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Rotavirus Vaccine for the Prevention of Rotavirus Gastroenteritis Among Children Recommendations of the Advisory Committee on Immunization Practices (ACIP)Summary These recommendations represent the first statement by the Advisory Committee on Immunization Practices (ACIP) on the use of an oral, live rotavirus vaccine licensed by the Food and Drug Administration on August 31, 1998, for use among infants. This report reviews the epidemiology of rotavirus, describes the licensed rotavirus vaccine, and makes recommendations regarding its use for the routine immunization of infants in the United States. These recommendations are based on estimates of the disease burden of rotavirus gastroenteritis among children in the United States and on the results of clinical trials of the vaccine. Rotavirus affects virtually all children during the first 5 years of life in both developed and developing countries, and rotavirus infection is the most common cause of severe gastroenteritis in the United States and worldwide. In the United States, rotavirus is a common cause of hospitalizations, emergency room visits, and outpatient clinic visits, and it is responsible for considerable health-care costs. Because of this large burden of disease, several rotavirus vaccines have been developed. One of these vaccines -- an oral, live, tetravalent, rhesus-based rotavirus vaccine (RRV-TV) -- was found to be safe and efficacious in clinical trials among children in North America, South America, and Europe and on the basis of these studies is now licensed for use among infants in the United States. The vaccine is an oral, live preparation that should be administered to infants between the ages of 6 weeks and 1 year. The recommended schedule is a three-dose series, with doses to be administered at ages 2, 4, and 6 months. The first dose may be administered from the ages of 6 weeks to 6 months; subsequent doses should be administered with a minimum interval of 3 weeks between any two doses. The first dose should not be administered to children aged greater than or equal to 7 months because of an increased rate of febrile reactions after the first dose among older infants. Second and third doses should be administered before the first birthday. Implementation of these recommendations in the United States should prevent most physician visits for rotavirus gastroenteritis and at least two-thirds of hospitalizations and deaths related to rotavirus. CLINICAL AND EPIDEMIOLOGIC FEATURES OF ROTAVIRUS DISEASE Rotavirus is the most common cause of severe gastroenteritis in infants and young children in the United States. Worldwide, rotavirus is a major cause of childhood death. The spectrum of rotavirus illness ranges from mild, watery diarrhea of limited duration to severe, dehydrating diarrhea with vomiting and fever, which results in death (1-5). Virtually all children become infected in the first 3-5 years of life, but severe diarrhea and dehydration occur primarily among children aged 3-35 months. Rotaviruses are shed in high concentrations in the stools of infected children and are transmitted by the fecal-oral route, both through close person-to-person contact and through fomites (6). Rotaviruses also might be transmitted by other modes, such as respiratory droplets (7). In the United States, rotavirus causes seasonal peaks of gastroenteritis from November to May each year, with activity beginning in the Southwest United States and spreading to the Northeast (8-10). Rotavirus appears to be responsible for approximately 5%-10% of all diarrheal episodes among children aged less than 5 years in the United States, and for a much higher proportion of severe diarrheal episodes (2,11). Although rotavirus gastroenteritis results in relatively few deaths in the United States (approximately 20 per year among children aged less than 5 years) (12), it accounts for more than 500,000 physician visits (13,14) and approximately 50,000 hospitalizations each year among children aged less than 5 years (4,9,15). Rotavirus is responsible for 30%-50% of all hospitalizations for diarrheal disease among children aged less than 5 years, and more than 50% of hospitalizations for diarrheal disease during the seasonal peaks (11,16-18). Among children aged less than 5 years in the United States, 72% of rotavirus hospitalizations occur during the first 2 years of life, and 90% occur by age 3 years (15). In the first 5 years of life, four out of five children in the United States will develop rotavirus diarrhea (2,19); one in seven will require a clinic or emergency room visit; one in 78 will require hospitalization; and one in 200,000 will die from rotavirus diarrhea (4,14). The risk for rotavirus diarrhea and its outcomes do not appear to vary by geographic region within the United States. Limited data suggest that children from disadvantaged socioeconomic backgrounds and premature infants have an increased risk for hospitalization from diarrheal disease, including rotavirus diarrhea (20). In addition, some children and adults who are immunocompromised because of congenital immunodeficiency, hematopoetic transplantation, or solid organ transplantation experience severe, prolonged, and sometimes fatal rotavirus diarrhea (21-23). Rotavirus is also an important cause of nosocomial gastroenteritis (1,11,16,24,25). Among adults in the United States, rotavirus infection infrequently causes diarrhea in travelers, persons caring for children with rotavirus diarrhea, and the elderly (26). Each year in the United States, rotavirus diarrhea results in $264 million in direct medical costs and more than $1 billion in total costs to society (14). Direct medical costs are primarily the result of hospitalizations for severe diarrhea and dehydration, and societal costs are attributable primarily to loss of work time among parents and other caregivers. Several reasons exist to adopt immunization of infants as the primary public health intervention to prevent rotavirus disease in the United States. First, similar rates of illness among children in industrialized and less developed countries indicate that clean water supplies and good hygiene have not decreased the incidence of rotavirus diarrhea in developed countries, so further improvements in water or hygiene are unlikely to have a substantial impact (2,27-31). Second, in the United States, a high level of rotavirus morbidity continues to occur despite currently available therapies. For example, hospitalizations for diarrhea in young children declined only 16% from 1979 to 1992 (9), despite the widespread availability of oral rehydration solutions and recommendations by experts, including the American Academy of Pediatrics, for the use of oral rehydration solutions in the treatment of dehydrating gastroenteritis (32-34). Third, studies of natural rotavirus infection indicate that initial infection protects against subsequent severe diarrheal disease, although subsequent asymptomatic infections and mild disease might still occur (30,35). Thus, immunization early in life, which mimics a child's first natural infection, will not prevent all subsequent disease but should prevent most cases of severe rotavirus diarrhea and its sequelae (e.g., dehydration, physician visits, and hospitalizations). Laboratory Testing for Rotavirus Because the clinical features of rotavirus gastroenteritis are nonspecific, confirmation of rotavirus infection in children with gastroenteritis by laboratory testing of fecal specimens will be necessary for reliable rotavirus surveillance and could be useful in clinical settings (1,36). The most available method is antigen detection by enzyme immunoassay directed at a group antigen common to all Group A rotaviruses. Several commercial enzyme immunoassay test kits are available that are inexpensive, easy to use, rapid, and highly sensitive (approximately 90% compared with detection by electron microscopy); these properties make rapid antigen detection kits suitable for use in rotavirus surveillance systems. Other techniques -- including electron microscopy, reverse transcription-polymerase chain reaction, nucleic acid hybridization, polyacrylamide gel electrophoresis, and culture -- are used primarily in research settings. Serologic methods that detect a rise in serum antibodies, primarily enzyme immunoassay for rotavirus serum immunogloblulin G (IgG) and immunogloblulin A (IgA) antibodies, have been used to confirm recent infections. In vaccine trials, detection of rotavirus-specific IgA and neutralizing antibodies to vaccine strains have been used to study the immunogenicity of rotavirus vaccines (37). Morphology, Antigen Composition, and Immune Response Rotaviruses are 70-nm nonenveloped RNA viruses in the family Reoviridae. The viral nucleocapsid is composed of three concentric shells that enclose 11 segments of double-stranded RNA. The outermost layer contains two structural proteins: VP7, the glycoprotein (G protein), and VP4, the protease-cleaved protein (P protein). These two proteins define the serotype of the virus and are considered critical to vaccine development because they are targets for neutralizing antibodies that might be important for protection (38,39). Because the two gene segments that encode these proteins can, in theory, segregate independently, a typing system has been developed to specify each protein; 14 VP7 (G) serotypes and 20 VP4 (P) genotypes have been described. Only viruses containing four distinct combinations of G and P proteins are known to commonly circulate in the United States -- G1P1A, G2P1B, G3P1A, G4P1A (40); these strains are generally designated by their G serotype specificity (serotypes 1-4). In some areas of the United States, recent surveillance has detected strains with additional combinations -- G9P6 and G9P8 (serotype 9) (41). In addition to these human strains, animal strains of rotavirus that are antigenically distinguishable are found in many species of mammals; these strains only rarely appear to cause infection in humans. Although children can be infected with rotavirus several times during their lives, initial infection after age 3 months is most likely to cause severe diarrhea and dehydration (30,42,43). After a single natural infection, 40% of children are protected against any subsequent infection with rotavirus, 75% are protected against diarrhea from a subsequent rotavirus infection, and 88% are protected against severe diarrhea. Second, third, and fourth infections confer progressively greater protection (30). The immune correlates of protection from rotavirus infection and disease are not completely understood. Both serum and mucosal antibodies are probably associated with protection from disease, and in some studies, serum antibodies against VP7 and VP4 have correlated with protection. However, in other studies, including vaccine studies, correlation between serum antibody and protection has been poor (44). The first infection with rotavirus elicits a predominantly homotypic, serum-neutralizing antibody response to the virus, and subsequent infections elicit a broader, heterotypic response (1,45). The influence of cell-mediated immunity is less clearly understood, but likely is related both to recovery from infection and to protection against subsequent disease (44,46). ROTAVIRUS VACCINE Background Research to develop a safe, effective rotavirus vaccine began in the mid-1970s when investigators demonstrated that previous infection with animal rotavirus strains protected laboratory animals from experimental infection with human rotaviruses (47). During the past two decades, two types of rotavirus vaccines have been evaluated, and one vaccine has been licensed for use in the United States. Monovalent vaccines. The first candidate rotavirus vaccines were derived from monovalent rotavirus strains isolated from either bovine or rhesus hosts. Trials, often with a single dose, demonstrated that these live, oral vaccines were safe and could prevent rotavirus diarrhea in young children (48-51). However, the efficacy of these vaccines varied in trials. Because these vaccines had relied on heterotypic protection, researchers postulated that a multivalent vaccine that provided serotype-specific immunity against all common human rotavirus strains might be more effective. Multivalent vaccines. Multivalent vaccine candidates were developed in 1985 by using gene reassortment (52). This process produces vaccine virus strains that have been modified from parent animal strains by single gene reassortment so that each strain contains 10 genes from the animal strain along with a single gene from a human rotavirus strain; this single gene encodes the VP7 protein. In theory, a reassortant strain maintains the attenuation of the parent animal strain in the human host but also has the neutralization specificity of a major G serotype of human rotavirus (53). The only rotavirus vaccine currently licensed by the Food and Drug Administration for use in the United States is rhesus-based rotavirus vaccine-tetravalent. A reassortant vaccine that is based on a bovine rotavirus parent strain (WC-3) is undergoing clinical trials (54). Rhesus-based rotavirus vaccine-tetravalent (RRV-TV). The
licensed tetravalent vaccine RRV-TV (RotaShield RRV-TV is supplied as a lyophilized pink solid. Because the
vaccine strains are acid-labile, RRV-TV is reconstituted with 2.5
mL of irradiated sterile diluent containing citrate-bicarbonate.
When reconstituted, the vaccine might contain a fine precipitate,
and it usually is yellow-orange in color but occasionally is
purple. Each dose of vaccine contains 1 x 105 plaque-forming units
(pfu) of each component rotavirus strain. Trace amounts of fetal
bovine serum, neomycin sulfate, and amphotericin B are present in
the vaccine (less than 1 ug per dose). The vaccine does not contain
preservatives. Studies to evaluate the safety, immunogenicity, and efficacy
of RRV-TV have involved 17,963 infants in the United States,
Venezuela, and Finland. The efficacy of this vaccine has been
evaluated in four field trials, two in the United States (55,56)
and one each in Venezuela (57) and Finland (58). Three additional
trials have been conducted with lower doses of RRV-TV in the United
States (59), Brazil (60), and Peru (61). Immunogenicity The immunogenicity of rotavirus vaccines is generally measured
by detecting rotavirus group-specific serum IgA seroconversion or
by detecting serum-neutralizing antibodies to vaccine strains and
to prevalent human strains. In industrialized countries,
immunogenicity studies of RRV-TV have produced consistent and
reproducible results similar to those found in U.S. trials
(Table_1)
(55) (unpublished data, Wyeth-Lederle, 1997). In all studies,
vaccinated children developed significantly higher IgA
enzyme-linked immunosorbent assay (ELISA) and neutralizing
antibodies to rotavirus than did children who received placebo (p
less than 0.01). In the three U.S. efficacy trials, greater than
90% of children who received RRV-TV demonstrated a serologic
response to vaccination that included a neutralizing antibody
response to rhesus rotavirus (83%-90%) or at least a fourfold rise
in rotavirus-specific IgA titers (56%-93%) (55,56,59). Neutralizing
antibody responses to human rotavirus strains were less common
(14%-43%). When administered simultaneously, a three-dose series of
RRV-TV does not diminish the immune response to oral poliovirus
vaccine (OPV) (62), diphtheria and tetanus toxoids and whole-cell
pertussis vaccine (DPT) (63), Haemophilus influenzae type b
conjugate (Hib) vaccine (63), inactivated poliovirus vaccine (IPV),
or hepatitis B vaccine (unpublished data, Wyeth-Lederle, 1998).
Studies of simultaneous administration of RRV-TV with diphtheria
and tetanus toxoids and acellular pertussis vaccine (DTaP) have not
yet been completed, but no diminished immune response is expected
on the basis of findings regarding the administration of RRV-TV
with DTP. Concurrent administration of RRV-TV with OPV does not
affect the immunogenicity and efficacy of a three-dose series of
rotavirus vaccine (64,65). Breastfeeding does not appear to
significantly diminish either the immune response to or the
efficacy of the three-dose series (p greater than 0.9) (64,66,67). Efficacy Four efficacy trials of RRV-TV have been completed in the
United States and Finland: three trials with the 4 x 105 pfu dose
submitted for licensure (55,56,58) and one trial with a lower dose
(4 x 104 pfu) (Table_2) (59). The findings of all four studies
were
similar; the vaccine demonstrated 49%-68% efficacy against any
rotavirus diarrhea, 69%-91% efficacy against severe diarrhea, and
50%-100% efficacy in preventing doctor visits for evaluation and
treatment of rotavirus diarrhea. The vaccine was also effective in
reducing the duration of rotavirus diarrhea. The trial in Finland
was large enough to examine the vaccine's efficacy in preventing
rotavirus hospitalizations: protection was 100% (13 children in the
placebo group were hospitalized compared with zero children in the
vaccine group) (58). In this study, vaccinated children also were
protected from nosocomially acquired rotavirus diarrhea. Extended
follow-up in the study in Finland demonstrated that protection
against severe disease persisted through three rotavirus seasons
(68). Because infections with serotype G1 viruses have predominated
in most studies, the efficacy of RRV-TV against this serotype is
well established. In studies conducted in the United States and
Finland, RRV-TV was also effective in preventing nonserotype G1
disease (55,56,58). In each study, the efficacy of the vaccine was
high despite low neutralizing antibody responses to human strains
among the vaccinated children -- a finding that illustrates the
variable correlation between serologic responses and efficacy. No
data are available on the efficacy of administration of fewer than
three doses of RRV-TV. Transmission of Attenuated Rotavirus Vaccine Strains In studies performed in U.S. day care centers, no evidence of
seroconversion to, or shedding of, vaccine strains was observed
among unvaccinated children (69-73). However, in a large vaccine
trial in Venezuela (57), stool samples from study children who had
rotavirus diarrhea were tested by multiple methods. Wild-type
rotavirus was found in high concentration in all samples. In
addition, rotavirus vaccine strains were detected by polymerase
chain reaction in stool samples from 15% of vaccinated and 13% of
nonvaccinated children in concentrations too low to be detected by
enzyme immunoassay or polyacrylamide gel electrophoresis. These
data support the possibility that vaccine strains spread to some
unvaccinated children but indicate that the vaccine strains alone
were not the cause of diarrhea. Vaccine Distribution, Handling, and Storage Each dose of RRV-TV is approximately 2.5 mL in volume,
supplied as a lyophilized vaccine containing 4 x 105 pfu total
virus and one dispette of buffer diluent for reconstitution; the
diluent contains 9.6 mg/mL of citric acid and 25.6 mg/mL of sodium
bicarbonate. Neither vaccine nor diluent contain preservatives.
Before reconstitution, RRV-TV is stable for at least 24 months when
stored at room temperatures less than 25 C (77 F). The lyophilized
vaccine and diluent may be refrigerated at temperatures between 2
C and 8 C (36 F and 45 F) but should not be frozen. Once
reconstituted, the vaccine is stable for up to 60 minutes at room
temperature (23-27 C {73-81 F}) and up to 4 hours at refrigeration
temperature (2-8 C {36-45 F}), after which the reconstituted
product must be discarded. Cost-Effectiveness of a Universal Childhood Immunization Program to
Prevent Rotavirus In a recent study that used current estimates of rotavirus
disease burden, vaccine efficacy, vaccine coverage rates, and
health costs, investigators estimated that a national rotavirus
immunization program in which three doses of RRV-TV are
administered at ages 2, 4, and 6 months would result in 227,000
fewer physician visits, 95,000 fewer emergency room visits, 34,000
fewer hospitalizations, and 13 fewer deaths per year (14). After
revising this study model by incorporating the costs of adverse
events, researchers estimated that a national rotavirus
immunization program would yield savings in direct medical costs if
the vaccine cost $8 or less per dose and would yield savings in
total societal costs if the vaccine cost $41 or less per dose (CDC,
unpublished data, 1998). RECOMMENDATIONS FOR THE USE OF ROTAVIRUS VACCINE
Routine Administration Routine immunization with three oral doses of RRV-TV is
recommended for infants at ages 2, 4, and 6 months. Because natural
rotavirus infections occur early in life, RRV-TV should be
incorporated into the routine childhood immunization schedule. The
first dose should be administered at age 2 months, the second dose
at age 4 months, and the third dose at age 6 months. However,
RRV-TV vaccination can be initiated at any time between the ages of
6 weeks and 6 months, with second and third doses following the
preceding dose by a minimum of 3 weeks. Vaccination should not be
initiated for children aged greater than or equal to 7 months
because these older infants might have an increased risk of fever
occurring 3-5 days after receiving the first dose of vaccine
(74-76).
All doses of vaccine should be administered during the first
year of life because data regarding the safety and efficacy of
RRV-TV among children aged greater than or equal to 1 year are
lacking. Special efforts should be made to vaccinate children
before onset of the winter rotavirus season. Infants documented to
have had rotavirus gastroenteritis before receiving the full course
of rotavirus vaccinations should still complete the three-dose
schedule because the initial infection frequently provides only
partial immunity. RRV-TV is recommended for children who are breastfed. Although
breastfeeding can slightly decrease the child's humoral immune
response to RRV-TV after a first dose, no significant decrease in
immune response or in overall efficacy has been observed among
breastfed babies compared with nonbreastfed babies after three
doses (p greater than 0.9) (64,66,77,78). RRV-TV can be administered together with DTP (or DTaP), Hib
vaccine, OPV, IPV, and hepatitis B vaccine. RRV-TV is safe and
effective when administered with other vaccines. Available evidence
suggests that the vaccine does not interfere significantly with the
immune response to DTP, Hib vaccine, IPV, or hepatitis B vaccine,
and interference with DTaP is not expected to occur (63)
(unpublished data, Wyeth-Lederle, 1998). Some children who receive
RRV-TV and OPV concurrently have slightly decreased immune
responses to RRV-TV and serotype 1 poliovirus after the first dose
of vaccine, but no decrease is evident after three doses of these
vaccines (56,62,64). No decrease in efficacy against rotavirus has
been found among children receiving OPV compared with children not
receiving OPV, although the sample size in this study was limited
(64). Like other vaccines, RRV-TV can be administered to infants
with transient, mild illnesses, with or without low-grade fever. Contraindications
Altered Immunity RRV-TV is not recommended for infants who have known or
suspected immuno-deficiency. Children with primary immunodeficiency
disorders and both children and adults who have received
hematopoetic, hepatic, or renal transplants are at risk for severe
or prolonged rotavirus gastroenteritis and can shed rotavirus for
prolonged periods (20-22,79-81). One study also identified
rotavirus infection of liver and kidney tissue in a small number of
severely immunodeficient children (79). Because the safety and
efficacy of RRV-TV is not established in these populations, RRV-TV
should not be administered to infants with compromised immune
status because of immunosuppressive disease or therapies, leukemia,
lymphoma, or other malignancies. The safety of RRV-TV has not been
established in children with chronic granulomatous disease and
other primary disorders of neutrophil function, but no evidence of
increased severity of rotavirus infection has been observed in
these children. RRV-TV should not be administered to infants born
to mothers with human immunodeficiency virus (HIV) infection,
unless a clinician has established that the infant is not
HIV-infected. Allergy to Vaccine Components RRV-TV should not be administered to persons who have
hypersensitivity to any component of the vaccine (e.g.,
aminoglycoside antibiotics, monosodium glutamate, or amphotericin
B) or who have experienced an anaphylactic reaction to a previous
dose of RRV-TV. Acute Gastrointestinal Disease RRV-TV should not be administered to infants with acute,
moderate to severe vomiting or diarrhea until the condition
resolves; however, vaccination might be warranted for infants with
mild gastrointestinal illness. RRV-TV has not been studied among
infants with concurrent gastrointestinal disease. Although RRV-TV
is probably safe for infants with gastrointestinal disease,
immunogenicity and efficacy can theoretically be compromised. For
example, infants who receive OPV during an acute diarrheal illness
might have diminished poliovirus antibody responses to OPV (82).
Although similar studies with RRV-TV have not been reported,
health-care providers should be aware of the theoretical potential
for diminished immunogenicity and efficacy among infants with
diarrhea. Therefore, RRV-TV should be withheld from infants with
acute, moderate to severe vomiting or diarrhea. Vaccination of
infants with mild gastrointestinal illness might be warranted if
the delay in vaccination against rotavirus is expected to be
substantial. Otherwise, infants with acute gastroenteritis should
be vaccinated as soon as the condition resolves. Moderate to Severe Febrile Illness Infants with moderate to severe febrile illness should be
vaccinated as soon as they have recovered from the acute phase of
the illness (83). This precaution avoids superimposing adverse
effects of the vaccine on the underlying illness or mistakenly
attributing a manifestation of the underlying illness to the
vaccine. Precautions and Special Situations
Premature Infants (i.e., those born at less than 37 weeks'
gestation) Practitioners should consider the potential risks and benefits
of vaccinating premature infants against rotavirus. Limited data
suggest that premature infants are at increased risk for
hospitalization from diarrheal disease during their first year of
life. The ACIP supports immunization of prematurely born infants if
they a) are at least 6 weeks of age, b) are being or have been
discharged from the hospital nursery, and c) are clinically stable.
However, the number of premature infants studied in clinical trials
is insufficient to confidently establish the safety and efficacy of
RRV-TV for all premature infants. The lower level of maternal
antibody to rotaviruses in very-low-birthweight, premature infants
theoretically could increase the risk of fever from rotavirus
vaccine. Until further data are available, the ACIP considers that
the benefits of RRV-TV vaccination of premature infants outweigh
the theoretical risks. Exposure of Immunocompromised Persons to Vaccinated Infants Infants living in households with persons who have or are
suspected of having an immunodeficiency disorder or impaired immune
status can be vaccinated. Most experts believe the protection of
the immunocompromised household member afforded by immunization of
young children in the household probably outweighs the small risk
of transmitting vaccine virus to the immunocompromised household
member and any subsequent theoretical risk of vaccine
virus-associated disease. To minimize potential virus transmission,
all members of the household should employ measures such as good
hand washing after contact with the feces of the vaccinated infant
(e.g., after changing a diaper). Recent Administration of Antibody-Containing Blood Products No restrictions are necessary regarding the timing of
administering RRV-TV and antibody-containing blood products.
Although no data are available concerning the efficacy of RRV-TV
administered simultaneously with antibody-containing blood
products, data from studies of OPV indicate that simultaneous
administration of OPV with these products does not affect OPV
immunogenicity. Preexisting Chronic Gastrointestinal Disease Practitioners should consider the potential risks and benefits
of administering rotavirus vaccine to infants. Infants with
preexisting chronic gastrointestinal conditions might benefit from
RRV-TV vaccination. However, the safety and efficacy of RRV-TV have
not been established for infants with these preexisting conditions
(e.g., congenital malabsorption syndromes, Hirschsprung's disease,
short-gut syndrome, or persistent vomiting of unknown cause). Regurgitation of Vaccine The practitioner should not readminister a dose of vaccine to
an infant who regurgitates, spits out, or vomits during or after
administration of vaccine. The infant can receive the remaining
recommended doses of RRV-TV at appropriate intervals outlined
previously (see Routine Administration). Data are limited regarding
the safety of administering a dose of RRV-TV higher than the
recommended dose and on the efficacy of administering a partial
dose. Additional data on safety and efficacy are needed to evaluate
the benefits and risks of readministration. Late or Incomplete Immunization Pending additional data, initial vaccination of children aged
greater than or equal to 7 months or administration of any dose of
RRV-TV to children on or after their first birthday is not
recommended. If a child fails to receive RRV-TV on the recommended
schedule of 2, 4, and 6 months together with other routine
immunizations, the child can receive the first dose of vaccine at
any time after age 6 weeks but before age 7 months. Second and
third doses of RRV-TV can be administered at any time during the
first year of life as long as at least a 3-week interval separates
doses. Data from the efficacy trials regarding administration of
second and third doses are limited to children aged less than or
equal to 8 months. Hospitalization After Vaccination If a recently vaccinated child is hospitalized for any reason,
no precautions other than routine universal precautions need be
taken to prevent the spread of vaccine virus in the hospital
setting. Latex Hypersensitivity Health-care workers with a history of latex sensitivity should
handle this vaccine with caution because its packaging contains dry
natural rubber. ADVERSE EVENTS AFTER ROTAVIRUS VACCINATION Serious adverse events that occur after administration of
rotavirus vaccine should be reported to the Vaccine Adverse Events
Reporting System (VAERS). The National Childhood Vaccine Injury Act
of 1986 requires health-care providers to report to VAERS any
serious adverse events that occur after vaccination, but persons
other than health-care workers can also report adverse events.
Adverse events that must be reported after rotavirus vaccination
are those described in the manufacturer's package insert as
contraindications to additional doses of vaccine (84). Other
adverse events occurring after administration of a vaccine,
especially events that are serious or unusual, also should be
reported to VAERS, regardless of the provider's opinion about
whether the association is causal. VAERS reporting forms and
information can be requested 24 hours a day by calling (800)
822-7967 or by accessing the VAERS World-Wide Web site at
http://www.cdc.gov/nip/vaers.htm. RRV-TV has been administered to almost 7,000 infants aged 6-28
weeks in three doses of at least 4 x 105 pfu, including 2,208
infants in placebo-controlled studies (55,56,58,76) (unpublished
data, Wyeth-Lederle, 1997), and 4,740 infants in three studies that
were not placebo-controlled (unpublished data, Wyeth-Lederle,
1997). The vaccine has been associated with a statistically
significant excess of fever following the first dose compared with
placebo ( greater than 38 C {100.4 F}, 21% versus 6% {p less than
0.001}; greater than 39 C {102.2 F}, 2% versus 1% {p less than
0.001}), with fever usually occurring 3-5 days after administration
(Figure_1), (Figure_2), and (Table_3). Decreased
appetite,
irritability, and decreased activity also were reported following
the
first dose of vaccine in some trials; these symptoms were highly
associated with the presence of fever in both vaccine and placebo
recipients (85). A statistically significant excess of fever
greater
than 38 C (100.4 F, 11% versus 9% {p less than 0.05}) also was
noted
after the second dose of RRV-TV; no increase in any symptoms was
noted
after the third dose of RRV-TV. In the placebo-controlled trials, investigators found no
overall difference in the rate of diarrhea (55,56,58,76)
(unpublished data, Wyeth-Lederle, 1997). However, in the efficacy
study in Finland (58), vaccinated children had a significantly
increased rate of diarrhea after the first dose of vaccine compared
with placebo recipients (2.8% versus 1.4% {p less than 0.05})
(Table_3); the diarrhea was associated with the presence of
fever
(85). No evidence exists that RRV-TV causes vomiting. Initial reports noted failure to thrive or growth delay rarely
but more frequently among RRV-TV recipients than among placebo
recipients in the Finland and U.S. efficacy trials (18/2,015 {0.9%}
among vaccinated children versus 6/2,023 {0.3%} among recipients of
placebo {p=0.02}) (unpublished data, Wyeth-Lederle, 1997). On
blinded expert review, most cases were found to represent normal
variation in growth rates; five cases (three among vaccinated
children and two among placebo recipients) were suspected of
representing abnormal growth delays. In all studies of rhesus rotavirus vaccines combined,
intussusception was noted in five of 10,054 (0.05%) recipients of
any reassortant rhesus vaccine (two of these five children received
RRV-TV) compared with one of 4,633 placebo recipients. The
difference between the rates of intussusception in these groups was
not statistically significant (p=0.92 for children receiving
vaccine; p=0.45 for children receiving placebo), and the rates
observed among vaccinated children were similar to those seen in
comparison populations (86). Although the association of these
events with RRV-TV appears to be temporal rather than causal,
postlicensure surveillance is needed for these and other rare
adverse events that might occur. Data are limited on adverse events after RRV-TV is
administered to premature infants. Of 23 premature infants who were
less than or equal to 35 weeks' gestational age and who received
RRV-TV, one infant developed fever (38.6 C on day 2 after
vaccination) and two infants developed diarrhea (one infant on days
2 and 5 after vaccination and the other infant on days 6 and 12)
(unpublished data, Wyeth-Lederle, 1997). The recommendation for routine rotavirus immunization is made
in view of the high morbidity associated with rotavirus
gastroenteritis and the favorable cost-effectiveness of
immunization. Among approximately 20,000 children immunized to
date, the vaccine has been found to be generally safe and well
tolerated. As with any new vaccine, rare adverse events might be
identified when many more children are immunized, and postlicensure
surveillance will be required to identify such rare events. FUTURE NEEDS IN ROTAVIRUS SURVEILLANCE, RESEARCH, EDUCATION, AND
IMPLEMENTATION
Surveillance
Incidence of Rotavirus Gastroenteritis Rotavirus gastroenteritis is not a reportable disease, and
testing for rotavirus infection is not always performed when a
child seeks medical care for acute gastroenteritis. Therefore,
additional efforts will be needed to establish rotavirus disease
surveillance systems that are adequately sensitive and specific to
document the effectiveness of immunization programs. Current
national surveillance systems include a) review of national
hospital discharge databases for rotavirus-specific or
rotavirus-compatible diagnoses and b) reports of rotavirus
isolation from a sentinel system of laboratories. Additional
systems will be needed to provide the timely representative data
necessary for monitoring the effectiveness of a national
immunization program. At state and local levels, additional
surveillance efforts -- by enhanced surveillance at sentinel
hospitals or by review of hospital discharge databases -- will be
necessary to monitor program effectiveness. Detection of Unusual Strains of Rotavirus A national strain surveillance system of sentinel laboratories
has been established to monitor the prevalence of rotavirus strains
before and after the introduction of rotavirus vaccines. This
system is designed to detect unusual strains that might not be
effectively prevented by vaccination and that might affect the
success of the immunization program. Research Future research should include studies to determine the safety
and efficacy of RRV-TV administered to infants born prematurely,
infants with immune deficiencies, infants who live in households
with immunocompromised persons, infants with chronic
gastrointestinal disease, and children aged greater than 1 year.
Postlicensure studies also should be conducted to determine the
relative efficacy of fewer than three doses of vaccine and to
address the cost-effectiveness of vaccination programs in various
settings. Education of Health-Care Providers and Parents The success of a rotavirus immunization program depends on the
acceptance and enthusiasm of physicians and other health-care
providers who care for children. Vaccination program personnel will
benefit from education about rotavirus disease and rotavirus
vaccine. Parental education on rotavirus diarrhea and on the
vaccine also will be essential to establish and maintain public
confidence in this vaccine and to avoid confusion by cases of
diarrhea in early childhood resulting from nonrotaviral etiologies
not preventable by RRV-TV. Implementation Physicians and health-care providers will require time and
resources to incorporate this new vaccine into practice. Therefore,
full implementation of these recommendations will not be achieved
immediately. During the period of implementation, postmarketing
surveillance should be conducted to further delineate the benefits
and risks of rotavirus vaccine.
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