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Japanese Encephalitis: New Options for Active Immunization

  1. Scott B. Halstead1 and
  2. Stephen J. Thomas2
  1. 1Research Program, Pediatric Dengue Vaccine Initiative, Rockville, Maryland
  2. 2Department of Virology, US Army Medical Component-Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
  1. Reprints or correspondence: Dr Scott B. Halstead, Research Program, Pediatric Dengue Vaccine Initiative, 5824 Edson Lane, Rockville, MD 20852 (halsteads{at}erols.com).
 
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Abstract

Japanese encephalitis (JE) is a mosquito-borne flavivirus infection responsible for significant morbidity and mortality across Asia. Indigenous populations and those who undertake short- and long-term travel to endemic regions are at risk of infection and development of neuroinvasive disease. Effective mouse brain-derived vaccines have been available in select countries, including the United States, for decades. Limited access in Asia and safety concerns with regard to mouse brain products prompted the Chinese to develop a live, attenuated virus vaccine (SA14-14-2; Chengdu Institute of Biological Products), which has proven to be safe and efficacious following administration of >300 million doses. Recently, the portfolio of JE vaccines increased again with licensure in the United States, Europe, and Australia of a purified, inactivated virus JE vaccine (IC51; Intercell AG) and filing for licensure in Thailand and Australia of a Yellow fever-JE chimeric vaccine (ChimeriVax-JE; Sanofi Pasteur). JE is a vaccine-preventable disease with numerous options now available for active immunization. Aggressive and responsible vaccination programs should greatly diminish the burden of disease.

Japanese encephalitis (JE), a mosquito-borne flaviviral zoonotic infection, is the leading recognized cause of viral encephalitis in Asia. JE virus is transmitted by Culex species mosquitoes throughout Asia, a region supporting high rates of tourism and with an indigenous population of 14 billion people. For many years, only an inactivated JE vaccine made from infected mouse brain was licensed for use by residents and travelers. This vaccine proved to have an unacceptable level of adverse safety events. Recently, the JE vaccine landscape has changed. A safe and efficacious single-dose, live-attenuated vaccine produced in China has become available to many Asian countries. A new, inactivated JE vaccine is now licensed for use in Europe, Australia, and the United States. A yellow fever (YF)-JE chimeric vaccine candidate is nearing licensure in developed and developing countries. This paper briefly reviews the epidemiology and clinical characteristic of JE and focuses on attributes of second-generation JE vaccines.

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Epidemiology

The rice paddy-breeding Culex tritaeniorhynchus summarosus, a night-biting mosquito that feeds preferentially on large domestic animals and birds and infrequently on humans, is the principal vector of zoonotic and human JE in northern Asia. A more complex ecology prevails in southern Asia, from Taiwan to India, where Cx. tritaeniorhynchus and members of the closely related Culex vishnui group are vectors. Before the introduction of JE vaccine, summer outbreaks of JE occurred regularly in Japan, Korea, China, Okinawa, and Taiwan. Over the past decade, there has been a pattern of steadily enlarging recurrent seasonal outbreaks in Vietnam, Thailand, Nepal, and India, with small outbreaks in the Philippines, Indonesia, and the northern tip of Queensland, Australia [1]. Seasonal rains are accompanied by increases in mosquito populations and increased transmission. Pigs serve as amplifying hosts. In contrast, humans are dead end hosts because they experience short duration and low level viremia [2]. There is no human-tohuman transmission.

In economically advanced Asian countries, such as Japan, Korea, and Taiwan, and in moderate- and low-income countries, such as Thailand, Sri Lanka, and Nepal, the integration of JE vaccine into routine vaccination programs has led to the near elimination of JE [3] (Nepal program; J.B. Tandan, personal communication). Despite widespread vaccination, >9000 cases were reported in the Southeast Asia and Western Pacific regions in 2007 [4]. From the standpoint of risk, it is important to understand that reported cases vastly underestimate the infectious burden. The ratio of infections to symptomatic JE cases has been estimated to vary between 1:25 and 1:300; the lower rates (1:200–1:300) were observed in northern Asian persons who were indigenous to the zoonotic heartland of JE, whereas higher rates were measured in nonindigenous military personnel [5–7]. Determinants for developing overt neurologic disease following infection are not completely understood. JE resembles West Nile infections in this respect [8].

In endemic areas, the incidence of JE disease is greater among young persons; attack rates in the 3–15-year age group are 5–10 times higher than among older persons [2, 9]. The higher disease rates in younger persons reflect high immunity rates in adults. Numerous studies and epidemiologic observations document a weak protective effect of prior dengue virus infection on subsequent overt JE disease [10–14].

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Clinical

Typically, symptoms start suddenly following a variable incubation period of 2 days to 2 weeks and a nonspecific viral prodrome. The earliest symptoms include lethargy, fever, headache, abdominal pain, nausea, and vomiting [15]. These may be followed by a combination of nuchal rigidity, photophobia, altered consciousness, hyperexcitability, masked facies, muscle rigidity, cranial nerve palsies, tremulous eye movements, tremors and involuntary movement of the extremities, paresis, incoordination, and pathological reflexes [9]. Neurologic manifestations may include meningeal (meningitis), parenchymal (encephalitis), or spinal cord (myelitis) involvement [16]. Sensory deficits are rare. Among infected children, 50%–85% develop focal or general seizures, compared with 10% of adult cases [15]. Seizures have been associated with poor clinical outcome [17].

Peripheral leukocytosis with left shift and hyponatremia may be observed. Cerebrospinal fluid opening pressure can be elevated in up to 50% of cases; protein levels are often normal or mildly elevated [2]. Cerebrospinal fluid pleocytosis ranges from 10 to a few thousand cells per cubic millimeter (median of several hundred cells per cubic millimeter) and are predominantly of lymphocytic origin [18]. Electroencephalogramdemonstrates diffuse delta wave activity and, rarely, spike and seizure patterns [15]. Imaging studies demonstrate diffuse white matter edema and abnormal signals in the thalamus (often bilateral and hemorrhagic), basal ganglia, cerebellum, midbrain, pons, and spinal cord [19, 20].

In nonfatal cases, clinical improvement occurs after ∼1 week, paralleling defervescence. Recovery of neurologic function may take weeks to years. Seizure disorders, motor and cranial nerve paresis, and movement disorders may persist in up to one-third of patients. Persistent behavioral and/or psychological abnormalities occur in 45%–75% of survivors and are more severe in children [21]. There is no specific therapy for JE; supportive care focuses on controlling seizures, ventilator support of respiratory failure, and monitoring and reducing cerebral edema [22]. Anecdotal use of interferon-α and ribavirin has been reported with negative results [23, 24]. Fatality rates vary between 5% and 40% and are often reflective of the available standard of medical care.

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Prevention of JE

Personal protective measures. Individuals traveling to endemic areas can reduce their risk of vector exposure and infection by use of mosquito repellent and long-sleeved shirts and trousers, by avoiding outdoor activities in the evening, and by sleeping under permethrin-impregnated mosquito nets or in screened or air-conditioned rooms [25, 26].

Active vaccination: general principals. The JE virus is a small (50 nm), enveloped virus containing a 10.7 kb, singlestranded RNA genome. The viral envelope protein serves as the cell receptor binding protein and the fusion protein for virus attachment and entry into the host. Antibodies directed against envelope protein neutralize the virus and play an important role in protection [27, 28]. A JE neutralizing antibody titer ⩾1:10 is commonly accepted as evidence of protection [29–32].

First-generation JE vaccines. JE vaccines have been available since the 1950s [33, 34]. For decades, 2 vaccines were routinely used: (1) an inactivated mouse brain-derived vaccine and (2) an inactivated vaccine cultivated on primary hamster kidney cells.

The inactivated mouse brain vaccine containing either Nakayama or Beijing-1 virus strains was developed in Japan. Local production of this vaccine has contributed toward decrease in the incidence of JE in Thailand, India, Korea, Taiwan, Vietnam, and areas of Malaysia and Sri Lanka [35]. For several decades, this JE vaccine has been available in the United States and Europe (BIKEN, distributed by Sanofi Pasteur as JE-Vax) [36, 37]. The Green Cross JE vaccine, manufactured by Green Cross Vaccine, was not licensed for use in the United Kingdom and was not widely available in Europe but was distributed by MASTA on a named patient basis [38, 39]. Seroconversion rates, quantitative neutralizing antibody titers following vaccination, and efficacy rates varied according to the population studied (indigenous vs nonindigenous) and number of doses administered (1, 2, or 3 doses in the primary vaccination series) [3, 32]. A single efficacy trial showed equivalent protection afforded by either Beijing-1 or Nakayama strains [31]. For travelers, a 3-dose vaccination series has been recommended [37].

Vaccine reactogenicity was acceptable over years of use, but the occurrence of a single case of acute disseminated encephalomyelitis temporally related to vaccination in Japan prompted the Japanese government (May 2005) to suspend routine childhood JE vaccination. The Global Advisory Committee on Vaccine Safety noted that there was no definite evidence of an increased risk of acute disseminated encephalomyelitis temporally associated with JE vaccine and that a causal link had not been demonstrated [40, 41]. Acute disseminated encephalomyelitis has been reported as a severe drug reaction following administration of inactivated mouse-brain vaccine in 5×10−4 to 1×10−6 administered doses [34, 42]. In addition, since 1989, numerous cases of moderate to severe hypersensitivity type reactions temporally associated with JE vaccination have been reported [40, 43, 44]. Adverse events have occasionally resulted in hospitalization requiring supportive care inclusive of parenteral steroids. Data collected on over 99,000 JE (BIKEN) vaccine recipients from Denmark, Sweden, United Kingdom, Australia, Canada, and the United States estimate the rate of hypersensitivity reactions at 0.7–104 reactions per 10,000 vaccinees [40].

The causes of temporally associated neurologic or hypersensitivity reactions are not clearly understood; the presence of murine neural proteins, gelatin, and/or thimerosal in vaccine preparations have all been implicated but none proven as causative. BIKEN ceased production of JE-VAX in 2005; supplies are nearing exhaustion.

A second inactivated vaccine has been in wide use. Approximately 70 million doses of the primary hamster kidney cell culture inactivated JE vaccine (Beijing-3, P-3 strain) were administered in China yearly until 2005. This was the country's principal JE vaccine since 1968 [45]. Randomized field trials demonstrated vaccine efficacy of 76%–95% [45, 46].

Second-generation JE vaccines. The development and licensure of second-generation, non-mouse brain-derived JE vaccines is important news for nations looking for options to protect travelers, expatriate workers, and military personnel. These vaccines provide new options of benefit to endemic countries because of their improved safety profile and lower dosage requirements.

SA14-14-2, a live attenuated vaccine, has progressively been introduced into China where it has demonstrated an excellent safety profile, effectiveness (88%–96%), and efficacy in large scale trials (involving >200,000 children) and is replacing the inactivate primary hamster kidney cell culture vaccine (Yu Yong Xin, personal communication) [47–50]. Since its licensure in China in 1988, >300 million doses have been produced and administered to >120 million children. Numerous large scale evaluations of vaccine safety demonstrate low rates (0.2%–6%) of short-lived local and systemic (ie, fever) reactogenicity and essentially no neurotoxicity [51]. Case-control studies of a large vaccine trial in Nepal showed rapid onset of protection followed by a 5-year efficacy of 96% after a single dose of vaccine [52–54]. In a small single study, SA14-14-2 vaccine was coadministered with live measles vaccine in children; normal immune responses were retained to each vaccine [55]. Recently, the vaccine has been licensed for use, and millions of doses have been administered in Nepal, India, Sri Lanka, and South Korea [56]. The Chinese manufacturer, Chengdu Institute of Biological Products, is seeking prequalification by the World Health Organization [57].

PATH has negotiated concessional prices for the use of SA14-14-2 in India, Sri Lanka, and Nepal for public health preventive programs [58]. The SA14-14-2 vaccine has recently been incorporated into the national extended program for immunizations in Nepal and China (Dr Jay Tandan and Dr Yu Yong Xin, respectively, personal communications)

IC51 (IXIARO; in Australia and New Zealand, JESPECT). The IC51 vaccine is a purified, formalin-inactivated, wholevirus JE vaccine developed by Intercell AG; the product was licensed for use in the United States, Australia, and Europe in the spring of 2009. Kollaritsch et al [34] have published a useful review of the product's development life cycle.

The vaccine construct was developed at the Walter Reed Army Institute of Research (Silver Spring, MD) [59]. The vaccine is based on a SA14-14-2 virus strain passaged 8 times in primary dog kidney cells, cultivated in Vero cells, and formulated with 0.1% aluminum hydroxide [60]. Vero cells maintained in serum-free medium were selected as the manufacturing cell substrate. The absence of serum allows for a simplified purification process and, potentially, a superior safety profile [61–64]. As an added safety advantage, this vaccine does not require additional stabilizers or additives.

Several early-phase clinical studies established the safety and immunogenicity of the IC51 candidate (Table 1) [34, 65]. Multinational phase 3 immunogenicity trials demonstrated that the IC51 vaccine was well tolerated and elicited noninferior immune responses, compared with control (JE-VAX) [66]. There was no evidence of an increased incidence of rare adverse events (including anaphylaxis or anaphylactoid reactions) compared with placebo [67].

Table 1.
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Table 1.

Safety and Immunogenicity Summary of Published Reports Testing IC51 in Phase 1–3 Clinical Trials

Additional studies demonstrated high seroconversion rates (83%) 1 year following vaccination; the superiority of the standard dosing regimen (2 × 6 μg), compared with using lowor high-dose strategies; that the presence of TBE antibodies had no safety impact but heightened the JE immune response following a single dose; and no adverse impact on safety or immunogenicity of either vaccine when IC51 was administered concomitantly with HAVRIX 1440 [68–71]. Intercell AG has entered into distribution partnerships to supply vaccine to markets in the United States, the European Union, Japan, South Korea, Latin America, India, Bhutan, Nepal, Bangladesh, Australia, New Zealand, Papua New Guinea, and Pacific Islands [73].

ChimeriVax-JE (IMOJEV). Sanofi Pasteur has developed a JE vaccine based on a chimeric virus generated at the St. Louis University Health Sciences Center (St. Louis, Missouri) and Acambis. ChimeriVax-JE virus is produced using infectious clone technology based on insertion of prM and envelope genes from SA JE SA14-14-2 virus into the nonstructural genes of YF 17D viral strain as the viral “backbone” [74]. The resulting chimeric RNA was electroporated into Vero cells. Progeny virus particles contain JE-specific antigenic determinants that elicit neutralizing antibodies as well as cytotoxic T lymphocytes [75]. YF 17D was chosen as backbone to the chimera because of its proven record of safety and efficacy.

Inoculation of ChimeriVax-JE in nonhuman primates resulted in no illness and transient, low viremia, followed by high titers of anti-JE neutralizing antibodies. A World Health Organization monkey neurovirulence test scored only minimal brain and spinal cord lesions. Vaccinated monkeys were protected against intracranial or intranasal virulent JE virus challenge [76, 77].

Because it is a living agent, ChimeriVax-JE virus has been evaluated for its ability to replicate in and to be transmitted by vector mosquitoes. Individual Cx. tritaeniorhynchus, Aedes albopictus, and Ae. aegypti mosquitoes ingested a virus-laden blood meal or were inoculated intrathoracically. ChimeriVax-JE virus did not replicate following oral feeding in any of the 3 mosquito species. In Cx. tritaeniorhynchus, replication was not detected after intrathoracic inoculation of ChimeriVax-JE. No genetic changes were associated with replication of vaccine virus in mosquitoes [78]. None of 3 Australian mosquitoes (Cx. annulirostris, Cx. gelidus, and Ae. vigilax) became infected after being fed orally with 6.1 log10 PFU/mL of ChimeriVax-JE vaccine [79].

Safety and immunogenicity of ChimeriVax-JE (high and low dose) was established in a phase 1 trial comparing immune responses in YF-immune and flavivirus-naive volunteers (Table 2). Low-level viremias were observed in both groups, and the frequency of all adverse events was similar between groups. Overall, 96% of subjects who received ChimeriVax-JE developed neutralizing antibodies to ⩾1 of the wild-type JE strains tested (Beijing, P3, Nakayama) [80]. In a phase 2 study, ChimeriVax-JE was well tolerated with viremias of short duration and low titer; 94% of subjects administered graded doses (1.8– 5.8 log10 PFU) of ChimeriVax-JE developed neutralizing antibodies. A second dose, administered 30 days later, had no booster effect. Previous inoculation with YF did not interfere with ChimeriVax-JE, but there was a suggestion (not statistically significant) that ChimeriVax-JE interfered with YF-VAX administered 30 days later. In an additional study involving a larger number of subjects, ChimeriVax-JE did not interfere with YF vaccine (Farshad Guirakhoo, personal communication). There is evidence that ChimeriVax-JE induces sterilizing immunity [81].

Table 2.
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Table 2.

Safety and Immunogenicity Summary of Published Reports Testing IMOJEV in Phase 1–2 Clinical Trials

As of July 2009, clinical studies involving 1400 children and 2400 adults had been conducted in the United States, Australia, Thailand, and the Philippines testing ChimeriVax-JE. A single dose of ChimeriVax-JE in adults achieved an equivalent immune response to 3 doses of JE-VAX. A single dose of ChimeriVax- JE elicited a protective level of neutralizing antibodies in 94% and 99% of subjects at 14 days and 1 month after vaccine administration, respectively. A phase 3 noninferiority study involving toddlers showed that 95% of JE virus-naive subjects were seroprotected within 1 month after a single dose of ChimeriVax-JE. No vaccine safety concerns were uncovered. For a review of nonclinical and clinical studies performed on ChimeriVax vaccines, see Guy et al [82]. Sanofi Pasteur has filed (7 July 2009) for marketing authorization with the Therapeutic Goods Administration in Australia and the Food and Drug Administration in Thailand [83].

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Discussion

On 12 July 2009, the United States Centers for Disease Control and Prevention Advisory Committee on Immunization Practices published provisional recommendations for use of JE vaccines. The Advisory Committee on Immunization Practices suggests that physicians and others should counsel travelers to be aware of the low-level but almost unavoidable risk of acquiring JE when traveling to countries where JE is enzootic. Risk can be reduced by using personal protective measures to avoid vector exposure. However, JE vaccination should be considered to be an important option to reduce the risk. Risk is a function of exposure which, in turn, is a function of disease epidemiology. Travel during the rainy season, residence in rural or agricultural areas, residence near pig farms, or long duration visits all increase risk for JE. Currently, vaccination is recommended for these individuals, noting that particularly high-risk activities are those that occur outdoors, near agricultural areas, during evening hours, and where lodging is in the open without use of bed nets. Travel to an area where JE is endemic without a defined destination calls for vaccination. JE vaccine is not recommended for short-term travelers whose visit will be restricted to urban areas or times outside of a well-defined JE virus transmission season. Lastly, JE vaccine is recommended for laboratory personnel who work with live, wild-type JE virus strains. Vaccinated, at-risk laboratory personnel should receive appropriate booster doses of JE vaccine or be evaluated regularly for JEV-specific neutralizing antibodies to assure adequate titers [84]. Other groups have offered recommendations for the expanded use of JE vaccines in travelers and expatriates, but data are currently lacking to support a consensus [85–86].

JE continues to be a significant and underestimated cause of morbidity and mortality in Asian countries. Successful implementation of JE vaccination programs among residents of areas where JE is enzootic have proven that active vaccination is capable of eliminating this disease. For travelers, military personnel, and expatriates who are also at risk of JE infection and who have a higher intrinsic risk of developing encephalitis than indigenous populations, vaccination options that previously were limited have decisively changed. Large clinical trials of 2 second-generation JE vaccines have demonstrated safety and that they generate a potent immune response. One product (IC51 or IXIARO) has been licensed for use in the United States, Europe, and Australia, and another (ChimeriVax-JE or IMOJEV) has recently filed for licensure in Australia and for “fast track” consideration for licensure in Thailand. These together with the inexpensive Chinese SA14-14-2 live attenuated vaccine available in some Asian countries change the vaccine landscape. Because of their excellent safety profiles, ability to protect against JE with <3 doses, and onset of effectiveness almost immediately or within 30 days of initial vaccination, new JE vaccines are particularly suitable for travelers or to combat JE epidemics.

Because there is no other effective public health option for the prevention of Japanese encephalitis and there is reason to believe that the new-generation vaccines are safe and will result in long-lasting protection, we believe that even a single case of JE must be judged to be inexcusable and that JE vaccines should be administered universally to all who live in or visit areas where JE is enzootic.

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Acknowledgments

Potential conflicts of interest. S.J.T was an associate investigator on a clinical trial evaluating the JE-PIV (IC51, IXIARO) vaccine.

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Footnotes

  • The opinions or assertions contained herein are the private views of the author (S.J.T.) and are not to be construed as reflecting the official views of the United States Army or the United States Department of Defense.

  • Received October 6, 2009.
  • Accepted January 4, 2010.
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