Japanese encephalitis: is there a need for a novel vaccine?

Nearly half the human population, 3 billion people, currently live in countries where Japanese encephalitis (JE) occurs. JE is concentrated in China, India and Southeast Asia, where it is the leading cause of viral neurologic disability with an incidence exceeding that of herpes simplex virus. Clinical JE is a severe disease with a high case–fatality rate (30%) and up to 50% of surviving patients suffer from permanent neurological sequelae [1]. Although rigorous surveillance is lacking in most endemic countries, transmission intensity is probably increasing in Bangladesh, Cambodia, Indonesia, Laos, Myanmar and Pakistan owing to growing human populations, and intensified pig-rearing. Countries such as Japan and South Korea, with long-standing childhood immunization programs, have almost completely controlled clinical disease.

In the absence of specific antiviral treatments, the continuing availability of vaccines against JE is considered by many as a public health priority for the most affected regions. A number of multilateral organizations including PATH, the WHO, UNICEF and the US CDC are together developing a strategic plan that could broadly control JE by 2015. In the face of this strategic focus is the reality that the ‘traditional’ and widely used JE vaccine has not been manufactured since 2005 and no highly scrutinized commercial alternatives are readily available in the majority of JE-endemic countries. This mouse brain-derived vaccine had been the principal JE vaccine available internationally for many years. Manufactured in Japan by the Biken Institute (Osaka, Japan), it effectively controlled the disease both in Japan and in several Asian countries where it was widely used [2]. Its formulation had several drawbacks: it was relatively expensive, difficult to produce, needed multiple doses, and several booster dosing issues for long-term protection remained unsolved, which all led to the decision to cease production. It was rates of adverse events (AEs) that caused the greatest concern [2–6]. In recent years, the WHO has discouraged the use of mouse brain-derived vaccines for any disease in any setting. With the mouse brain-derived JE vaccine, potentially life-threatening AEs that included upper airway angioedema and related hypersensitivity reactions were estimated to occur at a rate of between one and 17 per 10,000 vaccinees [7–12]. Initially, the pathogenesis of these AEs were thought to be due to gelatin, which was used as a stabilizer in the vaccine, and later thought to be caused by residual murine proteins in the vaccine, but remain largely unexplained. In addition, severe and occasionally fatal cases of acute disseminated encephalomyelitis (ADEM) were reported. In 2005, Japan suspended routine immunization with this vaccine after a case of ADEM in a Japanese recipient, although a definite causal link was never established. The manufacturer ceased production in that year, although stockpiles of exports to many countries are expected to last until later this year.

Whether the 30,000–50,000 cases of JE that are reported annually [13] justify the development of a new vaccine, given the high cost of clinical trials manufacturing and regulatory issues, may be questioned. Surveillance generally underestimates the true burden of disease, as the majority of infections are asymptomatic, resulting in a case-to-infection ratio of approximately one in 250 [14]. Furthermore, only approximately 20% of all cases are reported, even if symptomatic [15]. According to the WHO, an estimated 175,000 JE cases resulting in 78,000 cases of newly disabled children and 45,000 deaths would occur annually in the absence of immunization [15]. JE has now spread to the Torres Strait Islands and northern Australia [1–16]. A major JE outbreak occurred in 2005 in Uttar Pradesh (India) and in Nepal [17,18], signaling an apparent increase in incidence in densely populated areas. The virus is transmitted by Culex tritaeniorhynchus and related ground pool-breeding mosquitoes to pigs and aquatic birds, which are the principal viral-amplifying hosts. JE cases are therefore more often acquired in rural areas, in particular areas where rice paddies are prevalent. Industrialization and the development of cities have led to a decline in JE cases in some areas owing to the local reduction in pig farming and paddy fields, but cases continue to be reported even from the edges of cities including Beijing and Hanoi, as increased population densities are in close proximity to vectors [19]. Furthermore, increasing pig farming and rice cultivation in some endemic areas is also worrisome. Climate change may increase the proliferation of mosquitoes and influence the migration patterns of birds [20]. Areas with irrigated rice-production systems may become more arid in the future, and the impact of flooding will be more dramatic, which in turn might result in JE outbreaks.

Japanese encephalitis also poses a risk to travelers to the region. The crude risk of JE in travelers to southeast Asia is generally not high and is of the order of one per 1 million travelers. However, most travelers only visit urban and low-risk tourist areas, not rural agricultural settings. The risk to travelers visiting rural foci at times of peak transmission has been estimated to be as high as one in 5000 to one in 20,000 [1]. Several dozen sporadic and unpredictable cases of JE among travelers, many on seemingly benign and short itineraries, have been reported in the past 30 years [21,22]. As Buhl and Lindquist say, “it seems that Culex tritaeniorhynchus hosting the JE virus are present at places and at times of the year contradicting expectation of no JE transmission” [23]. Continued availability of a JE vaccine is therefore also paramount for international travelers.

In addition to the long-standing and successful vaccination programs in Japan and South Korea, countries such as Taiwan, China, Vietnam and Thailand have adopted some form of childhood vaccination programs against JE [2]. With the exception of the People’s Republic of China, all countries practicing JE vaccination use formalin-inactivated mouse brain vaccines. China developed a cell culture-derived (primary hamster kidney) live-attenuated vaccine using the SAR 14-14-12 strain, which has been in use since the late 1980s and administered to more than 200 million children [24]. The vaccine is administered subcutaneously at 1 and 2 years of age [25]. Efficacy studies have shown that a single dose is 72–100% effective, while an additional dose administered 1–3 months or 1 year after the first dose is 97.5% effective [26]. Despite much experience, it has not gained wide international acceptance owing to its potential for adventitious viruses, due to its production on primary hamster kidney cells and the nonclonal nature of seed stock [24]. These concerns have led to other approaches to vaccine development.

Novel vaccines against JE

The WHO has placed a high priority on the development of a new vaccine for the prevention of JE. Two vaccine approaches – a chimeric live-attenuated and an inactivated vaccine – have completed Phase II trials and are now registered in a limited number of countries or are in the process of being registered. Each has certain advantageous characteristics.

ChimeriVax™-JE is a lyophilized formulation of a recombinant, attenuated, single-dose, live-virus vaccine containing chimeric virus consisting of structural genes (prM and prE) from the JE strain SA 14-14-12. The chimeric viral vaccine was produced by incorporating JE virus genes from SA 14-14-12 into an attenuated strain of yellow fever (YF) virus, YF 17D. The resultant chimeric virus has been shown in several studies to be less neurovirulent than YF 17D in both mice and nonhuman primates [27]. It has been tested in humans and was demonstrated to be safe and efficacious [24,28–31]: a single dose is sufficient to induce a 100% seroconversion rate and no safety concerns were evident [32]. Pre-existing YF immunity did not reduce seroconversion to JE [32]. Animal models suggest that this live chimeric JE virus vaccine will also offer some protection against other viruses belonging to the JE virus serocomplex, consistent with the observation of cross-protection following live virus infections [33]. This vaccine is also expected to be cheaper to produce than the mouse brain-derived Biken vaccine. The combination of ease of administration (single dose), low cost, high immunogenicity and potential cross-protective activity are promising. However, some have expressed concern about the theoretical possibility of untoward recombination events or very rare serious AEs as occurred with the YF vaccine [34–36].

Recently licensed in the USA and the EU, the JE vaccine IC-51 (IXIARO, Novartis) is an inactivated, alum-adjuvanted vaccine that is manufactured in cultured Vero cells. It is administered in a two-dose regimen at 0 and 28 days. Seroprotection was achieved 1 week after the second vaccination. Immune responses at 56 days postvaccination, including seroconversion rates and geometric mean titres, were noninferior to those seen with the Biken vaccine [37]. The vaccine was shown to be safe [37,38]. Questions regarding duration of protection, the need or timing of booster doses, and whether or not to consider a previous history of vaccination with mouse-brain vaccine or not are yet to be answered. This vaccine is expected to be more expensive than the chimeric vaccine, but the potential for ra educed cost or high-volume pricing for public-health programs is not clear at present.

Control of JE in endemic areas will require a multifactorial approach, including adequate surveillance, changes to agricultural practices and possibly pig vaccination, as well as resources and political will. Human vaccination will still play a key component and the need for new and effective vaccines with long durations of efficacy with minimal doses will be paramount.

Financial & competing interests disclosure

Both Annelies Wilder-Smith and David Freedman have accepted speaking fees, travel, and have served on Advisory Boards for Novartis Vaccines and Diagnostics. Annelies Wilder-Smith is currently the principal investigator of a vaccine trial for Sanofi Pasteur. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.