Chapter I.4. Immunizations
Dennis A. Conrad, MD
May 2013

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Flush with the enthusiasm of past success and anticipation of his bright future, Dr. Te’o, having completed his pediatric residency training and surveying his office on the first day of business, was confident in his ability to care for children. Therefore, he was especially pleased that his first scheduled appointment of the morning was an expectant couple whose visit was for prepartum counseling in anticipation of Dr. Te’o becoming their unborn child’s pediatrician. “Dr. Te’o,” asked the mother, “what can we do to ensure the health and well-being of our child?” “One of the most important aspects of pediatric healthcare is to ensure that your child receives all recommended immunizations at the age-appropriate times,” responded Dr. Te’o sagely. “But aren’t vaccines potentially dangerous, and haven’t most of those diseases gone away anyway?” interjected the worried father. Realizing that parents regard healthcare providers as the most important single source for vaccine immunization, that many anxieties and parental concerns are stated primarily to seek reassurance of the validity of offered medical advice, and that a pediatrician must be a knowledgeable and persuasive advocate for the health of all children, Dr. Te’o replied, “Actually, immunization is the most cost-effective intervention we do to maintain a child’s health, and has been the primary reason that these diseases have seemed to have ‘gone away;’ thus, I strongly recommend that your child be immunized according to current recommendations to protect his or her health and to ensure that these diseases do not ‘come back.’ However, please allow me to specifically address the benefits and potential risks of immunizations.” That which follows is what Dr. Te’o told the parents on that fateful morning, which resulted in their immense satisfaction, and confirmed that their choice of a pediatrician was a very wise one indeed.


Immunizations children routinely receive during childhood are those that protect against hepatitis B, rotavirus, diphtheria, pertussis, tetanus, polio, Haemophilus influenzae type b, Streptococcus pneumoniae, hepatitis A, influenza, measles, mumps, rubella, and varicella (1). Adolescents should be immunized with the quadrivalent meningococcal conjugate and human papillomavirus vaccines, and receive a tetanus/diphtheria/acellular pertussis vaccine booster dose. The number and ages of administration for these vaccines differ, but the goal of the recommended schedule for childhood and adolescent immunizations is to provide full protection against vaccine-preventable diseases.

Immunization policy has established the practice of universal childhood immunization to provide vaccines at a time (childhood) when an individual is more likely to have contact with health care providers (to increase convenience and minimize delivery costs), to protect children from vaccine-preventable diseases, to establish the foundation for an immune adult population, and to have an enforceable mechanism in order to ensure compliance (required for school entry).

Hepatitis B virus (HBV) vaccine is a recombinant subunit vaccine containing purified hepatitis B surface antigen, synthesized by insertion of a plasmid encoding for the hepatitis B surface antigen protein into baker's yeast (2). Hepatitis B vaccine exists as monovalent vaccine (RecombivaxHB®; Engerix-B®), in combination with Haemophilus influenzae type b vaccine (Comvax®), and in combination with hepatitis A vaccine (Twinrix®). The monovalent hepatitis B vaccines are administered as a 3-dose series, with the first dose given at birth before hospital discharge, the second dose between 1 and 2 months of age, and the third dose between 6 and 18-months of age. Comvax® should not be given before 6-weeks of age due to the Haemophilus influenzae type b component, and Twinrix® is not approved in the United States for use in persons less than 18-years old.

Universal immunization of infants with hepatitis B vaccine is recommended to provide global protection of that birth cohort against hepatitis B infection, to provide vaccine at a time health care visits are otherwise being made, and to afford protection to infants born to mothers who have chronic hepatitis B infection. If hepatitis B vaccination is not provided in infancy at the recommended ages, then at least a 4-week interval should separate administration of the first and second vaccine doses, and at least an 8-week interval should separate the second and third vaccine doses (with the third dose given at least 16-weeks after the first dose).

The most common adverse reactions to hepatitis B immunization are fever and local reactions at the injection site. Allergic reactions occur infrequently. No causal association with multiple sclerosis or sudden infant death syndrome has been demonstrated.

Rotavirus infection was the leading cause of hospitalization due to diarrhea in children under the age of 2-years prior to the development of rotavirus vaccines. An orally administered tetravalent rotavirus vaccine derived from rhesus monkey virus strains was the first rotavirus vaccine licensed for use in the United States, but an increased incidence of intussusception temporally associated with vaccine administration resulted in the vaccine being voluntarily removed from the market. Two additional rotavirus vaccines subsequently have been licensed for use in infants following comprehensive clinical trials demonstrating efficacy and safety of the vaccines (3). Post-licensure evaluations have been mixed in determining whether an increased risk for intussusception is temporally associated with use of the current rotavirus vaccines, so both vaccines are contraindicated for infants with a history of intussusception.

Monovalent rotavirus vaccine (Rotarix®) is a live attenuated vaccine derived from human rotavirus serogroup G1P8 and approved as a two-dose series, with the first dose administered at age 6-weeks or older, and the second dose administered by age 24-weeks and at least four weeks following the first dose. The vaccine protects against rotavirus infection by strains producing either the G1 or P8 antigen (G1, G3, G4, and G9) but is not protective against rotavirus G2P4, which accounted for approximately 15% of rotavirus disease occurring in the United States annually in the pre-vaccine era.

Pentavalent rotavirus vaccine (RotaTeq®) is a live attenuated bovine reassortant vaccine expressing human rotavirus antigens G1, G2, G3, G4, and P8 approved as a three-dose series administered at ages 2, 4, and 6-months, and not before the age of 6-weeks or after the age of 32-weeks. This vaccine protects against rotavirus disease due to human rotavirus serogroups G1, G2, G3, G4, and P8, including serogroup G2P4, and has been demonstrated protective against G9 in post hoc evaluation of clinical data.

In an attempt to harmonize discrepant schedules for rotavirus immunization, the Advisory Committee for Immunization Practices has recommended administration of the first dose of either rotavirus vaccine between the ages 6-weeks and 14-weeks, 6-days, and administration of the final dose of either rotavirus vaccine no later than age 8-months, 0-days. If two doses of the monovalent rotavirus vaccine have been administered, a third dose is not needed, whereas infants receiving less than two doses of monovalent rotavirus vaccine for the first two doses should receive a third dose of either rotavirus vaccine.

Gastrointestinal disturbance is the most common adverse event reported following rotavirus immunization with the two current rotavirus vaccines. Neither vaccine should be administered to infants who have a known underlying immunodeficiency, and immunization should be delayed until the immune status of the infant has been ascertained (such as by neonatal screening for severe combined immunodeficiency).

Diphtheria (D; d) vaccine is a toxoid vaccine that provides formalin-inactivated diphtheria toxin, derived from a potent exotoxin produced by Corynebacterium diphtheriae (4). A "toxoid" is a denatured (nonpathogenic) toxin that stimulates an immune response against the toxin but not necessarily the organism as a whole. Diphtheria immunization promotes an antibody response that can neutralize the exotoxin, protecting against the cardiotoxic and neurotoxic effects of exotoxin produced during infection. Diphtheria toxoid is combined with tetanus toxoid in a pediatric (DT) and adult (dT) formulation that differs by amount of diphtheria antigen.

Tetanus (T) vaccine is a toxoid vaccine that provides formalin-inactivated tetanus toxin, derived from the neuromuscular toxin tetanospasmin produced by Clostridium tetani (4). Immunization promotes an antibody response that neutralizes the toxin. Tetanus vaccine may be monovalent (TT), or combined with either diphtheria toxoid (DT or dT) or with diphtheria toxoid and acellular pertussis (DTaP).

Persons who sustain injuries more likely to become infected with Clostridium tetani (crush wounds with devitalized tissue, deep puncture wounds, wounds contaminated with soil or vegetative matter) should receive a booster dose of tetanus vaccine if at least 5 years have passed since last receiving a tetanus vaccine booster.

The most common adverse reactions to tetanus immunization are fever and local reactions at the injection site. Severe allergic reactions, Guillain-Barre syndrome, and brachial neuritis occur rarely.

Two acellular pertussis (aP) vaccines are currently licensed and available for use in the United States (Infanrix®; Daptacel®) for immunization of children less than 7-years old. These vaccines are called acellular, to distinguish this formulation from the older whole-cell pertussis vaccine. Whole-cell pertussis vaccine consisted of inactivated ("killed") but otherwise complete Bordetella pertussis bacteria. Administration provided protection against disease but was associated with the potential for adverse effects that occurred frequently and could be quite severe on rare occasions. In order to provide a vaccine that was better-tolerated, individual bacterial components that contributed to organism virulence and pathogenicity were identified and purified as individual cell-free (acellular) antigens that comprise the current acellular pertussis vaccines (4,5).

Diphtheria and tetanus toxoids combined with the acellular pertussis vaccine (DTaP) is the recommended vaccine for use during routine childhood immunization. DTaP is given by intramuscular injection as a primary 3-dose series at 2, 4, and 6-months of age, and as a 2-dose booster series at between 12 and 18-months and 4 and 6-years of age.

The most common adverse reactions to acellular pertussis immunization are fever and local reactions at the injection site. Allergic reactions occur infrequently. Rare but potentially serious reactions, including high fevers, prolonged crying, hypotonic-hyporesponsive episodes, and seizures have occurred, but at significantly lower frequency than was true for whole cell pertussis vaccine.

Two tetanus booster vaccines are available that combine reduced antigenic content of diphtheria and tetanus toxoids in combination with acellular pertussis antigens (Tdap) for immunization of children 7-years-old and older, adolescents, and adults. The Tdap booster Boostrix® contains three pertussis-specific antigens (inactivated pertussis toxin, formaldehyde-treated filamentous hemagglutinin, and pertactin), whereas the Tdap booster Adacel® contains five pertussis-specific antigens (detoxified pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae types 2 and 3 antigens). The three pertussis antigens contained in Boostrix® are the same three pertussis antigens contained in Infantrix®, and the five pertussis antigens contained in Adacel® are the same five pertussis antigens contained in Daptacel®.

Either of the two Tdap boosters is recommended for immunization at the preferred ages of 11-through-12 years. Currently, however, neither Tdap boosters is recommended to be administered for more than a single dose for adolescents and adults, with the exception that pregnant women receive a Tdap booster dose at 20-weeks gestation or later during that pregnancy and for all subsequent pregnancies in order to protect the unborn infant from acquiring pertussis prior to receiving the primary series in infancy beginning at 2 months (6). With the exception of pregnancy, for all individuals who have been immunized against pertussis, the reduced diphtheria-antigen tetanus toxoid formulation (dT) should be administered as subsequent booster doses at 10-year intervals throughout life, unless injury requiring tetanus boosting should occur within any decennial interval at least 5 years after the most recent tetanus booster dose.

Inactivated polio vaccine (IPV) is a trivalent killed virus vaccine (Salk vaccine; IPOL®) that contains formalin-inactivated poliovirus 1, poliovirus 2, and poliovirus 3, which are the three neurovirulent strains. Improvement in manufacturing techniques has enhanced the immunogenicity of inactivated polio vaccine (eIPV) beyond that achieved by the original vaccine. Immunization effectively protects against paralytic poliomyelitis, but may not protect against subclinical enteric infection due to lack of secretory antibody response to inactivated polio vaccine (7). Inactivated polio vaccine is administered as a 4-dose regimen by intramuscular injection at 2-months, 4-months, between 6 and 18-months (3 dose primary series), and between 4 and 6-years of age (booster dose). If the third dose of polio vaccine is administered at age 4-years or later, a fourth dose is not required.

The most common adverse reactions to inactivated polio immunization are fever and local reactions at the injection site. Allergic reactions occur infrequently. Inactivated polio vaccine cannot cause vaccine associated paralytic poliomyelitis.

A second formulation of polio vaccine, trivalent oral live attenuated polio vaccine (tOPV; Sabin vaccine; Orimune®), also provides protective immunity against paralytic poliomyelitis. In addition, oral polio vaccine uniquely protects against enteric infection by promoting mucosal immunity and offering the benefit of herd immunity by secondary immunization of susceptible persons exposed to vaccine-strain virus being asymptomatically shed by vaccine recipients. Unfortunately, as paralytic poliomyelitis due to wild-type virus was eradicated in the United States by effective immunization programs, the rare risk of paralytic poliomyelitis due to vaccine strain virus (3 to 12 cases annually) ultimately became greater than the risk due to wild-type poliovirus. Therefore, only inactivated polio vaccine is used in the United States, whereas the effective, economically favorable, convenient trivalent oral polio vaccine continues to be used in wild-virus polio endemic regions in an attempt to eradicate paralytic poliomyelitis worldwide.

A vaccine containing DTaP, HBV, and IPV (Pediarix®) is licensed for use in the United States to provide the primary series of immunizations (first 3 doses) for children 6-months to 7-years old. This combination vaccine may be used for all 3 vaccine doses, or used to complete the primary series in infants who have already received 1 or 2 doses of DTaP, HBV, or IPV separately. This combination vaccine was developed to reduce the number of injections infants receive during routine childhood immunization, providing the same vaccines that had previously existed individually (Infanrix®, IPV, and Engerix-B®). A vaccine containing DTaP and IPV (Kinrix®) is licensed to provide the fifth dose of DTaP and the fourth dose of IPV at ages 4-6 years, and can be used in children receiving Pediarix® for the primary series.

A second combination vaccine containing DTaP, Hib, and IPV (Pentacel®) is also licensed for use in the United States to provide the primary series of immunizations (first 3 doses) for children at ages 2, 4, and 6-months, and as a fourth-dose booster at ages 15-18 months. The combination vaccine was also developed to reduce the number of injections infants receive during routine childhood immunization, to coincide more closely with the recommended childhood immunization schedule, to allow the combination to also be administered as a fourth-dose booster, and to provide the same vaccines that have previously existed individually (Daptacel®, Poliovax®, and ActHIB®)

Haemophilus influenzae type b (Hib) vaccine is a conjugated vaccine containing the Haemophilus influenzae type b capsular polysaccharide polyribosylribitol phosphate (PRP), which is the major virulence factor, conjugated with a carrier protein to enhance immunogenicity (8). Infants less than 6-weeks old should not be exposed to vaccines containing Haemophilus influenzae type b PRP antigen, as premature exposure may create immune tolerance, causing suboptimal antibody response upon subsequent antigen exposure and resulting in failure to develop protective antibody concentrations.

The two monovalent conjugated Haemophilus influenzae type b vaccines currently available are differentiated by their respective carrier proteins; ActHIB® utilizes a tetanus toxoid, and PedVaxHib® utilizes Neisseria meningitidis serogroup B outer-membrane protein.

Infants receive either a 2-dose (PedVaxHib®) or 3-dose (ActHIB®) series of Haemophilus influenzae type b immunization during the first year of life, and a single booster dose between 12 and 15-months of age (resulting in either a 3-dose or 4-dose regimen to completely immunize the child). A third monovalent conjugated Haemophilus influenzae type b vaccine (Hiberix®) utilizes a tetanus toxoid conjugate, but is only approved as a final-dose booster administered after completion of the primary series and after age 12-months.

The number of conjugated Haemophilus influenzae type b vaccine doses required to immunize older children not receiving vaccine in infancy diminishes due to brisker antibody response seen when older children receive conjugated Haemophilus influenzae type b vaccine. If the first dose of vaccine is not administered until the child is between 7 and 11-months of age, then only 3 doses are required to complete the regimen. If the first dose of vaccine is not administered until the child is between 12 and 14-months of age, then only 2 doses are required to complete the regimen. If the first dose of vaccine is not administered until the child is between 15 and 59-months of age, then only a single dose is required to complete the regimen. Non-immunized children 5-years old and older do not require Haemophilus influenzae type b vaccine unless they possess underlying risk factors (impairment in immunity) that would increase their risk for invasive disease.

The most common adverse reactions to conjugated Haemophilus influenzae type b vaccines are fever and local reactions at the injection site. Allergic reactions occur infrequently.

Streptococcus pneumoniae conjugate vaccine (PCV; Prevnar®) contains the capsular polysaccharides of medically important stains of Streptococcus pneumoniae conjugated with a nontoxic mutant diphtheria toxin to enhance immunogenicity when administered to infants; a 7-valent (PCV7) was developed initially and was anticipated to be protective against 85-90% of all cases of invasive pneumococcal disease occurring in children in the United States in the pre-vaccine era (9). More recently, a 13-valent pneumococcal conjugate vaccine (PCV13) has been licensed (10); the 6 additional serotypes included in this newer formulation collectively account for approximately 65% of strains causing invasive disease in children that had not been previously covered by the 7-valent vaccine.

Infants receive a 4-dose regimen of pneumococcal conjugate vaccine. The primary series is administered by intramuscular injection at 2, 4, and 6 months of age, and a fourth (booster) dose is administered between the ages of 12 and 15-months.

The number of conjugated pneumococcal vaccine doses required to immunize older children not receiving vaccine in infancy is reduced due to the brisker antibody response seen when older children receive conjugated pneumococcal vaccine. If the first dose of vaccine is not administered until the child is between 7 and 11-months of age, then only 3 doses are required to complete the regimen. If the first dose of vaccine is not administered until the child is between 12 and 23-months of age, then only 2 doses are required to complete the regimen.

All children less than 60-months of age should receive at least one dose of the 13-valent pneumococcal conjugate vaccine (PCV13), even if they have completed a four-dose series with the older 7-valent pneumococcal conjugate vaccine (PCV7). Those children less than 72-months old with underlying risk factors that increase the risk for invasive pneumococcal disease should receive at least one dose of the 13-valent pneumococcal conjugated vaccine (PCV13), even if they completed a four-dose series with the older 7-valent pneumococcal conjugated vaccine (PCV7).

The most common adverse reactions following conjugated Streptococcus pneumoniae immunization are fever and local reactions at the injection site. Allergic reactions occur infrequently. Occasionally, fever may be high and local reactions severe, especially with subsequent doses of vaccine. Febrile seizures may complicate vaccine-induced fevers.

Capsular polysaccharide is an important virulence factor for Streptococcus pneumoniae, existing in antigenically distinct permutations that confer type specificity to the individual bacterium, and requiring a type-specific host immune response to protect against disease. Non-conjugated pneumococcal polysaccharide vaccine (PPV), which was developed before conjugated pneumococcal vaccine, currently exists as two 23-valent vaccines (PPV23; PNU-IMUNE 23®; Pneumovax 23®) that protects against more than 90% of strains causing invasive pneumococcal disease in children and adults in the United States, but is poorly immunogenic in children under 2-years of age.

Use of the non-conjugated polysaccharide vaccine is indicated for persons at least 2-years of age, and is administered as a single intramuscular injection. Persons at high risk for invasive pneumococcal disease (asplenia, sickling hemoglobinopathy, congenital and acquired immunodeficiency, immunosuppression, spinal fluid leak, cochlear implants, chronic cardiac, pulmonary, hepatic, or renal disease) should receive a second dose of unconjugated pneumococcal polysaccharide vaccine, administered between 3 and 5 years following the initial dose. Previously unimmunized persons at the highest risk for invasive pneumococcal disease (asplenia, sickling hemoglobinopathy, congenital and acquired immunodeficiency, immunosuppression, spinal fluid leak, cochlear implants) should receive a dose of 13-valent pneumococcal conjugate vaccine, a dose of 23-valent pneumococcal polysaccharide vaccine 8 or more weeks later, and then a second dose of 23-valent pneumococcal polysaccharide vaccine 5 years after the first dose.

Measles (Me) vaccine is an attenuated live virus vaccine that causes subclinical infection following administration, provoking a host immune response that protects against subsequent infection following exposure to wild-type virus. The first measles vaccine developed was a killed virus vaccine, which was associated with the potential development of an infection called "atypical measles" when vaccinated individuals were subsequently infected with wild-type virus. The current measles vaccine is an attenuated live virus vaccine that contains the Moraten ("more attenuated") strain of measles virus, which effectively confers immunity while reducing the incidence of adverse events following vaccination that occurred when less attenuated live virus measles strains had been used previously.

Measles vaccine is administered in combination with mumps vaccine and rubella vaccine as a live attenuated virus vaccine (MMR) given as a subcutaneous injection to children between the ages of 12 and 15-months. Approximately 95% of vaccine recipients respond to a single dose of vaccine; however, due to an increase in wild-type measles observed in vaccine recipients during the 1980s and more recently, an increase in mumps imported by previously immunized college-aged students who had visited Europe during the mid-2000s, current recommendations require a second dose of vaccine, generally administered between the ages of 4 and 6-years prior to school entry (11).

The most common adverse reactions to MMR immunization are fever and local reactions at the injection site. Occasionally, transient rashes and transient thrombocytopenia may occur. Allergic reactions occur infrequently. Encephalitis has been suggested as an extremely rare complication of measles immunization, but definitive proof is lacking. No valid scientific evidence supports measles vaccine as causation for autism despite sensational claims to the contrary. Orchitis and parotitis have been rarely reported from mumps vaccine. Occasionally, transient arthralgia and arthritis and peripheral neuritis may occur from rubella vaccine.

Varicella (Var) vaccine is an attenuated live virus vaccine that causes subclinical infection following administration, provoking a host immune response that protects against subsequent infection following exposure to wild-type virus. Oka strain varicella virus was initially developed in Japan; this same strain was subsequently modified and is currently used in the United States.

Varicella vaccine exists as monovalent vaccine (Varivax®), which is administered as a two-dose regimen for children with the first dose given between 12 and 15-months of age with the second dose administered between the ages of 4-through-6 years in anticipation of school entry. For children beginning the series after the age of 13 years, the doses should be separated by an interval of at least 4-weeks. A single dose of varicella vaccine was associated with a 97% seroconversion rate in children less than 13-years old and a 94% seroconversion rate in older persons; a second dose of vaccine was associated with 99% seroconversion.

Young children should routinely receive varicella vaccine as a component of universal childhood immunization, and older children and adolescents who have not had chickenpox should be identified and immunized (12,13).

The most common adverse reactions to varicella immunization are fever and local reactions at the injection site. Occasionally, recipients may have a localized (at the injection site) or more generalized varicella-like rash due to vaccine strain virus. A minority of vaccine recipients may have a mild case of chickenpox ("breakthrough chickenpox") due to wild-type virus following exposure to naturally occurring disease. Allergic reactions occur infrequently. Shingles can also occur after the varicella vaccine, but at a lower rate compared to the wild-type virus.

A vaccine combining measles, mumps, rubella, and varicella (MMRV) is available for immunization against those diseases. Indications and age of administration for MMRV vaccine is the same as for the constituents, but an increased incidence of febrile seizures occurring in infants receiving the first dose of MMRV has resulted in MMRV recommendations being limited to the second vaccine dose only unless the parents state a preference for the combination to be administered for the first dose as well.

Hepatitis A virus (HAV) vaccine is a killed virus vaccine containing formalin-inactivated hepatitis A virus that exists as monovalent vaccine (Havrix®; Vaqta®) and as bivalent vaccine in combination with hepatitis B vaccine (Twinrix®). The first dose of vaccine produces protective antibody response within two weeks following administration. A second dose is administered to provide long term, durable protection against disease.

Hepatitis A vaccine is indicated for use as a two-dose series administered by intramuscular injection in children at age 12-months, with the second dose administered between 6 and 18-months following the first dose. Routine childhood immunization with hepatitis A vaccine is recommended for all children (14).

Hepatitis A immunization is also recommended for community control of recent outbreaks of infection, for travelers to hepatitis A endemic areas, for persons who have chronic liver disease, for homosexual and bisexual men, for injectors of illicit drugs, and for individuals with clotting factor disorders.

The most common adverse reaction to hepatitis A immunization is a local reaction at the injection site. No serious adverse reaction is associated with hepatitis A vaccine.

Injectable influenza vaccine is a split-virus vaccine (subvirion vaccine; purified surface antigen vaccine) that contains the hemagglutinins of the predominately circulating strains of influenza virus. The vaccine traditionally contains antigens from two influenza A virus strains and one influenza B virus strain, determined by those most frequently isolated at the end of the current year's respiratory virus season and predicted to predominate in the next respiratory virus season, although several formulations, some now approved and some still in development, utilize a second influenza B virus strain to create a quadrivalent influenza vaccine.

Influenza vaccines are formulated and administered annually to compensate for antigenic shifts that occur in virus isolates in order to enhance strain-specific immunity during the current respiratory virus season. All persons 6-months old and older should be immunized against influenza annually; those persons targeted specifically include infants, children, and adolescents, health care workers and others who may be significant vectors for contagion, persons aged 50-years old or older, persons with underlying diseases (immunodeficiency, pulmonary, cardiac, metabolic, renal, and hemoglobinopathies), individuals receiving immunosuppression or chronic aspirin therapy, and pregnant women.

All children beginning at 6-months of age should be immunized annually due to increased morbidity of influenza infection in this age group (15). Children younger than 9-years old receiving influenza vaccine for the first time should receive two doses of vaccine administered in the age-appropriate volume separated by at least a one month interval in order to enhance immunologic response and protection against infection.

A live attenuated, cold-adapted viral influenza vaccine (FluMist®) prepared by viral reassortment is also available for use in the United States; initially developed as a trivalent vaccine, the current formation is now a quadrivalent vaccine composed of two influenza A virus and two influenza B virus strains. This vaccine exists as a spray for intranasal instillation. Use is limited to healthy individuals 2 to 49-years of age.

Children 2 to 8-years old not previously immunized should receive two doses of intranasal influenza vaccine administered at least four weeks apart. Children 5 to 8-years old previously immunized with the intranasal vaccine, and all persons 9 to 49-years of age, should receive a single dose annually.

The most common adverse reactions to influenza immunization are fever and local reactions at the injection site. Allergic reactions occur infrequently. Guillain-Barre syndrome is a rare complication of influenza vaccination, apparently limited to adults. Upper respiratory tract complaints have been associated with the intranasal influenza vaccine, and an increased incidence of wheezing events has been seen in young children following administration of intranasal influenza vaccine.

Three vaccines utilized to protect children against Neisseria meningitidis serogroups A, C, Y, and W-135 are licensed for use in the United States (16). One vaccine is an unconjugated polysaccharide vaccine (Menomune®) initially developed to protect adults at high risk for invasive disease, but also indicated for protection of high-risk children 2-years old and older. However, development and licensure of the two quadrivalent meningococcal conjugate vaccines have largely supplanted the recommended used of unconjugated polysaccharide vaccine in children.

The two quadrivalent meningococcal conjugate vaccines can be distinguished by the conjugating protein; Menactra® utilizes a diphtheria toxoid, and is licensed as a two-dose administered at ages 9 and 12 months for children at high-risk for invasive meningococcal disease, a single-dose series for children 2-10 years of age at increased risk for invasive meningococcal disease, and as a single dose series for children 11-18 years of age. Menveo® utilizes a carrier protein derived from Corynebacterium diphtheriae, and is licensed as a single-dose series for children 2-10 years of age at increased risk for invasive meningococcal disease, and as a single-dose series for children 11-18 years of age. However, despite product labeling, a two-dose series of quadrivalent vaccine is recommended for all children and adolescents at high-risk for invasive meningococcal disease (congenital and acquired immunodeficiency, splenic dysfunction, and sickling hemoglobinopathy) with booster doses subsequently administered every 5 years thereafter for individuals at highest risk for invasive meningococcal disease.

A bivalent meningococcal vaccine protecting against Neisseria meningitidis serogroups C and Y in combination with Haemophilus influenzae b vaccine (MenHibrix®) is licensed as a four-dose series for use in infants at high risk for invasive meningococcal disease, administered at ages 2, 4, 6, and 12-15 months. High-risk infants who complete the four-dose regimen of the bivalent meningococcal conjugate do not require the two-dose regimen of quadrivalent meningococcal conjugate vaccine unless traveling to an area hyperendemic for meningococcal disease (sub-Saharan Africa), but do require receiving a booster dose of quadrivalent meningococcal conjugate vaccine either 3 years (if completing the primary series between ages 2-months and 6-years) or 5 years later (if completing the primary series at age 7-years or older), and then subsequent booster doses every 5 years thereafter.

The most common adverse events associated with receipt of meningococcal conjugate vaccine were local site reactions, fever, fatigue, and malaise. Due to concern about cases of Guillain-Barre syndrome temporally associated with quadrivalent meningococcal conjugate vaccination in adolescents, post-licensure analysis was done that estimated a range of none to at most 1.25 excess cases of Guillain-Barre syndrome occurring in vaccine recipients for every one-million doses of vaccine delivered. In those reported cases of Guillain-Barre syndrome following immunization, all were self-limited and resolved completely.

Adolescents should receive the human papillomavirus immunization, ideally at 11-12 years of age (17). Two human papillomavirus vaccines are currently available; one is a bivalent vaccine (Cervarix®) that is an inactivated engineered subunit vaccine containing self-assembled virus-like particles of the L1 major capsid protein molecules for human papillomavirus types 16 and 18; approximately 70% of cervical cancer can be attributed to infection with these two types of human papillomavirus (HPV16 and HPV18). The vaccine is approved as a 3-dose series administered at times 0, 1, and 6 months, and is indicated for the prevention of cervical cancer and precancerous conditions due to HPV16 and HPV18 in females aged 10 to 25-years. This vaccine is not approved for use in males.

The second human papillomavirus vaccine is a quadrivalent vaccine (Gardasil®), which is an inactivated engineered subunit vaccine containing self-assembled virus-like particles of the L1 major capsid protein molecules for human papillomavirus types 16 and 18 (HPV16 and HPV18), and in addition, human papillomavirus types 6 and 11 (HPV6 and HPV11), the two latter causing approximately 90% of all genital warts in both females and males. The vaccine is approved as a 3-dose series administered at times 0, 2, and 6 months, and is indicated for the prevention of cervical cancer and precancerous conditions, and vulvar and vaginal cancers and precancerous conditions due to HPV16 and HPV18 in females aged 9 to 26-years, and for prevention of anal cancers and precancerous conditions due to HPV16 and HPV18 and genital warts due to HPV6, HPV11, HPV16, and HPV18 in both females and males aged 9 to 26-years (18).

The most common adverse effects reported for the two human papillomavirus vaccines are local site reactions, fever, headache, fatigue, and myalgia. No serious adverse events, including autoimmune disease, thromboembolism, and death could be attributed as being causal by the vaccines.

TABLE 1. RECOMMENDED CHILDHOOD IMMUNIZATIONS AGES BIRTH-6 MONTHS
VACCINE/AGE
2 months
4 months
6 months
Hepatitis B
X (1)
X (1)
X (1)
Rotavirus
X
X
X (2)
Diphtheria/Tetanus/acellular Pertussis
X
X
X
Haemophilus influenzae b
X
X
X (3)
Pneumococcal conjugate 13-valent
X
X
X
Inactivated polio
X
X
X (4)
Influenza
------
------
X (5)

(1) First dose at birth; second dose at 1-2 months; third dose at 6-18 months; alternative dosing at birth, 2, 4, and 6-18 months (providing 4 doses of hepatitis b vaccine is recommended if using hepatitis B combination vaccines [Pediarix® or Comvax®]; if Comvax® is used, either a monovalent hepatitis b vaccine is administered at 6 months or four dose of Comvax® are administered at 2, 4, 6 [for the hepatitis b component], and 12-15 months [for the Haemophilus influenza b component], which would provide five doses of hepatitis b vaccine). If mother’s hepatitis B status is positive, administer first dose of hepatitis b vaccine and hepatitis b immunoglobulin (HBIG) within 12-hours of birth.  If mother’s hepatitis B status is unknown, administer first dose of hepatitis b vaccine and hepatitis b immunoglobulin (HBIG) within 12-hours of birth if birth weight less than 2,000 grams; if birth weight greater than 2,000 grams, may defer HBIG until mother's serostatus known (HBIG is protective if administered within the first 7 days of life).

(2) Three-dose series for pentavalent vaccine RotaTeq®; omit third dose if receiving two doses of monovalent vaccine Rotarix®.

(3) Omit the third dose if receiving two doses of Haemophilus influenzae b-outer membrane complex PedvaxHIB®.

(4) Third dose administered between 6-18 months.

(5) Injectable formulation only for 6 months-2 years; either injectable or intranasal spray after age 2-years; annually thereafter.

TABLE 2. RECOMMENDED CHILDHOOD IMMUNIZATIONS AGES 1-6 YEARS
VACCINE/AGE
12-15 months
15-18 months
4-6 years
Diphtheria/Tetanus/acellular Pertussis
------
X
X
Haemophilus influenzae b
X
------
------
Pneumococcal conjugate 13-valent
X
------
------
Inactivated polio
------
------
X
Hepatitis A
X
X (1)
------
Measles/Mumps/Rubella
X
------
X
Varicella
X
------
X

(1) Second dose 6-18 months following first dose.

TABLE 3. RECOMMENDED ADOLESCENT IMMUNIZATIONS AGES 11-18 YEARS
VACCINE/AGE
11-12 years
13-18 years
Human papillomavirus
X (1)
------
Tetanus/diphtheria/acellular pertussis
X
------
Tetanus/diphtheria
------
X (2)
Meningococcal conjugate
X
X (3)

(1) Three dose series administered at times 0, 1-2, 6 months; bivalent and quadrivalent vaccine approved for females; only quadrivalent vaccine approved for males.

(2) Ten-year intervals following tetanus/diphtheria/acellular pertussis immunization.

(3) Second dose at age 16-years if first dose at 11-12 years; second dose at ages 16-18 years if first dose at ages 13-15 years; no second dose if first dose at age 16-years or older.

Active immunization (as opposed to passive immunization) with vaccines provokes a host response that potentially confers durable immunity and protects against subsequent infection and disease following exposure to naturally occurring infection. In the special circumstance of a susceptible person requiring immediate protection against disease, either prior to or following exposure to infection, transient immunity may be conferred by passive immunization, where preformed protective antibodies are administered (19).

The advantage of passive immunization is the potential to provide immediate protection to the host. The major disadvantage of passive immunity is the subsequent decay of passively acquired antibody by metabolism and elimination, ultimately rendering the host potentially susceptible to infection once passively acquired antibody titers fall to sub-protective concentrations.

Active immunization utilizes a live or killed antigen to stimulate the immune system to form an active immune response, while passive immunization is merely the injecting or infusing human or animal-derived antibodies into the body. Passive immunization preparations currently available include serum immunoglobulin, existing in formulations for intramuscular (IM-IG) and intravenous administration (IVIG), which can provide global protection against infections that are prevalent in the populations from whom these products are derived. In fact, this is why the administration of attenuated live virus vaccines (measles, mumps, rubella, varicella) is deferred for persons who have recently received blood products (including immunoglobulin preparations), since passively acquired antibody may prevent the vaccine-induced subclinical infection and the active immune response from developing.

Killed virus, toxoid, conjugated polysaccharide, recombinant subunit, and bacterial antigen vaccines are not as adversely affected by the presence of passively acquired antibodies, and thus may be administered without consideration of blood products (including immunoglobulin preparations) recently received by the potential vaccine recipient. Passive immunization products may also be specific for selected infections. These agents are labeled "hyperimmune" because effective concentrations of neutralizing antibody have been specifically ascertained. Those diseases for which passive immunity may be provided include palivizumab ("humanized" murine monoclonal anti-RSV antibody), hepatitis B (hepatitis B immune globulin, called HBIG), varicella (varicella zoster immune globulin; called VariZIG), cytomegalovirus (cytomegalovirus immune globulin), and rabies (rabies immune globulin).

Passive immunization products that protect against virulent toxins associated with infection are often called "antitoxins", and are administered to mitigate the significant systemic toxicity associated with infection. Tetanus immune globulin is derived from human serum. Botulism antitoxin (trivalent against botulism toxins A, B, and E) and diphtheria antitoxin are derived from horse serum (20).

Attenuated live virus vaccines (rotavirus, measles, mumps, rubella, varicella, and the intranasal influenza vaccine) should not be administered to persons who have impairment in immunity (congenital or acquired immunodeficiency, receiving immunosuppressive therapy, have malignancy or have undergone bone marrow or organ transplant) or are pregnant, due to the potential risk for the expected subclinical infection following immunization to become clinical, and potentially severe, posing risk to the vulnerable host or unborn child. Moreover, attenuated live virus vaccines should be administered simultaneously (during the same office visit), or individually separated by an interval of at least 4 weeks to prevent immunological interference with the second vaccine. Additional doses of attenuated live virus vaccines in excess of those recommended for childhood immunization may be administered without increased risk of adverse reactions.

Noninfectious vaccines (killed virus, recombinant subunit, toxoid, conjugated polysaccharide, bacterial antigen) may be administered to persons who have impairment in immunity without increased risk, since these vaccines are incapable of causing infection. Immunologically impaired hosts may have suboptimal response to these vaccines, and may not be protected against subsequent development of disease following exposure. Noninfectious vaccines may be administered simultaneously or separated at any interval without appreciable risk of impaired immunologic response (21). Additional doses of these vaccines in excess of those recommended for childhood immunization are generally well tolerated, although the risk for enhanced systemic and local reactions may increase. Diphtheria vaccine and pneumococcal polysaccharide vaccine may be particularly prone to provoke exaggerated reactions with excessive doses of vaccine.

Vaccines are the single most cost-effective interventions performed to improve and maintain the health of citizens of the United States, and have been cited as one of the most significant advancements in medical practice occurring during the 20th century (22). Vaccines are not without risks, but the anxiety expressed by some parents is almost always the result of misperceptions fueled by misinformation. When considered against the risk of infection with concomitant associated morbidity and mortality, the benefits of universal childhood immunization far outweigh all risks for each of the vaccine-preventable diseases. In those circumstances where rare but potentially serious adverse reactions to immunization are demonstrated, the national Vaccine Adverse Event Reporting System (VAERS) provides identification of these rare complications and promotes the appropriate corrective actions. Health care providers should strongly endorse routine childhood immunization, and be capable and willing to adequately address any parental concerns.


Questions

1. Which of the following vaccines would be contraindicated in a 2-month-old boy who has severe combined immunodeficiency?
. . . . a. Hepatitis B vaccine
. . . . b. Bivalent meningococcal/Haemophilus influenzae b vaccine
. . . . c. Acellular pertussis vaccine
. . . . d. Inactivated polio vaccine
. . . . e. Monovalent rotavirus vaccine

2. Which of the following brands of Haemophilus influenzae type b conjugate vaccines is limited to being administered only as a booster (final) dose in children aged 12-months through 4-years?
. . . . a. ActHIB®
. . . . b. Comvax®
. . . . c. MenHibrix®
. . . . d. Hiberix®
. . . . e. PedvaxHIB®

3. For a child receiving the first dose of hepatitis A vaccine at age 12-months, when should the second dose of hepatitis A vaccine preferentially be administered?
. . . . a. As soon as is feasible after the first hepatitis A vaccine dose
. . . . b. One month following the first hepatitis A vaccine dose
. . . . c. Between ages 18-through-30 months
. . . . d. Between ages 4-through-6 years
. . . . e. A second dose of hepatitis A vaccine is not indicated

4. Which passive or active immunization is specifically recommended for a 16-year-old pregnant adolescent at or after 20-weeks gestation?
. . . . a. Cytomegalovirus immune globulin
. . . . b. Tetanus/diphtheria/acellular pertussis booster vaccine
. . . . c. Rubella vaccine
. . . . d. Respiratory syncytial virus monoclonal antibody
. . . . e. Varicella vaccine

5. Both the bivalent human papillomavirus vaccine and the quadrivalent human papillomavirus vaccine are indicated for the prevention of which conditions(s) listed below?
. . . . a. Cervical cancer
. . . . b. Vulvar cancer
. . . . c. Anal cancer
. . . . d. Genital warts
. . . . e. All four conditions listed above (a., b., c., and d.)

6. Immunization with which of the following vaccines should be delayed for a 12-month-old child who received intravenous immunoglobulin for treatment of Kawasaki disease two months previously?
. . . . a. Haemophilus influenzae b vaccine
. . . . b. Pneumococcal conjugate vaccine
. . . . c. Diphtheria/tetanus/acellular vaccine
. . . . d. Measles/mumps/rubella vaccine
. . . . e. Inactivated influenza vaccine

7. Indicate whether the follow are examples of active or passive immunity:
. . . . a. Palivizumab
. . . . b. Botulism antitoxin
. . . . c. Diphtheria/Tetanus toxoid
. . . . d. Diphtheria immune globulin
. . . . e. Inactivated polio vaccine
. . . . f. Influenza vaccine


References

1. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices (ACIP) Recommended Immunization Schedules for Persons Aged 0 Through 18 Years -- United States, 2013. MMWR 2013;62(Suppl 01):2-8.

2. Centers for Disease Control and Prevention. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood immunization: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991;40(RR13):1-19.

3. Centers for Disease Control and Prevention. Prevention of Rotavirus Gastroenteritis Among Infants and Children -- Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2009;58(RR02):1-25.

4. Centers for Disease Control and Prevention. Diphtheria, tetanus, and pertussis: recommendations for vaccine use and other preventative measures -- Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991;40(RR10):1-28.

5. Centers for Disease Control and Prevention. Pertussis vaccination: use of acellular vaccine among infants and young children --- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1997;46(RR07):1-25.

6. Centers for Disease Control and Prevention. Updated Recommendations for Use of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccine (Tdap) in Pregnant Women — Advisory Committee on Immunization Practices (ACIP), 2012. MMWR 2013;62(07):131-135.

7. Centers for Disease Control and Prevention. Poliomyelitis prevention in the United States: updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2000;49(RR05):1-22.

8. Centers for Disease Control and Prevention. Recommendations for use of Haemophilus b conjugate vaccine and a combined diphtheria, tetanus, pertussis, and Haemophilus b vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1993;42(RR13):1-21.

9. Centers for Disease Control and Prevention. Preventing pneumococcal disease among infants and young children: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2000;49(RR09):1-38.

10. Centers for Disease Control and Prevention. Licensure of a 13-Valent Pneumococcal Conjugate Vaccine (PCV13) and Recommendations for Use Among Children -- Advisory Committee on Immunization Practices (ACIP), 2010. MMWR 2010;59(09):258-261.

11. Centers for Disease Control and Prevention. Measles, mumps, and rubella -- Vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1998;47(RR08):1-57.

12. Centers for Disease Control and Prevention. Prevention of varicella: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1996;45(RR11):1-25.

13. Centers for Disease Control and Prevention. Prevention of varicella: Updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1999;48(RR06):1-5.

14. Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55(RR07):1-23.

15. Centers for Disease Control and Prevention. Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP) -- United States, 2012–13 Influenza Season. MMWR 2012;61(32):613-618.

16. Centers for Disease Control and Prevention. Prevention and Control of Meningococcal Disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2013;62(RR02):1-22.

17. Centers for Disease Control and Prevention. FDA Licensure of Bivalent Human Papillomavirus Vaccine (HPV2, Cervarix) for Use in Females and Updated HPV Vaccination Recommendations from the Advisory Committee on Immunization Practices (ACIP). MMWR 2010;59(20):262-269.

18. Centers for Disease Control and Prevention. Recommendations on the Use of Quadrivalent Human Papillomavirus Vaccine in Males -- Advisory Committee on Immunization Practices (ACIP), 2011. MMWR 2011;60(50):1705-1708.

19. Marshall GS. 2012. The Vaccine Handbook: A Practical Guide for Clinicians (4th ed). West Islip, NY. Professional Communications, Inc., pp. 21-23.

20. American Academy of Pediatrics. Passive Immunization. In: Pickering LK, et al (eds). 2000 Red Book: Report of the Committee on Infectious Diseases. 25th edition. 2000, Elk Grove Village, IL: American Academy of Pediatrics, pp. 41-53.

21. Centers for Disease Control and Prevention. General Recommendations on Immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2011;60(RR02):1-60.

22. Centers for Disease Control and Prevention. Achievement in public health, 1900-1999: Impact of vaccines universally recommended for children -- United States, 1990-1998. MMWR 1999;48(12):243-248.


Answers to questions

1.e, 2.d, 3.c, 4.b, 5.a, 6.d

7.a.passive, 7.b.passive, 7.c.active, 7.d.passive, 7.e.active, 7.f.active


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