Matthew F. Daley, MD
Sean T. O’Leary, MD, MPH
Ann-Christine Nyquist, MD, MSPH
Immunization is widely recognized as one of the greatest public health achievements of modern times. Largely as a consequence of immunization, the annual incidences of diphtheria, paralytic poliomyelitis, measles, mumps, rubella, and Haemophilus influenzae type b (Hib) in the United States have fallen by more than 99% compared with the average annual incidences of these diseases in the 20th century. Invasive pneumococcal disease in children less than 5 years of age has declined steeply since routine pneumococcal vaccination began in 2000. Similarly, rotavirus vaccination has been associated with substantial declines in hospitalizations and emergency department visits for diarrheal illnesses in young children. Childhood immunization has also led, through herd immunity, to significant decreases in several infectious illnesses in adults, including pneumococcal, rotavirus, and varicella disease. Through routine vaccination, children and adolescents can now receive protection against at least 16 different diseases, and many new vaccines are under development.
Every year, roughly 4 million children are born in the United States, and successful immunization of each birth cohort requires the concerted effort of healthcare providers, public health officials, vaccine manufacturers, and the public. Public perceptions about immunizations, particularly routine childhood immunizations, are generally positive. However, parent concerns about the safety of vaccines have risen in recent years, in part fueled by unfounded speculation about an association between various vaccines or vaccine components and autism. Modern vaccines have a high degree of safety, and serious adverse events following vaccination are rare. Nonetheless, healthcare providers need to be prepared to discuss the benefits and risks of vaccination with uncertain parents, providing factual information in a clear and empathic fashion.
This chapter starts with general principles regarding immunizations and the recommended pediatric and adolescent vaccination schedules, followed by a discussion of vaccine safety. Each routinely recommended vaccine is then discussed further. Vaccines that are only given in special circumstances are discussed in the final section. Several abbreviations that are commonly used in this and other vaccine-related publications are summarized in Table 10–1.
Table 10–1. Vaccine-related abbreviations.
Because the field of immunizations is rapidly changing, it is important for healthcare providers to seek the most cup-to-date information available. The immunization recommendations outlined in this chapter are current but will change as technology evolves and our understanding of the epidemiology of vaccine-preventable diseases changes. The most useful sources for regularly updated information about immunization are the following:
1. National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention (CDC). Maintains a website with extensive vaccine-related resources, including the recommendations of the Advisory Committee on Immunization Practices (ACIP), vaccination schedules, Vaccine Information Statements, information for the public and providers, and links to other vaccine materials. Available at: http://www.cdc.gov/vaccines.
2. CDC Contact Center. The CDC-INFO contact center provides services to the public and healthcare professionals regarding a variety of health-related issues, including immunizations; available 24 hours a day, 7 days a week, at 1-800-232-4636 (English and Spanish).
3. The Red Book: Report of the Committee on Infectious Diseases. Published at 2- to 3-year intervals by the American Academy of Pediatrics (AAP). The 2012 Red Book is available from the AAP. Updates are published in the journal Pediatrics and can also be accessed at http://aapredbook.aappublications.org.
4. Immunization Action Coalition. This nonprofit organization creates and distributes educational materials for healthcare providers and the public related to vaccines. All materials are provided free of charge and can be accessed at http://www.immunize.org.
5. Morbidity and Mortality Weekly Report (MMWR). Published weekly by the CDC. Available at: http://www.cdc.gov/mmwr.
STANDARDS FOR PEDIATRIC IMMUNIZATION PRACTICES
In the United States, every infant requires more than 25 doses of vaccine by age 18 months to be protected against 14 or more childhood diseases. In 2011, immunization coverage rates for children aged 19–35 months were more than 90% for poliovirus, measles-mumps-rubella, varicella, and hepatitis B vaccines, and were steadily increasing for more recently recommended vaccines such as pneumococcal conjugate, rotavirus, and hepatitis A vaccines. However, achieving and maintaining high immunization coverage rates remains challenging. The CDC recommends the following specific proven strategies to increase vaccination coverage rates: (1) assessing and providing feedback on practice/provider immunization rates; (2) keeping accurate immunization records; (3) recommending vaccination to parents, and reinforcing when to return for vaccination; (4) sending reminder messages to parents; (5) sending reminder messages to providers; (6) reducing missed opportunities to vaccinate; and (7) reducing barriers to immunize within the practice.
The National Childhood Vaccine Injury Act of 1986 requires that for each vaccine covered under the Vaccine Injury Compensation Program, caretakers should be advised about the risks and benefits of vaccination in a standard manner, using Vaccine Information Statements (VIS) produced by the CDC. Each time a Vaccine Injury Compensation Program–covered vaccine is administered, the current version of the VIS must be provided to the nonminor patient or legal caretaker. Vaccination documentation that is required in the medical record includes the vaccine manufacturer, lot number, and date of administration and expiration. The VIS version and date, and site and route of administration should also be recorded.
Needles used for vaccination should be sterile and disposable to minimize the opportunity for contamination. A 70% solution of alcohol is appropriate for disinfection of the stopper of the vaccine container and of the skin at the injection site. A 5% topical emulsion of lidocaine-prilocaine applied to the site of vaccination for 30–60 minutes prior to the injection minimizes the pain, especially when multiple vaccines are administered.
Compliance with the manufacturer’s recommendations for route and site of administration of injectable vaccines are critical for safety and efficacy. With few exceptions (intradermal influenza vaccine and Bacillus Calmette-Guérin [BCG] vaccine), all vaccines are given either intramuscularly or subcutaneously. All vaccines containing an adjuvant must be administered intramuscularly to avoid granuloma formation or necrosis. Intramuscular injections are given at a 90-degree angle to the skin, using a needle that is sufficiently long to reach the muscle tissue, but not so long as to injure underlying nerves, blood vessels, or bones. The anterolateral thigh is the preferred site of vaccination in newborns and children up to 2 years of age, and the deltoid muscle of the arm is the preferred site for children aged 3–18 years. Needle length and location should be as follows: ⅝ inch in newborn infants in the thigh; 1 inch in infants 1- to 12-month-olds (thigh), 1–1¼ inches in 1- to 18-year-olds (thigh), and ⅝–1 inch in 1- to 18-year-olds (deltoid). Subcutaneous injections should be administered at a 45-degree angle into the anterolateral aspect of the thigh (for infants younger than 12 months) or the upper outer triceps area (for children 12 months and older) using a 23- or 25-gauge, ⅝-inch needle. Pulling back on the syringe prior to vaccine injection (aspiration) is not required in CDC recommendations. A separate syringe and needle should be used for each vaccine.
Many combinations of vaccines can be administered simultaneously without increasing the risk of adverse effects or compromising immune response. Inactivated vaccines can be given simultaneously with, or at any time after, a different vaccine. Injectable or intranasal live-virus vaccines, if not administered on the same day, should be given at least 4 weeks apart (eg, measles-mumps-rubella [MMR] and varicella [VAR]). Extra doses of hepatitis B (HepB), Hib, MMR, and VAR are not harmful, but repetitive exposure to tetanus vaccine beyond the recommended intervals can result in hypersensitivity reactions and should be avoided. If an immunoglobulin (Ig) or blood product has been administered, live-virus vaccination should be delayed 3 to 11 months, depending on the product, to avoid interference with the immune response (eg, 3 months for tetanus Ig, hepatitis B Ig, and pooled Ig for hepatitis A; 5–6 months for measles Ig or cytomegalovirus Ig; and 11 months for intravenous Ig for Kawasaki disease).
With the large number of vaccine preparations available, interchangeability of vaccines is an issue. All brands of Hib conjugate, HepB, and hepatitis A (HepA) vaccines are interchangeable. For vaccines containing acellular pertussis antigens, it is recommended that the same brand be used, but when the brand is unknown or the same brand is unavailable, any vaccine with diphtheria and tetanus toxoids and acellular pertussis should be used to continue vaccination. Longer than recommended intervals between vaccinations does not reduce final antibody titers, and lapsed schedules do not require restarting the series.
The numerous vaccines and other immunologic products used in routine practice vary in the storage temperatures required. The majority of vaccines should never be subjected to freezing temperatures. Varicella-containing vaccines (MMRV, VAR, and herpes zoster) should be stored frozen. Product package inserts should be consulted for detailed information on vaccine storage conditions and shelf life.
Vaccines very rarely cause acute anaphylactic-type reactions. All vaccine providers should have the equipment, medications, staff, established protocols, and training to manage emergencies that may occur following vaccination.
CDC: General recommendations on immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2011;60(RR-02):1 [PMID: 21293327].
CDC: National and state vaccination coverage among children aged 19–35 months—United States, 2011. MMWR 2012;61:689 [PMID: 22951450].
ROUTINE CHILDHOOD & ADOLESCENT IMMUNIZATION SCHEDULES
Each year, the CDC recommends immunization schedules for children and adolescents. While variation from these schedules may be necessitated by epidemiologic or individual clinical circumstances, these schedules are an important guide for vaccination providers. Vaccines in the schedules are roughly ordered by the age at which the vaccines are first given. For example, HepB vaccination begins at birth, followed at 2 months of age by rotavirus, diphtheria-tetanus-acellular pertussis (DTaP), Hib, pneumococcal conjugate 13-valent (PCV13), and inactivated poliovirus (IPV) vaccines. Table 10–2 sets forth the 2014 schedule of routine immunizations for normal infants, children, and adolescents from birth through 18 years of age. Table 10–3 presents the 2014 schedule for persons aged 4 months through 18 years who started vaccination late or are more than 1 month behind the routine immunization schedule. Updated immunization schedules are available at http://www.cdc.gov/vaccines.
Combination vaccines help solve the problem of large numbers of injections during a clinic visit. Currently available combination vaccines include MMR, measles-mumps-rubella-varicella (MMRV), and various combinations of Hib, HepB, IPV, and DTaP, including DTaP-HepB-IPV and DTaP-IPV-Hib combination vaccines. Separate vaccines should not be combined into one syringe by the provider unless approved by the Food and Drug Administration (FDA), because this could decrease the efficacy of components in the vaccine.
Table 10–2. Recommended immunization schedule for persons aged 0 through 18 years – United States, 2014. (For those who fall behind or start late, see the catch-up schedule [Table 10–3]).
Table 10–3. Catch-up immunization schedule for persons aged 4 months through 18 years who start late or who are more than 1 month behind —United States, 2014.
Vaccine Safety Monitoring
The United States has a sophisticated, multifaceted system to monitor the safety of licensed vaccines. The Vaccine Adverse Events Reporting System (VAERS), the Vaccine Safety Datalink (VSD), and the Clinical Immunization Safety Assessment (CISA) Network each provide distinct contributions to the ongoing monitoring of vaccine safety. VAERS is a national passive surveillance system administered jointly by the FDA and CDC. VAERS accepts reports from healthcare providers and the public about possible vaccine-related adverse events. Reports of adverse events possibly related to vaccination may be made via the Internet (http://vaers.hhs.gov) or by telephone (1-800-822-7967). As a passive surveillance system, VAERS is subject to certain limitations, including underreporting, overreporting, the reporting of events that are temporally but not causally related to vaccination, and the lack of denominator data. The VSD, in comparison, is an active surveillance system with continuous safety monitoring of vaccines in defined patient populations. The VSD can conduct timely investigations of newly licensed vaccines or emerging vaccine safety concerns. The CISA Network is designed to develop protocols for the evaluation, diagnosis, and treatment of adverse events following immunization, and to provide a better understanding of adverse events following immunization at the individual level. Patients with rare and serious adverse events following immunization can be referred to the CISA Network for evaluation.
Vaccine Risk-Benefit Communication
Most parents in the United States choose to vaccinate their children: in 2011, less than 1% of young children had received no vaccines. However, parents’ concerns about vaccines are on the rise, and an increasing number of parents are choosing to delay or decline vaccination for their children. While there are myriad reasons why some parents may not vaccinate, several themes recur. Some parents do not believe their children are at risk for diseases such as poliomyelitis, measles, and tetanus. Other parents do not believe that certain vaccine-preventable diseases, such as varicella and pertussis, are particularly serious. There are also widespread concerns about the safety of vaccines. In a recent survey of more than 1500 parents, one-quarter believed that vaccines can cause autism in healthy children (despite no scientific evidence to support this claim), and more than one in 10 parents had refused at least one recommended vaccine. Healthcare providers have a critically important role in discussing the known risks and benefits of vaccination with parents. In this context, it is important that providers recognize that parent decisions are often based on inaccurate information about vaccine risk provided by the media or Internet sources. Parents with questions about vaccine safety should be directed to trusted websites, such as those of the AAP, the American Academy of Family Physicians (AAFP), the CDC (http://www.cdc.gov/vaccines), and the Immunization Action Coalition (http://www.immunize.org).
Vaccine Contraindications and Precautions
All vaccines have certain contraindications and precautions that guide their administration. A contraindication indicates that the potential vaccine recipient is at increased risk of a serious adverse event. A vaccine should not be given when a contraindication to that vaccine is present, whereas a precaution indicates a circumstance that might increase the risk of adverse events or diminish the effectiveness of the vaccine. In the setting of precautions, the risks and benefits of vaccination must be carefully weighed prior to a decision regarding vaccination. Precautions are often temporary, in which case vaccination can resume once the precaution no longer applies. Contraindications and precautions are listed below with each vaccine. Additional, more detailed, information is available from the CDC (http://www.cdc.gov/vaccines), in the AAP’s Red Book, and in vaccine package inserts.
Baggs J et al: The Vaccine Safety Datalink: a model for monitoring immunization safety. Pediatrics 2011;127 (Suppl 1):S45 [PMID: 21502240].
Freed GL et al: Parental vaccine safety concerns in 2009. Pediatrics 2010;125:654 [PMID: 20194286].
Glanz JM et al: A population-based cohort study of undervaccination in 8 managed care organizations across the United States. JAMA Pediatr 2013;167:274 [PMID: 23338829].
VACCINATION IN SPECIAL CIRCUMSTANCES
Minor Acute Illnesses
Minor acute illnesses, with or without low-grade fever, are not contraindications to vaccination, because there is no evidence that vaccination under these conditions increases the rate of adverse effects or decreases efficacy. A moderate to severe febrile illness may be a reason to postpone vaccination. Routine physical examination and temperature assessment are not necessary before vaccinating healthy infants and children.
Children with Chronic Illnesses
Most chronic diseases are not contraindications to vaccination; in fact, children with chronic diseases may be at greater risk of complications from vaccine-preventable diseases, such as influenza and pneumococcal infections. Premature infants are a good example. They should be immunized according to their chronologic, not gestational, age. Vaccine doses should not be reduced for preterm or low-birth-weight infants. One exception to this rule is children with progressive central nervous system disorders. Vaccination with DTaP should be deferred until the child’s neurologic status has been clarified and is stable.
Congenitally immunodeficient children should not be immunized with live-virus vaccines (oral polio vaccine [OPV, available only in developing countries], rotavirus, MMR, VAR, MMRV, yellow fever, or live-attenuated influenza vaccine [LAIV]) or live-bacteria vaccines (BCG or live typhoid fever vaccine). Depending on the nature of the immunodeficiency, other vaccines are safe, but may fail to evoke an immune response. Children with cancer and children receiving high-dose corticosteroids or other immunosuppressive agents should not be vaccinated with live-virus or live-bacteria vaccines. This contraindication does not apply if the malignancy is in remission and chemotherapy has not been administered for at least 90 days. Live-virus vaccines may also be administered to previously healthy children receiving low to moderate doses of corticosteroids (defined as up to 2 mg/kg/d of prednisone or prednisone equivalent, with a 20 mg/d maximum) for less than 14 days; children receiving short-acting alternate-day corticosteroids; children being maintained on physiologic corticosteroid therapy without other immunodeficiency; and children receiving only topical, inhaled, or intra-articular corticosteroids.
Contraindication of live-pathogen vaccines also applies to children with HIV infection who are severely immunosuppressed. In general, those who receive MMR should have at least 15% CD4 cells, a CD4 lymphocyte count equivalent to CDC immunologic class 2, and be asymptomatic from their HIV. MMR for these children is recommended at 12 months of age (after 6 months during an epidemic). For HIV-infected children, a booster MMR dose may be given at least 1 month after the initial dose; in fact, giving this booster dose earlier than at 4–6 years of age is often encouraged. The booster dose may be given as early as 1 month later, but doses given before 1 year of age should not be considered part of a complete series. VAR vaccination is also recommended for HIV-infected children with CD4 cells preserved as listed above. The ACIP recommends only IPV vaccination for all children. Thus, immunodeficient children should no longer be exposed to OPV through household contacts. MMR and VAR are not contraindicated in household contacts of immunocompromised children. The recommended immunization schedule for immunocompromised children is available at http://www.cdc.gov/vaccines/pubs/pinkbook/.
Allergic or Hypersensitive Children
Hypersensitivity reactions are rare following vaccination (1.53 cases per 1 million doses). They are generally attributable to a trace component of the vaccine other than to the antigen itself; for example, MMR, IPV, and VAR contain microgram quantities of neomycin, and IPV also contains trace amounts of streptomycin and polymyxin B. Children with known anaphylactic responses to these antibiotics should not be given these vaccines. Trace quantities of egg antigens may be present in both inactivated and live influenza and yellow fever vaccines. Guidelines for influenza vaccination in children with egg allergies have recently changed. Children with only hives following exposure to egg can be vaccinated, as long as injectable influenza vaccine is used as opposed to LAIV, vaccination is by a healthcare provider experienced in recognizing allergic reactions, and the child is observed for 30 minutes following vaccination. Children with more serious allergic reactions to egg, such as angioedema, respiratory symptoms, or anaphylaxis, may be eligible for injectable influenza vaccine, but should be referred to an allergist for an assessment of vaccination risk. Some vaccines (MMR, MMRV, and VAR) contain gelatin, a substance to which persons with known food allergy may develop an anaphylactic reaction. For any persons with a known history of anaphylactic reaction to any component contained in a vaccine, the vaccine package insert should be reviewed and additional consultation sought, such as from a pediatric allergist. Some tips and rubber plungers of vaccine syringes contain latex. These vaccines should not be administered to individuals with a history of severe anaphylactic allergy to latex, but may be administered to people with less severe allergies. Thimerosal is an organic mercurial compound used as a preservative in vaccines since the 1930s. While there is no evidence that thimerosal has caused serious allergic reactions or autism, all routinely recommended vaccines for infants have been manufactured without thimerosal since mid-2001. Thimerosal-free formulations of injectable influenza vaccine are available, and LAIV does not contain thimerosal.
Detailed recommendations for preterm low-birth-weight infants; pediatric transplant recipients; Alaskan Natives/American Indians; children in residential institutions or military communities; or refugees, new immigrants, or travelers are available from the CDC (at http://www.cdc.gov/vaccines) and from the AAP’s Red Book.
CDC: General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2011;60(RR-02):1 [PMID: 21293327].
Greenhawt MJ et al: Administering influenza vaccine to egg allergic recipients: a focused practice parameter update. Ann Allergy Asthma Immunol 2011;106:11 [PMID: 1195939].
HEPATITIS B VACCINATION
The incidence of reported cases of acute hepatitis B has declined dramatically in the United States, largely attributable to vaccination. Based on surveillance data from 2007, acute hepatitis B incidence has declined by 82% since 1990, to the lowest rate ever measured. The greatest declines have been seen in children younger than 15 years of age, in whom rates have decreased by 98%.
Success in reducing the burden of hepatitis B in the United States is due, in large part, to a comprehensive hepatitis B prevention strategy initiated in 1991. The four central elements of this approach are (1) immunization of all infants beginning at birth; (2) routine screening of all pregnant women for hepatitis B infection, and provision of hepatitis B immune globulin (HBIg) to all infants born to infected mothers; (3) routine vaccination of previously unvaccinated children and adolescents; and (4) vaccination of adults at increased risk of hepatitis B infection.
While high immunization rates have been achieved in young children (more than 91% were fully immunized in 2011), there has been less success in identifying hepatitis B–infected mothers and at immunizing high-risk adults. Of the estimated 23,000 mothers who deliver each year who are hepatitis B surface antigen (HBsAg) positive, only 9000 are identified through prenatal screening. While there is an average of 90 cases of perinatally acquired hepatitis B infection reported to the CDC every year, the actual number of perinatal HBV infections is estimated to be 10–20 times higher than the number currently detected and reported. This circumstance represents a significant missed opportunity for prevention, given that administration of hepatitis B vaccine (HepB) in conjunction with HBIg is 95% effective at preventing mother-to-infant transmission of the virus. Further, many hospitals do not routinely offer HepB to all newborns, despite ACIP recommendations for universal newborn HepB vaccination. Similarly, while HepB alone is 90%–95% effective at preventing hepatitis B infection, only 45% of high-risk adults have been vaccinated.
All pregnant women should be routinely screened for HBsAg. Infants born to HBsAg-positive mothers should receive both HepB and HBIg immediately after birth. Infants for whom the maternal HBsAg status is unknown should receive vaccine (but not HBIg) within 12 hours of birth. In such circumstances, the mother’s HBsAg status should be determined as soon as possible during her hospitalization, and the infant given HBIg if the mother is found to be HBsAg positive. For all infants, the hepatitis B immunization series should be started at birth, with the first dose given prior to discharge from the hospital. The ACIP has recommended that any decision to defer the birth dose require an explanation in the medical record, accompanied by a copy of the mother’s negative HBsAg test during the current pregnancy. In 2011, 69% of infants nationally received HepB within 3 days after birth, with wide variation by state (23%–84%).
Routine immunization with three doses of HepB is recommended for all infants and all previously unvaccinated children aged 0–18 years. A two-dose schedule is available for adolescents as well. In addition, persons 19 years and older with an increased risk of exposure to hepatitis B virus should be vaccinated. This includes men who have sex with men, persons with multiple sexual partners, intravenous and injection drug users, recipients of clotting factor concentrates, hemodialysis patients, household contacts and sexual contacts of persons with chronic hepatitis B infection, long-term international travelers to endemic areas, all adults 19 through 59 years of age with type 1 or 2 diabetes mellitus, and all healthcare personnel. HepB is also recommended for persons with chronic liver disease or HIV. Screening for markers of past infection before vaccinating is not indicated for children and adolescents, but may be considered for high-risk adults. Because HepB vaccines consist of an inactivated subunit of the virus, the vaccines are not infectious and are not contraindicated in immunosuppressed individuals or pregnant women.
1. Hepatitis B vaccine (Recombivax HB, Merck) contains recombinant HepB only.
2. Hepatitis B vaccine (Engerix-B, GlaxoSmithKline) contains recombinant HepB only.
3. Hepatitis B-Hib (Comvax, Merck) contains vaccines against hepatitis B and Hib.
4. DTaP-HepB-IPV (Pediarix, GlaxoSmithKline) contains vaccines against diphtheria, tetanus, pertussis, hepatitis B, and poliovirus.
Only the noncombination vaccines (Recombivax HB and Engerix-B) can be given between birth and 6 weeks of age. Any single or combination vaccine listed above can be used to complete the hepatitis B vaccination series. Thimerosal has been removed from all pediatric HepB formulations. A combination vaccine against hepatitis A and hepatitis B (Twinrix, GlaxoSmithKline) is available, but is only licensed in the United States for persons 18 years and older.
Dosage Schedule of Administration
HepB is recommended for all infants and children in the United States. Table 10–4 presents the vaccination schedule for newborn infants, dependent on maternal HBsAg status. Infants born to mothers with positive or unknown HBsAg status should receive HepB vaccine within 12 hours of birth. Infants born to HBsAg-negative mothers should receive the vaccine prior to hospital discharge.
Table 10–4. Hepatitis B vaccine schedules for newborn infants, by maternal hepatitis B surface antigen (HBsAg) status.a
For children younger than 11 years of age not previously immunized, three intramuscular doses of HepB are needed. Adolescents aged 11–15 years have two options: the standard pediatric three-dose schedule or two doses of adult Recombivax HB (1.0 mL dose), with the second dose administered 4–6 months after the first dose. The vaccine should be given intramuscularly in either the anterolateral thigh or deltoid, depending on the age and size of the patient.
Certain patients may have reduced immune response to HepB vaccination, including preterm infants weighing less than 2000 g at birth, the elderly, immunosuppressed patients, and those receiving dialysis. Preterm infants whose mothers are HBsAg-positive or with unknown HBsAg status should receive both HepB and HBIg within 12 hours of birth. For preterm infants whose mothers are known to be HBsAg-negative, initiation of the vaccination series should be delayed until 30 days of chronologic age if the infant is medically stable or prior to hospital discharge if the infant is discharged before 30 days of age. Pediatric hemodialysis patients and immunocompromised persons may require larger doses or an increased number of doses, with dose amounts and schedules available in the most recent CDC hepatitis B recommendations (see references).
Contraindications & Precautions
HepB should not be given to persons with a serious allergic reaction to yeast or to any vaccine components. Individuals with a history of serious adverse events, such as anaphylaxis, after receiving HepB should not receive additional doses. Vaccination is not contraindicated in persons with a history of Guillain-Barré syndrome, multiple sclerosis, autoimmune disease, other chronic conditions, or in pregnancy.
The overall rate of adverse events following vaccination is low. Those reported are minor, including fever (1%–6%) and pain at the injection site (3%–29%). There is no evidence of an association between vaccination and sudden infant death syndrome, multiple sclerosis, autoimmune disease, or chronic fatigue syndrome.
Postexposure prophylaxis is indicated for unvaccinated persons with perinatal, sexual, household, percutaneous, or mucosal exposure to hepatitis B virus. When prophylaxis is indicated, unvaccinated individuals should receive HBIg (0.06 mL/kg) and the first dose of HepB at a separate anatomic site. For sexual contact or household blood exposure to an acute case of hepatitis B, HBIg and HepB should be given. Sexual and household contacts of someone with chronic infection should receive HepB (but not HBIg). For individuals with percutaneous or permucosal exposure to blood, HepB should be given, and HBIg considered depending on the HBsAg status of the person who was the source of the blood and on the vaccination response status of the exposed person. All previously vaccinated persons exposed to hepatitis B should be retested for anti-HBs. If antibody levels are adequate (≥ 10 mIU/mL), no treatment is necessary. If levels are inadequate and the exposure was to HBsAg-positive blood, HBIg and vaccination are required.
HBIg is prepared from HIV-negative and hepatitis C virus-negative donors with high titers of hepatitis B surface antibody. The process used to prepare this product inactivates or eliminates any undetected HIV and hepatitis C virus.
CDC: A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States, part 1: immunization of infants, children, and adolescents. MMWR Recomm Rep 2005;54(RR-16):1 [PMID: 16371945].
Wasley A et al: The prevalence of hepatitis B virus infection in the United States in the era of vaccination. J Infect Dis 2010;202:192 [PMID: 20533878].
Willis BC et al: Gaps in hospital policies and practices to prevent perinatal transmission of hepatitis B virus. Pediatrics 2010;125:704 [PMID: 20211952].
Rotavirus is the leading cause of hospitalization and death from acute gastroenteritis in young children worldwide. The burden of rotavirus is particularly severe in the developing world, where as many as 500,000 children die each year from rotavirus-associated dehydration and other complications. While deaths from rotavirus were uncommon in the United States (20–60 deaths per year), prior to the introduction of rotavirus vaccine, rotavirus infections caused substantial morbidity annually with an estimated 2.7 million diarrheal illnesses, 410,000 office visits, and 55,000–70,000 hospitalizations.
A rhesus-based rotavirus vaccine (RotaShield, Wyeth-Lederle) was licensed by the FDA and recommended for routine use by the ACIP in 1998 but was withdrawn from the market within one year after it was noted that there was an increased risk of intussusception after the first dose. Two other rotavirus vaccines were in development at the time, and underwent extensive prelicensure testing. No association with intussusception was found in prelicensure studies for either new rotavirus vaccine. The ACIP made a recommendation to include pentavalent rotavirus vaccine (RV5; RotaTeq) in the routine infant series in February 2006, a recommendation that was updated in June 2008 to include the monovalent rotavirus vaccine (RV1; Rotarix).
Since the introduction of these vaccines, their use has increased steadily. Vaccination coverage in 2011 in the United States for ≥ 2 doses of rotavirus vaccine was 67%, up from 44% just two years earlier. The impact of the vaccines has been substantial, reducing both hospitalizations and outpatient visits. Death from rotavirus disease was a rare occurrence in the United States prior to licensure, but rotavirus vaccine has had a profound impact on deaths in the developing countries where it has been introduced.
However, there were two recent findings that raised concern about the safety of the newer rotavirus vaccines. In March 2010, the FDA recommended temporarily suspending use of RV1 due to the detection of porcine circovirus, a nonhuman pathogen, in the vaccine. This recommendation was lifted 2 months later after investigations showed that there was likely no threat to human health. Shortly thereafter, in August 2010, the Global Advisory Committee on Vaccine Safety of the World Health Organization reviewed preliminary data from postmarketing studies that showed a possible increased risk of intussusception for RV1 in Mexico. On September 22, 2010, the FDA recommended a label change for RV1 advising providers of the new data.
1. RV5 (Rotateq, Merck) is a pentavalent, live, oral, human-bovine reassortant rotavirus vaccine. The vaccine is a liquid, does not require any reconstitution, and does not contain any preservatives. The dosing tube is latex-free.
2. RV1 (Rotarix, GlaxoSmithKline) is a monovalent, live, oral, attenuated human rotavirus vaccine. The vaccine needs to be reconstituted with 1 mL of diluent using a prefilled oral applicator. The vaccine does not contain any preservatives. The oral applicator contains latex.
Dosage & Schedule of Administration
Either RV5 or RV1 can be used to prevent rotavirus gastroenteritis. RV5 should be administered orally, as a three-dose series, at 2, 4, and 6 months of age. RV1 should be administered orally, as a two-dose series, at 2 and 4 months of age. For both rotavirus vaccines, the minimum age for dose 1 is 6 weeks, and the maximum age for dose 1 is 14 weeks and 6 days. The vaccination series should not be started at 15 weeks of age or older, because of the lack of safety data around administering dose 1 to older infants. The minimum interval between doses is 4 weeks. All doses should be administered by 8 months and 0 days of age. While the ACIP recommends that the vaccine series be completed with the same product (RV5 or RV1) used for the initial dose, if this is not possible, providers should complete the series with whichever product is available.
Either rotavirus vaccine can be given simultaneously with all other recommended infant vaccines. Rotavirus vaccine can be given to infants with minor acute illness. No restrictions are placed on infant feeding before or after receiving rotavirus vaccine. Infants readily swallow the vaccine in most circumstances; however, if an infant spits up or vomits after a dose is administered, the dose should not be readministered; the infant can receive the remaining doses at the normal intervals.
Contraindications & Precautions
Rotavirus vaccine should not be given to infants with a severe hypersensitivity to any components of the vaccine, to infants who had a serious allergic reaction to a previous dose of the vaccine, or to infants with a history of intussusception from any cause. Because the RV1 oral applicator contains latex rubber, RV1 should not be given to infants with a severe latex allergy; RV5 is latex-free. Both vaccines are contraindicated in infants with severe combined immunodeficiency (SCID). Vaccination should be deferred in infants with acute moderate or severe gastroenteritis. Limited data suggest that rotavirus vaccination is safe and effective in premature infants. A small trial in South Africa also demonstrated that RV1 was well tolerated and immunogenic in HIV-infected children. However, vaccine safety and efficacy in infants with immunocompromising conditions other than SCID, preexisting chronic gastrointestinal conditions (eg, Hirschsprung disease or short-gut syndrome), or a prior episode of intussusception, has not been established. Clinicians should weigh the potential risks and benefits of vaccination in such circumstances. Infants living in households with pregnant women or immunocompromised persons can be vaccinated.
Because of new information regarding a possible increased risk of intussusception after the first dose from postmarketing surveillance done in Mexico, the FDA recently recommended a change to the labeling of RV1 (Rotarix), but not RV5 (Rotateq), informing providers of the possible increased risk.
Data from a large study in Mexico and Brazil found that there may be a small increase in the risk of intussusception in the 1–7 day time frame after the first dose of RV1 in Mexico (incident rate ratio 5.3, 95% confidence interval [CI] 3.0–9.3), but not in Brazil (incident rate ratio 1:1, 95% CI 0.3–3.3). A possible explanation for the discrepancy is that live oral poliovirus vaccine is given in Brazil, but not in Mexico, where inactivated poliovirus vaccine is given. It is important to note that the same study showed that the benefits of rotavirus vaccination far exceeded any possible risk, and recommendations for use of RV1 have not changed in Mexico or elsewhere. Also, the background rate of intussusception in Mexico, between 60 and 90 per 100,000 children per year, is higher than in the United States. Active surveillance conducted in the United States has not shown an increased risk of intussusception following RV5 vaccination; comparable data are not yet available for RV1 vaccination.
CDC: Prevention of rotavirus gastroenteritis among infants and children. MMWR Recomm Rep 2009;58(RR-2):1 [PMID: 19194371].
CDC. Addition of history of intussusception as a contraindication for rotavirus vaccination. MMWR 2011;60:1427 [PMID: 22012117].
Patel MM et al: Intussusception risk and health benefits of rotavirus vaccination in Mexico and Brazil. N Engl J Med 2011;364:2283 [PMID: 21675888].
Staat MA et al: Effectiveness of pentavalent rotavirus vaccine against severe disease. Pediatrics 2011;128:e267 [PMID: 21768317].
Yen C et al: Diarrhea-associated hospitalizations among US children over 2 rotavirus seasons after vaccine introduction. Pediatrics 2011;127:e9 [PMID: 21172995].
DIPHTHERIA-TETANUS-ACELLULAR PERTUSSIS VACCINATION
Diphtheria, tetanus, and pertussis (DTP) vaccines have been given in a combined vaccine for many decades, and have dramatically reduced each of these diseases. The efficacy with antigens in the combined vaccine is similar to that with antigens in single component vaccines. The pertussis component of DTP vaccines contains whole-cell pertussis antigens. Although these vaccines are used widely in the world, DTP vaccines have been entirely replaced in the United States with DTaP vaccines, which are acellular pertussis vaccines made with purified, inactivated components of the bacterium.
Diphtheria is caused by a gram-positive bacillus, Corynebacterium diphtheriae. It is a toxin-mediated disease, with diphtheria toxin causing local tissue destruction, as in pharyngeal and tonsillar diphtheria, as well as systemic disease, particularly myocarditis and neuritis. The overall case fatality rate is between 5% and 10%, with higher death rates in persons younger than 5 years, or older than 40 years of age. As many as 200,000 cases of diphtheria occurred each year in the 1920s in the United States. Largely because of successful vaccination programs, only five cases of diphtheria have been reported in the United States since 2000, and a confirmed case has not been reported since 2003. In the last several decades, the majority of diphtheria cases in the United States have been in unimmunized or inadequately immunized persons. The clinical efficacy of diphtheria vaccine is not precisely known, but has been estimated to be greater than 95%.
The anaerobic gram-positive rod Clostridium tetani causes tetanus, usually through infection of a contaminated wound. When C tetani colonizes devitalized tissue, the exotoxin tetanospasmin is disseminated to inhibitory motor neurons, resulting in generalized rigidity and spasms of skeletal muscles. Tetanus-prone wounds include (1) puncture wounds, including those acquired due to body piercing, tattooing, and intravenous drug abuse; (2) animal bites; (3) lacerations and abrasions; and (4) wounds resulting from nonsterile neonatal delivery and umbilical cord care (neonatal tetanus). In persons who have completed the primary vaccination series and have received a booster dose within the past 10 years, vaccination is virtually 100% protective. In 2010, 26 cases of tetanus occurred in the United States with almost all cases in persons who have had inadequate, distant (> 10 years) or no tetanus immunization.
Pertussis is also primarily a toxin-mediated disease. Called whooping cough because of the high-pitched inspiratory whoop that can follow intense paroxysms of cough, pertussis is caused by the bacterium Bordetella pertussis. Complications from pertussis include death, often from associated pneumonia, seizures, and encephalopathy. Prior to the widespread use of pertussis vaccines in the 1940s, roughly 1 million pertussis cases were reported over a 6-year period. Pertussis incidence in the United States declined dramatically between the 1940s and 1980s, but beginning in the early 1980s, incidence has been slowly increasing, with adolescents and adults accounting for a greater proportion of reported cases. Reasons for increased incidence include improved detection of cases with better laboratory testing methodology (polymerase chain reaction, serology), improved recognition of cases in adolescents and adults, and waning protection from childhood vaccination or prior infection. Infants less than 6 months of age have the highest rate of pertussis infection (143 cases per 100,000) and greater than 90% of pertussis deaths occur in neonates and infants less than 3 months of age.
In 2010, 27,550 cases of pertussis were reported in the United States with many localized outbreaks necessitating enhanced vaccination programs. California had the highest reported incidence since 1958 with a rate of 26.0 cases/100,000; over 9143 cases; and 10 infant deaths. A single booster dose of a different formulation, Tdap, is now recommended for all adolescents and adults, as is discussed in more detail later in this chapter. Providing a booster dose of pertussis-containing vaccine may prevent adolescent and adult pertussis cases, and also has the potential to reduce the spread of pertussis to infants, who are most susceptible to complications from the disease. Currently the ACIP is considering expanding recommendations to include regular booster doses of Tdap in an attempt to protect infants and mitigate current pertussis outbreaks.
Diphtheria, Tetanus, and Acellular Pertussis Combinations
1. DTaP (Daptacel, sanofi pasteur; Infanrix, GlaxoSmithKline) contains tetanus toxoid, diphtheria toxoid, and acellular pertussis vaccine. This DTaP is licensed for ages 6 weeks through 6 years and can be used for doses 1 through 5.
2. Tdap (Boostrix, GlaxoSmithKline) is a tetanus-reduced dose diphtheria-acellular pertussis vaccine formulated for persons 10 years of age and older, including adults and the elderly.
3. Tdap (Adacel, sanofi pasteur) is a tetanus-diphtheria-acellular pertussis vaccine approved for persons 11 through 64 years of age.
DTaP Combined With Other Vaccines
1. DTaP-IPV-Hepatitis B (Pediarix, GlaxoSmithKline) contains DTaP combined with poliovirus and HepB vaccines. It is approved for the first three doses of the DTaP and IPV series, given at 2, 4, and 6 months of age. Although it is approved for use through age 6 years, it is not licensed for booster doses. It cannot be used, for example, as the fourth dose of DTaP (the dose typically given at 15–18 months of age).
2. DTaP-IPV-Hib (Pentacel, sanofi pasteur) contains DTaP, IPV, and Hib vaccines. The Hib component is Hib capsular polysaccharide bound to tetanus toxoid. This vaccine is approved for use as doses 1 through 4 of the DTaP series among children 6 weeks to 4 years of age. It is typically given at 2, 4, 6, and 15–18 months of age, and should not be used as the fifth dose in the DTaP series.
3. DTaP-IPV (Kinrix, GlaxoSmithKline) contains DTaP and IPV vaccines. The vaccine is licensed for children 4–6 years of age, for use as the fifth dose of the DTaP vaccine series and the fourth dose of the IPV series. Using this vaccine would reduce by one the number of injections a 4- to 6-year-old child would receive.
Diphtheria and Tetanus Combinations
1. DT (generic, sanofi pasteur) contains tetanus toxoid and diphtheria toxoid to be used only in children younger than age 7 years with a contraindication to pertussis vaccination.
2. Td (Decavac, sanofi pasteur; generic, Massachusetts Biological Labs) contains tetanus toxoid and a reduced quantity of diphtheria toxoid, which is typically used for adults requiring tetanus prophylaxis.
TT (generic, sanofi pasteur) contains tetanus toxoid only, and can be used for adults or children. However, the use of this single-antigen vaccine is generally not recommended, because of the need for periodic boosting for both diphtheria and tetanus.
Dosage & Schedule of Administration
Although several different vaccines are available, a few general considerations can help guide their use in specific circumstances. DTaP (alone or combined with other vaccines) is used for infants and children between 6 weeks and 6 years of age. Children 7–10 years of age not fully immunized against pertussis (meaning those who have not received five prior doses of DTaP, or four doses of DTaP if the fourth dose was given on or after the fourth birthday), who have no contraindications to pertussis immunization, should receive a single dose of Tdap for pertussis protection. For adolescents and adults, a single dose of Tdap is used, followed by booster doses of Td every 10 years; a detailed description of Tdap use is provided later in this chapter.
The primary series of DTaP vaccination should consist of four doses, given at 2, 4, 6, and 15–18 months of age. The fourth dose may be given as early as 12 months of age if 6 months have elapsed since the third dose. Giving the fourth dose between 12 and 15 months of age is indicated if the provider thinks the child is unlikely to return for a clinic visit between 15 and 18 months of age. Children should receive a fifth dose of DTaP at 4–6 years of age. However, a fifth dose of DTaP is not needed if the fourth dose was given after the child’s fourth birthday. The same brand of DTaP should be used for all doses if feasible.
Contraindications & Precautions
DTaP vaccines should not be used in individuals who have had an anaphylactic-type reaction to a previous vaccine dose or to a vaccine component. DTaP should not be given to children who developed encephalopathy, not attributable to another identified cause, within 7 days of a previous dose of DTaP or DTP. DTaP vaccination should also be deferred in individuals with progressive neurologic disorders, such as infantile spasms, uncontrolled epilepsy, or progressive encephalopathy, until their neurologic status is clarified and stabilized.
Precautions to DTaP vaccination include: high fever (≥ 40.5°F), persistent inconsolable crying, or shock-like state within 48 hours of a previous dose of DTP or DTaP; seizures within 3 days of a previous dose of DTP or DTaP; Guillain-Barré syndrome less than 6 weeks after a previous tetanus-containing vaccine; or incident moderate or severe acute illness with or without a fever.
Local reactions, fever, and other mild systemic effects occur with acellular pertussis vaccines at one-fourth to two-thirds the frequency noted following whole-cell DTP vaccination. Moderate to severe systemic effects, including fever of 40.5°C, persistent inconsolable crying lasting 3 hours or more, and hypotonic-hyporesponsive episodes, are less frequent than with whole-cell DTP. These are without sequelae. Severe neurologic effects have not been temporally associated with DTaP vaccines in use in the United States. A recent study from Canada showed no evidence of encephalopathy related to pertussis vaccine (< 1 case per 3 million doses of DTP and < 1 per 3.5 million doses of DTaP). Data are limited regarding differences in reactogenicity among currently licensed DTaP vaccines. With all currently licensed DTaP vaccines, reports of substantial local reactions at injection sites have increased with increasing dose number (including swelling of the thigh or entire upper arm after receipt of the fourth and fifth doses).
Diphtheria Antibody Preparations
Diphtheria antitoxin is manufactured in horses. Dosage depends on the size and location of the diphtheritic membrane and an estimate of the patient’s level of intoxication. Sensitivity to diphtheria antitoxin must be tested before it is given. Consultation on the use of diphtheria antitoxin is available from the CDC’s National Center for Immunization and Respiratory Diseases. Diphtheria antitoxin is not commercially available in the United States and must be obtained from the CDC.
Tetanus Antibody Preparations
Human tetanus immune globulin (TIg) is indicated in the management of tetanus-prone wounds in individuals who have had an uncertain number or fewer than three tetanus immunizations. Persons fully immunized with at least three doses do not require TIg, regardless of the nature of their wounds (Table 10–5). The optimal dose of TIg has not been established, but some sources recommend 3000–6000 units as a single dose, with part of the dose infiltrated around the wound.
Table 10–5. Guide to tetanus prophylaxis in routine wound management.
CDC: Updated recommendations for the use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine from the Advisory Committee on Immunization Practices, 2011. MMWR 2011;60:13 [PMID: 21228763].
CDC: Diphtheria. In: Atkinson W et al (eds): Epidemiology and Prevention of Vaccine-Preventable Diseases, 12th ed., second printing. Public Health Foundation; 2012:75.
CDC: Pertussis. In: Atkinson W et al (eds): Epidemiology and Prevention of Vaccine-Preventable Diseases, 12th ed., second printing. Public Health Foundation; 2012:215.
CDC: Tetanus. In: Atkinson W et al (eds): Epidemiology and Prevention of Vaccine-Preventable Diseases, 12th ed., second printing. Public Health Foundation; 2012:291.
HAEMOPHILUS INFLUENZAE TYPE B VACCINATION
H influenzae type b (Hib) causes a wide spectrum of serious bacterial illnesses, particularly in young children, including meningitis, epiglottitis, pneumonia, septic arthritis, and cellulitis. Before the introduction of effective vaccines, Hib was the leading cause of invasive bacterial disease in children younger than 5 years of age in the United States with two-thirds of cases occurring in children younger than 18 months of age.
Hib is surrounded by a polysaccharide capsule (polyribosylribitol phosphate [PRP]) that contributes to virulence, and antibodies to this polysaccharide confer immunity to the disease. When Hib polysaccharide is chemically bonded (conjugated) to certain protein carriers, the conjugate vaccine induces long-term T-cell dependent immune memory that is highly effective in young children. Importantly, polysaccharide-protein conjugate vaccines also prevent carriage of the bacterium, and therefore limit spread from asymptomatic carriers to others in the community. All current Hib vaccines are based on this polysaccharide-protein conjugate technology.
Bacterial serotyping is required to differentiate Hib caused infections from those caused by other encapsulated and nonencapsulated H influenzae species. In the early 1980s, roughly 20,000 cases of invasive Hib disease occurred each year in the United States. Since the introduction of protein conjugate Hib vaccines, disease incidence has declined by more than 99% to less than one case per 100,000. In the United States in 2010, 23 cases of invasive Hib disease occurred in children younger than age 5 years. An additional 423 cases were caused by H influenzae species, which were not serotype b or the serotype was not reported.
Six vaccines against Hib disease are available in the United States; three are Hib-only vaccines, and three are combination vaccines. Each vaccine contains Hib polysaccharide conjugated to a protein carrier, but different protein carriers are used. The Hib conjugate vaccine that uses a meningococcal outer membrane protein carrier is abbreviated PRP-OMP; and PRP-T vaccine uses a tetanus toxoid carrier.
1. Hib (PedvaxHIB, Merck, uses PRP-OMP), for use at 2, 4, and 12–15 months of age.
2. Hib (ActHIB, sanofi pasteur, uses PRP-T), for use at 2, 4, 6, and 12–15 months of age.
3. Hib (Hiberix, GlaxoSmithKline, uses PRP-T), for use as the booster (final) dose in the Hib vaccine series for children 15 months of age and older; it is not licensed for the primary series.
Hib Combined With Other Vaccines
1. Hepatitis B-Hib (Comvax, uses PRP-OMP, Merck), for use at 2, 4, and 12–15 months of age. It should not be given prior to 6 weeks of age.
2. DTaP-IPV-Hib (Pentacel, sanofi pasteur, uses PRP-T) contains DTaP, IPV, and Hib vaccines. This vaccine is approved for use in children 6 weeks to 4 years of age.
3. Hib-MenCY-TT (MenHibrix, GlaxoSmithKline Biologicals): A single 0.5 mL dose contains 5 mcg of Neisseria meningitidis C capsular polysaccharide conjugated to approximately 5 mcg of tetanus toxoid, 5 mcg of Neisseria meningitidis Y capsular polysaccharide conjugated to approximately 6.5 mcg of tetanus toxoid, and 2.5 mcg of Hib capsular polysaccharide conjugated to approximately 6.25 mcg of tetanus toxoid.
Dosage & Schedule of Administration
Hib vaccination is recommended for all infants in the United States. The vaccine dose is 0.5 mL given intramuscularly. As shown in Table 10–6, the vaccination schedule depends on which type of Hib vaccine is used. The recommended interval between doses in the primary series is 8 weeks, but a minimal interval of 4 weeks is permitted. For infants who missed the primary vaccination series, a catch-up schedule is used (see Table 10–3). Hib-MenCY-TT is recommended for infants at increased risk of meningococcal disease (see meningococcal section of this chapter). Hib vaccine is not generally recommended for children 5 years of age or older.
Table 10–6. Schedule for Haemophilus influenzae type b (Hib) vaccination depending on type of protein conjugate used.
Contraindications & Precautions
Hib vaccine should not be given to anyone who has had a severe allergic reaction to a prior Hib vaccine dose or to any vaccine components. Hib vaccine should not be given to infants before 6 weeks of age.
Adverse reactions following Hib vaccination are uncommon. Between 5% and 30% of vaccine recipients experience swelling, redness, or pain at the vaccination site. Systemic reactions such as fever and irritability are rare.
MacNeil JR et al: Current epidemiology and trends in invasive Haemophilus influenzae disease—United States, 1989–2008. Clin Infect Dis 2011;53:1230 [PMID: 22080119 ].
Before the routine use of pneumococcal conjugate vaccines in infants, Streptococcus pneumoniae (pneumococcus) was the leading cause of invasive bacterial disease in children. Pneumococcus remains a leading cause of febrile bacteremia, bacterial sepsis, meningitis, and pneumonia in children and adults in the United States and worldwide. It is also a common cause of otitis media and sinusitis. At least 90 different serotypes of pneumococcus have been identified, and immunity to one serotype does not confer immunity to other serotypes.
A conjugate vaccine against seven pneumococcal serotypes (PCV7) was first licensed in the United States in 2000. The routine use of PCV7 led to a dramatic decrease in pneumococcal disease in the United States. However, as disease from PCV7 serotypes has declined greatly, disease caused by pneumococcal serotypes not included in this vaccine, particularly serotype 19A, increased.
In 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) was licensed for use in the United States. Made by the same manufacturer and using the same processes as for PCV7 development, the vaccine contains the seven serotypes included in PCV7 as well as six additional pneumococcal serotypes (including serotype 19A). PCV13 has replaced PCV7 in the United States, and PCV7 is no longer available. PCV13 contains the capsular polysaccharide antigens of 13 serotypes, each individually conjugated to a nontoxic diphtheria carrier protein.
An older, 23-valent pneumococcal vaccine (PPSV23) is also available in the United States, but its use in children is limited to those with certain chronic medical conditions. PPSV23 is a polysaccharide vaccine that protects against 23 serotypes, and provides protection against approximately 25% of pneumococcal infections not prevented by pneumococcal conjugate vaccines. However, the vaccine does not produce long-lasting immune response and does not reduce nasopharyngeal carriage.
While all children and adults are at risk of pneumococcal disease, certain children are at particularly high risk of invasive pneumococcal disease. As seen in Table 10–7, these include children with congenital or acquired immunodeficiency, those without a functioning spleen, and immunocompetent children with certain chronic conditions. These children need enhanced protection against pneumococcal disease, with a more extensive vaccination schedule than healthy children, including the use of PPSV23.
Table 10–7. Chronic medical conditions that are indications for enhanced pneumococcal vaccination among children, by risk group.
1. PCV13 (Prevnar13, Wyeth). The vaccine contains an aluminum phosphate adjuvant, and does not contain thimerosal preservative. It is licensed for use in children 6 weeks through 17 years of age, and in adults 50 years of age and older.
2. PPSV23 (Pneumovax23, Merck). It contains the capsular polysaccharide antigens of 23 pneumococcal serotypes. It contains phenol as a preservative. It is licensed for children 2 years of age and older, and for adults.
Dosage & Schedule of Administration
PCV13 is given as a 0.5-mL intramuscular dose. PPSV23 is given as a 0.5-mL dose by either the intramuscular or subcutaneous route.
The recommended immunization schedule for infants and children is complicated by several factors, including the age at first vaccination, the transition from PCV7 to PCV13, and the need to provide enhanced protection to children at an increased risk of pneumococcal disease (Tables 10–7 and 10-8). Updated and detailed schedule information is available from the CDC (at http://www.cdc.gov/vaccines) and the Immunization Action Coalition (at http://www.immunize.org).
PCV13 is routinely recommended for infants at 2, 4, 6, and 12–15 months of age. The dosing schedule for children 24–71 months of age is shown in Table 10–8. These tables highlight several important features of pneumococcal vaccination recommendations. Healthy children 24–59 months of age who completed a 4-dose PCV7 series should nonetheless receive a single dose of PCV13, to provide them with protection against additional serotypes contained in PCV13. Children 24–71 months of age with certain underlying medical conditions (see Table 10–7) should also receive additional PCV13 doses.
Table 10–8. Recommended schedule for administering doses of 13-valent pneumococcal conjugate vaccine (PCV13) to children aged ≥ 24 months by PCV vaccination history and age.
Children with certain chronic medical conditions (see Table 10–7) should receive PPSV23 in addition to PCV13. The rationale for this recommendation is that, while less immunogenic than PCV13, PPSV23 covers additional serotypes that may cause significant disease in this population. For children ≥ 2 years of age with chronic medical conditions, one dose of PPSV23 should be given at least 8 weeks after the most recent PCV13 dose. Children 24–71 months of age with chronic medical conditions with any incomplete PCV7 series should receive PCV13 (see Table 10–8), followed ≥ 8 weeks later by PPSV23 vaccination. A second dose of PPSV23 is recommended 5 years after the first dose of PPSV23 for children with anatomic or functional asplenia, HIV infection, or immunocompromising conditions. Immunocompetent children with chronic illness should receive the first dose of PPSV23, but are not recommended for PPSV23 revaccination after 5 years.
Contraindications & Precautions
For both PCV13 and PPSV23, vaccination is contraindicated in individuals who suffered a severe allergic reaction such as anaphylaxis after a previous vaccine dose or to a vaccine component (including to any diphtheria toxoid-containing vaccine). PCV13 and PPV23 vaccination should be deferred during moderate or severe acute illness, with or without fever. A history of invasive pneumococcal disease is not a contraindication to vaccination.
The most common adverse effects associated with PCV13 administration are fever, injection site reactions, irritability, and increased or decreased sleep. Although not definitely proven, PCV13 administered simultaneously with inactivated influenza vaccine may lead to a small increased risk of febrile seizures. With PPSV23, 50% of vaccine recipients develop pain and redness at the injection site. Fewer than 1% develop systemic side effects such as fever and myalgia. Anaphylaxis is rare. PPSV23 appears to be safe and immunogenic during pregnancy, although safety data are lacking regarding vaccination during the first trimester of pregnancy.
CDC: Prevention of pneumococcal disease among infants and children—use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine—recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2010;59:1 [PMID: 21150868].
CDC: Invasive pneumococcal disease and 13-valent pneumococcal conjugate vaccine (PCV13) coverage among children aged ≤ 59 months—selected U.S. regions, 2010–2011. MMWR 2011; 60:1477 [PMID: 22048728].
Frenck R Jr et al: Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in children previously immunized with 7-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J 2011;30:1086 [PMID: 21983216].
Gladstone RA et al: Pneumococcal 13-valent conjugate vaccine for the prevention of invasive pneumococcal disease in children and adults. Expert Rev Vaccines 2012;11:889 [PMID: 23002969].
Tse A et al: Signal identification and evaluation for risk of febrile seizures in children following trivalent inactivated influenza vaccine in the Vaccine Safety Datalink Project, 2010–2011. Vaccine 2012;30:2024 [PMID: 22361304].
The polioviruses are highly infectious, spread primarily by a fecal-oral route, and cause acute flaccid paralysis via destruction of motor neurons. Poliomyelitis can be prevented by vaccination, and in 1988 the World Health Assembly resolved to eradicate poliomyelitis from the world by the year 2000. While that goal was not met, the global incidence of polio has decreased from roughly 350,000 cases annually to fewer than 300 cases detected worldwide in 2012. Polio remains endemic in three countries (Afghanistan, Nigeria, and Pakistan), and poliovirus transmission has been reestablished in three previously polio-free countries (Angola, Chad, and the Democratic Republic of the Congo).
The recent substantial accomplishments in polio control have been made despite a number of challenges. Wild-type polioviruses can spread to previously polio-free countries, and sustained transmission can occur in areas with low vaccination coverage rates. In polio-endemic countries, armed conflict and limited infrastructure have led to serious limitations in the ability of public health officials to access and vaccinate susceptible children. Finally, vaccine-derived pathogenic polioviruses can revert from OPV and spread in poorly vaccinated populations. OPV can also persist in immunodeficient patients for years, so any pathogenic revertants that emerge may be shed for extended periods. Updates on the worldwide polio eradication program can be found at www.polioeradication.org.
IPV is an inactivated vaccine that has a higher content of antigens than prior polio vaccines. IPV is the only vaccine against poliomyelitis available in the United States, and cannot cause poliomyelitis, whereas OPV can do so rarely.
Completely immunized adult visitors to areas of continuing wild-type poliovirus circulation should receive a booster dose of IPV. Unimmunized or incompletely immunized adults and children should have received at least two (preferably three) doses of the vaccine prior to travel.
1. IPV (IPOL, sanofi pasteur) is given intramuscularly or subcutaneously.
2. DTaP-HepB-IPV (Pediarix, GlaxoSmithKline) contains diphtheria and tetanus toxoids and acellular pertussis adsorbed, hepatitis B, and inactivated poliovirus vaccine. Approved for use at 2, 4, and 6 months of age; not approved for use as the fourth dose of IPV or the fourth or fifth doses of DTaP; given intramuscularly.
3. DTaP-IPV-Hib (Pentacel, sanofi pasteur) contains DTaP, IPV, and Hib vaccines. Approved for use at 2, 4, 6, and 15–18 months of age; not approved for use as the final 4- to 6-year-old booster dose of IPV; given intramuscularly.
4. DTaP-IPV (Kinrix, GlaxoSmithKline) contains DTaP and IPV vaccines. The vaccine is licensed for children 4–6 years of age, for use as a final booster dose of IPV; given intramuscularly.
Dosage & Schedule of Administration
In the United States, all children without contraindications should receive an IPV-containing vaccine at 2 months, 4 months, 6–18 months, and 4–6 years of age. A dose of IPV should be given at 4 years of age or older, regardless of the number of prior doses of IPV. For example, if four doses of DTaP-IPV-Hib are given prior to 4 years of age, a fifth dose of IPV (in the form of IPV-only or DTaP-IPV) is still needed at 4–6 years of age.
Contraindications & Precautions
IPV vaccination is contraindicated in individuals who suffered a severe allergic reaction such as anaphylaxis after a previous vaccine dose or to a vaccine component. IPV vaccination should be deferred during moderate or severe acute illness with or without fever. Pregnancy is also a precaution to IPV vaccination. Receipt of previous doses of OPV is not a contraindication to IPV.
Minor local reactions, such as pain or redness at the injection site, may occur following IPV vaccination. No serious adverse reactions following IPV vaccination have been described.
Aylward B, Yamada T: The polio endgame. N Engl J Med 2011; 364:2273 [PMID: 21675884].
CDC: Updated recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding routine poliovirus vaccination. MMWR 2009;58:829 [PMID: 19661857].
CDC. Progress toward interruption of wild poliovirus transmission—worldwide, January 2011–March 2012. MMWR 2012; 61:353 [PMID: 22592275].
Thompson KM, Tebbens RJ. Current polio global eradication and control policy options: perspectives from modeling and prerequisites for oral poliovirus vaccine cessation. Expert Rev Vaccines 2012;11:449 [PMID: 22551030].
Influenza occurs each winter-early spring period, often associated with significant morbidity and mortality in certain high-risk persons. Up to 36,000 deaths per year in the United States are attributable to influenza, and global epidemics (pandemics) can occur. The most recent pandemic H1N1 strain began circulation in the spring of 2009 and infected millions throughout the world with varying degrees of morbidity and mortality. In the United States, there were an estimated more than 60 million illnesses, more than 270,000 hospitalizations, and 12,500 deaths. This H1N1 strain is now incorporated into the seasonal trivalent vaccine. Each year, recommendations are formulated in the spring regarding the constituents of influenza vaccine for the coming season. These recommendations are based on the results of surveillance in Asia and the southern hemisphere during the preceding 6 months. Previous influenza vaccines have contained three strains (two influenza A strains, and one of the two lineages of influenza B that may commonly circulate in any given year)). However, a quadrivalent vaccine will be available in limited supply for the 2013–2014 influenza season. The new quadrivalent vaccine contains antigens from two strains of influenza A that are chosen as being likely to circulate in the United States during the upcoming season, and both lineages of influenza B. Children at high risk of seasonal influenza-related complications include those with hemoglobinopathies or with chronic cardiac, pulmonary (including asthma), metabolic, renal, and immunosuppressive diseases (including immunosuppression caused by medications or by HIV); and those with any condition (eg, cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretions, or that can increase the risk of aspiration. Children and adolescents receiving long-term aspirin therapy are also at risk of influenza-related Reye syndrome. Healthy children aged 6–23 months are at substantially increased risk of influenza-related hospitalizations, and children aged 24–59 months (ie, 2–4 years) remain at increased risk of influenza-related clinic and emergency department visits and hospitalizations, but less so than younger children.
Annual influenza vaccination is routinely recommended for all persons older than 6 months of age. Multiple studies have shown increased efficacy of LAIV over inactivated influenza vaccine in the pediatric population with equal efficacy noted in the adult population. Physicians should identify high-risk children in their practices and encourage parents to seek influenza vaccination for them as soon as influenza vaccine is available. Influenza prevention will help prevent lower respiratory tract disease or other secondary complications in high-risk groups, thereby decreasing hospitalizations and deaths.
The inactivated influenza vaccine virus is grown in eggs, formalin-inactivated, and may contain trace quantities of thimerosal as a preservative. Only split-virus or purified surface antigen preparations are available in the United States. Several manufacturers produce similar vaccines each year. Fluzone split-virus (sanofi pasteur) is approved for children 6 months and older; Fluvirin (Novartis) is approved only for children 4 years and older, Fluarix (GlaxoSmithKline) is approved for children 3 years and older, and Afluria (CSL Biotherapies) is recommended for children 9 years and older. Additional manufacturers (ID Biomedical Corporation) produce influenza vaccines approved for adults.
To eliminate the need for injections, and potentially to enhance mucosal and systemic immune response to vaccination, a live attenuated intranasal vaccine has been developed. This vaccine consists of cold-adapted and temperature-sensitive viruses that replicate poorly in the lower respiratory tract, but well in the nasal mucosa (thereby producing immunity). The intranasal live attenuated influenza virus vaccine (LAIV [FluMist, MedImmune]) formulation uses the virus strains present in the inactivated vaccine. It is also made in eggs and comes in a single-use prefilled sprayer that should be stored refrigerated at 2°C–8°C.
Dosage & Schedule of Administration
Inactivated Influenza Virus Vaccine
Because influenza can circulate yearly from November through early March in the United States, the optimal time to initiate vaccination is as soon as vaccine is available in the late summer/early fall. However, providers should continue vaccinating individuals as long as vaccine is available and there is still influenza activity in the community. Children younger than age 6 months should not be immunized. Two doses are recommended for children younger than age 9 years who did not receive a vaccine in the recent season. Older children receiving vaccine for the first time require only a single dose. The dose for children aged 6–35 months is 0.25 mL given intramuscularly; for older children the dose is 0.5 mL given intramuscularly. The recommended site of vaccination is the anterolateral aspect of the thigh for younger children and the deltoid for older children. Pregnancy is not a contraindication to use of inactivated vaccine, and vaccine is recommended for all pregnant women and those contemplating pregnancy during the influenza season. Simultaneous administration with other routine vaccines is acceptable.
Live Attenuated Influenza Virus Vaccine
This vaccine is supplied in a prefilled single-use sprayer containing 0.2 mL of the vaccine, approximately half of which is sprayed into each nostril. A dose divider clip is provided to assist in dividing the dose. If the patient sneezes during administration, the dose should not be repeated. It can be administered to children with minor illnesses, but should not be given if significant nasal congestion is present. Because it is a live vaccine it should be administered 48 hours after cessation of therapy in children receiving anti-influenza antiviral drugs, and these should not be given for 2 weeks after vaccination. Two doses are recommended for children younger than age 9 years who did not receive influenza vaccine in the recent season. One dose is recommended for individuals 9–49 years of age.
Contraindications & Precautions
Inactivated Influenza Virus Vaccine
Inactivated influenza vaccine is contraindicated in individuals with a severe allergic reaction, such as anaphylaxis, to a previous dose of an inactivated influenza vaccine component. However, guidelines for influenza vaccination in children with egg allergies have recently changed. Children with only hives following exposure to egg can be vaccinated, as long as inactivated influenza vaccine is used as opposed to LAIV, vaccination is by a healthcare provider experienced in recognizing and treating allergic reactions, and the child is observed for 30 minutes following vaccination. Children with more serious allergic reactions to egg, such as angioedema, respiratory symptoms, or anaphylaxis, may be eligible for inactivated influenza vaccine but should be referred to an allergist for an assessment of vaccination risk.
Live Attenuated Influenza Virus Vaccine
LAIV is contraindicated in individuals with history of hypersensitivity to eggs, egg proteins, gentamicin, gelatin, or arginine, or with life-threatening reactions to previous influenza vaccinations, and in children and adolescents receiving concomitant aspirin or aspirin-containing therapy. LAIV should not be administered to the following persons: (1) children younger than 24 months of age, because of an increased risk of hospitalization and wheezing that was observed in clinical trials; (2) any individual with asthma or children younger than age 5 years with recurrent wheezing unless the potential benefit outweighs the potential risk; (3) individuals with severe asthma or active wheezing; or (4) within 48 hours of influenza antiviral therapy. Healthcare providers should wait 2 weeks after antiviral therapy to administer LAIV unless medically necessary.
All healthcare workers, including those with asthma and other underlying health conditions (except severe immune compromise), can administer LAIV. Healthcare workers who are vaccinated with LAIV can safely provide care to patients within a hospital or clinic, except for severely immunosuppressed patients that require a protected environment (ie, bone marrow transplant patients). In this instance, there should be a 7-day interval between receiving LAIV and care for these patients.
Inactivated Influenza Virus Vaccine
Injection site reactions are the most common adverse events after inactivated influenza vaccine administration. A small proportion of children will experience some systemic toxicity, consisting of fever, malaise, and myalgias. These symptoms generally begin 6–12 hours after vaccination and may last 24–48 hours. Cases of Guillain-Barré syndrome followed the swine influenza vaccination program in 1976–1977, but careful study by the Institute of Medicine showed no association with that vaccine in children and young adults – nor in any age group that received vaccines in subsequent years.
Live Attenuated Influenza Virus Vaccine
The most common adverse reactions (occurring at < 10% in individuals receiving LAIV and at least 5% greater than in placebo) are runny nose or nasal congestion in recipients of all ages and fever higher than 37.7°C in children 2–6 years of age. These reactions were reported more frequently with the first dose and were all self-limited.
AAP Committee on Infectious Diseases: Policy statement-recommendations for prevention and control of influenza in children, 2012–2013. Pediatrics 2012;130:780 [PMID: 22966032].
CDC: Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2010;59(RR-8):1 [PMID: 20689501].
CDC: Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP)-United States, 2012–2013 influenza season. MMWR 2012;61:613 [PMID: 22895385].
Glezen WP: Clinical practice. Prevention and treatment of seasonal influenza. N Eng J Med 2008;359:2579 [PMID: 19073977].
Greenhawt MJ et al: Administering influenza vaccine to egg allergic recipients: a focused practice parameter update. Ann Allergy Asthma Immunol 2011;106:11 [PMID: 1195939].
MEASLES, MUMPS, & RUBELLA VACCINATION
Due to an effective vaccination program beginning in 1963, measles was declared eliminated from the United States in the year 2000. From 2000 to 2008, there were sporadic importations of measles from countries with lower vaccination rates. However, because measles is one of the first diseases to reappear when vaccination coverage falls, since 2008 there have been numerous outbreaks of measles, primarily from viral transmission within the United States after initial exposure to imported cases. In 2011, there were 222 cases and 17 outbreaks of measles confirmed in the United States, the highest number reported since 1996. Of these cases, 86% were unvaccinated and 90% were associated with United States residents traveling internationally. The increasing number of outbreaks and cases of measles demonstrates the ongoing risk of measles and emphasizes the importance of vaccination.
In the United States, after the introduction of mumps vaccine in 1967 and the recommendation for its use in 1977, there was a 99% decline in mumps from 185,691 cases reported in 1968 to fewer than 300 cases each year between 2001 and 2003. However, between 2005 and 2006, there was a large multistate outbreak of mumps with almost 6000 confirmed or probable mumps cases reported to the CDC. Six states—Iowa, Kansas, Wisconsin, Illinois, Nebraska, and South Dakota—recorded 85% of the cases. This outbreak occurred mostly on college campuses, but also involved high schools and middle schools. Several factors may have contributed to the outbreaks: conditions on college and high school campuses may be conducive to spread of respiratory infections; two doses of MMR vaccine may not be 100% effective in preventing mumps and even less effective in preventing asymptomatic infection; and waning immunity may have occurred in young adults who had last received mumps-containing vaccine 6–17 years earlier.
The rubella vaccine is not primarily intended to protect individuals from rubella infection, but rather to prevent the serious consequences of rubella infection in pregnant women: miscarriage, fetal demise, and congenital rubella syndrome. Congenital rubella syndrome is a group of birth defects including deafness, cataracts, heart defects, and mental retardation. In the United States and the United Kingdom, the approach has been to vaccinate young children and thereby reduce transmission to susceptible women of childbearing age via a herd immunity effect. With the use of rubella vaccines since 1970, rubella incidence rates have declined more than 99% and rubella is now essentially eliminated in the United States with less than 10 cases per year. However, approximately 10% of persons older than 5 years remain susceptible to rubella. Currently most cases of rubella are seen in foreign-born adults, and outbreaks have occurred in poultry- and meat-processing plants that employ many foreign-born workers. There were only four cases of congenital rubella syndrome in the United States between 2008 and 2012.
Despite many reports in the lay press and on the Internet of a link between MMR and autism, there is overwhelming scientific evidence that there is no causal association between the two. There is also no evidence that separation of MMR into its individual component vaccines lessens the risk of any vaccine adverse event, and such practice is not recommended.
It has been known for some time that there is a small but increased risk of febrile seizures after MMR. A recent study found that in 12- to 23-month-old children, the risk for febrile seizures with the MMRV preparation appears to be twice that of MMR and VAR given separately, resulting in one additional febrile seizure per 2300–2600 children vaccinated with MMRV at this age.
1. Measles-mumps-rubella (MMR II, Merck): MMR II is a lyophilized preparation of measles, mumps, and rubella vaccines. The measles and mumps portions are prepared using chick embryo tissue cultures and rubella is grown in human diploid cells. There is no adjuvant and no preservative. It does contain small amounts of gelatin, sorbitol, and neomycin. The individual components of MMR II are no longer available.
2. MMRV: In September 2005, the FDA licensed a combined live attenuated measles, mumps, rubella, and varicella vaccine (ProQuad, Merck) for use in children 1–12 years of age. The measles, mumps, and rubella components are identical to MMR II. The varicella component has a higher varicella zoster virus titer than the varicella-only (VAR) vaccine.
Dosage & Schedule of Administration
Measles, mumps, and rubella vaccinations should be given as MMR or MMRV at 12–15 months and again at 4–6 years of age. Both MMR and MMRV can cause febrile seizures, although uncommonly. Because febrile seizures following MMRV occur at a rate twice that of MMR (see “Adverse Effects”), the ACIP recommends that after a discussion of the benefits and risks of both vaccination options with the parents or caregivers, either MMR or MMRV may be given at 12–15 months of age. MMRV is the preferred vaccine at 4–6 years of age if available; no excess risk of febrile seizures following MMRV vaccination has been observed at 4–6 years of age. A personal or family history of febrile seizures in an infant is considered a precaution for the use of MMRV, and MMR and VAR given separately is preferred. A dose of 0.5 mL should be given subcutaneously. The second dose of MMR or MMRV is recommended at school entry to help prevent school-based measles and mumps outbreaks. Children not reimmunized at school entry should receive their second dose by age 11–12 years. If an infant receives the vaccine before 12 months of age, two doses are required to complete the series, the first after at least 12 months of age and the second at least 1 month later. Ig interferes with the immune response to the attenuated vaccine strains of MMR and MMRV. Therefore, after Ig administration MMR and MMRV immunization should be deferred by 3–11 months, depending on the type of Ig product received. Consult the AAP’s 2012 Red Book for specific recommendations.
For measles, mumps, and rubella, a person can be considered immune if they were born before 1957, or if there is laboratory evidence of serologic immunity or disease. Otherwise, all persons should be vaccinated according to the recommended schedule. A clinical diagnosis of any of these diseases is not acceptable evidence of immunity. For rubella, susceptible pubertal girls and postpubertal women identified by prenatal screening should be immunized after delivery. Whenever rubella vaccination is offered to a woman of childbearing age, pregnancy should be ruled out and the woman advised to prevent conception for 3 months following vaccination. If a pregnant woman is vaccinated or becomes pregnant within 3 weeks of vaccination, she should be counseled regarding the risk to her fetus, although no cases of rubella vaccine-related fetal anomalies have been reported. The risk of congenital rubella syndrome after wild-type maternal infection in the first trimester of pregnancy is 20%–85%. All susceptible adults in institutional settings (including colleges), day care center personnel, military personnel, and hospital and healthcare personnel should be immunized.
Vaccination of Travelers
People traveling abroad should be immune to measles and mumps. Infants 6–11 months of age traveling to high-risk areas should receive one dose of MMR prior to travel followed by either MMR or MMRV at 12–15 months of age (given at least 4 weeks after the initial dose) and either MMR or MMRV at 4–6 years of age to complete the series. Children over 12 months of age who are traveling to high-risk areas should receive two doses separated by at least 4 weeks. Children traveling internationally to lower-risk areas should be immunized as soon as possible after their first birthday and complete the series at 4–6 years of age in the usual fashion.
Revaccination Under Other Circumstances
Persons entering college and other institutions for education beyond high school, medical personnel beginning employment, and persons traveling abroad should have documentation of immunity to measles and mumps, defined as receipt of two doses of measles vaccine after their first birthday, birth before 1957, or a laboratory documented measles or mumps history.
Outbreak Control of Measles
A community outbreak is defined as a single documented case of measles. Control depends on immediate protection of all susceptible persons (defined as persons who have no documented immunity to measles in the affected community). In the case of unvaccinated individuals, the following recommendations hold: (1) age 6–11 months, give MMR if cases are occurring in children younger than age 1 year, followed by two doses of MMR or MMRV at age 12–15 months and again at age 4–6 years; and (2) age 12 months or older, give MMR or MMRV followed by revaccination at age 4–6 years. A child with an unclear or unknown vaccination history should be reimmunized with MMR or MMRV. Anyone with a known exposure who is not certain of having previously received two doses of MMR should receive an additional dose. Unimmunized persons who are not immunized within 72 hours of exposure, which is the acceptable interval for active postexposure prophylaxis, should be excluded from contact with potentially infected persons until at least 2 weeks after the onset of rash of the last case of measles.
Contraindications & Precautions
MMR and MMRV vaccines are contraindicated in pregnant women, women intending to become pregnant within the next 28 days, immunocompromised persons, and persons with anaphylactic egg or neomycin allergy. It is also contraindicated in children receiving high-dose corticosteroid therapy (≥ 2 mg/kg/d, or 20 mg/d total, for longer than 14 days) with the exception of those receiving physiologic replacement doses. In these patients, an interval of 1 month between cessation of steroid therapy and vaccination is sufficient. Leukemic patients who have been in remission and off chemotherapy for at least 3 months can receive MMR and MMRV safely. Persons with HIV infection should receive two doses of MMR vaccine according to the recommended schedule if they do not have evidence of current severe immunosuppression [for persons aged ≤ 5 years, they must have CD4 percentages ≥ 15% for ≥ 6 months; and for persons aged > 5 years, they must have CD4 percentages ≥ 15% and CD4 ≥ 200 lymphocytes/mm3 for ≥ 6 months]. Children with minor acute illnesses (including febrile illnesses), egg allergy whether severe or mild, or a history of tuberculosis should be immunized. MMR and MMRV may be safely administered simultaneously with other routine pediatric immunizations. A personal or family history of febrile seizures in an infant is considered a precaution for the use of MMRV, and MMR and VAR separately is preferred.
Between 5% and 15% of vaccinees receiving MMR become febrile to 39.5°C or higher about 6–12 days following vaccination, lasting approximately 1–2 days, and 5% may develop a transient morbilliform rash. Transient thrombocytopenia occurs at a rate of 1 per 40,000 vaccine recipients. Encephalitis and other central nervous system conditions, such as aseptic meningitis and Guillain-Barré syndrome, are reported to occur at a frequency of 1 case per 3 million doses in the United States. This rate is lower than the rate of these conditions in unvaccinated children, implying that the relationship between them and MMR vaccination is not causal. Reactions after mumps vaccination are rare and include parotitis, low-grade fever, and orchitis. In children, adverse effects from rubella vaccination are very unusual. Between 5% and 15% of vaccinees develop rash, fever, or lymphadenopathy 5–12 days after rubella vaccination. Rash also occurs alone or as a mild rubella illness in 2%–4% of adults. Arthralgia and arthritis occur in 10%–25% of adult vaccinees, as opposed to only 0%–2% of 6- to 16-year-old vaccinees. Chronic arthritis, which may be causally related to rubella vaccination, occurs more often in women aged 45 or older, starting 10–11 days after vaccination and lasting for up to 1 year. Possible rare complications include peripheral neuritis and neuropathy, transverse myelitis, and diffuse myelitis.
MMR vaccination is associated with an increased risk of febrile seizures 8–14 days after vaccination with the first dose, but no subsequent long-term complications have been seen. The risk associated for febrile seizures in children 12–23 months old with MMRV appears to be twice that of MMR and VAR given separately, resulting in one additional febrile seizure per 2300–2600 children vaccinated with MMRV.
Antibody Preparations Against Measles
If administered within 6 days of exposure, Ig can prevent or modify measles in a nonimmune person. However, the immunity conferred should be considered temporary. Infants under 12 months of age who have been exposed to measles should receive 0.5 mL/kg of Ig, given intramuscularly (maximum dose is 15 mL). MMR vaccine should also be used, as appropriate, for infants aged 6–11 months. Pregnant women without evidence of measles immunity and severely immune-compromised persons (regardless of evidence of measles immunity) who are exposed to measles should receive 400 mg/kg of Ig given intravenously. Ig given intramuscularly (0.5 mL/kg, maximum dose, 15 mL) may be given to more immune competent exposed persons without evidence of immunity, with priority for those with the most intense contact to a case.
CDC: Measles: United States, 2011. MMWR 2012;61:253–257 [PMID: 22513526].
CDC: Update: recommendations from the Advisory Committee on Immunization Practices (ACIP) regarding administration of combination MMRV vaccine. MMWR 2008;57:258 [PMID: 18340332].
CDC: Two measles outbreaks after importation—Utah, March–June 2011. MMWR 2013;62:222–225 [PMID: 23535688].
Klein NP et al: Measles-containing vaccines and febrile seizures in children age 4 to 6 years. Pediatrics 2012;129:809 [PMID: 22473362].
Prior to the availability of vaccine, about 4 million cases of varicella-zoster virus (VZV) infection occurred annually in the United States, mostly in children younger than 10 years old. This resulted in 11,000 hospitalizations and 100 deaths per year due to severe complications such as secondary bacterial infections, pneumonia, encephalitis, hepatitis, and Reye syndrome.
A live, attenuated varicella vaccine (VAR) was licensed in the United States in 1995 and routine immunization of children 12 months of age and older has been recommended since then. The vaccine is almost 100% effective at preventing severe disease. The morbidity, mortality, and medical costs associated with varicella infection have significantly declined since VAR was first licensed. Vaccination prevents an estimated 3.5 million cases of varicella, 9000 hospitalizations, and 100 deaths from varicella in the United States each year. Once the routine use of VAR was achieved, it became apparent that there is “breakthrough” (usually very mild) varicella occurring in about 15% of immunized patients. Outbreaks of wild-type infectious VZV have been reported in schools with high one-dose VAR vaccination coverage (96%–100%). The vaccine efficacy in those outbreaks against any disease was similar (72%–85%) to that previously observed. Varicella attack rates among these children varied between 11% and 17% and thus, it was concluded that a single VAR dose could not prevent varicella outbreaks completely.
A second dose of VAR in children, when given 3 months or 4–6 years after the initial dose, greatly increased the magnitude of the anti-VZV antibody response, which is a correlate of vaccine efficacy. A combination MMRV vaccine has also been shown to be immunologically noninferior to the individual components administered compared with MMR and VAR administered concomitantly, either as primary immunization or as a booster administered to children age 4–6 years. The two-dose regimen is almost 100% effective against severe varicella, and the risk of breakthrough varicella is threefold less than the risk with a one-dose regimen. Therefore, ACIP and the AAP recommend two doses of VAR for children older than 12 months of age, and for adolescents and adults without evidence of immunity.
Data from the United States and Japan suggest that the vaccine is also effective in preventing or modifying VZV severity in susceptible individuals exposed to VZV if used within 3 days (and possibly up to 5 days) of exposure. A study in the United States suggests that the efficacy of postexposure vaccination is 95% for prevention of any disease and 100% for prevention of moderate or severe disease. There is no evidence that postexposure prophylaxis will increase the risk of vaccine-related adverse events or interfere with development of immunity.
1. A cell-free preparation of Oka strain VZV is produced and marketed in the United States as Varivax (Merck). Each dose of VAR contains not less than 1350 plaque-forming units of VZV and trace amounts of neomycin, fetal bovine serum, and gelatin. There is no preservative.
2. MMRV (measles-mumps-rubella-varicella, ProQuad, Merck) is licensed for use in children 1–12 years of age. MMRV is well-tolerated and provides adequate immune response to all of the antigens it contains. In MMRV, the varicella component is present in higher titer than in the VAR. Concomitant administration of MMRV with DTaP, Hib, and HepB vaccines is acceptable.
Dosage & Schedule of Administration
Two doses (0.5 mL) of VAR are recommended for immunization of all healthy children aged 12 months and older, and for adolescents and adults without evidence of immunity. For children aged 12 months to 12 years the immunization interval is 3 months, and for persons 13 years or older it is 4 weeks. MMRV is approved only for healthy children aged 12 months to 12 years. A second dose of catch-up vaccination is required for children, adolescents, and adults who previously received one dose of VAR vaccine. All children should have received two doses of VAR before prekindergarten or school. HIV-infected children (≥ 15% CD4+ cells) should receive two doses of the single-antigen vaccine (with a 3-month interval between doses).
VAR may be given simultaneously with MMR at separate sites. If not given simultaneously, the interval between administration of VAR and MMR must be greater than 28 days. Simultaneous VAR administration does not appear to affect the immune response to other childhood vaccines. VAR should be delayed 5 months after receiving intravenous immune globulin, blood, or plasma. In addition, persons who received VAR should not be administered an antibody-containing product for at least two weeks or an antiviral medication active against varicella for at least 3 weeks, and if needed in that interval, the individual may need to be tested for immunity or revaccinated. After a discussion of the benefits and risks of both vaccination options with the parents or caregivers (see below, “Adverse Effects”), either MMR or MMRV may be given at 12–15 months. MMRV is the preferred vaccine if available at 4–6 years of age.
Contraindications & Precautions
Contraindications to VAR vaccination include a severe allergic reaction after a previous vaccine dose or to a vaccine component. Because VAR and MMRV are live-virus vaccines, they are also contraindicated in children who have cellular immunodeficiencies, including those with leukemia, lymphoma, other malignancies affecting the bone marrow or lymphatic systems, and congenital T-cell abnormalities (although VAR vaccine administration to children with acute lymphocytic leukemia is under investigation). The exception to this rule is the recommendation that VAR be administered to HIV-infected children who are not severely immunosuppressed. Children receiving immunosuppressive therapy, including high-dose steroids, should not receive VAR or MMRV. Household contacts of immunodeficient patients should be immunized. VAR should not be given to pregnant women; however, the presence of a pregnant mother in the household is not a contraindication to immunization of a child within that household. A personal or family history of febrile seizures in an infant is considered a precaution for the use of MMRV; administration of MMR and VAR separately is preferred for the first dose.
The most commonly recognized adverse reactions, occurring in approximately 20% of vaccinees, are minor injection site reactions. Additionally, 3%–5% of patients will develop a rash at the injection site, and an additional 3%–5% will develop a sparse varicelliform rash outside of the injection site. These rashes typically consist of two to five lesions and may appear 5–26 days after immunization. The two-dose vaccine regimen is generally well tolerated with a safety profile comparable to that of the one-dose regimen. The incidence of fever and varicelliform rash is lower after the second dose than the first. Although VAR is contraindicated in pregnancy, there have now been several hundred inadvertent administrations of vaccine to pregnant women tracked by the “Pregnancy Registry for Varivax” with no known cases of congenital varicella syndrome.
Studies comparing MMRV to MMR and VAR administered concomitantly showed more systemic adverse events following MMRV (fever 21.5% vs 14.9% and measles-like rash 3% vs 2.1%, respectively). The risk of febrile seizures in children 12–23 months old with the MMRV preparation is twice that of MMR and VAR given separately, resulting in one additional febrile seizure per 2300–2600 children vaccinated with MMRV.
Transmission of vaccine virus from healthy vaccinees to other healthy persons is very rare; has never been documented in the absence of a rash in the index case; and has only resulted in mild disease. Herpes zoster infection has occurred in recipients of VAR in immunocompetent and immunocompromised persons within 25–722 days after immunization. Many of these cases were thought to be due to unappreciated latent wild-type virus. Vaccine-strain varicella does cause herpes zoster in children, but the age-specific risk of herpes zoster infection seems much lower in children following VAR immunization than after natural infection, and it also tends to be milder.
In the event of an exposure to varicella, there are currently two antibody preparations potentially available in the United States for postexposure prophylaxis, VariZIG and intravenous Ig. Exposure is defined as a household contact or playmate contact (> 1 h/d), hospital contact (in the same or contiguous room or ward), intimate contact with a person with herpes zoster deemed contagious, or a newborn contact. Susceptibility is defined as the absence of a reliable history of varicella or varicella vaccination. Uncertainty in this diagnosis can be resolved with an appropriate test for anti-VZV antibody.
A Canadian preparation (VariZIG, Cangene Corporation) is FDA-approved. VariZIG should be administered as soon as possible after exposure but may be given within 10 days post–exposure. In the past, the interval for passive prophylaxis was limited to 96 hours postexposure. If VariZig is not available, it is recommended that intravenous Ig be used in its place. The dose is 400 mg/kg administered once. A subsequent exposure does not require additional prophylaxis if this occurs within 3 weeks of intravenous Ig administration.
AAP Committee on Infectious Diseases: Prevention of varicella: recommendations for use of quadrivalent and monovalent varicella vaccines in children. Pediatrics 2011;128:630 [PMID: 21873692].
CDC: Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56(RR-4):1 [PMID: 17585291].
CDC: Use of combination measles, mumps, rubella, and varicella vaccine: recommendations of the Advisory Committee on Immunization Practices. MMWR 2010;59:1 [PMID: 20448530].
Marin M, Zhang JX, Seward JF: Near elimination of varicella deaths in the US after implementation of the vaccination program. Pediatrics 2011;128:214 [PMID: 21788222].
Shapiro ED, et al: Effectiveness of 2 doses of varicella vaccine in children. J Infect Dis 2011;203:312 [PMID 21208922].
HEPATITIS A VACCINATION
The incidence of hepatitis A in the United States has decreased dramatically in recent years. An average of 28,000 cases was reported annually in the years prior to availability of a hepatitis A vaccine. Hepatitis A infection rates are now at historical lows, with fewer than 2000 reported cases annually.
Hepatitis A vaccines first became available in the United States in 1995. Initially, vaccination was recommended for certain high-risk groups, such as international travelers, users of illegal drugs, and men who have sex with men. Children, who are more likely than adults to be asymptomatic while infected, have often contributed to the spread of hepatitis A through households and communities. Therefore, since 2006 hepatitis A vaccination has been routinely recommended for all children 12–23 months of age. As a consequence of vaccination, the epidemiology of hepatitis A infection has changed substantially: in a recent investigation, more than 40% of reported cases were associated with international travel, often in foreign-born persons returning to their countries of origin.
In addition to routine immunization of all children 12–23 months of age, hepatitis A vaccination is indicated for the following groups: (1) travelers to countries with moderate to high rates of hepatitis A, (2) children with chronic hepatitis B or hepatitis C infections or other chronic liver disease, (3) children with clotting factor disorders, (4) adolescent and adult males who have sex with men, (5) persons with an occupational exposure to hepatitis A, (6) illegal drug users, and (7) all previously unvaccinated persons who anticipate close personal contact with an international adoptee from countries with moderate to high rates of hepatitis A. Vaccination should also be considered in previously unimmunized children 2–18 years old, even if none of the above risk factors are present.
1. HepA (Havrix, GlaxoSmithKline): An inactivated vaccine against hepatitis A. Contains an aluminum adjuvant; does not contain a preservative. Approved for use in children 12 months of age and older and adults.
2. HepA (Vaqta, Merck): An inactivated vaccine against hepatitis A. Contains an aluminum adjuvant; does not contain a preservative. Approved for use in children 12 months of age and older and adults.
3. HepA-HepB (Twinrix, GlaxoSmithKline): A combined inactivated vaccine against hepatitis A and hepatitis B. Approved for use in adults 18 years of age and older.
Dosage & Schedule of Administration
The two HepA vaccines given in childhood (Havrix and Vaqta) are given as a 2-dose series. The first dose is recommended at 12–23 months of age; the second dose is recommended 6–18 months following the initial dose. For individuals 12 months through 18 years of age, these vaccines are administered intramuscularly in a dose of 0.5 mL. Adults 19 years of age and older can receive Havrix (two doses of 1.0 mL each, separated by at least 6 months), Vaqta (two doses of 1.0 mL each, separated by at least 6 months), or Twinrix (for adults 18 years and older, 1.0 mL per dose, in a 3- or 4-dose series).
Contraindications & Precautions
Hepatitis A vaccine should not be given to anyone with a prior severe allergic reaction, such as anaphylaxis, after a previous vaccine dose or to a vaccine component. Precautions to vaccination include pregnancy and moderate or severe acute illness. The vaccine should not be administered to children with hypersensitivity to neomycin (in the case of Havrix) or alum (for Havrix and Vaqta).
Adverse reactions, which are uncommon and mild, consist of pain, swelling, and induration at the injection site (10%–15%), headache, and loss of appetite. There have been no reports of serious adverse events attributed definitively to hepatitis A vaccine.
Postexposure prophylaxis is recommended for household or sexual contacts of persons with serologically confirmed hepatitis A, and for daycare staff and attendees in outbreak situations. Postexposure prophylaxis may also be recommended in food-borne outbreaks, depending on the extent and timing of exposure. Postexposure prophylaxis of unimmunized persons who are exposed to hepatitis A should consist of either a single dose of hepatitis A vaccine or Ig (0.02 mL/kg), given as soon as possible after exposure. The efficacy of Ig when given more than 2 weeks after exposure has not been established. For healthy people 12 months through 40 years of age, hepatitis A vaccine is preferred to Ig for postexposure prophylaxis because of the advantages of vaccination, including long-term protection and ease of administration. For those over 40 years of age, Ig is preferred, although the vaccine should be used if Ig is not available. Ig should also be used for children < 12 months of age, immunocompromised persons, those with chronic liver disease, and anyone for whom vaccination is contraindicated. People who are given Ig, and for whom hepatitis A vaccine is recommended for other reasons, should receive a dose of vaccine simultaneously with Ig. If given at the same time, the vaccine and Ig should be administered at different anatomic injection sites.
Ig can be used as preexposure as well as postexposure prophylaxis. Ig is indicated as preexposure prophylaxis in children younger than age 12 months at increased risk of hepatitis A infection (eg, those traveling to endemic areas, or those with clotting factor disorders). For preexposure prophylaxis, recommended dosages are 0.02 mL/kg in a single intramuscular dose if the duration of exposure is likely to be less than 3 months and 0.06 mL/kg if exposure is likely to be more than 3 months. For long-term prophylaxis of persons not eligible for vaccination, prophylactic doses can be repeated every 5 months.
Byrd KK et al: Predictors of hepatitis A vaccination among young children in the United States. Vaccine 2011;29:3254 [PMID: 21352942].
CDC: Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006; 55(RR-7):1 [PMID: 16708058].
CDC (hepatitis A vaccine information): http://www.cdc.gov/hepatitis/HAV.htm.
Ott JJ et al: Long-term protective effects of hepatitis A vaccines. A systematic review. Vaccine 2012;31:3 [PMID: 22609026].
WHO: WHO position paper on hepatitis A vaccines—June 2012. Wkly Epidemiol Rec 2012;87:261 [PMID: 22905367].
Infections with Neisseria meningitidis cause significant morbidity and mortality, with an estimated 1400–2800 cases of meningococcal disease occurring in the United States annually. Even with appropriate treatment, meningococcal disease has an estimated case-fatality rate of 10%–14%, and up to 19% of survivors are left with serious disabilities, such as neurologic deficits, loss of limbs or limb function, or hearing loss. Five serogroups of meningococcus (A, B, C, W-135, and Y) cause the vast majority of disease worldwide. Serogroups B, C, and Y are the predominant causes of invasive meningococcal disease in the United States, while serogroups A and C cause most disease in developing countries. Intensive research efforts have been made to develop an effective vaccine against serogroup B, which causes more than 50% of cases among children younger than 1 year of age. However, the bacterial capsule proteins of serogroup B are poorly immunogenic in humans, presenting a significant obstacle to vaccine development.
There are two tetravalent meningococcal polysaccharide-protein conjugate vaccines (MCV4) available, Menactra, licensed in 2005, and Menveo, licensed in 2010. Both vaccines are recommended by the ACIP and are indicated for use in persons 2–55 years of age, with Menactra also licensed for use in children aged 9–23 months. MCV4 is recommended for all persons 11–18 years of age, as well as for persons 2–55 years who are at increased risk of meningococcal disease. Persons at increased risk include college freshmen living in dormitories, microbiologists who are routinely exposed to isolates of Neisseria meningitidis, military recruits, persons who travel to or reside in countries where meningococcal disease is hyperendemic or epidemic, persons with persistent complement component deficiencies, and persons with anatomic or functional asplenia.
Because of mounting evidence of waning immunity by 5 years postvaccination, a booster dose is now recommended for adolescents aged 16 years and older who received their first dose at ages 11–15 years. A booster dose is not recommended for persons who received their first dose at age 16 years or older. A two-dose primary series administered 2 months apart is indicated for persons age 2 through 55 years with persistent complement component deficiency, functional or anatomic asplenia, and for adolescents 11–18 years with human immunodeficiency virus (HIV) infection. Whenever meningococcal vaccination is indicated, MCV4 is preferred for persons 2–55 years old, while tetravalent meningococcal polysaccharide vaccine (MPSV4, Menomume) should be used for persons older than 55 years. If MCV4 is not available, MPSV4 is an appropriate alternative for persons 2–55 years old for the initial dose. For a booster dose, MPSV4 is not recommended and either MCV4 product may be used (Menactra or Menveo). There are limited data available on the interchangeability of MCV4 products, and whenever feasible the same brand of vaccine should be used for all doses of the vaccine series. However, providers should use every opportunity to provide the booster dose when indicated, regardless of the vaccine brand used (Menactra or Menveo) for previous doses.
In October 2012, the ACIP voted to recommend vaccination against meningococcal serogroups C and Y for high risk children from 6 weeks to 18 months of age. Meningococcal groups C and Y and Hib tetanus toxoid conjugate vaccine (Hib-MenCY-TT [MenHibrix, GlaxoSmithKline Biologicals]) is available and licensed for use in this age group. Infants at high risk include those with recognized persistent complement pathway deficiencies and also those with functional or anatomic asplenia, including sickle cell disease. The recommended four-dose schedule is the same as for other Hib-containing vaccines at 2, 4, 6, and 12–15 months of age.
1. MCV4 (Menactra, sanofi pasteur): A single 0.5-mL dose contains 4 mcg each of capsular polysaccharide from serogroups A, C, Y, and W-135 conjugated to 48 mcg of diphtheria toxoid. Available in single-dose vials only.
2. MCV4 (Menveo, Novartis): A single 0.5-mL dose contains 10 mcg of serogroup A capsular polysaccharide and 5 mcg each of serogroups C, Y, and W-135 capsular polysaccharide, all of which is conjugated to CRM197, a nontoxic mutant of diphtheria toxoid.
3. Hib-MenCY-TT (MenHibrix, GlaxoSmithKline Biologicals): A single 0.5-mL dose contains 5 mcg of serogroup C capsular polysaccharide conjugated to approximately 5 mcg of tetanus toxoid, 5 mcg of serogroup Y capsular polysaccharide conjugated to approximately 6.5 mcg of tetanus toxoid, and 2.5 mcg of Hib capsular polysaccharide conjugated to approximately 6.25 mcg of tetanus toxoid.
4. MPSV4 (Menomune-A/C/Y/W-135, sanofi pasteur): Each dose consists of 50 mcg each of the four bacterial capsular polysaccharides. Available in 1- and 10-dose vials.
Dosage & Schedule of Administration
MCV4 is given as a single intramuscular dose of 0.5 mL. If a dose is inadvertently administered subcutaneously, it does not need to be repeated. Hib-MenCY-TT is given as a single intramuscular dose of 0.5 mL. MPSV4 is administered as a single subcutaneous dose of 0.5 mL. MCV4, Hib-MenCY-TT, and MPSV4 can be given at the same time as other vaccines, at a different anatomic site. If a 4-dose schedule of Hib-MenCY-TT is given, no additional Hib doses are needed. Protective antibody levels are typically achieved within 10 days of vaccination. The schedule of administration of meningococcal vaccines is described above.
Contraindications & Precautions
MCV4 and MPSV4 are contraindicated in anyone with a known severe allergic reaction to any component of the vaccine, including diphtheria toxoid (for MCV4) and rubber latex. Although MCV4 vaccination is not contraindicated in someone with a prior history of Guillain-Barré syndrome, providers should discuss the possible risks and benefits of vaccination in anyone with a history of Guillain-Barré syndrome. Both MCV4 and MPSV4 can be given to individuals who are immunosuppressed. MPSV4 is thought to be safe during pregnancy; no information is available regarding the safety of MCV4 during pregnancy.
Both MCV4 products and MPSV4 are generally well tolerated in adolescent patients. Local vaccination reactions (redness, swelling, or induration) occur in 11%–16% of persons 11–18 years old receiving MCV4 and in 4%–6% of persons the same age receiving MPSV4. The most common solicited complaints among children aged 2–10 years were injection site pain and irritability. More severe systemic reactions (presence of any of the following: fever of 39.5°C or above; headache, fatigue, malaise, chills, or arthralgias requiring bed rest; anorexia; multiple episodes of vomiting or diarrhea; rash; or seizures) occur in 4.3% of MCV4 recipients and 2.6% of MPSV4 recipients. Although cases of Guillain-Barré syndrome have been reported after MCV4, the current data does not suggest that the rate is above that which would be expected in the absence of vaccination. Any cases of suspected Guillain-Barré syndrome after vaccination should be reported to VAERS.
CDC: Licensure of a meningococcal conjugate vaccine (Menveo) and guidance for use—Advisory Committee on Immunization Practices (ACIP), 2010. MMWR 2010;59(9):273 [PMID: 20224545].
CDC: Licensure of a meningococcal conjugate vaccine for children aged 2 through 10 years and updated booster dose: guidance for adolescents and other persons at increased risk for meningococcal disease—Advisory Committee on Immunization Practices (ACIP), 2011. MMWR 2011;60:1018 [PMID: 21814165].
CDC: Prevention and control of meningococcal disease. MMWR 2013;62(RR-2):1–22 [PMID: 23515099].
CDC: Updated recommendations for use of meningococcal conjugate vaccines—Advisory Committee on Immunization Practices (ACIP), 2010. MMWR 2011;60:72 [PMID: 21270745].
Poland GA: Prevention of meningococcal disease: current use of polysaccharide and conjugate vaccines. Clin Infect Dis 2010;50 (Suppl 2):S45 [PMID: 20144016].
TETANUS-REDUCED DIPHTHERIA-ACELLULAR PERTUSSIS VACCINATION (ADOLESCENTS & ADULTS)
Pertussis is increasingly recognized as a disease affecting older children and adults, including fully vaccinated persons with waning immunity. In the United States, the most dramatic increases in pertussis incidence are among adolescents and young adults, prompting development of booster pertussis vaccines for this population. FDA approval in 2005 of the tetanus-reduced dose diphtheria-acellular pertussis (Tdap) vaccine was based on comparable seroresponse to pertussis antigens and a safety profile similar to control Td. Adolescent, adult, and elderly immunization not only has the capacity to protect adolescents from pertussis, but also should limit spread of pertussis from adults to infants and decrease overall pertussis endemicity. Because pertussis incidence has been rising nationally, and waning immunity may be contributing, studies are being conducted to evaluate whether additional booster doses of pertussis-containing vaccines are needed.
1. Tdap (Boostrix, GlaxoSmithKline) contains tetanus toxoid, diphtheria toxoid, and three acellular pertussis antigens (detoxified pertussis toxin [PT], filamentous hemagglutinin [FHA], and pertactin) and is licensed for use in persons aged 10 years and older; this vaccine can be used in adults and the elderly.
2. Tdap (Adacel, sanofi pasteur) contains tetanus toxoid, diphtheria toxoid, and five acellular pertussis antigens (PT, FHA, pertactin, and fimbriae types 2 and 3) and is licensed for use in persons aged 11–64 years.
Dosage & Schedule of Administration
Adolescents 11–18 years of age should receive a 0.5-mL dose of Tdap intramuscularly in the deltoid, instead of the tetanus and diphtheria toxoids (Td) vaccine for booster immunization. The preferred age for Tdap immunization is 11–12 years. Adults 19–64 years of age should receive a single dose of Tdap. Adults 65 years of age and older should receive a single dose of Tdap if they have not previously received Tdap and if they anticipate close contact with an infant less than 12 months of age. Women who are pregnant should receive a Tdap booster with each pregnancy. Tdap can be administered regardless of the interval since the last tetanus- or diphtheria-toxoid containing vaccine. Tdap and MCV4 should be administered during the same visit if both vaccines are indicated. If not administered at the same time, a minimum interval of 1 month between vaccines is suggested.
Contraindications & Precautions
Contraindications to Tdap include severe allergic reaction to any vaccine component and encephalopathy (eg, coma, prolonged seizures) not attributable to an identifiable cause within 7 days of administration of a vaccine with pertussis components. Precautions for Tdap administration include Guillain-Barré syndrome occurring within 6 weeks of a previous dose of a tetanus toxoid-containing vaccine, a progressive neurologic disorder, uncontrolled epilepsy, or progressive encephalopathy until the condition has stabilized. If there is a history of a severe Arthus reaction after a previous tetanus toxoid-containing or diphtheria toxoid-containing vaccine, Tdap should be deferred for at least 10 years.
Pain at the injection site was the most frequently reported local adverse event among adolescents. Headache and fatigue were the most frequently reported systemic adverse events.
AAP, Committee on Infectious Diseases: Additional recommendations for use of tetanus toxoid, reduced-content diphtheria toxoid, and acellular pertussis vaccine (Tdap). Pediatrics 2011; 128:809 [PMID: 21949151].
CDC: Updated recommendations for the use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine from the Advisory Committee on Immunization Practices, 2010. MMWR 2011;60:13 [PMID: 21228763].
Misegades LK et al: Association of childhood pertussis with receipt of 5 doses of pertussis vaccine by time since last vaccine dose, California, 2010. JAMA 2012;308:2126 [PMID: 23188029].
HUMAN PAPILLOMAVIRUS VACCINATION
Genital human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. Most of the estimated 6.2 million persons newly infected every year have no symptoms. Up to 75% of new infections occur among persons 15–24 years of age. Over 40% of the 100 HPV types identified can infect the genital area. Approximately 70% of cervical cancers are caused by the high cancer risk types 16 and 18. Over 90% of genital warts are caused by low cancer risk types 6 and 11.
Two HPV vaccines are currently licensed in the United States. Quadrivalent HPV vaccine (HPV4) types 6, 11, 16, and 18 (Gardasil, Merck) is approved for females and males 9 through 26 years of age. Bivalent HPV (HPV2) types 16 and 18 vaccine (Cervarix, GlaxoSmithKline) is approved for females 10 through 25 years of age. Routine vaccination of females and males aged 11–12 years is recommended. Catch-up vaccination for females aged 13–26 years and males aged 13–21 years who were not previously vaccinated or have not completed the full vaccine series is also recommended. Females who might have been exposed to HPV, test positive for high-risk HPV types, or have an abnormal Pap test, should be vaccinated and are still likely to benefit from HPV vaccine. Immunization of males prevents genital warts and anal cancer but may also benefit females through herd immunity by decreasing the overall prevalence of HPV infection.
1. Quadrivalent HPV vaccine (Gardasil, Merck), a nonlive vaccine; a 0.5-mL dose contains 20 mcg each of HPV-6 and HPV-18 L1 proteins, and 40 mcg each of HPV-11 and HPV-16 L1 proteins. Licensed for use in females and males.
2. Bivalent HPV vaccine (Cervarix, GlaxoSmithKline), a nonlive vaccine is a 0.5-mL dose that contains 40 mcg HPV-16 L1 protein and 20 mcg HPV-18 L1 protein. Licensed for use in females only.
Dosage & Schedule of Administration
HPV vaccine is administered intramuscularly as three separate 0.5-mL doses. The second dose should be administered 1–2 months after the first dose and the third dose 6 months after the first dose. The minimum interval between the first and second dose is 4 weeks; the minimum recommended interval between the second and third doses of vaccine is 12 weeks. HPV vaccine may be administered with other vaccines. If the vaccine schedule is interrupted, the series need not be restarted. When feasible, the same HPV vaccine should be used for the complete series. However, if the HPV vaccine previously administered is unknown or not available, either HPV vaccine can be used to complete the series to protect against HPV types 16 and 18.
Contraindications & Precautions
HPV vaccine is contraindicated in persons with a history of anaphylaxis to any vaccine component. HPV vaccine is not recommended for use in pregnancy. The vaccine can be administered to persons with minor acute illnesses and to immunocompromised persons.
Injection site pain (83.9%) and mild to moderate swelling and erythema were the most common adverse events reported by vaccine recipients. Fever (10.3%), nausea (4.2%), and dizziness (2.8%) were reported as systemic adverse events. Postmarketing reports of syncope, which were reported after vaccination with HPV vaccine, may follow any vaccination, so vaccine recipients should be observed for 15 minutes after vaccination.
AAP: Committee on Infectious Diseases. HPV vaccine recommendations. Pediatrics 2012;129:602 [PMID: 22371460].
CDC: Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2007;56(RR-2):1 [PMID: 17380109].
CDC: 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;59:626 [PMID: 20508593].
CDC: Recommendations on the use of quadrivalent human papillomavirus vaccine in males: Advisory Committee on Immunization Practices (ACIP). MMWR 2011;60:1705 [PMID: 22189893].
Gee J et al: Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine 2011;29:8279 [PMID: 21907257].
VACCINATIONS FOR SPECIAL SITUATIONS
After symptoms of infection develop, rabies is almost invariably fatal in humans. Only eight persons are known to have recovered from rabies infection, five of whom had either been vaccinated prior to infection or received some form of postexposure prophylaxis. While animal rabies in the United States is common, the incidence of human rabies is very low, with fewer than three cases per year. Although dogs represent the most important vector for human rabies worldwide, in the United States, because of widespread vaccination of dogs and cats the most common rabies virus variants responsible for human rabies are bat-related. Rabies is also common in skunks, raccoons, and foxes; it is uncommon in rodents.
Human rabies is preventable with appropriate and timely postexposure prophylaxis. Postexposure care consists of local wound care, passive immunization, and active immunization. Immediately after an animal bite, all wounds should be flushed and aggressively cleaned with soap and water. If possible, the wound should not be sutured. Passive immunization after high-risk exposure consists of the injection of human rabies immune globulin (RIG) near the wound, as described later. Active immunization is accomplished by completing a schedule of immunization with one of the two available rabies vaccines licensed in the United States. Because bites from bats are often unrecognized, prophylaxis should be given if a bat is found indoors even if there is no history of contact, especially if found in the same room with a sleeping or unattended child or with an intoxicated or otherwise incapacitated individual.
Local public health officials should be consulted before postexposure rabies prophylaxis is started to avoid unnecessary vaccination and to assist in the proper handling of the animal (if confinement or testing of the animal is appropriate). To facilitate consultation, the healthcare provider should know the species of animal, its availability for testing or confinement, the nature of the attack (provoked or unprovoked), and the nature of the exposure (bite, scratch, lick, or aerosol of saliva). Preexposure prophylaxis is indicated for veterinarians, animal handlers, and any persons whose work or home environment potentially places them in close contact with animal species in which rabies is endemic. Rabies immunization should also be considered for children traveling to countries where rabies is endemic; this is particularly important for travelers to rural areas where there is no prompt access to medical care should an exposure occur.
Rabies vaccines stimulate immunity after 7–10 days, and the immunity persists for 2 years or more postvaccination. Two inactivated preparations are licensed in the United States.
1. Imovax Rabies (sanofi pasteur) human diploid cell vaccine (HDCV)
2. RabAvert (Novartis) purified chick embryo cell vaccine (PCEC)
Dosage & Schedule of Administration
The two rabies vaccines available in the United States are equally safe and efficacious for both preexposure and postexposure prophylaxis. For each vaccine, 1 mL is given intramuscularly in the deltoid (for adults and older children) or anterolateral thigh (for infants and young children). The volume of the dose is not reduced for children. Vaccine should not be given in the gluteal region.
Primary Preexposure Vaccination
Preexposure rabies immunization should be considered for individuals at high risk of exposure to rabies (eg, veterinarians, animal handlers, spelunkers, and people moving to or extensively traveling in areas with endemic rabies). Three intramuscular injections in the deltoid area of 1 mL of any vaccine are given on days 0, 7, and 21 or 28.
After an individual has possibly been exposed to rabies, decisions about whether to initiate postexposure prophylaxis need to be made urgently, in consultation with local public health officials.
In previously unvaccinated individuals—After prompt and thorough wound cleansing, an individual exposed to rabies should receive rabies vaccination and RIG. Vaccination is given on the day of exposure (day 0) and on days 3, 7, and 14 following exposure. Immune suppressed individuals should receive five doses of vaccine, on days 0, 3, 7, 14, and 28. RIG should also be given as soon as possible after exposure, ideally on the day of exposure, in a recommended dose of 20 IU/kg. If anatomically possible, the entire dose of RIG should be infiltrated into and around the wound. Any remaining RIG should be administered intramuscularly at an anatomic site distant from the location used for rabies vaccination. If RIG was not administered when vaccination was begun, it can be administered up to 7 days after the first dose of vaccine. Postexposure failures have occurred only when some deviation from the approved protocol occurred (eg, no cleansing of the wound, less than usual amount of RIG, no RIG at the wound site, or vaccination in the gluteal area).
In previously vaccinated individuals—RIG should not be administered, and only two doses of vaccine on days 0 and 3 after exposure are needed.
Previously vaccinated individuals with potential continued exposure to rabies should have a serum sample tested for rabies antibody every 2 years. If the titer is less than 1:5 for virus neutralization, a booster dose of rabies vaccine should be administered.
The rabies vaccines are relatively free of serious reactions and rates of adverse reactions may differ between the vaccines. Local reactions at the injection site such as pain, swelling, induration, or erythema range in frequency from 11% to 89% of vaccinees. These are more common than mild systemic reactions, such as headache, nausea, muscle aches, and dizziness, which range from 6% to 55% of vaccinees. An immune complex-like reaction occurs in about 6% of adults 2–21 days after receiving booster doses of the rabies vaccine; symptoms may include generalized urticaria, arthralgias, arthritis, and angioedema.
Travelers to countries where rabies is endemic may need immediate postexposure prophylaxis and may have to use locally available vaccines and RIG. In many developing countries, the only vaccines readily available may be nerve tissue vaccines derived from the brains of adult animals or suckling mice, and the RIG may be of equine origin. Although adverse reactions to RIG are uncommon and typically mild, the nervous tissue vaccines may induce neuroparalytic reactions in 1:200–1:8000 vaccinees; this is a significant risk and is another justification for preexposure vaccination prior to travel in areas where exposure to potentially rabid animals is likely.
In the United States, RIG is prepared from the plasma of human volunteers hyperimmunized with rabies vaccine. The recommended dose is 20 IU/kg body weight. The rabies-neutralizing antibody content is 150 IU/mL, supplied in 2- or 10-mL vials. It is very safe.
CDC: Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies: recommendations of the Advisory Committee on Immunization Practices. MMWR 2010;59(RR-2):1 [PMID: 20300058].
CDC (rabies information page): http://www.cdc.gov/rabies/.
Manning SE et al: CDC: Human rabies prevention—United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR 2008;57(RR-3):1 [PMID: 18496505].
TYPHOID FEVER VACCINATION
Globally, the burden of typhoid fever is substantial, causing an estimated 21 million illnesses and 200,000 deaths each year. In the United States, typhoid fever is relatively uncommon, with approximately 400 laboratory-confirmed cases each year. In a review of typhoid fever cases reported to the CDC, 79% of patients reported recent travel outside the United States, only 5% of whom had received typhoid vaccination.
Two vaccines against Salmonella enterica typhi, the bacterium that causes typhoid fever, are available in the United States: a live attenuated vaccine given orally (Ty21a), and an inactivated vaccine composed of purified capsular polysaccharide (ViCPS) given parenterally. Both vaccines protect 50%–80% of vaccine recipients. The oral vaccine is most commonly used because of its ease of administration. However, noncompliance with the oral vaccine dosing schedule occurs frequently, and correct usage should be stressed or the parenteral ViCPS vaccine used.
Routine typhoid vaccination is recommended only for children who are traveling to typhoid-endemic areas or who reside in households with a documented typhoid carrier. While CDC recommendations emphasize typhoid vaccination for travelers expected to have long-term exposure to potentially contaminated food and drink, vaccination should also be considered for short-term travel to high-risk countries. Although typhoid fever occurs throughout the world, areas of highest incidence include southern Asia and southern Africa. Travelers should be advised that because the typhoid vaccines are not fully protective, and because of the potential for other food- and waterborne illnesses, careful selection of food and drink and appropriate hygiene remain necessary when traveling internationally.
1. Parenteral ViCPS (Typhim Vi, sanofi pasteur) is for intramuscular use.
2. Oral live attenuated Ty21a vaccine (Vivotif Berna Vaccine, Swiss Serum and Vaccine Institute) is supplied as enteric-coated capsules.
Dosage & Schedule of Administration
ViCPS is administered as a single intramuscular dose (0.5 mL) in the deltoid muscle, with boosters needed every 2 years if exposure continues. It is approved for children aged 2 years and older.
The dose of the oral preparation is one capsule every 2 days for a total of four capsules, taken 1 hour before meals. The capsules should be taken with cool liquids and should be kept refrigerated. All doses should be administered at least 1 week prior to potential exposure. A full course of four capsules is recommended every 5 years if exposure continues. Mefloquine and chloroquine may be given at the same time as the oral vaccine although proguanil should be administered only if 10 days have lapsed since the last dose of oral vaccine. This vaccine is not approved for children younger than age 6 years. As with all live attenuated vaccines, Ty21a should not be given to immunocompromised patients.
Both the oral and parenteral vaccines are well tolerated, and adverse reactions are uncommon and usually self-limited. The oral vaccine may cause gastroenteritis-like illness, fatigue, and myalgia, whereas the parenteral vaccine may cause injection site pain, abdominal pain, dizziness, and pruritus.
Lynch MF et al: Typhoid fever in the United States, 1999–2006. JAMA 2009;302:859 [PMID: 19706859].
Martin LB: Vaccines for typhoid fever and other salmonelloses. Curr Opin Infect Dis 2012;25:489 [PMID: 22825288].
Sur D et al: A cluster-randomized effectiveness trial of Vi typhoid vaccine in India. N Engl J Med 2009;361:335 [PMID: 19625715].
JAPANESE ENCEPHALITIS VACCINATION
Japanese encephalitis virus (JE) is a mosquito-borne flavivirus that carries a high morbidity and mortality for those infected. It is endemic in parts of Asia, although the risk to most travelers to Asia is low. Travel to rural areas and extended travel in endemic areas may increase the risk. Only one safe and effective vaccine is available in the United States. This is not yet licensed for use in children. Healthcare providers may choose to administer the vaccine off-label to children or refer children to Travelers Health Clinics in Asia (see CDC link below). Travelers to JE-endemic countries should be advised of risks of JE and the importance of measures to reduce mosquito bites. Vaccination is recommended for travelers who plan to spend more than 1 month in endemic areas during the JE transmission season. Vaccination should be considered for short-term travelers to endemic areas during the JE transmission season if they will travel outside of an urban area and their activities will increase the risk of JE exposure. It should also be considered for travelers to an area with an ongoing JE outbreak. Vaccination is not recommended for short-term travelers whose visit will be restricted to urban areas or outside of a well-defined JE transmission season. If the primary series of JE-VC was administered > 1 year previously, a booster dose may be given before potential JE virus exposure.
Vaccines Available and Schedule of Administration
1. JE-VAX (sanofi pasteur) is an inactivated mouse brain-derived JE vaccine first licensed in the United States in 1992. It was the only JE vaccine FDA licensed for use in children in the United States but is no longer available.
2. Ixiaro (JE-VC) (Novartis) is an inactivated Vero cell-derived JE vaccine. It contains aluminum hydroxide as an adjuvant and has no preservative. It is given intramuscularly in a two-dose series at 0 and 28 days. It is licensed for persons aged 17 or older, but three pediatric clinical trials with JE–VC have been conducted, and a healthcare provider may choose to administer the vaccine off-label in children < 17 years of age. The manufacturer has completed studies using a 6-mcg per 0.5 mL dose (regular adult dose) for children ≥ 3 years of age and a 3-mcg per 0.25 mL dose (half adult dose) for children aged 2 months through 2 years. Additional information about the use of JE-VC in children is available from Novartis Medical Communications by telephone (877-683-4732) or e-mail (email@example.com).
CDC: Japanese encephalitis vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2010;59(RR-1):1 [PMID: 20224546].
CDC: Recommendations for use of a booster dose of inactivated vero cell culture-derived Japanese encephalitis vaccine: Advisory Committee on Immunization Practices, 2011. MMWR 2011;60:661 [PMID: 21617632].
CDC: Updated on Japanese encephalitis vaccine for children: United States, May 2011. MMWR 2011;60:664 [PMID: 21617633].
Erlanger TE et al: Past, present, and future of Japanese encephalitis. Emerg Infect Dis 2009;15:1 [PMID: 19116041].
Approximately one-third of the world’s population is infected with Mycobacterium tuberculosis, which is a leading cause of death in low- and middle-income nations, killing approximately 1.4 million people annually. It is relatively uncommon in the United States, and most cases occur in persons born abroad or their close contacts. Bacille Calmette-Guérin vaccine (BCG) consists of live attenuated Mycobacterium bovis. BCG is the most widely used vaccine in the world and has been administered to over 3 billion people, with a low incidence of adverse events following immunization. BCG vaccine is inexpensive, can be given any time after birth, sensitizes the vaccinated individual for 5–50 years, and stimulates both B-cell and T-cell immune responses. BCG reduces the risk of tuberculous meningitis and disseminated TB in pediatric populations by 50%–100% when administered in the first month of life. Efficacy against pulmonary tuberculosis has been variable (0%–80%) depending on the study setting and other factors.
BCG is indicated for use in the United States in two circumstances: (1) in tuberculin-negative infants or older children residing in households with untreated or poorly treated individuals with active infection with isoniazid- and rifampin-resistant M tuberculosis, and (2) in infants or children that live under constant exposure without the possibility of removal or access to prophylaxis and treatment. It is not recommended for travel.
The two currently licensed BCG vaccines in the United States are produced by Organon Teknika Corporation (Tice BCG) and sanofi pasteur (Mycobax). They are given intradermally in a dose of 0.05 mL for newborns and 0.1 mL for all other children. Tuberculin skin testing (TST) is advised 2–3 months later, and revaccination is advised if the TST result is negative. Adverse effects occur in 1%–10% of healthy individuals, including local ulceration, regional lymph node enlargement, and very rarely lupus vulgaris. The vaccine is contraindicated in pregnant women and in immunocompromised individuals, including those with HIV infection, because it has caused extensive local adenitis and disseminated or fatal infection.
BCG almost invariably causes its recipients to be tuberculin-positive (5–7 mm), but the reaction often becomes negative after 3–5 years. Thus, a positive TST test in a child with a history of BCG vaccination who is being investigated for TB as a case contact should be interpreted as indicating infection with M tuberculosis.
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CDC: Updated guidelines for using interferon-gamma release assays to detect Mycobacterium tuberculosis—United States, 2010. MMWR 2010;59:1 [PMID: 20577159].
CDC: Trends in tuberculosis—United States, 2011. MMWR 2012; 61:181 [PMID: 22437911].
Perez-Velez CM, Marais BJ: Tuberculosis in children. N Engl J Med 2012;367:348 [PMID: 22830465].
YELLOW FEVER VACCINATION
A live, attenuated vaccine against yellow fever is available for use in the United States. However, the vaccine is available only at official yellow fever vaccination locations (typically public health departments), and should only be given after consultation with travel medicine specialists or public health officials. Immunization against yellow fever is indicated for children age 9 months and older traveling to endemic areas or to countries that require it for entry. Yellow fever vaccine is made from the 17D yellow fever attenuated virus strain grown in chick embryos. It is contraindicated in infants younger than age 6 months, in persons with anaphylactic egg allergy, and in immunocompromised individuals or individuals with a history of thymus disease. In children 6–8 months of age, the vaccine risks and benefits should be weighed on an individual basis. When yellow fever vaccine is indicated, a single subcutaneous injection of 0.5 mL of reconstituted vaccine is administered. International health regulations may require revaccination at 10-year intervals, although immunity following vaccination may be long-lasting. Adverse reactions are generally mild, consisting of low-grade fever, mild headache, and myalgia 5–10 days after vaccination, occurring in fewer than 25% of vaccinees. Although relatively uncommon, several types of severe adverse reactions can occur following vaccination. Serious allergic reactions occur in roughly 1 case per every 55,000 vaccine recipients. The risk of vaccine-associated neurotropic disease within 30 days following vaccination has been estimated to be 1 case per every 125,000 vaccine recipients. The risk of severe multiple organ system failure following vaccination has been estimated at 1 case per every 250,000 vaccine recipients. Healthcare providers should be careful to administer yellow fever vaccine only to persons truly at risk of exposure to yellow fever. There is no contraindication to giving other live-virus vaccines simultaneously with yellow fever vaccine.
CDC: Yellow fever vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2010; 59(RR-7):1 [PMID: 20671663].
Monath TP: Review of the risks and benefits of yellow fever vaccination including some new analyses. Expert Rev Vaccines 2012;11:427 [PMID: 22551029].
Thomas RE et al: Active and passive surveillance of yellow fever vaccine 17D or 17DD-associated serious adverse events: systematic review. Vaccine 2011;29:4544 [PMID: 21549787].
1. Intramuscular & Specific Intravenous Immune Globulin
Ig may prevent or modify infection with hepatitis A virus if administered in a dose of 0.02 mL/kg within 14 days after exposure. Measles infection may be prevented or modified in a susceptible person if Ig is given in a dose of 0.5 mL/kg within 6 days after exposure. Pathogen-specific preparations of Ig include tetanus Ig (TIg), hepatitis B Ig (HBIg), rabies Ig (RIg), rubella Ig, CMV Ig (IV), botulism Ig (IV), and varicella-zoster Ig (VariZig). These are obtained from donors known to have high titers of antibody against the organism in question. Ig must be given only by the route (IV or IM) for which it is recommended. The dose varies depending on the clinical indication. Adverse reactions include pain at the injection site, headache, chills, dyspnea, nausea, and anaphylaxis, although all but the first are rare.
Prophylaxis to prevent respiratory syncytial virus (RSV) in infants and children at increased risk of severe disease is available as an intramuscular immune globulin. Palivizumab (Synagis, MedImmune) is a humanized monoclonal antibody against RSV that is used to prevent RSV infection in high-risk populations with monthly doses during RSV season. Palivizumab should be considered for (1) infants and children younger than age 2 years with chronic lung disease who have required medical therapy (supplemental oxygen, bronchodilator, diuretic, or corticosteroid therapy) for their disease within 6 months before the anticipated RSV season; (2) infants born between 32 weeks 0 days and 34 weeks 6 days gestation or earlier without chronic lung disease with at least one out of two of the following risk factors: child care attendance or siblings under age 5 years (this recommendation is for those infants who are born during or within 3 months of the onset of RSV season); prophylaxis for these infants should be discontinued once they reach 3 months of age; (3) infants with congenital airway abnormalities or severe neuromuscular disease up to age 12 months; (4) infants born at less than 32 weeks’ gestation; and (5) infants and children who are 24 months old or younger with hemodynamically significant cyanotic or acyanotic congenital heart disease.
Palivizumab is administered in a dose of 15 mg/kg once a month beginning with the onset of the RSV season and continuing until the end of the season, regardless of breakthrough RSV illness during that RSV season. The maximum number of doses recommended in any one season is five (the maximum is three doses for 32- to 35-week premature infants without chronic lung disease). Palivizumab is packaged in 50- and 100-mg vials. Palivizumab does not interfere with response to routine childhood vaccinations.
Environmental tobacco smoke is no longer considered a specific risk factor when considering RSV prophylaxis. Due to a lack of data, there are no specific recommendations for palivizumab prophylaxis in infants with immune deficiencies or cystic fibrosis. However, prophylaxis may be considered in these patients in certain circumstances (severe immune compromise such as severe combined immunodeficiency syndrome).
2. Intravenous Immune Globulin
The primary indications for IVIg are for replacement therapy in antibody-deficient individuals; for the treatment of Kawasaki disease, immune thrombocytopenic purpura, Guillain-Barré syndrome, and other autoimmune diseases; and replacement therapy in chronic B-cell lymphocytic leukemia. IVIg may be beneficial in some children with HIV infection, toxic shock syndrome, and for anemia caused by parvovirus B19. It may also be used as postexposure prophylaxis for varicella in at-risk persons when VariZIG is not available.
AAP: Policy statement—modified recommendations for use of palivizumab for prevention of respiratory syncytial virus infections. Pediatrics 2009;124:1694 [PMID: 19736258].
Frogel M et al: Improved outcomes with home-based administration of palivizumab: results from the 2000–2004 palivizumab outcomes registry. Pediatr Infect Dis J 2008;27:870 [PMID: 18776822].
Hall CB et al: The burden of respiratory syncytial virus infection in young children. N Engl J Med 2009;360:588 [PMID: 19196675].