INTRODUCTION — Rotavirus was the most common cause of severe, acute gastroenteritis in infants and children worldwide in the prevaccine era, during which it was estimated to cause approximately 440,000 deaths, 2 million hospitalizations, and 25 million outpatient visits per year worldwide among children <5 years of age [1-3]. More than 120 countries have introduced national rotavirus vaccination programs, and approximately 15 additional countries are planning to introduce them [4].
Rotavirus vaccination of infants will be discussed below. The pathogenesis, clinical presentation, and diagnosis of rotavirus gastroenteritis are discussed separately, as are general measures to prevent viral gastroenteritis in children. (See "Clinical manifestations and diagnosis of rotavirus infection" and "Acute viral gastroenteritis in children in resource-abundant countries: Management and prevention".)
MICROBIOLOGY — Rotavirus is a double-stranded RNA virus in the Reoviridae family [5]. The outer capsid contains two proteins that define rotavirus serotypes: a G protein (VP7) and a P protein (VP4) (figure 1). Five G-P combinations accounted for approximately 90 percent of human rotaviruses circulating worldwide: G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8] in the prevaccine era [3]. However, in countries in Africa and Asia, strain diversity is greater; within one geographic area, multiple types may circulate simultaneously, and the prevalent strains may vary from season to season. During 2014 to 2016, genotype G12P[8] predominated in the United States [6]. The effects of infant immunization on rotavirus serotype prevalence are discussed below. (See 'Serotype selection' below.)
ROTAVIRUS VACCINES
Vaccine development — Rotavirus vaccines have been developed from animal rotavirus strains, human-animal rotavirus reassortants (genes from human and animal strains), attenuated human rotaviruses, subunits of rotavirus virions, and virus-like particles [7-13]. For live virus-based vaccines, reassortants are necessary because most human rotaviruses grow too poorly in cell culture for production of standard vaccine lots for large-scale immunization programs. Monovalent vaccines prepared from animal rotaviruses have not been promising in humans. Assessment of rotavirus subunit vaccine candidates has reached human studies [14].
Vaccines licensed in the United States — Two live, attenuated oral rotavirus vaccines are licensed for use in the United States and many other countries (table 1). The vaccines have similar efficacy and safety, and no preference for one over the other vaccine exists [1,3,5,15]. (See 'Contraindications' below and 'Efficacy/effectiveness' below and 'Adverse events and safety' below.)
●Pentavalent human-bovine rotavirus reassortant vaccine (RV5, PRV, RotaTeq) is based upon the bovine strain, WC3, which is naturally attenuated for humans but not broadly cross-protective. Each reassortant component contains a single gene derived from a human rotavirus strain encoding a major outer capsid protein from the most common human serotypes: G1, G2, G3, G4, and P1[8] (figure 2). This vaccine induces homologous (ie, serotype-specific) protection against the common types of exposure, as well as the nonvaccine type G9 [16].
●Attenuated human rotavirus vaccine (RV1, HRV, Rotarix) is a monovalent vaccine derived from the most common human rotavirus serotype combination (G1P[8]) that has been attenuated by serial passage in cell culture (figure 2) [10]. Observational studies of natural rotavirus infection suggest that infection with one serotype provides at least partial cross-protection against most other serotypes [17].
Other vaccines
●Human-bovine reassortant vaccine (116E, Rotavac) and oral bovine rotavirus pentavalent vaccine (BRV-PV, Rotasiil) – These vaccines are licensed for use in India and have World Health Organization (WHO) prequalification for use in resource-limited countries [18-21].
•116E – The 116E rotavirus vaccine is a nonpathogenic strain (G9P[11]) that occurs naturally in India. It contains a virus reassortant strain in which one gene was from a rotavirus strain naturally occurring in bovines (P[11]) and 10 genes were from a rotavirus strain naturally occurring in humans. Phase 3 clinical trials in India have been completed (demonstrating efficacy of 56 percent against severe rotavirus gastroenteritis and 34 percent against rotavirus gastroenteritis in the first year of follow-up) [12,22]. The 116E vaccine is licensed for use in India and has World Health Organization (WHO) prequalification for use in resource-limited countries [18-20].
•BRV-PV – BRV-PV is a heat-stable bovine-human reassortant vaccine that contains serotypes G1, G2, G3, G4, and G9 [23,24]. It is administered in three doses at 6, 10, and 14 weeks.
A randomized trial compared BRV-PV with placebo in 3508 Nigerian infants [23,24]. Four weeks after the third dose, infants who received BRV-PV had fewer episodes of laboratory-confirmed, severe rotavirus gastroenteritis than those who received placebo (31 versus 87 episodes; efficacy of 67 percent, 95% CI 50-78 percent). The rates of adverse events were similar between groups. None of the participants had confirmed intussusception. In a multicenter randomized trial in 7500 infants in India, the efficacy of BRV-PV in preventing severe rotavirus gastroenteritis before age two years was 39 percent (95% CI 26-49 percent) [25].
BRV-PV is less expensive than RV5 and RV1 and may be more suitable for vaccination programs in remote areas where cold-chain capacity is limited [23]. It is licensed for use in India and has WHO prequalification for use in resource-limited countries [20].
In a multicenter, open-label, randomized trial, a mixed schedule of116E and BRV-PV was safe and immunogenic, suggesting that the two vaccines can be used interchangeably for routine immunization [26].
●Lanzhou lamb rotavirus vaccine – A monovalent, G10P[12] oral lamb rotavirus vaccine is licensed in China. In a randomized trial in China, the efficacy of the lamb rotavirus vaccine was 57 percent efficacious in reducing rotavirus gastroenteritis and 70 percent efficacious in reducing severe rotavirus gastroenteritis [27]. However, a mouse study suggests that monovalent rotavirus vaccines may not be sufficiently immunogenic against heterotypic strains for protection against rotavirus disease in China [19]. Previous studies indicate that strain variation and induction of antibody response is well correlated in mice and humans [28].
●Oral human neonatal rotavirus vaccine (RV3-BB) – RV3-BB is a naturally attenuated oral vaccine developed from a strain initially recovered from an outbreak in a nursery in which infections were asymptomatic (G3P[6]) [29]. In a phase 2 randomized trial in Indonesia, RV3-BB was efficacious in preventing severe rotavirus gastroenteritis before age 18 months when administered to neonates (at age 0 to 5 days, 8 weeks, and 14 weeks) and infants (at age 8, 14, and 18 weeks). RV3-BB also appears to be safe and immunogenic [29-31].
●Human attenuated rotavirus vaccine (G1P[8]) in lyophilized (Rotavin-M1) and liquid formulation (Rotavin) – A lyophilized human attenuated rotavirus vaccine (G1P[8]) was licensed in Vietnam in 2012. Although the lyophilized formulation and a liquid formulation appear to be safe and immunogenic [32], additional data from phase 3 trials are necessary before use of these vaccines can be expanded.
●Tetravalent human-rhesus reassortant vaccine – An oral tetravalent human-rhesus rotavirus reassortant vaccine (RRV-TV, RotaShield) was licensed in 1998 and recommended for universal immunization of term infants in the United States, but was withdrawn from the market in 1999 because of an epidemiologic link to intussusception occurring within two weeks after vaccine administration [33-37]. (See 'Intussusception' below.)
INDICATIONS — We recommend universal immunization of infants against rotavirus, as recommended by the Centers for Disease Control and Prevention [1], the World Health Organization [38], the American Academy of Pediatrics [5], the American Academy of Family Physicians, the European Society for Pediatric Infectious Diseases, and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition [15].
In randomized trials and meta-analyses, rotavirus vaccines are highly efficacious in preventing rotavirus gastroenteritis and rotavirus gastroenteritis-associated hospitalization and health care utilization [39-41]. (See 'Efficacy/effectiveness' below.)
CONTRAINDICATIONS — Rotavirus vaccines are contraindicated in those infants [1,5,15,42-44]:
●Who are allergic to any of the ingredients of the vaccine
The oral dose applicator presentations of the attenuated human rotavirus vaccine (RV1) are contraindicated in infants with severe (anaphylactic) allergy to latex because the applicator contains latex; the squeezable tube presentation of RV1 or the pentavalent human-bovine rotavirus reassortant vaccine can be administered to such infants [45,46] (see "Allergic reactions to vaccines", section on 'Latex')
●Who had a severe (anaphylactic) allergic reaction after a previous dose
●With severe combined immunodeficiency (SCID) – Vaccine-acquired rotavirus disease has been reported in infants who subsequently were diagnosed with SCID [42,47-52] (see "Severe combined immunodeficiency (SCID): An overview")
●With a history of intussusception – Fatal intussusception after the second dose has been reported in infants with a history of intussusception after the first dose [43,53]
Although few data exist upon which to base recommendations, the 2013 Infectious Diseases Society of America guidelines on vaccination of the immunocompromised host consider the following conditions to also be contraindications to rotavirus vaccination because of the potential risk of serious adverse effects [44]:
●Combined immunodeficiencies – Di George syndrome and other combined immunodeficiencies with a CD3 count <500 cells/microL, Wiskott-Aldrich syndrome, X-linked lymphoproliferative disease, and familial disorders that predispose to hemophagocytic lymphohistiocytosis (eg, Griscelli syndrome, Chediak-Higashi syndrome, Hermansky-Pudlak syndrome) (see "Combined immunodeficiencies: An overview")
●Certain phagocytic cell deficiencies – Leukocyte adhesion deficiency, defects of cytotoxic granule release (eg, Chediak-Higashi), and other undefined phagocytic cell defects (see "Leukocyte-adhesion deficiency" and "Chediak-Higashi syndrome")
●Major antibody deficiencies treated with immunoglobulin therapy (see "Primary humoral immunodeficiencies: An overview")
●Planned or status-post hematopoietic stem cell transplant
●Planned or current receipt of cancer chemotherapy
●Status-post solid organ transplant
●Chronic inflammatory disease treated with immunosuppressive medications (ie, prednisone, azathioprine, 6-mercaptopurine, biologic agents [eg, tumor necrosis factor antagonists, rituximab])
These conditions are uncommon to rare among infants in the age group for rotavirus vaccine administration (six weeks to eight months). (See 'Schedule' below.)
The following conditions are not contraindications to rotavirus vaccination [1,5,44]:
●Immunocompromised family member or household member (see 'Immunocompromised household contact' below)
●Breastfeeding (efficacy trials included breastfeeding infants, with no alteration in normal breastfeeding patterns) [54,55]
●Pregnant family member or household contact
PRECAUTIONS
●Immunodeficiency other than severe combined immunodeficiency – Decisions regarding immunization of children with known or suspected immunodeficiency other than severe combined immunodeficiency (SCID) (which is a contraindication to rotavirus vaccine) should be made on a case-by-case basis after considering the risks and benefits. Although there are few data regarding the efficacy or safety of rotavirus vaccine in infants who are potentially immunocompromised, systemic infections or severe mucosal infections due to a rotavirus vaccine have been extremely rare [50].
In this setting, the United States Advisory Committee on Immunization Practices (ACIP) advises consultation with an immunologist or infectious disease specialist and the American Academy of Pediatrics (AAP) advises precaution for administration of rotavirus vaccine for manifestations of altered immunocompetence other than SCID [1,5,42].
Consultation with an expert in pediatric infectious diseases is also warranted for infants born to women who received certain biologic response modifiers (eg, adalimumab, golimumab) other than certolizumab during pregnancy [5]. Although data are limited, these infants may have detectable drug concentrations for months after delivery, which may increase their risk of vaccine-type rotavirus disease [56-59]. Certolizumab is an exception because it does not cross the placenta. Rotavirus vaccine should be avoided for up to 12 months after the last in utero exposure; the duration of avoidance varies with the agent but is usually at least 6 months. (Refer to the drug interactions program included within UpToDate for details.) In resource-abundant countries where rotavirus gastroenteritis is rarely life threatening and there is evidence of community ("herd") immunity to rotavirus infection, the risk of developing vaccine-type rotavirus disease with prenatal exposure to biologic response modifiers is greater than the risk of developing severe wild-type rotavirus disease without vaccination.
The Infectious Diseases Society of America (IDSA) guidelines on vaccination of the immunocompromised host suggest that rotavirus vaccine may be administered to infants with the following conditions [44]:
•HIV exposure or infection – Rotavirus gastroenteritis may be particularly severe in children with HIV infection. In a prospective study in South Africa, children with HIV infection were more likely to have a prolonged hospitalization and had a fourfold increased mortality rate compared with children without HIV infection admitted to the same hospital [60]. The AAP also supports administration of rotavirus vaccine to infants with HIV exposure or infection, regardless of the CD4+ T-lymphocyte percentage or count [5].
Rotavirus vaccine trials that included infants with HIV infection have found no evidence of enhanced disease associated with HIV infection [44]. In randomized trials, administration of attenuated human rotavirus vaccine (RV1) and pentavalent human-bovine rotavirus reassortant vaccine (RV5) was safe and immunogenic when administered to infants with HIV infection in a three-dose schedule [61,62].
Groups other than the IDSA (eg, the Department of Health and Human Services, Centers for Disease Control and Prevention) suggest that the potential risks and benefits of rotavirus vaccination be considered before vaccination [63]; however, they suggest that the potential delay in establishment of definitive diagnosis of HIV infection beyond the recommended age for the first dose of rotavirus vaccine and considerable attenuation of rotavirus vaccine strains support vaccination of infants with suspected HIV infection or exposure.
•Primary (congenital) complement deficiencies. (See "Inherited disorders of the complement system".)
•Chronic granulomatous disease. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis".)
•Congenital or cyclic neutropenia. (See "Congenital neutropenia" and "Cyclic neutropenia".)
•Immunoglobulin A deficiency, provided that all other components of the immune system are normal. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis".)
•Specific polysaccharide antibody deficiency provided that all other components of the immune system are normal. (See "Specific antibody deficiency".)
For infants with innate immune defects that result in defects of cytokine generation or response or cellular activation (eg, defects of the interferon-gamma/interleukin-12 axis), the IDSA recommends consultation with a specialist before administration of live vaccines [44].
●Other precautions – The ACIP and AAP suggest the following conditions are precautions for the administration of rotavirus vaccines, because the safety and efficacy of the vaccine were not specifically evaluated in infants with these conditions [1,5]:
•Acute moderate-to-severe gastroenteritis – Immunization of infants with acute, moderate-to-severe gastroenteritis should be deferred until the illness resolves. A concern is that the antibody response may be diminished.
•Moderate-to-severe febrile illness – Immunization of infants with moderate to severe illness of any type should be deferred until the illness resolves. Deferral of the immunization makes it easier to differentiate possible adverse effects related to the vaccine from manifestations of the underlying disease.
•Pre-existing or acquired chronic gastrointestinal disease excluding intussusception – Infants with pre-existing or acquired gastrointestinal conditions (eg, congenital malabsorption syndromes, Hirschsprung disease, short-bowel syndrome, some forms of cystic fibrosis-related gastrointestinal disease) who are not receiving immunosuppressive therapy should benefit from rotavirus vaccines, and the benefits outweigh the theoretic risks. In a pilot study, RV1 appeared to be safe and immunogenic in 14 children with early intestinal failure [64]. In another small study, RV5 appeared to be safe and immunogenic in five infants with a history of bowel resection [65]. There is one case report of pneumatosis intestinalis following rotavirus vaccination in a three-month-old with short bowel syndrome [66].
•Spina bifida or bladder exstrophy – Infants with spina bifida or bladder exstrophy have a high risk of developing latex allergy. To minimize latex exposure, some experts suggest that RV5 or the latex-free presentation of RV1 (table 1) be used for such infants. The ACIP recommends rotavirus vaccination even if latex-free presentations are not available because the benefit of vaccination is greater than the risk of sensitization [1].
SCHEDULE
Routine schedule — The recommended routine schedules for pentavalent human-bovine rotavirus reassortant vaccine (RV5) and attenuated human rotavirus vaccine (RV1) differ [1,5]:
●RV5 is administered in three oral doses at two, four, and six months of age.
●RV1 is administered in two oral doses at two and four months.
Whenever possible, the rotavirus vaccine series should be completed with the same vaccine product [1]; however, vaccination should not be deferred if the product used for previous doses is not known. A total of three doses of vaccine should be given to infants who received RV5 for any dose and infants in whom the vaccine product for previous dose(s) is unknown.
An open-label, multicenter randomized trial confirmed that completion of rotavirus immunization using a combination of RV5 and RV1 was as immunogenic as completion with RV5 or RV1 and was well tolerated [67]. In postlicensure surveillance, completion of immunization with a combination of RV5 and RV1 (eg, two doses of RV5 and one dose of RV1 or two doses of RV1 and one dose of RV5) was 80 percent (95% CI 51-92 percent) effective in preventing rotavirus gastroenteritis [68]. Although mixed schedules and single formulation schedules were not directly compared, this is similar to published rates of effectiveness for three doses of RV5 or two doses of RV1 in the same population [69].
Catch-up schedule — The catch-up schedules for RV5 and RV1 differ:
●RV5 – In the United States, the first dose of RV5 should be given between 6 and 15 weeks of age [1,5]. Two subsequent doses are administered with a minimum interval of four weeks between doses. The third dose should not be administered after eight months, zero days of age.
The vaccine series should not be initiated in infants who are older than 14 weeks, 6 days of age [1]. The safety of the first dose of rotavirus vaccine in older infants was not studied in the prelicensure trials; however, for infants in whom the first dose is inadvertently administered at 15 weeks or older, the rest of the rotavirus immunization series should be completed as described above [1]. The timing of the first dose should not affect the safety and efficacy of the second and third dose.
In Europe, the first dose of RV5 should be given between 6 and 12 weeks, preferably at 6 to 8 weeks, and the full schedule completed by 24 weeks of age, but preferably earlier [15].
For resource-limited countries, to avoid missed opportunities, the World Health Organization (WHO) loosened the age restriction to permit completion of the three-dose RV5 schedule by age 24 months (although earlier completion is preferred) [3]. This recommendation has not been fully adopted [70].
●RV1 – In the United States, the first dose of RV1 should be given between 6 and 15 weeks of age and the full schedule completed by eight months, zero days of age [1,5].
In Europe, the first dose of RV1 should be given between 6 and 12 weeks, preferably at 6 to 8 weeks, and the full schedule completed by 24 weeks of age, but preferably earlier [15].
For resource-limited countries, to avoid missed opportunities, the WHO loosened the age restriction to permit completion of the two-dose RV1 schedule by age 24 months (although earlier completion is preferred) [3]. This recommendation has not been fully adopted [70].
There is no maximum interval between doses.
Special circumstances
Preterm infants — In the United States, rotavirus vaccines can be administered to preterm infants who are clinically stable and at least six weeks old [1,5,71,72]. For hospitalized infants who are due for rotavirus vaccine during admission, individual institutions may choose to administer the vaccine during admission or at the time of discharge [5]. The European Society for Paediatric Infectious Diseases and the Australian government recommend rotavirus vaccination of preterm infants according to their chronologic age, whether or not they have been discharged from the nursery, with appropriate precautions to prevent transmission to high-risk contacts [15,73]. (See 'Shedding and transmission of vaccine virus' below.)
In retrospective reviews, age-appropriate administration of RV5 to preterm enterally-fed infants in the neonatal intensive care unit was well tolerated and did not appear to be associated with transmission [74,75]. Subsequent prospective studies support the low risk of transmission [76,77]. The larger prospective study evaluated rotavirus shedding and transmission among infants age <15 weeks admitted to an intensive care unit with single or double room assignments of an academic medical center that permitted RV5 administration during hospitalization [76]. Rotavirus was detected in 13 of 1192 stool specimens (1.1 percent) collected weekly: one wild-type strain from an unvaccinated infant and 12 vaccine-type strains from nine vaccinated infants. No vaccine-type rotavirus cases were observed among unvaccinated infants during 1952 days of potential exposure, and no reassortants were identified. These findings suggest that delaying RV5 vaccination until hospital discharge may be unnecessary in hospitals with comparable infection control standards. In making decisions for individual infants, attending clinicians must consider the benefit of vaccination with possible asymptomatic transmission and the risk of missed opportunity for rotavirus vaccination in an infant who may be at increased risk of severe rotavirus disease [78].
Infants with rotavirus gastroenteritis — The rotavirus vaccine series should be initiated or completed in infants who have had rotavirus gastroenteritis before receiving the full two- or three-dose series because natural first infections do not provide complete immunity against subsequent severe disease and multiple serotypes of rotavirus usually are present in any community [1,5,79].
Receipt of blood products — Rotavirus vaccines may be administered at any time in relation to the receipt of blood products, including antibody-containing products [1,80].
Hospitalization of vaccinated infant — In the event that an infant requires hospitalization after administration of rotavirus vaccine, standard precautions should be used to prevent the spread of vaccine virus in the hospital setting [5]. No additional infection control measures are necessary. Co-rooming with children with severe combined immunodeficiency or suspected severe immunodeficiency is not recommended. (See "Infection prevention: Precautions for preventing transmission of infection", section on 'Standard precautions' and 'Shedding and transmission of vaccine virus' below.)
Immunocompromised household contact — Rotavirus vaccines can be administered to infants living in households with immunocompromised persons [1,5,44]. (See 'Shedding and transmission of vaccine virus' below.)
Resource-limited countries with high child mortality — The World Health Organization recommends routine rotavirus vaccination for all its member countries [24]. Rotavirus vaccine effectiveness varies among the countries that have introduced a rotavirus vaccine into the routine infant immunization schedule [81-92]. Although poverty is a surrogate marker for poorer population vaccine effectiveness [93-96], rotavirus vaccine remains effective in reducing rotavirus-related hospitalization and emergency department visits in resource-limited countries with high child mortality [92,97-99]. (See 'Efficacy/effectiveness' below.)
Factors that may explain variation in vaccine effectiveness include:
●Greater portion of missed vaccination opportunities, related to the narrow age range for administration [87,89]
●Failure to adopt a universal recommendation for rotavirus vaccination (which may prevent or reduce herd immunity) [100,101]
●Variation in herd effect with increasing interval from initiation of universal vaccination with high uptake [83,102,103]
●Relatively increased natural, wild-type rotavirus circulation, reducing rotavirus vaccine effectiveness with increasing interval from initiation of universal vaccination [85,104-106]
●Naturally acquired rotavirus disease in infants too young to be vaccinated [82]
●Attenuation of vaccine response by transplacental maternal antibody [107] or in infants who are exclusively breast-fed [108]
●Coinfection with another diarrheal pathogen (eg, adenovirus 40/41, Shigella, norovirus) [109]
●Malnutrition or poor diet (which may affect the intestinal biome) [82,91,110-112]
●Immunogenic competition with simultaneous administration of oral polio vaccine, discussed below (see 'Administration with other vaccines' below)
●Infant histo-blood group antigens and infant or maternal secretor status [113-116]
ADMINISTRATION — The licensed rotavirus vaccines are administered orally [1]. The dose varies with the vaccine and vaccine presentation (table 1) [1,45,46]:
●Pentavalent human-bovine rotavirus reassortant vaccine (RV5) – 2 mL
●Attenuated human rotavirus vaccine (RV1)
•Ready-to-use presentations (squeezable tube or oral dose applicator without vial) – 1.5 mL
•Presentation requiring reconstitution (oral dose applicator with vial) – 1 mL
To avoid loss of a portion of the dose and of splashes into the eyes of infants, caregivers, or health care providers, the vaccine should be administered gently inside the cheek [117].
Dietary restriction, including breastfeeding, is not needed before or after rotavirus vaccine is administered. Doses that are regurgitated, spit out, or vomited should not be repeated (they were not repeated in prelicensure studies of efficacy) [1,5,80]. Multiple randomized trials have demonstrated that breastfeeding does not affect rotavirus vaccine efficacy; normal breastfeeding was not altered in the prelicensure trials [39,40,54,55]. In randomized trials that specifically evaluated this issue, immune response was not affected by abstaining from breastfeeding for ≥1 hour before and after each dose of rotavirus vaccine [118-120].
In the event that rotavirus vaccine is injected rather than administered orally, the dose is not considered valid and should be repeated within the appropriate age and dosing schedule [117]. In a review of reports to the Vaccine Adverse Reporting System, adverse reactions to intramuscular injection were uncommon and mild (eg, local reactions, brief irritability).
ADMINISTRATION WITH OTHER VACCINES — Rotavirus vaccines can be administered at the same visit as the other routine infant immunizations [1,5,121,122].
Simultaneous administration of oral polio vaccine (OPV) may be associated with decreased immune response to the first dose of rotavirus vaccine, but this interference does not persist after subsequent doses [123-128]. OPV is not used in the United States. In countries where OPV continues to be used, the European Society for Pediatric Infectious Disease and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition suggest that rotavirus vaccines and OPV not be administered at the same visit [15].
EFFICACY/EFFECTIVENESS
Rotavirus gastroenteritis — The protection against rotavirus gastroenteritis provided by the licensed vaccines is similar to that observed following natural infection [79].
●Overall effectiveness – The effectiveness of rotavirus immunization is difficult to determine because many children with rotavirus gastroenteritis do not seek medical attention; however, the number of stool samples sent for rotavirus testing and the number of positive samples can serve as a marker of vaccine effectiveness. Such laboratory surveillance indicates that during each rotavirus season since reintroduction of rotavirus vaccine in the United States in 2006, rotavirus activity was delayed in onset and diminished in magnitude compared with the 2000-2006 rotavirus seasons (figure 3) [129-131]. A pattern of alternating reduced and markedly reduced seasonality occurred from 2007-2008 through the 2017-2018 rotavirus seasons [131].
In an impact analysis of surveillance data from 198 sites in 69 predominantly low- and middle-income countries participating in the Global Rotavirus Surveillance Network, introduction of rotavirus vaccine was associated with a 40 percent relative reduction (95% CI 35-44 percent) in rotavirus-associated hospitalizations among children <5 year of age [90]. A similar decline in rotavirus hospitalizations among children <5 years of age following implementation of rotavirus vaccine was noted in the World Health African Region [132].
●Efficacy and effectiveness of RV5 – In randomized trials and meta-analyses, pentavalent human-bovine rotavirus reassortant vaccine (RV5) was efficacious in preventing rotavirus gastroenteritis, rotavirus gastroenteritis hospitalization, and rotavirus gastroenteritis-associated health care utilization in infants [39,41,133,134]. RV5 protection appears to be sustained through the first four years of life [135-137].
A systematic review identified 15 randomized trials (88,934 participants) comparing RV5 with placebo [41]. Meta-analyses assessed vaccine efficacy separately for countries with low, medium, and high levels of child mortality:
•In low-child-mortality countries, RV5 prevented 97 percent of cases of severe rotavirus gastroenteritis in the first year (risk ratio [RR] 0.03, 95% CI 0.01-0.11; five trials, 7688 participants) and 96 percent of cases in the second year (RR 0.04, 95% CI 0.01-0.11; two trials, 5442 participants).
•In medium-child-mortality countries, RV5 prevented 79 percent of cases of severe rotavirus gastroenteritis at two years (RR 0.21, 95% CI 0.11-0.41; 1 trial, 1937 participants).
•In high-child-mortality countries, RV5 prevented 57 percent of cases of severe rotavirus gastroenteritis in the first year (RR 0.43, 95% CI 0.29-0.64; two trials, 6775 participants) and 44 percent of cases in the second year (RR 0.56, 95% CI 0.41-0.77; two trials, 6744 participants). (See 'Resource-limited countries with high child mortality' above.)
The largest trial (the Rotavirus Efficacy and Safety Trial), which included 68,038 infants from both low- and high-child mortality countries, also noted protection against rotavirus gastroenteritis of any severity, reduced rotavirus gastroenteritis-associated hospitalization and emergency department visits, and reduced hospitalization for gastroenteritis from any cause [39].
In a systematic review of rotavirus vaccine effectiveness from 2006 to 2016, the median effectiveness of RV5 in preventing rotavirus hospitalizations, emergency department visits, and outpatient visits was 90 percent (range 63 to 100 percent) in 20 studies from countries with low child mortality and 45 percent (range 43 to 92 percent) in seven studies from countries with high child mortality [98].
●Efficacy and effectiveness of RV1 – In randomized trials and meta-analyses, attenuated human rotavirus vaccine (RV1) is efficacious in preventing rotavirus gastroenteritis, rotavirus gastroenteritis hospitalizations, and rotavirus-gastroenteritis-associated health care utilization in infants [40,41,99,138,139].
A systematic review identified 36 randomized trials (119,114 participants) comparing RV1 with placebo [41]. Meta-analyses assessed vaccine efficacy separately for countries with low, medium, and high levels of child mortality:
•In low-child-mortality countries, RV1 prevented 93 percent of cases of severe rotavirus gastroenteritis after one year (RR 0.07, 95% CI 0.03-0.18; four trials, 14,976 participants) and 90 percent of cases in the second year (RR 0.10, 95% CI 0.07-0.14; six trials, 18,145 participants). RV1 also prevented severe diarrhea from any cause.
•In medium-child-mortality countries, RV1 prevented 79 percent of cases of severe rotavirus gastroenteritis in the first year (RR 0.21, 95% CI 0.16-0.29; four trials, 31,671 participants) and 78 percent of cases in the second year (RR 0.23, 95% CI 0.17-0.29; three trials, 23,834 participants).
•In high-child-mortality countries, RV1 prevented 58 percent of cases of severe rotavirus gastroenteritis in the first year (RR 0.42, 95% CI 0.28-0.61; four trials, 9951 participants) and 35 percent of cases in the second year (RR 0.65, 95% CI 0.51-0.83; two trials, 7113 participants). (See 'Resource-limited countries with high child mortality' above.)
The largest trial comparing RV1 with placebo, which included 63,225 infants from both low- and high-child-mortality countries, also noted protection against rotavirus gastroenteritis of any severity and reduced rotavirus gastroenteritis-associated hospitalization and emergency department visits [40].
In a systematic review of rotavirus vaccine effectiveness from 2006 to 2016, the median effectiveness of RV1 in preventing rotavirus hospitalizations, emergency department visits, and outpatient visits was 84 percent (range 19 to 97 percent) in 13 studies from countries with low child mortality, 75 percent (range -2 to 94 percent) in eight studies from countries with medium child mortality, and 57 percent (range 18 to 69 percent) in nine studies from countries with high child mortality [98]. Protection appears to be sustained through the first four years of life [98,136,137]. A before-after cohort study from the Netherlands suggests that the effectiveness of RV1 may be reduced in infants with high-risk medical conditions (preterm birth, low birth weight, severe congenital disorders) [38].
In pooled analysis of phase 2 and 3 clinical trials, genotype-specific efficacy of RV1 was 92 percent against genotypes containing either the G1 or the P[8] antigen and 83 percent against genotypes containing neither the G1 nor the P[8] antigen [140].
●Efficacy of Rotavac – A systematic review identified four randomized trials (8432 participants) comparing Rotavac with placebo in high-child-mortality countries [41]. Rotavac prevented 57 percent of cases of severe rotavirus gastroenteritis in the first year (RR 0.43, 95% CI 0.30-0.60; one trial, 6799 participants) and 54 percent by up to two years (RR 0.46, 95% CI 0.35-0.60; one trial, 6541 participants).
●Efficacy of Rotasiil – In a meta-analysis of two trials (11,008 participants) comparing Rotasiil with placebo in high-child-mortality countries, Rotasiil prevented 48 percent of cases of severe rotavirus gastroenteritis in the first year (RR 0.52, 95% CI 0.33-0.81) and 44 percent of cases in the second year (RR 0.56, 95% CI 0.42-0.74) [41].
●Incomplete immunization – A systematic review of postlicensure studies (2006 to 2016) found that incomplete immunization with RV5 or RV1 was effective in preventing rotavirus health care utilization but less effective than complete immunization [98].
Community ("herd") immunity — Rotavirus immunization in infants is associated with reduced rotavirus morbidity among unvaccinated neonates and young infants too young for vaccination, older children, and adults (ie, indirect protection or community ["herd"] immunity) [141-148]. Seventy percent vaccine uptake by 2010 significantly altered natural rotavirus disease peaks in most of the United States [142,149]. Even partial (approximately 50 percent) uptake of RV5 under a recommendation for universal immunization of infants with rotavirus vaccine was associated with reduced rotavirus disease in unvaccinated older children and adults [143-145,150,151]. As an example, compared with 2006, rates of hospitalization for rotavirus infection in 2008 were reduced among children younger than three years, whether or not they were vaccinated [151]. An 87 percent reduction occurred in the 6- to 11-month age group (with vaccine coverage 77 percent), a 96 percent reduction occurred in the 12- to 23-month age group (vaccine coverage 46 percent), and a 92 percent reduction occurred in the 24- to 35-month age group (vaccine coverage 1 percent). Similar results were observed at several and widely dispersed sites in North America [142,145,146,150,151]. Protection in older nonvaccinated children indicating community immunity has also been reported in England [152].
Other potential benefits — Rotavirus vaccine appears to reduce the risk of seizures [153-157]. In a cohort of >1.7 million commercially insured children in the United States, complete rotavirus vaccination was associated with a decreased risk of hospitalization for seizure before age five years compared with no vaccination (adjusted hazard ratio 0.76, 95% CI 0.67-0.87) [157]. The differential effects of febrile versus afebrile seizures could not be determined because of rarity of seizure hospitalization (estimated five-year risk of 0.35 percent).
In some observational studies, universal infant immunization against rotavirus has been associated with decreased incidence of type 1 diabetes mellitus [158-160], but this finding is inconsistent [161-164].
ADVERSE EVENTS AND SAFETY
Overview — Rotavirus immunization is safe. In prelicensure studies, the rates of death (<0.1 percent) and serious adverse events (approximately 2.5 percent) were similar among vaccine and placebo recipients [39,40]. Vaccine and placebo recipients also reported similar rates of solicited events, including of fever (approximately 42 percent), vomiting (approximately 13 percent), and diarrhea (approximately 19 percent), all of which were mild [39].
Intussusception
●Risk with RV5, RV1, and Rotavac – Intussusception is a rare potential adverse effect of oral rotavirus vaccination, estimated to occur in approximately 1 in 20,000 to 1 in 100,000 vaccine recipients in resource-abundant countries [165-171].
Limited data are available on the rate of intussusception following rotavirus vaccination in resource-limited countries. In a study conducted in five African countries of 318 children (<12 months of age) with intussusception and rotavirus vaccination, the incidence of intussusception during the 21 days following vaccination with RV5 was compared with the incidence during all other time periods [172]. The incidence of intussusception was not increased following dose 1 (relative risk [RR] 1.16, 95% CI 0.35–3.11), dose 2 (RR 0.56, 95% CI 0.25–1.05), or dose 3 (RR 0.63, 95% CI 0.37–1.02).
A history of intussusception is a contraindication to rotavirus vaccination [43], yet for infants without a history of intussusception, the risk of intussusception after rotavirus vaccination is much lower than the risk of severe rotavirus gastroenteritis in children who do not receive rotavirus vaccine [173-178].
Caregivers should contact their child's health care provider if the child develops signs of intussusception (ie, stomach pain, vomiting, diarrhea, blood in the stool, or change in bowel habits) any time after vaccination, but especially within the first 14 days after a dose was given [179]. (See "Intussusception in children", section on 'Clinical manifestations'.)
Prelicensure studies of pentavalent human-bovine rotavirus reassortant vaccine (RV5) and attenuated human rotavirus vaccine (RV1) found no increased risk of intussusception among vaccine recipients compared with placebo recipients [39,40]. Although postlicensure studies suggested a rare association between RV5 and RV1 vaccination and intussusception within 21 days of the first dose in high- and middle income countries [165-171,180,181], in two meta-analyses of pre- and postlicensure randomized trials from low-, middle-, and high-income countries, no differences in the rates of intussusception were detected between rotavirus vaccine (RV5, RV1, or Rotavac) and placebo groups [41,182]. In active surveillance, the risk of intussusception following RV1 administration was not increased in lower-income sub-Saharan African countries or following Rotavac administration in India [183,184]. Despite the small potential risk of intussusception, the absolute number of estimated rotavirus hospitalizations prevented by rotavirus vaccines far exceeds that of cases of intussusception associated with rotavirus vaccine (eg, 65,000 hospitalizations prevented and 40 to 120 cases of intussusception per year in the United States) [173]. The Centers for Disease Control and Prevention and World Health Organization Global Advisory Committee on Vaccine Safety continue to recommend universal rotavirus vaccine for infants [185,186].
●Risk with RRV-TV – In 1999, just over a year after human-rhesus rotavirus reassortant vaccine (RRV-TV, RotaShield) was licensed, it was withdrawn from the market because of a strong epidemiologic link to intussusception [34-37]. The increased risk was estimated to be approximately 22-fold over the background risk within five to seven days of vaccination and overall approximately one excess case for every 10,000 to 12,000 infants vaccinated [36,187].
The mechanism of this association is unclear. One hypothesis is that vaccination triggered intussusception in infants who were likely to develop intussusception with any enteric infection, based upon the observation that rates of intussusception were actually lower among vaccine recipients than nonvaccinees in the period 4 to 12 weeks after vaccination [37]. Thus, RRV-TV may have caused intussusception in infants who otherwise would not have experienced intussusception, but it also may have protected against natural rotavirus infection-induced intussusception in others.
Rotavirus strain differences appear to make a difference in intussusception risk, as demonstrated by the reduced intussusception risk after RV5 or RV1 compared with RRV, and supported by results in a mouse model [188].
Kawasaki disease — Although cases of Kawasaki disease were reported during clinical trials of rotavirus vaccines and in postmarketing surveillance [45,46,189,190], no evidence of an association was identified in surveillance of >2 million doses of rotavirus vaccine administered to infants born from 2006 to 2017 [191].
Caregivers should contact their child's health care provider if the child develops signs of Kawasaki disease (eg, fever, conjunctivitis, erythema of the lips and oral mucosa, rash, swelling of the hands and feet, cervical lymphadenopathy), whether or not the child recently received rotavirus vaccine. (See "Kawasaki disease: Clinical features and diagnosis".)
Shedding and transmission of vaccine virus — Rotavirus shedding in the stool peaks within approximately seven days of administration and is most common after the first dose [45,46,192-195]. Viral shedding may be prolonged in infants with immunodeficiency [48,52,196].
Transmission of vaccine virus resulting in symptomatic gastroenteritis is known from three case reports [197-199]; separately, zero of 100 participants in a placebo-controlled twin study experienced symptomatic transmission of RV1 [200].
To minimize the risk of vaccine-derived rotavirus infections transmitted by the fecal-oral route, individuals who care for infants should wash their hands after changing a diaper. Particular care should be taken with this precaution for at least one week after the first dose. Highly immunocompromised individuals should avoid handling diapers of infants who have received rotavirus vaccine for at least four weeks after vaccination [44]. Highly immunocompromised individuals include (but are not limited to) those with combined primary immunodeficiency; receiving cancer chemotherapy; within two months of solid organ transplant; with HIV infection and CD4 count <200 cells/microL (adults and adolescents) or CD4 percentage <15 percent (infants and children); receiving daily glucocorticoid therapy for ≥14 days at a dose equivalent to prednisone ≥20 mg/day or >2 mg/kg per day, if they weigh <10 kg.
In the phase 3 prelicensure trial of RV5, 9 percent of subjects who were evaluated had fecal shedding of vaccine virus, detected by polymerase chain reaction (PCR), four to six days after the first dose [192,194]. None and 0.3 percent of recipients shed vaccine virus four to six days after the second and third dose, respectively. In studies of RV1, 50 to 80 percent of infants shed vaccine virus (PCR detection) at approximately one week and 24 percent at approximately one month after the first dose [201]. After the second dose, between 4 and 18 percent of recipients shed virus at one week and 1.2 percent at approximately one month. Because vaccine virus detection relies on PCR (a highly sensitive gene amplification method), the exact correlation between shedding of vaccine virus and viability/transmission is uncertain.
Transmission of vaccine virus has not been well studied; it appears to occur more frequently among recipients of RV1 than RV5 [193]; however, it rarely results in symptoms. In a randomized trial, in which one twin in each of 100 twin pairs received two doses of RV1 and the other twin received placebo, transmission of vaccine virus occurred in 15 of 80 evaluable cases (18.8 percent) but was not associated with symptomatic gastroenteritis [200]. In an observational study in Malawi, RV1 fecal shedding was detected in 68 percent of 60 vaccinated infants but only 1.4 percent of 147 household contacts, indicating that horizontal transmission of vaccine virus is also uncommon [202]. Asymptomatic transmission may contribute to community ("herd") immunity [193]. (See 'Community ("herd") immunity' above.)
Serotype selection — RV5 was first introduced into a national vaccine program in 2006. After introduction of RV5 (and subsequently of RV1), surveillance of rotavirus genotypes and rotavirus disease prevalence in countries with and without rotavirus vaccine programs has not demonstrated sustained selection of one or more serotypes due to vaccine selective pressure [203], although transient increases of a given serotype and decreased incidence of simultaneous infections with multiple rotavirus types (ie, "mixed infections") have been documented [88,204-207].
After nearly 15 years of rotavirus vaccine use, vaccine-related serotype selection/replacement seems to be at most a limited phenomenon, although continued surveillance is necessary to understand the epidemiologic significance of potential genetic/antigenic modifications in novel circulating strains for which licensed rotavirus vaccines may not be effective [87,88,206,208-213]. (See 'Microbiology' above.)
Reporting adverse events — In the United States, any clinically significant or unexpected adverse events that occur after administration of rotavirus vaccine (including intussusception and Kawasaki disease) should be reported to the Vaccine Adverse Event Reporting System (telephone number 1-800-822-7967) [1]. (See "Standard immunizations for children and adolescents: Overview", section on 'Reporting adverse events'.)
Porcine circovirus contamination — In 2010, an academic group using a novel technique found components of porcine circovirus (PCV1) in RV1 and the US Food and Drug Administration (FDA) temporarily suspended use of RV1 [214]. Additional review by the FDA and vaccine manufacturers determined that PCV1 components were present from the early stages of RV1 development, including during the prelicensure clinical trials, and that RV5 contained components of PCV1 and PCV2 [214,215].
Given that PCV1 and PCV2 are not known to cause illness in humans, and the absence of any evidence that millions of rotavirus vaccine recipients suffered adverse effects related to PCV, the FDA recommended resumption of use of RV1 and continued use of RV5 [215,216]. In a subsequent observational study, PCV1 did not appear to replicate in RV1 recipients [217].
The known benefits of the oral vaccination outweigh the theoretic risk related to PCV1 or PCV2 [218].
RESOURCES — Resources related to immunization in infants include:
●The American Academy of Pediatrics
●The Centers for Disease Control and Prevention
●The Immunize.org
●The Vaccine Information Statement for Rotavirus vaccine
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immunizations in children and adolescents".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)
●Basics topic (see "Patient education: Rotavirus infection (The Basics)")
●Beyond the Basics topic (see "Patient education: Vaccines for infants and children age 0 to 6 years (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Introduction – Rotavirus is the most common cause of severe gastroenteritis in infants and children around the world. (See 'Introduction' above.)
●Rotavirus vaccines – Two oral vaccines are globally available for the prevention of rotavirus disease: pentavalent human-bovine reassortant rotavirus vaccine (RV5, PRV, RotaTeq) and attenuated human rotavirus vaccine (RV1, HRV, Rotarix) (table 1 and figure 2). The vaccines have similar efficacy and safety, and neither vaccine is preferred over the other. Two other vaccines are used in more restricted settings, and novel vaccine candidates, including parenteral vaccines, are under investigation. (See 'Rotavirus vaccines' above.)
●Indications – We recommend universal immunization of infants against rotavirus (Grade 1A). Rotavirus vaccines are highly effective in preventing rotavirus gastroenteritis and rotavirus gastroenteritis-associated hospitalization and health care utilization. (See 'Indications' above and 'Efficacy/effectiveness' above.)
●Contraindications and precautions – Contraindications to rotavirus vaccine include allergy to any of the vaccine ingredients, severe allergic reaction (anaphylaxis) to a previous dose, severe combined immunodeficiency (SCID), certain other primary and secondary immunodeficiencies, and history of intussusception. Latex-free presentations of RV1 and RV5 are available for infants with a history of severe allergic reaction to latex (table 1). (See 'Contraindications' above.)
Conditions that are precautions for administration of rotavirus vaccine include immunodeficiency other than SCID, acute moderate or severe illness, certain pre-existing or acquired gastrointestinal conditions (eg, congenital malabsorption syndromes, Hirschsprung disease, short-bowel syndrome, previous bowel surgery), and spina bifida or bladder exstrophy. (See 'Precautions' above.)
●Schedule – The recommended dose and schedule for RV5 and RV1 differ (table 1). Whenever possible, the vaccine series should be completed with the same product; however, vaccination should not be deferred if the product used for previous doses is not known. (See 'Schedule' above.)
●Adverse events and safety – Intussusception is a rare potential adverse effect of oral rotavirus vaccination in some settings; however, the risk of intussusception after rotavirus vaccination is much lower than the risk of severe rotavirus gastroenteritis in children who do not receive rotavirus vaccine. (See 'Adverse events and safety' above.)
Continued surveillance of rotavirus genotypes and rotavirus disease prevalence in countries with and without rotavirus vaccine programs is necessary to understand the epidemiologic significance of potential genetic/antigenic modifications in novel circulating strains for which licensed rotavirus vaccines may not be effective. (See 'Serotype selection' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge David O Matson, MD, PhD, who contributed to an earlier version of this topic review.
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