Author(s): Andrew Kroger, Mark Freedman

The pretravel health consultation is an opportunity to administer routine vaccines that are recommended based on age and other individual characteristics, and travel medicine practitioners should therefore be familiar with the general principles of vaccination and immunoprophylaxis. Routine vaccinations that are usually administered during childhood and adolescence in the United States include diphtheria, tetanus, pertussis (DTaP); Haemophilus influenzae type b (Hib); hepatitis A (HepA), hepatitis B (HepB); human papillomavirus (HPV); measles-mumps-rubella (MMR); meningococcal vaccine (MenACWY); pneumococcal disease, including pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide vaccine (PPSV23); poliomyelitis (IPV); rotavirus; and varicella. Influenza vaccine routinely is recommended for all people aged ≥6 months each year. Herpes zoster (shingles) vaccine is recommended for adults aged ≥50 years old. PPSV23 is recommended for all adults ≥65 years old.

Some routine vaccinations are administered at earlier ages for international travelers. For example, measles-mumps-rubella (MMR) vaccine is indicated for infants aged 6–11 months who travel abroad, and hepatitis A vaccine is indicated for some infants aged 6–11 months who travel abroad, whereas these vaccines are not routinely given before age 12 months in the United States.

The Advisory Committee on Immunization Practices (ACIP) website outlines recommendations, background, adverse reactions, precautions, and contraindications for vaccines and toxoids. For information on vaccinating travelers with altered immune function, see Sec. 3, Ch. 1, Immunocompromised Travelers.

Spacing of Vaccines & Immunobiologics

In general, most common vaccines can be given at the same visit, at separate injection sites, without impairing antibody responses or increasing rates of adverse reactions, except as outlined below. Simultaneous administration of indicated vaccines is particularly advantageous for international travelers for whom exposure to several infectious diseases might be imminent. Injectable live vaccines should be administered at intervals of ≥28 days, if not administered simultaneously.

Coronavirus Disease 2019 Vaccines

Coronavirus disease 2019 (COVID-19) vaccines can be administered concomitantly with any other vaccines. See COVID-19 vaccine and immunization information, including interim clinical considerations.

Live-Virus Vaccines

The immune response to an injected or intranasal live-virus vaccine (e.g., MMR, varicella, live attenuated influenza vaccines [LAIV]), might be impaired if administered within 28 days of another live-virus vaccine. Typically, the immune response is impaired only for the second live-virus vaccine administered. Whenever possible, providers should administer injected or intranasal live-virus vaccines on different days ≥28 days apart. If 2 injected or intranasal live-virus vaccines are administered on separate days, but administered <28 days apart, the second vaccine is invalid and should be readministered ≥28 days after the invalid dose.

Measles and other live-virus vaccines can interfere with the response to tuberculin skin testing and the interferon-γ release assay. Tuberculin testing, if otherwise indicated, can be done either on the same day that live-virus vaccines are administered or ≥4 weeks later.

Yellow Fever Vaccine

There is no evidence that inactivated vaccines interfere with the immune response to yellow fever vaccine. Therefore, inactivated vaccines can be administered at any time around yellow fever vaccination, including simultaneously. ACIP recommends that yellow fever vaccine be given at the same time as most other live-virus vaccines.

Notwithstanding ACIP’s recommendation, limited data suggest that coadministration of yellow fever vaccine with measles-rubella or MMR vaccines might decrease the immune response. One study involving the simultaneous administration of yellow fever and MMR vaccines and a second involving simultaneous administration of yellow fever and measles-rubella vaccines in children demonstrated a decreased immune response against all antigens (except measles) when the vaccines were given on the same day versus 30 days apart. Additional studies are needed to confirm these findings, but the findings suggest that, if possible, yellow fever and MMR vaccines should be given ≥30 days apart.

No data are available on immune response to nasally administered LAIV given simultaneously with yellow fever vaccine. Data from LAIV and MMR vaccines found no evidence of interference, however. If yellow fever vaccine and another injectable live-virus vaccine are not administered simultaneously or ≥30 days apart, providers might consider measuring the patient’s neutralizing antibody response to vaccination before travel. Contact the state health department or the Centers for Disease Control and Prevention (CDC) Arboviral Disease Branch (970-221-6400) to discuss serologic testing.

Meningococcal & Pneumococcal Vaccines

In people with conditions that increase the risk for invasive pneumococcal disease (e.g., HIV infection, anatomic or functional asplenia [including sickle-cell disease]), the quadrivalent meningococcal vaccine Menactra (MenACWY-D), should be administered at least 4 weeks after completion of the pneumococcal conjugate vaccine (PCV13) series. Menactra should not be used in children <2 years of age with these risk conditions; MenACWY-CRM (Menveo) can be used instead (see Sec. 5, Part 1, Ch. 13, Meningococcal Disease, for meningococcal vaccine schedules).

Menactra can be administered before or concomitantly with DTaP. If this is not possible, Menactra should be administered 6 months after DTaP in people with HIV infection, anatomic or functional asplenia (including sickle-cell disease), or persistent complement component deficiency, conditions that increase the risk for invasive meningococcal disease.

PCV13 and the pneumococcal polysaccharide vaccine (PPSV23) should be administered at least 8 weeks apart. The minimum interval might be longer than 8 weeks depending on risk-condition and the order in which the vaccines are administered.

Missed Doses & Boosters

In some cases, a scheduled dose of vaccine might not be given on time. Travelers might forget to return to complete a series or receive a booster at a specified time. If this occurs, the dose should be given at the next visit. Available data indicate that intervals longer than those routinely recommended between doses do not affect seroconversion rates or titer when the vaccine schedule is completed. Consequently, an extended interval between doses does not necessitate restarting the series or adding doses of any vaccine. One exception is the preexposure rabies vaccine series. If an extended interval passes between doses of the preexposure rabies vaccine series, clinicians should assess the patient’s immune status by serologic testing 7–14 days after the final dose in the series.

Antibody-Containing Blood Products

Antibody-containing blood products from the United States (e.g., immune globulin [IG] products) do not interfere with the immune response to yellow fever vaccine and are not believed to interfere with the response to LAIV or rotavirus vaccines. When MMR and varicella vaccines are given shortly before, simultaneously with, or after an antibody-containing blood product, response to the vaccine can be diminished. The duration of inhibition of MMR and varicella vaccines is related to the dose of IG in the product. MMR and varicella vaccines should either be administered ≥2 weeks before receipt of a blood product or should be delayed 3–11 months after receipt of the blood product, depending on the dose and type of blood product (see Timing and Spacing of Immunobiologics, General Best Practice Guidelines for Immunization: Best Practices Guidance of the Advisory Committee on Immunization Practices; Table 3-6. Recommended intervals between administration of antibody-containing products and measles- or varicella-containing vaccine, by product and indication for vaccination).

If IG administration becomes necessary for another indication after MMR or varicella vaccines have been given, the IG might 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 live vaccines and the subsequent administration of an IG preparation is ≥14 days, the vaccine need not be readministered. If the interval is <14 days, the vaccine should be readministered after the interval shown in Table 3-5 (referenced in the previous paragraph), unless serologic testing indicates that antibodies have been produced. Such testing should be performed after the interval shown in Table 3-5 to avoid detecting antibodies from the IG preparation.

In some circumstances, MMR or varicella vaccine might be indicated for a patient for preexposure (travel) or postexposure prophylaxis. The patient might have received an antibody-containing blood product unrelated to prophylaxis; nevertheless, a potential for vaccine interference exists. Providers can administer MMR or varicella vaccines because the increased risk for disease and the protection afforded by the vaccine outweigh the concern that the vaccine might be less effective because of interference. If the dose is administered, it does not count toward the routine vaccination series and an additional dose of MMR or varicella vaccine should be administered no earlier than the minimum interval for the antibody-containing blood product (highlighted in ACIP’s General Best Practice Guidelines for Immunization) applied to the invalid dose of vaccine.

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 still many times higher than those considered protective, the reduced immunogenicity is not expected to be clinically relevant. However, the effect of reduced antibody concentrations on long-term protection is unknown.

IG preparations interact minimally with other inactivated vaccines and toxoids. Other inactivated vaccines can be given simultaneously or at any time interval before or after an antibody-containing blood product is used. However, such vaccines should be administered at different injection sites from the IG.

Vaccinating People With Acute Illnesses

Clinicians should take every opportunity to provide needed 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.

Antimicrobial therapy is not a contraindication to vaccination, except for antiviral agents active against influenza virus (e.g., baloxavir, oseltamivir, peramivir, zanamivir), since these antivirals can interfere with the replication of the live vaccine. If LAIV is administered first, any of these 4 antiviral drugs should be delayed ≥2 weeks, if feasible. Conversely, clinicians should delay LAIV for 48 hours after oseltamivir or zanamivir; for 5 days after peramivir; and for 17 days after baloxavir. Alternatively, clinicians can substitute inactivated influenza vaccine (IIV) for LAIV. Use of antiviral agents active against herpes viruses (e.g., acyclovir), are a precaution against administration of varicella-containing vaccines (varicella, MMRV) because the antiviral agent will interfere with the live vaccine.

Antimicrobial agents can prevent adequate immune response to live attenuated oral typhoid and cholera vaccines.

Vaccination Scheduling for Selected Travel Vaccines

Table 2-04 lists the minimum ages and minimum intervals between doses for available travel vaccines recommended in the United States. Available travel vaccines, including Japanese encephalitis vaccine, rabies vaccine, inactivated typhoid vaccine, and yellow fever vaccine, do not have routine non-travel recommendations.

Allergies to Vaccine Components

Vaccine components can cause allergic reactions in some recipients. Reactions can be local or systemic and can include anaphylaxis or anaphylactic-like responses. A previous severe allergic reaction to any vaccine, regardless of the component suspected of being responsible for the reaction, is a contraindication to future receipt of the vaccine. Vaccine components responsible for reactions can include adjuvants, animal proteins, antibiotics, the vaccine antigen, preservatives (e.g., thimerosal), stabilizers (e.g., gelatin), or yeast.

Antibiotics & Preservatives

Some vaccines contain trace amounts of antibiotics or preservatives to which people might be allergic. Antibiotics used during vaccine manufacture include gentamicin, neomycin, polymyxin B, and streptomycin. The antibiotics most likely to cause severe allergic reactions (e.g., penicillin, cephalosporins, and sulfa drugs) are not contained in vaccines. Providers administering vaccines should carefully review the prescribing information before deciding if a person with antibiotic allergy should receive the vaccine.

Hepatitis A vaccine, some hepatitis B vaccines, some influenza vaccines, MMR vaccine, IPV, rabies vaccine, smallpox vaccine, and varicella vaccine 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 neomycin generally should not receive these vaccines. Most often, neomycin allergic response 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.

Egg Protein

The most common animal protein allergen is egg protein in vaccines prepared by using embryonated chicken eggs (e.g., yellow fever vaccine, some influenza vaccines). People who can eat lightly cooked eggs (e.g., scrambled eggs) without a reaction are unlikely to be egg allergic. Egg-allergic people might tolerate egg in baked products (e.g., bread or cake). Tolerance to egg-containing foods does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reactions to eggs and egg-containing foods, plus skin or blood testing for immunoglobulin E directed against egg proteins.

People with a history of egg allergy who have experienced only hives after exposure to egg may receive influenza vaccine. Any licensed and recommended influenza vaccine that is otherwise appropriate for the recipient’s age and health status may be used.

Those who report having had reactions to egg involving symptoms other than hives (e.g., angioedema, recurrent emesis, lightheadedness, or respiratory distress), or who required epinephrine or another emergency medical intervention, may similarly receive any licensed and recommended influenza vaccine that is otherwise appropriate for the recipient’s age and health status. The selected vaccine should be administered in an inpatient or outpatient medical setting, and vaccine administration should be supervised by a health care provider who is able to recognize and manage severe allergic conditions. Cell-culture influenza vaccine (ccIIV4) and recombinant influenza vaccine do not require administration in a supervised setting, since neither vaccine is isolated or grown in eggs nor contains egg protein.

If a person has an egg allergy or a positive skin test to yellow fever vaccine but the vaccination is recommended because of their travel destination–specific risk, desensitization can be performed under direct supervision of a physician experienced in the management of anaphylaxis.

Thimerosal

Thimerosal, an organic mercurial compound in use since the 1930s, has been added to certain immunobiologic products as a preservative for multidose vials. Receiving thimerosal-containing vaccines has been postulated to lead to allergy induction. However, limited scientific evidence is available for this assertion. Allergy to thimerosal usually consists of local delayed-type hypersensitivity reactions. Thimerosal elicits positive delayed-type hypersensitivity to patch tests in 1%–18% of people tested, but these tests have limited or no clinical relevance. Most people 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, non-influenza vaccines routinely recommended for infants have been manufactured without thimerosal. Vaccines that still contain thimerosal as a preservative include some influenza vaccines, one DT vaccine [PDF], and one Td vaccine. Additional information about thimerosal and the thimerosal content of vaccines is available on the US Food and Drug Administration website.

Injection Route & Injection Site

Injectable vaccines are administered by intramuscular and subcutaneous routes. The injection method depends in part on the presence of an adjuvant in some vaccines. Adjuvant refers to a vaccine component, distinct from the antigen, which enhances the immune response to the antigen. Providers should inject vaccines containing an adjuvant (DTaP, DT, HepA, HepB, Hib, HPV, PCV13, Td, Tdap, recombinant zoster vaccine [RZV]) into a muscle mass because subcutaneous or intradermal administration can cause local induration, inflammation, irritation, skin discoloration, and granuloma formation.

Detailed discussion and recommendations about vaccination for people with bleeding disorders or receiving anticoagulant therapy are available in the ACIP’s General Best Practices Guidelines for Immunization.

Immunobiologic manufacturers recommend the routes of administration for each product. Deviation from the recommended route of administration can reduce vaccine efficacy or increase local adverse reactions. ACIP publishes detailed recommendations on the route and site for all vaccines. CDC compiled a list of these publications.

Post-Immunization Adverse Event Reporting

Modern vaccines are safe and effective. Benefits and risks are associated with the use of all immunobiologics. Adverse events after immunization have been reported with all vaccines, ranging from frequent, minor, local reactions (e.g., pain at the injection site), to extremely rare, severe, systemic illness, such as that associated with yellow fever vaccine. Adverse events following specific vaccines and toxoids are discussed in detail in each ACIP statement.

In the United States, clinicians are required by law to report selected adverse events occurring after vaccination with any vaccine in the recommended childhood series. 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 or can be requested by telephone at 800-822-7967 (toll-free). Clinicians are encouraged to report electronically.