Approximately 2.2 million US children younger than age 18 years traveled internationally in 2010. Increasing numbers are traveling to developing countries in Central and South America, Africa, and Asia. Thirty-five percent of all US travelers gave visiting friends and relatives (VFR) as the reason for travel.1 VFR travelers are often immigrants and their families, ethnically and racially distinct from the majority population of the country of residence (a higher-income country), who return to their home country (lower-income country) to visit friends or relatives. VFRs experience a disproportionate number of preventable infectious diseases such as malaria, typhoid, and hepatitis A. In 2010, 54% of imported malaria cases and 66% of typhoid in the US occurred in VFR travelers.1 Sixty-five percent of hepatitis A VFR cases in a Canadian study were younger than age 20 years.2
An increasing number of adolescents are also traveling with their schools, community organizations, and religious groups for volunteer and mission work to developing countries, and families and students are choosing more nontraditional and exotic destinations for vacation and studying abroad. Unfortunately, children are less likely to receive pretravel medical advice. In a review of children with posttravel illnesses, 59% of adults versus 51% of children—and only 32% of VFR children—had a pretravel medical visit.3
Efforts to increase awareness among travelers regarding their risk for acquiring disease during travel are clearly critical, and primary care providers can play a key role in educating parents and young travelers. Many health care professionals are already being approached for pretravel advice and vaccines. This article reviews the currently recommended pediatric travel vaccines as well as an update on prospective ones for significant tropical diseases like malaria, dengue, chikungunya, and Ebola.
Currently Recommended Pediatric Travel Vaccines
All vaccines should be up-to-date according to the appropriate US immunization schedule. These routine vaccines protect recipients against infections responsible for significant morbidity and mortality in underdeveloped countries. Table 1 summarizes current travel recommendations for the routine vaccines, with specific comments for hepatitis A and B, polio, measles, influenza, and meningococcal disease.
United States Routine Pediatric Vaccines to Review/Update/Consider Prior to Travel as of March 2015
Typhoid fever, caused by Salmonella Typhi, is rare in the US, with most of the 5,700 estimated annual cases acquired during travel.1 Over 21 million people in the world are affected every year. After an incubation period of 6 to 30 days, there is insidious onset of gradually increasing fatigue and fever (“step ladder fever”), along with cough and gastrointestinal symptoms (vomiting, severe diarrhea, and abdominal pain). Nonspecific symptoms of headache, malaise, and anorexia are universal. The classic transient macular rose-colored truncal rash and relative bradycardia described for adults are usually absent in children. If left untreated, mortality can approach 30% (in both adults and children), from gastrointestinal hemorrhage, intestinal perforation, renal failure, and sepsis.
Typhoid vaccine is recommended for travelers going to developing countries in Asia (especially South Asia), Latin America, and Africa. There are currently two vaccines available: an inactivated intramuscular shot and a live attenuated oral capsule. Age guidelines, usage, and adverse events with each are provided in Table 2.
United States Licensed Travel-Specific Vaccines as of March 2015
To improve immunogenicity and extend coverage to children younger than age 2 years, conjugate vaccines have been developed for typhoid, following successes with Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis. Vi capsular polysaccharide has been conjugated with a Pseudomonas aeruginosa recombinant exoprotein A (Vi-rEPA), and recombinant diphtheria toxoid (Vi-CRM197) and shown to be safe and effective in infants as young as age 14 weeks.4 Two conjugate typhoid toxoid vaccines (Vi-TT), Peda Typh (M/s Bio-med Pvt. Ltd., Uttar Pradesh, India), and Typbar-TCV (Bharat Biotech International Ltd., Hyderabad, India) are available in India, although only Typbar-TCV is approved and recommended by the Indian Academy of Pediatrics for routine use between ages 9 and 12 months, with a booster at age 2 years.5
Yellow fever virus (YFV) occurs in tropical and subtropical regions in South America and Africa—transmitted by infected Aedes mosquitoes. The incubation period ranges from 3 to 6 days. Although most infections are asymptomatic, symptomatic travelers usually develop a self-limited febrile illness with chills, back pain, generalized myalgias, fatigue, nausea, and vomiting. After a few hours of remission, 15% develop jaundice, hemorrhage, shock, and multiorgan failure with up to 50% mortality. Between 1970 and 2011, 9 cases of yellow fever were reported in unvaccinated American and European travelers, and 8 died.1 The only treatment is supportive care.
The yellow fever vaccine available in the US is a live attenuated vaccine. Vaccination is recommended for travelers age 9 months and older who will travel to endemic countries (see Figure 1, Figure 2, and Table 2). Infants younger than age 9 months are at higher risk for developing encephalitis from yellow fever vaccine, with 14 of 18 reported cases of postvaccination encephalitis occurring in infants younger than age 4 months.1 The Advisory Committee on Immunization Practices recommends that yellow fever vaccine never be given to infants younger than age 6 months, although other expert recommendations only exclude infants younger than age 4 months. Travelers with infants younger than age 9 months should be advised against travel to YFV endemic areas. Infants ages 4 to 8 months should be vaccinated only if they must travel to YFV areas and if a high level of protection against mosquito bites is not possible.
Yellow fever vaccine recommendations in the Americas. From the Centers for Disease Control and Prevention (permission is not required).15
Yellow fever vaccine recommendations in Africa. From the Centers for Disease Control and Prevention (permission is not required).15
Yellow fever vaccination may be necessary for entry into many African and South American countries. The latest country requirements can be found on the Centers for Disease Control and Prevention website.6 The only acceptable proof of vaccination is the International Certificate of Vaccination or Prophylaxis aka the “Yellow Card,” only available from certified vaccine administration sites. A booster vaccine is available every 10 years for travelers who remain at risk.
However, 2013 World Health Organization (WHO) recommendations deemed a single dose of yellow fever vaccine sufficient to provide lifelong immunity and that a booster dose is not necessary.7 Even so, a prospective travel clinics study found that 30% of people vaccinated against yellow fever returned for a booster dose, a number projected to decrease as a result of the recommendations.8 As of March 2015, the Centers for Disease Control still recommends a 10-year booster for at-risk travelers.
Japanese Encephalitis (JE) virus is a flavivirus, transmitted to humans by Culex mosquitoes, with pigs and birds serving as natural reservoirs. JE virus is endemic in Asia and the western Pacific, especially in rural agricultural locations. JE peaks in summer and fall, and can be present year-round near irrigation areas.
Like yellow fever, most patients infected with JE virus are asymptomatic. JE incubation is 5 to 15 days, and symptomatic patients develop fever, headache, and vomiting. JE may progress to encephalitis and coma. Seizures are common in children. About 25% of encephalitis patients die and 30% to 50% of the survivors have permanent neurologic, cognitive, and psychiatric sequelae.
JE is a childhood disease in endemic countries where adults have developed immunity through natural infection. Risk of infection mostly depends on the traveler’s itinerary and time of year. See Figure 3 for an endemic country map and Table 2 for age guidelines, usage, and adverse events.
Geographic distribution of Japanese encephalitis. From the Centers for Disease Control and Prevention (permission is not required).16
In a recent phase III study in South Korea in 274 children between ages 12 and 24 months, a new live attenuated JE chimeric virus vaccine (JE-CV) was compared with a current vaccine—SA14-14-2. JE-CV had a 100% seroprotection rate in the JE-CV group compared with 99.1% for SA14-14-2. These results were comparable with prior studies in toddlers using JE-CV.9
Rabies is caused by neurotrophic lyssaviruses, transmitted by infected saliva from animal bites. After an incubation period of months, an acute progressive encephalomyelitis occurs, beginning with fever and nonspecific vague symptoms, followed by a neurologic phase with anxiety, paresis, paralysis, and other signs of encephalitis. The classic hydrophobia stems from spasms of swallowing muscles triggered by the sight, sound, or perception of water. Coma and death follow within 7 to 14 days after symptoms begin. Thirty percent of rabies cases present with a more protracted and less overt paralytic form that can be difficult to recognize.
Over 55,000 people die from rabies annually, mostly in Asia and Africa, and 40% are children younger than age 15 years. Although any carnivore can transmit rabies, dogs are the cause of all rabies deaths in Asia and Africa. Bats are the primary cause of rabies deaths in the Americas and Europe.
Pre-exposure prophylaxis information is presented in Table 2. However, two doses of rabies vaccine at day 0 and 3 are still required after rabies exposure, even if the pre-exposure series was completed.
Future Travel Vaccines
There are no approved or commercially available vaccines for many common and high-profile global infectious diseases. However, research is ongoing because of the morbidity and mortality associated with the causative pathogens, along with the numbers of people afflicted. Several of these infections are discussed below, with the current status of their vaccine development.
Malaria is a potentially life-threatening infection, caused by Plasmodium protozoa species such as Plasmodium falciparum and Plasmodium vivax, and transmitted via Anopheles mosquitoes. Malaria is endemic in many areas in Africa, South Asia, and South America. WHO estimates over 200 million cases of malaria in 2014, and over a half million deaths. The highest risk of infection appears to be in West Africa and Oceania, and most of the mortality occurs in African children younger than age 5 years. Although mortality has fallen by half since 2000, a child dies from malaria every minute in Africa.
The incubation period can range from 7 days to several months. Malarial symptoms include fever and flu-like symptoms. Anemia may occur, and if symptoms proceed without treatment, patients may develop seizures, renal failure, acute respiratory distress syndrome, coma, or even death.
A malaria vaccine has been in development for over 30 years, and in 2014, a first-generation malaria vaccine, RTS,S/AS01, was submitted for approval to the European Medicines Agency. RTS,S/AS01 triggers the immune system to prevent P. falciparum from infecting, maturing, and multiplying in the liver. This is necessary for the parasite to re-enter the bloodstream and infect erythrocytes, causing disease. In the phase III trial with 6,537 infants (ages 6 to 12 weeks) and 8,923 children (ages 5 to 17 months) in seven African countries, RTS,S/AS01 was administered in three doses, 1 month apart. The impact of the vaccine was higher in children, with malaria cases reduced by 46% in children, but only 27% in infants.10
Other malaria vaccines in development include viral vector vaccines (ChAd63-MVA) that present malaria antigens and induce cell-mediated immunity, a PfSPZ vaccine using whole irradiated P. falciparum, and Pfs25 transmission blocking vaccines, which prevent parasite development in mosquitoes and subsequent spread to humans.11
Dengue is caused by infection with any of the four serotypes of dengue virus. Like YFV, dengue virus is a flavi-virus primarily transmitted via infected Aedes mosquito bites. Dengue has become a major and emerging global health problem since the 1950s. Dengue is endemic in at least 100 countries in Asia, the Pacific, the Americas, Africa, and the Caribbean where 2.5 billion people, or 40% of the world’s population lives. Annual human infections range between 50 to 100 million, with at least 22,000 deaths—mostly children. Dengue is endemic in Puerto Rico and many popular tourist destinations in Latin America, Southeast Asia, and the Pacific islands.
About 75% of dengue infections are asymptomatic, and most symptomatic disease presents in three phases: (1) a febrile phase, with severe headache, retro-orbital pain, muscle/joint/bone pain (“breakbone fever”), macular rash, and minor hemorrhagic manifestations (petechiae, purpura, ecchymoses, epistaxis, bleeding gums, hematuria); (2) a critical phase, where most patients improve, but some develop severe plasma leak, causing pleural effusions, ascites, and hypovolemic shock. Abdominal pain/tenderness, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy, restlessness, and hepatomegaly are warning signs of severe dengue; and (3) a convalescent phase. There are no specific dengue therapeutics.
Although several vaccine candidates are currently being evaluated in clinical trials, a recombinant live attenuated tetravalent vaccine (CYD-TDV) has completed phase III trials in Asian and Latin American children. Over 10,000 children ages 2 to 14 years in Indonesia, Malaysia, the Philippines, Thailand, and Vietnam received three doses of vaccine 6 months apart, and overall vaccine efficacy was 56% with an 80% reduction in severe dengue cases. No increase in severe adverse events was found in the 25 months after vaccine administration. Over 20,000 children ages 9 to 16 years in Colombia, Brazil, Mexico, Puerto Rico, and Honduras received three doses of CYD-TDV on the same schedule, with overall vaccine efficacy of 60.8% and a 95% reduction in severe dengue. The safety profile was similar to placebo.12 CYD-TDV is currently awaiting regulatory approval and could be available by 2016.
Chikungunya virus (CHIKV) is an alphavirus transmitted through infected Aedes mosquitoes. CHIKV was first recognized in 1952 and became widespread in Africa and Asia. In 2013 it appeared in the Caribbean, and as of 2015, local transmission has been identified in 42 countries in the Americas, including the US. Over 1 million suspected and 26,606 laboratory-confirmed chikungunya cases have been reported from these areas. Because CHIKV is new to the Americas, the spread is expected to continue through infected people and Aedes mosquitoes that are present globally.
Clinical presentation of CHIKV varies between asymptomatic and symptomatic presentations. The incubation period is about 3 to 7 days and symptoms include high fever, joint pain, rash, headache, fatigue, nausea, and vomiting. The main symptoms are fever and joint pain, which can be severe in some cases. Common laboratory findings include thrombocytopenia, lymphopenia, and elevated liver function tests and creatinine.
Although no proven vaccine currently exists for CHIKV, a phase I National Institutes of Health trial found no serious adverse events and neutralizing antibodies detected after two doses of the trial vaccine, with a significant increase after the third dose. The neutralizing antibody titers after vaccination were similar to those in two recovering CHIKV patients, showing promise for future development.13
Ebola Virus Disease
Ebola virus disease (EVD) caught the world’s attention in 2014 because of an outbreak in Liberia extending into Guinea, Sierra Leone, and Nigeria. It is a filovirus that causes a viral hemorrhagic fever with up to 90% mortality. Although outbreaks have occurred since 1976, the 2014 epidemic is the largest to date, with over 21,000 cases and 8,500 deaths. Ten cases were diagnosed in the US, two of which contracted EVD from caring for an infected patient. Transmission is person-to-person via direct contact with body fluids, cadavers, symptomatic patients, or sometimes in a hospital environment as a result of improper infection control. Zoonotic transmission is also possible. Signs and symptoms of EVD include fever, myalgia, and prostration. This may be followed by coagulopathy and bleeding. Shock and pulmonary edema may occur as a result of vascular endothelial damage. A careful travel history is crucial in detecting people at risk, especially due to incubation periods lasting as long as 3 weeks.
Preliminary data from phase I trials of two potential Ebola viral vector vaccines—adenoviral ChAd3-ZEBOV and (vesicular stomatitis virus) rVSV-ZEBOV—have shown encouraging results in animals. Phase II trials of ChAd3-ZEBOV started in West Africa in February 2015, to be followed by phase III trials. Other vaccine candidates include a two-dose series using two different vaccines (Ad26-EBOV and MVA-EBOV), a recombinant protein vaccine based on the 2014 Guinea strain, an oral adenovirus platform, alternative VSV and recombinant protein candidates, a DNA vaccine, and a recombinant Ebola/rabies vaccine.14