65.  Childhood Immunizations



RECOMMENDATION



All children without established contraindications should receive diphtheria-tetanus-pertussis

(DTP), oral poliovirus (OPV), measles-mumps-rubella (MMR), conjugate Haemophilus

influenzae type b, hepatitis B, and varicella vaccines, in accordance with recommended schedules

(see Clinical Intervention). Hepatitis A vaccine is recommended for children and adolescents at

high risk for hepatitis A virus (HAV) infection. Pneumococcal vaccine and annual influenza

vaccine are recommended for children and adolescents at high risk (see Clinical Intervention and

Chapter 66). See Chapter 67 for recommendations on postexposure prophylaxis against selected

infectious diseases, and Chapter 25 for recommendations regarding the Bacille Calmette-GuÇrin

(BCG) vaccine.



Burden of Suffering



A number of infectious diseases are preventable through routine childhood immunizations. Largely

as a result of widespread childhood vaccination over the past several decades, diphtheria,

pertussis, tetanus, poliomyelitis, measles, mumps, rubella, and congenital rubella syndrome have

become remarkably less common in the U.S. than in prevaccination years, and the numbers of

cases reported are at or near the lowest levels ever.1 Comparisons of the total numbers of

reported cases in the U.S. in 1994 and in the years preceding vaccination reveal an impressive

decrease in reported cases of diphtheria (from 9,493 [1948] to 2 cases), tetanus (from 601

[1948] to 51 cases), paralytic poliomyelitis (from 18,308 [1954] to 0 cases due to endemic

wild virus), measles (from 481,530 [1962] to 963 cases), mumps (from 152,209 [1968] to

1,537 cases), rubella (from 57,686 [1969] to 227 cases), and congenital rubella syndrome

(from 77 [1970] to 7 cases).2,2a Before the introduction of poliovirus vaccine in 1955, polio

occurred in epidemic waves of increasing magnitude, reaching a peak incidence of more than

20,000 paralytic cases in 1952.3 The last outbreak, in 1979, totaled only 10 paralytic cases.

Although the number of pertussis cases has also declined markedly since the prevaccination years

(from 74,715 [1948] to 4,617 cases), long-term trends suggest an overall increase in the

reported incidence of pertussis since 1976, rising from 0.5/100,000 to 2.6/100,000 in 1993

and 1.8/100,000 in 1994.4,4a Many of these cases occurred in unvaccinated or inadequately

vaccinated infants and children.



Newer childhood vaccines include H. influenzae type b (Hib), hepatitis B, hepatitis A, and

varicella vaccines. Systemic illness from Hib disease, including meningitis, pneumonia, arthritis,

and epiglottitis, previously occurred before age 5 in about 1 of every 200 children born in the

U.S.5 The highest rates of Hib disease in the U.S. have been reported in Alaska Native and certain

Native American populations. The incidence of invasive Hib disease in children <5 years old

declined by an estimated 95% (from 41 to 2/100,000) between 1987, when the first Hib

vaccine was licensed, and 1994.6,6a



Children less than 5 years old account for only 1% of reported cases of hepatitis B and 1-3% of

the 200,000 to 300,000 hepatitis B virus (HBV) infections estimated to occur annually in the

U.S., but 20-30% of chronic infections.7 The likelihood of developing chronic infection has been

estimated to be 80-90% in perinatally infected neonates, decreasing to 25% for those infected at

age 5, and to <10% for infected adults.8 Chronic infection can lead to severe complications

including chronic active hepatitis, cirrhosis, and hepatocellular carcinoma.9-11



Nearly 27,000 cases of hepatitis A were reported in the U.S. in 1994 (10.3/100,000),2a

although the actual number of cases is estimated to be several times higher.9 Children aged 5-14

years have the highest rate of reported hepatitis A (about 15 cases per 100,000 in 1993).2

About half of reported cases of hepatitis in the U.S. are attributable to hepatitis A.9 High-risk

groups include travelers to countries with intermediate or high hepatitis A endemicity,12 some

religious communities, and Alaska Native, Pacific Islander, and Native American populations;

persons institutionalized for custodial care may also have an increased risk. Day care centers may

be an important source of epidemic HAV infection.13



Because chickenpox, caused by infection with varicella-zoster virus (VZV), infects nearly

everyone by adulthood, its annual incidence approximates the birth cohort (4 million in

1993).14,15 At least 90% of cases occur in children less than 15 years old.14 Most adults are

immune.16 Although generally mild in healthy children, chickenpox often results in missed school

days for the child, missed work days for their parents, and visits to health care providers, and it

occasionally leads to serious complications (e.g., encephalitis, pneumonia, bacterial

superinfection), hospitalizations, and, rarely, death.14,17-20 Complication rates per case of

varicella and case-fatality rates are substantially higher for older adolescents and adults than for

children.14,17 Infants are also at high risk of complications.



Efficacy of Vaccines



DTP Vaccine.  The efficacy of the DTP vaccine is established on the basis of clinical studies and

decades of experience with universal childhood immunization.21-24 Substantial declines in

diphtheria, tetanus, and pertussis disease followed the introduction of whole-cell pertussis

vaccine combined with diphtheria and tetanus toxoids in the late 1940s.24,25 The diphtheria and

tetanus toxoids are generally safe and are most commonly associated with self-limited local

reactions,26 although case reports have described allergic or Arthus-like reactions and

peripheral neuropathy following frequent tetanus boosters. Anaphylaxis occurs in rare

instances.27-29



Increased attention has focused in recent years on the efficacy and safety of the pertussis

component of the vaccine.30-32 In a national surveillance study of households with

laboratory-confirmed pertussis, the efficacy of currently used whole-cell pertussis vaccines in

fully vaccinated (three or more doses) children 1 through 4 years of age was estimated to be 59-

89% for prolonged cough, 78% for typical paroxysmal cough, and 96-97% for severe clinical

illness.22 In another national surveillance study, vaccine efficacy in preventing pertussis,

defined as either any culture-proven cough illness or typical pertussis illness, was 64% for

three doses and 82% for four or more doses.4a The whole-cell preparation commonly produces

local redness, swelling, and pain, and systemic events such as fever, fretfulness, and protracted,

inconsolable crying.33 DTP has also been associated with more serious adverse events such as

febrile seizures in about 57/100,000 doses and hypotonic/hyporesponsive episodes in 3.5-

291/100,000 doses.33 The risk of seizures may be higher in certain children, such as those with

a personal or family history of seizures.34,35 Limited follow-up of such cases, however,

suggests that most, if not all, are associated with benign outcomes.36,37 The National Childhood

Encephalopathy Study (NCES), a large British case-control study, reported that

pertussis-containing vaccines were associated with more severe neurologic illnesses at a rate of

6.8 per million doses (95% CI, 2.1-15.9 per million), including acute encephalopathy in 2.7

(0-10.5) per million doses.38 A 10-year follow-up study reported an association between death

or permanent neurologic dysfunction and DTP vaccine only among children who had developed a

serious acute neurologic illness within 7 days of receiving DTP.39 The NCES has been criticized

for possible bias and error in case ascertainment and other methodologic problems.33 Detailed

analysis of this and other controlled and uncontrolled observational studies led the Institute of

Medicine t conclude that evidence was consistent with (but did not establish) a causal relationship

between DTP vaccine and acute encephalopathy, with a range of excess risk between 0 and 10.5 per

million doses,33 and between DTP and chronic neurologic dysfunction in those rare children who

experienced a serious acute neurologic illness within 7 days after receiving DTP.40 The incidence

of serious neurologic disorders following DTP administration is substantially less than that

following pertussis disease.38 Nevertheless, the high rate of adverse local and mild systemic

reactions, as well as the possibility of rare adverse neurologic sequelae, has stimulated interest in

development of less reactogenic vaccines.41



Acellular forms of pertussis vaccine induce fewer local and systemic side effects than does the

whole cell vaccine when administered to infants and children up to 6 years old.42-48 In a

randomized placebo-controlled trial of 3,801 Swedish children aged 5-11 months, the efficacy of

two acellular pertussis vaccines was 79-80% in preventing severe culture-proven pertussis and

54-69% for preventing culture-proven cases with any cough.49-51 Four-year follow-up

indicates persistent efficacy ranging from 69% to 95%, depending on case definition.52 Household

exposure studies in Japan have reported efficacy >90% against typical pertussis among children

receiving acellular vaccines at age Ú2 years.53-55a In a prospective institutional exposure

study, children vaccinated with acellular pertussis-component DTP (DTaP) beginning at a median

age of 5 months (range, 3-26) were significantly less likely to develop typical pertussis

symptoms compared with unvaccinated children.56 None of these studies directly compared the

acellular vaccine to the whole-cell vaccine. Immunogenicity appears comparable to the whole cell

vaccine for the antigens present in the acellular vaccines.44,57 Preliminary results from two

European randomized, double-blind trials indicate that DTaP at 2, 4, and 6 months of age was at

least as efficacious as DTP with significantly fewer side effects; DTaP is likely to be licensed for

use in infancy in the near future (personal communication, John R. La Montagne, PhD, National

Institutes of Health (NIH), Bethesda, Aug. 15, 1995). DTaP is currently licensed in the U.S. for

use in children Ú15 months of age as the fourth and/or fifth doses of the recommended DTP

series.58,59



OPV Vaccine.  Three doses of live oral poliovirus (OPV) vaccine offers protection against all three

poliovirus types in 95-100% of children. As a result, disease caused by indigenous wild

poliovirus has been eliminated in the U.S.60 An estimated 1 out of every 2.5 million vaccine doses

results in paralytic poliomyelitis, however, and all cases of endemic paralytic poliomyelitis in the

U.S. since 1980 (about eight cases per year) have been associated with the vaccine.60 The vaccine

has also resulted in several cases of fatal vaccine-strain poliovirus infections, primarily in

immunocompromised patients.29 The licensing of enhanced-potency inactivated poliovirus vaccine

(IPV), which has no documented serious adverse effects and appears to have comparable

immunogenicity,61,62 has led some to propose replacment of the live vaccine with this

product.63 IPV may be less effective, however, in limiting transmission of wild poliovirus among

susceptible members of the population.64 OPV has few significant adverse effects other than the

risk of paralytic poliomyelitis.29 The rare occurrence of Guillain-BarrÇ syndrome (GBS) was

associated with a one-time OPV mass vaccination program in controlled studies in Finland, where

IPV had been used routinely.29 A retrospective epidemiologic survey of GBS in southern

California, however, found no correlation between the usual age of OPV immunization and the

incidence of GBS.65 Because it requires injection, IPV is associated with greater discomfort and

possibly greater administrative costs than is OPV. Combining IPV with other infant vaccines66,67

would alleviate this problem.



MMR Vaccine.  A single dose of MMR is highly protective against measles, mumps, and rubella and

its widespread use has resulted in substantial declines in the incidence of all three diseases.2,68 It

is generally associated with only mild adverse effects in healthy individuals.68,69 MMR vaccine

rarely causes thrombocytopenia (2.5-3.3/100,000 vaccinated persons), urticaria

(0.6/100,000), and anaphylaxis (estimated at 0.1-5/100,000).29,70 Several deaths from

vaccine-strain viral infection have been reported, all in severely immunocompromised children;

none has been reported in children infected with human immunodeficiency virus (HIV).29 The

efficacy and adverse effects of rubella vaccine are described in detail in Chapter 32.



Despite the efficacy and safety of the vaccine, measles remains an important public health problem

in the U.S. due to failure to immunize and to immunization failure. Between 1989 and 1994, 27-

64% of measles cases occurred among unvaccinated but vaccine-eligible persons and 19-22%

among persons who had received one vaccine after 12 months of age (immunization failure).71-

72a Most immunization failures appear to occur in children who fail to respond to the vaccine

(primary immunization failure), an estimated 5% of children immunized after 15 months of

age.73,74 In the past, the rate of primary immunization failure has been higher among children

vaccinated before 15 months of age, presumably because maternal antibody interfered with

response.75 More recent studies indicate excellent serologic response and similar clinical efficacy

in children vaccinated at 12-14 months, perhaps because maternal antibody levels achieved in a

vaccinated cohort of mothers decline earlier than levels achieved by natural infection.76-82

Antibody response remains lower than when the vaccine is given at 15 months, however. Current

evidence indicates that revaccination of primary immunization failures results in seroconversion

rates comparable to that of never vaccinated persons83 and prevents measles outbreaks.84



Although some evidence suggests that waning immunity (secondary immunization failure) may

also be a factor in immunization failure,85-91 seropositivity rates generally remain high at

least 10-15 years following vaccination,92-94 anamnestic antibody responses occur in

vaccinated persons who apparently lack antibody,83,93 and cohorts of known seroconverters

followed through time in Great Britain and Japan have shown little evidence of increasing disease

incidence with time since immunization.93 In 27-year follow-up of a British vaccine trial, there

was no significant decline in vaccine efficacy with time (although the number of cases was quite

small).95



Because of immunization failures, a two-dose vaccination protocol against measles appears

necessary to eliminate transmission of this highly communicable disease.88,96-98 Indirect

evidence in support of a two-dose regimen comes from studies showing that attack rates during

outbreaks are lower among populations of individuals who have had two doses of vaccine,82,88-

91,99 and from the rarity of reported measles cases among persons who had received two doses of

vaccine.72,72a In Finland, a two-dose vaccination program administered at 14-18 months and at

6 years (with >95% coverage), along with "catch-up" vaccination for children 11-13 years and

for individuals at occupational risk, has essentially eliminated indigenous measles, mumps, and

rubella.70 Adverse reactions to a second dose of vaccine seem to be no more common than to the

first.



Hib Vaccine.  The efficacy of a capsular polysaccharide (polyribosyl-ribitol phosphate [PRP])

vaccine in preventing infection with Hib in children over age 2 was first demonstrated in Finland

in 1984.100 Newer vaccines with substantially improved immunogenicity were subsequently

developed by covalently conjugating PRP with protein antigens and were licensed for use in

children 15-18 months of age in the late 1980s. Postlicensure studies have indicated vaccine

efficacy of 74-88% for children 18-59 months of age.101-103 Licensure of Hib conjugate

vaccines for infants under 6 months of age followed demonstration of 93% efficacy of two doses of

PRP-OMP conjugate vaccine in a randomized trial, and 100% efficacy of three doses of Hib

oligosaccharide conjugate (HbOC) in a quasi-randomized trial.104-106 A postlicensure

case-control study reported protective efficacies of 71%, 89%, and 94% after one, two, and three

doses, respectively, of HbOC.107 Although U.S. controlled trials of a third vaccine (PRP-T) were

terminated after the licensure of other Hib conjugate vaccines for use in infancy, no cases of

invasive Hib disease were reported among more than 6,200 vaccine recipients at the time of

termination,108 and protective efficacy has been reported from a British trial in which infants

were given this vaccine at 2, 3, and 4 months,109 and from a Finnish immunization program

using historical controls.110 A combined DTP-HbOC vaccine and use of PRP-T vaccine

reconstituted with DTP (from a single manufacturer) have been licensed based on immunogenicity

similar to that of the individual vaccines, although no clinical efficacy information is

available.111,112 These combined vaccines allow a reduced number of injections when both

vaccines are indicated. Other combination vaccines are currently being evaluated.113 Declines in

antibody levels occur with all vaccines after administration of the primary series, but booster

vaccination at Ú12 months of age elicits a good antibody response.114-116 Surveillance in a

number of different populations indicates a 55-95% decline in the incidence of Hib disease with

widespread use of Hib conjugate vaccines.6,117-122 A substantial decline in the incidence of Hib

disease among unvaccinated children120 and in persons Ú5 years6 may be due to reduced carriage

and transmission of the bacteria from vaccinated children.123,124 In randomized controlled

trials, serial combinations of different vaccines (PRP-OMP, HbOC, or PRP-T) were as safe and at

least as immunogenic as single conjugate vaccine series, supporting the interchangeability of these

vaccines.125-127 Adverse effects of the Hib vaccine are generally mild (local tenderness,

redness and swelling, irritability, fever, malaise, etc.).128



Hepatitis B Vaccine.  In the U.S., infants born to hepatitis B surface antigen-positive (HBsAg+)

mothers are at high risk of becoming infected with HBV, but most other infants have little risk of

infection before adolescence. Controlled trials,129-135a cohort studies,136,137 and a time

series study,138 have demonstrated that hepatitis B vaccine given alone to infants of HBsAg+

mothers is 62-92% effective (depending on dosage, interval, vaccine, and maternal antigen

status) in preventing the development of the HBV chronic carrier state during the first 1-5 years

of life. The protective efficacy of vaccine combined with hepatitis B immune globulin (HBIG) is

somewhat higher (85-95%) than for vaccine alone in these infants (see Chapter 24).



Because universal vaccination of low-risk infants has only been introduced recently in the U.S.,

its ability to protect these infants later in life must be inferred from studies in other populations.

From controlled trials139-141 and time series studies142-147 conducted in populations where

horizontal HBV transmission is common, universal vaccination of infants, children, and/or

adolescents with a three- or four-dose regimen is estimated to be >84% effective in preventing

HBV infection and >80% effective in preventing the development of chronic HBV carriage. Mass

vaccination of children in New Zealand142 and infants in Taiwan,148 American Samoa,149 and

Alaska Native communities150 has led to substantial reductions in acute HBV events and the

prevalence of chronic infection in both vaccinated and unvaccinated populations. Controlled trials

and time series indicate protection against HBV infection and chronic carriage lasting from 3 to as

long as 11-12 years in vaccinated infants, children, and adolescents, despite declines in antibody

levels. 130,142,143, 146,151-155 Breakthrough infections appear to be associated more with

low initial antibody response than with declining antibody levels.139,146,156 The recombinant

vaccines currently in use in the U.S. induce antibody responses and short-term (up to 5 years)

efficacy in children similar to those of the plasma-derived vaccine.131,133,138,142,147,157-

163 Mild reactions_including local soreness and induration, low-grade fever, irritability, and

poor feeding_are reported by the parents of up to 13% of vaccinated children and 4-7% of

vaccinated infants.161,162,164 There have been several case reports of nonfatal anaphylaxis

from recombinant hepatitis B vaccine.29



Hepatitis A Vaccine.  Inactivated hepatitis A vaccine, delivered in two doses 1 month apart,

protected against hepatitis A for at least 1 year in a double-blind randomized controlled trial in

more than 30,000 Thai children aged 1-16 years.165 Protective efficacy was 94% at 12

months, and 100% at 17.5 months after a booster dose at 12 months. After the trial ended, all

controls received two doses of the vaccine and were followed for an additional 10 months. The

subsequent attack rate was 6 cases per 100,000, compared to 114 cases per 100,000 in this

control group during the same interval while the trial was ongoing, and to 52-101 cases per

100,000 in historical controls. In a smaller U.S. trial of healthy children aged 2-16 years, a

single dose of a different inactivated vaccine was 100% efficacious (lower bound 87%) in

preventing hepatitis A at mean 103-day follow-up.166 In other high-risk populations,

seroconversion rates of 82-95% after one dose and 100% after two to three doses of inactivated

hepatitis A vaccine have been reported in children ranging in age from 1 to 15 years.167-169

Although the duration of clinical immunity has not been established, protective levels of antibody

have been shown to persist at least four years after administration of three doses of vaccine.170-

173 Estimates derived from models of antibody decline after vaccination predict that protective

levels of antibody could last for at least 20 years.170 Vaccine efficacy is low in the first week

after vaccination, rising to 77-90% at 2 weeks and 90-100% at 3-4 weeks.166,174-176,179

To provide immediate protection for those at high risk of exposure (e.g., travelers to endemic

areas), administration of immune globulin (IG) with the first vaccine dose may be necessary.

Although several studies have reported lower mean antibody titers when the vaccine is

administered concomitantly with IG, vaccine seroconversion rates appear to be

comparable.177,179 In direct comparisons with IG, traditionally used as preexposure

prophylaxis against hepatitis A for high-risk persons such as international travelers (see

Chapter 67), thevaccine led to higher and longer-lasting antibody titers.178-184 The reported

94-100% protective efficacy of hepatitis A vaccine is higher than that reported for IG (80-

90%) (see Chapter 67), but the clinical efficacies of the two interventions have not been directly

compared in clinical trials.



Adverse effects of the vaccine, including mild local reactions (pain, tenderness, redness, and

swelling) and minor systemic symptoms such as fever, headache, and malaise, occur in 10-30%

of recipients, and are more common after the second and third doses.165-167,169 Serious

allergic reactions, without long-term consequences, have been reported rarely in temporal

association with hepatitis A vaccination.12



Varicella Vaccine.  The efficacy of a live attenuated Oka strain varicella-zoster vaccine was 98%

in preventing chickenpox through two varicella seasons in a randomized, double-blind,

placebo-controlled trial in healthy children and adolescents aged 1-14 years.185,186 Other

studies in children and adolescents have compared the attack rate after household or other close

exposure to that of historical controls and estimated vaccine efficacy at 86-98%.186-190

Breakthrough infections occur at a rate of about 1-2% per year, but illness is attenuated, with

fewer lesions and a reduced incidence of fever compared to natural infections.186,191,192

Protective efficacy and antibody levels have been shown to persist for at least 7-10

years.186,193 In a 17-20-year follow-up study, only 2 of 96 adults who received vaccine in

childhood (age 10 months to 13 years) developed breakthrough infections (both mild cases),

despite 100 documented episodes of contact with persons infected with VZV.194 Antibody levels

were higher than those observed 10 years earlier. It is unclear what effect immune boosting

caused by reinfection with wild-type VZV had on the level or duration of protection against disease.



The vaccine has been less well studied in older adolescents and adults than in children. Adolescents

Ú13 years and adults have a poorer immune response to the varicella vaccine, and two doses are

required to achieve optimal seroconversion rates.187,190,195 A hospital and household exposure

study, conducted in health care workers and parents of young children, reported a protective

efficacy of only 50%, but all breakthrough infections were mild.196



Adverse effects of the vaccine have included injection site reactions and, less commonly,

varicella-like rashes and fever.185,187,190 Experience with substantially greater numbers of

vaccine recipients would be required to rule out rare, serious adverse reactions. Mild herpes

zoster has been reported in several healthy children after varicella vaccine, but it 



appears to occur at a reduced rate compared to that associated with natural varicella,197 as has

been demonstrated for vaccinated children with leukemia.198,199 Herpes zoster has been

reported in one adult recipient of the vaccine.200 The most important potential adverse

consequence of universal preschool varicella vaccination is a shift of the age distribution of cases

into adulthood, when the disease is more severe.14,17 Such a shift would occur if immunity from

childhood vaccination wanes in adulthood, or if a large number of older children enter adolescence

and adulthood without having been vaccinated and without having acquired natural immunity to VZV

because of reduced circulation of wild virus. An age-structured theoretical transmission model

suggests, however, that over a plausible range of values for vaccine efficacy, duration of

immunity, and levels of coverage, routine immunization of preschool children would greatly

reduce the number of primary varicella cases and would therefore reduce overall morbidity (as

measured by hospitalizations) despite a shift in the age distribution of cases.201 This model also

suggests that "catch-up" immunization of 12-year-olds for the first 11 years of the vaccination

program would reduce the likelihood that a large pool of susceptible adolescents and adults would

be created by universal preschool vaccination.



Recommendations of Other Groups



Recommendations on the administration of childhood vaccines are issued regularly by the Advisory

Committee on Immunization Practices (ACIP),202,203 the American Academy of Pediatrics

(AAP),13 and the American Academy of Family Physicians (AAFP).204 These three groups,

working with federal agencies, have approved a unified childhood immunization schedule.205 The

recommendations for the vaccines in the synthesized schedule are generally similar to those

recommended by the Task Force(see Clinical Intervention), except: giving a second dose of MMR at

either age 4-6 or 11-12 years is considered equally acceptable in this schedule, whereas the Task

Force recommends 4-6 years as the preferred age (see Discussion); and routine hepatitis B

vaccine was recommended only in infancy in the unified schedule, whereas the Task Force also

recommends its routine use in all children and adolescents not previously 



immunized. ACIP and AAP have subsequently revised their recommendations for hepatitis B

vaccine to include all children aged 11-12 years who have not previously been vaccinated; ACIP

also recommends vaccinating unimmunized children under 11 years who are Pacific Islanders or

who reside in households of first-generation immigrants from countries with high or intermediate

HBV endemicity.206,216 ACIP and AAP recommend one dose of varicella vaccine for all healthy

children age 12 months to the 13th birthday who have not been previously immunized and who

lack a reliable history of varicella, with a target age of 12-18 months for routine vaccination;

two doses of vaccine 4-8 weeks apart are recommended for susceptible adolescents aged Ú13

years.207,207a AAP recommends optional serologic testing in healthy adolescents older than 18

years who lack a history of varicella.207 Recommendations for the use of varicella vaccine are

being developed by AAFP and other organizations. The Food and Drug Administration has approved

inactivated hepatitis A vaccine for use in selected groups including travelers, military personnel,

and laboratory workers.208 Recommendations for the use of hepatitis A vaccine in children are

being developed by ACIP, AAP, AAFP, and other groups. ACIP has issued recommendations for the

use of inactivated hepatitis A vaccine for susceptible persons aged Ú2 years traveling to or

working in countries with intermediate or high HAV endemicity.208a



Discussion



All of the vaccines licensed for routine use in children have been proved efficacious in controlled

studies or multiple time series. Those that have been in widespread use for some years

(diphtheria, pertussis, tetanus, polio, measles, mumps, rubella, Hib) have already demonstrated

a dramatic effect on the incidence of childhood disease. In the case of polio, more than a decade has

passed since the last documented transmission of wild poliovirus in the U.S., and more recently

poliomyelitis has been eradicated in the entire Western hemisphere.209 Global eradication efforts

are now concentrated on interrupting transmission in Asia and sub-Saharan Africa. All cases of

endemic paralytic poliomyelitis in the U.S. are now caused by vaccine-strain poliovirus

infections, indicating that there may be a benefit from replacing OPV with enhanced-potency IPV.

The use of combination vaccines that include IPV may reduce the costs and adverse effects

associated with adding another injection to the infant vaccine schedule. Such combination vaccines

are not yet available in the U.S.



Whether universal hepatitis B and varicella vaccination will lead to benefits similar to those

attributable to previously approved vaccines is unknown. Their appropriateness for routine use in

healthy children is a policy decision that must take into account other issues in addition to vaccine

efficacy, including cost-effectiveness, available resources, and competing priorities. Routine

infant vaccination against hepatitis B in the U.S. has been recommended primarily as a way to

prevent HBV infection in adolescents and adults, but this benefit has not yet been documented.

Universal vaccination in early adolescence (e.g., age 11-12) would be effective in preventing

adolescent HBV infection, but it would not prevent transmission in early childhood, when the risk

of developing chronic carriage is highest and which continued to occur in the U.S. despite selective

vaccination of infants born to HBsAg+ mothers. One cost-effectiveness analysis reported an

incremental cost of universal newborn vaccination relative to screening pregnant women and

selective vaccination of high-risk newborns to be $30,347 per discounted life-year gained,

which is comparable to that of other health care strategies commonly used in North America, such

as treatment for mild hypertension.210 Another cost-effectiveness analysis211 reported that

screening all pregnant women and giving vaccine plus HBIG to neonates of HBsAg+ mothers (as

currently recommended in Chapter 24), combined with universal vaccination of children at age

10 with a booster at age 20, was more cost-effective than universal vaccination of newborns

(with boosters at age 10 and 20) or universal vaccination of adolescents at age 10 (with a booster

at age 20) without screening in pregnancy. This analysis did not account, however, for the

consequences of horizontal transmission and consequent chronic infection during childhood. A

cost-effectiveness analysis has evaluated prevaccination testing for hepatitis B in adolescents or

preadolescents; this strategy was not effective in term of cost or rate of completed vaccination

unless the seroprevalence of antibodies to HBsAg was at least 40% (also see Chapter 24).211a



For varicella vaccine, there are few data regarding protective efficacy beyond about 10 years after

vaccination. The likely change in VZV epidemiology as a result of universal childhood

immunization, i.e., that chickenpox would occur primarily in adulthood when it tends to be more

severe, remains an important concern. While the previously cited model201 found that the overall

effect of universal preschool vaccination would be beneficial, longer experience will be necessary

to demonstrate this. Cost effectiveness analysis suggests that routine vaccination for preschool-age

children results in cost savings when the analysis includes both direct medical costs and indirect

costs (i.e., current work-loss of parents and of infected adults, and future work-loss of those who

die or who are permanently disabled from encephalitis).212 Vaccination before age 13 is

preferable because two doses 4-8 weeks apart are required to achieve optimal seroconversion

rates when the vaccine is given after age 12. The use of combined vaccines (e.g., MMRV,213,214

which is not currently available in the U.S.) would reduce the number of injections needed,

reducing the adverse effects associated with multiple needlesticks and potentially reducing costs.

Vaccinating all adolescents and adults with a negative or uncertain history of chickenpox is likely

to be more effective in preventing chickenpox than serologic testing followed by immunization of

test-negative adolescents and adults, because with the latter strategy, loss to follow-up and

false-positive test results will reduce the proportion protected. Serologic testing prior to

vaccination may be more cost-effective, however, because many adolescents and most adults with

negative or uncertain histories of chickenpox are in fact immune, and because the need for two

doses to be given at two separate visits increases the costs of vaccination.215



Recommendations have been made to give a second MMR dose at either 4-6 years or 11-12

years.205 Giving the second dose at 4-6 years has two apparent advantages: primary

immunization failures are corrected sooner and the health care and school systems are poised to

capture the most individuals for immunization at the time of school entry. The advantage of a dose

at 11-12 years is that it should have a more immediate impact on outbreaks involving middle,

junior high, and high schools, and colleges. Studies directly comparing different two-dose

schedules are under way. The weight of the currently available evidence would not appear to favor

delaying the second dose into late childhood with the intent of preventing secondary immunization

failure. Efforts should be made, however, to vaccinate all children aged 11-12 years who have not

previously received a second dose of MMR.



CLINICAL INTERVENTION



All children without established contraindications should receive diphtheria-tetanus-pertussis

(DTP), oral poliovirus (OPV), measles-mumps-rubella (MMR), conjugate H. influenzae type b

(Hib), hepatitis B, and varicella vaccines ("A" recommendation).



The recommended childhood immunization schedule includes DTP vaccine at ages 2 months, 4

months, and 6 months; DTP at 12-18 months or DTaP at 15-18 months; and DTP or DTaP

between ages 4 and 6 years, just prior to school entry. A combined tetanus-diphtheria (Td)

booster should be administered at age 11-12 years (14-16 years is an acceptable alternative)

and periodically in adulthood (see Chapter 66). OPV vaccine is recommended at ages 2 months, 4

months, 6-18 months, and 4-6 years.



MMR vaccine should be administered at age 12-15 months and again at 4-6 years of age; 11-12

years is an acceptable alternative for the second dose. Giving the first dose at 15 months may be

preferable when compliance with a visit at this age is assured, because efficacy and

immunogenicity are slightly higher than at 12 months. Children over 6 years of age who present

for care and have not yet received two doses of measles vaccine should be vaccinated with MMR,

with the goal that all children will have had two doses of measles or MMR vaccine by 11-12 years

of age.



Hib conjugate vaccine should be given at 2, 4, and 6 months (HbOC or PRP-T) or 2 and 4 months

(PRP-OMP), with a booster dose at 12-15 months of age using any of the conjugate vaccines.

While giving a single conjugate Hib vaccine for the primary series is preferred because of proven

clinical efficacy, there is good evidence for the safety and immunogenicity of heterogenous Hib

conjugate vaccine series. Therefore, immunization at the recommended intervals (2, 4, 6, and

12-15 months) should not be delayed by efforts to determine the type of vaccine previously

received. When this information is unavailable, any of the conjugate vaccines approved for use in

infants may be given to complete the series. Licensed combined vaccines (e.g., DTP-HbOC

[Tetrammune]*) may be substituted for the relevant individual vaccines in cases where both

vaccines would normally be given in order to reduce the total number of injections given.



Hepatitis B vaccine is recommended for all infants, and for all children and adolescents not

previously immunized, particularly those in high-risk populations (see Chapters 24 and 66).

For infants, the first dose is recommended at 0-2 months (preferably prior to hospital

discharge), the second dose 1-2 months after the first, and the third dose at 6-18 months

(preferably at least 4 months after the second dose). Giving hepatitis B vaccine at 0, 1, 2, and 12

months of age is also acceptable. After infancy, the vaccine schedule is at the current visit and 1

and 6 months latter. Clinicians may wish to inform parents that booster doses may be required in

the future to maintain immunity through adolescence and adulthood.



Varicella vaccine, administered subcutaneously in one 0.5-mL dose, is recommended for routine

use in healthy children 12-18 months of age, and in children under age 13 with no reliable

history of varicella infection or previous immunization. Clinicians should inform parents that

varicella disease in adulthood is associated with increased risk of serious complications, the

duration of immunity provided by varicella vaccine has not been established, and booster doses of

the vaccine may be required to maintain protection throughout adulthood. Two doses of vaccine

delivered 4-8 weeks apart are recommended for healthy adolescents Ú13 years of age with no

reliable history of varicella infection or previous vaccination. Given the relatively high

prevalence of immunity in adolescents with no history of chickenpox and the results of

cost-effectiveness analysis, clinicians may wish to offer serologic testing for varicella

susceptibility to history-negative adolescents Ú13 years who are likely to comply with return

visits.



Clinicians may wish to conduct an assessment of immunization status for all children at age 11-

12, in particular to determine whether the patient needs Td, MMR, varicella, or hepatitis B

vaccines. Clinicians are referred to published guidelines for details on vaccine contraindications,

instructions for immunizing children with medical disorders (including human immunodeficiency

virus infection), and modified protocols recommended during community outbreaks or epidemics

or for children with delayed immunization.13,202



Hepatitis A vaccine is recommended for all high-risk children aged Ú2 years and all high-risk

adolescents ("A" recommendation). High-risk groups include persons living in, traveling to, or

working in areas where the disease is endemic and periodic outbreaks occur (e.g., countries with

high or intermediate endemicity, Alaska Native, Pacific Islander, and Native American

communities, certain religious communities) (see Chapter 66 for additional high-risk groups and

recommendations for adult immunization). Hepatitis A vaccination may also be considered for

institutionalized persons (e.g., those living in chronic care facilities). Where tracking or

identification of high-risk patients is not practical or cost-effective, universal vaccination may

be a reasonable policy given the minimal adverse consequences of the vaccine. At this writing, the

only licensed hepatitis A vaccine is Havrix (SmithKline Beecham Pharmaceuticals).* Three

doses (360 ELISA units/dose), administered intramuscularly, are recommended for persons aged

2-18 years; the second and third doses are given 1 and 6-12 months after the first dose. The need

for periodic booster doses has not been established. For persons requiring immediate protection

against hepatitis A (e.g., travelers to high-risk areas who have not previously been vaccinated),

IG (0.02 mL/kg) should be given simultaneously with the first dose of hepatitis A vaccine,

although the clinical efficacy of this approach has not been established. IG can also be recommended

as an efficacious intervention for short-term (Û5-6 months) preexposure prophylaxis against

hepatitis A (see Chapter 67). While some evidence suggests that the vaccine may be more

efficacious than IG, the clinical efficacies of the two regimens have not been directly compared in

clinical trials. Other factors to consider in choosing between the two interventions are patient

preference, the likely frequency and duration of exposure, the need for immediate protection, and

cost.



Annual influenza vaccine is recommended for adolescents and children Ú6 months of age who are

residents of chronic care facilities or have chronic cardiopulmonary disorders, metabolic diseases

(including diabetes mellitus), hemoglobinopathies, immunosuppression, or renal dysfunction

("B" recommendation) (see Chapter 66 for the review of evidence regarding influenza vaccine).

Split-virus vaccine is recommended for children Û12 years; the recommended vaccine dose is

0.25 mL for children 6-35 months of age and 0.5 mL for children Ú3 years of age.13 Amantadine

and rimantadine prophylaxis against influenza A is discussed in Chapter 66.



Pneumococcal vaccine is recommended for immunocompetent adolescents and children (Ú2 years of

age) with chronic cardiac or pulmonary disease, diabetes mellitus, and anatomic asplenia

(excluding sickle cell disease), and those living in special environments or social settings with an

identified increased risk of pneumococcal disease (e.g., certain Native American and Alaska Native

populations) ("B" recommendation) (see Chapter 66 for the review of evidence regarding

pneumococcal vaccine). Routine revaccination is not recommended, but it may be appropriate to

consider periodic revaccination in immunocompetent individuals at highest risk for morbidity and

mortality from pneumococcal disease (e.g., those with severe chronic disease) who were

vaccinated more than 5 years previously. There is insufficient evidence to recommend for or

against pneumococcal vaccine as an efficacious vaccine for immunocompromised children Ú2 years

of age, but recommendations for vaccinating these persons may be made on other grounds,

including high incidence and mortality rates of pneumococcal disease and minimal adverse effects

from vaccine ("C" recommendation). Examples of immunocompromised conditions associated with

high risk for pneumococcal disease include acquired or congenital immunodeficiency (including

HIV infection), sickle cell disease, nephrotic syndrome, chronic renal failure, metastatic or

hematologic malignancy, and other conditions associated with immunosuppression, such as organ

transplant. It may be appropriate to consider periodic revaccination in these patients, who are

likely to have poor initial antibody response and rapid decline of antibodies after vaccination.



See Chapter 25 (screening for tuberculous infection) for recommendations regarding the BCG

vaccine. Recommendations on postexposure prophylaxis against selected infectious diseases,

including tetanus, hepatitis A, hepatitis B, and Hib, are given in Chapter 67.



The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by

Carolyn DiGuiseppi, MD, MPH, based in part on background papers on measles and Hib vaccines

prepared by Modena Wilson, MD, MPH, and Donald Robinson, MD, MPH.



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