Journal of Pediatric Gastroenterology & Nutrition:
European Society for Paediatric Infectious Diseases/European Society for Paediatric Gastroenterology, Hepatology, and Nutrition Evidence-Based Recommendations for Rotavirus Vaccination in Europe: Executive Summary
Vesikari, Timo*; Van Damme, Pierre†; Giaquinto, Carlo‡; Gray, Jim§; Mrukowicz, Jacek||; Dagan, Ron¶; Guarino, Alfredo#; Szajewska, Hania**; Usonis, Vytautas††; Expert Working Group
*Vaccine Research Centre, University of Tampere Medical School, Tampere, Finland
†Centre for the Evaluation of Vaccination, Vaccine and Infectious Disease Institute, Faculty of Medicine, University of Antwerp, Antwerp, Belgium
‡Department of Paediatrics, University of Padova, Padova, Italy
§Centre for Infections, Health Protection Agency, London, UK
||Polish Institute for Evidence-Based Medicine, Krakow
¶Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of Negev, Beer Sheva, Israel
#Department of Pediatrics, University Federico II, Naples, Italy
**Medical University of Warsaw, Second Department of Paediatrics (II Katedra Pediatrii), Warsaw, Poland
††Centre of Paediatrics, Vilnius University, Vilnius, Lithuania
Address correspondence and reprint requests to Prof Timo Vesikari, Vaccine Research Centre, University of Tampere Medical School, University of Tampere, FIN-33014 Tampere, Finland (e-mail: email@example.com).
Development support for the recommendations came from an unrestricted educational grant from GlaxoSmithKline Biologicals and Sanofi Pasteur MSD.
The rotavirus recommendations have been approved by the European Society for Paediatric Infectious Diseases and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition.
Conflicts of interest of the working group members are listed at the end of the article.
Rotavirus (RV) is the single most common cause of severe, acute gastroenteritis (AGE) in infants and young children worldwide. By the age of 5 years, almost all children will have experienced at least 1 RV infection, with or without evidence of gastroenteritis symptoms. It is estimated that 1 in 5 cases globally will present to a doctor and 1 in 65 will require hospitalisation (1,2). Furthermore, the latest estimates suggest that more than 600,000 children die from RV-related gastroenteritis (RVGE) each year worldwide (3).
In European and other industrialised countries, death from RVGE is comparatively rare, but nevertheless more than 200 deaths may occur in European Union (EU-25) countries each year (2). Rotavirus causes a considerable burden of disease due to the large number of cases that require treatment in hospital, estimated at a minimum of 87,000 in EU-25 countries (1,2). (The number of hospitalisations was calculated using data from 2000–2003, when there were 25 EU member states. As of January 2007, there were 27 member states of the EU.) The burden on health care resources is particularly prominent during the colder months, when the seasonal peak of RV cases coincides with a peak in incidence of other infections such as influenza and respiratory syncytial virus bronchiolitis (4,5). In addition to community-acquired RV, children who are infected with RV while in hospital present a significant burden on health care systems, mainly as a result of an extended hospital stay and closure of wards to new admissions to prevent further transmission of the disease (4–6). Rotavirus-related gastroenteritis therefore puts considerable pressure on medical resources and is disruptive to the everyday life of infected children and their families.
Natural infection with RV reduces the frequency of subsequent RV episodes and protects against clinically significant RV disease (7–11), thus providing the rationale for the development of a vaccine against RVGE. Early studies with live attenuated, oral RV vaccines of animal origin (bovine or rhesus) mimicking a natural human RV infection showed that oral vaccination can also protect against severe RV disease in children (12–17). The combined experience of the natural history of RV infection and empirical findings in vaccine trials led researchers to the realisation that the primary goal for RV vaccination is, and can only be, to protect children against moderate-to-severe RVGE (13).
In 1998, after several safety and efficacy trials (18–20), the live oral rhesus–human reassortant RV vaccine (RotaShield, Wyeth-Lederle Vaccines, New York) became the first licensed vaccine against RVGE to be approved by the US Food and Drug Administration (FDA). RotaShield was recommended for universal vaccination of infants (21). However, 9 months after it first became available, RotaShield was withdrawn voluntarily by its manufacturer due to safety concerns over an apparent, albeit rare, association with intussusception among vaccinated children (22–25). All of the recommendations for the use of RotaShield were subsequently withdrawn (24). It was later determined that most of the cases (∼80%) of intussusception occurred in infants given the first dose of vaccine at age 90 days or older (25).
Two new live vaccines against RVGE—an oral live attenuated human G1P vaccine (Rotarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) and an oral live human–bovine reassortant vaccine (RotaTeq; Sanofi Pasteur MSD, Lyon, France)—were approved by the European Medicines Agency in 2006. Both Rotarix (26–32) and RotaTeq (33–35) have undergone testing for safety and efficacy, including 2 large-scale trials (each in more than 60,000 infants) that were designed specifically to evaluate safety for intussusception (30,35). In brief, both vaccines have shown >90% protective efficacy against severe RVGE, low reactogenicity, and a safety profile for intussusception not significantly different from placebo.
Taking into consideration the issues described below, a group of European experts in the field of paediatrics, infectious diseases, virology, epidemiology, gastroenterology, and public health systematically developed evidence-based recommendations for RV vaccination 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 their development. These recommendations have been developed primarily to guide individual physicians regarding RV vaccination, but may also serve as the basis for future national recommendations.
The evidence-based recommendations are based on a systematic review of the literature, addressing the disease burden of RVGE in infants in Europe and all of the available published or publicly presented evidence from clinical trials of Rotarix and RotaTeq. This review was carried out by the Polish Institute for Evidence-Based Medicine. Data are presented as evidence tables, which were systematically reviewed by the expert group. Previous issues that have arisen in RV vaccination history, particularly with regard to the association between RotaShield and intussusception in the United States, were also taken into consideration.
The recommendations for RV vaccination have been developed according to the GRADE methodology (36), assigning a strength to each recommendation. The methodology, along with the evidence tables used as the basis of this technique, are presented in the Appendix of the supplement to the May 2008 issue of the Journal of Pediatric Gastroenterology and Nutrition.
The ESPID/ESPGHAN evidence-based recommendations for RV vaccination in Europe are summarised below. (The official use of both RV vaccines [Rotarix and RotaTeq], as recommended by the European Medicines Agency, is outlined in the Summary of Product Characteristics [SPC] for each vaccine (37,38). The SPC is the legally binding document for physicians.)
Recommendation 1: It is recommended that RV vaccination should be offered to all healthy infants in Europe (high-quality data; net benefit; strong recommendation; 1A).
Recommendation 2: Both RV vaccines licensed for use in Europe can be administered separately or concomitantly with inactivated, injectable childhood vaccines. Rotavirus vaccination can be integrated into the majority of European vaccination schedules (high-quality data; net benefit; strong recommendation; 1C+).
Recommendation 3: In European countries where oral poliovirus vaccine is still in use, concomitant administration with RV vaccine is not suggested (low-quality data; no clear net benefit; weak strength recommendation; 2B).
Recommendation 4: It is recommended that the first dose of RV vaccine should be given between the age of 6 and 12 weeks, and the full schedule (Rotarix 2 doses; RotaTeq 3 doses) should be completed by the age of 6 months (high-quality data; net benefit; strong recommendation; 1A).
Recommendation 5: It is suggested that for some special populations of infants—premature infants or those with HIV infection—RV vaccination may be considered at calendar age according to recommendations for healthy infants, at the discretion of the physician (low-quality data; less certain of the magnitude of benefit; very weak strength recommendation; 2C).
Recommendation 6: For infants with severe immunodeficiency, RV vaccination is not recommended (low-quality data; no clear net benefit; strong recommendation; 1C).
Recommendation 7: It is recommended that continued monitoring for serious adverse events should be in place for RV vaccination (high-quality data; net benefit; strong recommendation; 1C+).
The full version of the ESPID/ESPGHAN evidence-based recommendations for RV vaccination in Europe, together with articles on RV and options for the prevention of RVGE, are contained in Volume 46, Supplement 2, of the Journal of Pediatric Gastroenterology and Nutrition.
Conflicts of Interest of the Working Group
Prof Vesikari has received honoraria for consultancy services and lectures from Chiron, Merck, GlaxoSmithKline (GSK), MedImmune, and Wyeth; he has been the principal investigator in clinical trials for RotaShield (Wyeth-Lederle Vaccines), RotaTeq (Merck), and Rotarix (GlaxoSmithKline Biologicals). Prof Van Damme has been the principal investigator in vaccine studies for Merck, Sanofi Pasteur, Sanofi Pasteur MSD, GSK Biologicals, Wyeth, and Berna Biotech, from which the University of Antwerp obtains unrestricted educational grants; the University of Antwerp received travel support grants and honoraria from Sanofi Pasteur MSD, Merck, and GSK Biologicals. Dr Giaquinto has been the principal investigator in epidemiological studies supported by Sanofi Pasteur MSD and GSK Biologicals; he has also received honoraria for consultancy services from GSK Biologicals and Sanofi Pasteur MSD. Dr Gray is the principal investigator and coordinator of a European RV strain surveillance programme supported jointly by Sanofi Pasteur MSD and GSK, and principal investigator of a burden of disease study funded by Sanofi Pasteur MSD; for both of these activities, Dr Gray is funded entirely by the Health Protection Agency (HPA), and he has received travel grants and honoraria for consultancy services from Sanofi Pasteur MSD. Dr Mrukowicz has received honoraria for consultancy services and lectures from GSK, MSD, Wyeth, Nutricia Poland, Nestlé Poland, Sanofi Pasteur Poland, and Pfizer, research grants from Nutricia and Wyeth, and financial support for scientific congresses from Nestlé Poland and GSK. Prof Dagan has been a scientific consultant to and a principal investigator in studies supported by Aventis Pasteur, Berna Biotech, GSK, MedImmune, Merck, Novartis, and Wyeth-Lederle Vaccines. Prof Guarino is a member of the Italian Rotavirus Advocacy Committee, and members of his group have received travel grants to attend meetings from companies active in the field of gastroenterology; he received research grants from Milupa, Dicofarm, and GSK. Prof Szajewska has received lecture fees and/or honoraria for consultancy services from Nestlé, Nutricia Poland, Numico, Mead Johnson Nutritionals Poland, Mead Johnson International, Biocodex France, Danone, Crotex, Merck, Biomed Lublin, Biomed Kraków, and GSK; she has received research grants or donations from Dicofarm Italy, Nutricia Research Foundation, and Biomed Lublin, and sponsorship to attend meetings from Nestlé Poland, Danone, and GSK. Prof Usonis has been the principal investigator in studies supported by GSK, Novartis, and Wyeth-Lederle Vaccines; he has been a scientific consultant to Aventis Pasteur, Baxter, GSK, Merck, and Wyeth-Lederle Vaccines and has received sponsorship from these companies to attend scientific meetings.
1. Parashar UD, Hummelman EG, Bresee JS, et al
. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis 2003; 9:565–572.
2. Soriano-Gabarro M, Mrukowicz J, Vesikari T, et al
. Burden of rotavirus disease in European Union countries. Pediatr Infect Dis J 2006; 25:S7–S11.
3. Parashar UD, Gibson CJ, Bresse JS, et al
. Rotavirus and severe childhood diarrhea. Emerg Infect Dis 2006; 12:304–306.
4. Rheingans RD, Heylen J, Giaquinto C. Economics of rotavirus gastroenteritis and vaccination in Europe: what makes sense? Pediatr Infect Dis J 2006; 25:S48–S55.
5. Roberts JA, Cumberland P, Sockett PN, et al
. The study of infectious intestinal disease in England: socio-economic impact. Epidemiol Infect 2003; 130:1–11.
6. Gleizes O, Desselberger U, Tatochenko V, et al
. Nosocomial rotavirus infection in European countries: a review of the epidemiology, severity and economic burden of hospital-acquired rotavirus disease. Pediatr Infect Dis J 2006; 25:S12–S21.
7. Bishop RF, Barnes GL, Cipriani E, et al
. Clinical immunity after neonatal rotavirus infection. A prospective longitudinal study in young children. N Engl J Med 1983; 309:72–76.
8. Bernstein DI, Sander DS, Smith VE, et al
. Protection from rotavirus reinfection: 2-year prospective study. J Infect Dis 1991; 164:277–283.
9. Velazquez FR, Matson DO, Calva JJ, et al
. Rotavirus infections in infants as protection against subsequent infections. N Engl J Med 1996; 335:1022–1028.
10. Velazquez FR, Matson DO, Guerrero ML, et al
. Serum antibody as a marker of protection against natural rotavirus infection and disease. J Infect Dis 2000; 182:1602–1609.
11. Fischer TK, Valentiner-Branth P, Steinsland H, et al
. Protective immunity after natural rotavirus infection: a community cohort study of newborn children in Guinea-Bissau, West Africa. J Infect Dis 2002; 186:593–597.
12. Vesikari T, Isolauri E, Delem A, et al
. Clinical efficacy of the RIT 4237 live attenuated bovine rotavirus vaccine in infants vaccinated before a rotavirus epidemic. J Pediatr 1985; 107:189–194.
13. Vesikari T, Isolauri E, D'Hondt E, et al
. Protection of infants against rotavirus diarrhoea by RIT 4237 attenuated bovine rotavirus strain vaccine. Lancet 1984; 1:977–981.
14. Vesikari T, Ruuska T, Delem A, et al
. Neonatal rotavirus vaccination with RIT 4237 bovine rotavirus vaccine: a preliminary report. Pediatr Infect Dis J 1987; 6:164–169.
15. Vesikari T, Ruuska T, Delem A, et al
. Efficacy of two doses of RIT 4237 bovine rotavirus vaccine for prevention of rotavirus diarrhoea. Acta Paediatr Scand 1991; 80:173–180.
16. Gothefors L, Wadell G, Juto P, et al
. Prolonged efficacy of rhesus rotavirus vaccine in Swedish children. J Infect Dis 1989; 159:753–757.
17. Ruuska T, Vesikari T, Delem A, et al
. Evaluation of RIT 4237 bovine rotavirus vaccine in newborn infants: correlation of vaccine efficacy to season of birth in relation to rotavirus epidemic period. Scand J Infect Dis 1990; 22:269–278.
18. Rennels MB, Glass RI, Dennehy PH, et al
. Safety and efficacy of high-dose rhesus–human reassortant rotavirus vaccines—report of the National Multicenter Trial. United States Rotavirus Vaccine Efficacy Group. Pediatrics 1996; 97:7–13.
19. Joensuu J, Koskenniemi E, Pang XL, et al
. Randomised placebo-controlled trial of rhesus–human reassortant rotavirus vaccine for prevention of severe rotavirus gastroenteritis. Lancet 1997; 350:1205–1209.
20. Perez-Schael I, Guntinas MJ, Perez M, et al
. Efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and young children in Venezuela. N Engl J Med 1997; 337:1181–1187.
21. Rotavirus vaccine for the prevention of rotavirus gastroenteritis among children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbid Mortal Wkly Rep
22. Murphy TV, Gargiullo PM, Massoudi MS, et al
. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med 2001; 344:564–572.
23. Suspension of rotavirus vaccine after reports of intussusception—United States, 1999. Morbid Mortal Wkly Rep
24. Withdrawal of rotavirus vaccine recommendation. Morbid Mortal Wkly Rep
25. Simonsen L, Viboud C, Elixhauser A, et al
. More on RotaShield and intussusception: the role of age at the time of vaccination. J Infect Dis 2005; 192(Suppl 1):S36–S43.
26. Vesikari T, Karvonen A, Puustinen L, et al
. Efficacy of RIX4414 live attenuated human rotavirus vaccine in Finnish infants. Pediatr Infect Dis J 2004; 23:937–943.
27. Vesikari T, Karvonen A, Korhonen T, et al
. Safety and immunogenicity of RIX4414 live attenuated human rotavirus vaccine in adults, toddlers and previously uninfected infants. Vaccine 2004; 22:2836–2842.
28. Salinas B, Perez Schael I, Linhares AC, et al
. Evaluation of safety, immunogenicity and efficacy of an attenuated rotavirus vaccine, RIX4414: a randomized, placebo-controlled trial in Latin American infants. Pediatr Infect Dis J 2005; 24:807–816.
29. Phua KB, Quak SH, Lee BW, et al
. Evaluation of RIX4414, a live, attenuated rotavirus vaccine, in a randomized, double-blind, placebo-controlled phase 2 trial involving 2464 Singaporean infants. J Infect Dis 2005; 192(Suppl 1):S6–S16.
30. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, et al
. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006; 354:11–22.
31. Dennehy PH, Brady RC, Halperin SA, et al
. Comparative evaluation of safety and immunogenicity of two dosages of an oral live attenuated human rotavirus vaccine. Pediatr Infect Dis J 2005; 24:481–488.
32. Vesikari T, Karvonen A, Prymula R, et al
. Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study. Lancet 2007; 370:1757–1763.
33. Block SL, Vesikari T, Goveia MG, et al
. Efficacy, immunogenicity, and safety of a pentavalent human–bovine (WC3) reassortant rotavirus vaccine at the end of shelf life. Pediatrics 2007; 119:11–18.
34. Vesikari T, Clark HF, Offit PA, et al
. Effects of the potency and composition of the multivalent human–bovine (WC3) reassortant rotavirus vaccine on efficacy, safety and immunogenicity in healthy infants. Vaccine 2006; 24:4821–4829.
35. Vesikari T, Matson DO, Dennehy P, et al
. Safety and efficacy of a pentavalent human–bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006; 354:23–33.
36. Atkins D, Best D, Briss PA, et al
. Grading quality of evidence and strength of recommendations. BMJ 2004; 328:1490–1498.
This article has been cited 14 time(s).
Cochrane Database of Systematic ReviewsVaccines for preventing rotavirus diarrhoea: vaccines in useCochrane Database of Systematic Reviews
Archives De Pediatrie
Rotavirus vaccination in 2012. Position of the Pediatric Infections Pathology Group (GPIP) and the French Association of Ambulatory Pediatrics (AFPA)
Archives De Pediatrie, 19():
Monatsschrift KinderheilkundeStatement on rotavirus vaccinationMonatsschrift Kinderheilkunde
British Medical BulletinRotaviruses and rotavirus vaccinesBritish Medical Bulletin
VaccineCost-effectiveness of infant vaccination with RIX4414 (Rotarix (TM)) in the UKVaccine
Wcpghan 3: World Congress of Pediatric Gastroenterology, Hepatology and Nutrition
Rotavirus Gastroenteritis in Children
Wcpghan 3: World Congress of Pediatric Gastroenterology, Hepatology and Nutrition, ():
Cochrane Database of Systematic ReviewsVaccines for preventing rotavirus diarrhoea: vaccines in useCochrane Database of Systematic Reviews
European Journal of PediatricsA 4-year study on clinical characteristics of children hospitalized with rotavirus gastroenteritisEuropean Journal of Pediatrics
Anales De PediatriaGastroenteritis due to rotavirus in two year old infants: Impact on the familyAnales De Pediatria
Epidemiology and InfectionA mathematical model of the indirect effects of rotavirus vaccinationEpidemiology and Infection
Journal of Pediatric Gastroenterology and Nutrition
European society for paediatric gastroenterology, hepatology, and nutrition/European society for paediatric infectious diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe
Journal of Pediatric Gastroenterology and Nutrition, 46():
Medecine Et Maladies InfectieusesAssessment of workload in pediatric emergency units due to acute gastroenteritis during the epidemic season in FranceMedecine Et Maladies Infectieuses
Bmc MedicineTargeted rotavirus vaccination of high-risk infants; a low cost and highly cost-effective alternative to universal vaccinationBmc Medicine
PediatricsHealth Care Provider and Caregiver Preferences Regarding Nasogastric and Intravenous RehydrationPediatrics
© 2008 Lippincott Williams & Wilkins, Inc.
Connect With Us
Visit JPGN.org on your smartphone. Scan this code (QR reader app required) with your phone and be taken directly to the site.