Chapter 4 Travel-Related Infectious Diseases
Susan L. Hills, Nicole P. Lindsey, Marc Fischer
Japanese encephalitis (JE) virus is a single-stranded RNA virus that belongs to the genus Flavivirus and is closely related to West Nile and Saint Louis encephalitis viruses.
JE virus is transmitted to humans through the bite of an infected mosquito, primarily Culex species. The virus is maintained in an enzootic cycle between mosquitoes and amplifying vertebrate hosts, primarily pigs and wading birds. Humans are incidental or dead-end hosts, because they usually do not develop a level or duration of viremia sufficient to infect mosquitoes.
JE virus is the most common vaccine-preventable cause of encephalitis in Asia, occurring throughout most of Asia and parts of the western Pacific (Map 4-07). Transmission principally occurs in rural agricultural areas, often associated with rice cultivation and flood irrigation. In some areas of Asia, these ecologic conditions may occur near, or occasionally within, urban centers. In temperate areas of Asia, transmission is seasonal, and human disease usually peaks in summer and fall. In the subtropics and tropics, seasonal transmission varies with monsoon rains and irrigation practices and may be prolonged or even occur year-round.
In endemic countries, where adults have acquired immunity through natural infection, JE is primarily a disease of children. However, travel-associated JE can occur among people of any age. For most travelers to Asia, the risk for JE is extremely low but varies based on destination, duration, season, and activities.
Before 1973, >300 cases of JE were reported among soldiers from the United States, the United Kingdom, Australia, and Russia. From 1973 through 2017, 84 JE cases among travelers or expatriates from nonendemic countries were published or reported to CDC. From the time a JE vaccine became available in the United States in 1993, through 2017, only 12 JE cases among US travelers were reported to CDC.
The overall incidence of JE among people from nonendemic countries traveling to Asia is estimated to be <1 case per 1 million travelers. However, expatriates and travelers who stay for prolonged periods in rural areas with active JE virus transmission might be at similar risk as the susceptible (pediatric) resident population (6–11 cases per 100,000 children per year). Travelers on even brief trips might be at increased risk if they have extensive outdoor or nighttime exposure in rural areas during periods of active transmission. Shorter-term (for example, <1 month) travelers whose visits are restricted to major urban areas are at minimal risk for JE. In some endemic areas, although there are few human cases among residents because of natural immunity among older people or vaccination, JE virus is still maintained locally in an enzootic cycle between animals and mosquitoes. Therefore, susceptible visitors may be at risk for infection.
Map 4-07. Distribution of Japanese encephalitis
Most human infections with JE virus are asymptomatic; <1% of people infected with JE virus develop neurologic disease. Acute encephalitis is the most commonly recognized clinical manifestation of JE virus infection. Milder forms of disease, such as aseptic meningitis or undifferentiated febrile illness, also can occur. The incubation period is 5–15 days. Illness usually begins with sudden onset of fever, headache, and vomiting. Mental status changes, focal neurologic deficits, generalized weakness, and movement disorders may develop over the next few days. The classical description of JE includes a parkinsonian syndrome with mask-like facies, tremor, cogwheel rigidity, and choreoathetoid movements. Acute flaccid paralysis, with clinical and pathological features similar to those of poliomyelitis, has also been associated with JE virus infection. Seizures are common, especially among children. The case-fatality ratio is approximately 20%–30%. Among survivors, 30%–50% have serious neurologic, cognitive, or psychiatric sequelae.
Common clinical laboratory findings include moderate leukocytosis, mild anemia, and hyponatremia. Cerebrospinal fluid (CSF) typically has a mild to moderate pleocytosis with a lymphocytic predominance, slightly elevated protein, and normal ratio of CSF to plasma glucose.
JE should be suspected in a patient with evidence of a neurologic infection (such as encephalitis, meningitis, or acute flaccid paralysis) who has recently traveled to or resided in an endemic country in Asia or the western Pacific. Laboratory diagnosis of JE virus infection should be performed by using a JE virus-specific IgM-capture ELISA on CSF or serum. JE virus-specific IgM can be measured in the CSF of most patients by 4 days after onset of symptoms and in serum by 7 days after onset. Plaque reduction neutralization tests can be performed to confirm the presence of JE virus-specific neutralizing antibodies and discriminate between cross-reacting antibodies from closely related flaviviruses (such as dengue and West Nile viruses). A ≥4-fold rise in JE virus-specific neutralizing antibodies between acute- and convalescent-phase serum specimens may be used to confirm recent infection. Vaccination history, date of onset of symptoms, and information regarding other flaviviruses known to circulate in the geographic area that may cross-react in serologic assays need to be considered when interpreting results.
Humans have low levels of transient viremia and usually have neutralizing antibodies by the time distinctive clinical symptoms are recognized. Virus isolation and nucleic acid amplification tests are insensitive in detecting JE virus or viral RNA in blood or CSF and should not be used for ruling out a diagnosis of JE. Clinicians should contact their state or local health department or CDC at 970-221-6400 for assistance with diagnostic testing.
There is no specific antiviral treatment for JE; therapy consists of supportive care and management of complications.
Personal Protection Measures
The best way to prevent mosquitoborne diseases, including JE, is to avoid mosquito bites (see Chapter 3, Mosquitoes, Ticks & Other Arthropods).
One JE vaccine is licensed and available in the United States—an inactivated Vero cell culture–derived vaccine, Ixiaro (Table 4-06). Ixiaro is manufactured by Valneva Austria GmbH. It was approved in March 2009 for use in people aged ≥17 years and in May 2013 for use in children aged 2 months through 16 years. Other inactivated and live attenuated JE vaccines are manufactured and used in other countries but are not licensed for use in the United States.
INDICATIONS FOR USE OF JE VACCINE FOR TRAVELERS
Travelers to JE-endemic countries should be advised of the risks of JE disease and the importance of personal protective measures to reduce the risk for mosquito bites. When making recommendations regarding the use of JE vaccine for travelers, clinicians must consider the risks related to the specific travel itinerary, likelihood of future travel to JE-endemic countries, the high rate of death and disability when JE occurs, availability of an effective vaccine, the possibility but low probability of serious adverse events after immunization, and the traveler’s personal perception and tolerance of risk. Evaluation of a traveler’s risk should take into account travel location, duration, activities, accommodations, and seasonal patterns of disease in the areas to be visited (Table 4-07). The data in the table should be interpreted cautiously, because JE virus transmission activity varies within countries and from year to year, and surveillance data are often incomplete. Additional information on factors that increase risk is provided in “Japanese encephalitis vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP)” (www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/je.html).
The Advisory Committee on Immunization Practices recommends JE vaccine for people moving to a JE-endemic country, longer-term (for example, ≥1 month) travelers to JE-endemic arears, and frequent travelers to JE-endemic areas. Vaccine should also be considered for shorter-term (for example, <1 month) travelers with an increased risk of JE based on planned travel duration, season, location, activities, and accommodations. Vaccination should also be considered for travelers going to endemic areas, but who are uncertain of specific destinations, activities, or duration of travel.
JE vaccine is not recommended for travelers with very low-risk itineraries, such as shorter-term travel limited to urban areas or travel that occurs outside a well-defined JE virus transmission season.
VACCINE EFFICACY AND IMMUNOGENICITY
There are no efficacy data for Ixiaro. The vaccine was licensed in the United States on the basis of its ability to induce JE virus–neutralizing antibodies as a surrogate for protection. In pivotal immunogenicity studies, 96% of adults and 100% of children aged 2 months through 17 years developed protective neutralizing antibodies at 28 days after receiving a primary immunization series of 2 doses administered 28 days apart. Among adults aged ≥65 years, 65% are seroprotected at 42 days after the 2-dose primary series.
A study in adults on persistence of protective neutralizing antibodies after a primary 2-dose series of Ixiaro showed that at 5 years postvaccination, 82% of subjects were seroprotected. However, the study was conducted in areas where tickborne encephalitis (TBE) vaccine is available. In a subgroup analysis, seroprotection rates at 24–60 months in the TBE vaccine group ranged from 94%–100%, compared with 64%–72% in the group in which TBE vaccine was not administered. TBE vaccine is not available in the United States; therefore, JE seroprotection rates for US travelers are likely to be most similar to the rates in the group not administered TBE vaccine.
One observational study investigated long-term protection following a booster dose of Ixiaro in adults. After a booster dose administered at 15 months, 96% of subjects were still seroprotected approximately 6 years later.
In a study conducted among children in a JE-endemic country, 90% of children were seroprotected at 36 months after the primary series. Seroprotection rates were variable by age group, but at least 81% of children in each age group were seroprotected. Among 150 children in this study who received a booster dose at 11 months after the primary series, 100% were seroprotected at 1 month, 12 months, and 24 months after the booster dose. In a study conducted among children from nonendemic countries, 89% were seroprotected at 3 years after a primary 2-dose series of Ixiaro.
An accelerated primary series of 2 doses of Ixiaro administered 7 days apart has been studied in adults aged 18–65 years. In the accelerated schedule group, 99% of adults were seroprotected, compared with 100% of adults in the standard schedule group. The accelerated primary series was noninferior to the conventional dosing schedule.
The primary vaccination dose and schedule for Ixiaro varies by age (Table 4-06). To administer a 0.25-mL dose, health care providers must expel and discard half of the volume from the 0.5-mL prefilled syringe by pushing the plunger stopper up to the edge of the red line on the syringe barrel before injection. For all age groups, the 2-dose series should be completed ≥1 week before travel.
For adults and children, a booster dose (third dose) should be given at ≥1 year after completion of the primary Ixiaro series if ongoing exposure or reexposure to JE virus is expected.
There are limited data on the use of Ixiaro as a booster dose after a primary series with the mouse brain–derived inactivated JE vaccine. Three studies have been conducted, 2 in US military personnel and the other at 2 travel clinics in Europe. In 1 US military study and the European study, among adults who had previously received at least a primary series of mouse brain–derived inactivated JE vaccine, a single dose of Ixiaro adequately boosted neutralizing antibody levels and provided at least short-term protection. In 1 US military study investigating longer-term protection, the immunologic response at 12–23 months after 1 dose of Ixiaro in adults previously vaccinated with ≥3 doses of mouse brain–derived JE vaccine was noninferior to the response after 2 doses of Ixiaro in JE vaccine-naïve adults. In addition, seroprotective titers against both vaccine virus strains persisted in all participants who could be followed up at 2 years in the European study (N = 18).
VACCINE SAFETY AND ADVERSE REACTIONS
Ixiaro was licensed in the United States based on safety evaluations in almost 5,000 adults. Since licensure, >1 million doses of Ixiaro have been distributed in the United States. Local symptoms of pain and tenderness were the most commonly reported symptoms in a safety study with 1,993 adult participants who received 2 doses of Ixiaro. Headache, myalgia, fatigue, and an influenzalike illness were each reported at a rate of >10%. In children, fever was the most commonly reported systemic reaction in studies. Serious adverse events are reported only rarely.
PRECAUTIONS AND CONTRAINDICATIONS
A severe allergic reaction after a previous dose of Ixiaro or any other JE vaccine, or to any component of Ixiaro, is a contraindication to administration of Ixiaro. Ixiaro contains protamine sulfate, a compound known to cause hypersensitivity reactions in some people. No studies of Ixiaro in pregnant women have been conducted. Pregnancy is a precaution for use of Ixiaro and in most instances, its administration to pregnant women should be deferred. However, pregnant women who must travel to an area where risk for JE virus infection is high should be vaccinated when the theoretical risk of immunization is outweighed by the risk of infection.
CDC website: www.cdc.gov/japaneseencephalitis
Table 4-06. Vaccine to prevent Japanese encephalitis (JE)
|VACCINE||TRADE NAME (MANU-
|JE vaccine, inactivated||Ixiaro (Valneva)||2 mo–2 y||0.25 mL||IM||0, 28 d||≥1 y after primary series|
|3–17 y||0.5 mL||IM||0, 28 d||≥1 y after primary series|
|18–65 y||0.5 mL||IM||0, 7–28 d||≥1 y after primary series|
|>65 y||0.5 mL||IM||0, 28 d||≥1 y after primary series|
Abbreviation: IM, intramuscular
1If potential for JE virus exposure continues.
Table 4-07. Risk areas and transmission season for Japanese encephalitis (JE), by country1,2,3
|COUNTRY||AFFECTED AREAS||TRANSMISSION SEASON||COMMENTS|
|Australia||Outer Torres Strait Islands, northern Cape York||December–May; all human cases reported February–April||Rare cases reported from Outer Torres Strait Islands and 1 case previously reported from northern Queensland mainland
Vaccine only recommended for Outer Torres Strait Islands
|Bangladesh||Widespread||Year-round with most cases reported May–November||Cases reported from multiple areas, including Chittagong, Dhaka, Khulna, Rajshahi, Ranjpur, and Sylhet Divisions, so transmission likely countrywide|
|Bhutan||Presumed transmission in nonmountainous areas||Unknown||Rare cases reported but limited data
Proximity to endemic areas of India and presence of vectors suggests transmission likely
|Brunei Darussalam||Presumed widespread||Unknown||Limited data but outbreak reported in 2013
Proximity to Sarawak, Malaysia suggests ongoing transmission likely
|Burma (Myanmar)||Presumed widespread||Year-round with most cases reported July–September|
|Cambodia||Widespread||Year-round with peak season May–October||Cases reported from majority of provinces, so transmission likely countrywide|
|China||All provinces except Xinjiang and Qinghai||Peak season June–October|
|India||Andhra Pradesh, Arunachal Pradesh, Assam, Bihar, Goa, Haryana, Jharkhand, Karnataka, Kerala, Maharashtra, Manipur, Meghalaya, Nagaland, Odisha, Punjab, Tamil Nadu, Telangana, Tripura, Uttar Pradesh, Uttarakhand, West Bengal||Peak season May–November, especially in northern India; the season may be extended or yearround in some areas, especially in southern India|
|Indonesia||Widespread||Year-round, with peak season varying by island||Cases reported from many islands, including Sumatra, Java, Kalimantan, Bali, Nusa Tenggara, and Papua, so transmission likely on all islands
Several traveler cases reported in recent years from Bali
|Japan||All islands||June–October||Rare sporadic cases reported from all islands except Hokkaido Enzootic transmission without reported human cases on Hokkaido|
|Lao People’s Democratic Republic||Widespread||Year-round with peak season June–September|
|Malaysia||Widespread||Year-round, with peak season in Sarawak from October–December||Much higher rates of disease reported from Sarawak than peninsular Malaysia|
|Nepal||Southern lowlands (Terai), some hill and mountain districts||Peak season June–October||Highest rates of disease reported from southern lowlands (Terai) Vaccine not routinely recommended for those trekking in high-altitude areas|
|North Korea||Presumed widespread||Unknown
Proximity to South Korea suggests peak transmission May–November
|Pakistan||Unknown||Unknown||Very limited data
Rare cases reported from Sindh Province
|Papua New Guinea||Widespread||Presumed year-round||Sporadic cases reported from Western Province, serologic evidence of disease from Gulf and Southern Highland Provinces, and 1 case reported from near Port Moresby, so transmission likely countrywide|
|Philippines||Widespread||Year-round with peak season April–August||Human, animal, and mosquito studies have indicated transmission in 32 provinces, so transmission likely on all islands|
|Russia||Primorsky Krai||June–September||Cases previously reported from Primorsky Krai
Vaccine not routinely recommended
|Singapore||Presumed in focal areas||Year-round||Very rare sporadic cases reported
Vaccine not routinely recommended
|Sri Lanka||Widespread except in mountainous areas||Year-round with peak season
|Taiwan||Widespread||Peak season May–October|
|Thailand||Widespread||Year-round with peak season May–October, especially in northern Thailand||Highest rates of disease reported from Chiang Mai Valley
Several traveler cases reported in recent years from resort and coastal areas of southern Thailand
|Timor-Leste||Presumed widespread||No data
Proximity to West Timor suggests year-round
|Viet Nam||Widespread||Year-round with peak season May–October, especially in northern Viet Nam|
1 Destination and transmission season information should be considered in association with travel duration and activities when making decisions on vaccination.
2 Data are based on published and unpublished reports. Risk assessments should be performed cautiously, because risk can vary within areas and from year to year, and surveillance data regarding human cases and JE virus transmission are often incomplete. In some endemic areas, human cases among residents are limited because of vaccination or natural immunity among older people. However, because JE virus is maintained in an enzootic cycle between animals and mosquitoes, susceptible visitors to these areas still may be at risk for infection.
3 Outbreaks previously occurred in the Western Pacific Islands of Guam (1947–1948) and Saipan (1990), but as they are no longer considered risk areas, they are not included in the table.
- Dubischar KL, Kadlecek V, Sablan JB, Borja-Tabora CF, Gatchalian S, Eder-Lingelbach S, et al. Immunogenicity of the inactivated Japanese encephalitis virus vaccine Ixiaro in children from a Japanese encephalitis virus-endemic region. Pediatr Infect Dis J. 2017 Sep;36(9):898–904.
- Dubischar KL, Kadlecek V, Sablan B Jr, Borja-Tabora CF, Gatchalian S, Eder-Lingelbach S, et al. Safety of the inactivated Japanese encephalitis virus vaccine Ixiaro in children: an open-label, randomized, active-controlled, phase 3 study. Pediatr Infect Dis J. 2017 Sep;36(9):889–97.
- Hills SL, Walter EB, Atmar RL, Fischer M. Japanese encephalitis vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2019. In press.
- Jelinek T, Cromer MA, Cramer JP, Mills DJ, Lessans K, Gherardin AW, et al. Safety and immunogenicity of an inactivated Vero cell–derived Japanese encephalitis vaccine (Ixiaro, Jespect) in a pediatric population in JE non-endemic countries: an uncontrolled, open-label phase 3 study. Travel Med Infect Dis. 2018 Mar–Apr;22:18–24. doi: 10.1016/j.tmaid.2018.03.003.
- Jelinek T, Burchard GD, Dieckmann S, Buhler S, Paulke-Korinek M, Nothdurft HD, et al. Short-term immunogenicity and safety of an accelerated preexposure prophylaxis regimen with Japanese encephalitis vaccine in combination with a rabies vaccine: a phase III, multicenter, observer-blind study. J Travel Med. 2015 Jul-Aug;22(4):225–31.
- Paulke-Korinek M, Kollaritsch H, Kundi M, Zwazl I, Seidl-Friedrich C, Jelinek T. Persistence of antibodies six years after booster vaccination with inactivated vaccine against Japanese encephalitis. Vaccine. 2015 Jul 9;33(30):3600–4.
- Rabe IB, Miller ER, Fischer M, Hills SL. Adverse events following vaccination with an inactivated, Vero cell culture-derived Japanese encephalitis vaccine in the United States, 2009–2012. Vaccine. 2015 Jan 29;33(5):708–12.