European Society for Paediatric Infectious Diseases/European Society for Paediatric Gastroenterology, Hepatology, and Nutrition Evidence‐Based Recommendations for Rotavirus Vaccination in Europe

Two live vaccines against rotavirus gastroenteritis (RVGE) were approved by the European Medicines Agency in 2006: oral live attenuated human rotavirus (RV) vaccine (RIX4414, Rotarix; GlaxoSmithKline Biologicals, Rixensart, Belgium) and oral live human–bovine reassortant RV vaccine (RotaTeq; Sanofi Pasteur MSD, Lyon, France). As of October 2007, Rotarix had been licensed in 102 countries with applications submitted to 18 others, and RotaTeq had been licensed in more than 61 countries with applications submitted to 131 others. In at least 5 countries, Rotarix is used in a national immunisation programme (Brazil, El Salvador, Mexico, Panama, and Venezuela), and RotaTeq is used for universal immunisation in the United States (1,2). In Europe, as of February 2007, Austria, Belgium, and Luxembourg had made recommendations for universal RV vaccination. A group of European experts in the field of paediatrics, infectious diseases, virology, epidemiology, gastroenterology, and public health herein present systematically developed evidence-based recommendations on RV vaccination for the prevention of RV disease in Europe. The European Society for Paediatric Infectious Diseases (ESPID) and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) played an active role in the development of these recommendations. These recommendations pertain to the available RV vaccines—Rotarix and RotaTeq. The official use of the vaccines, as recommended by the European Medicines Agency, is outlined in the summary of product characteristics available for each vaccine (3,4). This is the legally binding document for physicians. The recommendations have considered the following: The need to vaccinate against RV, as based on country-specific estimates of the disease burden of RVGE among infants (5) and other options for the prevention of RV disease relevant to the European setting (6) Evidence gathered from clinical studies of Rotarix and RotaTeq (final and nonfinal formulations) up to January 30, 2007, including peer-reviewed papers; abstracts (those published between January 30 and August 31, 2007 were also considered if presenting data previously supplied in an unpublished form by vaccine manufacturers); and raw data from these studies obtained through personal communication with authors and manufacturers. Previous issues that have arisen in RV vaccination history, particularly the temporal association between RotaShield and intussusception in the United States OBJECTIVES The aims of the recommendations presented are to provide evidence-based advice on the use of RV vaccines in Europe, and provide a framework for RV vaccination at a national level. As such, these recommendations are sufficiently general and flexible for widespread application, taking into account the diversity and complexity of health care systems and practices across Europe. These recommendations are designed for use primarily by individual physicians. They also should provide policymakers in European countries with the information and tools necessary to assist in decision making regarding vaccination policy (eg, evidence tables) and to develop their own practical guidelines through local or national bodies. METHODOLOGY The expert group recommendations were formulated according to systematic evidence-based methodology as proposed by the Grading of Recommendations Assessment, Development and Evaluation working group (7,8). Clinical questions were defined, and each group of questions (efficacy, safety, coadministration) provided the basis for eligibility criteria that guided a systematic review of the literature. This review was performed by independent guideline methodologists at the Polish Institute of Evidence-Based Medicine (Appendix I). Peer-reviewed papers and other data were included, as described above. Independent peer review of available information was performed by the European expert group, and the quality of the evidence was considered (high, medium, low, or very low) according to study design and directness and consistency of results (Table 1) (7). The quality of evidence indicates the extent to which one can be confident that an estimate of effect (or no effect) is correct. Recommendations were developed and graded according to the quality of the evidence during panel meetings of the European expert group (Table 2) (8). The expert group included members of the European paediatric societies, ESPID, and ESPGHAN. Panel meetings also were attended by representatives from the RV vaccine manufacturers, in a supporting role only. The methodology, scope, content, and nature of the recommendations issued reflect the opinions of the authors, and the final document has been approved by ESPID and ESPGHAN.TABLE 1: Grading the strength of the evidence (7)TABLE 2: Grading the quality of recommendations8The methodology used for developing the recommendations, together with the tables of evidence for Rotarix and RotaTeq, are provided in Appendices I, II, and III, respectively. RATIONALE FOR RV VACCINATION OF HEALTHY INFANTS IN EUROPE There are several compelling reasons for adopting RV vaccination of healthy infants in countries across Europe. First, RV universally affects young infants (<5 years of age), and there are no other known risk factors that can predict progression of the disease to severe diarrhoea and dehydration with sufficient sensitivity or specificity to create a selective immunisation programme (9–11). Second, improvements in hand hygiene and sanitation have limited benefits for the prevention of disease, and long-term compliance with these regimens can be a problem (12–17). In addition, other measures for the prevention of RVGE (eg, passive immunisation, probiotics) have limited long-term effectiveness and are not suitable for large-scale use (6). Third, in Europe, oral rehydration solutions and medical management of infants with RVGE is widespread, yet RV still causes considerable morbidity, with at least 87,000 young children hospitalised each year from severe RVGE in 25 EU countries (18,19). Although rare, deaths also still occur from RVGE in previously healthy children. These deaths are not acceptable given the high standard of European health care (18). Finally, natural infection with different RV serotypes reduces the frequency of subsequent RV episodes and protects against clinically significant RV disease in the future (15,20–22). Vaccination early in life, before the first RV infection, should therefore prevent most severe cases of the disease and sequalae in healthy children. Proof of this concept was demonstrated in the early RV vaccine studies of the 1980s in Europe (23,24). BACKGROUND OF RV VACCINATION The development of RV vaccines and their widespread uptake is considered a matter of global priority by the World Health Organization, the Global Alliance for Vaccines and Immunization, and the Rotavirus Vaccine Program at the Program for Appropriate Technology in Health (25,26). Candidate RV vaccines have been derived from the attenuation of human strains (live attenuated) in cell culture (27,28) or the reassortment of human strains with bovine strains that replicate poorly in the human host (naturally attenuated) (23,29,30). These live vaccines are administered orally to infants to mimic natural infection. After standard safety and efficacy trials (31–33) in 1998, the US Food and Drug Administration approved a tetravalent rhesus–human reassortant RV vaccine, RRV-TV (RotaShield; Wyeth-Lederle Vaccines, New York, NY) for use in humans (34,35). The vaccine was endorsed by the Advisory Committee for Immunization Practices and the American Academy of Pediatrics for universal use in infancy (35,36). However, 9 months after it first became available, RotaShield was voluntarily withdrawn by its manufacturer in response to reports of intussusception in infants (ie, an obstruction of the bowel, due to 1 portion becoming telescoped within another), occurring particularly after the first dose of RotaShield (37–39). Prelicensure studies had identified a weak signal for an association between RotaShield and intussusception (35,40). In light of these findings, the possibility of intussusception as an adverse effect of vaccination was included on the RotaShield package insert and the Advisory Committee for Immunization Practices recommended postlicensure studies should be carried out (35). The Vaccine Adverse Event Reporting System regularly monitored cases of intussusception occurring among RotaShield recipients (41). In response to 15 reports of intussusception, the Centers for Disease Control and Prevention and the American Academy of Pediatrics recommended that physicians suspend use of the vaccine, pending a case-control investigation (42). This investigation was carried out in more than 19 states and assessed the potential association between RotaShield and intussusception among infants of at least 1 to 12 months of age (37). The study concluded that there was an increased risk for intussusception 3 to 14 days after the first dose of RotaShield (adjusted odds ratio OR 21.7; 95% confidence interval CI 9.6–48.9), interpreted to be a result of a unique property of rhesus RV (37). Most (80%) of the cases of intussusception occurred in infants who were 90 days of age or older at the time of the first dose (43). An early study estimated the risk for intussusception after the first dose of RotaShield to be 1 in 4300 vaccinated infants, but later a consensus revised the figure to 1 in 10,000 (23,44). A recent reappraisal has suggested that the risk for intussusception with RotaShield was lower, at between 1 in 10,000 and 1 in 32,000 vaccinated infants (45,46). Wyeth-Lederle Vaccines voluntarily withdrew RotaShield from the market in October 1999, and all of the recommendations for its use were subsequently retracted (38,39). The license for RotaShield has since been passed on to another company, BIOVIRx (26,34), although at present it remains uncertain whether RotaShield will re-enter the market. Candidate RV (human and human–bovine reassortant) vaccines in development at the time that RotaShield was withdrawn were reassessed in light of these findings. Live attenuated human vaccine strains were regarded to be safer for intussusception because wild-type human RVs were not known to cause this adverse event, hence the rationale—from a safety perspective—for the inclusion of an attenuated human strain in the vaccine. Bovine-RV–derived candidate vaccine strains were known to replicate poorly in the human host and be less reactogenic (for fever) than those derived from rhesus RV strains, and therefore also were regarded to be less likely to be associated with serious adverse events (34,37,47). RV VACCINES LICENSED FOR USE IN EUROPE Technical descriptions of RV vaccines licensed for use in Europe, Rotarix and RotaTeq, have been compiled based on the vaccines' summaries of product characteristics, which are approved by European regulatory authorities (3,4). Rotarix Rotarix is based on an RV of entirely human origin. The vaccine contains the RIX4414 strain of the human RV G1P8 Wa strain. The RIX4414 strain was developed further by GlaxoSmithKline Biologicals from RV strain 89–12, which was originally derived from a wild-type isolate collected from a young boy in Cincinnati, OH (Table 3) (27). RV strain 89–12 was cloned and passaged 10 times in Vero cells to develop the RIX4414 vaccine strain (28), which expresses the outer capsid protein G1 and the attachment protein P8.TABLE 3: Profiles of RV vaccines licensed for use in EuropeTechnical Description Rotarix is administered to infants in 2 oral doses. Each dose contains not less than 106.0 median cell culture–infective dose (CCID50) (4). It is supplied as a lyophilised white solid that must be reconstituted with 1 mL of liquid diluent (supplied) before use. Excipients contained in the vaccine are sucrose, dextran, sorbitol, amino acids, and Dulbecco modified eagle medium. The diluent contains calcium carbonate, xanthan gum, and sterile water. Rotarix should be stored in a refrigerator at 2° to 8°C in its original packaging to protect it from light. The shelf life of the lyophilised vaccine is 3 years, and the reconstituted vaccine should be given promptly by oral administration, although the reconstituted vaccine has been shown to be stable when stored at ambient temperature (18°–25°C) for 24 hours (4). RotaTeq RotaTeq is a human–bovine reassortant vaccine developed from an original Wistar calf 3 (WC3) strain of bovine RV. The vaccine contains 5 live reassortant RV strains. Four reassortant RVs express 1 of the human outer capsid proteins, VP7 of G1, G2, G3, and G4 derived from the human RV parent strains and the attachment protein VP4, P75 from the bovine RV parent strain (Table 3). The fifth reassortant RV expresses the outer capsid protein G6, from the bovine RV parent strain, and the attachment protein VP4, P8 derived from the human parent strain (3). Technical Description RotaTeq is given to infants as 3 oral doses. Each dose contains a viral titre of not less than 2 to 2.8 × 106 infectious units (IUs) of each viral strain (3). It is supplied in a 2-mL liquid formulation. Vaccine excipients include sucrose, sodium citrate, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polysorbate 80, culture media (containing inorganic salts, amino acids, and vitamins), and purified water. RotaTeq should be stored in a refrigerator at 2° to 8°C in the original carton to protect it from exposure to light. The shelf life of the vaccine is 2 years and the vaccine should be administered promptly after removal from the refrigerator (3). EVIDENCE FOR RV VACCINATION OF HEALTHY INFANTS The following sections on efficacy, safety, and coadministration of RV vaccines in healthy infants are derived from the evidence tables presented in Appendices II and III. Data have been analysed from international studies including European infants. The safety and efficacy of Rotarix and RotaTeq for the prevention of RVGE in healthy infants have been evaluated in 11 randomised controlled trials (RCTs) involving more than 146,000 infants worldwide. This includes 7 RCTs for Rotarix (28,48–53) and 3 RCTs for RotaTeq (47,54,55). Vaccine Efficacy In all of the studies, the case definition for RV has been detection of RV antigen in stools by enzyme-linked immunosorbent assay along with clinical criteria (≥3 loose stools per 24-hour period and/or forceful vomiting, depending on vaccine used). Serotype identification was carried out via polymerase chain reaction on enzyme-linked immunosorbent assay–positive samples. The efficacy of the RV vaccines was evaluated against the following endpoints in healthy infants: any RVGE (Rotarix and RotaTeq), severe RVGE (Rotarix and RotaTeq), RVGE requiring an office visit (RotaTeq) or medical attention (Rotarix), RVGE requiring hospitalisation (Rotarix and RotaTeq) or an emergency department visit (RotaTeq), and RVGE caused by different RV serotypes (G1P8, G2P4, G3P8, G4P8, G9P8; Rotarix and RotaTeq). The percentages quoted in the following sections are point estimates of vaccine efficacy determined from according to protocol populations of vaccine trials; further information, together with the confidence intervals, can be found in the evidence tables in Appendices II and III, Table 1. Any RVGE European data indicate that efficacy against RVGE of any severity over 2 years after vaccination ranges from 68% to 79% (49,56). Severe RVGE The severity of RV disease in clinical trials of each vaccine was assessed using different clinical scales (Vesikari vs Clark), and the definition of severity was influenced by the scale applied (≥11/20 vs ≥16/24, respectively) (57,58). To date, no studies have been published that bridge the differences between these 2 scales. European data indicate that efficacy against severe RVGE over 2 years after vaccination ranges from 90% to 98% (49,56). Hospitalisations and Emergency Department Visits for RVGE Efficacy against RVGE hospitalisations during the first year ranges from 85% to 100% (49,52). European data indicate that efficacy against hospitalisations up through the of the after the dose of vaccine is RVGE emergency department and hospitalisations in Europe, efficacy up to 2 years after the dose of RotaTeq was and for RVGE RV vaccination was shown to the need for any medical attention to RVGE Data available for Rotarix from Europe indicate that efficacy against medical attention visit to to is for up through the of the of RotaTeq, European data indicate that efficacy against office is for up to 2 years of Efficacy the Most Efficacy has been for vaccines against clinically for the most serotypes (G1P8, G3P8, G4P8, and However, the point estimate with vaccines is less for than the other serotypes Efficacy data and confidence are presented in the evidence tables II and III, Table Vaccine The evidence to the final vaccine as in the evidence tables II and III, Table 3). in these studies, the endpoints are vomiting, and data consistency of no and of no was in the of or severe or severe vomiting, and or severe within 14 days of vaccination with any dose RotaTeq, no significant was in the of or severe and or severe A in the of diarrhoea and 1 in vaccinated infants, within 7 days after dose 1) was with RotaTeq, but these were and not vaccines are with a when given with other vaccines, not cause clinically significant in Two trials were designed to the of the effect of RV vaccination on risk for intussusception vaccines, the risk for intussusception was no than that in up to days after each dose of vaccine, cases of intussusception were in vaccine recipients 7 cases in recipients risk In a of infants, up to 1 year after each dose of cases of intussusception were among vaccine recipients and 14 in recipients RotaTeq, up to days after each dose of vaccine, cases of intussusception were among vaccine recipients 5 cases in recipients to 1 year after each dose of RotaTeq, 12 cases of intussusception were among vaccine recipients and 15 in recipients trials have also evaluated this Although of intussusception have been no can be based for RotaTeq from the United States that of intussusception cases to not the based on of 18 to per per year for an of children to with this data the of intussusception to be cases per of vaccine which is than the of intussusception Although this figure is the of administered and children vaccinated with RotaTeq are not known at this is The Centers for Disease Control and Prevention to vaccination with RotaTeq in the United Rotarix is not in the United therefore data are not yet with Rotarix has been in Mexico, and are likely to be available Adverse There was no significant increased risk for or other serious adverse events with vaccine with and There is evidence of vaccine for RV vaccines during early clinical there have been a cases of to The of is and no cases have developed of RVGE There are no cases of of RotaTeq, although in 2 the vaccine was in the stools of recipients to the nature of the attenuated RV vaccine strains, and is not considered a significant safety Vaccine Two endpoints were the of infants and the Vaccines The that the RV vaccines be given in the first months of The of coadministration of RV vaccines (Rotarix and RotaTeq) with used paediatric vaccines has been evaluated in 7 studies involving infants Rotarix and RotaTeq can be with cell data are available for Rotarix vaccine, vaccine, vaccine, and vaccine, with no for any Rotarix also can be given together with vaccine. are not yet available for coadministration of RotaTeq with Vaccine of 2 oral attenuated vaccines result in with the response to 1 or Administration of RV vaccines at the time as oral vaccine is Data from a study that of Rotarix and not with the response to (for all 3 and not with the response to Rotarix after a of RV vaccine given at 10 and 14 of age Data from a study performed in that of RotaTeq and not with the response to (for all 3 and not with the response to RotaTeq after a of RV vaccine administered at and 24 of age In large-scale clinical trials of efficacy data were obtained when RV vaccine was given 2 from was not used in clinical efficacy trials of RotaTeq data are not sufficient to coadministration with of efficacy data for of oral vaccines is There were no studies available during the period by the review to the safety (eg, of RV vaccines when with EVIDENCE FOR RV VACCINATION OF INFANTS INFANTS Data on the efficacy, safety, and of RV vaccine in infants with are RCTs have shown that RV vaccines licensed for use in Europe can be administered to infants who are the efficacy of the was not for infants in large-scale clinical of vaccines study by that RVGE is no more severe in human infants than in infants. However, case reports have described severe diarrhoea in European infants. infants a for RV infection, and diarrhoea in these infants be severe in infants are for Rotarix and for RotaTeq. Evidence indicates that RotaTeq can be given to healthy infants older than of of if administered according to at the of Rotarix in infants are The evidence-based recommendations for RV vaccination in Europe are presented and in the summary presented in the of the of and Administration is recommended that RV vaccination be to all healthy infants in Europe RV is a universal disease with a high burden in European There are 2 licensed RV vaccines in Europe (Rotarix and RotaTeq), of which can be used to and prevent severe RCTs have shown that of these RV vaccines are have a safety and are in infants to prevent severe and Administration RV vaccines licensed for use in Europe can be administered or with RV vaccination can be into the of European vaccination the of the vaccination vaccines must into the It has been shown that RV vaccines can be with most vaccines given in the first months of life efficacy or European countries is still in with RV vaccine is not suggested no weak strength There were clinical efficacy and safety (eg, data available to a for of RV vaccines with that in the European setting vaccine safety is over efficacy, the expert group a this is recommended that the first dose of RV vaccine be given between the of and 12 and the (Rotarix 2 RotaTeq 3 be by the age of months There were data available to the risk for intussusception when the first dose of RV vaccine is given to infants older than 3 the that the risk for intussusception was in infants who the first dose of vaccine after 3 months of and that the natural of intussusception at to 9 months of age it is that the first dose of RV vaccine be given before the age of 3 and the (Rotarix 2 RotaTeq 3 be by months of age was used in all clinical trials of these vaccination with the first dose of RV vaccine given to infants older than 3 months and any dose given to infants older than months is therefore not Evidence for efficacy of the available RV vaccines is limited to a However, of RV vaccines is likely to result in at least efficacy against RV There were no data available a (Rotarix first by RotaTeq or no can be issued with to of these Vaccination of is suggested that for populations of infants or those with vaccination be considered at age according to recommendations for healthy infants, at the of the less of the of very weak strength Prelicensure clinical trials have been performed in healthy infants and have not the possibility of using RV vaccines in infants with (eg, diseases, of the following because of evidence at no can be made for RV vaccination of infants with However, because it is that infants with infection RV vaccination be in infants. data are evidence of RotaTeq efficacy and in healthy infants was in the infants with severe RV vaccination is not recommended no the of this has been by of evidence from other live is recommended that for serious adverse events be in for RV vaccination vaccines, and long-term data no increased risk for intussusception after vaccination. However, in light of the between RotaShield and intussusception, should be on this for These data should intussusception and vaccination in a It is that these results will the of an association between intussusception and RV vaccines that was in trials of vaccines in healthy infants (45,46). that intussusception is the most cause of obstruction in young infants, cases will occur within the time of RV vaccination systems need to between those cases by with RV and those that have occurred as a result of the vaccine. The recent of Rotarix and RotaTeq by European authorities has the need for European recommendations to RV vaccination. The recommendations presented individual physicians on the evidence-based use of RV vaccination in Europe and provide a framework for use of the vaccine at a national level. European countries will need to which vaccination policy to vaccination of all infants or vaccination. It should be that all infants and young children are at risk for with RV the of risk factors to predict progression to severe disease, and vaccination programme is not an for RV vaccination of all infants has the potential to the burden of RVGE in Europe. of of has for and from and has been the in clinical trials for RotaShield RotaTeq and Rotarix has been the of vaccine studies for Sanofi Sanofi Pasteur MSD, GlaxoSmithKline Biologicals, and a company, for which the of the of and from Sanofi Pasteur MSD, and GlaxoSmithKline has been in studies by Sanofi Pasteur and GlaxoSmithKline also has for and and from GlaxoSmithKline Biologicals, Sanofi Pasteur MSD, and is and of a European rotavirus strain programme by Sanofi Pasteur and also is of a burden of disease study by Sanofi Pasteur of these is entirely by the Health also has and for from Sanofi Pasteur has for and from MSD, Sanofi Pasteur and from and and for from and has been a for and a of studies by and Wyeth-Lederle has also for from Sanofi and is a of the Rotavirus members of group have to meetings from active in the field of gastroenterology, and from and has and/or for from and has or from and and to meetings from and has been the for studies by and Wyeth-Lederle also has been a for and Wyeth-Lederle Vaccines, and has from these to and of GlaxoSmithKline Biologicals, and and of Sanofi Pasteur MSD, for clinical of the European for Disease Prevention and Control for and the Paediatric Rotavirus European Committee for their into this also to and of for medical