration of oral rehydration therapy. References 1 Gairdner P. An analysis of 216 cases with special reference to institutional outbreaks. Arch. Dis. Child. 1945; 20: Zahorsky J. Hyperemesis hiemsis or the winter vomiting disease. Arch. Pediatr. 1929; 45: Light JS, Hodes HL. Studies on epidemic diarrhea of the newborn: isolation of a filterable agent causing diarrhea in calves. Am. J. Public Health 1943; 33: Cramblett HG, Azimi P, Haynes RE. 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5 22 Ruben AR, Walker AC. Malnutrition among rural aboriginal children in the top end of the Northern Territory. Med. J. Aust. 1995; 162: Schultz R. Rotavirus gastroenteritis in the Northern Territory Med. J. Aust. 2006; 185: Pitson GA, Grimwood K, Coulson BJ et al. Comparison between children treated at home and those requiring admission for rotavirus and other enteric pathogens associated with acute diarrhea in Melbourne, Australia. J. Clin. Microbiol. 1986; 24: Liddle JLM, Burgess MA, Gilbert GL et al. Rotavirus gastroenteritis: impact on young children, their families and the healthcare system. Med. J. Aust. 1997; 167: Marshall J, Botes J, Gorrie G et al. Rotavirus detection and characterisation and characterisation in outbreaks of gastroenteritis in aged-care facilities. J. Clin. Virol. 2003; 28: Blakey JMS, Bishop RF, Barnes GL. Infectious diarrhea in children undergoing bone marrow transplantation. Aust. N. Z. J. 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N. Engl. J. Med. 1983; 309: Velazquez FR. Protective effects of natural rotavirus infection. Pediatr. Infect. Dis. J. 2009; 28: Velazquez FR, Matson DO, Calva JJ et al. Rotavirus infections in infants as protection against subsequent infections. N. Engl. J. Med. 1996; 335: Grimwood K, Lund JCS, Coulson BS, Hudson IL, Bishop RF. Comparison of serum and mucosal antibody responses following severe acute gastroenteritis in young children. J. Clin. Microbiol. 1988; 26: Gorrell RJ, Bishop RF. Homotypic and heterotypic serum neutralizing antibody response to rotavirus proteins following natural primary infection and reinfection in children. J. Med. Virol. 1999; 57: Ward R. Mechanisms of protection against rotavirus infection and disease. Infect. Dis. J. 2009; 28: S Anon. Intussusception among recipients of rotavirus vaccine-united States MMR Morb Mortality Weekly Report. 1999; 48: Ruiz-Palacios GM, Perez-Schael I, Velazquez FR et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N. Engl. J. Med. 2006; 354: Vesikari T, Matson DO, Dennehy P et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N. Engl. J. Med. 2006; 354: Barnes GL, Uren E, Stevens KB, Bishop RF. Etiology of acute gastroenteritis in hospitalized children in Melbourne, Australia from April 1980 to March J. Clin. Microbiol. 1998; 36: Crawley JMS, Bishop RF, Barnes GL. Rotavirus gastroenteritis in infants aged 0 6 months in Melbourne, Australia: Implications for vaccination. J. Pediatr. Child Health 1993; 29: Galati JC, Horsley S, Richmond P, Carlin JP. The burden of rotavirus-related illness among young children on the Australian health care system. Aust. N. Z. J. Public Health 2006; 30: Carlin JB, Jackson T, Lane L, Bishop RF, Barnes GL. Cost-effectiveness of rotavirus vaccination in Australia. Aust. N. Z. J. Public Health 1999; 23: Barnes GL, Lund JS, Adams L et al. Phase I trial of a candidate rotavirus vaccine (RV3) derived from a human neonate. J. Pediatr. Child Health 1997; 33: Barnes GL, Lund JS, Mitchell SV et al. Early phase II trial of a human rotavirus vaccine candidate RV3. Vaccine 2002; 20: S85