A decision support tool for risk-benefit analysis of Japanese encephalitis vaccine in travellers.

BACKGROUND: During pre-travel consultations, clinicians and travellers face the challenge of weighing the risks verus benefits of Japanese encephalitis (JE) vaccination due to the high cost of the vaccine, low incidence in travellers (~1 in 1 million), but potentially severe consequences (~30% case-fatality rate). Personalised JE risk assessment based on the travellers' demographics and travel itinerary is challenging using standard risk matrices. We developed an interactive digital tool to estimate risks of JE infection and severe health outcomes under different scenarios to facilitate shared decision-making between clinicians and travellers. METHODS: A Bayesian network (conditional probability) model risk-benefit analysis of JE vaccine in travellers was developed. The model considers travellers' characteristics (age, sex, co-morbidities), itinerary (destination, departure date, duration, setting of planned activities) and vaccination status to estimate the risks of JE infection, the development of symptomatic disease (meningitis, encephalitis), clinical outcomes (hospital admission, chronic neurological complications, death) and adverse events following immunization. RESULTS: In low-risk travellers (e.g. to urban areas for <1 month), the risk of developing JE and dying is low (<1 per million) irrespective of the destination; thus, the potential impact of JE vaccination in reducing the risk of clinical outcomes is limited. In high-risk travellers (e.g. to rural areas in high JE incidence destinations for >2 months), the risk of developing symptomatic disease and mortality is estimated at 9.5 and 1.4 per million, respectively. JE vaccination in this group would significantly reduce the risk of symptomatic disease and mortality (by ~80%) to 1.9 and 0.3 per million, respectively. CONCLUSION: The JE tool may assist decision-making by travellers and clinicians and could increase JE vaccine uptake. The tool will be updated as additional evidence becomes available. Future work needs to evaluate the usability of the tool. The interactive, scenario-based, personalised JE vaccine risk-benefit tool is freely available on www.VaxiCal.com.

Safety and immunogenicity of a purified inactivated Zika virus vaccine candidate in adults primed with a Japanese encephalitis virus or yellow fever virus vaccine in the USA: a phase 1, randomised, double-blind, placebo-controlled clinical trial.

BACKGROUND: Zika virus infection is a threat to at-risk populations, causing major birth defects and serious neurological complications. Development of a safe and efficacious Zika virus vaccine is, therefore, a global health priority. Assessment of heterologous flavivirus vaccination is important given co-circulation of Japanese encephalitis virus and yellow fever virus with Zika virus. We investigated the effect of priming flavivirus naive participants with a licensed flavivirus vaccine on the safety and immunogenicity of a purified inactivated Zika vaccine (ZPIV). METHODS: This phase 1, placebo-controlled, double-blind trial was done at the Walter Reed Army Institute of Research Clinical Trials Center in Silver Spring, MD, USA. Eligible participants were healthy adults aged 18-49 years, with no detectable evidence of previous flavivirus exposure (by infection or vaccination), as measured by a microneutralisation assay. Individuals with serological evidence of HIV, hepatitis B, or hepatitis C infection were excluded, as were pregnant or breastfeeding women. Participants were recruited sequentially into one of three groups (1:1:1) to receive no primer, two doses of intramuscular Japanese encephalitis virus vaccine (IXIARO), or a single dose of subcutaneous yellow fever virus vaccine (YF-VAX). Within each group, participants were randomly assigned (4:1) to receive intramuscular ZPIV or placebo. Priming vaccinations were given 72-96 days before ZPIV. ZPIV was administered either two or three times, at days 0, 28, and 196-234. The primary outcome was occurrence of solicited systemic and local adverse events along with serious adverse events and adverse events of special interest. These data were analysed in all participants receiving at least one dose of ZPIV or placebo. Secondary outcomes included measurement of neutralizing antibody responses following ZPIV vaccination in all volunteers with available post-vaccination data. This trial is registered at ClinicalTrials.gov, NCT02963909. FINDINGS: Between Nov 7, 2016, and Oct 30, 2018, 134 participants were assessed for eligibility. 21 did not meet inclusion criteria, 29 met exclusion criteria, and ten declined to participate. 75 participants were recruited and randomly assigned. 35 (47%) of 75 participants were male and 40 (53%) were female. 25 (33%) of 75 participants identified as Black or African American and 42 (56%) identified as White. These proportions and other baseline characteristics were similar between groups. There were no statistically significant differences in age, gender, race, or BMI between those who did and did not opt into the third dose. All participants received the planned priming IXIARO and YF-VAX vaccinations, but one participant who received YF-VAX dropped out before receipt of the first dose of ZPIV. 50 participants received a third dose of ZPIV or placebo, including 14 flavivirus-naive people, 17 people primed with Japanese encephalitis virus vaccine, and 19 participants primed with yellow fever vaccine. Vaccinations were well tolerated across groups. Pain at the injection site was the only adverse event reported more frequently in participants who received ZPIV than in those who received placebo (39 [65%] of 60 participants, 95% CI 51·6-76·9 who received ZPIV vs three [21·4%] of 14 who received placebo; 4·7-50·8; p=0·006). No patients had an adverse event of special interest or serious adverse event related to study treatment. At day 57, the flavivirus-naive volunteers had an 88% (63·6-98·5, 15 of 17) seroconversion rate (neutralising antibody titre ≥1:10) and geometric mean neutralising antibody titre (GMT) against Zika virus of 100·8 (39·7-255·7). In the Japanese encephalitis vaccine-primed group, the day 57 seroconversion rate was 31·6% (95% CI 12·6-56·6, six of 19) and GMT was 11·8 (6·1-22·8). Participants primed with YF-VAX had a seroconversion rate of 25% (95% CI 8·7-49·1, five of 20) and GMT of 6·6 (5·2-8·4). Humoral immune responses rose substantially following a third dose of ZPIV, with seroconversion rates of 100% (69·2-100; ten of ten), 92·9% (66·1-99·8; 13 of 14), and 60% (32·2-83·7, nine of 15) and GMTs of 511·5 (177·6-1473·6), 174·2 (51·6-587·6), and 79 (19·0-326·8) in the flavivirus naive, Japanese encephalitis vaccine-primed, and yellow fever vaccine-primed groups, respectively. INTERPRETATION: We found ZPIV to be well tolerated in flavivirus naive and primed adults but that immunogenicity varied significantly according to antecedent flavivirus vaccination status. Immune bias towards the flavivirus antigen of initial exposure and the timing of vaccination may have impacted responses. A third ZPIV dose overcame much, but not all, of the discrepancy in immunogenicity. The results of this phase 1 clinical trial have implications for further evaluation of ZPIV's immunisation schedule and use of concomitant vaccinations. FUNDING: Department of Defense, Defense Health Agency; National Institute of Allergy and Infectious Diseases; and Division of Microbiology and Infectious Disease.

Immunogenicity of a single fractional intradermal dose of Japanese encephalitis live attenuated chimeric vaccine.

BACKGROUND: Japanese encephalitis (JE) is endemic in Asia and the western Pacific. Vaccination is recommended for travellers to endemic regions, but the high cost of the vaccine is a major barrier to uptake. METHODS: A quasi-experimental, pre-post intervention clinical trial without a control group was conducted to assess the immunogenicity and safety of intradermal (ID) JE vaccine. Healthy adults (18-45 years) received one dose of 0.1 mL (20% of standard dose) ID Imojev® (JE live attenuated chimeric vaccine, Sanofi-Aventis). Adverse events following immunization (AEFIs) were recorded 10 days post-vaccination. Blood samples were collected at baseline, 4 and 8 weeks post-vaccination. Neutralizing antibodies were measured using 50% plaque reduction neutralization test (PRNT50). Seroconversion was defined as PRNT50 titre ≥10. An in vitro study was also conducted to quantify the rate of decay of vaccine potency after reconstitution. RESULTS: In total, 51 participants (72.6% females, median age 31 years), all non-reactive to JE virus at baseline were enrolled. Mild and moderate AEFIs were reported by 19.6% of participants; none required medical attention or interfered with normal daily activities. All participants seroconverted at 4 weeks (GMT 249.3; 95%CI:192.8-322.5) and remained seropositive at 8 weeks (GMT 135.5; 95%CI:104.5-175.6). Vaccine potency declined at a rate of 0.14 log plaque-forming units/0.5 mL per hour. CONCLUSIONS: In healthy adults, a single 0.1 mL ID dose of Imojev was safe and immunogenic, at least in the short term. Reconstituted vials of Imojev vaccine may not retain their potency after 6 hours. Fractional JE ID vaccination could be a cheaper yet effective alternative for short-term travellers. Further studies need to investigate the immune response in a wider age range of individuals and the long-term immunogenicity of fractional JE ID vaccines. CLINICAL TRIALS REGISTRATION: ACTRN12621000024842.

An evaluation of adverse events following an immunization campaign with the live, attenuated SA14-14-2 Japanese encephalitis vaccine in Cambodia.

INTRODUCTION: Japanese encephalitis (JE) virus is the most common cause of vaccine-preventable encephalitis in Asia. The SA14-14-2 JE vaccine manufactured by Chengdu Institute of Biological Products has been shown to be safe and effective in clinical trials and childhood routine immunization programs. However, there are few published reports describing results of surveillance for adverse events following immunization (AEFI) when the vaccine is used in mass campaigns. We describe the results of AEFI surveillance following a 2013 vaccination campaign among almost 310,000 children aged 9 months-12 years in Battambang Province, Cambodia. METHODS: Routine AEFI surveillance was strengthened by staff training and supplemented by active hospital surveillance. An AEFI was defined as any sign, symptom, or disease temporally associated (i.e., within 4 weeks) with receipt of the vaccine, irrespective of whether it was considered related to immunization. Data were collected on standardized forms and causality assessments were conducted for serious AEFI. RESULTS: Passive and active surveillance detected 28 AEFI for an overall incidence of 9.0 AEFI per 100,000 doses administered. The most frequent events were vasovagal episodes (n = 7, 25%) and rash (n = 6, 21%), and most other events were common childhood conditions such as fever and vomiting. Three AEFI were classified as serious, including one hypersensitivity reaction and two meningoencephalitis cases. Of these, the hypersensitivity event was the only serious AEFI classified as being consistent with a causal association to immunization. CONCLUSIONS: Most reported adverse events were conditions that commonly occur after other childhood vaccinations or independently of vaccination, and in the context of careful monitoring for serious AEFI only one serious event consistent with a causal association with immunization was identified. These results support the good safety profile of the SA14-14-2 JE vaccine, and provide reassuring data as the vaccine's use expands.

Safety and dose-sparing effect of Japanese encephalitis vaccine administered by microneedle patch in uninfected, healthy adults (MNA-J): a randomised, partly blinded, active-controlled, phase 1 trial.

BACKGROUND: It is unclear whether microneedle vaccinations of Japanese encephalitis virus can induce sufficient neutralising antibodies and reduce the amount of vaccine needed. We aimed to assess the safety and dose-sparing effect of a microneedle vaccine patch against Japanese encephalitis in healthy individuals who are naive to both the vaccine and natural infection. METHODS: The MNA-J study was a randomised, partly blinded, active-controlled, phase 1 clinical trial at Hokkaido University (Sapporo, Japan) that enrolled healthy adults aged 20-34 years with no history of Japanese encephalitis vaccination nor of infection as confirmed by seronegativity. We excluded individuals who had been infected with or vaccinated against Japanese encephalitis. Eligible participants were randomly assigned (1:1:1) to one of three groups to receive inactivated Japanese encephalitis vaccine administered twice, 3 weeks apart, by either 2·5 µg per injection by subcutaneous injection, 0·63 µg per patch by high-dose microneedle array (MNA-25%), or 0·25 µg per patch by low-dose microneedle array (MNA-10%). The randomisation sequence, using stratification by cohort and blocks of six, was computer-generated by a statistician who was unaware of group assignment. After administration, the remaining amount of unadministered vaccine was measured by ELISA and calculated as the delivered amount of vaccine. The primary outcome was the neutralising antibody titre at day 42 after first immunisation. Successful seroconversion was defined as post-vaccination titres of 1·3 (log10) or higher in individuals whose pre-vaccination titres had been less than 1 (log10). This study is registered with the Japan Registry of Clinical Trials (s011190004). FINDINGS: Between Aug 31 and Sept 2, 2019, 39 participants were enrolled and each was randomly assigned to a group (n=13 per group). No serious adverse events were observed. All participants in the microneedle array groups had a localised erythematous reaction. The amount of vaccine delivered by microneedle array to each participant was 0·63-1·15 µg (50-92%) of the full 1·26 µg for the MNA-25% group and 0·25-0·41 µg (51-84%) of the full 0·50 µg for the MNA-10% group. All participants demonstrated seroconversion at day 42, and the mean titres (log10) were 2·55 for MNA-25%, 2·04 for MNA-10%, and 2·08 for subcutaneous injection. INTERPRETATION: A microneedle patch of the Japanese encephalitis vaccine is safe, well tolerated, and immunogenically effective. The dose-sparing effect suggests a significant potential to reduce the amount of immunogens needed. However, improved delivery is needed to make it more tolerable and user friendly. FUNDING: FUJIFILM.

Antibody persistence upto 5 years after primary immunization and booster with an inactivated chromatographically purified Vero cell-derived Japanese encephalitis vaccine in Thai children.

Japanese encephalitis is the main cause of viral encephalitis in Asia. In a previous single-arm vaccine trial, an inactivated chromatographically purified Japanese encephalitis Vero cell vaccine (CVI-JE; JEVACTM) was safe and immunogenic in 152 Thai children aged 1-3 years receiving a 2-dose primary immunization and booster dose 1 year later. We conducted a 5-year follow-up assessment of the persistence of the immune response the 144 children remaining in this cohort after first booster dose. Immunity was assessed by 50% plaque reduction neutralization test annually for up to 5 years post-booster. Seroprotection rates (95%CI) decreased from 100% (97.1-100) at 1 year post-booster to 93% (85.0-98.3) at 5 years post-booster. No serious vaccine-related adverse events or Japanese encephalitis infections were reported. A 2-dose primary immunization and booster 1 year later with CVI-JE provided long-lasting immunity in the majority of children.

Immunogenicity and safety of an inactivated enterovirus 71 vaccine co-administered with measles-mumps-rubella vaccine and live-attenuated Japanese encephalitis vaccine: a phase 4, single-center, randomized controlled trial.

Co-administration of vaccines could be an efficient strategy to increase vaccination uptake and reduce the number of clinic visits. This randomized controlled study aimed to evaluate the immunogenicity and safety of enterovirus 71 (EV71) vaccine co-administered with measles-mumps-rubella (MMR) vaccine and live-attenuated Japanese encephalitis vaccine (LA-JEV). A total of 372 healthy infants were randomly assigned in a 1:1:1 ratio to receive simultaneous administration of EV71 vaccine (dose 1) and MMR on d 0 and EV71 vaccine (dose 2) and LA-JEV on d 30 (Group 1); administration of MMR and LA-JEV on d 0 and 30, respectively (Group 2); or administration of doses 1 and 2 of EV71 vaccine on d 0 and 30, respectively (Group 3). The non-inferiority analysis of the seroconversion for EV71 neutralizing antibody after vaccination was the primary outcome. According to per protocol set, antibody response against EV71, measles, mumps, rubella, and Japanese encephalitis (JE) virus was similar regardless of administration schedule. After vaccination, the seroconversion rate of EV71 neutralizing antibody in Group 1 (107 [97.27%] of 110) was non-inferior to that in Group 3 (109 [97.32%] of 112; difference - 0.05% [95% CI - 5.38 to 5.21]). The incidences of adverse reactions were 62.60% (77/123) in Group 1, 54.84% (68/124) in Group 2, and 37.70% (46/122) in Group 3, and most of them were mild to moderate in severity. No vaccine-related serious adverse events were reported. In total, the co-administration of combined EV71 vaccine with MMR and LA-JEV showed no interference with antibody response and demonstrated good safety profiles.

Safety of Japanese encephalitis vaccines.

Japanese encephalitis (JE) is an endemic disease dominantly in the Asia-Pacific region with mortality rate varying between 3% and 30%. Long-term neuropsychiatric sequelae developed in 30-50% of the survivors. There is no available antiviral therapy for JE. JE vaccines play a major role in preventing this devastating disease. The incidence of JE declined over years and the age distribution shifted toward adults in countries where JE immunization program exists. Mouse brain-JE vaccine is currently replaced by inactivated Vero cell-derived vaccine and live-attenuated vaccine using SA14-14-2 strain, and live chimeric JE vaccines. These three types of JE vaccines are associated with favorable efficacy and safety profiles. Common adverse reactions include injection site reactions and fever, and severe adverse reactions are rare.

Comparison of immunogenicity and safety of licensed Japanese encephalitis vaccines: A systematic review and network meta-analysis.

INTRODUCTION: Annually more than 100,000 Japanese encephalitis (JE) cases and 25,000 deaths worldwide are caused by JE virus infection. More than 15 JE vaccines are currently in use worldwide. It is unknown whether any of the vaccines is superior to the others in terms of immunogenicity and safety. METHODS: Four databases were systematically searched for randomised controlled trials that compared two or more types of JE vaccines. Vaccines were classified into four classes: inactivated mouse brain-derived (oldest class), inactivated Vero cell, live chimeric, and live attenuated. Network meta-analysis was used to generate mixed effect estimates against inactivated mouse brain-derived vaccines for seroconversion, and against placebo for adverse event (AE) and severe adverse event (SAE). RESULTS: 23 studies (38,496 participants) were included. All newer vaccine classes had better immunogenicity, the difference was statistically significant for inactivated Vero cell (OR = 2.98; 95 %CI: 1.02-8.65) and live chimeric (OR = 5.93; 95 %CI: 1.73-20.32) vaccines. Inactivated mouse-derived vaccines had the highest odds for AEs (OR = 2.27; 95 %CI: 1.59-3.23), the odds of AE of newer vaccines was not different to placebo. There was no difference in SAEs across vaccine classes. CONCLUSIONS: All newer JE vaccines have comparable safety profiles, live chimeric and inactivated Vero cell vaccines are the most immunogenic among the newer vaccine classes.

Novel Japanese encephalitis virus NS1-based vaccine: Truncated NS1 fused with E. coli heat labile enterotoxin B subunit.

BACKGROUND: Current vaccines against Japanese encephalitis virus (JEV) of flaviviruses have some disadvantages, such as the risk of virulent reversion. Non-structural protein NS1 is conserved among flaviviruses and confers immune protection without the risk of antibody-dependent enhancement (ADE). Therefore, NS1 has become a promising vaccine candidate against flaviviruses. METHODS: A NS1-based vaccine (LTB-NS1∆63) with a truncated NS1 protein (NS1∆63) fused to E. coli heat-labile enterotoxin B subunit (LTB) was expressed in E.coli and explored for its ability to induce immune responses. Safety of LTB-NS1∆63 was assessed by determining its toxicity in vitro and in vivo. Protective capability of LTB-NS1∆63 and its-induced antisera was evaluated in the mice challenged with JEV by analyzing mortality and morbidity. FINDINGS: LTB-NS1∆63 induced immune responses to a similar level as LTB-NS1, but more robust than NS1∆63 alone, particularly in the context of oral immunization of mice. Oral vaccination of LTB-NS1∆63 led to a higher survival rate than that of NS1∆63 or live-attenuated JEV vaccine SA14-14-2 in the mice receiving lethal JEV challenge. LTB-NS1∆63 protein also significantly decreases the morbidity of JEV-infected mice. In addition, passive transfer of LTB-NS1∆63-induced antisera provides a protection against JEV infection in mice. INTERPRETATION: NS1∆63 bears JEV NS1 antigenicity. Besides, LTB-NS1∆63 could serve as a novel protein-based mucosa vaccine targeting JEV and other flaviviruses. FUNDING: This work was supported by the National Natural Science Foundation, Jiangxi Province Science and Technology Committee, Education Department of Jiangxi Province.

Immunogenicity and safety of the third booster dose of the inactivated Japanese encephalitis vaccine in Korean children: A prospective multicenter study.

The immunization schedule for the inactivated Japanese encephalitis (JE) vaccine in Korea is a two-dose primary series at 12-24 months of age and three booster doses at 12 months after primary schedule and at 6 and 12 years of age. The aim of this study was to investigate immunogenicity and safety of the third booster dose of the inactivated JE vaccine, as well as the long-term immunogenicity of the second booster dose in Korean children. Healthy children aged 11-13 years, primed and given four doses of inactivated JE vaccines were included. All subjects received the third booster dose of the JE vaccine. Neutralizing antibody (NTAb) titers were assessed before and 4-6 weeks after vaccination using plaque reduction neutralization test (PRNT), and were considered to be protective at ≥ 1:10. Local and systemic adverse events were monitored for 4 weeks after vaccination. Before and after booster vaccination, all seroprotection rates were 100%. Geometric mean titer (GMT) showed a 6.05-fold increase, from 139.11 (95% CI: 110.76, 174.71) to 841.53 (95% CI, 714.25, 991.50). The local tolerability and systemic safety profiles were favorable, with no serious adverse events. In conclusion, the third booster dose of the inactivated JE vaccine was demonstrated to be safe and immunogenic in Korean children when administered according to the current immunization schedule.

Japanese Encephalitis Vaccine.

Travelers to 24 endemic countries in Asia may be at risk for Japanese encephalitis. The ACIP has recently expanded guidelines on the use of Ixiaro, the inactivated Japanese encephalitis vaccine. This article reviews the disease burden of Japanese encephalitis and the role of a travel clinic in guiding travelers to Asia regarding decision-making about the use of this highly protective vaccine.

Immunogenicity and safety of two-visit, intradermal pre-exposure rabies prophylaxis simultaneously administrated with chimeric live-attenuated Japanese encephalitis vaccine in children living in rabies and Japanese encephalitis endemic country.

BACKGROUND: Reducing the number of doses required for pre-exposure prophylaxis (PrEP) would make it more feasible and cost-effective to implement in children at the highest risk of rabies exposure in Asia. We studied immune response of 2-site intradermal (ID) injection of rabies vaccine on days 0 and 28 for rabies PrEP simultaneously administrated with live-attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) for children living in endemic area. RESEARCH DESIGN AND METHODS: Seronegative children (n = 49) aged 12-16 months were randomized 2:1 into two groups: Group A subjects were vaccinated with 0.1-mL ID injection of purified Vero cell rabies vaccine (PVRV), each at two sites on day (D) 0 and D28; Group B subjects were vaccinated with conventional 0.5-mL intramuscular PVRV on D0, D7 and D28. Both groups received one dose of JE-CV subcutaneously on D0 and D365. Rabies virus neutralizing antibody (RVNA) titers were measured on D0, D42 and D365 after vaccination; Japanese Encephalitis (JE) neutralizing antibody titers were determined on D0, D42, D365 and D379. RESULTS: All children had RVNA ≥ 0.5 IU/mL on D42 (geometric mean titers [GMTs] of RVNA 14.35 IU/mL [Group A] and 14.83 IU/mL [Group B], p > 0.05]). On D365, RVNA GMTs of subjects in group A and B were 1.50 IU/mL and 2.00 IU/mL (p > 0.05), respectively. All children had seroprotection following booster dose of JE-CV. There were no vaccine-related SAEs observed. CONCLUSION: The 2-site ID PrEP with PVRV on days 0 and 28 co-administrated with JE-CV are safe and immunogenic.

Adverse events following immunization with the live-attenuated recombinant Japanese encephalitis vaccine (IMOJEV®) in Taiwan, 2017-18.

BACKGROUND: Japanese encephalitis (JE) is a significant public health concern in the Asia-Pacific region, with a case-fatality rate of around 20% for those who develop encephalitis. Mouse-brain derived vaccines against JE have been used in the publicly funded national immunization program (NIP) in Taiwan since 1968. They were replaced with a live-attenuated recombinant vaccine (JE-CV, IMOJEV®) in May 2017. We assessed reports of adverse events (AE) following the introduction of JE-CV into the Taiwan NIP to characterize its post-licensure safety profile. METHODS: AEs reported between 1 May 2017 and 31 December 2018 post vaccination with JE-CV were extracted from the National Adverse Drug Reactions (ADR) Reporting System, a passive surveillance system run by the Taiwan Food and Drug Administration. The report rates were calculated based on the number of doses distributed by the manufacturer during the assessment period. RESULTS: There were 51 AEs reported among 30 subjects (12 girls and 18 boys; mean age 25 months), with a reporting rate of 4.7 AEs per 100,000 doses distributed. The AEs occurred after a median of. 1-day post vaccination. Eight subjects had received concomitant vaccination with another vaccines. There were four serious AEs reported: febrile seizure, acute renal failure, viral respiratory tract infection, and injection site cellulitis. None of these serious AEs were classified as being causally related to JE-CV vaccination. CONCLUSION: These post-licensure AE surveillance data confirm the favorable safety profile of JE-CV.

Japanese encephalitis vaccination in pregnancy among U.S. active duty military women.

INTRODUCTION: Japanese encephalitis (JE) vaccine is an inactivated vaccine that has shown no risks in pregnancy in animal models, but epidemiologic studies are lacking. U.S. military service members located in JE endemic regions are required to be vaccinated; understanding the potential adverse events (AEs), including AEs that may occur in pregnancy, is needed. Here, we assessed pregnancy and infant health outcomes in association with JE vaccination in pregnancy. METHODS: The study population consisted of 192,570 pregnancies to active duty women (2003-2014), captured in the Department of Defense Birth and Infant Health Research program. JE vaccine in pregnancy, vaccine count, formulation, trimester, and whether first career dose coincided with pregnancy were compared with unexposed pregnancies to assess risk of pregnancy and infant health outcomes. Adjusted risk estimates and 95% confidence intervals (CIs) were calculated by multivariable models. RESULTS: Of the 192,570 identifed pregnancies, 513 were exposed to the JE vaccine; 474 exposures occurred in the first trimester. For all outcomes, elevated risk estimates ranging from 1.53 to 1.70, were observed with receipt of >1 JE vaccine in pregnancy, though 95% CIs were wide and encompassed the null. First dose of JE vaccination in pregnancy was associated with a 1.87 (95% CI: 1.12-3.13) times increased risk of low birthweight (LBW) when excluding pregnancies exposed to other non-routinely recommended vaccinations in pregnancy. All other associations were null in both main and subset analyses. CONCLUSIONS: The overall results of these analyses provide reassuring findings for the safety of JE vaccination in pregnancy. Higher counts of JE vaccine received in pregnancy yielded large yet non-statistically significant risk estimates for all outcomes, though likely driven by lack of pregnancy awareness. An association was observed with LBW in subset analyses, but it was limited to women receiving their first JE vaccine and not observed in the larger main analyses.

A novel amino acid site closely associated with the neurovirulence of live, attenuated Japanese encephalitis vaccine (SA14-14-2 strain).

Japanese encephalitis (JE) poses a serious threat to the world's public health yet without a cure, the only way to prevent Japanese encephalitis virus (JEV) infection is vaccination. Live attenuated vaccine (SA14-14-2 strain) is the most widely used JE vaccine, and clinical data have confirmed its safety and effectiveness. Eight sitesassociated with virulence in the Envelope (E) protein are often the focus of quality control of JE vaccine. However, sequences retrieved from NCBI, as well as our previous results showed that the wild strain SA14 may harbor two different amino acids at amino acid residue 244 of the E glycoprotein (E244), and it may be related to virulence. In this study, we introduced a single mutation at nt1708 (G â†’ A) in the full-length cDNA clone of SA14-14-2, replacing a Gly with Glu at amino acid residue 244 of the E glycoprotein, and successfully constructed the mutant virus (JEV E244). JEV E244 exhibited a similar plaque morphology and growth characteristics to JEV SA14-14-2 in cell culture. However, it had lethal neurovirulence in mice and could enter the brain following intraperitoneal inoculation. Moreover, the virulence of JEV E244 in the context of vaccine in mice is significantly different from that of the JEV E244 alone. These results suggested that E244 site should be included in the assessment of the genetic stability of the attenuated JE vaccine. The detection of minor mutations in vaccine population and influence on the safety of vaccine is discussed.

Vaccination against Japanese encephalitis with IC51: systematic review on immunogenicity, duration of protection and safety.

Japanese encephalitis is a disease caused by a flavivirus which is transmitted by mosquitos in endemic countries. Considering the potentially severe outcomes of the disease, vaccination is recommended for those at risk of exposure. During recent years, IC51 (IXIARO®, JESPECT®, JEVAL®) has increasingly been used to protect travellers from Europe and the USA. However, no systematic review exists that summarizes the currently available evidence on the immunogenicity and safety of this vaccine. We conducted a systematic review on the immunogenicity and safety of IC51, using the databases PubMed, MEDLINE, EMBASE and ClinicalTrials.gov (search date: 31 August 2019). Data extracted from included studies were grouped by outcomes and stratified by population and setting. Risk of bias (ROB) was assessed using the RoB 2 tool for randomized controlled trials (RCTs) and ROBINS-I for non-randomized studies. Due to high heterogeneity, meta-analysis was not performed. A total of 32 studies from 16 countries met the inclusion criteria (15 RCTs, 17 non-randomized studies). ROB was serious or high in the majority of studies. Seroprotection rates ranged from 93 to 100% in adults (seven studies) and from 91 to 100% in children (four studies). In the study involving adults aged 64 years and older, seroprotection was 65% with higher rates in persons who were previously vaccinated against tick-borne encephalitis virus. Safety was investigated in 27 studies. Rates of serious adverse events were below 5% in all age groups, with the majority not being causally related to the vaccine. IC51 is a safe vaccine with good seroprotective abilities in persons aged >2 months to <64 years. The body of evidence, however, is weakened by a large amount of heterogeneity in study and clinical trial methodology. Further well-designed RCTs with special risk groups are needed.

Perceptions among the U.S. population of value of Japanese encephalitis (JE) vaccination for travel to JE-endemic countries.

INTRODUCTION: Japanese encephalitis (JE) is a rare but potentially severe disease among travelers. JE vaccine in the United States costs $500-$600 for a 2-dose series and is safe and effective but rare serious adverse events can occur. Our survey investigated likelihood of vaccine receipt for travel. METHODS: An electronically-administered survey was conducted among U.S. adults. Participants were presented a hypothetical scenario on travel to a JE-endemic country and JE vaccine characteristics and responded on likelihood of vaccination. RESULTS: Overall, 6384 (59%) of 10,904 persons completed the questions. Population estimates indicated 32% would be likely and 42% were unlikely to be vaccinated, and 26% were unsure. Among those likely to get vaccinated, important factors were disease risk and severity, and vaccine safety. Among those unlikely, cost, disease risk, and possibility of serious side effects ranked highest. CONCLUSIONS: There is population heterogeneity in perception of JE disease risk and value of vaccination.

The Effects of Japanese Encephalitis Vaccine and Accelerated Dosing Scheduling on the Immunogenicity of the Chimeric Yellow Fever Derived Tetravalent Dengue Vaccine: A Phase II, Randomized, Open-Label, Single-Center Trial in Adults Aged 18 to 45 Years in the United States.

BACKGROUND: Dengue is a global health problem requiring an effective, safe dengue vaccine. METHODS: We report the results of a phase II, randomized, open-label, single-center trial in adults aged 18 to 45 years in the United States designed to explore the effects of the Chimeric Yellow Fever Derived Tetravalent Dengue Vaccine (CYD-TDV, Dengvaxia) when administered on its designated schedule (months 0, 6, and 12) or on an accelerated dosing schedule (months 0, 2, and 6) and/or given before, or concomitantly with, a vaccine against Japanese encephalitis (JE). RESULTS: Based on dengue virus serotype-specific neutralizing antibody (NAb), the accelerated dosing schedule was comparable to the 0, 6, and 12-month schedule. Giving JE vaccine concurrently with CYD-TDV did not result in an increase in overall NAb titers. Immunophenotyping of peripheral blood mononuclear cells revealed an increase in activated CD8+ T cells after CYD-TDV vaccination, a phenomenon that was greatest for the JE vaccine primed. CONCLUSIONS: We conclude that an accelerated dosing schedule of CYD-TDV results in essentially equivalent dengue serotype-specific NAb titers as the currently used schedule, and there may be an early benefit in antibody titers and activated CD8+ T cells by the administration of the JE vaccine before CYD-TDV vaccination.

Japanese Encephalitis Vaccine: Recommendations of the Advisory Committee on Immunization Practices.

This report updates the 2010 recommendations from the CDC Advisory Committee on Immunization Practices (ACIP) regarding prevention of Japanese encephalitis (JE) among U.S. travelers and laboratory workers (Fischer M, Lindsey N, Staples JE, Hills S. Japanese encephalitis vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2010;59[No. RR-1]). The report summarizes the epidemiology of JE, describes the JE vaccine that is licensed and available in the United States, and provides recommendations for its use among travelers and laboratory workers.JE virus, a mosquitoborne flavivirus, is the most common vaccine-preventable cause of encephalitis in Asia. JE occurs throughout most of Asia and parts of the western Pacific. Approximately 20%-30% of patients die, and 30%-50% of survivors have neurologic, cognitive, or behavioral sequelae. No antiviral treatment is available.Inactivated Vero cell culture-derived JE vaccine (Ixiaro [JE-VC]) is the only JE vaccine that is licensed and available in the United States. In 2009, the U.S. Food and Drug Administration (FDA) licensed JE-VC for use in persons aged ≥17 years; in 2013, licensure was extended to include children aged ≥2 months.Most travelers to countries where the disease is endemic are at very low risk for JE. However, some travelers are at increased risk for infection on the basis of their travel plans. Factors that increase the risk for JE virus exposure include 1) traveling for a longer period; 2) travel during the JE virus transmission season; 3) spending time in rural areas; 4) participating in extensive outdoor activities; and 5) staying in accommodations without air conditioning, screens, or bed nets. All travelers to countries where JE is endemic should be advised to take precautions to avoid mosquito bites to reduce the risk for JE and other vectorborne diseases. For some persons who might be at increased risk for JE, the vaccine can further reduce the risk for infection. The decision about whether to vaccinate should be individualized and consider the 1) risks related to the specific travel itinerary, 2) likelihood of future travel to countries where JE is endemic, 3) high morbidity and mortality of JE, 4) availability of an effective vaccine, 5) possibility (but low probability) of serious adverse events after vaccination, and 6) the traveler's personal perception and tolerance of risk.JE vaccine is recommended for persons moving to a JE-endemic country to take up residence, longer-term (e.g., ≥1 month) travelers to JE-endemic areas, and frequent travelers to JE-endemic areas. JE vaccine also should be considered for shorter-term (e.g., <1 month) travelers with an increased risk for JE on the basis of planned travel duration, season, location, activities, and accommodations and for travelers to JE-endemic areas who are uncertain about their specific travel duration, destinations, or activities. JE vaccine is not recommended for travelers with very low-risk itineraries, such as shorter-term travel limited to urban areas or outside of a well-defined JE virus transmission season.