Recommendations for the use of vaccines and other biologic products (such as 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 theMorbidity and Mortality Weekly Report (www.cdc.gov/mmwr). This chapter is based primarily on the ACIP General Recommendations on Immunization (1).

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 child-hood 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. The fact that a person is seeing a travel health provider or a primary provider for immunizations for travel should be an opportunity to vaccinate when recommended vaccines have not been received.

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 National Immunization Program website, http://www.cdc.gov/vaccines/. The text and Tables 1-1 through 1-3, 4-2 through 4-7, 4-9, 4-13, 4-15 through 4-17, 4-19, 4-21, 4-22, 8-2 through 8-4, 9-1, and 9-4 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 (that is, on the same day) without impairing antibody responses or increasing rates of adverse reactions (1). This knowledge is particularly helpful for international travelers, for whom exposure to several infectious diseases might be imminent.

Inactivated vaccines may be administered at the same visit but at separate sites. 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.

Limited data suggest that the immunogenicity and safety of Japanese encephalitis (JE) vaccine are not compromised by simultaneous administration with DTaP or whole-cell pertussis (DTP) vaccine. No data exist on the effect of concurrent administration of other vaccines, drugs (e.g., chloroquine or mefloquine), or biologicals on the safety and immunogenicity of JE vaccine.

Inactivated vaccines generally do not interfere with the immune response to other inactivated or live-virus vaccines. An inactivated vaccine may be given either simultaneously or at any time before or after a different inactivated vaccine or a live-virus vaccine.

The immune response to an injected live-virus vaccine (e.g., MMR, varicella, or yellow fever) 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 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 later (1).

Live-virus vaccines can interfere with a person’s 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

Persons will often 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 National Immunization Program website at http://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 oral typhoid. (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 (see Table 1-1).

TABLE 1-1. Revaccination (booster) schedules

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 immune globulin 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 (Table 1-2).

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 1-2, 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 in a body site different from that chosen for the IG injection. Vaccination should be repeated after the interval noted in Table 1-2, unless serologic testing indicates antibodies have been produced.

When IG is given with the first dose of hepatitis A vaccine (HAV), the proportion of recipients who develop protective levels of antibody is not affected, but antibody concentrations are lower. Because the final concentrations of anti-HAV 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. Therefore, 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 (not from each other).

TABLE 1-2. Recommended intervals between administration of antibody containing products and measles-containing vaccine or varicella containing vaccine¹

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 (such as diarrhea, mild upper respiratory infection with or without low-grade fever, or other low-grade febrile illness) are not contraindications to vaccination (1). People 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 (such as acyclovir) may interfere with the response to varicella vaccine; and antiviral agents active against influenza virus (such as amantadine and oseltamivir) may interfere with the response to live attenuated influenza vaccine (1).

Routine physical examinations or temperature measurements are not prerequisites for vaccinating anyone 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 immunization programs.

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 (such as leukemia or HIV infection) or by drugs or other therapies (such as cancer chemotherapy or prolonged high dose corticosteroids). It can also include conditions such as asplenia and chronic renal disease.

Determination of altered immunocompetence is important to the vaccine provider 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 and pneumococcal vaccines) are recommended specifically for persons with these diseases. Vaccines may be less effective during the period of altered immunocompetence. Inactivated vaccine may be safely administered to a person with altered immunocompetence, although response to the vaccine may be suboptimal. Administration may need to be repeated after immune function has improved.

Live vaccines generally need to be deferred, particularly for those with severe immunosuppression, until immune function has improved. Persons with altered immunocompetence may also be at increased risk for an adverse reaction following administration of live attenuated vaccines because of reduced ability to mount an effective immune response. Some vaccines (MMR and varicella) are recommended for persons with mild or moderate immunosuppression. A detailed discussion of this issue has been published (1) and is available as well in Chapters 4 and 9.

Vaccination Scheduling for Last-Minute Travelers

In general, as noted above under “Simultaneous Administration,” most vaccine products can be given during one visit for those 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. The use of doses less than those recommended by the manufacturer, or doses given at less than minimum intervals between doses, can lessen the antibody response (6). Administration of a vaccine earlier than the recommended minimum age or at an interval shorter than the recommended minimum is discouraged. Table 1-3 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 several 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 (see Chapter 4). With imminent travel, a clinician may opt to accelerate these vaccine schedules, with the understanding that such schedules may not have been approved by the Food and Drug Administration and are not endorsed by CDC. However, many travel medicine experts administer vaccines using shortened intervals, with the belief that multiple doses on an accelerated schedule may provide better protection than the administration of just one dose of vaccine before travel. It is unclear what level of protection any given traveler will have if a full series of multidose vaccination is not completed.

TABLE 1-3. Recommended and minimum ages and intervals between vaccine doses¹

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, people who can eat eggs or egg products safely may receive these vaccines, while people with histories of anaphylactic allergy (e.g., hives, swelling of the mouth and throat, difficulty breathing, hypotension, or shock) to eggs or egg proteins ordinarily should not. Screening people 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 (1). 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 people with anaphylactic reactions to egg ingestion (7).

Some vaccines contain preservatives 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, 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, people who have experienced anaphylactic reactions to the 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 (1).

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 some brands of inactivated influenza vaccine, pediatric DT, single antigen tetanus toxoid, meningococcal polysaccharide vaccine and Japanese encephalitis vaccines. Receiving thimerosal-containing vaccines has been postulated to lead to induction of allergy. However, limited scientific basis exists for this assertion. Allergy to thimerosal usually consists of local delayed-type hypersensitivity reactions (1). 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.

A joint statement issued by the U.S. Public Health Service and the American Academy of Pediatrics in 1999 established the goal of removing thimerosal as soon as possible from vaccines routinely recommended for infants. Although no evidence exists of any harm caused by low levels of thimerosal in vaccines and the risk was only theoretical, this goal was established as a precautionary measure (8). The public is concerned about the health effects of mercury exposure of any type, and the elimination of mercury from vaccines was judged a feasible means of reducing an infant’s total exposure to mercury in a world where other environmental sources of exposure are more difficult or impossible to eliminate (e.g., certain foods). 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 web site at http://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 (9). Information on 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 causal relation to vaccination is not certain. VAERS reporting forms and information are available electronically at http://www.vaers.hhs.gov or 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 adjuvants 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, 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 (1).

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 2005;54(RR-8);1-40.
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(RR-7);1-21.
5. CDC. Preventing tetanus, diphtheria, and pertussis among adolescents: 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-3);1-34.
6. Plotkin SA. Immunologic correlates of protection induced by vaccination. Pediatr Infect Dis J. 2001;20:63-75.
7. Murphy KR, Strunk RC. Safe administration of influenza vaccine in asthmatic children hypersensitive to egg proteins. J Pediatr. 1985;106:931-3.
8. Ball LK, Ball R, Pratt RD. An assessment of thimerosal use in childhood vaccines. Pediatrics 2001;107:1147-54.
9. Varricchio F, Iskander J, Destefano F, Ball R, Pless R, Braun MM, et al. Understanding vaccine safety information from the Vaccine Adverse Event Reporting System. Pediatr Infect Dis J. 2004;23:287-94.

WILLIAM ATKINSON