Vaccines for International Travel

THEMATIC REVIEW ON VACCINES

Vaccines for International Travel David O. Freedman, MD, and Lin H. Chen, MD Abstract The pretravel management of the international traveler should be based on risk management principles. Prevention strategies and medical interventions should be based on the itinerary, preexisting health factors, and behaviors that are unique to the traveler. A structured approach to the patient interaction provides a general framework for an efficient consultation. Vaccine-preventable diseases play an important role in travel-related illnesses, and their impact is not restricted to exotic diseases in developing countries. Therefore, an immunization encounter before travel is an ideal time to update all age-appropriate immunizations as well as providing protection against diseases that pose additional risk to travelers that may be delineated by their destinations or activities. This review focuses on indications for each travel-related vaccine together with a structured synthesis and graphics that show the geographic distribution of major travel-related diseases and highlight particularly high-risk destinations and behaviors. Dosing, route of administration, need for boosters, and possible accelerated regimens for vaccines administered prior to travel are presented. Different underlying illnesses and medications produce different levels of immunocompromise, and there is much unknown in this discipline. Recommendations regarding vaccination of immunocompromised travelers have less of an evidence base than for other categories of travelers. The review presents a structured synthesis of issues pertinent to considerations for 5 special populations of traveler: child traveler, pregnant traveler, severely immunocompromised traveler, HIV-infected traveler, and traveler with other chronic underlying disease including asplenia, diabetes, and chronic liver disease. ª 2019 Mayo Foundation for Medical Education and Research From the Division of Infectious Diseases, William C. Gorgas Center for Geographic Medicine, University of Alabama at Birmingham (D.O.F.); Division of Infectious Diseases and Travel Medicine, Mount Auburn Hospital, Cambridge, MA (L.H.C.); and Department of Medicine, Harvard Medical School, Boston, MA (L.H.C.).

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he pretravel management of the international traveler should be based on risk management principles. Prevention approaches and medical interventions should be individualized according to both the itinerary and factors such as behaviors that are dependent on the traveler. A structured approach to the patient interaction is the most efficient way to cover the necessary educational and preventive interventions.1 Vaccine-preventable disease (VPD) in travelers is not restricted to exotic diseases in developing countries. For example, nonimmune adult US travelers are at significant risk of measles in wealthy industrialized countries including Western European countries and Mexico.2,3 In addition, imported measles and mumps have resulted in travel-related domestic outbreaks in the United States.4 Figure 1 illustrates the large numbers of measles cases in developed

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countries in the 6 months ending August 2018 alone. Vaccine hesitancy is increasing in these countries as it is in the United States.5 The following sections, which focus on the main indications for each vaccine as used in the pretravel consultation, should be used in conjunction with the information in Figure 26-12 and Table 1,13-47 which show the geographic distribution of major travelrelated diseases and highlight particularly high-risk destinations and behaviors. Table 2 includes dosing, route of administration, need for boosters, and possible accelerated regimens for vaccines administered before travel.48-77 The Advisory Committee on Immunizations Practices provides comprehensive background and recommendations for administration of each individual vaccine48; unreferenced statements in this review can be assumed to reflect information found in these documents.

Mayo Clin Proc. n November 2019;94(11):2314-2339 n https://doi.org/10.1016/j.mayocp.2019.02.025 www.mayoclinicproceedings.org n ª 2019 Mayo Foundation for Medical Education and Research

VACCINES FOR INTERNATIONAL TRAVEL

≥1000 (23 countries or 12%) 100-999 (39 countries or 20%) 10-99 (37 countries or 19%) 1-9 (34 countries or 17%) 0 (52 countries or 27%) No data reported 0

Not available Map probuction: Data source:

World Health Organization, WHO, 2018. All rights reserved IVB Database

875 1750

3500 Kilometers

Disclaimer: The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement.

FIGURE 1. Number of cases of measles reported to the World Health Organization for the 6 months ending August 2018; 23 countries including many in Europe reported more than 1000 cases during this period.

EPIDEMIOLOGY OF VPDS RELATED TO TRAVEL Influenza is the most common VPD of travelers, especially for those on cruise ships and those going to mass-gathering events such as the Hajj pilgrimage; risk is present at all destinations during transmission season at the destination.20-23,78,79 The rate of serologically confirmed influenza cases has been estimated at 8.9 per 100 person-months of travel.20,79 For other VPDs, the risk for nonimmune travelers to developing countries is most significant for symptomatic hepatitis A (HA), at an estimated attack rate of 3.5 cases per 100,000 travelers to high or intermediate endemic regions.16,78 The risk of symptomatic hepatitis B (HB) is most significant for long-stay travelers and expatriates, at 25 to 420 cases per 100,000 travelers.18 Enteric fever (typhoid and paratyphoid) has a risk of 3 cases per 100,000 travelers per month on the Indian subcontinent and is 10 times lower in Africa and parts of Latin America.78 Among Swedish residents who traveled abroad, measles and pertussis incidence are estimated at about 3 cases per 100,000 travelers per Mayo Clin Proc. n November 2019;94(11):2314-2339 www.mayoclinicproceedings.org

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month each. Risk of yellow fever (YF) may be high in an area with current epidemic transmission; at least 10 unvaccinated foreign travelers to Brazil acquired YF during a 2018 outbreak in Brazil. At the same time, the overall risk varies greatly between destinations encompassed by the endemic area map. The risk of meningococcal meningitis, rabies, cholera, polio, varicella, and Japanese encephalitis in travelers is not well characterized but is thought to be small even for travel to highly endemic areas.78 Travelers visiting friends and relatives in their country of origin are a group of travelers with especially high risk, particularly from malaria and typhoid; these travelers require special attention to illness prevention and education. The worldwide epidemiology of travel-related diseases is constantly changing. Online and print resources (Table 3) should be consulted frequently to keep current. Finally, additional considerations are required for special populations such as child travelers, pregnant travelers, immunocompromised travelers, HIVinfected travelers, and travelers with other underlying health conditions including

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The risk of infection is based on the estimated prevalence rate of antibody to hepatitis A virus (anti-HAV) -a marker of previous HAV infection-among population. This marker is based on limited data and may not reflect current prevalence.

Countries or areas with moderate to high risk

0

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement.

A Hepatitis A

1’250 2’500

Data Source: World Health Organization. Jacobsen KH, Wiersma ST. Hepatitis A virus seroprevalence by age and world region, 1990 and 2005. Vaccine 2010 Sep;28(41):6653-7 Map Production: Public Health Information and Geographic Information Systems (GIS) World Health Organization

5’000 Kilometers

© WHO 2012. All rights reserved.

Incidence rate (per 100,000 py) <20 20-49.9 50-99.9 100-199.9 200-499.9 500+

B Typhoid fever FIGURE 2. Distribution of diseases preventable with travel vaccines. A, Hepatitis A. B, Typhoid fever. C, Japanese encephalitis. D, Tickborne encephalitis. E, Yellow fever, Africa. F, Yellow fever, Americas. G, Rabies. H, African meningitis belt. From the World Health Organization6 (A); Am J Trop Med Hyg7 (B); the Centers for Disease Control and Prevention8 (C); the European Centre for Disease Prevention and Control9 (D); the Centers for Disease Control and Prevention10 (E and F); the World Health Organization11 (G); and the Centers for Disease Control and Prevention12 (H).

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VACCINES FOR INTERNATIONAL TRAVEL

RUSSIA

NORTH KOREA SOUTH KOREA

JAPAN

PAKISTAN CHINA NEPAL

BHUTAN

INDIA BANGLADESH

ARABIAN SEA

PHILIPPINE SEA

BURMA LAOS

BAY OF BENGAL

THAILAND CAMBODIA VIETNAM

SRI LANKA

INDIAN OCEAN

PACIFIC OCEAN

TAIWAN

SOUTH CHINA SEA

PHILIPPINES

BRUNEI MALAYSIA SINGAPORE

INDONESIA

PAPUA NEW GUINEA

Japanese encephalitis risk TIMOR-LESTE

Known risk areas No known risk areas

CORAL SEA AUSTRALIA

C Japanese encephalitis TBE incidence 0 >0-0.5 >0.5-4.0 >4.0-8.5 >8.5-18.5 >18.5 Data not available at NUTS2 or NUTS3 Data not available for the report No surveillance Not included

Non visible countries Malta Lichtenstein 0

250

500

1,000 Kilometers © ECDC 2012 / SRS-EM / EVD © EuroGeographics for the administrative boundaries

D Tickborne encephalitis FIGURE 2. Continued Mayo Clin Proc. n November 2019;94(11):2314-2339 www.mayoclinicproceedings.org

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WESTERN SAHARA

SAUDI ARABIA

MAURITANIA Nouakchott Aleg

CAPE VERDE Praia

Dakar

MALI

Tidjikdja

Timbuktu

Nema

SENEGAL Banjul

GAMBIA

EGYPT

LIBYA

ALGERIA

Arlit

Kidal

Agadez

Gao

Bamako

Bissau

BURKINA Niamey FASO

Khartoum

CHAD

Mao

SÃO TOMÉ AND PRINCIPE

DJIBOUTI Djibouti

Addis Ababa

SOUTH SUDAN

SOMALIA

ETHIOPIA

Juba

Yaoundé

Mogadishu

EQ GUINEA São Tomé

YEMEN

Asmara

El Obeid

NIGERIA CÔTE BENIN Conakry Freetown D’IVOIRE Abuja TOGO Yamoussoukro SIERRA LEONE Cotonou CEN AFR REP GHANA Monrovia Lome CAMEROON Bangui LIBERIA Accra Malabo

ERITREA

El Fasher

Abeche Ndjamena

Ouagadougou

GUINEA-BISSAU GUINEA

OMAN

SUDAN

NIGER

REP GABON OF CONGO Libreville

UGANDA

DEM REP OF CONGO

Brazzaville

KENYA Kampala Nairobi RWANDA Kigali Bujumbura

BURUNDI Kinshasa

TANZANIA Dar es Salaam

Luanda

MALAWI

ANGOLA

Yellow fever vaccine

ZAMBIA Lusaka

Vaccination recommended Vaccination generally not recommended2 Vaccination not recommended

COMOROS

MOZAMBIQUE

ZIMBABWE NAMIBIA

MADAGASCAR

BOTSWANA

E Yellow fever, Africa JAMAICA

GUADELOUPE MARTINIQUE BARBADOS

Kingston

CURACAO NICARAGUA Santa Marta San José

Port-of-Spain

Cartagena Panama City

PANAMA

Caracas

TRINIDAD

Maturin

VENEZUELA

Bogotá Cali

Georgetown

GUYANA Paramaribo SURINAME Cayenne FRENCH GUIANA

Medellin

COLOMBIA

Quito

ECUADOR Puyo

Riobamba

Manaus

Iquitos

Fortaleza

PERU Chachapoyas

BRAZIL

Recife

Huanuco Aracaju Lima

Salvador Cusco

BOLIVIA Brasilia La Paz Sucre

Santa Cruz Bela Horizonte

Tarija

PARAGUAY

CHILE

Asunción

Salta

Rio de Janeiro São Paulo

Resistencia Porto Alegre

Santiaco

ARGENTINA URUGUAY Buenos Aires

Montevideo

Yellow fever vaccine Vaccination recommended Vaccination recommended since 2017 due to yellow fever outbreak2 Vaccination generally not recommended3 FALKLAND ISLANDS

Vaccination not recommended

F Yellow fever, Americas FIGURE 2. Continued

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VACCINES FOR INTERNATIONAL TRAVEL

In countries of category 2, 3 and 4, contacts with suspect rabid animals, including bats should be followed by rabies post-exposure prophylaxis

Level 1, no risk: No risk, no pre-exposure prophylaxis Level 2, low risk: Pre-exposure prophylaxis recommended for people likely to have regular, direct contact with bats and wild carnivores Level 3, moderate risk: Pre-exposure prophylaxis recommended for travellers to remote areas and people likely to have contact with bats and other wildlife Level 4, high risk: Pre-exposure prophylaxis recommended for travellers and people with occupational risks likely to have contact with rabid domestic animals, particularly dogs, bats and wild carnivores

No risk Low risk Moderate risk

No data

High risk

Not applicable

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. © WHO 2018. All rights reserved.

Data Source: World Health Organization Map Production: Control of Neglected Tropical Diseases (NTD) World Health Organization

G Rabies

MAURITANIA

MALI

RED SEA

NIGER CHAD

SENEGAL GAMBIA GUINEA GUINEABISSAU

BURKINA FASO BENIN TOGO CÔTE D'IVOIRE GHANA

NIGERIA

CENTRAL AFRICAN REPUBLIC

ERITREA

SUDAN

SOUTH SUDAN

ETHIOPIA

CAMEROON

ATLANTIC OCEAN

UGANDA KENYA DEMOCRATIC REPUBLIC OF CONGO

Meningitis risk Meningitis Belt - areas at high epidemic risk Countries at risk for meningitis epidemics

H Meningitis Belt of Africa FIGURE 2. Continued Mayo Clin Proc. n November 2019;94(11):2314-2339 www.mayoclinicproceedings.org

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asplenia, diabetes, and chronic liver disease (Table 480-93). RISK ASSESSMENT FOR VACCINE SELECTION The choice of vaccines for an individual traveler is based on risk of exposure to VPDs on the chosen itinerary; the severity of disease, if acquired; and any risks presented by the vaccine itself. Risk of infection often varies within a risk country so that an exact itinerary needs to be ascertained during the pretravel consultation. Detailed references may need to be consulted (Table 3) for many itineraries. Specific risk and risk-taking behaviors related to travel style, type of accommodation, food, use of repellents, sexual behavior, and outdoor activities also affect risk of infection. Travel medicine physicians as well as travelers differ in their perception and tolerance of risk. Requests for immunization against diseases that are actually of negligible risk to the traveler but have the potential for poor outcome if acquired are often difficult for the physician to refuse because sporadic travel-related cases do occur each year. ADMINISTRATION OF TRAVEL VACCINES General best practices for adult vaccines are found elsewhere in this Mayo Clinic Proceedings vaccine thematic series.94 Several best practices are specific to travel vaccines. Testing may be useful to assess immunity to HA or HB virus in persons from countries with high endemicity or in persons with a history of jaundice or to assess immunity to measles, mumps, and rubella (MMR) in someone lacking documentation.95 This scenario must be weighed against cost factors and possible loss to follow-up in those busy preparing for travel. Different brands of HA, HB (except Heplisav-B; Dynavax Technologies Corporation), rabies, and meningococcal ACYW-135 vaccine are interchangeable for subsequent doses if necessary. Acyclovir and related drugs and influenza antivirals (neuraminidase and polymerase inhibitors) preclude concomitant use of live attenuated varicella and zoster vaccines 2320

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and influenza vaccines, respectively, but not YF vaccine. Antibacterial drugs should not be given within 3 days of a dose of live oral typhoid or 14 days prior to oral cholera vaccine. Anaphylactic egg allergy precludes administration of YF and MMR vaccines, which contain more egg protein than influenza vaccines. No current vaccine contains penicillin. Women who are breastfeeding newborns and infants should avoid YF vaccination but not other travel vaccines. Translations of VPD terms in multiple languages are available when travelers provide foreign-language vaccine records.96 An interruption in a vaccination schedule generally does not require restarting the entire vaccine series, nor does it require the addition of extra doses.88 The series should be continued with the next dose in the series, and any subsequent doses should be administered at the same interval as if the series had not been interrupted. Rabies and oral typhoid vaccines present exceptions to this rule but still have some overall flexibility. All currently used immunizations may be given at the same time and in any combination. If 2 live viral antigens are not administered on the same day, they must be spaced by a month. Live oral vaccines (typhoid, cholera, polio) can be administered at any interval with respect to any live virus vaccine. Baseline purified protein derivative skin tests or interferon-g release assays, often done in the pretravel setting, can be given on the day that live virus vaccines are administered or else must be done more than 4 weeks later. ROUTINE VACCINES OFTEN ADMINISTERED IN THE TRAVEL CLINIC This section considers routine vaccines that are normally readministered at regular intervals or vaccine series that need to be finished in a healthy adult regardless of the current plans for international travel and when there are no specific medical or behavioral risk factors. The text of this and the next 2 sections provides general information on vaccine indications and logistic issues that arise in the clinic and

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VACCINES FOR INTERNATIONAL TRAVEL

TABLE 1. Highlights of Vaccines for International Travel Noting Trip Characteristics Putting Travelers at Particularly High Risk and Examples of Recent Outbreaks With Implications for Travelers Trip characteristics suggesting particularly high risk

Recent outbreaks or new findings with impact on travelers

Cholera

Destination with poor hygiene and sanitation where cholera is endemic; humanitarian aid work; some VFR travelers

Haiti Somalia Yemen

14

Hepatitis A

Destinations with poor hygiene and sanitation practices; adventurous eating habits; men who have sex with men

Widespread

15-17

Hepatitis B

Adventure travel; medical tourism; health condition that may require medical intervention; injections or infusions; possibility of sexual contact at destination

None

18,19

Influenza (þ avian influenza)

Mass gatherings; cruise ships; exposure to live poultry

Saudi Arabia China Vietnam Indonesia

20-23

Japanese encephalitis

Adventure travel in agricultural areas; open-air accommodations; rural home stays; some VFR travelers

Bali China Thailand

24-26

Measles, mumps, rubella

Mass gatherings; travel to one of many areas with current outbreaks; travel to areas with antivaccine community

Venezuela, Brazil, Democratic Republic of the Congo Europe (England, France, Greece, Italy, Romania, Serbia, Ukraine) Indonesia Philippines

2-4,27

Meningococcal, quadrivalent ACYW-135

Mass gatherings; sub-Saharan Africa

Saudi Arabia

28,29

Poliovirus

Endemic destinations with low vaccine coverage or disruption in health care infrastructure; humanitarian aid work

Afghanistan, Nigeria, Pakistan Papua New Guinea Somalia, Democratic Republic of Congo

30

Rabies

Remote destinations in areas with high incidence of canine rabies; behaviors with close contact with canines, wildlife, and bats

Indonesia (Bali) Malaysia (Sarawak) India Thailand

31-35

Tetanus diphtheria pertussis (Tdap) or tetanus diphtheria (Td)

Tetanus: participating in injury-prone activities such as cycling, riding motorcycle, construction Diphtheria: humanitarian aid, destinations with low vaccine coverage

Diphtheria: Haiti, Venezuela, Bangladesh, Thailand, South Pacific, Vanuatu Pertussis: exposure occurs widely

36-38

Tick-borne encephalitis

Hiking; camping; consuming unpasteurized dairy products

Austria, Czech Republic, Finland, Germany, Latvia, Norway, Sweden, Switzerland.

39-43

Vaccine

References13,48

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TABLE 1. Continued Trip characteristics suggesting particularly high risk

Recent outbreaks or new findings with impact on travelers

References13,48

Typhoid

Destinations with poor hygiene and sanitation practices

Pakistan

44

Yellow fever

Destinations with known outbreaks or irregular requirements

Brazil: expanded risk areas to include Rio de Janeiro, Salvador, and Sao Paulo Angola, DRC, Nigeria

45-47

Vaccine

DRC ¼ Democratic Republic of the Congo; VFR ¼ visiting friends or relatives.

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complement the information in Table 2. Full details of routine adult immunization are found elsewhere in this Mayo Clinic Proceedings vaccine thematic series.94 Verification and update of these routine vaccines, regardless of itinerary, is part of the pretravel consultation. However, for many VPDs, the risk of disease is also increased in developing countries.

Varicella Varicella, which is highly contagious, is primarily a disease of adolescents and young adults in tropical, nonindustrialized countries.97 Two doses of varicella vaccine, administered at least 4 weeks apart, should be considered for adult travelers without evidence of varicella immunity. Adults born before 1980 in the United States are considered immune.

Tetanus-DiphtheriaeAcellular Pertussis If no adult doses of tetanus-diphtheriaeacellular pertussis have ever been given, a dose is indicated regardless of the time elapsed since the last tetanus-diphtheria vaccination, but travelers to remote areas where tetanus toxoid (indicated in cases of dirty trauma) will be inaccessible should get boosters at 5-year intervals. Trauma during travel is common, and unsafe needles or uncertain vaccine quality at the destination is another reason for assuring immunity pretravel. Although immunity to tetanus after a primary childhood vaccination series tends to be very long-lived, the short-lived immunity to diphtheria and pertussis conferred by vaccination mandates strict validation of vaccine history and booster doses according to schedule. Evidence indicates that pertussis immunity, at least in children and adolescents, is significantly shorter than the standard 10-year interval, but no special accelerated dosing guidelines for travelers at very high risk of pertussis exposure exist.72

Zoster Data are lacking to determine whether travel poses additional risk for shingles due to reactivation of varicella zoster virus. The newly approved recombinant zoster vaccine should be given to all adults aged 50 years and older regardless of travel plans and regardless of having received a previous dose of the live zoster vaccine.98

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Pneumococcal Travelers are at increased risk of all types of respiratory infections. Healthy travelers who are 65 years of age or older should be current with pneumococcal vaccination with sequential doses of PCV13 and PPSV23. Beginning in 2019, ACIP no longer recommends routine (now optional) PCV13 for healthy nontraveler adults 65 years and older. Travelers may face PCV13 strains at their destinations making travel an indication for PCV13 in this age cohort. A minimum interval of 8 weeks (as used for patients with underlying medical conditions) between a dose of Pneumovax 23 (Merck & Co, Inc) (if indicated) and a

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Vaccine Cholera

Vaccine type (specific type)

Adult dose

Pediatric dose

Route

Standard schedule of immunization

Accelerated schedule for series

1 Sachet

NA

Oral

1 Dose

Not live (inactivated virus)

1 mL

Age 12 mo: 0.5 mL

IM

2 Doses: days 0, 612 mo

Traveling children aged 6 mo should receive 1 dose pretravel and receive 2 doses of hepatitis A at age 12 mo Available in combined hepatitis A and B formulation: days 0, 7, 21 and 12 mo

Hepatitis B

Not live (recombinant hepatitis B surface antigen)

1 mL

From birth: 0.5 mL

IM

3 Doses: day 0, 1 mo, and 6 mo

Hepatitis B-CpG

Not live (recombinant hepatitis B with adjuvant)

0.5 mL

NA

IM

Combined hepatitis A and B

Not live (inactivated virus and recombinant viral antigen)

1 mL

NA in US (pediatric formulation licensed in Canada, Europe, and other countries)

Not live (inactivated virus, trivalent or quadrivalent)

0.5 mL

Age 6 mo but dose varies per product. Age 6-35 mo: 0.25 mL or 0.5 mL Age 36 mo: 0.5 mL

Not live (inactivated high-dose trivalent)

0.5 mL (age 65 y)

Not live (inactivated virus, adjuvanted trivalent)

0.5 mL (age 65 y)

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Live

Hepatitis A

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Influenza

Live (attenuated virus, quadrivalent)

NA

Estimated duration of protection

Reference

3-6 mo

49

>25 y based on seropositivity; >40 y based on antibody modeling

50-54

Various options including: (1) days 0, 7, 21 and 12 mo; (2) days 0, 1, 2 and 12 mo

>30 y

55, 56

2 Doses: day 0, 1 mo

NA

No data, but appears noninferior to standard hepatitis B vaccine

57, 58

IM

3 Doses: day 0, 1 mo, and 6 mo

4 Doses: days 0, 7, 21 and 12 mo

>20 y based on seropositivity and anamnestic response; >40 y based on mathematical modeling

52

IM

1 Dose (children <8 y require 2 doses administered 4 wk apart with a first receipt of influenza vaccination)

NA

1y

59

NA

IM

1 Dose

NA

1y

NA

IM

1 Dose

NA

1y

Intranasal spray

1 Dose (children <8 y require 2

NA

1y

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TABLE 2. Alphabetic VPD List With Dosing, Route, Schedule (Including Accelerated for Imminent Departures), and Duration of Protectiona,b

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TABLE 2. Continued Vaccine

Vaccine type (specific type)

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Accelerated schedule for series

Estimated duration of protection

1 Dose

NA

1y

IM

1 Dose

NA

1y

Age 2 mo through 2 y: 0.25 mL Age 3 y: 0.5 mL

IM

2 Doses: days 0, and between 7-28

0.5 mL

Age 12 mo: 0.5 mL

SC

2 Doses: day 0, 4 wk

Not live (bacterial polysaccharide, conjugated)

0.5 mL

Age 2 mo for MenACYW-CRM, 9 mo for MenACYW-D: 0.5 mL

IM

Not live (inactivated virus)

0.5 mL

Age 2 mo: 0.5 mL

Not live (inactivated virus, human diploid cell)

1 mL

From birth: 1 mL

Adult dose

Pediatric dose

0.2 mL (0.1 mL in each nostril for age 2-49 y)

Age 2-49 y: 0.2 mL (0.1 mL in each nostril)

Not live (recombinant, trivalent)

0.5 mL (age 18 y)

NA

IM

Not live (cell cultureebased inactivated virus, trivalent)

0.5 mL

Age 4 y: 0.5 mL

Japanese encephalitis, tissue culture ederived

Not live (Vero cell ederived inactivated virus)

0.5 mL

Measles, mumps. rubella

Live (attenuated virus)

Meningococcal, quadrivalent ACYW-135

n

Rabies

Standard schedule of immunization

Reference

doses administered 4 wk apart with a first receipt of influenza vaccination)

1-2 y (booster with third dose leads to seropositivity for 6 y)

60-62

Traveling children aged 6 mo who are not yet vaccinated should receive 1 dose pretravel and receive 2 doses at age 12 mo

Lifelong after 2 doses (third dose may be recommended for contacts during mumps outbreaks)

63, 64

2 Doses in adolescents: age 11-12 y, then age 16-18 y

NA

5y

65, 66

SC

1 Dose in those with primary childhood series

NA

Lifelong, after primary series plus an adult (age 18 y) booster

48

IM

3 Doses preexposure: days 0, 7 and 21 or 28

Abbreviated course days 0, 7 dosing proposed by WHO SAGE, under evaluation by ACIP

“Boostable” lifelong; 2 additional doses are required on days 0 and 3 after rabies exposure

62,67-71

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Poliovirus

Route

Vaccine

Vaccine type (specific type)

Standard schedule of immunization

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Pediatric dose

Route

Not live (inactivated virus, purified chick embryo)

1 mL

From birth: 1 mL

IM

3 Doses preexposure: days 0, 7 and 21 or 28

Abbreviated course days 0, 7 dosing proposed by WHO SAGE, under evaluation by ACIP

“Boostable” lifelong; 2 additional doses are required on days 0 and 3 after rabies exposure

62,67-71

Tetanus, diphtheria, pertussis (Tdap) or tetanus, diphtheria (Td)

Not live (toxoid, protein antigen)

0.5 mL

Age 2 mo: 0.5 mL

IM

1 Dose in those with primary childhood series; boost with Tdap if no previous dose of Tdap

NA

10 y

72

Tick-borne encephalitis

Not live (inactivated virus)

0.5 mL

Age 3-16 y: 0.25 mL dose 1 followed by 0.5 mL

IM

3 Doses: day 0, 1-3 mo, and 5-12 mo

3 Doses: days 0, 7, 21

3y

73

Not live (bacterial cell wall polysaccharide)

0.5 mL

Age 2 y: 0.5 mL

IM

1 Dose

NA

2y

74

Live (attenuated bacteria)

4 Capsules

Age 6 y: 4 capsules

Oral

4-Capsule series, 1 every other day

NA

5y

Live (attenuated virus)

0.5 mL

Age 9 mo: 0.5 mL

SC

1 Dose

NA

Lifelong

Typhoid

Yellow fever

Accelerated schedule for series

Estimated duration of protection

Adult dose

Reference

75-77

ACIP ¼ Advisory Committee on Immunization Practices; IM ¼ intramuscular; NA ¼ not applicable; SC ¼ subcutaneous; US ¼ United States; VPD ¼ vaccine-preventable disease; WHO SAGE ¼ World Health Organization Strategic Advisory Group of Experts. b See respective ACIP recommendations48; only the most recent relevant ACIP publications are listed in the References column. a

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TABLE 2. Continued

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TABLE 3. In-depth Information Resources for Travel Vaccines Authoritative websites updated constantly with epidemiological and outbreak information Centers for Disease Control and Prevention (CDC) Travelers Health13 https://wwwnc.cdc.gov/travel World Health Organization (WHO) International Travel and Health https://www.who.int/ith/en/ Public Health Agency of Canada. Committee to Advise on Tropical Medicine and Travel (CATMAT) https://www.canada.ca/en/public-health/services/catmat.html WHO Disease Outbreak News https://www.who.int/csr/don/en/ WHO Weekly Epidemiological Record https://www.who.int/wer/en CDC Morbidity and Mortality Weekly Report https://www.cdc.gov/mmwr/index.html In-depth references on specialized topics Centers for Disease Control and Prevention. Health Information for International Travel 2020 (the “CDC Yellow Book”). New York, NY: Oxford University Press; 2020. Updated in even-numbered years. Full text and hard copy order information available at https://wwwnc.cdc.gov/travel/page/ yellowbook-home World Health Organization. International Travel and Health (WHO “Green” Book). Full text online at https://www.who.int/ith/en/ Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases (the “CDC Pink Book”). 13th ed. Washington, DC: Public Health Foundation; 2015. https://www.cdc.gov/vaccines/pubs/pinkbook/index.html Keystone JS, Kozarsky PE, Connor BA, Nothdurft HD, Mendelson M, Leder K, eds. Travel Medicine. 4th ed. Philadelphia, PA: Saunders; 2018. (ISBN: 9780323546966) Plotkin SA, Orenstein WA, Offit PA, Edwards KM. Plotkin’s Vaccines. 7th ed. Philadelphia, PA: Elsevier; 2017. (ISBN: 9780323357616) Centers for Disease Control and Prevention. ACIP vaccine recommendations and guidelines.48 https://www.cdc.gov/vaccines/hcp/acip-recs/index. html Immunization Action Coalition. Food and Drug Administration: package inserts & FDA product approvals. http://www.immunize.org/fda/ World Health Organization. Vaccine Position Papers. https://www.who.int/immunization/documents/positionpapers/en/

previously given dose of Prevnar 13 (Pfizer Inc) may be used to ensure optimal immunity of healthy travelers 65 years of age and older needing maximal protection prior to the trip.80 No data support an advantage of the current 1-year over an 8-week PCV13 to PPSV23 interval in healthy individuals; the 1-year interval was introduced solely for a number of logistic considerations.88 Human Papillomavirus Substantial evidence of increased rates of sexual activity, often unplanned, during travel exists. No specific indication for travelers has been studied or recommended, but all travelers in the indicated age groups (now includes optional vaccinaition for males and females age 27-45) for human papillomavirus vaccination should be fully immunized according to standard schedules.

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ROUTINE ADULT VACCINES WITH ADDITIONAL TRAVEL INDICATIONS Measles-Mumps-Rubella Imported measles and mumps have caused travel-related outbreaks in the United States, and nonimmune adult US travelers are at significant risk, including in Western Europe and Mexico.3,4 Persons (except traveling health care workers) born in the United States before 1957 or born at any time in the developing world are considered immune to measles; other adult travelers should have received a lifetime total of at least 2 doses of live measlesecontaining vaccine during their life, unless measles immunity can be documented (definitive laboratory evidence of acute infection or current antibody titers). Two doses of MMR should be considered for health care or humanitarian workers without other evidence

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Consideration of contraindications/ precautions for special populations

Additives/residuals/cell lines highlighting substances with potential sensitivity concernsc

Special indication beyond general ACIP recommendations

Attention to dosing recommendations for specific populations

None

Not applicable

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Cholera

C: no data for <18 y P: vaccine strain may be shed in stool for 7 d, with a potential to transmit the vaccine strain to infant during vaginal delivery I: no data for immunocompromised individuals O: no contraindication for asplenia, despite this being a live vaccine

Hydrolyzed casein, dried lactose

Hepatitis A

P: no contraindication; may be used based on risk vs benefit

Aluminum, formalin, MRC-5 cells, nonviral proteins, neomycin sulfate, bovine albumin

I: specifically recommended especially with transplant H: specifically recommended O: specifically recommended for liver disease, diabetes mellitus

C: different pediatric dose (vs adult dose); administer noncountable dose at age 6-11 mo if travelling I: 1 dose provides suboptimal serologic response; administer 2 doses pretravel, consider second dose 1 mo after first dose for imminent travel or supplemental immunogloblulin O: chronic liver disease dose as per I

Hepatitis B

P: no contraindication; may be used if indicated

Yeast protein, Saccharomyces cerevisiae cell line

I: specifically recommended especially with transplant H: specifically recommended O: specifically recommended for liver disease, diabetes mellitus, renal failure

C: different pediatric dose (vs adult dose) O: use double-dose formulation for dialysis patients

Influenza

P: live-attenuated vaccine contraindicated; nonlive vaccines are recommended I: live-attenuated vaccine contraindicated; nonlive vaccines are recommended O: no contraindication for asplenia

For inactivated quadrivalent or trivalent: b-propiolactone or formaldehyde in different formulations, thimerosal in multidose vials Check package insert because different cell lines used (embryonated chicken eggs, Madin-Darby Canine Kidney cells, Spodoptera frugiperda): þ/baculovirus and insect cell proteins and DNA, ovalbumin, neomycin, polymyxin B, non-HA protein, MDCK cell protein/

P: specifically recommended I: specifically recommended H: specifically recommended O: specifically recommended for all those with underlying chronic diseases

C: children aged 6 mo through 8 y who are receiving their initial influenza vaccination should receive 2 doses >4 wk apart

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TABLE 4. Considerations for 5 Special Populationsa,b

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TABLE 4. Continued

Vaccine

Consideration of contraindications/ precautions for special populations

Additives/residuals/cell lines highlighting substances with potential sensitivity concernsc

Special indication beyond general ACIP recommendations

Attention to dosing recommendations for specific populations

DNA, polysorbate 80, gentamicin sulfate

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Aluminum, formaldehyde, bovine serum albumin, Vero cells, host cell DNA, host cell proteins

None

C: different pediatric dose for children <3 y

Measles, mumps, rubella

P: contraindicated I: contraindicated H: contraindicated for CD4 cells <200 O: no contraindication for asplenia, despite this being a live vaccine

Hydrolyzed gelatin, chick embryo cell culture, WI-38 cells, recombinant human albumin, neomycin, bovine serum albumin

C: specifically recommended for traveling children 6 mo who are not yet vaccinated

C: traveling children 6 mo should receive 1 dose pretravel, and receive 2 doses at 12 mo

Meningococcal, quadrivalent ACYW-135, conjugated

P: no contraindication; may be used if indicated

Diphtheria toxoid protein, formaldehyde

C: specifically recommended for age 223 mo if at increased risk (complement deficiency, asplenia, outbreak setting, travel) I: specifically recommended H: specifically recommended O: specifically recommended for asplenia or complement deficiency

C: if at increased risk, administer either 4-dose series starting at 8 wk or 2dose series depending on product and age at initial dose H: administer 2 doses 8-12 wk apart O: administer to persons with asplenia or complement deficiency every 5 y

Pneumococcal, 13valent conjugated (PCV13) and/or 23-valent polysaccharide (PPSV23)

P: no data

PCV13: CRM197 carrier protein, aluminum phosphate adjuvant PPSV23: phenol

I: Both PCV13 and PPSV23 are recommended for immunocompromised individuals H: specifically recommended O: specifically recommended for chronic liver disease, chronic lung disease, diabetes mellitus, cerebrospinal fluid leak, cochlear implant, sickle cell disease, asplenia, cigarette smoking

I: PCV13 followed by PPSV23 with an interval of 8 wk; additional dose of PPSV23 recommended 5 y after initial dose for immunocompromised individuals O: PPSV23 only for chronic liver disease, chronic lung disease, diabetes mellitus, cerebrospinal fluid leak, cochlear implant, sickle cell disease, asplenia, cigarette smoking

Poliovirus, inactivated

P: no contraindication; may be used if indicated

2-Phenoxyethanol, formaldehyde, neomycin, streptomycin, polymyxin B, calf serum protein, Vero cells

None

None

Rabies

P: no contraindication; may be used if indicated

Human diploid cell vaccine: MRC-5 cells, human serum albumin, neomycin chicken fibroblasts,

None

I: additional PEP dose recommended

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P: no data

n

Japanese encephalitis, tissue cultureederived

Additives/residuals/cell lines highlighting substances with potential sensitivity concernsc

Special indication beyond general ACIP recommendations

Attention to dosing recommendations for specific populations

P: Tdap specifically recommended every pregnancy

None

ovalbumin, neomycin, chlortetracycline, amphotericin B Tetanus, diphtheria, pertussis (Tdap) or tetanus, diphtheria (Td)

P: no contraindication

Alum or aluminum, formaldehyde

Tick-borne encephalitis

P: precaution

FSME-Immun: aluminum, human albumin

None

None

Typhoid

Amino acid mixture

None

None

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P: live-attenuated vaccine contraindicated; may consider polysaccharide vaccine I: live-attenuated vaccine contraindicated; may administer polysaccharide vaccine

Yellow fever

C: contraindicated age <6 mo; precaution age 6-8 mo P: precaution; may be used based on risk vs benefit I: contraindicated H: contraindicated for uncontrolled viral load, CD4 cells <200, or those with AIDS-defining conditions O: no contraindication for asplenia, despite this being a live vaccine

Gelatin, chicken embryo

None

C: additional dose recommended if vaccinated previously at age <5 y P: additional dose recommended if vaccinated previously during pregnancy I: additional dose recommended for those with prior yellow fever vaccination before hematopoietic stem cell transplant and who are at risk for yellow fever but are now immunocompetent H: additional dose recommended if vaccinated previously while HIV infected

ACIP ¼ Advisory Committee on Immunization Practices; C ¼ child traveler; H ¼ HIV-infected traveler; I ¼ severely immunocompromised traveler; O ¼ traveler with other chronic underlying disease including asplenia, diabetes, and chronic liver disease; P ¼ pregnant traveler; PEP ¼ postexposure prophylaxis. b See references 80 through 93 in addition to those listed in Table 2. c Data from Plotkin’s Vaccines82 and manufacturer’s vaccine package inserts for cholera (Vaxchora; PaxVac, Inc), meningococcal conjugate (Menactra; Sanofi Pasteur Inc), pneumococcal conjugate (Prevnar; Pfizer Inc), pneumococcal polysaccharide (Pneumovax; Merck & Co, Inc), and tick-borne encephalitis (FSME-Immun; Pfizer Inc). a

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Vaccine

Consideration of contraindications/ precautions for special populations

n

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of immunity. A third lifetime dose of MMR vaccine may be given during specific mumps outbreak situations.63 Many persons born in the United States before 1970 have not been vaccinated with MMR at all, and many born in the 1970s have not received the second dose in the series, which has been in the guidelines only since 1990. Children who are 6 to 11 months of age need one dose of MMR prior to travel regardless of destination country. This dose is noncountable, and 2 doses still should be given at the recommended ages (at least 28 days apart). Hepatitis B Travelers born in the United States after 1992 will most often already have received an HB vaccine series. For previously nonimmune travelers, pretravel HB vaccination is indicated for all nonvaccinated travelers with standard indications, such as health care workers, and also for all longer-stay travelers who will be visiting or residing in high- or moderate-risk areas. Transmission via routes such as sexual contact, blood transfusions, contaminated medical equipment, body piercing, tattooing, and acupuncture is difficult to control or predict in the context of travel. Vaccination is usually advocated for short-term travelers, especially younger travelers and those anticipating close contact with local populations, even if they have no specific risk factors. Adventure travelers who are by definition at high risk of injury, as well as backpackers and those with underlying medical conditions, are more likely to require contact with the medical system. Business and other frequent travelers who take multiple short trips have a cumulative risk that increases with time,99 and such individuals should receive the HB vaccine. Persons likely to engage in future international travel should consider a vaccine that confers lifelong protection. Accelerated and hyperaccelerated schedules (Table 2) are used widely in travel medicine practice and are approved in many countries. These schedules are not as well known among pharmacists and primary care clinicians, so travelers in whom an accelerated series is initiated may have 2330

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difficulty completing them when seeking subsequent doses at a location other than a dedicated travel clinic. For conventional HB vaccines, all 3 primary doses before travel are necessary for high assurance of protection. A newly licensed HB vaccine, Heplisav-B, which is not yet widely integrated into clinical practice, produces protection with a standard schedule of 2 doses spaced by 1 month, making it especially convenient for travelers.57,58 With the overlap of indications for use of the individual vaccines, the combined HA and HB vaccine provides convenience for travelers and has a licensed accelerated 3-week schedule (Table 2).52 Influenza Influenza is the most common VPD of travelers, especially those on cruise ships and those going to mass-gathering events such as the Hajj pilgrimage.20 Vaccination clearly protects against influenza complications such as pneumonia, hospitalization, or death even if some breakthrough respiratory illness does occur. Influenza virus circulates yearround in tropical and subtropical regions, and influenza season occurs in winter in temperate regions in the Southern Hemisphere (which is summer in the Northern Hemisphere). All travelers visiting the tropics at any time of year and visiting temperate countries where it is currently winter should be current on the most recent influenza vaccine available at home before the trip. Vaccine will not protect for at least 1 week postimmunization. Recent evidence suggests that travelers immunized with the current vaccine formulation more than 6 months earlier may consider revaccination because immunity clearly declines to close to zero by this time.100 Data supporting revaccination is limited but enticing. Travelers may consider baloxavir or oseltamivir as standby therapy, especially for those who are at high risk for complications from influenza or who are inadequately vaccinated. Travelers who carry baloxavir or oseltamivir should be advised to make every effort to institute therapy only under medical advice. This advice could be obtained at the

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destination or after telephone consultation with the prescribing physician at home. In China and Southeast Asia, avoiding poultry markets and farms may decrease risk of avian influenzas such as H7N9, H5N1, and H5N6, against which currently available vaccines are ineffective; in vitro data indicate efficacy of baloxavir against all the aforementioned avian influenza strains. Meningococcal Quadrivalent (ACWY) meningococcal vaccine is recommended for travelers to Africa’s sub-Saharan “meningitis belt” (Figure 2) during the dry season from December through June, especially if prolonged contact with the local population is likely. Health care workers to the meningitis belt might consider vaccination year-round. Out-of-season epidemics have occurred in Ethiopia, Somalia, and Tanzania. Muslims undertaking Hajj and Umrah pilgrimages in Saudi Arabia are at a higher risk of meningococcal disease, and proof of current vaccination with quadrivalent vaccine within the previous 5 years is required to obtain pilgrimage visas. Immunity to some serotypes in the tropics may wane in as little as 3 years, a consideration for most travelers to the developing world not included in US recommendations.65,66 Many travel advisors recommend revaccination after 3 years for very high-risk travelers. Meningococcal B vaccine is not indicated for travel unless the traveler has another routine indication such as asplenia or complement deficiency. The incidence of meningococcal B infection is not increased in developing countries when compared with the United States.101 Sporadic outbreaks may occur, as in the United States, so if a traveler was going to a closed setting such as a school outbreak, vaccination could be considered. Polio Because of eradication efforts, poliomyelitis remains endemic in only Afghanistan, Pakistan, and Nigeria, but complete control remains elusive. A handful of other countries periodically have outbreaks of human polio cases due to circulating vaccine-derived Mayo Clin Proc. n November 2019;94(11):2314-2339 www.mayoclinicproceedings.org

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polio viruses. Adults who have previously completed a primary vaccine series and plan to travel to countries that are polioendemic or have had cases of vaccinederived polio in the previous year (updated information is available from the Global Polio Eradication Initiative30) should receive a one-time single dose of inactivated polio vaccine as a booster. Completely unvaccinated adults traveling to risk countries may need to receive an entire primary series prior to the trip. However, even a single dose is beneficial. Revaccination with an inactivated polio vaccine primary series may be needed for a child who had been vaccinated with a routine oral polio vaccine series outside the United States. Vaccination is occasionally required for travelers going to certain polio-free countries that have a mandatory entry requirement for travelers (residents or long-stay visitors) coming from countries on a defined list of suspected polio-endemic countries.13 TRAVEL-ONLY VACCINES FOR ADULTS Hepatitis A and typhoid vaccines are considerations for most travelers to developing countries. The remaining vaccines in this section are indicated for specific risk areas (Figure 2) and for specific risk activities within the specified countries, with the exception of YF. Hepatitis A Unless routine or catch-up vaccination has been administered since 2005, young adults in the United States generally have little to no immunity to HA. Hepatitis A vaccine is indicated for every nonimmune traveler to countries or areas with moderate to high risk of infection, which includes essentially every destination other than the United States, Canada, Japan, Australia, New Zealand, Scandinavian countries, and developed countries in Europe. A single dose of HA vaccine given any time before travel, even on the way to the airport, provides adequate protection to the healthy adult. The Centers for Disease Control and Prevention (CDC) recommends ancillary concomitant

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immunoglobulin for travelers older than 40 years who are planning to depart in 2 weeks or less, but this recommendation has not been widely adopted in practice. Individuals born in the developing world may already be immune to HA. Persons with a history of hepatitis or who previously lived in an endemic country for a prolonged period may benefit from prevaccination serum antibody testing.95 Nevertheless, they merit HA vaccine unless immunity can be confirmed. When considering the combination HA/HB vaccine, the accelerated schedule should not be used unless at least 2 doses can be given prior to departure because the combination vaccine contains half of the HA antigen compared with that in a dose of monovalent adult HA vaccine. In this circumstance, monovalent HA and HB vaccines should be administered separately. Infants aged 6 to 11 months should be given one dose (noncountable) prior to travel.54 Following this dose, routine vaccination with HA vaccine (2 additional ageappropriate doses) should be administered. When pretravel vaccination cannot be given, intramuscular immunoglobulin dosing is (1) 0.1 mL/kg for trips of less than 1 month’s duration, (2) 0.2 mL/kg for trips of less than 2 months, and (3) 0.2 mL/kg every 2 months for trips of 2 months or longer. For unvaccinated travelers who have had a specific HA exposure while traveling, a single dose of HA vaccine for postexposure prophylaxis is now recommended for all persons aged 12 months or older, preferably within 2 weeks of exposure; additionally, immunoglobulin (if available) may be administered to immunocompromised adults of all ages as well as to those older than 40 years, depending on the physician’s risk assessment (eg, chronic liver disease, risk level of the exposure).54,102 Typhoid Typhoid vaccine is indicated for all travelers to the Indian subcontinent and considered for those traveling to other endemic areas (Figure 2) under all but the most deluxe and protected conditions. Risk increases with trip duration, lodging and/or eating 2332

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with local residents, and extent of travel off the usual tourist itineraries. In risk areas, food and water precautions should still be followed rigorously because typhoid vaccines are only 53% to 72% protective, and a large oral inoculum may overwhelm even an optimal antibody response.74 The recent increase in quinolone-resistant Salmonella enterica serotype Typhi in Asia and extremely resistant typhoid in Pakistan has decreased the threshold for typhoid vaccination because infection, once acquired, may require inpatient parenteral therapy with sophisticated antibiotics. Current typhoid vaccines do not protect against S enterica serotype Paratyphi, which is emerging in many areas. Adherence to the oral vaccine regimen may be as low as 70%. Although revaccination with the injectable Vi polysaccharide vaccine is recommended by the US Food and Drug Administration every 2 years, revaccination every 3 years is recommended in Canada, Australia, the United Kingdom, and other countries if continued or repeated exposure exists.

Yellow Fever The main indication for YF vaccination is to prevent infection in individuals at risk. However, YF is currently the only vaccine that falls under the International Health Regulations (IHR) that may necessitate vaccination purely for regulatory reasons. Neither YF vaccine nor any other vaccine is currently required on return to the United States. In general, all healthy adult travelers to areas with a risk of YF transmission (Figure 2) should be vaccinated. This endemic area may be restricted to only a portion of a country. Because of rare but serious vaccineassociated adverse effects, persons who are not at any risk of exposure should not be vaccinated. Only first doses of YF vaccine, but not booster doses, are associated with rare but severe or fatal adverse events. The overall rate is 1 event per 334,000 doses,89 but severe events occur most frequently in persons older than 60 years (increasing with advancing age) and in any person with a thymus disorder.76,89

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Urban YF rarely occurs in South America, but the situation is currently evolving in Brazil and up-to-date maps should be checked. Persons who have anything less than a definite, fixed itinerary and who will travel anywhere close to regions with risk of transmission should be vaccinated. Decisions about YF vaccination depend on riskbenefit for the person, the itinerary, and the destination country entry requirements. A number of African countries and one in South America (French Guiana) require proof of YF vaccination from all arriving travelers. Other countries, both within and outside the risk zone, have submitted more complex requirements to the World Health Organization (WHO). They may require an official vaccination certificate only for individuals arriving directly from or via a country in the YF endemic zone but not from travelers arriving from other countries. Such transits may include even an airplane connection in an affected country. These YF-free countries usually have the conditions and vectors to initiate a YF transmission cycle, and the purpose of the vaccine requirement is to prevent entry of viremic travelers. Current country-by-country YF entry requirements are available from the WHO.103 The requirement often applies even if the arriving traveler has not visited an area within a country of departure that is endemic for YF. A special permit, obtainable in the United States from state health departments, is required to legally stamp an international certificate of vaccination as being from an authorized YF vaccine center. The IHR specify that clinicians who decide that YF vaccine is contraindicated on medical grounds can provide a letter stating the reasons for an exemption, which is shown on arrival at the destination. Acceptance of a “waiver letter” depends on the discretion of the authorities at the port of entry. On arrival, the destination country may also quarantine the traveler for up to 6 days or request that the traveler be placed under surveillance. The variable risk within the endemic regions of the world must be considered (in consultation with an expert, Mayo Clin Proc. n November 2019;94(11):2314-2339 www.mayoclinicproceedings.org

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if necessary), and cancellation of travel should be recommended strongly if the risk is more than negligible and YF vaccine cannot be given or is declined by the traveler. A YF certificate becomes valid for entry 10 days after it is stamped and dated. The YF vaccine has until several years ago been thought to provide protection for 10 years. Currently, the CDC recommends that 10-year boosters should be restricted to healthy travelers planning a long stay in any country with any risk of YF transmission, to all travelers spending any amount of time in high-risk areas (notably West Africa), and to all persons going to locations with a current outbreak. A CDC analysis found that 92% of vaccine recipients have virus-neutralizing antibody at 10 years and 80% have the antibody at 20 years. Thus, almost all healthy persons appear to have long-term immunity.76 For the purposes of the IHR, documentation of a single dose of YF vaccine at any time during the person’s life suffices for entry to any country. Rabies A preexposure rabies series is indicated for long-stay travel to endemic areas of Latin America, Asia, or Africa, where the rabies threat is constant and access to adequate postexposure rabies immunoglobulin and vaccine is likely to be limited. Preexposure vaccination does not eliminate the need for vaccination after an exposure. However, it dramatically simplifies the postexposure vaccine schedule to 2 injections and eliminates the need for rabies immunoglobulin, which is often very difficult to access abroad. Countries with the highest risk of rabies include the Indian subcontinent, Thailand, Vietnam, and most sub-Saharan African countries. For short-term travel, risk groups for whom immunization should be considered include adventure travelers, bikers, hikers, cave explorers, or business travelers who travel for short but frequent trips and plan to go running outdoors on these trips. Regardless of vaccination status, travelers should be instructed to cleanse well with soapy water any bite or animal scratch involving broken skin immediately and to seek postexposure

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treatment for rabies within a maximum of 48 hours. Seeking quality biologicals and additional postexposure vaccine doses is critical to prevent rabies. In 2018, the WHO recommended that preexposure prophylaxis rabies regimens can be shortened to intradermal rabies vaccine at 2 separate sites on 2 visits (days 0 and 7).67 Recent evaluations add support to the reduced-dose preexposure prophylaxis.68-71 Changes to existing national guidelines (0, 7, 28 days, intramuscular dosing) in major countries (United States, Canada, Australia, France) have yet to be considered; the United Kingdom has formally considered the WHO advice and has elected to stay with the status quo. Japanese Encephalitis Japanese encephalitis is endemic to many rural farming areas of Southeast Asia and the Indian subcontinent (Figure 2). Sporadic cases with severe sequelae continue to occur in travelers. Overall risk is very low for short-stay travelers and for those who confine their travel to urbanized areas or brief daytime rural exposures during typical tourist excursions. However, cases may be sporadic and have occurred in short-stay visitors traveling out of season whose only rural travel had been to beach resorts. In temperate regions, the transmission season is from April through November. In tropical or subtropical regions of Oceania and Southeast Asia, transmission may occur yearround. Vaccination is recommended for (1) long-stay travel to an endemic rural area, (2) expatriation to anywhere in an endemic country, (3) short-term travel to endemic rural areas with potential unprotected outdoor exposure, such as with adventure travel, or (4) short-term travel during a current local epidemic.62 Cholera Cholera vaccination is no longer required by any country, and the risk to typical travelers is insignificant. However, aid, refugee, and health care workers in areas where cholera is endemic or epidemic may consider cholera vaccine. A live attenuated oral cholera vaccine was approved in 2016 by US Food and 2334

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Drug Administration for use only in immunocompetent adults in the United States; duration of immunity is unknown at present.49 A highly effective oral, killed, whole-celleB subunit cholera vaccine is available widely outside the United States. This vaccine also has about 50% efficacy against enterotoxigenic Escherichia coli and a 7% to 23% efficacy against all traveler’s diarrhea, but this indication is not generally recommended by authoritative sources. Tick-Borne Encephalitis Tick-borne encephalitis is an emerging, important, and serious flavivirus central nervous system infection in endemic areas. Distribution is highly focal in a range that extends in a swath from Germany through Scandinavia and the Baltic states to Siberia and Vladivostok in the east. Risk to travelers is low unless extensive outdoor activities are planned in forested regions in endemic areas. Immunization against tick-borne encephalitis is recommended for adventure travel, extensive outdoor exposure, or camping in the forests of the endemic countries between April and October. Tick precautions are also recommended. The vaccine is available in most endemic countries but not in the United States or Canada.73,104 Three to 4 weeks are required for accelerated vaccination and development of immunity, making vaccination on arrival impractical for shortstay travelers. TRAVEL VACCINES FOR SPECIAL POPULATIONS Immunocompromised travelers and travelers living with HIV comprise up to 4% of travelers seen in some US travel clinics and pursue itineraries largely similar to those of immunocompetent travelers.105 Different conditions and medications produce widely varying degrees of immunocompromise, and there are many unknowns in this field. Guidance regarding vaccination of immunocompromised travelers is less evidence-based than with other categories of travelers. Health hazards at the destination that would exacerbate the underlying condition can be

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more severe in an immunocompromised traveler. Advice from a specialized travel clinic is of benefit for persons who are severely immunocompromised (transplants, active malignancy, congenital immunodeficiency) or have underlying chronic disease, especially those who are planning to live abroad for a long time or who have complicated itineraries. Travelers with autoimmune diseases (eg, systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis) who are not being treated with immunosuppressive or immunomodulatory drugs are not considered significantly immunocompromised, but definitive data are lacking. Immunocompromised persons including those taking immunosuppressive drugs and most biological responseemodifying drugs should not receive live vaccines.84,87,88,91 In the context of specific travel vaccines, this includes YF, MMR, oral cholera, and oral typhoid. Asplenia is not a contraindication for live viral vaccines. Nonlive vaccines, although safe, may have suboptimal efficacy in immunocompromised hosts, and the implications of this issue should be discussed with the traveler. In general, such vaccines are indicated because of specific risk of potentially serious infection at the destination. Unvaccinated travelers with severe immune compromise should be strongly discouraged from travel to destinations that present a true risk for YF. If travel is unavoidable to an area where YF vaccine is recommended for personal protection and the vaccine has not been given, these travelers should be informed of the risk of YF and carefully instructed in methods to avoid mosquito bites. Significant immunosuppression is a contraindication to YF vaccination.89 Recent data suggest that YF vaccination before solid organ transplant, even long before transplant, generally provides protective antibody levels after transplant. Patients with asymptomatic HIV or CD4 cell counts greater than 200/mL may be offered YF vaccine if Mayo Clin Proc. n November 2019;94(11):2314-2339 www.mayoclinicproceedings.org

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travel to YF-endemic areas is unavoidable; recipients should be monitored closely for possible adverse effects. Patients with undetectable viral loads respond well to YF vaccination regardless of CD4 cell count. Because vaccine response may be suboptimal, such vaccinees are candidates for serologic testing 1 month after vaccination. If international travel requirements, and not true exposure risk, are the only reasons to vaccinate a traveler with asymptomatic HIV infection or a limited immune deficit, the physician should provide a waiver letter. The period of time clinicians should wait after discontinuation of immunosuppressive therapies before administering a live vaccine such as YF is not consistent across all live vaccines. No specific data exist for the safety or efficacy of YF vaccine in this regard. For cancer chemotherapy, radiation therapy, and highly immunosuppressive medications (exclusive of lymphocyte-depleting agents and organ transplant immunosuppression), the waiting period is 3 months.84,87,88,91 For lymphocyte-depleting agents (alemtuzumab and rituximab), the waiting period is 6 months or more, although some experts believe the waiting period should be 1 year or more. For corticosteroid regimens considered immunosuppressive, the waiting period is 1 month. Restarting immunosuppression after live vaccination has not been studied, but some experts would recommend waiting at least 1 month. Immunocompromised travelers may require additional nontravel vaccines compared with healthy travelers. All travelers are at increased risk of respiratory illness. Unvaccinated persons who have the accepted routine indications for the pneumococcal vaccines, which includes most individuals with chronic disease and immunocompromising conditions, should receive this vaccine during the pretravel consultation if not already done.80,81 Adult asplenic or functionally asplenic individuals often arrive at the clinic incompletely vaccinated against meningococcal disease (ACWY and B), Haemophilus influenzae type B, and pneumococcal infection. Asymptomatic adults with HIV and reconstituted CD4 cell

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counts of more than 200/mL are considered to have limited immune deficits and should receive additional vaccines according to the usual guidelines found elsewhere in this Mayo Clinic Proceedings vaccine thematic series.94 The HB vaccine high-dose regimen is recommended for all immunocompromised persons and adult hemodialysis patients.58 Titers should be determined for HB surface antibody response after vaccination; patients should be revaccinated if response is absent. Immunocompromised travelers may have inadequate seroconversion after a single dose of HA vaccine.83 Efforts should be made to administer 2 doses over a 6-month period prior to their trip. Instead of concomitant immunoglobulin with the first dose, the approach of giving a second dose of vaccine at least 4 weeks after the first dose for timeconstrained travelers who can get both doses before travel has been effective in selected studies.90 CONCLUSION Vaccine-preventable diseases occur during travel, including in developed countries, and impact the need for otherwise routinely recommended immunizations as well as for specific travel immunizations based on destinations or activities. The pretravel evaluation is an ideal setting to update all ageappropriate immunizations and provide protection against travel-associated diseases. Malaria chemoprophylaxis and education is an additional critical component of the pretravel health encounter. Prevention of other potential risks such as traveler’s diarrhea, altitude illness, and blood-borne and sexually transmitted pathogens should be addressed, and travelers should be prepared to recognize or self-manage certain illnesses should they arise. Abbreviations and Acronyms: CDC = Centers for Disease Control and Prevention; HA = hepatitis A; HB = hepatitis B; IHR = International Health Regulations; MMR = measles, mumps, and rubella; VPA = vaccine-preventable disease; WHO = World Health Organization; YF = yellow fever Potential Competing Interests: Dr Freedman receives salaried compensation from Shoreland Travax for writing and

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editing an online clinical decision support tool and royalties from UpToDate, Inc. Dr Chen receives editing and advisory fees from Shoreland, Inc. Correspondence: Address to David O. Freedman, MD, Division of Infectious Diseases, University of Alabama at Birmingham, 1720 2nd Ave S, BBRB #203, Birmingham, AL 35294-2170 ([email protected]). The Thematic Review on Vaccines will continue in an upcoming issue.

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