Japanese Encephalitis Virus Vaccination Elicits Cross-Reactive HLA-Class I-Restricted CD8 T Cell Response Against Zika Virus Infection.

Japanese encephalitis virus (JEV) exposure or vaccination could elicit cross-reactive CD8 T cell immunity against heterologous flaviviruses in humans. In addition, cross-reactive CD8 T cells induced by dengue virus (DENV) have been shown to play a protective role against Zika virus (ZIKV). However, how JEV exposure or vaccination affects ZIKV infection in humans remains unclear. In this report, epitope prediction algorithms were used to predict the cross-reactive CD8 T cell epitope restricted to human HLA between JEV and ZIKV. We found that these predicted CD8 T cell epitopes are immunogenic and cross-reactive in humanized HLA transgenic mice. Moreover, JEV vaccine immunization provided cross-protection against ZIKV infection. Furthermore, CD8 T cells were involved in the protection against ZKIV infection in vivo. Our results have an important clinical implication that vaccination with JEV SA14-14-2 may provide protection against ZIKV infection in humans.

Neutralizing antibody persistence in pediatric travelers from non-JE-endemic countries following vaccination with IXIARO® Japanese encephalitis vaccine: An uncontrolled, open-label phase 3 follow-up study.

BACKGROUND: In an initial study among children from non-Japanese encephalitis (JE)-endemic countries, seroprotection rates remained high 6 months after completion of the primary series with IXIARO®. METHODS: In this open-label follow-up study, a subset of 23 children who received a 2-dose primary series of IXIARO® in the parent study, were evaluated for safety and neutralizing antibody persistence for 36 months. RESULTS: Seroprotection rates (SPRs) remained high but declined from 100% one month after primary immunization to 91.3% at month 7 and 89.5% at month 36. Geometric mean titers (GMTs) declined considerably from 384.1 by day 56-60.8 at month 36. No long-term safety concerns were identified. CONCLUSIONS: The substantial decline in GMT observed in this study, together with previously published data on children vaccinated with IXIARO® support the recommendation for a booster dose in children who remain at risk of JE from 1 year after the primary series of IXIARO®, consistent with the recommendation for adults. CLINICAL TRIAL REGISTRY NUMBER: NCT01246479.

Bivalent vaccine platform based on Japanese encephalitis virus (JEV) elicits neutralizing antibodies against JEV and hepatitis C virus.

Directly acting antivirals recently have become available for the treatment of hepatitis C virus (HCV) infection, but there is no prophylactic vaccine for HCV. In the present study, we took advantage of the properties of Japanese encephalitis virus (JEV) to develop antigens for use in a HCV vaccine. Notably, the surface-exposed JEV envelope protein is tolerant of inserted foreign epitopes, permitting display of novel antigens. We identified 3 positions that permitted insertion of the HCV E2 neutralization epitope recognized by HCV1 antibody. JEV subviral particles (SVP) containing HCV-neutralization epitope (SVP-E2) were purified from culture supernatant by gel chromatography. Sera from mice immunized with SVP-E2 inhibited infection by JEV and by trans-complemented HCV particles (HCVtcp) derived from multi-genotypic viruses, whereas sera from mice immunized with synthetic E2 peptides did not show any neutralizing activity. Furthermore, sera from mice immunized with SVP-E2 neutralized HCVtcp with N415K escape mutation in E2. As with the SVP-E2 epitope-displaying particles, JEV SVPs with HCV E1 epitope also elicited neutralizing antibodies against HCV. Thus, this novel platform harboring foreign epitopes on the surface of the particle may facilitate the development of a bivalent vaccine against JEV and other pathogens.

Japanese encephalitis vaccine in travelers.

Extensive vaccination against Japanese encephalitis (JE) has been carried out in many Asian countries for the past 20 years and is also increasingly recommended for travelers to endemic areas. Concerns have been raised regarding potential neurological and allergic side effects of the currently available JE vaccine, which is manufactured from mouse brain. A new purified, inactivated JE virus vaccine (IC51) has been developed, which is manufactured in a Vero cell culture substrate. Studies show that the vaccine is both safe and immunogenic and the product will be licensed very soon for use in many industrialized countries. Once a highly immunogenic and safe product is available, wider use of JE vaccine in travelers will be prudent. Currently, vaccination is restricted to travelers with an increased risk of acquiring JE. Individuals at increased risk have been defined quite arbitrarily as travelers with increased behavioral contact to JE-transmitting mosquitoes, in particular, during stays in rural areas and during the transmission season. However, the possibility of an infection with JE virus can never be ruled out when traveling to endemic areas and infection can prove disastrous for the individual concerned. Since a safe product will be available very soon, guidelines and recommendations will have to be reconsidered.

Novel strategy for treatment of Japanese encephalitis using arctigenin, a plant lignan.

UNLABELLED: OBJECTIVES; To evaluate therapeutic efficacy of arctigenin in an experimental model of Japanese encephalitis (JE). METHODS: Four- to 5-week-old BALB/c mice of either sex were infected intravenously with lethal dose of 3 x 10(5) pfu of Japanese encephalitis virus (JEV). By the 9th day post-infection, all untreated animals succumbed to the infection. Arctigenin was dissolved in DMSO at a concentration of 0.5 mg/mL and stored at 4 degrees C. After one day following virus inoculation, animals were given arctigenin intraperitoneally, twice daily (10 mg/kg of body weight) for next 7 days. RESULTS: Treatment with arctigenin provided complete protection against experimental JE. Arctigenin's neuroprotective effect was associated with marked decreases in: (i) viral load; (ii) active caspase-3 activity; (iii) reactive oxygen species and reactive nitrogen species; (iv) microgliosis and proinflammatory cytokines; (v) levels of stress-associated signalling molecules; and (vi) neuronal death. Furthermore, treatment with arctigenin also improves the behavioural outcome following JE. CONCLUSIONS: In conclusion, our findings provide a novel mechanistic insight into the actions of arctigenin in JE. Results from our in vivo and in vitro experiments clearly indicate that arctigenin reduced (i) viral load and viral replication within the brain, (ii) neuronal death and (iii) secondary inflammation and oxidative stress resulting from microglial activation, thereby suggesting its potential for treating JE. The antiviral, neuroprotective, anti-inflammatory and antioxidative effects of arctigenin successfully reduced the severity of disease induced by JEV.

Japanese encephalitis: development of new candidate vaccines.

Japanese encephalitis (JE) is the most common form of viral encephalitis that appears in the form of frequent epidemics of brain fever throughout Southeast Asia, China and India. The disease is caused by a Flavivirus named Japanese encephalitis virus that is spread to humans by mosquitoes. An internationally approved mouse brain-derived inactivated vaccine has been available that is relatively expensive, gives immunity of uncertain duration and is not completely safe. Cell culture-derived inactivated and attenuated JE vaccines are in use in China, but these are not produced as per the norms acceptable in most countries. Several new promising JE vaccine candidates have been developed, some of which are under different stages of clinical evaluation. These new candidate JE vaccines have the potential to generate long-lasting immunity at low cost.

Immunogenicity of a Japanese encephalitis DNA vaccine candidate in cynomolgus monkeys.

A Japanese encephalitis (JE) vaccine candidate encoding JE virus premembrane (prM) and envelope (E) genes, designated pNJEME, was evaluated for safety and immunogenicity in non-human primate, cynomolgus monkeys. pNJEME was constructed using a vector (pNGVL4a) designed to address some of the safety concerns of DNA vaccine. In two different experiments, two immunizations with 300 microg of pNJEME by intramuscular (i.m.) injection, and 3 microg of pNJEME using a gene gun, and three immunizations by i.m. injection with 500 microg of pNJEME were performed. All the three protocols induced low to high levels of neutralizing antibody, indicating an ability of pNJEME to induce neutralizing antibody in monkeys with a wide individual variation in response to pNJEME. In one experiment designed to compare the DNA vaccine with a commercial inactivated JE vaccine, three immunizations by i.m. inoculation with 300 microg of pNJEME or by gene gun administration with 3 microg of pNJEME induced similar levels of neutralizing antibody to those induced by three immunizations with a human dose of the inactivated vaccine in most monkeys. After intranasal challenge with the Beijing P3 or JaTH160 strain of JE virus, pNJEME-immunized monkeys showed anamnestic neutralizing antibody responses, indicating that pNJEME induced memory B cells which were responsive to infection with JE virus. No systemic and local reactions were observed in any monkeys after i.m. or gene gun inoculations with plasmid DNAs.