CHAPTER 37

Immunizations

ChrisAnna M. Mink, MD, FAAP

The Centers for Disease Control and Prevention (CDC) considered immunizations among the top 10 greatest health accomplishments of the 20th century, and vaccines continue to play a major role in the improvement of the health of the world’s population. In the United States, the incidence of nearly all the pathogens for which there are routine vaccinations has decreased by 95% to 100% since the early 20th century. The only exception to this is pertussis, which has undergone an approximately 80% reduction. In 2017, the immunization rates for children in the United States remained high, with 84% to 94% of children aged 19 to 35 months immunized for the 4:3:1:3:3 series (4 diphtheria, tetanus toxoids, and acellular pertussis [DTaP]; 3 polio; 1 measles, mumps, and rubella [MMR]; 3 Haemophilus influenzae type b [Hib]; 3 hepatitis B virus [HBV]). Worldwide, the percentage of children immunized with 3 doses of diphtheria, tetanus toxoids, and pertussis (DTP) and oral polio vaccines (OPV) and a measles-containing vaccine is at a record high of nearly 85%. Since 1990 the mortality rate has declined for children younger than 5 years in every region in the world, which is directly related to increased rates of vaccinations. Generally, immunizations are safe, well tolerated, and cost-effective, with savings of $5 to $16.50 for every $1 spent.

Another less recognized benefit of vaccinations is that the schedule has essentially provided the backbone for routine pediatric care in the United States, with regular visits scheduled around the recommended intervals for immunizations. These visits have afforded health professionals opportunities for serial evaluation of newborns, infants, and young children as well as education and anticipatory guidance for parents. Increasing availability of new vaccines targeted for older children and adolescents should permit opportunities for improved health care delivery to these age groups. Additionally, health professionals who treat adults have a growing appreciation for the critical role of vaccinations in protecting their patients as well as all members of their patients’ family.

General Principles

When planning immunizations for a patient, 2 important factors to consider are the health status of the recipient and the type of immunization to be given. The risks and benefits of using the vaccine in the specific host should be weighed carefully. Vaccines are intended for a host with the capacity for mounting an appropriate immune response, who will likely benefit from the protection provided, and, ideally, who is at little to no risk for adverse effects.

Types of Immunization: Passive and Active

The 2 major types of immunizations are passive and active.

Passive immunization refers to the delivery of preformed antibodies, usually as immune globulin (IG), which may be a general formulation or hyperimmune IG developed with high concentrations of antibodies against a specific disease, such as hepatitis B IG for hepatitis B.

Delivery of IG may be useful in any of the following 3 settings: in a host who cannot manufacture antibodies (eg, congenital immunodeficiency); as a preventive measure, either pre- or post-exposure, especially when the host may be unable to mount an antibody response (eg, immunocompromised naïve child with acute exposure to varicella); or for treatment, in which IG may be used to ame-liorate symptoms in the patient in whom disease is already present (eg, intravenous IG for the management of Kawasaki disease).

With active immunization all, part, or a modified product (eg, toxoid, purified antigen) of a microorganism is given to the host to elicit an immune response. The intact organisms may be inactivated (ie, killed) or live-attenuated (ie, weakened). Usually, the elicited immune response mimics the response to natural infection and, ideally, poses little to no risk to the recipient.

Inactivated Vaccines

Inactivated vaccines may contain inactivated or killed organisms, purified components (ie, subunit), or inactivated toxins (ie, toxoids) of the organism. These vaccines are not capable of replication in the host. Most inactivated vaccines are delivered by intramuscular injection. Generally, inactivated vaccines may be administered simultaneously with other inactivated vaccines, as well as live viral vaccines.

The common viral vaccines that are inactivated include inactivated influenza vaccine (IIV), trivalent and quadrivalent formulations, hepatitis A vaccine (HAV), HBV, inactivated poliovirus vaccine (IPV), human papillomavirus (HPV), Japanese encephalitis, and rabies vaccines. Toxoid vaccines that are used routinely include tetanus and diphtheria toxoids alone or in combination with whole-cell or acellular pertussis components (eg, DTaP; DTP; tetanus and diphtheria toxoids; tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis [Tdap]). The acellular pertussis vaccines are composed of 1 or more purified antigens of Bordetella pertussis, in contrast with the whole-cell pertussis vaccines, which are made with killed, whole B pertussis organisms. Diphtheria and tetanus toxoids combined with whole-cell pertussis (ie, DTP) vaccines are no longer marketed in the United States but are used in many developing countries. Other inactivated bacterial vaccines include capsular polysaccharide (CPS) vaccines, such as the 23-valent pneumococcal polysaccharide vaccine and tetravalent meningococcal CPS vaccine.

Conjugate Vaccines

Capsular polysaccharide antigens are chemically linked to a protein carrier, which converts the T-cell independent polysaccharides to T-cell dependent antigens. These conjugate vaccines can elicit an immune response, even in young infants. The first CPS-protein conjugate vaccine available was for Hib. The Hib bacterium is covered with a CPS, polyribitol-phosphate. Children younger than 2 years of age are not efficient at mounting antibodies to the polyribitol- phosphate CPS; however, with linkage to a protein carrier the CPS is immunogenic. Since licensure for infants of the Hib conjugate vaccines in 1991, a more than 98% reduction in Hib disease has occurred. With the success of the Hib CPS-protein conjugate vaccines, conjugation techniques have been used for other CPS pathogens, including Streptococcus pneumoniae and Neisseria meningitidis.

Live-Attenuated Vaccines

Live-attenuated vaccines are infectious agents that replicate in the host to elicit an immune response. The administration is generally not intramuscular but by other delivery routes, such as oral, intra-nasal, or subcutaneous. Often the live vaccines are viral, including MMR, varicella-zoster virus (VZV), rotavirus, live-attenuated influenza virus (LAIV), OPV, and yellow fever vaccines. Two live bacterial vaccines are available: BCG used against Mycobacterium tuberculosis and oral typhoid (Ty21a) vaccine.

A transient suppression of T-cell immunity occurs 2 to 4 weeks after measles vaccination. Because of this, when vaccinating with live viral vaccines, 2 or more live vaccines should be administered at the same time or vaccine administrations should occur at least 4 weeks apart. This principle also holds true for tuberculosis skin testing; either the purified protein derivative should be placed at the same time as a live viral vaccine, or they should be administered at least 4 weeks apart to avoid a false-negative purified protein derivative result because of the transient T-cell suppression. Although this phenomenon has primarily been studied with measles vaccine, the same guidelines should be followed with other live viral vaccines.

Vaccination Schedule

Factors for developing the schedule include the host ability to respond (eg, lost maternal antibody), the need for multiple doses (eg, IPV), the minimal intervals needed between serial doses, and the available products (eg, combination vaccines). Each year, a synchronized immunization schedule is posted by the American Academy of Pediatrics (AAP), American College of Obstetricians and Gynecologists, American Academy of Family Physicians, and the CDC Advisory Committee on Immunization Practices. Separate immunization schedules are available for children from birth through 18 years as well as for adults 19 years and older. The schedules for the United States are posted each January at https://www.cdc.gov/vaccines/schedules. Schedules for countries worldwide are available from the World Health Organization.

Vaccine Recipients

Healthy Pediatric Populations

Routine immunizations on the synchronized schedule are targeted for healthy newborns, infants, children, and adolescents. All licensed vaccines have undergone review by the US Food and Drug Administration (FDA) and have proven safety and immunogenicity or efficacy for the target population. No vaccine is completely free of adverse events or provides 100% protection for every recipient, however. Every effort should be made to provide immunizations when the recipient is healthy and has the best chance to mount an optimal immune response without delaying vaccination or risking a missed opportunity.

Special-Risk Pediatric Populations

Although immune responses to vaccinations are likely most favorable in healthy recipients, a growing segment of the pediatric population has underlying health problems. Because of congenital or acquired immune dysfunctions, some individuals should not receive immunizations as directed by the routine schedules. Special accommodations need to be made for immunizing these individuals, such as adjusting the schedule or possibly not administering some agents. Administration of decreased or partial doses of vaccines is not indicated. Some of the select populations or circumstances that warrant special consideration include immunocompromised status, immunodeficiency, pregnancy, preterm birth status, low birth weight status, allergy to egg protein, planned international travel, patients from other countries, adolescence, and vaccines administered in other countries.

Immunocompromised Child

The vaccination plan for the immunocompromised child should be determined by the nature and degree of immunosuppression. The health professional should weigh risks and benefits for each child individually, with consideration for some general principles. For example, live vaccines should not be given to severely compromised individuals because of the possible risks. In general, inactivated vaccines may be safely administered to nearly all recipients; however, immunocompromised individuals may not mount an optimal immune response. In this setting, the health professional should attempt to adjust timing of vaccination to optimize the chance of a good immune response. Guidelines for immunizing immunocompromised children and adults have been established by the Infectious Diseases Society of America in conjunction with the AAP, CDC, and other professional groups and are posted at www.idsociety.org/Templates/Content.aspx?id=32212256011.

Types of Immunodeficiency

Newborns, infants, and children may have abnormalities of any aspect of the immune system, which may affect their ability to receive vaccinations. Weighing the risks of both the disease and the vaccine and the benefits of protection is essential. A reasonable approach to developing a vaccination plan for children with immune abnormalities is to consider the mechanism of immune defense against the vaccine agents; if the needed defense mechanism is deficient, immunizing with that agent may not be appropriate. For example, cellular immunity is essential in defending against viral agents. Thus, children with abnormalities of cell-mediated immunity, whether primary or acquired, may not be candidates for live viral vaccines.

Primary immunodeficiencies are generally inherited, and secondary immunodeficiencies are acquired. Examples of acquired immunodeficiencies include HIV infection, malignancy, and illnesses (eg, malnutrition, uremia) as well as those caused by medications (eg, chemotherapy, immunosuppressive agents). The OPV is contraindicated for individuals with primary humoral immunity abnormalities (ie, those who cannot make antibodies); however, MMR vaccine may be indicated for some of these individuals because of the potential risks of natural infection. Receipt of all vaccines, including live viral vaccines, is acceptable for most individuals with complement deficiencies. For abnormal phagocytic function, live bacterial vaccines should not be given. For individuals with traumatic or surgical asplenia, vaccination with pneumococcal, meningococcal, and Hib vaccines is indicated and should be considered emergently in the case of trauma. Chemoprophylaxis also may have a role in protection for compromised individuals.

For children with immunocompromised household contacts, it is generally acceptable for them to receive MMR, VZV, and oral rotavirus vaccines. However, the live viral vaccines of OPV and LAIV should not be given in some settings. In contrast, use of some vaccines, such as IIV, is encouraged to protect the vaccinated individuals as well as their compromised contacts.

Pregnancy

Pregnancy is associated with some impairment of cell-mediated immunity. With this decreased immunity, pregnant women may not mount protective immune responses to some infectious agents. Thus, in general, live vaccines should not be administered to pregnant women; however, the risks and benefits should be weighed for each individual patient. Live-attenuated influenza virus should not be given to pregnant women. Neither should rubella vaccine be given to pregnant women, although no cases of rubella embryopathy following inadvertent immunization of a pregnant woman have been reported.

Both IIV and Tdap are recommended during pregnancy to provide protection for the mother and the fetus. These vaccines may be given anytime during pregnancy, although the preferred timing for Tdap administration is 27 through 36 weeks to optimize transfer of pertussis antibodies to the fetus. Pediatricians are often asked whether administration of live viral vaccines is contraindicated for children residing with a pregnant household contact; generally, such administration is not contraindicated.

Preterm and Low Birth Weight Infants

In general, medically stable preterm (<37 weeks of gestation) and low birth weight infants (<2,500 g [<5 lb 5 oz]) may be immunized at the same dose, schedule, and postnatal age as full-term and normal birth weight infants.

Special consideration should be given to use of HBV vaccine in newborns weighing less than 2,000 g (<4 lb 4 oz) as follows. For the hepatitis B surface antigen (HBsAg)-positive mother or mother whose status cannot be determined within 12 hours, monovalent hepatitis B vaccine and hepatitis B IG should be administered within 12 hours of birth. The birth dose of vaccine does not count as part of the series; thus, the infant requires 3 additional vaccine doses starting at 1 month of age. The HBsAg and antibodies should be checked after completing the vaccine series, usually at the 9- or 12-month check-up. For the HBsAg-negative mother, monovalent hepatitis B vaccine is administered to the newborn at 1 month of age (sooner if the newborn is stable for discharge), after which the usual schedule is followed, such that the infant receives a total of 3 doses. Serologic testing is not necessary.

Other Conditions Affecting Immunization Schedule

Allergy to Egg

Children with allergic reactions to egg protein—including severe hypersensitivity—are at low risk for anaphylactic reactions to measles, mumps, and influenza (both IIV and LAIV) vaccines. Special precautions for immunizing children with egg allergy are no longer routinely recommended.

Yellow fever vaccine may contain egg protein in higher concentrations than in influenza vaccines and may rarely induce an immediate allergic reaction. Guidelines for skin testing and graded vaccine dosing are provided in the vaccine package insert.

International Adoptees, Travelers, Immigrants, and Refugees

Travel is not restricted to persons of any particular socioeconomic status; thus, physicians should inquire about foreign travel in all routine clinical visits. In preparing patients for travel, the health professional should review the child’s record to ensure that all routine vaccines are up-to-date. The child should receive vaccinations and other preventive measures (eg, malaria prophylaxis) targeted for his or her destination. An accelerated schedule may be necessary, for example, early administration of MMR for infants 6 to 12 months of age traveling to a measles-endemic area. Use of IG prophylaxis to prevent HAV is recommended for susceptible individuals who are not candidates for active immunization (eg, too young to receive the HAV vaccine, immunocompromised status) traveling to areas with elevated risk of hepatitis A. To help ensure healthy travel, the health professional should check the current recommendations for the traveler’s desti-nation at the CDC Travelers’ Health website (https://wwwnc.cdc.gov/travel) and the World Health Organization International Travel and Health website (www.who.int/ith/en).

Immigrants, refugees, and international adoptees often have health care issues. Immunization status, underlying health, and possible intercurrent illnesses should be evaluated soon after arrival. Many of these children have been in poor living conditions and exposed to health hazards of environments such as refugee camps and orphanages. The United States requires proof of the first dose of vaccines for entry into the country, although exemptions exist for refugees and adoptees younger than 10 years of age. Often these high-risk children have not been immunized or their records are missing. Written, dated, and appropriate records (ie, patient age, dates, interval, number of doses) may be considered valid, and subsequent immunization may resume according to the US schedule. Another option, especially in cases in which documentation is questionable, is to perform serologic studies for antibodies to vaccine antigens with available valid testing.

Adolescents

The AAP recommends a routine health visit at 11 to 12 years of age, including receipt of immunizations needed for adolescents. One of these vaccines is Tdap for use as a single booster dose at 11 to 18 years of age. Currently, Tdap is licensed only for a single booster dose. Off-label use of additional doses is recommended in special situations, however, such as during pregnancy and for close contacts of infants. With recognition of waning vaccine-induced immunity to pertussis, additional Tdap doses may be routinely recommended in the future.

Meningococcal vaccine and HPV are also indicated for adolescents at the 11- to 12-year-old visit. Four meningococcal vaccines are available in the United States: 2 CPS-protein conjugate vaccine (meningococcal conjugate vaccine [MenACWY]), and 2 B meningococcal (MenB) vaccines. The CPS vaccines contain 4 serotypes (A, C, Y, and W-135). The MenACWY-D vaccine (Menactra) is licensed for use in persons age 9 months to 55 years. The MenACWY-CRM vaccine (Menveo) is licensed for use in persons age 2 months to 55 years. Routine immunization with MenACWY is recommended at age 11 to 12 years, with a booster dose at age 16 years. For adolescents who received the first dose between age 13 and 15 years, the second dose may be given at ages 16 to 18 years (up to 5 years after the first dose); however, no booster dose is needed for teenagers who receive their first dose at age 16 years or older. The MenACWY vaccine is also recommended for catch-up dosing for older adolescents who have not been immunized, as well as for individuals 9 months to 55 years of age who are at increased risk of meningococcal diseases. The 2 MenB vaccines (Bexsero and Trumenba) are prepared using different virulence factors of the bacteria. The vaccines are licensed for individuals 10 through 25 years of age and recommended for those at increased risk of meningococcal infection. The vaccines may also be used during MenB outbreaks. The MenB vaccines are not routinely recommended at the 11- to 12-year-old visit.

The only HPV vaccine available in the United States is 9-valent (9vHPV) and is recommended for routine use in adolescents at 11 to 12 years of age. The vaccine is composed of virus-like particles prepared from recombinant L1 capsid protein. The 9vHPV vaccine (Gardasil 9), contains serotypes 6, 11, 16, 18, 31, 33, 45, 52, and 58 and it is licensed for females and males age 9 through 26 years to protect against cancers caused by HPV infections. For individuals younger than 15 years, 9vHPV is administered in a 2-dose regimen, with the second dose given 6 to 12 months after the first dose. For those age 15 years and older, 9vHPV is given in a 3-dose regimen at day 0, 1 to 2 months, and 6 months.

In addition, at adolescent visits (including precollege visits), health professionals should review the patient’s records to ensure that all recommended vaccines have been received, inquire about household contacts of infants or compromised hosts, and provide anticipatory guidance for safe and healthy living for the adolescent and parent.

Immunizations Received in Other Countries

Most vaccines used worldwide are produced with adequate quality control and may be considered reliable. Healthy immigrants immunized in countries outside the United States should receive vaccines according to the recommended schedule for age in the United States. Only written documentation should be accepted as proof of previous vaccination. Written, dated, and appropriate records (ie, correct age, dates, interval, number of doses) may be considered as valid, and immunizations may resume according to the US schedule.

Although most globally prepared vaccines are acceptable, concern may exist for vaccine potency because of unsuitable storage and handling. Other concerns include inaccurate documentation and inadequate immune response in some children resulting from other factors (eg, malnutrition, underlying illness). If vaccination status is uncertain, options include vaccinating with the antigen in question or, if available, serologic testing. Generally, receipt of additional doses of diphtheria and tetanus toxoids alone or in combination with a pertussis-containing vaccine (ie, DTP, DTaP, tetanus and diphtheria toxoids, Tdap) may result in an increase in reactions (especially injection site reactions), and checking antibody titers against diphtheria and tetanus toxoids is encouraged. Currently, commercially available assays for pertussis antibodies are of unknown clinically accuracy and testing is not recommended. A serological assay developed by the CDC and FDA has been used to confirm the diagnosis of pertussis, especially during outbreaks. For other vaccines, if the status is unknown, vaccination may be performed because extra doses are generally well tolerated. Additionally, extra doses are less expensive and more time efficient than performing serology. Most developing countries do not have VZV, conjugated pneumococcal, or Hib vaccines; thus, these should be given as indicated per the US schedule.

Adverse Events and Vaccine Information Adverse Events

As noted previously, no vaccine is completely free of adverse events, and known adverse events should be discussed with non-minor vaccine recipients or the parent(s)/legal guardian(s) of the minor vaccine recipient. In addition to discussing the risks and benefits of vaccination, health professionals should include education about the risks associated with the natural disease. This is especially important today, because many individuals have not seen the diseases that vaccines have been successful in controlling or eradicating.

In addition to safety information from the AAP and CDC, the manufacturer’s package insert provides information about the rates of adverse events and contraindications for the specific vaccine. Most adverse events observed following routine immunizations are local injection site reactions (eg, erythema, swelling, pain) and systemic reactions (eg, fever, fussiness). Although most of these adverse events are mild and self-limiting, some may be associated with significant dysfunction for the child (eg, not using a limb because of pain).

Rarely, serious adverse events may occur following immunization, and these may be associated with permanent disability or life-threatening illness. The occurrence of an adverse event after immunization does not prove a cause-and-effect relationship of the vaccine and the event but a temporal relationship. If a vaccine recipient experiences a serious adverse event, a complete evaluation for all plausible causes, including the role of the vaccine antigen, should be performed. Additionally, all clinically significant adverse events should be reported to the Vaccine Adverse Event Reporting System (https://vaers.hhs.gov), which is maintained by the CDC and FDA. Adverse event reporting is important because it helps identify possible unexpected events that were not observed in pre-licensure clinical trials.

Precautions and Contraindications

The Vaccine Information Statement (VIS) and package insert provide information for health professionals, the non-minor vaccinated individual, and the parent(s)/legal guardian(s) of minor vaccinated individuals about the precautions and contraindications for specific products.

A precaution suggests that careful analysis of risks and benefits of the vaccine should be performed; if benefits outweigh risks, the vaccine may be given. A contraindication means that a vaccine should not be administered. An example of a contraindication is known anaphylaxis to any component of the vaccine. Breastfeeding does not interfere with oral immunization with rotavirus or OPV vaccines and is not a contraindication.

Minor illness without fever (temperature ≤38°C [≤100.4°F]) should not be considered a contraindication to vaccination. Temperature above 38°C (>100.4°F) may not be a contraindication, depending on the physician’s assessment of the child, the illness, and the particular vaccine. If the child is evaluated early in the disease process and the course is not predictable or the illness is moderate to severe, delaying immunization is reasonable. Deferring immunization without appropriate justification can cause a missed opportunity and may result in inadequate immunization of the child.

Informing Vaccine Recipients and Parents and Vaccine Refusal

Vaccine recipients and parents should be informed about the risks and benefits of vaccination and the disease the vaccine is designed to prevent. The National Childhood Vaccine Injury Act of 1986 requires that parents receive a VIS each time a child receives a vaccine covered under this legislation, whether the vaccine was purchased with public or private funds. The VISs are available from the CDC (www.cdc.gov/vaccines/hcp/vis/index.html). Health professionals should document in the patient’s chart the vaccine manufacturer, lot number, and date of administration and that VISs were provided and discussed with the non-minor vaccinated individual and the parent or legal guardian of the minor vaccinated individual.

In the United States, proof of immunization is required for entry into elementary and secondary school. In addition, some child care centers and colleges also require vaccines for entry. All states permit medical exemptions (eg, immunocompromised child), and most states have provision for religious or philosophic exemption for individuals whose beliefs prohibit immunizations. Three states— California, Mississippi, and West Virginia—do not permit personal belief exemptions for children attending child care or schools. Less than 1% of US children are from families who refuse all vaccines. An increasing number of parents decline some immunizations for their child, however, despite best efforts to educate parents about the effectiveness of vaccines and the realistic chances of vaccine-associated adverse events. At times, parents have a genuine fear of the risks of vaccines without fear of the natural disease, because many parents have not seen the diseases in the current, post-vaccine era. For others, their exaggerated fear of vaccine risks results from deeply held family beliefs, or their fears are fueled by biased anti- vaccine information presented in the media without scientific support.

A reasonable approach for the health professional is to address the concerns of parents or guardians in a non-condescending fashion, provide education about the known risks and benefits of immunization, and initiate a candid discussion of the risks of the natural infections. The discussion should be documented in the child’s chart and the topic revisited at future encounters. The AAP encourages a presumptive rather than a participatory approach in counseling about vaccinations. With the presumptive approach, instead of asking the parents or guardians whether they want the vaccines to be administered, the pediatrician informs them that shots are due. Researchers have shown that parents with whom this strategy is used are more likely to accept vaccines. Because of strong convictions that immunization benefits outweigh risks, some health professionals choose not to provide care for children of families who refuse vaccines.

Vaccine Information

Information about current immunizations for health professionals and laypersons is available from many resources, including the CDC, AAP, FDA, and World Health Organization (Table 37.1). Multiple web-based applications with vaccine information are available for smart devices from the AAP and US Department of Health and Human Services (ie, CDC, FDA, National Institutes of Health), as well as other professional organizations.

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