The present status of rotavirus vaccine development

Rotavirus infection is one of the most important causes of morbidity in young children throughout the world. The high associated mortality in Southeast Asia (and elsewhere) warrants the development of a vaccine. It is probable that most of the life-threatening watery diarrhoea due to rotavirus infection occurs as a result of primary infection in children aged 6-18 months after protection due to maternal antibody has diminished. Thus rotavirus vaccines are targeted at young infants from birth to 3 months of age. At present three candidate rotavirus vaccines (RIT-4237, MMU-18007, WC3) have undergone trials in young children. A bovine rotavirus strain (RIT-4237), was shown to be safe, immunogenic and efficacious in prevention of severe rotavirus diarrhoea in young children in Finland. However it was found to be weakly immunogenic in infants in developing countries, and to have only low efficacy in prevention of disease. A simian rotavirus strain (RRV, MMU-18006) has proved to be highly immunogenic and its reactinogenicity to be diminished by pre-existing maternal antibody (in infants aged 1-4 months). It has high efficacy against clinically severe rotavirus infection. However protection is homotypic against human serotype 3 only so that eventually a multivalent vaccine incorporating reassortant rotavirus strains that protect against human serotypes 1, 2, 4 (and other newer serotypes) may be required. It is hoped that, once safe immunogenic and protective candidate rotavirus vaccines are identified, they can be administered in an acceptable form with no alteration to existing immunization schedules.     

Treatment and Prevention of Rotavirus Infection in Children

Rotavirus infection is the most common cause of severe diarrhea disease in infants and young children worldwide and continues to have a major global impact on childhood morbidity and mortality. No antiviral therapy is available. Treatment of rotavirus gastroenteritis is limited to rehydration therapy. Recently, therapies, such as probiotics, have been developed as adjuncts to rehydration therapy. Two effective rotavirus vaccines are available and recommended for routine immunization of all infants. These vaccines have been introduced in both developed and developing countries. As rotavirus vaccines are implemented, studies that assess health impact, indirect benefits, and strain changes after the introduction of rotavirus vaccine have been reported. In the United States, rotavirus vaccination has led to dramatic drops in severe rotavirus-related hospitalizations and has reduced emergency room visits. Herd immunity has also been noted after routine rotavirus immunization. There have been no significant strain shifts or escape mutants noted since the introduction of rotavirus vaccines.     

Rotavirus vaccines: entering a new stage of deployment

PURPOSE OF REVIEW: Rotavirus is the single most important cause of severe diarrhoea in infants and young children. This review provides updated information concerning three rotavirus vaccines that are being evaluated and introduced globally. RECENT FINDINGS: Two large, phase III clinical trials, each involving more than 60,000 infants in both developing and developed countries, demonstrated that both RotaTeq (Merck & Co., Whitehouse Station, New Jersey, USA), the pentavalent human-bovine reassortant vaccine, and Rotarix (GlaxoSmithKine Biologicals, Rixensart, Belgium), the monovalent live-attenuated human rotavirus vaccine, are safe with respect to intussusception when the first dose is administered between 6 and 12 weeks of age, and that both vaccines are 90-95% efficacious in preventing severe rotavirus gastroenteritis including hospitalization. The bovine (UK)-human rotavirus reassortant tetravalent (BRV-TV) vaccine, developed at the National Institutes of Health (USA), was licensed for local production in several developing countries. SUMMARY: Rotavirus vaccines are entering a new stage of deployment toward the goal of reducing morbidity and mortality attributed to rotavirus infection in developing countries, and hospitalizations and emergency visits caused by rotavirus in developed countries. High vaccine prices appear to offset cost savings, and may make policymakers even in wealthy countries hesitate to introduce a rotavirus vaccine into their childhood immunization programmes.     

A prospective study of rotavirus infection in infants and young children

Diarrhea in neonates, followed as a cohort, and their families was studied prospectively. The families were followed for an average of 16.3 months. Stool and serum specimens were obtained at least every three months. Stool specimens were examined for viruses by electron microscopy and cultured for enteropathogens, and serum specimens were tested for antibodies to rotavirus and Norwalk virus. During the study, 237 episodes of gastroenteritis were observed in 104 infants and their 62 siblings. Rotavirus, detected 82 times in 72 children, was by far the most common enteropathogen. It was associated with gastrointestinal symptoms in 72% (with diarrhea in 65%). Rotavirus diarrhea occurred mostly in winter months and was significantly more frequently associated with respiratory symptoms than were diarrheas with other etiologies. Rotavirus infection was uncommon in the first six months of life, but by two years of age, 62% of the infants had had at least one infection. Neither breast feeding nor the presence of antibody to rotavirus in cord blood appeared to be protective.     

Rotavirus vaccines: current prospects and future challenges

Rotavirus is the most common cause of severe diarrhoea in children worldwide and diarrhoeal deaths in children in developing countries. Accelerated development and introduction of rotavirus vaccines into global immunisation programmes has been a high priority for many international agencies, including WHO and the Global Alliance for Vaccines and Immunizations. Vaccines have been developed that could prevent the enormous morbidity and mortality from rotavirus and their effect should be measurable within 2-3 years. Two live oral rotavirus vaccines have been licensed in many countries; one is derived from an attenuated human strain of rotavirus and the other combines five bovine-human reassortant strains. Each vaccine has proven highly effective in preventing severe rotavirus diarrhoea in children and safe from the possible complication of intussusception. In developed countries, these vaccines could substantially reduce the number and associated costs of child hospitalisations and clinical visits for acute diarrhoea. In developing countries, they could reduce deaths from diarrhoea and improve child survival through programmes for childhood immunisations and diarrhoeal disease control. Although many scientific, programmatic, and financial challenges face the global use of rotavirus vaccines, these vaccines-and new candidates in the pipeline-hold promise to make an immediate and measurable effect to improve child health and survival from this common burden affecting all children.     

轮状病毒拮抗宿主先天性免疫机制研究进展

轮状病毒(Rotavirus,RV)是世界范围内引起婴幼儿和多种幼龄动物严重肠胃炎的主要病原之一,全世界每年有近50万婴幼儿因感染轮状病毒而死亡。轮状病毒对IFN介导的抗病毒效应敏感,因此,为了拮抗宿主先天性免疫,轮状病毒非结构蛋白1(NSP1)通过作用于IFN表达通路的多个成分,如IFN调节因子家族(IRFs),转录因子NF-κB,细胞胞质模式识别受体RIG-I等来拮抗宿主先天性免疫。此外轮状病毒NSP2、VP2、VP3和NSP4蛋白也发挥了一定的拮抗作用。本文综述了轮状病毒拮抗机体先天性免疫的相关机制,为轮状病毒的分子生物学研究和疫苗、治疗性药物的研制提供参考。     

Rotavirus vaccines in developed countries

PURPOSE OF REVIEW: Rotavirus is the most common cause of diarrhoea and dehydration in early childhood. The recent licensure in many nations of vaccines against rotavirus offers promise to significantly reduce this toll. The present review describes recent developments regarding rotavirus vaccines and the challenges they face. RECENT FINDINGS: Rotavirus causes significant morbidity and impact upon healthcare systems, at both inpatient and outpatient levels. An earlier rotavirus vaccine, since withdrawn, was temporally associated with intussusception causing small bowel obstruction, especially in infants receiving their first dose at an older age. Large-scale safety and efficacy studies of two new live, oral, attenuated vaccines have shown excellent efficacy against severe rotavirus gastroenteritis. Importantly, both studies detected no association with intussusception with these new vaccines when administered at the scheduled ages. Developed using different rotavirus vaccinology philosophies, questions remain regarding their coverage against new rotavirus serotypes. Ongoing intussusception surveillance following introduction should answer whether they may be safely administered beyond scheduled ages. SUMMARY: Safe, efficacious rotavirus vaccines are available in many developed countries, offering significant promise to reduce the burden of gastroenteritis and dehydration. The impact of these vaccines upon not only morbidity, but also circulating rotavirus serotypes, will be monitored with interest.     

Fulfilling the promise of rotavirus vaccines: how far have we come since licensure?

Rotavirus is the most common cause of fatal and severe childhood diarrhoea worldwide. Two new rotavirus vaccines have shown efficacy against severe rotavirus disease in large clinical trials. Between 2006 and 2010, 27 countries introduced rotavirus vaccination into national immunisation programmes and, subsequently, the burden of severe rotavirus disease in these countries has decreased substantially in both vaccinated and unvaccinated children. Rotavirus vaccination has led to large, sustained declines in childhood deaths from diarrhoea in Brazil and Mexico, which supports estimates that rotavirus was the leading cause of diarrhoeal deaths in these countries. Studies after licensing have provided new insights into these vaccines, such as the duration of protection, relative effectiveness in poor populations, and strain evolution after vaccine introduction. The challenge for policy makers worldwide is to analyse the effect of vaccination in early adopter countries and to assess whether the benefits outweigh the costs and encourage wider dissemination of these vaccines.     

人轮状病毒疫苗的研究进展

轮状病毒(RV)是引起全球5岁以下婴幼儿腹泻最重要的病原之一,普遍流行于发达国家和发展中国家,然而在发展中国家该病的病死率较高。由于目前RV腹泻尚无有效治疗药物,并且改善卫生条件对预防RV感染并无明显的效果。因此,疫苗是目前证实能预防和控制RV腹泻唯一有效的手段。尽管RV疫苗研制已取得很大的进展,由于轮状病毒毒株的多样化和流行分布很广,故而继续研制一种新的适合的安全、有效的RV疫苗显得尤为重要。本文针对人RV疫苗的研究进展、质量控制、保护效力及安全性评价作一综述,以期促进后期相关研究。     

Review of varicella zoster seroepidemiology in India and South-east Asia

Summary Varicella zoster virus (VZV) predominantly affects children in temperate countries, with near-universal seroconversion occurring by late childhood. However, in tropical regions, VZV infection is common in adolescents and adults. This review identifies age-related VZV seroprevalence patterns in a number of Asian countries which indicate that seroconversion in tropical countries occurs at a later age than in temperate countries. Seasonal and regional variations in acute disease within some Asian countries suggest that temperate climates might favour transmission of the varicella virus, with incidence peaking during cooler months and in cooler, more temperate regions. VZV infection is often more severe in adults than in children, suggesting that tropical countries may be at risk of greater morbidity and mortality as a result of later-age seroconversion. Susceptibility of pregnant women and their infants, and of people infected with HIV/AIDS is also cause for concern. Vaccination may be beneficial in reducing the impact of VZV in Asian populations.     

Rotavirus infection in adults

Rotavirus has been recognised for 30 years as the most common cause of infectious gastroenteritis in infants and young children. By contrast, the role of rotavirus as a pathogen in adults has long been underappreciated. Spread by faecal-oral transmission, rotavirus infection in adults typically manifests with nausea, malaise, headache, abdominal cramping, diarrhoea, and fever. Infection can also be symptomless. Rotavirus infection in immunocompromised adults can have a variable course from symptomless to severe and sustained infection. Common epidemiological settings for rotavirus infection among adults include endemic disease, epidemic outbreak, travel-related infection, and disease resulting from child-to-adult transmission. Limited diagnostic and therapeutic alternatives are available for adults with suspected rotavirus infection. Because symptoms are generally self-limiting, supportive care is the rule. Clinicians caring for adults with gastroenteritis should consider rotavirus in the differential diagnosis. In this review we intend to familiarise clinicians who primarily provide care for adult patients with the salient features of rotavirus pathophysiology, clinical presentation, epidemiology, treatment, and prevention.     

Severe diarrhea due to rotavirus infection in a Belgian hospital 1981-2002

Rotavirus infections are a major cause of severe diarrhea in children younger than 2 years. In Belgium they cause many hospitalizations because of dehydration. A study of the laboratory diagnosis of rotavirus infections in 28.251 stool samples at a university teaching hospital in Belgium during a twenty-year period (1981-2002) showed a marked seasonality. The virus was most often diagnosed during the winter months: 54% of the rotavirus isolates were found in the first three months of the year, with 21% of the positive samples occurring in February. Recently, rotaviruses can be genotyped based on differences in the viral outer capsid protein VP7. Vaccines are currently being developed against the four most prevalent genotypes G1, G2, G3 and G4. During the last three epidemic seasons (1999-2002) in Belgium, G1 was the most prevalent genotype and accounted for 62% of the rotavirus isolates recovered. G2, G3 and G4 were also isolated, and other emerging types need to be carefully monitored too, since G9 (45%) was co-dominant with G1 (42%) in the 2000-2001 rotavirus season in Belgium. The future development of an efficient rotavirus vaccine will need to take the diversity of the rotavirus genotypes into account.     

Discovery of rotavirus: Implications for Child health

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 > 600 000 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.     

Sentinel hospital surveillance for rotavirus diarrhea in Taiwan, 2001-2003

We examined the epidemiological profile of rotavirus infection among children hospitalized for diarrhea in Taiwan, to assess the burden of this disease. From 1 April 2001 through 31 March 2003, children <5 years old with gastroenteritis admitted to 4 sentinel hospitals were enrolled in a surveillance study and had stool specimens tested for the presence of rotavirus, enteric adenovirus, and the bacterial pathogens for which routine screening is performed. For 52% of patients, a recognized enteric pathogen was identified, including rotavirus (43% of patients), bacteria (11%), enteric adenovirus (2.5%), and a mixture of pathogens (3.9%). Rotavirus was detected year-round, but great month-to-month variability made it difficult to identify a distinct seasonal pattern. Rotavirus disease was most common among children 7-23 months old, but the rate of rotavirus detection varied little between the youngest and oldest age groups. The novel strain P[8]G9 was detected most commonly (37% of strains), followed by strains P[8]G1 (31%), P[4]G2 (10%), P[8]G3 (9.3%), and P[8]G4 (3.7%). Rotavirus infection is the most important cause of diarrhea among hospitalized children in Taiwan, and a rotavirus vaccination program for young children might significantly reduce this problem.     

Diarrhea associated with rotavirus in rural Guatemala: a longitudinal study of 24 infants and young children.

A population of 24 infants and young children followed prospectively during the first 3 years of life was studied for the occurrence of rotavirus infection by using enzyme-linked immunosorbent assay to detect virus in stools. Infection with rotavirus was associated with 26 (14.2%) of 183 selected diarrheal episodes. Twenty of the 24 infants and young children had diarrhea associated with rotavirus on at least one occasion and six had two such episodes. Rotavirus infection was documented in over 50% of the dehydrating episodes studied, thus further indicating the importance of rotavirus in this population.     

Hospital-based surveillance for rotavirus diarrhea in children in Yangon, Myanmar

Diarrhea is a common childhood illness in Myanmar, and rotavirus is the single most important etiological agent of diarrhea. Surveillance for rotavirus diarrhea in children <5 years of age was conducted in a tertiary pediatric hospital in Yangon, Myanmar, from January 2002 through December 2003. Stool specimens obtained from children admitted to the hospital for acute diarrhea were tested for the presence of rotavirus by use of an enzyme-linked immunosorbent assay. Diarrhea was the cause of 5671 (18%) of all hospitalizations of children <5 years of age during the 2-year study period (n = 30,869). Rotavirus was identified in 923 (53%) of the 1736 stool specimens tested, and rotavirus infection was associated with approximately 10% of all hospitalizations of children. Rotavirus diarrhea most frequently occurred in children 6-17 months of age, and it was more commonly identified in boys (62% of children with rotavirus diarrhea were boys). The seasonal pattern of rotavirus disease mimicked that of diarrheal illness due to all causes, with the peak season for rotavirus disease occurring from November through February (i.e., during the cool, dry season). During the study period, 53 of the children who were hospitalized for diarrhea died. The present study confirms the importance of the etiological role that rotavirus plays in childhood diarrhea.     

Viral gastroenteritis

A large number of viruses can be found in the human intestine. Some (bacteriophages) infect the bacteria present as normal flora and others use the gut as a portal of entry. This review examines the virology, pathogenesis, immunology, epidemiology, clinical features, treatment and prevention of the viral enteropathogens. Rotavirus is undoubtedly the most important, causing an estimated 800,000 deaths each year, especially in developing countries. Recently, an oral live quadrivalent rhesus rotavirus vaccine has been licensed for use in the USA. It has great potential but there are a number of hurdles to be overcome before it can be given to infants in developing countries. Molecular techniques are revolutionizing our understanding of rotavirus pathogenesis, and the tremendous diversity of Caliciviridae and Astroviridae, as well as producing new diagnostic techniques and vaccines.     

A long-term survey of rotavirus infection in Japanese children with acute gastroenteritis.

Human rotavirus was detected by electron microscopic examination of the stools of 320 (63%) of 506 infants and young children hospitalized with acute gastroenteritis between December 1974 and March 1977. Serologic responses to infection with the rotavirus were revealed by the complement-fixation test in 130 (70%) of 185 patients examined. During the study period three epidemics of human rotavirus infection occurred during the winter months. The peak incidences occurred in January 1975 (88% of patients positive by serologic analysis or electron microscopy of stools), January 1976 (92%), and February 1977 (96%). Rotavirus was detected in the stools of 288 (79%) of 365 patients tested during the cooler months (December to March) and 35 (25%) of 141 during the rest of the year. In the summer (June to August), rotavirus infection occurred rarely. The frequency of human rotavirus infection was highest among patients aged six to 11 months. These results indicate that human rotavirus can be regarded as a major etiologic agent of acute gastroenteritis in infants and young children, of which wintertime epidemics are common in Japan.     

Rotavirus epidemiology and vaccine demand: considering Bangladesh chapter through the book of global disease burden

Background

Rotavirus is the major cause of gastroenteritis in children throughout the world. Every year, a large number of children aged < 5 years die from rotavirus-related diarrhoeal diseases. Though these infections are vaccine-preventable, the vast majority of children in low-income countries suffer from the infection. The situation leads to severe economic loss and constitutes a major public health problem.

Methods

We searched electronic databases including PubMed and Google scholar using the following words: “features of rotavirus,” “epidemiology of rotavirus,” “rotavirus serotypes,” “rotavirus in Bangladesh,” “disease burden of rotavirus,” “rotavirus vaccine,” “low efficacy of rotavirus vaccine,” “inactivated rotavirus vaccine”. Publications until July 2017 have been considered for this work.

Results and conclusion

Currently, two live attenuated vaccines are available throughout the world. Many countries have included rotavirus vaccines in national immunization program to reduce the disease burden. However, due to low efficacy of the available vaccines, satisfactory outcome has not yet been achieved in developing countries such as Bangladesh. Poor economic, public health, treatment, and sanitation status of the low-income countries necessitate the need for the most effective rotavirus vaccines. Therefore, the present scenario demands the development of a highly effective rotavirus vaccine. In this regard, inactivated rotavirus vaccine concept holds much promise for reducing the current disease burden. Recent advancements in developing an inactivated rotavirus vaccine indicate a significant progress towards disease prophylaxis and control.

     

Gastroenteritis in children: a two-year review in Manitoba. I. Etiology.

During two years, 1,217 children hospitalized with gastroenteritis at the Children's Centre in Winnipeg, Manitoba, Canada were studied. Bacterial pathogens were present in 25% of these children: enteropathogenic Escherichia coli in 120, Shigella in 139, Salmonella in 24, and multiple pathogens in 18. Rotavirus was detected in 54 (11%) of 472 patients examined. Rotavirus and enteropathogenic E. coli were the most common pathogens in infants, and Shigella was the most common in older children. Bacterial diarrhea occurred more commonly in summer, whereas rotavirus infection occurred more commonly in winter. Among 276 children screened, enterotoxigenic E. coli was found in three, and Aeromonas shigelloides that produced a similar toxin in two others. Enteroinvasive E. coli was not detected in 70 children. Organisms producing toxins "cytotoxic" to HeLa cells were isolated from three of 90 children. Screening for enterotoxigenic or enteroinvasive organisms was not productive of a significant number of pathogens, and, although screening for rotavirus did improve the number of etiologic diagnoses, the etiology of the majority of cases of diarrhea remained unknown.