Rotavirus Vaccines For Infants

Rotavirus vaccines for infants
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2019. | This topic last updated: Apr 01, 2019.
Authors:
David O Matson, MD, PhD
Miguel G O'Ryan, MD
Section Editors:
Morven S Edwards, MD
Teresa K Duryea, MD
Deputy Editor:
Mary M Torchia, MD
Contributor Disclosures
INTRODUCTION — Rotavirus is the most common cause of severe, acute gastroenteritis in infants and
children worldwide [1-3]. In the prevaccine era, rotavirus 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 [2].
More than 60 percent of countries and more than 85 percent of countries in the Global Alliance for
Vaccines and Immunization have introduced or are planning to introduce rotavirus vaccines into national
or subnational vaccine programs [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-rich countries: Management and prevention".)
MICROBIOLOGY — Rotavirus is a double-stranded RNA virus in the Reoviridae family [3]. 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 account for approximately 90 percent of human rotaviruses circulating
worldwide: G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8], but serotype prevalence varies from time to
time and from place to place for reasons that are not understood. 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 [5-11]. 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 [12].
Vaccines licensed in the United States — Two live, attenuated oral rotavirus vaccines are licensed for use
in the United States and other countries (table 1). The vaccines have similar efficacy and safety, and no
preference for one over the other vaccine exists, with a few exceptions (eg, latex allergy) [1,3,13,14]. (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 [15].
●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) [8]. Observational studies of natural rotavirus infection suggest that infection with
one serotype provides at least partial cross-protection against most other serotypes [16].
Other vaccines
●Human-bovine reassortant vaccine (116E, ROTAVAC) – 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 have been completed (demonstrating
efficacy of 54 percent against severe rotavirus gastroenteritis) [10]. The 116E vaccine is licensed for use
in India and has World Health Organization (WHO) prequalification for use in developing countries [17-
19].
●Lamb rotavirus vaccine – A monovalent, G10P[12] oral rotavirus vaccine is licensed in China, where
its effectiveness was demonstrated in two population-based studies [20,21]. However, a mouse study
suggests that monovalent rotavirus vaccines are not sufficiently immunogenic against heterotypic strains
for protection against rotavirus disease in China [18]. Previous studies indicate that strain variation and
induction of antibody response is well correlated in mice and humans [22].
●Oral bovine rotavirus pentavalent vaccine (BRV-PV, ROTASIIL) – 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 developing countries [19].
●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]) [26]. 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 [26,27].
●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 [28-
32]. (See 'Risk with RRV-TV' below.)
INDICATIONS — We recommend universal immunization of infants against rotavirus, as recommended

by the Centers for Disease Control and Prevention, the World Health Organization, the American
Academy of Pediatrics, the American Academy of Family Physicians, the European Society for Pediatric
Infectious Diseases, and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition
[1,3,13,14].
In randomized trials and meta-analyses, rotavirus vaccines are highly efficacious in preventing rotavirus
gastroenteritis and rotavirus gastroenteritis-associated hospitalization and health care utilization [33-35].
(See 'Efficacy/effectiveness' below.)
CONTRAINDICATIONS — Rotavirus vaccines are contraindicated in those infants [1,13,14,36-38]:
●Who are allergic to any of the ingredients of the vaccine; attenuated human rotavirus vaccine is
contraindicated in infants with severe (anaphylactic) allergy to latex because the applicator contains latex;
pentavalent human-bovine rotavirus reassortant vaccine can be administered to such infants (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 [36,39-43] (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 [37,44]
●Born in the United States (or other countries with evidence of community ["herd"] immunity and good
outcomes after severe rotavirus disease) to women who received a biologic response modifier (eg,
infliximab, adalimumab) during pregnancy [14]; these infants can have detectable drug concentrations for
up to nine months [45-47] (see "Fertility, pregnancy, and nursing in inflammatory bowel disease", section
on 'Anti-tumor necrosis factor agents')
Rotavirus vaccine should be avoided for the first 12 months after the final in utero exposure. Catch-up
vaccination is not recommended given that the maximum age for the first dose is 14 weeks, 6 days [14].
In countries where there is evidence of community immunity and good outcomes after severe rotavirus
disease, the risk of developing vaccine-type rotavirus disease in an infant with prenatal exposure to a
biologic response modifier is greater than the risk of developing severe or fatal wild type rotavirus disease
if unvaccinated.
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
[38]:
●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")
●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 [1,14,38]:
●Immunocompromised family member or household member (see 'Immunocompromised household

contact' below)
●Breastfeeding (efficacy trials included breastfeeding infants, with no alteration in normal breastfeeding
patterns) [48,49]
●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; however, there are few data regarding the efficacy
or safety of rotavirus vaccine to infants who are potentially immunocompromised.
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 advises precaution for administration of rotavirus vaccine for manifestations of altered
immunocompetence other than SCID [1,14,36]. The 2013 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 [38]:
•HIV exposure or infection – Rotavirus gastroenteritis may be particularly severe in HIV-infected

children. In a prospective study in South Africa, HIV-infected children were more likely to have a
prolonged hospitalization and had a fourfold increased mortality rate compared with HIV-uninfected
children admitted to the same hospital [50].
Rotavirus vaccine trials that included HIV-infected infants have found no evidence of enhanced disease
in HIV-infected children [38]. 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 HIV-positive infants in a three-dose schedule [51,52].
Groups other than the IDSA (eg, the Department of Health and Human Services, Centers for Disease
Control and Prevention, American Academy of Pediatrics) suggest that the potential risks and benefits of
rotavirus vaccination be considered before vaccination [53]; 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 HIV-
exposed and infected infants.
•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 [38].
●Other precautions – The ACIP and American Academy of Pediatrics 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 [1,14]:
•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 [54]. In another small study, RV5 appeared to be safe and immunogenic in five infants
with a history of bowel resection [55].
•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 be used for such
infants because the applicator is latex-free. If RV5 is not available, the ACIP recommends that RV1 be
used 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 [1,14]:
●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 [56]. 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 [57]. 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 [58].
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 [1,14].
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 [13].
●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 [1,14].
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 [13].
There is no maximum interval between doses.
Special circumstances
Premature infants — In the United States, rotavirus vaccines can be administered to premature infants
who are clinically stable, at least six weeks old, and are going to be or have been discharged from the
nursery [1,14,59-61]. The European Society for Paediatric Infectious Diseases and the Australian
government recommend rotavirus vaccination of premature 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 [13,62]. (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
[63,64]. Subsequent prospective studies support the low risk of transmission [65,66]. 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 [65]. 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.
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 [1,14,67].
Receipt of blood products — Rotavirus vaccines may be administered at any time in relation to the receipt
of blood products, including antibody-containing products [1,68].
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 [14]. 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 [1,14,38]. (See 'Shedding and transmission of vaccine
virus' below.)
Resource-poor 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
[69-77]. Although poverty is a surrogate marker for poorer population vaccine effectiveness [78-81],
rotavirus vaccine remains effective in reducing rotavirus-related hospitalization and emergency
department visits in resource-poor countries with high child mortality [82-84]. (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
[75,77]
●Failure to adopt a universal recommendation for rotavirus vaccination (which may prevent or reduce
herd immunity) [85,86]
●Variation in herd effect with increasing interval from initiation of universal vaccination with high uptake
[71,87,88]
●Relatively increased natural, wild-type rotavirus circulation, reducing rotavirus vaccine effectiveness
with increasing interval from initiation of universal vaccination [73,89-91]
●Naturally acquired rotavirus disease in infants too young to be vaccinated [70]

●Attenuation of vaccine response by transplacental maternal antibody [92] or in infants who are
exclusively breast-fed [93]
●Malnutrition or poor diet (which may affect the intestinal biome) [70,94,95]
●Immunogenic competition with simultaneous administration of oral polio vaccine [96] (see
'Administration with other vaccines' below)
●Histo-blood group antigens and secretor status [97,98]
ADMINISTRATION — The licensed rotavirus vaccines are administered orally [1]. Each dose of
pentavalent human-bovine rotavirus reassortant vaccine (RV5) is 2 mL (table 1). Each dose of attenuated
human rotavirus vaccine (RV1) is 1 mL. To avoid loss of a portion of the dose and of splashes into the
eyes of infants, parents, or health care providers, the vaccine should be administered gently inside the
cheek [99].
Dietary restriction, including breastfeeding, is not needed before or after rotavirus vaccine is administered.
Doses that are regurgitated, spit out, or vomited need not be repeated (they were not repeated in
prelicensure studies of efficacy) [1,14,68]. Multiple randomized trials have demonstrated that
breastfeeding does not affect rotavirus vaccine efficacy; normal breastfeeding was not altered in the
prelicensure trials [33,35,48,49]. 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 [100-102].
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 [99].
ADMINISTRATION WITH OTHER VACCINES — Rotavirus vaccines can be administered at the same
visit as the other routine infant immunizations [1,14,103,104].
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
[3,96,105-108].
The United States Advisory Committee on Immunization Practices suggests that rotavirus vaccine can be
administered simultaneously or at any interval before or after other injectable or intranasal live vaccines
[68]. The American Academy of Pediatrics suggests that rotavirus vaccine can be administered
concurrently with other childhood vaccines [14]. 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 [13].
EFFICACY/EFFECTIVENESS
Rotavirus gastroenteritis — The protection against rotavirus gastroenteritis provided by the two licensed
vaccines is similar to that observed following natural infection [67].
●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) [109-111]. A pattern of alternating
reduced and markedly reduced seasonality has occurred from 2007-2008 through the 2013-2014 rotavirus
seasons.
In a systematic review of 57 observational studies from 27 countries, rotavirus immunization reduced

rotavirus-related hospitalization and emergency department visits among children <5 years by 67 percent
[82].
●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
[33,34,112,113]. In the largest trial comparing RV5 with placebo (the Rotavirus Efficacy and Safety
Trial), 68,038 healthy infants from 11 countries were randomly assigned to receive three doses of vaccine
or placebo at 4- to 10-week intervals [33]. The following results were reported:
•In the first rotavirus season after immunization, efficacy against severe G1-G4 rotavirus gastroenteritis
(defined by an established clinical score based upon intensity and duration of symptoms [9]) was 98
percent (95% CI 88-100 percent) and against G1-G4 rotavirus gastroenteritis of any severity was 74
percent (95% CI 67-80 percent).
•RV5 reduced hospitalization for G1-G4 rotavirus gastroenteritis by 96 percent (95% CI 90-98 percent)
and for any gastroenteritis by 59 percent (95% CI 52-65 percent).
•RV5 reduced emergency department visits related to G1-G4 rotavirus gastroenteritis by 94 percent (95%
CI 89-96 percent) and clinic visits by 86 percent (95% CI 74-93 percent).
•In the second rotavirus season after immunization, the efficacy against severe rotavirus gastroenteritis
was 88 percent (95% CI 49-99 percent) and against rotavirus gastroenteritis of any severity was 63 percent
(95% CI 44-75 percent).
•In an extension study of 20,736 original participants followed for up to 3.1 years after the last dose of
RV5, the efficacy against hospitalization and emergency department visits related to rotavirus
gastroenteritis of any serotype was 94 percent (95% CI 91-96 percent) [114].
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 [83]. RV5 protection
appears to be sustained through the first four years of life [58,115-117]. (See 'Resource-poor countries
with high child mortality' above.)
●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
[34,35,84,113,118-123]. In the largest trial comparing RV1 with placebo, 63,225 healthy infants from 11
countries in Latin America and Finland were randomly assigned to receive RV1 or placebo at two and
four months of age [35]. Episodes of severe gastroenteritis were identified by active surveillance of 20,169
infants from two weeks after the second dose until one year of age. Severe gastroenteritis was defined by
the passage of ≥3 loose or watery stools within a 24-hour period, with or without vomiting, that required
overnight hospitalization or rehydration therapy in a medical facility. The following results were noted:
•The efficacy against severe rotavirus gastroenteritis was 85 percent (95% CI 72-92 percent) and against
severe gastroenteritis from any cause was 40 percent (95% CI 28-50 percent).
•The efficacy against gastroenteritis caused by G1P[8] strains was 92 percent (95% CI 74-98 percent) and
against strains sharing only the P[8] antigen (G3P[8], G4P[8], G9P[8]) was 87 percent.
•The efficacy against hospitalization for rotavirus gastroenteritis was 85 percent (95% CI 70-94 percent)
and against hospitalization for gastroenteritis from any cause was 42 percent (95% CI 29-53 percent).
The efficacy of RV1 during the first two years of life was assessed in a subgroup of patients and found to
be similar to that during the first year [123].
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 [83]. Protection appears to be sustained
through the first four years of life [58,83,116,117,124,125]. (See 'Resource-poor countries with high child
mortality' above.)
RV1 also appears to provide protection against G2P[4], which shares neither the G1 nor the P[8] antigen
[124].
●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 [83].
Reduced risk of seizures — Rotavirus vaccine appears to reduce the risk of seizures [126-130]. 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) [130]. 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).
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) [131-141]. Seventy percent vaccine
uptake by 2010 significantly altered natural rotavirus disease peaks in most of the United States [109,132].
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 [133-137]. 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 [134]. 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 [132-134,137,138]. Protection in older nonvaccinated children indicating community
immunity has also been reported in England [142].
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
[33,35]. 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 [33].
Intussusception
Risk with RV5 and RV1 — 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 high- and middle-
income countries [143-149]. A history of intussusception is a contraindication to rotavirus vaccination
[37,150], 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 [151-155].
Parents 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 [156]. (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 [33,35]; however, postlicensure studies suggest a rare association
between RV5 and RV1 vaccination and intussusception within 21 days of the first dose in high- and middle
income countries [143-149,157,158]. In active surveillance, the risk of intussusception following RV1
administration was not increased in lower-income sub-Saharan African countries [159].
Despite the small 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) [151]. 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 [160,161].
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 [29-32]. 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 [31,162].
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 [32]. 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 [163].
Kawasaki disease — Cases of Kawasaki disease were reported during clinical trials of rotavirus vaccines
and in postmarketing surveillance [150,164,165]; however, the number of cases of Kawasaki disease
reported after administration of rotavirus vaccine did not exceed the number of cases that would be
expected to occur in infants who did not receive rotavirus vaccine, and there is no known cause-and-effect
relationship between rotavirus vaccine and Kawasaki disease [150,165,166].
Parents 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 [150,167-170]. Viral shedding may
be prolonged in infants with immunodeficiency [40,171].
Transmission of vaccine virus resulting in symptomatic gastroenteritis is known from three case reports
[172-174]; separately, zero of 100 participants in a placebo-controlled twin study experienced
symptomatic transmission of RV1 [175].
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 [38]. 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 four to six days after the first dose [167,169]. 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 approximately one week and 24 percent at approximately one month after the
first dose [176]. After the second dose, between 4 and 18 percent of recipients shed virus at one week and
1.2 percent at approximately one month.
Transmission of vaccine virus has not been well studied; it appears to occur more frequently among
recipients of RV1 than RV5 [168]; 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 [175]. 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 [177]. Asymptomatic transmission may
contribute to community ("herd") immunity [168]. (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 [178], although transient increases of
a given serotype and decreased incidence of simultaneous infections with multiple rotavirus types (ie,
"mixed infections") have been documented [76,179-181]. 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 [75,76,181-187]. (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 [188]. 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 [188,189].
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 [189,190]. In a subsequent
observational study, PCV1 did not appear to replicate in RV1 recipients [191].
The known benefits of the oral vaccination outweigh the theoretic risk related to PCV1 or PCV2 [192].
RESOURCES — Resources related to immunization in infants include:

●The American Academy of Pediatrics
●The Centers for Disease Control and Prevention
●The Immunization Action Coalition
●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
●Rotavirus is the most common cause of severe gastroenteritis in infants and children around the world.
(See 'Introduction' above.)
●Two oral vaccines are 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. (See 'Rotavirus vaccines' above.)
●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 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. RV1 is contraindicated in
infants with a history of severe allergic reaction to latex, but RV5 may be administered to such infants.
(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.)
●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.)
●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.)
Use of UpToDate is subject to the Subscription and License Agreement.
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●Human-bovine reassortant vaccine (116E, ROTAVAC) – The 116E rotavirus vaccine is a

●Oral bovine rotavirus pentavalent vaccine (BRV-PV, ROTASIIL) – BRV-PV is a heat-stable

●Tetravalent human-rhesus reassortant vaccine – An oral tetravalent human-rhesus rotavirus

INDICATIONS — We recommend universal immunization of infants against rotavirus, as recommended

CONTRAINDICATIONS — Rotavirus vaccines are contraindicated in those infants [1,13,14,36-38]:

●Who had a severe (anaphylactic) allergic reaction after a previous dose

●Combined immunodeficiencies – Di George syndrome and other combined immunodeficiencies with a

●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,

The following conditions are not contraindications to rotavirus vaccination [1,14,38]:

●Immunocompromised family member or household member (see 'Immunocompromised household

●Immunodeficiency other than severe combined immunodeficiency – Decisions regarding

•HIV exposure or infection – Rotavirus gastroenteritis may be particularly severe in HIV-infected

•Chronic granulomatous disease. (See "Chronic granulomatous disease: Pathogenesis, clinical

•Congenital or cyclic neutropenia. (See "Congenital neutropenia" and "Cyclic neutropenia".)

•Acute moderate-to-severe gastroenteritis – Immunization of infants with acute, moderate-to-severe

●RV1 is administered in two oral doses at two and four months.

There is no maximum interval between doses.

In retrospective reviews, age-appropriate administration of RV5 to preterm enterally-fed infants in the

Immunocompromised household contact — Rotavirus vaccines can be administered to infants living in

Factors that may explain variation in vaccine effectiveness include:

●Naturally acquired rotavirus disease in infants too young to be vaccinated [70]

●Histo-blood group antigens and secretor status [97,98]

In a systematic review of 57 observational studies from 27 countries, rotavirus immunization reduced

ADVERSE EVENTS AND SAFETY

RESOURCES — Resources related to immunization in infants include:

●The Centers for Disease Control and Prevention

●The Immunization Action Coalition

●The Vaccine Information Statement for Rotavirus vaccine

●Basics topic (see "Patient education: Rotavirus infection (The Basics)")

SUMMARY AND RECOMMENDATIONS

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Topic 6023 Version 63.0

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