In the late 1960s, before the discovery of enteric viruses, an etiologic agent could only be identified in ~20% of children hospitalized with diarrhea. In 1973, by examination of the duodenal epithelium of children with diarrhea using electronic microscopy, Bishop and colleagues visualized a 70-nm virus that was subsequently named rotavirus because of it wheel-like (Latin, rota = wheel) morphology.¹1. Davidson GP, Bishop RF, Townley RR, Holmes IH. Importance of a new virus in acute sporadic enteritis in children. Lancet. 1975;305(7901):242-6. https://doi.org/10.1016/S0140-6736(75)91140-X
https://doi.org/https://doi.org/10.1016/... The subsequent development and application of sensitive enzyme immunoassays for rotavirus detection in fecal specimens soon led to numerous studies showing the important role of rotavirus in the etiology of severe childhood diarrhea. Before the widespread global implementation of rotavirus vaccines, data from sentinel hospital-based surveillance using a standardized protocol in more than 50 countries showed that 36% of hospitalizations for childhood diarrhea were caused by rotavirus.²2. Agocs MM, Serhan F, Yen C, Mwenda JM, de Oliveira LH, Teleb N, et al. WHO global rotavirus surveillance network: a strategic review of the first 5 years, 2008-2012. MMWR Morb Mortal Wkly Rep. 2014;63(29):634-7. Furthermore, in developing countries with suboptimal access to health care including basic hydration therapy, rotavirus is an important cause of childhood mortality, accounting for ~200 000 deaths in the year 2013 worldwide.³3. Tate JE, Burton AH, Boschi-Pinto C, Parashar UD, World Health Organization-Coordinated Global Rotavirus Surveillance Network. Global, regional, and national estimates of rotavirus mortality in children <5 years of age, 2000-2013. Clin Infect Dis. 2016;62(suppl 2):S96-105. https://doi.org/10.1093/cid/civ1013
https://doi.org/https://doi.org/10.1093/... ^,44. Lanata CF, Fischer-Walker CL, Olascoaga AC, Torres CX, Aryee MJ, Black RE, Child Health Epidemiology Reference Group of the World Health Organization and UNICEF. Global causes of diarrheal disease mortality in children <5 years of age: a systematic review. PLoS One. 2013;8(9):e72788. https://doi.org/10.1371/journal.pone.0072788
https://doi.org/https://doi.org/10.1371/... ^,55. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet . 2015;385(9963):117-71. https://doi.org/10.1016/S0140-6736(14)61682-2
https://doi.org/https://doi.org/10.1016/...

Given its important etiologic role, efforts to reduce the burden of severe childhood diarrhea have targeted rotavirus. Data showing that nearly all children in both industrialized and developing countries were infected with rotavirus by five years of age indicated that interventions to improve hygiene and sanitation and provide safe food and water may not alone fully control rotavirus. This hypothesis was supported by data from Mexico showing that as childhood diarrhea deaths declined following the implementation of safe water and hygiene measures after cholera epidemics in the early 1990s, the decline was greatest for deaths during the summer months when bacterial diarrheas were more prevalent whereas winter diarrhea deaths when rotavirus was more prevalent were less affected.⁶6. Villa S, Guiscafre H, Martinez H, Munoz O, Gutierrez G. Seasonal diarrhoeal mortality among Mexican children. Bull World Health Organ. 1999;77(5):375-80.Conversely, data from a classic longitudinal cohort study showed that Mexican children infected with rotavirus were partially protected from subsequent infections, with the level of protection increasing with each subsequent infection and being greatest against moderate to severe rotavirus disease.⁷7. Velazquez FR, Matson DO, Calva JJ, Guerrero L, Morrow AL, Carter-Campbell S, et al. Rotavirus infection in infants as protection against subsequent infections. N Engl J Med. 1996;335(14):1022-8. https://doi.org/10.1056/NEJM199610033351404
https://doi.org/https://doi.org/10.1056/... These findings supported the development of attenuated rotavirus vaccines that could induce protective immunity by simulating the effect of natural rotavirus infection.

In 1998, only 25 years after the discovery of rotavirus, the first rotavirus vaccine (RotaShield, Wyeth Lederle) was licensed and recommended for routine immunization of US children. However, less than one year after vaccine implementation when about 1 million US infants were vaccinated with RotaShield, this vaccine was withdrawn from the US market because it caused an excess of one case of intussusception -- a potentially serious form of bowel obstruction -- per 10 000 vaccinated infants.⁸8. Centers for Disease Control and Prevention. Intussusception among recipients of rotavirus vaccine--United States, 1998-1999. MMWR Morb Mortal Wkly Rep . 1999;48(27):577-81.^,99. Murphy TV, Gargiullo PM, Massoudi MS, Nelson DB, Jumaan AO, Okoro CA, et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med . 2001;344(8):564-72. https://doi.org/10.1056/NEJM200102223440804
https://doi.org/https://doi.org/10.1056/... ^,1010. Peter G, Myers MG, National Vaccine Advisory C, National Vaccine Program O. Intussusception, rotavirus, and oral vaccines: summary of a workshop. Pediatrics. 2002; 110(6):e67. https://doi.org/10.1542/peds.110.6.e67
https://doi.org/https://doi.org/10.1542/... This abrupt and unanticipated setback caused considerable uncertainty over ongoing rotavirus vaccine development.

Some unique biologic properties of the parent rhesus rotavirus strain in RotaShield - such as its high rates of intestinal replication and shedding in vaccinated infants, its propensity to cause fever, and its capacity to cause extra-intestinal infection in animal models - suggested that other candidate rotavirus vaccines might carry less of a risk of intussusception. However, the international community was only reassured after large and expensive clinical trials of 60 000 to 70 000 infants each conducted over the next seven years with two new rotavirus vaccines - a monovalent human vaccine (Rotarix, GlaxoSmithKline, Rixensart, Belgium) and a pentavalent, bovine-human reassortant rotavirus vaccine (RotaTeq, Merck, West Point, PA, USA) - did not show an association with intussusception.¹¹11. Vesikari T, Matson DO, Dennehy P, Van Damme P, Santosham M, Rodriguez Z, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006;354(1):23-33. https://doi.org/10.1056/NEJMoa052664
https://doi.org/https://doi.org/10.1056/... ^,1212. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, Abate H, Breuer T, Clemens SC, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med . 2006;354(1):11-22. https://doi.org/10.1056/NEJMoa052434
https://doi.org/https://doi.org/10.1056/... In 2006, the region of the Americas was the first to implement these new vaccines and in 2009 the World Health Organization issued a global recommendation for rotavirus vaccine use^.1313 Conclusions and recommendations from the Immunization Strategic Advisory Group. Wkly Epidemiol Rec. 2006;81(1):2-11.^,1414 World Health Organization. Rotavirus vaccines:an update. Wkly Epidemiol Rec. 2009;84(50):533-40.

As of July 2018, a total of 90 countries globally have implemented national rotavirus vaccination programs, including 45 low income countries that have received funding support for vaccine purchase through Gavi, the Vaccine Alliance (figure 1).¹⁵15. International Vaccine Access Center. Current Vaccine Intro status. Bloomberg School of Public Health, 2018 [cited 2019]. Available from:Available from: http://www.view-hub.org/viz/
http://www.view-hub.org/viz/... A systematic review of 48 postlicensure evaluations from 24 countries published during 2006-2016 showed that the vaccine effectiveness of Rotarix was 84, 75, and 57% in countries with low, medium, and high child mortality, respectively, and effectiveness of RotaTeq was 90 and 45% in countries with low and high child mortality, respectively.¹⁶16. Jonesteller CL, Burnett E, Yen C, Tate JE , Parashar UD . Effectiveness of rotavirus vaccination: A systematic review of the first decade of global postlicensure data, 2006-2016. Clin Infect Dis. 2017;65(5):840-50. https://doi.org/10.1093/cid/cix369
https://doi.org/https://doi.org/10.1093/... Despite variations in effectiveness, however, the impact of routine childhood rotavirus vaccination in reducing the burden of severe diarrhea across many settings has been rapid and substantial. A systematic review of 57 articles from 27 countries published from 2006-2016 showed that, following implementation of rotavirus vaccination, overall acute gastroenteritis hospitalizations were reduced by 41, 30, and 46% in countries with low, medium, and high child mortality, respectively, whereas hospitalizations and emergency department visits caused by rotavirus gastroenteritis were reduced by a median of 71, 59, and 60% in countries with low, medium, and high child mortality, respectively.¹⁷17. Burnett E, Jonesteller CL, Tate JE , Yen C, Parashar UD . Global impact of rotavirus vaccination on childhood hospitalizations and mortality from diarrhea. J Infect Dis. 2017;215(11):1666-72. https://doi.org/10.1093/infdis/jix186
https://doi.org/https://doi.org/10.1093/...

Besides affirming the effect of rotavirus vaccination on reducing morbidity from diarrhea in vaccinated children, post-licensure data have expanded the evidence on vaccine benefits. First, beginning with data from Mexico, several countries in Latin America have seen declines in childhood deaths from diarrhea following rotavirus vaccination, providing the first direct evidence of the life-saving potential of these vaccines.¹⁸18. Gurgel RQ, Ilozue C, Correia JB, Centenari C, Oliveira SM, Cuevas LE. Impact of rotavirus vaccination on diarrhoea mortality and hospital admissions in Brazil. Trop Med Int Health. 2011;16(9):1180-4. https://doi.org/10.1111/j.1365-3156.2011.02844.x
https://doi.org/https://doi.org/10.1111/... ^,1919. Lanzieri TM, Linhares AC, Costa I, Kolhe DA, Cunha MH, Ortega-Barria E, Colindres RE. Impact of rotavirus vaccination on childhood deaths from diarrhea in Brazil. Int J Infect Dis . 2011;15(3):e206-10. https://doi.org/10.1016/j.ijid.2010.11.007
https://doi.org/https://doi.org/10.1016/... ^,2020. Sanchez-Uribe E, Esparza-Aguilar M, Parashar UD , Richardson V. Sustained reduction of childhood diarrhea-related mortality and hospitalizations in Mexico after rotavirus vaccine universalization. Clin Infect Dis . 2016;62(suppl 2): S133-9. https://doi.org/10.1093/cid/civ1205
https://doi.org/https://doi.org/10.1093/... ^,2121. Gastanaduy PA, Sanchez-Uribe E, Esparza-Aguilar M, Desai R, Parashar UD , Patel M, Richardson V. Effect of rotavirus vaccine on diarrhea mortality in different socioeconomic regions of Mexico. Pediatrics. 2013;131(4):e1115-20. https://doi.org/10.1542/peds.2012-2797
https://doi.org/https://doi.org/10.1542/... ^,2222. Richardson V, Hernandez-Pichardo J, Quintanar-Solares M, Esparza-Aguilar M, Johnson B, Gomez-Altamirano CM, et al. Effect of rotavirus vaccination on death from childhood diarrhea in Mexico. N Engl J Med . 2010;362(4):299-305. https://doi.org/10.1056/NEJMoa0905211
https://doi.org/10.1056/NEJMoa0905211... ^,2323. do Carmo GM, Yen C, Cortes J, Siqueira AA, de Oliveira WK, Cortez-Escalante JJ, et al. Decline in diarrhea mortality and admissions after routine childhood rotavirus immunization in Brazil: a time-series analysis. PLoS Med. 2011;8(4):e1001024. https://doi.org/10.1371/journal.pmed.1001024
https://doi.org/10.1371/journal.pmed.100... ^,2424. Inchauste L, Patzi M, Halvorsen K, Solano S, Montesano R, Iniguez V. Impact of rotavirus vaccination on child mortality, morbidity, and rotavirus-related hospitalizations in Bolivia. IntJ Infect Dis . 2017;61:79-88. https://doi.org/10.1016/j.ijid.2017.06.006
https://doi.org/10.1016/j.ijid.2017.06.0... ^,2525. Bayard V, DeAntonio R, Contreras R, Tinajero O, Castrejon MM, Ortega-Barría E, Colindres RE. Impact of rotavirus vaccination on childhood gastroenteritis-related mortality and hospital discharges in Panama. IntJ Infect Dis . 2012;16(2):e94-8. https://doi.org/10.1016/j.ijid.2011.09.003
https://doi.org/10.1016/j.ijid.2011.09.0... Second, in many settings, vaccination of young infants and children has led to declines in severe gastroenteritis in older unvaccinated children and adults, likely because of reduction in community transmission of rotavirus by direct protection of young children who are an important source of transmission.²⁶26. Gastanaduy PA, Curns AT, Parashar UD , Lopman BA. Gastroenteritis hospitalizations in older children and adults in the United States before and after implementation of infant rotavirus vaccination. JAMA. 2013;310(8):851-3. https://doi.org/10.1001/jama.2013.170800
https://doi.org/10.1001/jama.2013.170800... ^,2727. Lopman BA, Curns AT, Yen C , Parashar UD . Infant rotavirus vaccination may provide indirect protection to older children and adults in the United States. J Infect Dis . 2011;204(7):980-6. https://doi.org/10.1093/infdis/jir492
https://doi.org/10.1093/infdis/jir492... This phenomenon, known as herd protection or community immunity, was not anticipated with rotavirus vaccines. Finally, in addition to protection against severe gastroenteritis caused by rotavirus, some data show a reduction in risk of childhood seizures among children vaccinated against rotavirus.²⁸28. Burke RM, Tate JE , Dahl RM, Aliabadi N, Parashar UD . Rotavirus vaccination is associated with reduced seizure hospitalization risk among commercially insured US children. Clin Infect Dis . 2018;67(10):1614-6. https://doi.org/10.1093/cid/ciy424
https://doi.org/10.1093/cid/ciy424... ^,2929. Pringle KD, Burke RM, Steiner CA, Parashar UD , Tate JE . Trends in rate of seizure-associated hospitalizations among children <5 years old before and after rotavirus vaccine introduction in the United Sates, 2000-2013. J Infect Dis . 2018;217(4):581-8. https://doi.org/10.1093/infdis/jix589
https://doi.org/10.1093/infdis/jix589... ^,3030. Payne DC, Baggs J, Zerr DM, Klein NP, Yih K, Glanz J, et al. Protective association between rotavirus vaccination and childhood seizures in the year following vaccination in US children. Clin Infect Dis . 2014;58(2):173-7. https://doi.org/10.1093/cid/cit671
https://doi.org/10.1093/cid/cit671... ^,3131. Pardo-Seco J, Cebey-Lopez M, Martinon-Torres N, Salas A, Gómez-Rial J, Rodriguez-Tenreiro C, et al. Impact of rotavirus vaccination on childhood hospitalization for seizures. Pediatr Infect Dis J. 2015;34(7):769-73. https://doi.org/10.1097/INF.0000000000000723
https://doi.org/10.1097/INF.000000000000... Reports showing that wild-type rotavirus frequently causes a systemic infection with viremia and has been linked to a variety of neurologic manifestations support the biologic plausibility of this association.³²32. Chitambar SD, Tatte VS, Dhongde R, Kalrao V. High frequency of rotavirus viremia in children with acute gastroenteritis: discordance of strains detected in stool and sera. J Med Virol. 2008;80(12):2169-76. https://doi.org/10.1002/jmv.21338
https://doi.org/10.1002/jmv.21338... ^,3333. Lloyd MB, Lloyd JC, Gesteland PH, Bale JF Jr. Rotavirus gastroenteritis and seizures in young children. Pediatr Neurol. 2010;42(6):404-8. https://doi.org/10.1016/j.pediatrneurol.2010.03.002
https://doi.org/10.1016/j.pediatrneurol.... ^,3434. Lynch M, Lee B, Azimi P, Gentsch J, Glaser C, Gilliam S, et al. Rotavirus and central nervous system symptoms: cause or contaminant? Case reports and review. Clin Infect Dis . 2001;33(7):932-8. https://doi.org/10.1086/322650
https://doi.org/10.1086/322650... ^,3535. Isik U, Caliskan M. Reversible EEG changes during rotavirus gastroenteritis. Brain Dev. 2008;30(1):73-6. https://doi.org/10.1016/j.braindev.2007.05.006
https://doi.org/10.1016/j.braindev.2007.... ^,3636. Iyadurai S, Troester M, Harmala J, Bodensteiner J. Benign afebrile seizures in acute gastroenteritis: is rotavirus the culprit? J Child Neurol. 2007;22(7):887-90. https://doi.org/10.1177/0883073807304703
https://doi.org/10.1177/0883073807304703...

Despite these promising post-licensure data on vaccine impact, the lower effectiveness of rotavirus vaccines in high mortality settings indicates further room for improvement in vaccine performance.¹⁶16. Jonesteller CL, Burnett E, Yen C, Tate JE , Parashar UD . Effectiveness of rotavirus vaccination: A systematic review of the first decade of global postlicensure data, 2006-2016. Clin Infect Dis. 2017;65(5):840-50. https://doi.org/10.1093/cid/cix369
https://doi.org/https://doi.org/10.1093/... The gradient of lower rotavirus vaccine performance in settings with higher child mortality is also seen with other orally administered vaccines such as those against polio, typhoid, and cholera,³⁷37. John TJ. Antibody response of infants in tropics to five doses of oral polio vaccine. Br Med J. 1976;1(6013):812. https://doi.org/10.1136/bmj.1.6013.812
https://doi.org/10.1136/bmj.1.6013.812... ^,3838. John TJ, Jayabal P. Oral polio vaccination of children in the tropics. I. The poor seroconversion rates and the absence of viral interference. Am J Epidemiol. 1972;96(4):263-9. https://doi.org/10.1093/oxfordjournals.aje.a121457
https://doi.org/10.1093/oxfordjournals.a... ^,3939. Patriarca PA, Wright PF, John TJ. Factors affecting the immunogenicity of oral poliovirus vaccine in developing countries: review. Rev Infect Dis. 1991;13(5):926-39. https://doi.org/10.1093/clinids/13.5.926
https://doi.org/10.1093/clinids/13.5.926... ^,4040. Suharyono, Simanjuntak C, Witham N, Punjabi N, Heppner DG, Losonsky G, et al. Safety and immunogenicity of single-dose live oral cholera vaccine CVD 103-HgR in 5-9-year-old Indonesian children. Lancet . 1992;340(8821):689-94. https://doi.org/10.1016/0140-6736(92)92231-4
https://doi.org/10.1016/0140-6736(92)922... ^,4141. Gotuzzo E, Butron B, Seas C, Penny M, Ruiz R, Losonsky G, et al. Safety, immunogenicity, and excretion pattern of single-dose live oral cholera vaccine CVD 103-HgR in Peruvian adults of high and low socioeconomic levels. Infect Immun. 1993;61(9):3994-7. and is likely related to factors such as passively transferred maternal antibodies, concurrent enteric infections, and infant malnutrition that inhibit the immune response to vaccination. To overcome these factors, clinical trials have evaluated approaches such as transient withholding of breast feeding at the time of vaccination, administration of additional vaccine doses, modifications to the schedule of administration of vaccine doses, and supplementation with zinc and probiotics prior to vaccination. While some of these interventions resulted in marginal improvement in vaccine immune response, the data were not convincing or consistent enough to support a programmatic recommendation for any strategy.⁴²42. Ali A, Kazi AM, Cortese MM, Fleming JA, Moon S, Parashar UD , et al. Impact of withholding breastfeeding at the time of vaccination on the immunogenicity of oral rotavirus vaccine--a randomized trial. PLoS One. 2015;10(6):e0127622. https://doi.org/10.1371/journal.pone.0127622
https://doi.org/10.1371/journal.pone.012... ^,4343. Groome MJ, Moon SS, Velasquez D, Jones S, Koen A, van Niekerk N, et al. Effect of breastfeeding on immunogenicity of oral live-attenuated human rotavirus vaccine: a randomized trial in HIV-uninfected infants in Soweto, South Africa. Bull World Health Organ 2014;92(4):238-45. https://doi.org/10.2471/BLT.13.128066
https://doi.org/10.2471/BLT.13.128066... ^,4444. Armah G, Lewis KD, Cortese MM, Parashar UD , Ansah A, Gazley L, et al. A randomized, controlled trial of the impact of alternative dosing schedules on the immune response to human rotavirus vaccine in rural Ghanaian infants. J Infect Dis . 2016;213(11):1678-85. https://doi.org/10.1093/infdis/jiw023
https://doi.org/10.1093/infdis/jiw023... ^,4545. Zaman K, Fleming JA, Victor JC, Yunus M, Bari TI, Azim T, et al. Noninterference of rotavirus vaccine with measles-rubella vaccine at 9 months of age and improvements in antirotavirus immunity: A randomized trial. J Infect Dis . 2016;213(11):1686-93. https://doi.org/10.1093/infdis/jiw024
https://doi.org/10.1093/infdis/jiw024... ^,4646. Lazarus RP, John J, Shanmugasundaram E, Rajan AK, Thiagarajan S, Giri S, et al. The effect of probiotics and zinc supplementation on the immune response to oral rotavirus vaccine: A randomized, factorial design, placebo-controlled study among Indian infants. Vaccine. 2018;36(2):273-9. https://doi.org/10.1016/j.vaccine.2017.07.116
https://doi.org/10.1016/j.vaccine.2017.0... Research is ongoing to develop parenterally administered rotavirus vaccines that would potentially avoid the effect of factors that interfere with the performance of oral rotavirus vaccines.⁴⁷47. Kirkwood CD, Ma LF, Carey ME, Steele AD. The rotavirus vaccine development pipeline. Vaccine. 2017;pii:S0264-410X(17)30410-3. https://doi.org/10.1016/j.vaccine.2017.03.076
https://doi.org/https://doi.org/10.1016/...

Concerns remain around the safety of oral rotavirus vaccines with regard to the risk of intussusception. While no increased intussusception risk was seen in large pre-licensure trials with Rotarix and RotaTeq, post-marketing data from several high- and middle-income countries have indicated a risk of 1 to 5 excess cases of intussusception per 100 000 infants vaccinated with either vaccine.⁴⁸48. Weintraub ES, Baggs J, Duffy J, Vellozzi C, Belongia EA, Irving S, et al. Risk of intussusception after monovalent rotavirus vaccination. N Engl J Med . 2014;370(6):513-9. https://doi.org/10.1056/NEJMoa1311738
https://doi.org/10.1056/NEJMoa1311738... ^,4949. Yih WK, Lieu TA, Kulldorff M, Martin D, McMahill-Walraven CN, Platt R, et al. Intussusception risk after rotavirus vaccination in US infants. N Engl J Med . 2014;370(6):503-12. https://doi.org/10.1056/NEJMoa1303164
https://doi.org/10.1056/NEJMoa1303164... ^,5050. 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
https://doi.org/10.1016/j.vaccine.2016.0... ^,5151. 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
https://doi.org/10.1093/cid/cit520... ^,5252. Yung CF, Chan SP, Soh S, Tan A, Thoon KC. Intussusception and monovalent rotavirus vaccination in Singapore: Self-controlled case series and risk-benefit study. J Pediatr. 2015;167(1):163-8 e1. https://doi.org/10.1016/j.jpeds.2015.03.038
https://doi.org/https://doi.org/10.1016/... ^,5353. Richardson V, Parashar U, Patel M. Childhood diarrhea deaths after rotavirus vaccination in Mexico. N Engl J Med . 2011;365(8):772-3. https://doi.org/10.1056/NEJMc1100062
https://doi.org/10.1056/NEJMc1100062... Data from these countries showing that the health benefits of vaccination far exceed this low risk of intussusception has led policy makers to make no changes to recommendations for rotavirus vaccination. Recently, the first large post-licensure assessment in low-income African countries showed no increased risk of intussusception, providing additional reassurance around the safety of rotavirus vaccines.⁵⁴54. Tate JE , Mwenda JM, Armah G, Jani B, Omore R, Ademe A, et al. Evaluation of Intussusception after Monovalent Rotavirus Vaccination in Africa. N Engl J Med . 2018;378(16): 1521-8. https://doi.org/10.1056/NEJMoa1713909
https://doi.org/10.1056/NEJMoa1713909... While not proven, it is possible that this lack of intussusception risk in low-income settings is related to the lower efficacy and lower rate of intestinal replication of the live rotavirus vaccine virus strains in these settings.

Assuring adequate supply of rotavirus vaccines at an affordable cost for the global community is vital to achieving their full public health potential. Financial support from the GAVI Alliance has allowed eligible low-income countries to procure rotavirus vaccines at a country co-pay cost of only $0.20 per child and has greatly facilitated vaccine implementation in these countries. In early 2018, an Indian-made rotavirus vaccine (Rotavac, Bharat Biotech Limited, Hyderabad, India)⁵⁵55. Bhandari N, Rongsen-Chandola T, Bavdekar A, John J, Antony K, Taneja S, et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian children in the second year of life. Vaccine. 2014;32(suppl 1):A110-6. https://doi.org/10.1016/j.vaccine.2014.04.079
https://doi.org/10.1016/j.vaccine.2014.0... ^,5656. Bhandari N, Rongsen-Chandola T, Bavdekar A, John J, Antony K, Taneja S, et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial. Lancet . 2014;383(9935):2136-43. https://doi.org/10.1016/S0140-6736(13)62630-6
https://doi.org/10.1016/S0140-6736(13)62... was pre-qualified for global procurement through the GAVI Alliance, and another vaccine (Rotasil, Serum Institute of India, Pune, India)⁵⁷57. Kulkarni PS, Desai S, Tewari T, Kawade A, Goyal N, Garg BS, et al. A randomized Phase III clinical trial to assess the efficacy of a bovine-human reassortant pentavalent rotavirus vaccine in Indian infants. Vaccine. 2017;35(45):6228-37. https://doi.org/10.1016/j.vaccine.2017.09.014
https://doi.org/10.1016/j.vaccine.2017.0... ^,5858. Isanaka S, Guindo O, Langendorf C, Matar-Seck A, Plikaytis BD, Sayinzoga-Makombe N, et al. Efficacy of a low-cost, heat-stable oral rotavirus vaccine in Niger. N Engl J Med . 2017;376(12):1121-30. https://doi.org/10.1056/NEJMoa1609462
https://doi.org/10.1056/NEJMoa1609462... was pre-qualified later in 2018 (table I). These two vaccines are being routinely administered to all Indian children (~26 million births per year), and their global availability will help assure stable vaccine supply and is likely to lower vaccine cost through increased competition.

In summary, substantial progress has been made in the past decade in the implementation of rotavirus vaccines into childhood immunization programs globally, which is particularly noteworthy given the great uncertainty after the abrupt withdrawal of the first licensed rotavirus vaccine. Routine rotavirus vaccination has led to rapid and large declines in the burden of severe rotavirus diarrhea in countries using vaccine, and vaccine safety has been demonstrated through well-designed, large, post-licensure evaluations. Efforts should continue to provide countries that have not yet introduced vaccines with evidence that will allow them to assess the value of this intervention, and assuring adequate and affordable rotavirus vaccine supply for the global market. Together with other interventions such as provision of safe food and water, improving environmental sanitation, promotion of breastfeeding, and prevention of childhood malnutrition, rotavirus vaccines will have a substantial impact in reducing the morbidity and mortality from severe childhood diarrhea worldwide.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

References

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