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.     

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 New safe and effective candidate rotavirus vaccines are needed to replace the withdrawn rhesus rotavirus-based oral vaccine.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.     

Preventing rotavirus gastroenteritis: do you have the facts?

From 1 July 2007 two new rotavirus vaccines licensed for use in Australia (RotaTeq CSL Biotherapies/Merck and Rotarix Glaxo Smith Kline) will be funded for the National Immunisation Program. The vaccines differ with respect to their composition and the timing and mode of administration. Both have been evaluated in huge randomised trials and shown to be highly effective in preventing rotavirus gastroenteritis, including severe disease requiring hospital admission. Neither has been associated with an increased rate of intussusception; however, surveillance for adverse effects following vaccination will be important. As rotavirus infection is ubiquitous in young children, funding of this vaccine will significantly decrease the enormous morbidity and costs associated with this disease in our community.     

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.     

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     

Rotavirus vaccine studies in Europe

Following the discovery and recognition of rotavirus as an important human enteropathogen, work towards the development of rotavirus vaccines was begun in the USA and Europe. The first candidate rotavirus vaccine was launched by SmithKline-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.     

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.     

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.     

Concomitant use of an oral live pentavalent human-bovine reassortant rotavirus vaccine with licensed parenteral pediatric vaccines in the United States

BACKGROUND: A live pentavalent rotavirus vaccine (PRV) containing 5 human-bovine (WC3) reassortants expressing human serotypes G1, G2, G3, G4 and P1A[8] was evaluated in a blinded, placebo-controlled study. Possible interactions between PRV and concomitantly administered licensed pediatric vaccines were investigated in a United States-based nested substudy (Concomitant Use Study) of the Rotavirus Efficacy and Safety Trial. METHODS: From 2002 to 2003, healthy infants approximately 6 to 12 weeks of age at entry were randomized to receive either 3 oral doses of PRV or placebo at 4- to 10-week intervals. Subjects were also to receive combined Haemophilus influenzae type b and hepatitis B vaccine (2 doses), diphtheria and tetanus toxoids and acellular pertussis vaccine (3 doses), inactivated poliovirus vaccine (2 doses) and pneumococcal conjugate vaccine (3 doses) on the same day; oral poliovirus vaccine was not administered. Immunogenicity was assessed by measuring antibody responses to PRV and antigens contained in the licensed vaccines. Cases of rotavirus gastroenteritis were defined by forceful vomiting and/or -3 watery or looser-than-normal stools within a 24-hour period, and detection of rotavirus antigen in the stool. Safety was assessed by reporting of adverse events using diary cards. RESULTS: The Concomitant Use Study enrolled 662 subjects in the PRV group and 696 subjects in the placebo group. For the 17 antigens in the concomitantly administered vaccines, antibody responses were similar in PRV and placebo recipients, except for moderately diminished antibody responses to the pertactin component of pertussis vaccine. Efficacy of PRV against rotavirus gastroenteritis of any severity was 89.5% (95% CI = 26.5-99.8%). PRV was generally well tolerated when given concomitantly with the prespecified vaccines. CONCLUSIONS: In this study, antibody responses to the concomitantly administered vaccines were generally similar in PRV and placebo recipients. PRV was efficacious and well tolerated when given concomitantly with pediatric vaccines licensed in the United States.     

Epidemiological changes in rotavirus gastroenteritis in children under 5 years of age after the introduction of rotavirus vaccines in Korea

Rotavirus gastroenteritis is the leading cause of severe acute gastroenteritis in children worldwide and is associated with high hospitalization and mortality rates in children younger than 5 years of age. Vaccination is necessary to prevent rotavirus infection. Two live attenuated and orally administered rotavirus vaccines became commercially available in Korea. The aim of this study is to describe epidemiological changes in rotavirus gastroenteritis after the introduction of rotavirus vaccines in Korea. The medical records of 11,199 children younger than 5 years of age and hospitalized for acute gastroenteritis from August 2007 to July 2010 in eight Korean hospitals were reviewed. Rotavirus was detected in stool samples obtained from 2,959 children (26.42 %). The authors evaluated the percentage of rotavirus gastroenteritis among all acute gastroenteritis hospitalizations in eight hospitals located in different geographical areas and analyzed epidemiological changes in rotavirus gastroenteritis according to age, geographical area, and season. According to the findings, the percentage of rotavirus gastroenteritis showed a decrease in children eligible for vaccination during the study period. After introduction of the vaccine, reduced rates of rotavirus detection were observed in all of the geographical areas, and the greatest reduction was observed in Seoul. In Seoul, there was a marked delay of the rotavirus season. Conclusion: Epidemiologic changes in Korea after the introduction of rotavirus vaccine are consistent with changes observed in other countries.     

Epidemiologic features of rotavirus infection in Taiwan: A review

Group A rotaviruses are a major cause of severe gastroenteritis in children under 4 years of age worldwide. Group A rotaviruses have been identified in many animal and bird species; they are antigenically complex, and multiple serotypes infect humans. Reassortant rotavirus vaccines are now available that confer protection against severe illness due to rotavirus serotypes G1-4. Before vaccines are introduced, it is necessary to establish their efficacy and to establish a baseline for future surveillance strategies. The purpose of the present review is to describe current knowledge of the diversity of rotavirus in Taiwan. The present review is based on the available published studies and data from China Medical College Hospital (Taiwan). In Taiwan, rotavirus has been detected year-round, with the epidemic peak swinging from November-December in 1984 to January-March in 1988-95 and then back to December-March in 1996-99. Most affected patients are under 2 years of age. Only group A rotavirus has been found. Neither group B nor group C rotavirus have been identified. G1 strains have been the predominant strains except for the year 1992-93, when G2 strains were prevalent. There has been no G4 strain detected in published studies. The electropherotype 'baba' has been observed every year. Five other electropherotypes have been sporadically found. Half of the strains that have been studied were genotype P[8] and their VP7 serotype was G1 or G3. All genotype P[4] strains have shown serotype G2. It is expected that the reassortant rotavirus vaccine will be effective in prevention of severe illness caused by rotavirus in Taiwan.     

Efficacy of pentavalent human-bovine (WC3) reassortant rotavirus vaccine based on breastfeeding frequency

The efficacy of a live, oral, pentavalent rotavirus vaccine against G1-4 rotavirus gastroenteritis (RVGE) was retrospectively assessed based on breastfeeding frequency among 5098 infants in a placebo-controlled trial. The efficacy against any RVGE severity for infants never breastfed, sometimes breastfed, or exclusively breastfed was 68.3%, 82.2%, and 68.0%, respectively. The efficacy against severe RVGE was 100%, 95.4%, and 100%, respectively. Breastfeeding did not seem to adversely impact the efficacy of pentavalent rotavirus vaccine.     

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.     

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.     

Rotavirus infection: an update on management and prevention

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. Vaccination is the only control measure likely to have a significant impact on the incidence of severe dehydrating rotavirus disease. Rotavirus vaccines have reduced the burden of rotavirus disease in the United States. Long-term monitoring will need to continue to assess the effects of rotavirus immunization programs and epidemiologic strain surveillance is necessary to determine whether changes in strain ecology will affect the rotavirus vaccine effectiveness and whether rotaviruses with the ability to evade vaccine immunity emerge.     

First rotavirus vaccine licensed: is there really a need?

The first rotavirus vaccine was licensed in the United States on 31 August 1998 for the prevention of severe rotavirus diarrhea in children. Despite this landmark in new vaccines, many pediatricians and public health professionals in Europe are uncertain of the need for this vaccine for the routine immunization of infants. In Europe, ample evidence suggests that rotavirus is the most common cause of hospitalizations for severe diarrhea among children, but proper studies documenting the disease burden of rotavirus or the cost-effectiveness of a rotavirus immunization program have only been conducted in the United Kingdom following epidemiologic models used in the United States. All children are infected with rotavirus during their first few years of life, 30-50% of diarrheal hospitalizations among children <5 years are due to this agent, and, by the age of 5 years, between 1 in 40 and 1 in 77 children in Europe and the United States may be hospitalized for rotavirus. The first vaccine is a live, oral preparation combining four different serotypes of rotavirus and administered in three doses with other childhood immunizations. The good efficacy against severe rotavirus diarrhea, the low risk of adverse side effects and the positive cost-effectiveness equation have led the two major immunization advisory groups in the U.S. to recommend this vaccine for routine use in American infants. European physicians and policy-makers should re-examine the epidemiology and disease burden of rotavirus diarrhea now that an effective method of prevention is at hand.     

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.