Rotavirus vaccines: an update

PURPOSE OF REVIEW: Rotavirus infection is the most common cause of severe diarrhea disease in infants and young children worldwide and has a major global impact on childhood morbidity and mortality. Vaccination is the only control measure likely to have a significant impact on the incidence of severe dehydrating rotavirus disease. RECENT FINDINGS: Rotavirus disease prevention efforts suffered a great setback in 1999 with the withdrawal of the RRV-TV vaccine less than a year after its introduction. Several new rotavirus vaccine candidates have now been developed and are undergoing clinical trials. SUMMARY: New safe and effective rotavirus vaccines offer the best hope of reducing the toll of acute rotavirus gastroenteritis in both developed and developing countries.     

Conquering rotavirus: From discovery to global vaccine implementation

Rotavirus, the commonest cause of severe dehydrating gastroenteritis world‐wide, was discovered less than 50 years ago. It causes about 450 000 deaths per year in children <5 years of age and hospitalises millions more. Rotavirus vaccines have been shown to have a major impact on hospital admissions due to rotavirus gastroenteritis and all‐cause gastroenteritis and reduce mortality in developing countries. In Australia, there has been a 71% decrease in rotavirus hospitalisations in children 0–5 years of age. From the discovery of rotavirus as the major causative agent for severe gastroenteritis, through vaccine development and vaccine post‐marketing surveillance activities, Australian scientists and clinicians have played a significant role in the global effort to reduce the burden of rotavirus infection.     

Live attenuated human rotavirus vaccine, Rotarix

Rotavirus infections are the leading cause of severe gastroenteritis in young children worldwide. Recently two new rotavirus vaccines have entered the world market. This review provides a summary of the rationale, development, and evaluation of one of these vaccines, Rotarix. Rotarix is a live oral rotavirus vaccine developed from a single protective human strain following multiple passages in tissue culture to attenuate the strain. The vaccine is administered as two oral doses at approximately 2 and 4 months of age. Large safety and efficacy trials have shown the vaccine is safe, not associated with intussusception, and effective against the most common circulating human serotypes. Efficacy against severe rotavirus gastroenteritis and hospitalization have ranged from 85 to 100 percent.     

Introduction of rotavirus vaccines in developing countries: remaining challenges

Rotavirus is the principal agent of severe, dehydrating gastro-enteritis in infants and young children worldwide. The main public health tool that can prevent hospitalisation and death from rotavirus is vaccination. One of two current rotavirus vaccines is now licensed in more than 80 countries and is incorporated into childhood immunisation schedules across several countries in the Americas and Europe. However, since the majority of childhood deaths from rotavirus occur in the developing countries of Africa and Asia, widespread use of vaccine in these two continents will be necessary before a major impact on global diarrhoea mortality is seen. Challenges in these latter settings which primarily relate to vaccine efficacy, safety and financing will be addressed within the next 3-5 years, and thus perhaps finally allow introduction of rotavirus vaccine into the populations in greatest need.     

Rotavirus in India: Forty years of research

Rotavirus was first identified as a human pathogen just over 40 years ago, and work on this pathogen in India started shortly thereafter. Subsequent studies have confirmed its pre-eminent role in gastroenteritis in children in India. Standardized surveillance has enabled the documentation of the high burden of disease, and has demonstrated that there is considerable geographic and temporal variation in strain circulation. Internationally licensed vaccines, vaccine candidates based on indigenous strains and out-licensed strains have been tested for safety, immunogenicity and efficacy; three vaccines are now licensed in India and are used in the private sector. Public sector vaccination has begun, and it will be path-breaking for Indian vaccinologists to measure impact of vaccine introduction in terms of safety and effectiveness. So far, India has kept pace with international epidemiologic and vaccine research on rotavirus, and these efforts should continue.     

Efficacy of RIX4414 live attenuated human rotavirus vaccine in Finnish infants

BACKGROUND: Rotavirus gastroenteritis, a major cause of mortality and morbidity worldwide, is a vaccine-preventable disease. New safe and effective candidate rotavirus vaccines are needed to replace the withdrawn rhesus rotavirus-based oral vaccine. METHODS: We evaluated a monovalent human rotavirus vaccine, serotype G1, strain RIX4414, for efficacy, immunogenicity and safety in a randomized, double blind, placebo-controlled trial in Finland. We randomly allocated 405 healthy infants to receive 2 doses of vaccine or placebo (ratio 2:1) at approximately 2 and 4 months of age. The infants were followed during 2 rotavirus epidemic seasons (2000-2002) for acute gastroenteritis. Rotaviruses in diarrheal stool samples were primarily detected by enzyme-linked immunosorbent assay and confirmed and G-typed by reverse transciption-polymerase chain reaction. RESULTS: The vaccine was well-tolerated. No vaccine-related serious adverse events were observed during the study period. Rotavirus IgA (enzyme-linked immunosorbent assay) seroconversion rate was 80% after 2 doses. Thirty-eight cases of rotavirus gastroenteritis were detected during the entire follow-up period; 35 of these were of the G1 type. RIX4414 vaccine significantly decreased the occurrence of any rotavirus compared with placebo. Efficacy during the first rotavirus epidemic season was 73% [95% confidence interval (95% CI), 27-91%] and 90% (95% CI 10-100%) against any and severe rotavirus gastroenteritis, respectively, and during the entire follow-up period 72% (95% CI 42-87%) against any and 85% (95% CI 42-97%) against severe rotavirus gastroenteritis (P < 0.05 for all comparisons). CONCLUSIONS: RIX4414 strain of G1 human rotavirus vaccine was well-tolerated, immunogenic and efficacious in infants against rotavirus gastroenteritis during a 2-year period. To further increase vaccine "take" and efficacy, a higher dose of this vaccine may be considered for future efficacy trials.     

Rotavirus gastroenteritis among children under five years of age in Izmir, Turkey

Little is known about the epidemiology of rotavirus infection in Turkey. The aim of the study was to determine the incidence and clinical significance of rotavirus gastroenteritis, in view of the potentially available prevention by rotavirus vaccination. The study also sought to determine possible risk factors for rotavirus gastroenteritis. Therefore, 920 children under five years of age with acute gastroenteritis admitted to three pediatric hospitals in Izmir were studied. Rotavirus was identified in 39.8% of the children. Most children with rotavirus gastroenteritis (80.7%) were younger than two years of age. Marked seasonality of rotavirus gastroenteritis was observed, with a peak incidence from January to March. A total of 91% of rotavirus strains that were typed were of serotypes G 1-4. There was no significant difference among rotavirus-positive and rotavirus-negative patients with regard to family income. Compared with children who were exclusively breast-fed, those who were not exclusively breast-fed were at a two-fold greater risk of rotavirus diarrhea. Rotavirus gastroenteritis was significantly more severe than non-rotavirus gastroenteritis; 69% of children with rotavirus infection had severe gastroenteritis (score > or = 11). In conclusion, rotavirus is the most common cause of severe gastroenteritis among children under five years of age in Izmir. A new potent rotavirus vaccine, when available, will provide effective protection against severe rotavirus infection. Promotion of breast-feeding would augment the impact of rotavirus vaccines in preventing severe childhood diarrhea.     

The epidemiology of human rotavirus associated with diarrhoea in Kenyan children: a review

Rotavirus gastroenteritis still remains a major cause of morbidity and mortality among young children in developing countries, with approximately 150,000-200,000 deaths occurring annually in sub-Saharan Africa. We reviewed papers published over the last 30 years on the epidemiology of rotavirus diarrhoea among the hospitalized and out-patient children in Kenya. The analysis shows rotavirus prevalence of 6-56% with diarrhoea occurring throughout the year and generally exhibiting distinct peaks during the dry months. Among the common genotype, G1 was the most predominant up to the year 2002 but more recently there has been an emergence of genotype G9 as the most predominant genotype and to a less extent G8. It is important to continue rotavirus surveillance in Kenya to determine accurately the burden of rotavirus disease and the emerging new genotypes. This will assist policy makers in decision making on rotavirus vaccine introduction and determining the impact of the vaccine.     

Rotavirus from children of an urban settlement of Papua New Guinea

Rotavirus is a leading cause of severe dehydrating diarrhoea among children admitted to hospitals in Papua New Guinea. A community-based study in an urban settlement of Port Moresby, the capital of Papua New Guinea, revealed that rotavirus was a major cause of diarrhoea, especially of the severe type, in this community. Two serotypes of rotavirus were observed and were explained on the basis of a 'shift and drift' phenomenon, or an introduction of a new strain from outside. Implications for such observations are far reaching in developing countries and it is recommended that intervention strategies other than vaccine development be explored.     

Characteristics of an ideal rotavirus vaccine

Rotavirus gastroenteritis primarily affects children younger than 5 years of age and is the leading cause of diarrhea-related hospitalizations worldwide. The substantial morbidity associated with this disease and the major burden on healthcare resources underscore the need for an effective vaccine. Two recently developed vaccines (RotaTeq [rotavirus vaccine, live, oral, pentavalent], and Rotarix [rotavirus vaccine, live]) share some characteristics of an ideal rotavirus vaccine. High efficacy, excellent tolerability, and no increased risk of intussusception were shown in separate clinical trials of more than 60,000 infants for each trial, as well as in smaller phase 3 clinical trials of each vaccine. Vaccination against rotavirus will substantially reduce rotavirus gastroenteritis-associated morbidity and mortality and, in so doing, bring about a significant reduction in rotavirus gastroenteritis-associated healthcare utilization.     

Vaccines for rotavirus gastroenteritis universally needed for infants

Rotavirus causes severe and often lifethreatening illness. Universal application of a safe and protective vaccine is justified in both developed and developing nations. Two vaccine candidates, one monovalent (Rotarix) and one multivalent (Rotateq), appear to meet these requirements and are likely to be licensed in the United States in the next 2 or 3 years. Both vaccines exhibited similar safety characteristics. There is little doubt that Rotateq and Rotarix will be shown to be effective for routine protection of infants. Unfortunately, despite numerous clinical trials, the most common serotype (PlaGa) commonly has been encountered as a natural challenge. Therefore, it is not known whether either vaccine possesses advantages in different epidemiological situations. Continuing the analogy with influenza virus, it may be that optimum protection against different serotypes requires a vaccine that is precisely homologous in antigen composition. If so, Rotateq would provide protection against the most common serotype PlaG1 because in includes both Pla and G1 rotavirus reassortants. Further, it would be expected to provide superior protection against G2, G3, and G4 wild-type virus because it contains reassortants of those specificities. In the case of a natural challenge with a serotype that was not G1, G2, G3, or G4, a Rotateq preparation containing a WC3 reassortant expressing the new G serotype could be formulated readily. The monotypic Rotarix may provide ideal protection against the PlaG1 rotavirus because it is composed solely of the PlaG1 strain. It may also provide cross-protection against other rotavirus serotypes adequate to protect against severe and life-threatening disease. In such a case, its monotypic composition may also provide significant economic savings in manufacturing. The resolution of these questions may have to await extensive post-licensure experience with each vaccine. In the future, possible application of rotavirus vaccine for other situations also should be explored, including use in older children to limit nosocomial infection, use in geriatric populations, use in the immunocompromised host, and possibly use in parents and other adults in contact with infants with rotavirus. Both Rotarix and Rotateq likely are to be launched at prices beyond those affordable in the poorest and neediest less-developed countries. It is essential that there be vigorous pursuit of new technologies to manufacture these products at drastically reduced cost if their true lifesaving potential is to be achieved.     

Intussusception,rotavirus, and oral vaccines: summary of a workshop

Rotavirus gastroenteritis continues to cause substantial morbidity and mortality worldwide, despite widespread breastfeeding and use of oral rehydration therapy. This burden of disease indicates that an effective, safe rotavirus vaccine is needed, and in 1998 the first rhesus-human reassortant rotavirus tetravalent vaccine, Rotashield, was licensed in the United States. However, the recommendations for its use were withdrawn in 1999 because of the recognition of an uncommon but serious adverse event, intussusception. A workshop in September 2001 was held to review the subsequent developments and research regarding this association, the proceedings of which are summarized here. Although the pathogenesis of this association remains unknown, epidemiologic evidence supports a causal relationship, with a population attributable risk of approximately 1 per 10 000 (range of 1 in 5000 to 1 in 12 000) vaccine recipients. Whether this association will exist with other candidate rotavirus vaccine strains and whether the attributable risk for intussusception would be similar in other populations administered this vaccine are unclear. Because perceptions of vaccine safety derive from the relative disease burdens of the illness prevented and adverse events induced, the acceptance of rare adverse events may vary substantially in different settings. Nevertheless, a continuing consensus on the need for a safe and effective vaccine to prevent rotavirus gastroenteritis, especially for use in developing countries, exists.     

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Scope for Rotavirus Vaccination in India: Revisiting the Scientific Evidence

Rotavirus vaccines have been developed to prevent deaths resulting from severe diarrhea of rotavirus origin. The use of vaccines as an intervention at scale to prevent and control the burden of rotavirus diarrhea is supported by the argument that prevailing public health measures such as hygiene and sanitation, breast feeding and use of ORS have failed to prevent severe dehydration resulting from diarrhea. The article reviews the existing evidence on the rationale of using rotavirus vaccine as against the feasibility of scaling it up in developing countries like India. The vaccines currently available may not cover the strains circulating in Indian population. The diversity of Rotavirus infection in the country is tremendous and since the safety, immunogenicity and efficacy data has not been collected for India, there is first a need to conduct studies to measure the extent of protection and cross-protection provided by the available vaccines for local strains, before venturing into Rotavirus vaccination program. The potential benefits of immunization have to be first vetted against the risks involved by the policymakers and other stakeholders.     

Epidemiology and impact of rotavirus diarrhoea in Poland

Hospital and laboratory data were analysed in three hospitals to estimate rotavirus disease burden in 1994-96. Community acquired gastroenteritis was diagnosed in 757 children of whom 41% tested positive for rotavirus. A total of 196 children had rotavirus nosocomial infections (39% of all rotavirus community-acquired and nosocomial cases) Infants less than 24 months old and children less than 3 months old comprised 74% and 11.9% of admissions for rotavirus, respectively. Almost 94% of children with rotavirus infection had severe gastroenteritis (score 11). The annual rate of rotavirus associated hospitalization in Poland in 1996 was 3.1/1000 children under the age of 60 months and 5.2/1000 infants under 24 months of age. The mean hospital stay was 9.5 d (±9.8 d). We estimated that 8918 children under 60 months of age were hospitalized for rotavirus gastroenteritis in 1996; they accounted for 84899 inpatient days. We conclude that rotavirus is a leading aetiological agent of severe gastroenteritis in young children in Poland and that the Burden of this infection is significant. Rotavirus vaccine could significantly decrease the hospitalization rate and the financial impact of rotavirus Gastroenteritis in Poland. □ Acute diarrhoea, disease burden, epidemiology, gastroenteritis, rotavirus     

Epidemiology and impact of rotavirus diarrhoea in Poland

Hospital and laboratory data were analysed in three hospitals to estimate rotavirus disease burden in 1994-96. Community acquired gastroenteritis was diagnosed in 757 children of whom 41% tested positive for rotavirus. A total of 196 children had rotavirus nosocomial infections (39% of all rotavirus community-acquired and nosocomial cases). Infants less than 24 months old and children less than 3 months old comprised 74% and 11.9% of admissions for rotavirus, respectively. Almost 94% of children with rotavirus infection had severe gastroenteritis (score > or =11). The annual rate of rotavirus associated hospitalization in Poland in 1996 was 3.1/1000 children under the age of 60 months and 5.2/1000 infants under 24 months of age. The mean hospital stay was 9.5 d (+/-9.8 d). We estimated that 8918 children under 60 months of age were hospitalized for rotavirus gastroenteritis in 1996; they accounted for 84899 inpatient days. We conclude that rotavirus is a leading aetiological agent of severe gastroenteritis in young children in Poland and that the burden of this infection is significant. Rotavirus vaccine could significantly decrease the hospitalization rate and the financial impact of rotavirus gastroenteritis in Poland.     

Rhesus Rotavirus candidate vaccine. Clinical trial in children vaccinated between 2 and 5 months of age

Live attenuated oral rhesus Rotavirus candidate vaccine (strain MMU 18006 [lot RRV-1]) was evaluated for immunogenicity, safety, and clinical protection in a double-blind, placebo-controlled trial involving 200 infants aged 2 to 5 months when vaccinated. Vaccine-induced fourfold or greater rise of Rotavirus antibodies was seen in 62% of the infants. Febrile reactions of short duration on days 3 and/or 4 after vaccination occurred in 26% of the vaccine recipients. The clinical follow-up covered two Rotavirus seasons, in which serotypes 1 and 4 were prevalent. There were 16 cases of confirmed Rotavirus diarrhea in the placebo-treated group and 10 in the vaccine-treated group; from this a vaccine protection rate of 38% was derived. Clinical severity of Rotavirus diarrhea was assessed by a score; 13 cases in the placebo-treated group and 5 in the vaccine-treated group were regarded as severe or moderately severe, giving a vaccine protection rate of 67%. The rhesus Rotavirus vaccine induces partial protection against heterotypic Rotavirus disease, but the level of protection achieved with the present vaccine dose in this age group appears to be insufficient for a general Rotavirus vaccination.     

Recommendations for the use of rotavirus vaccines in infants

Rotavirus infection occurs in the majority of healthy children before five years of age, and is the most common diarrheal illness associated with hospitalization. The majority of children present with symptoms of vomiting, diarrhea and fever. As a result, rotavirus gastroenteritis is responsible for greater morbidity than other common childhood diarrheal illnesses. The highest risk of severe disease is in children younger than two years of age. It is estimated that one in 20 children will require an emergency department visit. In addition to community-acquired infections, hospital-acquired infections are also significant. There are currently two licensed rotavirus vaccines in Canada. Both vaccines are administered orally and are highly effective against severe disease and hospitalization. Large pre- and postmarketing studies have shown no increased risk of intussusception with the current rotavirus vaccines. The present statement provides information concerning the clinical disease and rotavirus vaccines in Canada.     

Intussusception incidence relative to rotavirus vaccine use in Honolulu

Rotavirus vaccine was in use during the period August 1998 to October 1999. Epidemics of intussusception during this period were allegedly due to rotavirus vaccine, which prompted the vaccine to be withdrawn. Hawaii's geographic location between Asia and the mainland United States may subject it to infectious disease epidemic periods midway between occurrence in Asia and occurrence in the mainland United States. In contrast, immunization recommendations are temporally identical across all 50 states. The purpose of this study was to determine whether an epidemic of intussusception was experienced in Honolulu during the period of rotavirus vaccine use. This is a retrospective study of data obtained from inpatient and emergency department discharge diagnosis codes of intussusception for children up to 36 months of age. The incidence data were plotted by time periods to identify possible epidemic periods. The data are graphed. The arrows on the graphs indicate the period of time that rotavirus vaccine was in use. These graphs are most consistent with an increase in the cases of intussusception during the period July 2000 to December 2000, and a possible decline of intussusception during the rotavirus vaccine period. These incidence data are inconsistent with a temporal association between rotavirus vaccine and an epidemic of intussusception in Honolulu.     

Rotavirus vaccine studies in Europe

Following the discovery and recognition of rotavirus as an important human enteropathogen, work towards the development of rotvirus vaccines was begun in the USA and Europe. The first candidate rotavirus vaccine was launched by Smith Kline-RIT, Belgium, and studied in clinical trials in Finland, Yugoslavia, Italy, Switzerland, Austria and the UK. Efficacy trials in Finland of RIT 4237 strain live oral bovine rotavirus vaccine resulted in some fundamental findings about rotavirus immunity in humans: protection against disease rather than infection; better protection against severe than mild disease and heterotypic rather than homotypic protection. Another bovine rotavirus vaccine, strain WC-3, was studied briefly in France. Also studies of rhesus rotavirus vaccine were started early in Europe, and efficacy studies were carried out in Finland and Sweden. Recently, rhesus-human re-assortant tetravalent (RRV-TV) rotavirus vaccine was tested in a field trial in Finland this study was pivotal for the registration of the vaccine in the USA and European Union countries. Despite extensive experience with rotavirus vaccines in Europe, the need for such vaccines in many European countries still requires further assessment. □ Bovine rotavirus, rhesus rotavirus, rotavirus vaccine