Vaccination and Immunoprophylaxis—General Principles

Introduction

The pre-travel health consultation is an opportunity to administer routinely recommended vaccines in addition to travel-related vaccines (see The Pre-Travel Consultation chapter). Thus, healthcare professionals should be familiar with the general principles of vaccination and immunoprophylaxis and with the Advisory Committee on Immunization Practices' (ACIP's) annual immunization schedules. Routine vaccine recommendations are summarized in ACIP's Recommended Child and Adolescent Immunization Schedule for ages 18 years or younger and in ACIP's Recommended Adult Immunization Schedule for ages 19 years or older. See a link to these and other helpful websites in Table 1.3.1.

Some routine vaccines can be administered at earlier ages for international travelers. For example, measles-mumps-rubella (MMR) vaccine and hepatitis A (HepA) vaccine can be given as early as 6–11 months of age for infants who are planning to travel abroad. This is earlier than the routinely recommended age of 12 months. However, doses that are given before the routinely recommended age of 12 months do not count toward the recommended 2-dose series for either vaccine. Children who receive vaccine doses earlier than the recommended age because of international travel still need to receive routine doses at recommended ages.

The ACIP website and ACIP Immunization Schedules for Healthcare Professionals include recommendations, background, adverse reactions, precautions, and contraindications for vaccines, other immunizing agents (e.g., monoclonal antibodies such as nirsevimab), and toxoids (Table 1.3.1).

For information on vaccinating travelers with altered immune function, see Travelers with HIV and Immunocompromised Travelers chapters.

Table 1.3.1: Reference resources for vaccination and immunoprophylaxis

Spacing of vaccine and immunobiologics

Most vaccines can be given at the same visit and at separate injection sites without impairing antibody responses or increasing rates of adverse reactions. Additionally, there is no "upper limit" on the number of vaccines a patient may receive at a single visit. Simultaneous administration of all indicated vaccines is particularly advantageous for international travelers for whom exposure to several infectious diseases might be imminent.

However, there are some notable exceptions, which are further described in the sections below. For more guidance on giving more than 1 vaccine at a single visit, refer to the General Best Practices for Immunization (Table 1.3.1).

Pneumococcal vaccines

If a patient needs to receive both pneumococcal conjugate 15 (PCV15) vaccine and pneumococcal polysaccharide 23 (PPSV23) vaccine, then PCV15 should be administered first, followed by PPSV23 at least 1 year later. A minimum interval of 8 weeks between these 2 doses may be considered for persons with certain medical conditions. For more information, see CDC's pneumococcal vaccine timing for adults.

Coronavirus disease 2019 vaccines

COVID-19 vaccines can be administered concomitantly with almost any other vaccine (Table 1.3.1).

Live vaccines

If not administered simultaneously, injectable or nasally administered live vaccines should be administered at intervals of ≥28 days. There is no recommended minimum interval between live oral and live injectable or nasally administered vaccines. For more guidance on giving more than 1 live vaccine at a single visit, refer to ACIP's General Best Practices for Immunization (Table 1.3.1).

The immune response to an injected or intranasal live-virus vaccine (e.g., MMR, varicella, live attenuated influenza vaccines [LAIV], dengue) 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 either on the same day or 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 re-administered ≥28 days after the invalid dose.

Measles and other live-virus vaccines can interfere with the response to tuberculin skin testing and the interferon-gamma 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

While ACIP recommends that yellow fever vaccine be given at the same time as most other live-virus vaccines, there are limited data to suggest that co-administration of yellow fever vaccine with MMR vaccines might decrease the immune response (see Yellow Fever and Measles [Rubeola] chapters). A study involving simultaneous administration of yellow fever and MMR vaccines 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. However, these findings suggest that, if possible, an interval of ≥30 days between the yellow fever and MMR vaccines may be considered if both vaccines are indicated. Note that this ≥30-day interval differs from the usual ≥28-day interval for other live-virus vaccines.

No data are available on immune response to nasally administered LAIV given simultaneously with yellow fever vaccine (see Influenza chapter). 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 local or state public health authorities, or the CDC Arboviral Disease Branch (970-221-6400) to discuss serologic testing.

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.

Oral typhoid vaccine and cholera vaccine

No data are available on concomitant administration of the currently available formulation of oral cholera vaccine with other vaccines, including the enteric-coated oral typhoid vaccine (see Cholera and Typhoid and Paratyphoid Fever chapters). Based on ACIP's opinion of how oral cholera vaccine buffer might interfere with the enteric-coated oral typhoid vaccine formulation, taking the first oral typhoid vaccine dose 8 or more hours after ingestion of oral cholera vaccine might decrease potential interference of the vaccine buffer with oral typhoid vaccine.

Missed doses and boosters

There may be instances when an individual is not able to return on time to receive a scheduled dose of vaccine. 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 titers when the vaccine schedule is completed. Consequently, an extended interval between doses does not necessitate restarting the series or adding doses of any vaccine, but travelers should be encouraged to complete full vaccine regimens before travel if feasible.

However, 1 exception is the pre-exposure rabies vaccine series. The consequences of a 2-week or more delay are unknown. If an extended interval passes between doses of the pre-exposure rabies vaccine series, clinicians should consult with local and state public health authorities.

Antibody-containing blood products

In general, antibody-containing blood products (e.g., immune globulin [IG] products) from the United States 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. Monoclonal antibodies (e.g., nirsevimab or palivizumab) do not interfere with the immune response to licensed live or non-live vaccines, so such products can be administered on the same day or at any interval with live or inactivated vaccines.

There are additional considerations regarding antibody-containing blood products from the United States and live-virus vaccines. While antibody-containing blood products do not interfere with the immune response to yellow fever, LAIV, Ty21a typhoid, or rotavirus vac­cines, if MMR or varicella vaccines are given shortly before, simultaneously with, or after an antibody-containing blood product, the 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 be either administered ≥2 weeks before receipt of a blood product or delayed 3–11 months after receipt of the blood product, depending on the dose and type of blood product (see Table 3-6 in Timing and Spacing of Immunobiologics General Best Practices for Immunization).

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 1 of these live vaccines and the subsequent administration of an IG preparation is ≥14 days, the vaccine need not be re-administered. If the interval is <14 days, the vaccine should be re-administered after an interval (see Table 3-5 in Timing and Spacing of Immunobio­logics General Best Practices for Immunization), unless serologic testing indicates that antibodies have been produced. Such testing should be performed after the recommended interval to avoid detecting antibodies from the IG preparation.

In some circumstances, MMR or varicella vaccine might be indicated for a patient for pre-exposure (travel) or post-exposure 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 applied to the invalid dose of vaccine (highlighted in the General Best Practices for Immunization, website in Table 1.3.1).

There are additional considerations to note with antibody-containing blood products and dengue vaccine virus. While antibody-containing blood products may contain dengue antibody that can interfere with the replication of dengue vaccine virus, more importantly, dengue antibody can affect the pre-dengue vaccination serologic test by causing a false-positive result. Dengue vaccine is only recommended for children with a positive laboratory result for dengue reflecting a prior natural infection. Because dengue-susceptible children who receive dengue vaccine have a higher risk of adverse reactions compared with children who are immune to at least 1 type of dengue virus prior to vaccination, dengue vaccine should only be given to children who have laboratory confirmation of previous dengue virus infection. Therefore, it is critical that a positively interpreted pre-vaccination serology test is a true positive. If antibody-containing blood products have been administered, and a serology test is used, the serology test should not be administered until 12 months after the antibody-containing blood product has been administered.

When IG is given with the first dose of HepA 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 in the short term. However, the effect of reduced antibody concentrations on long-term protection is unknown.

Vaccinating people with acute illness

Healthcare professionals should take every opportunity to provide needed vaccines. The decision to delay vaccination because of a current or recent acute illness depends on the severity of the symptoms and their cause. A moderate or severe acute illness is considered a precaution to vaccination (i.e., vaccination should generally be deferred but might be indicated if the benefit of protection from the vaccine outweighs the risk for an adverse reaction). However, minor illnesses, such as diarrhea, mild upper respiratory infection with or without low-grade fever, other low-grade febrile illness, are not considered precautions or contraindications to vaccination (Table 1.3.1)

Antivirals active against influenza virus (e.g., baloxavir, oseltamivir, peramivir, zanamivir) can interfere with the response to LAIV. If 1 of these antivirals is administered within 14 days after LAIV administration, then subsequent revaccination with inactivated influenza vaccine or recombinant influenza vaccine may be considered. If 1 of the aforementioned antivirals was administered first, clinicians should delay LAIV for 48 hours after oseltamivir or zanamivir; for 5 days after peramivir; and for 17 days after baloxavir. Use of antiviral agents active against herpes viruses (e.g., acyclovir) is a precaution against administration of varicella-containing vaccines (such as the single antigen varicella vaccine or the combination measles, mumps, rubella, and varicella vaccine) because the antiviral agent may interfere with the live vaccine.

Antimicrobial agents can prevent adequate immune response to live attenuated oral typhoid (Ty21a) and cholera vaccines. Ty21a typhoid vaccine should not be administered to persons receiving antibiotics until 72 hours after the last dose. If feasible, to avoid a possible reduction in vaccine effectiveness, antibiotics should not be started or resumed until 3 days after the last dose of Ty21a. Two malaria chemoprophylaxis medicines—chloroquine and mefloquine—can be administered concomitantly with the oral typhoid vaccine. Atovaquone-proguanil should not be administered until at least 10 days after the last dose of Ty21a, whereas other malaria chemoprophylaxis options should not be administered until at least 3 days after the last vaccine dose.

Cholera vaccine (CVD 103-HgR) should not be given to patients who have received oral or parenteral antibiotics during the preceding 14 days, although a duration shorter than 14 days may be unavoidable under certain circumstances, such as travel. Malaria chemoprophylaxis with chloroquine should begin ≥10 days after administration of CVD 103-HgR.

Antimicrobial or immunosuppressive agents may interfere with the immune response to BCG and should only be used under medical supervision.

Vaccination scheduling for selected travel vaccines

Table 1.3.2 lists the number of doses, recommended ages, and minimum intervals between doses for select travel vaccines that do not have a routine non-travel recommendation in the United States. Vaccines that are routinely recommended are still applicable to travelers and may be found at the website listed in Table 1.3.1.

Table 1.3.2: Number of doses, recommended ages, and minimum intervals for travel vaccines¹

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 (Table 1.3.1).

Vaccine components responsible for reactions can include adjuvants, animal proteins, antibiotics, the vaccine antigen, preservatives (e.g., thimerosal), stabilizers (e.g., gelatin), or yeast. See package inserts of vaccines for a full list of vaccine ingredients for each of the routinely recommended vaccines (Table 1.3.1).

Antibiotics and 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.

HepA vaccine, some hepatitis B (HepB) vaccines, some influenza vaccines, MMR vaccine, inactivated poliovirus 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

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 anaphylaxis management. ACIP recommends that persons with an egg allergy can receive any influenza vaccine (i.e., egg-based or non-egg-based) appropriate for age and health status.

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 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 and 1 tetanus-diphtheria (Td) vaccine. Additional information about thimerosal and the thimerosal content of vaccines is available on the U.S. Food and Drug Administration website (Table 1.3.1).

Injection route and injection site

Routine 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, that enhances the immune response to the antigen. Vaccines containing an adjuvant (diphtheria, tetanus, and acellular pertussis [DTaP] vaccine; HepA vaccine; HepB vaccine; Haemophilus influenzae type b [Hib] vaccine; human papillomavirus [HPV] vaccine; some influenza vaccines; meningococcal serogroup B [MenB] vaccine; pneumococcal conjugate vaccines [PCV15, PCV20, and PCV21]; Td vaccine; tetanus, diphtheria, and acellular pertussis [Tdap] vaccine; recombinant zoster vaccines [RZV]; and some respiratory syncytial virus [RSVPreF3] vaccines) should be administered via injection into a muscle mass, as stated in vaccine package inserts, 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 General Best Practices for Immunization (Table 1.3.1).

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.

For more information on vaccine administration, visit ACIP Vaccine Administration Guide­lines for Immunization (Table 1.3.1).

Post-immunization adverse event reporting

All U.S. Food and Drug Administration–licensed vaccines and other immunizing agents (e.g., monoclonal antibodies such as nirsevimab) are considered safe and effective. However, adverse events after immunization have been reported with all products, ranging from frequent, minor, local reactions (e.g., pain at the injection site) to extremely rare, severe, and systemic illness. 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 certain adverse events that occur after immunization. In addition, CDC strongly recommends that all vaccine adverse events be reported to the Vaccine Adverse Event Reporting System, even if a causal relation to vaccination is uncertain (Table 1.3.1).

Acknowledgements

The following authors contributed to the previous version of this chapter: Mark Freedman.