William Atkinson, Andrew Kroger

Recommendations for the use of vaccines and other biologic products (e.g., immune globulin products) in the United States are developed by the Advisory Committee on Immunization Practices (ACIP) and other groups, such as the American Academy of Pediatrics. These recommendations are based on scientific evidence of benefits (immunity to the disease) and risks (vaccine adverse reactions) and, where few or no data are available, on expert opinion. The recommendations include information on general immunization issues and the use of specific vaccines. When these recommendations are issued or revised, they are published in CDC’s Morbidity and Mortality Weekly Report (MMWR) (www.cdc.gov/mmwr). This section is based primarily on the ACIP General Recommendations on Immunization.

Vaccinations against diphtheria, tetanus, pertussis, measles, mumps, rubella, varicella, poliomyelitis, hepatitis A, hepatitis B, Haemophilus influenzae type b, rotavirus, influenza, human papillomavirus, and pneumococcal and meningococcal invasive disease are routinely administered in the United States, usually in childhood or adolescence. If persons do not have a history of adequate protection against these diseases, immunizations appropriate to their age and previous immunization status should be obtained, whether or not international travel is planned. A visit to a provider for immunizations for travel should be seen as an opportunity to bring an incompletely vaccinated person up-to-date on his or her routine vaccinations.

Both the child and adolescent vaccination schedule and an adult vaccination schedule are published annually in the MMWR. Vaccine providers should obtain the most current schedules from the CDC Vaccines and Immunization website at www.cdc.gov/vaccines/. The text and Tables 2-1–2-7, 2-9–2-10, 2-18–2-19, 2-21, 5-2, 7-2–7-5, 8-1, 8-7 and 8-8 of this publication present recommendations for the use, number of doses, dose intervals, adverse reactions, precautions, and contraindications for vaccines and toxoids that may be indicated for travelers. For specific vaccines and toxoids, additional details on background, adverse reactions, precautions, and contraindications are found in the respective ACIP statements.

Spacing of Immunobiologics

Simultaneous Administration

All commonly used vaccines can safely and effectively be given simultaneously (i.e., on the same day) at separate sites without impairing antibody responses or increasing rates of adverse reactions. This knowledge is particularly helpful for international travelers, for whom exposure to several infectious diseases might be imminent. Simultaneous administration of all indicated vaccines is encouraged for persons who are the recommended age to receive these vaccines and for whom no contraindications exist. If not administered on the same day, an inactivated vaccine may be given at any time before or after a different inactivated vaccine or a live-virus vaccine.

The immune response to an injected or intranasal live-virus vaccine (e.g., measles, mumps and rubella (MMR); varicella; yellow fever; or live attenuated influenza vaccine) might be impaired if administered within 28 days of another live-virus vaccine. Whenever possible, injected live-virus vaccines administered on different days should be given at least 28 days apart. If two injected or intranasal live-virus vaccines are not administered on the same day but less than 28 days apart, the second vaccine should be readministered at least 4 weeks after the first vaccine was administered.

Live-virus vaccines can interfere with the response to tuberculin testing. Tuberculin testing, if otherwise indicated, can be done either on the day that live-virus vaccines are administered or 4–6 weeks later. Tuberculin skin testing is not a prerequisite for administration of any vaccine.

Missed Doses and Boosters

Travelers may forget to return for a follow-up dose of vaccine or booster at the specified time. Occasionally the demand for a vaccine may exceed its supply, and providers may have difficulty obtaining vaccines. (Information on vaccine shortages and recommendations can be found on the CDC Vaccines and Immunization website at www.cdc.gov/vaccines/vac-gen/shortages/default.htm.) It is unnecessary in these cases to restart the interrupted series or to add any extra doses except for oral typhoid. The next scheduled dose should be given when the patient presents. (There are no data for interrupted dosing with oral typhoid vaccine; thus, a travel medicine specialist should be consulted.) Some vaccines require periodic booster doses to maintain protection (Table 2-1).

Antibody-Containing Blood Products

When MMR and varicella vaccines are given shortly before, simultaneously with, or after an antibody-containing blood product, such as immune globulin (IG) or a blood transfusion, response to the vaccine can be diminished. Antibody-containing blood products from the United States do not interfere with the immune response to yellow fever vaccine and are not believed to interfere with the response to live attenuated influenza vaccine or rotavirus vaccine. The duration of inhibition of MMR and varicella vaccines is related to the dose of IG in the product. MMR or its components and varicella vaccines either should be administered at least 2 weeks before receipt of a blood product or should be delayed 3–11 months after receipt of the blood product, depending on the vaccine (Table 2-2).

Immunoglobulin (IG) administration may become necessary for another indication after MMR or its individual components or varicella vaccines have been given. In such a situation, the IG may interfere with the immune response to the MMR or varicella vaccines. Vaccine virus replication and stimulation of immunity usually occur 2–3 weeks after vaccination. If the interval between administration of one of these vaccines and the subsequent administration of an IG preparation is 14 days or more, the vaccine need not be readministered. If the interval is less than 14 days, the vaccine should be readministered after the interval shown in Table 2-2, unless serologic testing indicates that antibodies have been produced. If administration of IG becomes necessary, MMR or its components or varicella vaccines can be administered simultaneously with IG, with the recognition that vaccine-induced immunity can be compromised. The vaccine should be administered at a body site different from that chosen for the IG injection. Vaccination should be repeated after the interval noted in Table 2-2, unless serologic testing indicates antibodies have been produced.

When IG is given with the first dose of hepatitis A vaccine, the proportion of recipients who develop a protective level of antibody is not affected, but antibody concentrations are lower. Because the final concentrations of antibody are many times higher than those considered protective, this reduced immunogenicity is not expected to be clinically important. IG preparations interact minimally with other inactivated vaccines and toxoids. Other inactivated vaccines may be given simultaneously or at any time interval after or before an antibody-containing blood product is used. However, such vaccines should be administered at different sites from the IG.

Vaccination of Persons with Acute Illnesses

Every opportunity should be taken to provide appropriate vaccinations. The decision to delay vaccination because of a current or recent acute illness depends on the severity of the symptoms and their cause. Although a moderate or severe acute illness is sufficient reason to postpone vaccination, minor illnesses (e.g., diarrhea, mild upper respiratory infection with or without low-grade fever, other low-grade febrile illness) are not contraindications to vaccination.

Persons with moderate or severe acute illness, with or without fever, should be vaccinated as soon as the condition has improved. This precaution is to avoid superimposing adverse effects from the vaccine on underlying illness or mistakenly attributing a manifestation of underlying illness to the vaccine. Antimicrobial therapy is not a contraindication to vaccination, with three exceptions. Antibacterial agents may interfere with the response to oral typhoid vaccine. Antiviral agents active against herpesviruses (e.g., acyclovir) may interfere with the response to varicella-containing vaccines (varicella, MMRV, zoster). Antiviral agents active against influenza virus (e.g., zanamivir, oseltamivir) may interfere with the response to live attenuated influenza vaccine.

A physical examination or temperature measurement is not a prerequisite for vaccinating a person who appears to be in good health. Asking if a person is ill, postponing a vaccination for someone with moderate or severe acute illness, and vaccinating someone without contraindications are appropriate procedures for clinic immunizations.

Altered Immunocompetence

Altered immunocompetence is a general term that is often used interchangeably with the terms immunosuppression and immunodeficiency. It can be caused either by a disease (e.g., leukemia, HIV infection) or by drugs or other therapies (e.g., cancer chemotherapy, prolonged high dose corticosteroids). It can also include conditions such as asplenia and chronic renal disease.

Determination of altered immunocompetence is important because the incidence or severity of some vaccine-preventable diseases is higher in persons with altered immunocompetence. Therefore, certain vaccines (e.g., inactivated influenza vaccine, pneumococcal vaccines) are recommended specifically for persons with these diseases. Inactivated vaccine may be safely administered to a person with altered immunocompetence, although response to the vaccine may be suboptimal. The vaccine may need to be repeated after immune function has improved.

Persons with altered immunocompetence may be at increased risk for an adverse reaction following administration of live attenuated vaccines because of reduced ability to mount an effective immune response. Live vaccines should generally be deferred until immune function has improved. This is particularly important when planning to give yellow fever vaccine (see the Yellow Fever section later in this chapter). MMR and varicella vaccines are recommended for persons with mild or moderate immunosuppression.

For an in-depth discussion, see The Immunocompromised Traveler section in Chapter 8.

Vaccination Scheduling for Last-Minute Travelers

As noted in the Simultaneous Administration section, most vaccine products can be given during one visit for persons anticipating imminent travel. Unless the vaccines given are booster doses of those typically given during childhood, vaccines may require a month or more to induce a sufficient immune response, depending on the vaccine and the number of doses in the series.

Some vaccines require more than one dose for best protection. Recommended spacing should be maintained between doses (Table 2-3). Doses given at less than minimum intervals can lessen the antibody response. Administration of a vaccine earlier than the recommended minimum age or at an interval shorter than the recommended minimum is discouraged. Table 2-3 lists the minimum age and minimum interval between doses for vaccines routinely recommended in the United States. Because some travelers visit their health-care providers without ample time for administration of the vaccine doses recommended for optimal protection against certain diseases, studies have been performed and others are ongoing to determine whether accelerated scheduling is adequate. This concern is primarily the case for hepatitis B vaccine or the combined hepatitis A and B vaccine. An accelerated schedule for combined hepatitis A and hepatitis B vaccine has been approved by the U.S. Food and Drug Administration (FDA). It is unclear what level of protection any given traveler will have if a full series of multidose vaccination is not completed.

Allergy to Vaccine Components

Vaccine components can cause allergic reactions in some recipients. These reactions can be local or systemic and can include anaphylaxis or anaphylactic-like responses. The vaccine components responsible can include the vaccine antigen, animal proteins, antibiotics, preservatives (e.g., thimerosal), or stabilizers (e.g., gelatin). The most common animal protein allergen is egg protein in vaccines prepared by using embryonated chicken eggs (influenza and yellow fever vaccines). Generally, persons who can eat eggs or egg products safely may receive these vaccines, while those with histories of anaphylactic allergy (e.g., hives, swelling of the mouth and throat, difficulty breathing, hypotension, shock) to eggs or egg proteins ordinarily should not. Screening persons by asking whether they can eat eggs without adverse effects is a reasonable way to identify those who might be at risk from receiving yellow fever and influenza vaccines. Recent studies have indicated that other components in vaccines in addition to egg proteins (e.g., gelatin) may cause allergic reactions, including anaphylaxis in rare instances. Protocols have been developed for testing and vaccinating persons with anaphylactic reactions to egg ingestion.

Some vaccines contain a preservative or trace amounts of antibiotics to which people might be allergic. Those administering the vaccine(s) should carefully review the information provided in the package insert before deciding if the rare person with such an allergy should receive the vaccine. No currently recommended vaccine contains penicillin or penicillin derivatives. Some vaccines (e.g., MMR and its individual component vaccines, inactivated polio vaccine [IPV], varicella, rabies) contain trace amounts of neomycin or other antibiotics; the amount is less than would normally be used for the skin test to determine hypersensitivity. However, persons who have experienced anaphylactic reactions to this antibiotic generally should not receive these vaccines. Most often, neomycin allergy is a contact dermatitis—a manifestation of a delayed-type (cell-mediated) immune response rather than anaphylaxis. A history of delayed-type reactions to neomycin is not a contraindication to receiving these vaccines.

Thimerosal, an organic mercurial compound in use since the 1930s, has been added to certain immunobiologic products as a preservative. Thimerosal is present at preservative concentrations (trace quantities) in multidose vials of some brands of inactivated influenza vaccine, pediatric DT, single-antigen tetanus toxoid, meningococcal polysaccharide vaccine, and Japanese encephalitis vaccine. Receiving thimerosal-containing vaccines has been postulated to lead to induction of allergy. However, there is limited scientific evidence for this assertion. Allergy to thimerosal usually consists of local delayed-type hypersensitivity reactions. Thimerosal elicits positive delayed-type hypersensitivity patch tests in 1%–18% of persons tested, but these tests have limited or no clinical relevance. The majority of persons do not experience reactions to thimerosal administered as a component of vaccines, even when patch or intradermal tests for thimerosal indicate hypersensitivity. A localized or delayed-type hypersensitivity reaction to thimerosal is not a contraindication to receipt of a vaccine that contains thimerosal.

Since mid-2001, vaccines routinely recommended for infants have been manufactured without thimerosal as a preservative. Additional information about thimerosal and the thimerosal content of vaccines is available on the FDA website at www.fda.gov/cber/vaccine/thimerosal.htm.

Reporting Adverse Events Following Immunization

Modern vaccines are extremely safe and effective. Benefits and risks are associated with the use of all immunobiologics—no vaccine is completely effective or completely free of side effects. Adverse events following immunization have been reported with all vaccines, ranging from frequent, minor, local reactions to extremely rare, severe, systemic illness, such as that associated with yellow fever vaccine (see Yellow Fever section later in this chapter). Side effects and adverse events following specific vaccines and toxoids are discussed in detail in each ACIP statement. Health-care providers are required by law to report selected adverse events occurring after vaccination with tetanus vaccine in any combination; pertussis in any combination; measles, mumps or rubella alone or in any combination, oral polio vaccine (OPV), IPV, hepatitis B; varicella; Haemophilus influenzae type b (conjugate); pneumococcal conjugate; and rotavirus vaccines. In addition, CDC strongly recommends that all vaccine adverse events be reported to the Vaccine Adverse Event Reporting System (VAERS), even if a causal relation to vaccination is not certain. VAERS reporting forms and information are available electronically at www.vaers.hhs.gov or may be requested by telephone: 800-822-7967. Health-care providers are encouraged to report electronically at https://secure.vaers.org/VaersDataEntryintro.htm.

Injection Route and Injection Site

Injectable vaccines are administered by intramuscular and subcutaneous routes. The method of administration of injectable vaccines depends in part on the presence of an adjuvant in some vaccines. The term adjuvant refers to a vaccine component distinct from the antigen, which enhances the immune response to the antigen. Vaccines containing an adjuvant (i.e., DTaP, DT, human papillomavirus, Td, Tdap, pneumococcal conjugate, Hib, hepatitis A, hepatitis B) should be injected into a muscle mass because administration subcutaneously or intradermally can cause local irritation, induration, skin discoloration, inflammation, and granuloma formation. Routes of administration are recommended by the manufacturer for each immunobiologic. Deviation from the recommended route of administration may reduce vaccine efficacy or increase local adverse reactions. Detailed recommendations on the appropriate route and site for all vaccines have been published in ACIP recommendations; a compiled list of these publications is available on the CDC website at www.cdc.gov/vaccines/pubs/ACIP-list.htm (also see Appendix C: Travel Vaccine Summary Table).

References

1. CDC. General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-15):1–48.
2. CDC. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-7):1–60.
3. CDC. Measles, mumps, and rubella—vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1998;47(RR-8);1–57.
4. CDC. Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2005;54(RR07);1–21.
5. CDC. Preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR 17);1–59.
6. Plotkin SA. Correlates of vaccine-induced immunity. Clin Infect Dis 2008; 47(3):401–9.
7. Murphy KR, Strunk RC. Safe administration of influenza vaccine in asthmatic children hypersensitive to egg proteins. J Pediatr. 1985;106(6):931–3.
8. Ball LK, Ball R, Pratt RD. An assessment of thimerosal use in childhood vaccines. Pediatrics 2001;107(5):1147–54.
9. Varricchio F, Iskander J, Destefano F, et al. Understanding vaccine safety information from the Vaccine Adverse Event Reporting System. Pediatr Infect Dis J. 2004;23(4):287–94.