Economic and disease burden of Japanese encephalitis in Zhejiang Province, 2013-2018.

BACKGROUND: Japanese encephalitis (JE) is a mosquito-borne disease and associated with high mortality and disability rate among symptomatic cases. In the absence of local data, this study estimated the economic burden and the disability-adjusted life years (DALYs) due to JE in Zhejiang Province, China during 2013-2018, to increase disease awareness and provide evidence for effective health policy. METHODOLOGY/PRINCIPLE FINDINGS: We merged multiple data sources, including National Notifiable Disease Registry System (NNDRS), patient interviews and medical records from corresponding hospitals for JE cases which occurred during 2013-2018 in Zhejiang Province. Direct costs were extracted from hospitals' billing systems and patient interviews. Indirect costs and disease burden were calculated based on questionnaire survey from patient interviews and follow-up assessment by general practitioners. Given under-reporting, an expansion factor (EF) was applied to extrapolate the JE burden to the provincial level. The total economic burden of JE during 2013-2018 was estimated at US $12.01 million with an EF = 3. Of this, $8.32 million was due to direct economic cost and $3.69 million to indirect cost. The disease burden of JE was 42.75 DALYs per million population (28.44 YLD, 14.28 YLL) according to the 1990 Global Burden of Disease (GBD 1990) methodology and 80.01 DALYs (53.67YLD, 26.34YLL) according to the GBD 2010 methodology. Sensitivity analysis demonstrated that the overall economic burden varied from US$ 1.73-36.42 million. The greatest variation was due to the prognosis of illness (-85.57%-203.17%), followed by occupation (-34.07%-134.12%) and age (-72.97%-47.69%). CONCLUSIONS/SIGNIFICANCE: JE imposes a heavy burden for families and society in Zhejiang Province. This study provides comprehensive empirical estimates of JE burden to increase awareness and strengthen knowledge of the public. These data may support provincial level public health decision making for prevention and control of JE. Ongoing surveillance for acute meningitis and encephalitis syndrome (AEMS) in sentinel hospitals, is needed to further refine estimates of JE burden.

How much does direct transmission between pigs contribute to Japanese Encephalitis virus circulation? A modelling approach in Cambodia.

Japanese Encephalitis (JE) is the most important cause of human encephalitis throughout Asia and the Pacific. Although JE is a vector-borne disease, it has been demonstrated experimentally that transmission between pigs can occur through direct contact. Whether pig-to-pig transmission plays a role in the natural epidemiological cycle of JE remains unknown. To assess whether direct transmission between pigs may occur under field conditions, we built two mathematical models of JE transmission incorporating vector-borne transmission alone or a combination of vector-borne and direct transmission. We used Markov Chain Monte Carlo (MCMC) techniques to estimate the parameters of the models. We fitted the models to (i) two serological datasets collected longitudinally from two pig cohorts (C1 and C2) during two periods of four months on a farm on the outskirts of Phnom-Penh, Cambodia and to (ii) a cross-sectional (CS) serological survey dataset collected from 505 swine coming from eight different provinces of Cambodia. In both cases, the model incorporating both vector-borne and direct transmission better explained the data. We computed the value of the basic reproduction number R0 (2.93 for C1, 2.66 for C2 and 2.27 for CS), as well as the vector-borne reproduction number Rpv and the direct transmission reproduction number Rpp. We then determined the contribution of direct transmission on R0 (11.90% for C1, 11.62% for C2 and 7.51% for CS). According to our results, the existence of pig-to-pig transmission is consistent with our swine serological data. Thus, direct transmission may contribute to the epidemiological cycle of JE in Cambodia. These results need to be confirmed in other eco-climatic settings, in particular in temperate areas where pig-to-pig transmission may facilitate the persistence of JE virus (JEV) during cold seasons when there are no or few mosquitoes.

Risk assessment for Japanese encephalitis vaccination.

Japanese encephalitis (JE) is the most commonly diagnosed viral encephalitis in Asia. JE is caused by a virus called JE virus (JEV), a member of the genus Flavivirus, family Flaviviridae, and is transmitted by Culex mosquitoes. Neutralising antibody to JEV protects against JE, and can be induced by vaccination. JE is a potential threat to travellers to endemic areas, which are most of South and Southeast Asia and some Pacific Islands. The risk of JE can be expected to increase with increasing mosquito exposure and time spent in regions and seasons of active transmission. JE is very rare in travellers, but mortality is high, around 1 in 3, and there is a high rate of lasting neurological damage. JE can therefore be a profoundly life changing event for a traveller. Travellers and their healthcare providers need to balance the low risk of disease against the very high severity of disease if it does occur. In order to make an informed decision, the severity of JE disease should be carefully explained to travellers to Asia.

Clinical development of IMOJEV ®--a recombinant Japanese encephalitis chimeric vaccine (JE-CV).

INTRODUCTION: Japanese encephalitis (JE) is a disease of the central nervous system (CNS) caused by Japanese encephalitis virus (JEV). JE is endemic in most of the South-East Asian countries and in some parts of the Western Pacific. As mosquito control is ineffective, currently vaccination is the only available control measure. A mouse brain-derived inactivated JE vaccine (MBDV) has been in use for a long time; however, it is not feasible for mass vaccination due to the ethical and safety issues. With the World Health Organization (WHO) appealing for the development of novel, safe and affordable JE vaccines, several vaccine candidates have been developed in the recent times and IMOJEV ® is one among them. AREAS COVERED: This review presents a brief account of various developmental, immunological and ethical issues related to IMOJEV® and provides an in-depth account of its clinical development and efficacy in comparison to other JE vaccines. EXPERT OPINION: IMOJEV® is a safe and efficacious vaccine. If made affordable through financial assistance from health agencies or by its production in set ups where operational costs are lower, it may become an ideal vaccine for mass vaccination in JE endemic regions.

An assessment of the interval between booster doses of Japanese encephalitis vaccine in the Torres Strait.

OBJECTIVE: Japanese encephalitis (JE) emerged for the first time in the Torres Strait, north Australia, in 1995. The inactivated mouse-brain derived JE vaccine was offered to all residents of the outer Torres Strait Islands prior to the 1996 wet season. This study was undertaken to determine the appropriateness of the recommended three-year interval between booster doses of the vaccine. METHODS: JE neutralising antibody was measured in residents of Badu Island for whom 30-36 months had passed since either a previous booster or the completion of the primary immunisation series. RESULTS: Only 70 (32%) of 219 eligible individuals had protective antibodies; 50 (37%) of the adults were immune, compared with 20 (24%) of the children (odds ratio (OR) 1.93; 95% confidence interval (CI) 1.01-3.74). CONCLUSIONS: This low level of immunity suggests that there is little in the way of natural boosting from either JE or other closely related viruses. Given the apparent low level of risk of exposure to the JE virus in the Torres Strait, and the logistical complexities involved in delivering the booster doses, the current recommendation of a three-year interval is not inappropriate. IMPLICATIONS: It would be advantageous to have a JE vaccine that is not only safer but also more immunogenic, so that it might be possible to further increase the booster dose interval.

A chimeric live attenuated vaccine against Japanese encephalitis.

Japanese encephalitis is a disease of the CNS, endemic in Asia and Oceania. The disease is refractory to drug treatments and whilst the rural economies remain heavily dependent on agriculture, conditions for propagation of the disease will persist. Thus, there is a need for effective vaccines. Although some currently exist, they have their shortcomings. ChimeriVax-JE (Acambis Inc.) is a chimeric, live attenuated vaccine which expresses protective Japanese encephalitis antigens and to date has proven to be safe, effective and well-tolerated in clinical trials. It therefore appears to be a cost-effective prophylactic vaccine against this debilitating disease.

Japanese encephalitis subunit vaccine composed of virus-like envelope antigen particles purified from serum-free medium of a high-producer J12#26 cell clone.

A stable cell clone, J12#26, which continuously secretes large amounts of the envelope (E) antigen of Japanese encephalitis (JE) virus (J. Virol. 77 (2003) 8745) was adapted to serum-free medium. The J12#26 antigen possessed hemagglutinating activity, as well as the viral E and M proteins. More than 10 and 1mg of the antigen quantified with the licensed JE vaccine (JE-VAX) as a standard by E-ELISA and protein determination, respectively, were recovered from 500 ml of serum-free medium by membrane ultrafiltration, Sephacryl S-300 chromatography, sucrose gradient centrifugation and Sephadex G-25 chromatography. SDS-PAGE and Western blot analyses confirmed the high yield and purity of the J12#26 E antigen, which was comprised of small spherical virus-like particles (VLP) of approximately 25 nm in diameter. This antigen induced in mice without adjuvant neutralizing antibody (NT Ab) titers, as high as or higher than the licensed JE vaccine, and complete protection against challenge with wild-type virus. These results suggest that the J12#26 antigen is a promising second-generation JE subunit vaccine.

Japanese encephalitis vaccines: current vaccines and future prospects.

Vaccination against JE ideally should be practiced in all areas of Asia where the virus is responsible for human disease. The WHO has placed a high priority on the development of a new vaccine for prevention of JE. Some countries in Asia (Japan, South Korea, North Korea, Taiwan, Vietnam, Thailand, and the PRC) manufacture JE vaccines and practice childhood immunization, while other countries suffering endemic or epidemic disease (India, Nepal, Laos, Cambodia, Bangladesh, Myanmar, Malaysia, Indonesia and the Philippines) have no JE vaccine manufacturing or policy for use. With the exception of the PRC, all countries practicing JE vaccination use formalin inactivated mouse brain vaccines, which are relatively expensive and are associated with rare but clinically significant allergic and neurological adverse events. New inactivated JE vaccines manufactured in Vero cells are in advanced preclinical or early clinical development in Japan, South Korea, Taiwan, and the PRC. An empirically derived, live attenuated vaccine (SA14-14-2) is widely used in the PRC. Trials in the PRC have shown SA14-14-2 to be safe and effective when administered in a two-dose regimen, but regulatory concerns over manufacturing and control have restricted international distribution. The genetic basis of attenuation of SA14-14-2 has been partially defined. A new live attenuated vaccine (ChimeriVax-JE) that uses a reliable flavivirus vaccine--yellow fever 17D--as a live vector for the envelope genes of SA14-14-2 virus is in early clinical trials and appears to be well tolerated and immunogenic after a single dose. Vaccinia and avipox vectored vaccines have also been tested clinically, but are no longer being pursued due to restricted effectiveness mediated by anti-vector immunity. Other approaches to JE vaccines--including naked DNA, oral vaccination, and recombinant subunit vaccines--have been reviewed.

Points to consider in the development of a surrogate for efficacy of novel Japanese encephalitis virus vaccines.

Although an effective killed virus vaccine to prevent illness due to Japanese encephalitis virus (JEV) infection exists, many authorities recognize that a safe, effective live JEV vaccine is desirable in order to reduce the cost and the number of doses of vaccine required per immunization. A large-scale clinical efficacy trail for such a vaccine would be both unethical and impractical. Therefore, a surrogate for the efficacy of JE vaccines should be established. Detection of virus-neutralizing antibodies in sera of vaccinees could constitute such a surrogate for efficacy. Field studies of vaccinees in endemic areas and studies done in mice already exist to support this concept. Also, titers of virus-neutralizing antibodies are already accepted as a surrogate for the efficacy of yellow fever virus vaccines and for the efficacy of other viral vaccines as well. In developing a correlation between N antibody titers and protection from JEV infection, standard procedures must be validated and adopted for both measuring N antibodies and for testing in animals. A novel live virus vaccine could be tested in the mouse and/or the monkey model of JEV infection to establish a correlation between virus-neutralizing antibodies elicited by the vaccines and protection from encephalitis. In addition, sera of subjects receiving the novel live JEV vaccine in early clinical trials could be passively transferred to mice or monkeys in order to establish the protective immunogenicity of the vaccine in humans. A monkey model for JEV infection was recently established by scientists at WRAIR in the US. From this group, pools of JEV of known infectivity for Rhesus macaques may be obtained for testing of immunity elicited by live JE vaccine virus.

Assessment of neutralizing antibodies elicited by a vaccine (Nakayama) strain of Japanese encephalitis virus in Taiwan.

A total of 368 blood specimens were resampled from a serum collection containing 2914 blood samples which were collected by a random sampling in Taiwan in 1991. The plaque reduction neutralization test was applied to evaluate the neutralizing ability to two strains of Japanese encephalitis viruses, i.e. Nakayama (the present vaccine strain) and JE5 (a Taiwan isolate). The result revealed that antibodies against JE virus were present in each stratified age group. Antibody positive rates were both highest in the group older than 70 years although the lowest rates were located in different groups. In addition, the result showed that the immunogenicity potency of the antibody induced by the vaccine strain did not have a good coverage against JE5. The rate of neutralizing antibodies above the level of protective efficacy of the present vaccine was limited as low as 37.93%. Efficacy of the vaccine used at present was apparently not efficient. Consideration of a more promising vaccine may be necessary.

Cost benefit analysis of Japanese encephalitis vaccination program in Thailand.

Using decision analysis, we estimated benefits, risks, and costs of implementing the Japanese encephalitis (JE) vaccination program in children aged 18 months and 6 years in Thailand. The costs for inclusion of JE vaccine into the routine immunization program at 18 months and 6 years are $2.16 and $3.68 per person, respectively. In the baseline model, the JE vaccination program will prevent 124 JE cases in the program for 18 months old children and 153 JE cases in the program for 6 years old children. The 18 month child program is more cost-effective than the 6 year child program. The cost-effectiveness ratio in the 18 month child program is $15,715 compared with $21,661 in the 6 year child program. The benefits of the JE vaccination program are the savings in treatment cost, disability care, and the future lifetime earnings from JE prevented. The 18 month child program will save $72,922 per one prevented JE compared with $66,197 in the 6 year child program. The JE vaccination program is cost-beneficial under the base-case assumption. Sensitivity analysis which alters various assumptions indicates that the JE vaccination program is worth implementing unless the incidence of JE is less than 3 per 100,000 population. Otherwise, the cost of vaccine has to be reduced.