INTRODUCTION — International travelers are frequently at risk of exposure to infectious pathogens and should seek advice about immunizations and other necessary prophylaxis prior to departure [1]. In preparation for a trip, individuals should arrange a pretravel consultation with either a specialized travel clinic or a primary care practice with expertise in travel medicine [2]. The traveler should come to the visits with a record of prior immunizations and an itinerary.
Immunization needs are based on the traveler's prior immunizations, health conditions, and likely exposures while traveling (table 1). Those exposures depend upon the countries and regions to be visited and on the nature of potential exposures to infectious agents. For example, travelers with short-term tourism itineraries may have different requirements from those with longer-term occupational exposures. A pretravel consultation enables updating of routine immunizations to protect against illness due to infections for which there is an increased risk of exposure during travel (such as diphtheria, measles, mumps, and varicella) [3].
Information on the indications, dosing, side effects, timing, and contraindications for immunizations in travelers are provided by the United States Centers for Disease Control and Prevention (CDC) in a second-yearly publication, Health Information for International Travel [4], with ongoing updates in an online version. The World Health Organization (WHO) also has online information that includes vaccines or dosing regimens approved outside the United States [5]. Information may be found on the CDC website and the WHO website. Guidance may also be found via GlobalTravEpiNet (GTEN), which has web-based tools for providers and patients based on CDC recommendations.
Issues related to immunizations for travelers are reviewed here. Other travel-related medical issues and measures to prevent malaria are discussed separately. (See "Travel advice" and "Prevention of malaria infection in travelers".)
TRAVEL IMMUNIZATIONS
General principles — A standard immunization form should be part of the patient's medical record; the dedicated immunization history available in electronic medical records should be complete for all patients. Details to be recorded include vaccine type, dose, date of administration, manufacturer, lot number, and site of administration. It is also important to document if a patient declines to receive any recommended vaccine.
There are a number of differences between countries with respect to vaccine availability and guidelines for vaccine use. A broad international perspective has been published by the World Health Organization (WHO) [5].
Available travel immunizations in the United States include yellow fever (YF) vaccine, meningococcal vaccine, typhoid vaccine, hepatitis A vaccine, hepatitis B vaccine, polio, rabies vaccine, cholera, and Japanese encephalitis vaccine (table 1). The indications, contraindications, precautions, dosing, and administration of these vaccines are discussed in the following sections.
Minimum intervals between doses of vaccines are summarized in the table (table 2) and may be important considerations for travelers with imminent departures.
Yellow fever vaccine — YF is a mosquito-borne viral infection endemic in equatorial Africa and in areas of South America but not in Asia [4,6]. Fatalities due to YF acquired by unvaccinated tourists have occurred [7-10]. YF vaccination is legally required for entrance into specific countries, usually if the traveler is arriving from an endemic country; an intermediate airport transit stop of <12 hours in an endemic country usually does not trigger the requirement in the arrival country. However, many countries that have YF transmission do not have a legal requirement for vaccination, and travelers to those countries need vaccination for their own protection.
The YF vaccine is a live virus vaccine grown in chick embryos. Following vaccine administration, a low-level viremia with the vaccine virus often develops within three to seven days and persists for one to three weeks [6]. (See "Yellow fever: Treatment and prevention", section on 'Prevention'.)
To meet entry requirements (for countries that have them), the YF vaccination certificate is valid beginning 10 days after administration of YF vaccine for primary vaccine recipients; this corresponds to the time at which the majority of vaccine recipients demonstrate immunity. A YF vaccination certificate for international travel is valid for the life of the recipient, no matter when it was issued. Authorized YF vaccination centers in the United States may obtain the International Certificate of Vaccination or Prophylaxis from the United States Government Printing Office [11,12]. (See "Yellow fever: Treatment and prevention", section on 'Immunization certificates'.)
Issues related to yellow fever booster vaccination for travelers are discussed separately. (See "Yellow fever: Treatment and prevention", section on 'Travelers'.)
Indications — Travelers aged ≥9 months who are traveling to or living in areas at risk for YF transmission in South America and Africa should be vaccinated. In addition, the International Health Regulations allow countries (with or without local disease), if they wish, to require proof of YF vaccination as a condition of entry for travelers arriving from certain countries to prevent importation and indigenous transmission of YF virus. Disease distribution maps and vaccine recommendations can be found on the WHO website and the United States Centers for Disease Control and Prevention (CDC) website [13].
Contraindications and precautions — Because the YF is a live attenuated vaccine, it should not be given to individuals with primary immunodeficiencies, transplant recipients, patients on immunosuppressive and immunomodulatory therapies, or patients with human immunodeficiency virus (HIV) whose CD4 count is <200/mL. Other contraindications include age <6 months, allergy to a vaccine component, and thymic disorders. There is a precaution against YF vaccination for travelers ≥60 years of age and infants aged 6 to 8 months; for these patients, the risk of severe illness and death due to YF infection should be balanced against the risk of serious vaccine effects [14].
Pregnancy is also a precaution for YF vaccine administration (in contrast with most other live vaccines that are contraindicated in pregnancy). If travel is unavoidable and the risks for YF virus exposure are felt to outweigh the vaccination risks, a pregnant woman should be vaccinated. If the risks for vaccination are felt to outweigh the risks for YF virus exposure, pregnant women should be issued a medical waiver to fulfill any international health regulation requirement [6].
In some circumstances, patients require proof of YF vaccination for travel, but YF vaccine administration is contraindicated. Official CDC and WHO resources distinguish between countries with International Health Regulation YF vaccine entry requirements and countries where vaccination is recommended because of potential exposure in an area with YF transmission. For circumstances in which YF vaccine documentation must be presented to international customs officials according to International Health Regulations, the traveler can be provided with a Medical Letter of Waiver. For individuals planning travel to an area for which YF vaccine is recommended to avoid risk of infection in the unvaccinated traveler, serious consideration to a change in itinerary should be advised.
Major adverse events — Three well-characterized serious adverse events occur following YF vaccine administration (see "Yellow fever: Treatment and prevention", section on 'Adverse effects'):
●Immediate hypersensitivity or anaphylactic reactions – These are uncommon (1.4 per 100,000 doses administered) and principally occur among persons with histories of allergies to egg or other substances [15,16]. The YF vaccine package insert contains a desensitization regimen that can be considered. (See "Allergic reactions to vaccines".)
●YF vaccine-associated neurologic disease (YEL-AND) – YEL-AND is a serious but rarely fatal adverse event. YEL-AND manifests as several distinct clinical syndromes, including meningoencephalitis, Guillain-Barré syndrome (GBS), acute disseminated encephalomyelitis (ADEM), and bulbar palsy. Meningoencephalitis occurs due to direct viral invasion of the central nervous system; the other syndromes are autoimmune manifestations [6]. The incidence rate of YF vaccine-associated encephalitis in very young infants has been estimated to be 50 to 400 cases per 100,000 population, and the overall reporting rate for YEL-AND is 0.4 to 0.8 cases per 100,000 doses distributed [15] (rate in 60- to 69-year-olds: 1.6 cases per 100,000 doses distributed; rate if ≥70 years: 1.1 to 2.3 cases per 100,000 doses distributed) [6]. These estimates most likely are low given underreporting.
●YF vaccine-associated viscerotropic disease (YEL-AVD) – YEL-AVD mimics naturally acquired YF disease, with proliferation and dissemination of the vaccine virus throughout the host tissues. This syndrome was first reported in 2001, and >100 cases have been described worldwide [4]. The median time from vaccination to symptom onset is three days (range one to eight days); death has occurred in 65 percent of cases. All known cases of YEL-AVD have occurred following a recipient's first YF vaccination, with no reported cases following booster doses. The reporting rate of YEL-AVD is 0.3 to 0.4 cases per 100,000 doses distributed [15], but higher rates have been reported in older individuals (1.0 to 1.1 cases per 100,000 doses distributed in persons aged 60 to 69 years and 2.3 to 3.2 cases per 100,000 doses distributed for persons aged ≥70 years) [6]. In addition to older age, history of thymus disease or thymectomy are specific risk factors. All primary vaccinees should clearly be told to call with any symptoms of any kind within one week of vaccination, and anyone with significant flu-like or febrile illnesses should be brought in for assessment as well as complete blood count and biochemistry.
Dosing and administration — Dosing consists of a single 0.5 mL subcutaneous injection. YF vaccine should be administered either simultaneously or 30 days apart from other live injectable viral vaccines. Other inactivated vaccines and oral live vaccines can be administered either simultaneously or at any time before or after YF vaccination.
Fractional dosing (a single 0.1 mL [one-fifth of the normal dose] subcutaneous injection) has been used in emergency situations to control outbreaks; thus far, data are complex and insufficient for most national and international authorities to support the use of fractional dosing in travelers [17]. A fractional dose does not meet the criteria for proof of vaccination to be documented on an International Certificate of Vaccination or Prophylaxis. (See "Yellow fever: Treatment and prevention", section on 'Fractional vaccine dosing'.).
Meningococcal vaccine — Meningococcal meningitis is a devastating bacterial infection with high mortality; large-scale epidemics mostly of type C and W occur in the so-called "meningitis belt" of Africa. Mass vaccination campaigns against type A have stopped outbreaks due to that type (which was previously dominant).
Quadrivalent meningococcal conjugate vaccine formulations (MenACWY-D [Menactra], MenACWY-CRM [Menveo], and MenACWY-TT [MenQuadfi]) have replaced quadrivalent meningococcal polysaccharide vaccine (MPSV4/Menomune).
Indications — Epidemics of meningococcal disease are frequent in the area of sub-Saharan Africa extending from Senegal in the west to Ethiopia in the east (figure 1) [5] (see "Epidemiology of Neisseria meningitidis infection"). Type B meningococcal infection is not a specific travel-related risk. A vaccine for prevention of serogroup B meningococcal disease has no specific or extraordinary travel indications but should be administered prior to travel to any traveler in whom vaccine is otherwise indicated (eg, asplenia or complement deficiency). (See "Meningococcal vaccination in children and adults", section on 'Immunization of persons at increased risk'.)
Meningococcal ACWY vaccine is recommended for travelers to the meningitis belt in Africa, especially during the dry season (from December through June) and year-round for health care workers. Travelers to Saudi Arabia during the Hajj are required to have a certificate of vaccination with quadrivalent (A,C,Y,W-135) meningococcal vaccine before entering, issued not more than 5 years and not less than 10 days before arrival if a conjugate vaccine was administered; the vaccination certificate should specifically state that a conjugate vaccine was given.
Other (non-traveler) groups for whom meningococcal vaccine is warranted are outlined separately. (See "Meningococcal vaccination in children and adults", section on 'Immunization of persons at increased risk'.)
Contraindications and precautions — Hypersensitivity to other meningococcal-containing vaccines is a contraindication to vaccination. Immunization is safe in immunocompromised hosts and is specifically indicated for patients with deficiencies of terminal complement components or functional or anatomic asplenia. Previous Guillain-Barré syndrome is not a contraindication to vaccination.
Dosing and administration — The schedules for the primary series and for revaccination are presented separately. (See "Meningococcal vaccination in children and adults".)
Boosters are recommended by the Advisory Committee on Immunization Practices (ACIP) for those with ongoing risk (table 3 and table 4) [18]. Published data indicate that protection significantly wanes after three years, including that against C and W serogroups responsible for African epidemics [17,19].
Typhoid vaccine — Typhoid fever is a systemic bacterial illness with fecal-oral transmission characterized by fever and abdominal symptoms. Salmonella enterica Typhi infection is prevalent in many areas of Asia, Africa, and Latin America, and multidrug-resistant strains of S. Typhi are increasingly prevalent globally. Available vaccines for protection against S. Typhi include Ty21a vaccine (a live oral vaccine), Vi polysaccharide vaccine (a parenteral vaccine), and Vi-TT typhoid conjugate vaccine (TCV; a parenteral vaccine available in India, Nepal, and some other locations outside the United States and Europe) [19]. None is completely effective against S. Typhi, and none provides protection against paratyphoid fever; protection against extensively drug-resistant strains of S. Typhi in Pakistan is likely but not well studied. (See "Enteric (typhoid and paratyphoid) fever: Treatment and prevention".)
Indications — Typhoid vaccination is recommended for travelers to areas with a risk of exposure to S. Typhi. Incidence of typhoid fever appears to be decreasing in the Americas, Southeast Asia, and some parts of Africa; recommendations for vaccination to these countries from most authorities remain cautious. The risk of acquiring typhoid fever increases with the duration of stay, although travelers have become ill during visits of less than one week to regions where the disease is endemic. Travelers visiting friends and relatives seem to be at particularly high risk of infection. A list of countries is available on the CDC website.
Contraindications and precautions — The oral typhoid vaccine is a live attenuated vaccine so should not be administered to individuals with immunodeficiency, acute febrile illness, or acute gastrointestinal illness. Many experts avoid its use in pregnancy and in individuals with chronic intestinal issues including irritable bowel syndrome.
Dosing and administration — The parenteral polysaccharide Vi vaccine is administered as a single 0.5 mL intramuscular injection (age ≥2 years). A booster dose is recommended two years later in the United States and three years later in Canada and many other countries.
The oral typhoid vaccine is administered as a four-dose course (days 1, 3, 5, and 7) for age ≥6 years and is supplied as a packet of enteric-coated capsules that must be kept refrigerated [20]. The primary course needs to be repeated five years after initial administration. It is acceptable to administer other live vaccines concurrently with the oral typhoid vaccine.
The oral typhoid vaccine should not be administered within 72 hours of antibiotics [21]. The antimalarial drugs atovaquone-proguanil, mefloquine, and chloroquine may be given concurrently with the oral typhoid vaccine at doses used for malaria chemoprophylaxis [22].
Hepatitis A vaccine — Hepatitis A is a viral infection transmitted via the fecal-oral route that can lead to hepatic failure in rare cases. In surveillance data collected from 1988 to 2004, the incidence of hepatitis A for travelers to countries of high or intermediate risk was 3 to 11 per 100,000 person-months abroad, and the incidence for travelers presumed to be nonimmune was 6 to 28 per 100,000 [23]. Risk in many countries is declining due to improvements in sanitation. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis" and "Hepatitis A virus infection: Treatment and prevention".)
Indications — Vaccination is warranted for travelers to countries with intermediate to high endemicity of hepatitis A. A list of countries is available on the CDC website. The list includes all resource-limited countries. Given the complexity of interpreting hepatitis A risk maps and potential risk of foodborne hepatitis A even in countries with low endemicity, some experts advise travelers to consider hepatitis A vaccination regardless of destination [4,24].
The ACIP recommends routine vaccination of children aged 12 to 23 months and catch-up vaccination for children and adolescents aged 2 to 18 years who have not previously received hepatitis A vaccine, irrespective of travel [25].
Contraindications and precautions — Hypersensitivity to hepatitis A vaccine or any component of the formulation is a contraindication to vaccination. The hepatitis A vaccines are acceptable for use in pregnancy and for immunocompromised individuals [26,27].
Dosing and administration — Available formulations of hepatitis A vaccine include monovalent vaccines HAVRIX or VAQTA (age ≥1 year). Available combination vaccine formulations include Twinrix (includes hepatitis B) and Vivaxim (includes typhoid Vi; not available in the United States).
One dose of single-antigen hepatitis A vaccine administered at any time prior to departure provides adequate initial protection for healthy individuals ≤40 years (table 1) [28]. A second dose of vaccine 6 to 12 months after the initial dose is recommended and provides longer-term protection. If the immunization schedule is interrupted, the second dose can be given without restarting the series. No additional booster doses are recommended, as data suggest that long-term protection is achieved. A vaccination series started with one brand of vaccine may be completed with the same or other brand of hepatitis A vaccine.
Children traveling outside the United States should receive hepatitis A vaccination sooner than the standard immunization schedule. Children aged 6 to 11 months should receive one dose (not countable toward routine vaccination schedule) of hepatitis A vaccine before departure. Following this dose, routine vaccination with hepatitis A vaccine (two additional age-appropriate doses) should occur.
Immunocompromised individuals (notably those being treated with immunosuppressive drugs) may have inadequate seroconversion after a single dose of hepatitis A vaccine. For immunocompromised individuals of any age who are traveling internationally, hepatitis A vaccine with additional immune globulin (IG) is recommended by the ACIP. The dose of IG varies according to planned duration of travel (0.1 mL/kg for travel up to one month, 0.2 mL/kg for travel up to two months, and, for travel of more than two months, repeat doses of 0.2 mL/kg every two months) [29]. However, such travelers should make efforts to receive two doses over a six-month period prior to their trip.
As an alternative to concomitant IG, administering a second dose of vaccine at least four weeks after the first dose (for travelers who can get both doses before travel) has been effective in select studies [26,30]. For unvaccinated travelers who require postexposure prophylaxis during or after travel, IG may be administered in addition to hepatitis A vaccine in persons older than 40 years, depending on the risk assessment (eg, patient age, immune status and underlying conditions, exposure type/risk of transmission, and availability of IG). (See "Hepatitis A virus infection: Treatment and prevention".)
Travelers who choose not to receive the vaccination or are allergic to a vaccine component should receive a single dose of IG in the doses outlined above.
Hepatitis B vaccine — Hepatitis B is a viral infection transmitted by bodily fluid exposure that can lead to hepatic failure and/or hepatocellular carcinoma. It is estimated that there are more than 350 million hepatitis B virus (HBV) carriers in the world, of whom roughly one million die annually from HBV-related liver disease. (See "Epidemiology, transmission, and prevention of hepatitis B virus infection" and "Hepatitis B virus immunization in adults".)
Indications — Vaccination is warranted for travelers to countries with intermediate to high endemicity of HBV (ie, with hepatitis B surface antigen [HBsAg] prevalence ≥2 percent); a list of countries is available on the CDC website. Risk groups include health care workers, adventure travelers, Peace Corps volunteers, missionaries, military personnel, and medical tourists [4]. Hepatitis B immunization should also be considered for any traveler with potential contact with blood or bodily secretions, potential sexual contact, or potential need for medical or dental procedures while traveling. The vaccine should be considered for all nonimmune travelers since it is often difficult to assess risk during the pretravel consultation.
Contraindications and precautions — Hypersensitivity to hepatitis B vaccine or any component of the formulation is a contraindication to vaccination.
Hepatitis B vaccine can be administered to immunosuppressed patients, although vaccine immunogenicity is lower in these groups [27]. For individuals with underlying comorbidities that may interfere with seroconversion, antibody titers can be checked to ensure adequate vaccine response has occurred.
Dosing and administration — There are three formulations of recombinant hepatitis B vaccine available in the United States (Recombivax HB, Engerix-B, and Heplisav-B). There is also a combination formulation that includes hepatitis A vaccine (Twinrix).
Many experts favor Heplisav-B optimal for travelers who require immunization and are not traveling for one month; it is an adjuvant vaccine administered in two doses one month apart and induces a very prominent immune responses.
For individuals with more time before travel, alternative vaccines include Recombivax HB and Engerix-B. These are unadjuvanted vaccines administered in three intramuscular doses; the initial dose is followed by repeat doses at one and six months after the first dose. The third dose should be given ≥2 months after the second dose and ≥4 months after the first dose. In infants, the third dose should not be administered before age 24 weeks.
Ideally, immunization with Recombivax HB or Engerix-B should begin six months prior to travel. Alternatively, an accelerated regimen (with doses given on days 0, 7, and 21) can be administered to travelers who cannot complete the full series prior to departure. Travelers who receive an accelerated regimen should receive a booster at least six months later to optimize long-term immunity. (See "Hepatitis B virus immunization in adults".)
The humoral immune response to unadjuvanted hepatitis B vaccine is diminished in immunocompromised individuals; therefore, adjuvanted Heplisav-B is favored for such individuals by many experts in the absence of specific data. Alternatively, limited data suggest that modified dosing regimens of unadjuvanted vaccine can also increase response rates. A three-dose series of Recombivax HB (40 mcg at zero, one, and six months) or a four-dose series of Engerix-B (40 mcg at zero, one, two, and six months) may be used. (See "Hepatitis B virus immunization in adults", section on 'Patients on dialysis and immunocompromised hosts'.)
The bivalent vaccine can be used to complete immunizations series started with monovalent hepatitis A and B vaccines [4].
Rabies vaccine — Rabies is a viral disease transmitted by dogs, bats, and other animals that leads to encephalopathy and death. Rabies is endemic in most countries of Asia, Africa, and Central and South America [4].
Indications — Rabies pre-exposure vaccination is indicated for travelers visiting areas where rabies is endemic who anticipate contact with animals and limited access to immediate medical care [31]. Children are at increased risk as they are more likely than adults to play with animals and they may not reliably report exposures not associated with significant injury. A list of countries is available on the CDC website.
Contraindications and precautions — Hypersensitivity to rabies vaccine or any component of the formulation is a contraindication to vaccination. The rabies vaccines are acceptable for use in pregnancy and for immunocompromised individuals.
Dosing and administration
●Formulations − There are two formulations of rabies vaccine available in the United States: human diploid cell vaccine (HDCV; Imovax) and purified chick embryo cell vaccine (PCECV; RabAvert). Additional vaccines are available outside the United States.
●Initial regimen – The CDC and the WHO have endorsed a pre-exposure prophylaxis (PrEP) regimen consisting of two doses on days 0 and 7 [32,33]; previously, the regimen (initial and subsequent priming) consisted of three doses. The CDC and WHO recommend that PrEP be given intramuscularly; the WHO also endorses an intradermal regimen [33]. (See "Rabies immune globulin and vaccine".)
●Subsequent priming regimens
•Travelers with significant risk of exposure for ≤3 years after completion of the two-dose PrEP series do not need a titer check or subsequent dose. PrEP is considered adequate for three years; exposures >3 years after completion of the two-dose PrEP series then require full postexposure prophylaxis. (See "Rabies immune globulin and vaccine", section on 'Post-exposure prophylaxis'.)
•Travelers with frequent or sustained exposure risk for >3 years after completion of the two-dose PrEP series should proceed in one of the following ways:
-Check one titer between one to three years after completing the initial regimen, and boost only if titer is <0.5 international units/mL
-Receive one additional vaccine dose between 21 days to 3 years after completion of the initial two-dose regimen
Thereafter, no further titers are needed, and no further vaccine doses are needed unless postexposure prophylaxis is warranted following an exposure.
●Role of postexposure vaccination − Pre-exposure immunization (priming) does not eliminate the need for postexposure administration of two booster doses spaced by three days. The approach to rabies postexposure prophylaxis is discussed separately. (See "Indications for post-exposure and pre-exposure rabies prophylaxis".)
Japanese encephalitis vaccine — Japanese encephalitis (JE) is an arboviral encephalitis endemic throughout most of Asia and parts of the western Pacific. The highest risk of JE exposure occurs in rural agricultural areas, often associated with rice production and flooding irrigation. (See "Japanese encephalitis".)
One JE vaccine is available in the United States: an inactivated Vero cell culture-derived vaccine (JE-VC; IXIARO) (licensed in 2009). JE-VC protects against all five JE virus genotypes. An inactivated mouse brain-derived vaccine (JE-MB; JE-VAX) was discontinued in 2009.
Outside the United States, a live attenuated YF-JE chimeric viral vaccine (IMOJEV) has been licensed in Australia and in some Asian countries as a single 0.5 mL subcutaneous dose for primary immunization of individuals over 12 months of age. For individuals ages 12 months to 17 years, a booster dose should be given one to two years after the first dose to provide long-term protection. For people over 18 years, there is no need for a booster dose for at least five years after the first vaccination. Since it is a live attenuated vaccine, it should not be used in immunocompromised individuals and its safety in pregnancy has not been evaluated.
Indications — JE vaccination is appropriate for travelers visiting endemic areas during periods of JE transmission. Indications for JE vaccination are summarized in the table (table 5) [34]. A list of countries can be found on the CDC website.
The likelihood of JE transmission to travelers is low, but the outcome is potentially severe. Factors that increase the risk of JE transmission include longer duration of travel, travel during peak JE season, extended time in rural areas, participating in extensive outdoor activities, and accommodations without air conditioning or screens. (See "Japanese encephalitis".)
Contraindications and precautions — Hypersensitivity to JE virus vaccine or any component of the formulation is a contraindication to vaccination. Since the licensure of JE-VC in 2009, approximately 1 million doses have been distributed with no pattern of severe adverse systemic or neurologic adverse events observed.
Dosing and administration — For adults and children ≥3 years, each dose is 0.5 mL; for children aged two months to two years of age, each dose is 0.25 mL [35] (one-half of the supplied prefilled adult syringe).
For adults 18 to 65 years of age, the primary immunization schedule for JE-VC is two doses administered intramuscularly administered on day 0 and then any time between day 7 and day 28 [4,36]. Seroprotection rates after primary vaccination approach 100 percent.
For children <18 years of age and for adults >65 years of age, the primary immunization schedule is two doses administered intramuscularly on days 0 and 28. The two-dose series should be completed at least one week prior to travel. In one study, seroprotection rates in those >65 years of age were substantially lower after a primary series; no data are available on the use of any additional primary doses in this age group.
For individuals with ongoing risk, a booster (third) dose should be administered >1 year after completion of the primary series [34]. Data demonstrate seroprotection for at least six years after the booster, and antibody decay models suggest seroprotection for at least 10 years or more [37]. Data regarding the need for subsequent booster doses are not available; a booster dose at 10 years may be considered for travelers wanting to ensure prolonged protection [37]. Following previous immunization with a complete three-dose series of JE-MB or other mouse brain vaccine, booster with JE-VC may be given; data suggest JE-VC effectively boosts immunity in travelers primed with mouse brain-derived JE vaccines [38].
Cholera vaccine — Cholera is a diarrheal illness caused by infection with the gram-negative bacterium Vibrio cholerae; it is characterized by severe watery diarrhea, which can rapidly lead to dehydration. Epidemics of cholera have occurred around the world, although infection among travelers is not common [39]. (See "Cholera: Clinical features, diagnosis, treatment, and prevention".)
CVD 103-HgR (Vaxchora) is a live attenuated oral cholera vaccine approved by the US Food and Drug Administration (FDA) and recommended by the ACIP for prevention of cholera caused by serogroup O1 in individuals 2 through 64 years of age traveling to affected areas [40].
Outside the United States, the following cholera vaccines are available:
●Dukoral, a killed whole-cell oral vaccine with the nontoxic B subunit of cholera toxin, also provides limited (<50 percent) protection against infection with enterotoxigenic Escherichia coli.
●Shanchol, a killed whole-cell oral cholera vaccine that lacks the nontoxic B subunit of cholera toxin, has received WHO prequalification and is being stockpiled with Dukoral by the WHO for emergency use.
●Euvichol, a killed whole-cell oral cholera vaccine that lacks the nontoxic B subunit of cholera toxin, has received WHO prequalification and is being stockpiled with Dukoral by the WHO for emergency use.
Indications — Live attenuated cholera vaccine CVD 103-HgR (Vaxchora) is indicated for prevention of cholera caused by serogroup O1 in patients age 2 to 64 years of age traveling to an area of active cholera transmission who are at immediate risk of epidemic cholera [40].
An area of active cholera transmission is defined as a region with endemic or epidemic cholera caused by toxigenic V. cholerae O1 and includes areas with cholera activity within the last year that are prone to recurrence of cholera epidemics; it does not include areas where only rare imported or sporadic cases have been reported.
Most people do not travel to areas of active cholera transmission, and most travelers are at extremely low risk for cholera infection. Groups that most warrant vaccination include aid, refugee, and health care workers in endemic and epidemic areas in proximity to displaced populations, especially in crowded camps and urban areas with unsanitary conditions.
Factors that increase the risk of getting cholera or having severe disease include blood type O, low gastric acidity from antacid therapy, partial gastrectomy, and lack of access to medical services; medical conditions associated with poor tolerance of dehydration (such as cardiovascular disease or kidney disease) might also be at increased risk for poor outcomes [40]. In addition, individuals visiting friends and relatives in the family's country of origin appear to be at higher risk.
The effectiveness of the vaccine for populations living in cholera-affected areas has not been established, and the vaccine has not been shown to protect against disease caused by serogroup O139 or other serogroups.
Contraindications and precautions — The safety and effectiveness of live attenuated oral cholera vaccine has not been established in immunocompromised individuals. The vaccine strain may be shed in the stool of recipients for at least seven days, with potential for transmission to nonvaccinated household contacts.
Dosing and administration — CVD 103-HgR (Vaxchora) is taken as a single oral dose at least 10 days before travel to a cholera-affected area. Eating and drinking should be avoided for one hour before and after vaccine administration.
CVD 103-HgR (Vaxchora) should not be administered within two weeks of systemic antibiotics, which may be active against the vaccine strain. The vaccine should be administered at least 10 days prior to use of antimalarial prophylaxis with chloroquine.
Monkeypox vaccine — Monkeypox virus is a zoonotic orthopoxvirus that causes a rash similar to smallpox virus. These viruses are closely related and immunologically cross-reactive; however, monkeypox infection is associated with a lower fatality rate. (See "Treatment and prevention of mpox (monkeypox)" and "Variola virus (smallpox)".)
●Epidemiology within Africa − Most reported cases of monkeypox (>1000 per year) have been in the Democratic Republic of Congo, where the disease is endemic; sporadic cases have been reported in tropical rainforests in the Congo basin and West Africa. Since 2016, human cases of monkeypox have also been reported in Cameroon, Central African Republic, Liberia, Nigeria, Republic of the Congo, and Sierra Leone [41].
●Global spread − The number of monkeypox cases throughout West and Central African countries is increasing; between 2018 and 2021, >10 cases in travelers returning from Nigeria presented in the United Kingdom, Singapore, Israel, and the United States [42-44]. This increase may be attributable to closer contact between humans and animals (due to population movement, civil unrest, deforestation, and climate change) and waning herd immunity from prior routine smallpox vaccination (discontinued in the 1980s). Ingestion of bush meat, exposure to rodents, and contact with infected individuals all appear to be risk factors.
Beginning in May 2022, a global outbreak involving hundreds of cases (West African strain) has been reported among individuals in nonendemic areas (Europe, North America, Australia) with no exposure in Africa. Transmission has been mostly from direct person-to-person contact (including sexual contact, especially among men who have sex with men [MSM]). Skin-to-skin contact is thought to be the predominant mode of spread; respiratory transmission is also possible but is considered less likely. Compared with previously reported monkeypox cases, a low frequency of prodromal symptoms and a low frequency of disseminated skin lesions have been reported; isolated genital lesions have been confused with typical sexually transmitted infections. Risk specific to travelers includes attendees of gay pride events and to venues where MSM activity occurs.
●Available vaccine − MVA-BN (Modified Vaccinia Ankara-Bavarian Nordic; United States trade name Jynneos) is a live attenuated, nonreplicating vaccinia vaccine approved by the FDA in September 2019 for prevention of smallpox and monkeypox [45]. In clinical trials, anti-vaccinia antibody titers following administration of MVA-BN were noninferior to titers induced by a traditional live replicating smallpox vaccine [46].
MVA-BN is the only vaccine approved for prevention of monkeypox. The smallpox vaccine ACAM2000 also provides protection against monkeypox but has higher toxicity. In Europe and Canada, MVA-BN is approved for the prevention of smallpox (under trade names Imvanex and Imvamune, respectively). MVA-BN is readily available from the CDC Drug Service but only via a request from state health departments on a case-by-case basis.
Indications — MVA-BN vaccine is indicated for prevention of monkeypox disease in adults ≥18 years at high risk for monkeypox infection including first responders at risk as specifically defined by a public health authority. Risk of monkeypox among travelers or responders to endemic areas has not been formally studied. Postexposure vaccination is indicated for high risk exposures as defined by CDC [47].
Contraindications and precautions — Vaccination is contraindicated for individuals with vaccine or vaccine-component allergies; however, in an exposure or outbreak situation, the risk for severe monkeypox likely outweighs the risk for a serious allergic reaction to vaccination. None of the contraindications for replicating vaccinia-based vaccines (such as cardiac disease, eczema, HIV, or immunosuppression) are applicable to MVA-BN. Cardiac toxicity (myocarditis or pericarditis) and other adverse effects observed with replicating vaccinia-based vaccines (eg, eczema vaccinatum, postvaccinial encephalitis, or vaccinia necrosum) have not been reported with MVA-BN.
Dosing and administration — MVA-BN is administered via subcutaneous injection with a regular syringe needle; there is no need for the special bifurcated needle used for traditional replicating smallpox vaccines. Two doses (0.5 mL each) are administered four weeks apart.
Tick-borne encephalitis vaccine — Tick-borne encephalitis is a viral infection of the central nervous system that is transmitted by ticks. The disease occurs in Scandinavia, countries of the former Soviet Union, and in western and central Europe and occasionally as far south as Greece or the former Yugoslavia [48]. The disease is primarily transmitted from April through September, when the tick vector is most active. Infection may also occur through the ingestion of raw milk or cheese from cows, sheep, or goats. (See "Arthropod-borne encephalitides", section on 'Tick-borne encephalitis virus'.)
Effective vaccines are available in Europe (FSME-IMMUN/Ticovac and Encepur; including Russia) and Australia [49,50]. In August 2021, the FDA approved tick-borne encephalitis vaccine (Ticovac) for adults and pediatric patients ≥1 year [51]. ACIP guidelines for use of tick-borne encephalitis vaccines by United States travelers have not yet been published.
Indications — Tick-borne encephalitis vaccination is recommended for:
●Expatriates and travelers with prolonged-stays in highly endemic countries, due to the likelihood of occasional travel to forested risk areas or exposure in the outskirts of urban areas
●Travelers with short or prolonged stays that include hiking, camping, or other outdoor activities in forested risk areas with more than minimal risk
●Travelers who consume unpasteurized dairy products from cows, goats, or sheep
Contraindications and precautions — Severe allergic reaction (eg, anaphylaxis) to any component.
Dosing and administration — For patients ≥16 years, the dose is 0.5 mL intramuscularly. For children 1 to 15 years, the dose is 0.25 mL intramuscularly.
The vaccine is administered as three doses (first dose on day 0, second dose 14 days to 3 months after the first dose, third dose 5 to 12 months after the second dose). A booster dose (fourth dose) may be given at least three years after completion of the primary series if ongoing exposure or re-exposure to tick-borne encephalitis virus is expected. Short-stay travelers are protected a week after the second dose (day 14), but should receive the third dose if further exposure is expected [52].
ROUTINE IMMUNIZATIONS — The pretravel visit provides an opportunity to ensure that routine immunizations (including influenza, Tdap [tetanus, diphtheria, and pertussis], MMR [measles, mumps, and rubella], poliovirus, and varicella vaccinations) are current, as discussed in the following sections.
Minimum intervals between doses of vaccines are summarized in the table (table 2). Guidelines for spacing of live and inactivated agents are summarized in the table (table 6).
SARS-CoV-2 vaccine — Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), spreads via direct person-to-person respiratory transmission. Information regarding vaccination for disease prevention is discussed separately. (See "COVID-19: Vaccines".)
Influenza vaccine — Influenza is a viral illness transmitted by respiratory secretions; it is a common vaccine-preventable infection in travelers [4,53,54]. Tropical and subtropical countries have distinct patterns of influenza seasonality, often involving more than one peak season and many have year-round activity [55]. In the northern and southern hemispheres, influenza occurs during the winter months (October through March or April to September, respectively), although summertime outbreaks have occurred on cruise ships [56-60]. (See "Influenza: Epidemiology and pathogenesis".)
Influenza vaccination is appropriate for all travelers to destinations where influenza is being transmitted at that time. Those for whom it is especially important include individuals over 50 years of age traveling to the tropics or to the northern or southern hemisphere during winter months and those traveling on cruise ships or in large groups [4]. Contraindications, precautions, dosing, and administration are discussed in detail separately. (See "Seasonal influenza vaccination in adults" and "Seasonal influenza in children: Prevention with vaccines", section on 'Travelers'.)
Tetanus, diphtheria, and pertussis vaccine — All travelers are at risk for pertussis, a communicable respiratory disease due to infection with Bordetella pertussis. All adults aged 19 to 64 years should receive a single dose of Tdap, even if Td booster has been administered recently. Tdap vaccination is also recommended by the Advisory Committee on Immunization Practices for adults ≥65 who have close contact with infants aged younger than one year (such as grandparents, childcare providers, and health care providers). (See "Pertussis infection in adolescents and adults: Treatment and prevention", section on 'Vaccination'.)
Tetanus is a nervous system disorder characterized by muscle spasms caused by the toxin-producing anaerobe Clostridium tetani; infection typically occurs following traumatic injury. All travelers should have current tetanus immunization (eg, within the last 10 years prior to travel). All adults should receive a single dose of Tdap as a tetanus booster (in place of the tetanus and diphtheria toxoid vaccine). Thereafter, subsequent tetanus boosters should be administered every 10 years with Td (not Tdap). (See "Tetanus-diphtheria toxoid vaccination in adults".)
Measles, mumps, and rubella — All travelers are at risk for measles and mumps infection (regardless of destination), and the pretravel visit is an important opportunity to reduce the likelihood of importation and transmission of measles [61,62]. Evidence of receipt of measles vaccine may be required in certain countries in the setting of outbreaks; entry requirements should be reviewed.
Measles is a highly contagious viral illness spread by respiratory droplets; complications include pneumonia, otitis media, and encephalitis. Several cases of measles acquired from infected patients on aircraft returning from international destinations have been reported [63-65]. Mumps is a contagious viral illness that leads to painful swelling of the salivary glands; complications include orchitis and central nervous system involvement. (See "Measles: Epidemiology and transmission" and "Mumps".)
Children traveling outside the United States should receive MMR vaccination sooner than the standard immunization schedule. Prior to departure, children 12 months of age or older should have received two doses of MMR vaccine separated by at least 28 days, with the first dose administered on or after the first birthday. Children aged 6 to 11 months should receive one dose of MMR before departure. (See "Measles, mumps, and rubella immunization in infants, children, and adolescents", section on 'Measles, mumps, and rubella disease'.)
MMR vaccination for adults is indicated for individuals born in 1957 or later in the United States (born in 1970 or later in Canada; born in 1966 or later in Australia) without evidence of immunity or without evidence of two doses of an adequate live vaccine at any time after age 12 months. Although individuals born before 1957 in the United States are presumed to be immune (exceptions include United States health care workers and women of childbearing age), two doses of MMR vaccine spaced by one month should be strongly considered for unvaccinated individuals without other evidence of immunity who were born before 1957 (in the United States) and are traveling for purposes of health care or humanitarian work potentially entailing close contact with ill individuals. (See "Measles, mumps, and rubella immunization in adults".)
MMR vaccination is contraindicated in pregnant and immunocompromised patients. (See "Travel advice for immunocompromised hosts" and "Measles, mumps, and rubella immunization in adults".)
Further details regarding measles vaccination are discussed separately. (See "Measles, mumps, and rubella immunization in adults".)
Poliovirus vaccine — Poliomyelitis is a viral infection transmitted via the fecal-oral route that can affect the central nervous system, leading to muscle weakness and flaccid paralysis. There are two types of polio vaccine: an oral polio vaccine (OPV) containing live attenuated polioviruses and an inactivated polio vaccine (IPV). In the United States and many regions of the world, only IPV is available given the rare risk of vaccine-associated paralytic poliomyelitis with OPV.
As of 2020, wild-type polio viruses persist in only three endemic countries (Pakistan, Nigeria, and Afghanistan). Several countries in Asia and Africa have circulation of vaccine-derived polio viruses, which may also cause human disease. The CDC recommends that travelers to areas with circulating vaccine-associated polio have completed a primary series; in addition, adults should receive a one-time adult booster. The WHO recommends that residents and long-term visitors (≥4 weeks) to these countries show proof of polio vaccination before exiting; such immunity is defined as receipt of a polio vaccine within 12 months prior to exiting [66]. Information about recent cases can be found on the Global Polio Eradication Initiative website.(See "Global poliomyelitis eradication".)
A number of countries require proof of recent polio vaccination for travelers arriving from countries with circulating wild poliovirus or circulating vaccine-derived poliovirus type 2. All travelers to Saudi Arabia from such countries during the Hajj are required to provide documentation of vaccination given between four weeks and one year prior to arrival. For information on the status of polio eradication efforts and vaccine recommendations, refer to the CDC website.
Poliovirus vaccination is discussed in greater detail separately. (See "Poliovirus vaccination".)
Varicella vaccine — Varicella is a contagious viral infection transmitted by respiratory droplets; complications include pneumonia and encephalitis. It is endemic in most countries. Varicella vaccine is recommended for all nonimmune adults and adolescents born after 1979 in the United States and all nonimmune persons born outside the United States regardless of travel plans. (See "Vaccination for the prevention of chickenpox (primary varicella infection)", section on 'Schedules in the United States'.)
IMMUNOCOMPROMISED PATIENTS — In general, severely immunocompromised patients should not receive live vaccines. Live vaccines include yellow fever vaccine, oral typhoid vaccine, nasal influenza vaccine, oral polio vaccine (OPV), MMR (measles, mumps, and rubella), varicella vaccine, the live Japanese encephalitis (JE) vaccine (IMOJEV), and the oral cholera vaccine (Vaxchora). Inactivated vaccines include meningococcal vaccine, parenteral typhoid vaccine, hepatitis A and B vaccines, rabies vaccine, the inactivated Japanese encephalitis vaccine (IXIARO), inactivated influenza vaccine, inactivated polio vaccine (IPV), Tdap (tetanus, diphtheria, and pertussis) vaccine, and Td (tetanus, diphtheria) vaccine.
Issues related to immunizations in immunocompromised patients are discussed in detail separately as are issues related to immunizations in individuals with HIV infection. (See "Travel advice for immunocompromised hosts" and "Immunizations in patients with primary immunodeficiency" and "Immunizations in persons with HIV".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rabies" and "Society guideline links: Travel medicine".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Vaccines for travel (The Basics)" and "Patient education: Vaccines for adults (The Basics)" and "Patient education: What you should know about vaccines (The Basics)")
●Beyond the Basics topic (see "Patient education: General travel advice (Beyond the Basics)")
SUMMARY
●International travelers are frequently at risk of exposure to infectious pathogens and should seek advice about immunizations and other necessary prophylaxis prior to departure. The immunizations should be tailored to individual itinerary details. Disease distribution maps and vaccine recommendations from the United States Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) can be found on the CDC website and the WHO website. (See 'Introduction' above.)
●Available travel immunizations in the United States include yellow fever (YF) vaccine, meningococcal vaccine, typhoid vaccine, hepatitis A vaccine, hepatitis B vaccine, polio, rabies vaccine, cholera vaccine, and Japanese encephalitis vaccine. The indications, contraindications, precautions, dosing, and administration of these vaccines are discussed above. (See 'Travel immunizations' above.)
●The pretravel visit provides an opportunity to ensure that routine immunizations (including influenza, Tdap [tetanus, diphtheria, and pertussis], MMR [measles, mumps, and rubella], poliovirus, and varicella vaccinations) are current. Travelers to resource-limited settings are at increased risk for infection due to these pathogens and, in some cases, additional doses are indicated. (See 'Routine immunizations' above.)
●Minimum intervals between doses of vaccines are summarized in the table (table 2). Guidelines for spacing of live and inactivated agents are summarized in the table (table 6).
●In general, severely immunocompromised patients should not receive live vaccines. Live vaccines include YF vaccine, oral typhoid vaccine, nasal influenza vaccine, oral polio vaccine, MMR, and varicella vaccine. Inactivated vaccines include meningococcal vaccine, parenteral typhoid vaccine, hepatitis A and B vaccines, rabies vaccine, Japanese encephalitis vaccine, inactivated influenza vaccine, inactivated polio vaccine, Tdap, and Td. Issues related to travel immunizations in immunocompromised hosts are discussed in detail separately, as are issues related to immunizations in individuals with HIV infection. (See "Travel advice for immunocompromised hosts" and "Immunizations in persons with HIV".)
