Research Open Access
Like 0



Rotavirus is a major cause of severe gastroenteritis in children worldwide. The disease burden has been substantially reduced in countries where rotavirus vaccines are used. Given the risk of vaccine-induced intussusception, the benefit–risk balance of rotavirus vaccination has been assessed in several countries, however mostly without considering indirect protection effects.


We performed a benefit–risk analysis of rotavirus vaccination accounting for indirect protection in France among the 2018 population of children under the age of 5 years.


To incorporate indirect protection effects in the benefit formula, we adopted a pseudo-vaccine approach involving mathematical approximation and used a simulation design to provide uncertainty intervals. We derived background incidence distributions from quasi-exhaustive health claim data. We examined different coverage levels and assumptions regarding the waning effects and intussusception case fatality rate.


With the current vaccination coverage of < 10%, the indirect effectiveness was estimated at 6.4% (+/− 0.4). For each hospitalisation for intussusception, 277.0 (95% uncertainty interval: (165.0–462.1)) hospitalisations for rotavirus gastroenteritis were prevented. Should 90% of infants be vaccinated, indirect effectiveness would reach 57.9% (+/− 3.7) and the benefit–risk ratio would be 192.4 (95% uncertainty interval: 116.4–321.3). At a coverage level of 50%, indirect protection accounted for 27% of the prevented rotavirus gastroenteritis cases. The balance remained in favour of the vaccine even in a scenario with a high assumption for intussusception case fatality.


These findings contribute to a better assessment of the rotavirus vaccine benefit–risk balance.


Article metrics loading...

Loading full text...

Full text loading...



  1. Parashar UD, Hummelman EG, Bresee JS, Miller MA, Glass RI. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis. 2003;9(5):565-72.  https://doi.org/10.3201/eid0905.020562  PMID: 12737740 
  2. Platts-Mills JA, Steele AD. Rotavirus vaccine impact in Africa: greater than the sum of its parts? Lancet Glob Health. 2018;6(9):e948-9.  https://doi.org/10.1016/S2214-109X(18)30356-5  PMID: 30103987 
  3. Leshem E, Moritz RE, Curns AT, Zhou F, Tate JE, Lopman BA, et al. Rotavirus vaccines and health care utilization for diarrhea in the United States (2007-2011). Pediatrics. 2014;134(1):15-23.  https://doi.org/10.1542/peds.2013-3849  PMID: 24913793 
  4. Poelaert D, Pereira P, Gardner R, Standaert B, Benninghoff B. A review of recommendations for rotavirus vaccination in Europe: Arguments for change. Vaccine. 2018;36(17):2243-53.  https://doi.org/10.1016/j.vaccine.2018.02.080  PMID: 29576308 
  5. Patel MM, Steele D, Gentsch JR, Wecker J, Glass RI, Parashar UD. Real-world impact of rotavirus vaccination. Pediatr Infect Dis J. 2011;30(1) Suppl;S1-5.  https://doi.org/10.1097/INF.0b013e3181fefa1f  PMID: 21183833 
  6. Carlin JB, Macartney KK, Lee KJ, Quinn HE, Buttery J, Lopert R, et al. Intussusception risk and disease prevention associated with rotavirus vaccines in Australia’s National Immunization Program. Clin Infect Dis. 2013;57(10):1427-34.  https://doi.org/10.1093/cid/cit520  PMID: 23964090 
  7. Yih WK, Lieu TA, Kulldorff M, Martin D, McMahill-Walraven CN, Platt R, et al. Intussusception risk after rotavirus vaccination in U.S. infants. N Engl J Med. 2014;370(6):503-12.  https://doi.org/10.1056/NEJMoa1303164  PMID: 24422676 
  8. Stowe J, Andrews N, Ladhani S, Miller E. The risk of intussusception following monovalent rotavirus vaccination in England: A self-controlled case-series evaluation. Vaccine. 2016;34(32):3684-9.  https://doi.org/10.1016/j.vaccine.2016.04.050  PMID: 27286641 
  9. Escolano S, Farrington CP, Hill C, Tubert-Bitter P. Intussusception after rotavirus vaccination--spontaneous reports. N Engl J Med. 2011;365(22):2139.  https://doi.org/10.1056/NEJMc1107771  PMID: 22129263 
  10. Escolano S, Hill C, Tubert-Bitter P. A new self-controlled case series method for analyzing spontaneous reports of adverse events after vaccination. Am J Epidemiol. 2013;178(9):1496-504.  https://doi.org/10.1093/aje/kwt128  PMID: 24013203 
  11. Halloran ME, Longini IM Jr, Struchiner CJ. Design and analysis of vaccine studies. New York: Springer; 2010.
  12. Pietsch C, Liebert UG. Rotavirus vaccine effectiveness in preventing hospitalizations due to gastroenteritis: a descriptive epidemiological study from Germany. Clin Microbiol Infect. 2019;25(1):102-6.  https://doi.org/10.1016/j.cmi.2018.03.046  PMID: 29649603 
  13. Panozzo CA, Becker-Dreps S, Pate V, Weber DJ, Jonsson Funk M, Stürmer T, et al. Direct, indirect, total, and overall effectiveness of the rotavirus vaccines for the prevention of gastroenteritis hospitalizations in privately insured US children, 2007-2010. Am J Epidemiol. 2014;179(7):895-909.  https://doi.org/10.1093/aje/kwu001  PMID: 24578359 
  14. Rosettie KL, Vos T, Mokdad AH, Flaxman AD, Khalil I, Troeger C, et al. Indirect rotavirus vaccine effectiveness for the prevention of rotavirus hospitalization: a systematic review and meta-analysis. Am J Trop Med Hyg. 2018;98(4):1197-201.  https://doi.org/10.4269/ajtmh.17-0705  PMID: 29436336 
  15. Baker JM, Dahl RM, Cubilo J, Parashar UD, Lopman BA. Effects of the rotavirus vaccine program across age groups in the United States: analysis of national claims data, 2001-2016. BMC Infect Dis. 2019;19(1):186.  https://doi.org/10.1186/s12879-019-3816-7  PMID: 30795739 
  16. Patel MM, Clark AD, Sanderson CFB, Tate J, Parashar UD. Removing the age restrictions for rotavirus vaccination: a benefit-risk modeling analysis. PLoS Med. 2012;9(10):e1001330.  https://doi.org/10.1371/journal.pmed.1001330  PMID: 23109915 
  17. Desai R, Cortese MM, Meltzer MI, Shankar M, Tate JE, Yen C, et al. Potential intussusception risk versus benefits of rotavirus vaccination in the United States. Pediatr Infect Dis J. 2013;32(1):1-7.  https://doi.org/10.1097/INF.0b013e318270362c  PMID: 22929172 
  18. Clark A, Jit M, Andrews N, Atchison C, Edmunds WJ, Sanderson C. Evaluating the potential risks and benefits of infant rotavirus vaccination in England. Vaccine. 2014;32(29):3604-10.  https://doi.org/10.1016/j.vaccine.2014.04.082  PMID: 24814524 
  19. Ledent E, Lieftucht A, Buyse H, Sugiyama K, Mckenna M, Holl K. Post-marketing benefit-risk assessment of rotavirus vaccination in Japan: a simulation and modelling analysis. Drug Saf. 2016;39(3):219-30.  https://doi.org/10.1007/s40264-015-0376-7  PMID: 26748506 
  20. Lamrani A, Tubert-Bitter P, Hill C, Escolano S. A benefit-risk analysis of rotavirus vaccination, France, 2015. Euro Surveill. 2017;22(50):17-00041.  https://doi.org/10.2807/1560-7917.ES.2017.22.50.17-00041  PMID: 29258644 
  21. Bruijning-Verhagen P, van Dongen JAP, Verberk JDM, Pijnacker R, van Gaalen RD, Klinkenberg D, et al. Updated cost-effectiveness and risk-benefit analysis of two infant rotavirus vaccination strategies in a high-income, low-endemic setting. BMC Med. 2018;16(1):168.  https://doi.org/10.1186/s12916-018-1134-3  PMID: 30196794 
  22. Pivette M. Surveillance des maladies infectieuses à partir des ventes de médicaments en pharmacies. [Surveillance of infectious diseases from pharmacy sales]. Doctoral thesis. Paris: Université Paris Descartes; 2015. French.
  23. de Haut C. Santé Publique (HCSP). Avis relatif à la vaccination des nourrissons vis-à-vis des gastroentérites à rotavirus. [Opinion on the vaccination of infants against rotavirus gastroenteritis]. Paris: HCSP; 2015. French. Available from: https://www.hcsp.fr/explore.cgi/avisrapportsdomaine?clefr=501
  24. Bauch CT, Anonychuk AM, Van Effelterre T, Pham BZ, Merid MF. Incorporating herd immunity effects into cohort models of vaccine cost-effectiveness. Med Decis Making. 2009;29(5):557-69.  https://doi.org/10.1177/0272989X09334419  PMID: 19605882 
  25. Institut national de la statistique et des études économiques (Insee). Bilan démographique. [Demographic balance sheet]. Paris: Insee. [Accessed: Aug 2020]. French. Available from: https://www.insee.fr/fr/statistiques/1892086?sommaire=1912926
  26. Vesikari T, Karvonen A, Ferrante SA, Ciarlet M. Efficacy of the pentavalent rotavirus vaccine, RotaTeq®, in Finnish infants up to 3 years of age: the Finnish Extension Study. Eur J Pediatr. 2010;169(11):1379-86.  https://doi.org/10.1007/s00431-010-1242-3  PMID: 20559656 
  27. Pitzer VE, Atkins KE, de Blasio BF, Van Effelterre T, Atchison CJ, Harris JP, et al. Direct and indirect effects of rotavirus vaccination: comparing predictions from transmission dynamic models. PLoS One. 2012;7(8):e42320.  https://doi.org/10.1371/journal.pone.0042320  PMID: 22912699 
  28. Stocks T, Britton T, Höhle M. Model selection and parameter estimation for dynamic epidemic models via iterated filtering: application to rotavirus in Germany. Biostatistics. 2020;21(3):400-16.  https://doi.org/10.1093/biostatistics/kxy057  PMID: 30265310 
  29. Jiang J, Jiang B, Parashar U, Nguyen T, Bines J, Patel MM. Childhood intussusception: a literature review. PLoS One. 2013;8(7):e68482.  https://doi.org/10.1371/journal.pone.0068482  PMID: 23894308 
  30. Yamin D, Atkins KE, Remy V, Galvani AP. Cost-effectiveness of rotavirus vaccination in France-accounting for indirect protection. Value Health. 2016;19(6):811-9.  https://doi.org/10.1016/j.jval.2016.05.011  PMID: 27712709 
  31. Verberk JDM, Bruijning-Verhagen P, de Melker HE. Rotavirus in the Netherlands. Bilthoven: National Institute for Public Health and the Environment; 2017. Available from: https://core.ac.uk/download/pdf/80557731.pdf
  32. Erlewyn-Lajeunesse M, Bonhoeffer J, Ruggeberg JU, Heath PT. Anaphylaxis as an adverse event following immunisation. J Clin Pathol. 2007;60(7):737-9.  https://doi.org/10.1136/jcp.2006.037457  PMID: 17483254 
  33. Duclos P, Ward BJ. Measles vaccines: a review of adverse events. Drug Saf. 1998;19(6):435-54.  https://doi.org/10.2165/00002018-199819060-00002  PMID: 9880088 
  34. O’Leary ST, Glanz JM, McClure DL, Akhtar A, Daley MF, Nakasato C, et al. The risk of immune thrombocytopenic purpura after vaccination in children and adolescents. Pediatrics. 2012;129(2):248-55.  https://doi.org/10.1542/peds.2011-1111  PMID: 22232308 
  35. Patja A, Mäkinen-Kiljunen S, Davidkin I, Paunio M, Peltola H. Allergic reactions to measles-mumps-rubella vaccination. Pediatrics. 2001;107(2):E27.  https://doi.org/10.1542/peds.107.2.e27  PMID: 11158501 
  36. Mantadakis E, Farmaki E, Buchanan GR. Thrombocytopenic purpura after measles-mumps-rubella vaccination: a systematic review of the literature and guidance for management. J Pediatr. 2010;156(4):623-8.  https://doi.org/10.1016/j.jpeds.2009.10.015  PMID: 20097358 
  37. Larson HJ, de Figueiredo A, Xiahong Z, Schulz WS, Verger P, Johnston IG, et al. The state of vaccine confidence 2016: global insights through a 67-country survey. EBioMedicine. 2016;12:295-301.  https://doi.org/10.1016/j.ebiom.2016.08.042  PMID: 27658738 
  38. Asch DA, Baron J, Hershey JC, Kunreuther H, Meszaros J, Ritov I, et al. Omission bias and pertussis vaccination. Med Decis Making. 1994;14(2):118-23.  https://doi.org/10.1177/0272989X9401400204  PMID: 8028464 
  39. Brown KF, Kroll JS, Hudson MJ, Ramsay M, Green J, Vincent CA, et al. Omission bias and vaccine rejection by parents of healthy children: implications for the influenza A/H1N1 vaccination programme. Vaccine. 2010;28(25):4181-5.  https://doi.org/10.1016/j.vaccine.2010.04.012  PMID: 20412878 
  40. Luyten J, Kessels R, Atkins KE, Jit M, van Hoek AJ. Quantifying the public’s view on social value judgments in vaccine decision-making: A discrete choice experiment. Soc Sci Med. 2019;228:181-93.  https://doi.org/10.1016/j.socscimed.2019.03.025  PMID: 30925392 
  41. Parez N, Giaquinto C, Du Roure C, Martinon-Torres F, Spoulou V, Van Damme P, et al. Rotavirus vaccination in Europe: drivers and barriers. Lancet Infect Dis. 2014;14(5):416-25.  https://doi.org/10.1016/S1473-3099(14)70035-0  PMID: 24758998 

Data & Media loading...

Supplementary data

Submit comment
Comment moderation successfully completed
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error