Investigating Nonspecific Effects of the Live-Attenuated Japanese Encephalitis Vaccine on Lower Respiratory Tract Infections in Children Aged 25-35 Months: Retrospective Cohort Study.

BACKGROUND: Live attenuated vaccines may be used to prevent nontargeted diseases such as lower respiratory tract infections (LRTIs) due to their nonspecific effects (NSEs). OBJECTIVE: We aimed to analyze the NSEs of the Japanese encephalitis vaccine on pediatric LRTIs in children aged 25 months to 35 months. METHODS: A retrospective cohort study was conducted by using a population-based electronic health record database in Zhejiang, China. Enrolled participants were children born from January 1, 2017, to December 31, 2017, and who were inoculated with the live-attenuated Japanese encephalitis vaccine (JE-L) or inactivated Japanese encephalitis vaccine (JE-I) as the most recent vaccine at 24 months of age. The study was carried out between January 1, 2019, and December 31, 2019. All inpatient and outpatient hospital visits for LRTIs among children aged 25 months to 35 months were recorded. The Andersen-Gill model was used to assess the NSEs of JE-L against LRTIs in children and compared with those of JE-I as the most recent vaccine. RESULTS: A total of 810 children born in 2017 were enrolled, of whom 585 received JE-L (JE-L cohort) and 225 received JE-I (JE-I cohort) as their last vaccine. The JE-L cohort showed a reduced risk of LRTIs (adjusted hazard ratio [aHR] 0.537, 95% CI 0.416-0.693), including pneumonia (aHR 0.501, 95% CI 0.393-0.638) and acute bronchitis (aHR 0.525, 95% CI 0.396-0.698) at 25 months to 35 months of age. The NSEs provided by JE-L were especially pronounced in female children (aHR 0.305, 95% CI 0.198-0.469) and children without chronic diseases (aHR 0.553, 95% CI 0.420-0.729), without siblings (aHR 0.361, 95% CI 0.255-0.511), with more than 30 inpatient and outpatient hospital visits prior to 24 months of age (aHR 0.163, 95% CI 0.091-0.290), or with 5 to 10 inpatient and outpatient hospital visits due to infectious diseases prior to 24 months old (aHR 0.058, 95% CI 0.017-0.202). CONCLUSIONS: Compared with JE-I, receiving JE-L as the most recent vaccine was associated with lower risk of inpatient and outpatient hospital visits for LRTIs among children aged 25 months to 35 months. The nature of NSEs induced by JE-L should be considered for policymakers and physicians when recommending JE vaccines to those at high risk of infection from the Japanese encephalitis virus.

Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for Use of Inactivated Vero Cell Culture-derived Japanese Encephalitis Vaccine in Children

Inactivated Vero cell culture-derived Japanese encephalitis vaccine (JE-VC [manufactured as IXIARO]) is the only JE vaccine licensed and available in the United States. JE-VC is manufactured by Intercell Biomedical (Livingston, United Kingdom) and distributed in the United States private market by Novartis Vaccines (Cambridge, Massachusetts). In March 2009, FDA licensed JE-VC for use in adults aged ≥17 years. ACIP recommendations for use of JE-VC in adults were approved in June 2009 and booster dose recommendations were approved in February 2011 [CDC 2010; CDC 2011]. There are no efficacy data for JE-VC. However, a JE virus 50% plaque reduction neutralization test (PRNT50) titer of ≥10 is an established immunologic correlate of protection [Markoff 2000; Hombach 2005]. JE-VC was licensed based on its ability to induce neutralizing antibodies and a non-inferiority comparison to a licensed inactivated mouse brain-derived JE vaccine (JE-MB [manufactured as JE-VAX]). Since JE-VC was licensed in 2009, >375,000 doses have been distributed in the United States for use in adults. In May 2013, FDA approved JE-VC for use in children aged 2 months through 16 years [FDA 2013]. The FDA-approved primary series for JE-VC is two intramuscular doses administered 28 days apart. For children aged 2 months through 2 years each dose is 0.25mL and for adults and children aged ≥3 years each dose is 0.5mL. The ACIP JE Vaccine Workgroup evaluated the evidence for use of JE-VC in children using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methods [Ahmed 2011]. The workgroup developed a policy question, identified outcomes of critical importance, performed a systematic review of the available data, and evaluated evidence of benefits, harms, values, and preferences for use of JE vaccine in U.S. children.

Persistence of Immune Responses With an Inactivated Japanese Encephalitis Single-Dose Vaccine, JENVAC and Interchangeability With a Live-Attenuated Vaccine.

BACKGROUND: This study reports immunogenicity, safety, and interchangeability of a single-dose, inactivated, Vero-cell derived, JENVAC to the live-attenuated SA 14-14-2 vaccine in healthy children. METHODS: This phase 4, multicenter, open-label, randomized, control trial enrolled 360 children who were equally randomized to receive a single dose of either JENVAC or SA 14-14-2. Children were followed at various time points, until 2 years (day 720) postvaccination, upon which a subset from each group was divided and allocated to a receive a booster dose or the other vaccine. RESULTS: At all time points, immunological measures were statistically higher in the JENVAC group. In the interchangeability study, children receiving 2 doses of JENVAC reported significantly higher response compared with 2 doses of SA 14-14-2. No difference in adverse events was observed. These corroborate with excellent seroprotection after the first dose of an earlier JENVAC study. CONCLUSIONS: A single-dose vaccination with JENVAC induces protective titers that persist up to 1 year. We report appreciable interchangeability between both vaccines, with JENVAC/JENVAC combination exhibiting the highest immune response. JENVAC is now licensed as a single-dose Japanese encephalitis vaccine.

'More than devastating'-patient experiences and neurological sequelae of Japanese encephalitis§.

BACKGROUND: Japanese encephalitis (JE), caused by the mosquito-borne JE virus, is a vaccine-preventable disease endemic to much of Asia. Travellers from non-endemic areas are susceptible if they travel to a JE endemic area. Although the risk to travellers of JE is low, the consequences may be severe. METHODS: Here, we describe three cases of JE in British travellers occurring in 2014-15. In addition, we report, through interviews with survivors and their families, personal experiences of life after JE. RESULTS: Three cases of JE were diagnosed in British travellers in 2014/15. One was acquired in Thailand, one in China and one in either Thailand, Laos or Cambodia. All three patients suffered severe, life-threatening illnesses, all were admitted to intensive care units and required medical evacuation back to the UK. One patient suffered a cardiac arrest during the acute stage but made a good recovery. The other two patients remain significantly paralysed and ventilator dependent. All three cases had clear indications for vaccination, and all have been left with life-changing neurological sequelae. CONCLUSIONS: Travel health providers should be aware of the severity of JE, as well as the risk, allowing travellers to make fully informed decisions on JE vaccination.

Immunogenicity and safety of measles-rubella vaccine co-administered with attenuated Japanese encephalitis SA 14-14-2 vaccine in infants aged 8 months in China: a non-inferiority randomised controlled trial.

BACKGROUND: In China, measles-rubella vaccine and live attenuated SA 14-14-2 Japanese encephalitis vaccine (LJEV) are recommended for simultaneous administration at 8 months of age, which is the youngest recommended age for these vaccines worldwide. We aimed to assess the effect of the co-administration of these vaccines at 8 months of age on the immunogenicity of measles-rubella vaccine. METHODS: We did a multicentre, open-label, non-inferiority, two-group randomised controlled trial in eight counties or districts in China. We recruited healthy infants aged 8 months who had received all scheduled vaccinations according to the national immunisation recommendations and who lived in the county of the study site. Enrolled infants were randomly assigned (1:1) to receive either measles-rubella vaccine and LJEV simultaneously (measles-rubella plus LJEV group) or measles-rubella vaccine alone (measles-rubella group). The primary outcome was the proportion of infants with IgG antibody seroconversion for measles 6 weeks after vaccination, and a secondary outcome was the proportion of infants with IgG antibody seroconversion for rubella 6 weeks after vaccination. Analyses included all infants who completed the study. We used a 5% margin to establish non-inferiority. This trial was registered at ClinicalTrials.gov (NCT02643433). FINDINGS: 1173 infants were assessed for eligibility between Aug 13, 2015, and June 10, 2016. Of 1093 (93%) enrolled infants, 545 were randomly assigned to the measles-rubella plus LJEV group and 548 to the measles-rubella group. Of the infants assigned to each group, 507 in the measles-rubella plus LJEV group and 506 in the measles-rubella group completed the study. Before vaccination, six (1%) of 507 infants in the measles-rubella plus LJEV group and one (<1%) of 506 in the measles-rubella group were seropositive for measles; eight (2%) infants in the measles-rubella plus LJEV group and two (<1%) in the measles-rubella group were seropositive for rubella. 6 weeks after vaccination, measles seroconversion in the measles-rubella plus LJEV group (496 [98%] of 507) was non-inferior to that in the measles-rubella group (499 [99%] of 506; difference -0·8% [90% CI -2·6 to 1·1]) and rubella seroconversion in the measles-rubella plus LJEV group (478 [94%] of 507) was non-inferior to that in the measles-rubella group (473 [94%] of 506 infants; difference 0·8% [90% CI -1·8 to 3·4]). There were no serious adverse events in either group and no evidence of a difference between the two groups in the prevalence of any local adverse event (redness, rashes, and pain) or systemic adverse event (fever, allergy, respiratory infections, diarrhoea, and vomiting). Fever was the most common adverse event (97 [19%] of 507 infants in the measles-rubella plus LJEV group; 108 [21%] of 506 infants in the measles-rubella group). INTERPRETATION: The evidence of similar seroconversion and safety with co-administered LJEV and measles-rubella vaccines supports the co-administration of these vaccines to infants aged 8 months. These results will be important for measles and rubella elimination and the expansion of Japanese encephalitis vaccination in countries where it is endemic. FUNDING: US Centers for Disease Control and Prevention, US Department of Health and Human Services; China-US Collaborative Program on Emerging and Re-emerging Infectious Diseases.

Decreases in Both the Seroprevalence of Serum Antibodies and Seroprotection against Japanese Encephalitis Virus among Vaccinated Children.

The incidence of Japanese encephalitis (JE) has significantly decreased in China due to JE vaccines. In this study, we investigated the post-JE vaccination seroprevalence and protection provided by vaccinated sera against Japanese encephalitis virus (JEV) to elucidate the persistence and waning of antibodies to JEV among JE-SA14-14-2-vaccinated children. A total of 300 serum samples were collected from vaccinated children aged 3-10 years in Zhaotong, Yunnan, China. The seroprevalence of anti-JEV antibodies was determined by enzyme-linked immune sorbent assay and plaque reduction neutralization test. The highest seropositivity of 82% was observed in vaccinated children during the first 0.5-1.5 years after booster vaccination. Then, the seropositivity began to decline and remained lower than the original level observed in the 0.5-1.5-year group. An association was found between the waning of seroprevalence and elapsed time of the post-booster vaccination. Similarly, the neutralizing antibody (nAb) titres gradually decreased over time, and the levels showed a positive correlation with the protective efficacy in mice. This finding suggests that nAbs play an important role in the antiviral process and that the nAb titre is an adequately credible parameter for evaluating the protective efficacy induced by the JE vaccine. Our results provide data that clarify the persistence and waning of antibodies to JEV, which may help elucidate the pathogenesis of JE.

Analysis of the Full Economic Cost for Japanese Encephalitis Under Different Risk Scenarios for Business Travelers to Asia.

OBJECTIVE: Methods for assessing the costs and benefits of administering vaccines to international business/occupational travelers, assignees, and expatriates have neglected the impact of health and treatment on work productivity. The research objective is to evaluate the benefit to cost ratio of the Japanese encephalitis (JE) vaccine for international business/occupational travelers to Asia and other endemic areas incorporating a health and productivity approach. METHODS: Costs and benefits were estimated using actuarial methods with data obtained from secondary sources describing prevalence of infection risk and health outcomes, and business traveler demographic and travel characteristics. Results assumed 2018 salaries and prices, with employee time valued according to total compensation. RESULTS: Risks contracting JE vary widely on the basis of length of trip, season, and destination. The productivity benefits of vaccinating a traveler outweigh the vaccination costs for those staying 30 days or longer in endemic areas during one or more transmission seasons ($2009 vs $750 per traveler), and for business travelers to endemic areas during the transmission season with outdoor activities for the average 2-week/15.4-day international business trip ($502 to $815 vs $500). Vaccination costs outweigh the productivity benefits for short-term travelers who remain in urban areas or travel outside of the transmission season ($10 vs $500). CONCLUSION: JE Vaccination for business travelers in the active transmission season has a net benefit under certain conditions that are not commonly considered risky, such as average-length trips to peri-urban areas, in situations where contracting disease would result in significant business disruption, or when multiple trips are anticipated over several years.

Update From the Advisory Committee on Immunization Practices.

The Advisory Committee on Immunization Practices (ACIP), a group of medical and public health experts, meets 3 times per year to develop recommendations for vaccine use in the United States. The group has 15 voting members, and each member's term is 4 years. ACIP members and Centers for Disease Control and Prevention staff discuss the epidemiology of vaccine-preventable diseases and vaccine research, effectiveness, safety data, and clinical trial results. Representatives from the American Academy of Pediatrics (J. D. C. and D. W. K.) and the Pediatric Infectious Diseases Society (S. T. O.) are present as liaisons to the ACIP. The ACIP met on June 20 and 21, 2018, to discuss influenza vaccine effectiveness and safety, anthrax vaccination in the setting of a mass exposure, human papillomavirus vaccine, mumps vaccine, Japanese encephalitis vaccine, and pneumococcal vaccination among adults.

Update From the Advisory Committee on Immunization Practices.

The Advisory Committee on Immunization Practices (ACIP), a group of medical and public health experts, meets 3 times per year to develop recommendations for vaccine use in the United States. There are 15 voting members, and their terms are for 4 years. ACIP members and Centers for Disease Control and Prevention staff discuss the epidemiology of vaccine-preventable diseases and vaccine research, effectiveness, safety data, and clinical trial results. Representatives from the American Academy of Pediatrics (including D. W. K.) and the Pediatric Infectious Diseases Society are present as liaisons to the ACIP. In the February 2018 meeting, important votes on the use of influenza vaccine and hepatitis vaccines were held, and updates on human papillomavirus, meningococcal, and anthrax vaccines, among others, were provided.

Recent developments in vaccines and biological therapies against Japanese encephalitis virus.

INTRODUCTION: Japanese encephalitis is the most common vaccine-preventable encephalitis in the Asia-Pacific region. AREAS COVERED: We provide an overview on Japanese encephalitis virus and associated disease, review the results of studies on the immunogenicity and efficacy of the licensed vaccines, and describe the new vaccines that are under development. We also discuss data on candidate anti-Japanese encephalitis drugs that have shown promising results in experimental models. EXPERT OPINION: The global burden of the Japanese encephalitis and associated mortality is still high, thus emphasizing the need to achieve the highest vaccination coverage in endemic areas. Clinical trials exhaustively demonstrated the safety and efficacy of current Japanese encephalitis vaccines. In addition, several new vaccine candidates, characterized by high immunogenicity and broad cross-protection, have been developed and evaluated in experimental models, warranting further clinical testing. No licensed anti-Japanese encephalitis drugs are available, notwithstanding intense research efforts. Some candidate antiviral agents that inhibit viral entry and replication have been identified, including compounds with broad-spectrum antiviral activity. Further research is needed to refine candidate compounds into drugs suitable for clinical evaluation, characterized by low toxicity, ability to penetrate the blood-brain barrier, activity during the late phase of infection, and high genetic barrier to resistance.

Antibody Persistence up to 3 Years After Primary Immunization With Inactivated Japanese Encephalitis Vaccine IXIARO in Philippine Children and Effect of a Booster Dose.

BACKGROUND: An inactivated Vero cell culture derived Japanese encephalitis virus vaccine (IXIARO) requires a booster dose 1 year after primary schedule for long-term antibody persistence in adults. The aim of this study is to evaluate immunogenicity and safety of a booster dose in children 2 months to <18 years of age. METHODS: This is a randomized, controlled open-label study in the Philippines. Three hundred children vaccinated with IXIARO in a previous trial were randomized 1:1 to receive either no booster or a booster 12 months after initiation of the primary series. Neutralizing antibody titers were assessed before and after the booster and up to 3 years after primary series. Safety endpoints included the rate of subjects with solicited adverse events (AEs), unsolicited AEs and serious AEs within 1 month after the booster. RESULTS: Geometric mean titer declined by 1 year after the primary series, but titers remained above the established protective threshold in 85%-100% of children depending on age group. The booster led to a pronounced increase in geometric mean titer and 100% seroprotection rate in all age groups. The booster was well tolerated, with AE rates lower compared with the primary series. Most AEs were mild. CONCLUSIONS: A booster dose of IXIARO administered 12 months after the primary immunization was well tolerated and highly immunogenic.

Genotype I of Japanese Encephalitis Virus Virus-like Particles Elicit Sterilizing Immunity against Genotype I and III Viral Challenge in Swine.

Swine are a critical amplifying host involved in human Japanese encephalitis (JE) outbreaks. Cross-genotypic immunogenicity and sterile protection are important for the current genotype III (GIII) virus-derived vaccines in swine, especially now that emerging genotype I (GI) JE virus (JEV) has replaced GIII virus as the dominant strain. Herein, we aimed to develop a system to generate GI JEV virus-like particles (VLPs) and evaluate the immunogenicity and protection of the GI vaccine candidate in mice and specific pathogen-free swine. A CHO-heparan sulfate-deficient (CHO-HS(-)) cell clone, named 51-10 clone, stably expressing GI-JEV VLP was selected and continually secreted GI VLPs without signs of cell fusion. 51-10 VLPs formed a homogeneously empty-particle morphology and exhibited similar antigenic activity as GI virus. GI VLP-immunized mice showed balanced cross-neutralizing antibody titers against GI to GIV viruses (50% focus-reduction micro-neutralization assay titers 71 to 240) as well as potent protection against GI or GIII virus infection. GI VLP-immunized swine challenged with GI or GIII viruses showed no fever, viremia, or viral RNA in tonsils, lymph nodes, and brains as compared with phosphate buffered saline-immunized swine. We thus conclude GI VLPs can provide sterile protection against GI and GIII viruses in swine.

Newer Vaccines against Mosquito-borne Diseases.

Mosquitos are responsible for a number of protozoal and viral diseases. Malaria, dengue, Japanese encephalitis (JE) and chikungunya epidemics occur commonly all over the world, leading to marked mortality and morbidity in children. Zika, Yellow fever and West Nile fever are others requiring prevention. Environmental control and mosquito bite prevention are useful in decreasing the burden of disease but vaccination has been found to be most cost-effective and is the need of the hour. RTS,S/AS01 vaccine is the first malaria vaccine being licensed for use against P. falciparum malaria. Dengvaxia (CYD-TDV) against dengue was licensed first in Mexico in 2015. A Vero-cell derived, inactivated and alum-adjuvanted JE vaccine based on the SA14-14-2 strain was approved in 2009 in North America, Australia and various European countries. It can be used from 2 mo of age. In India, immunization is carried out in endemic regions at 1 y of age. Another inactivated Vero-cell culture derived Kolar strain, 821564XY, JE vaccine is being used in India. Candidate vaccines against dengue, chikungunya and West Nile fever are been discussed. A continued research and development of new vaccines are required for controlling these mosquito-borne diseases.

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.

[Fever and Headache after a Vacation in Thailand]. / Fieber und Kopfschmerzen nach Thailandurlaub.

History 50 year-old man with fever and headache starting one week after returning from his vacation in Thailand. His general practitioner prescribed amoxicillin/clavulanic acid, without further analyses to pinpoint the infection. Examinations The examination of cerebro-spinal fluid was crucial for the final diagnosis. Lumbar puncture demonstrated a predominantly mononuclear pleocytosis of 80 cells/µl (< 5) with an elevated protein of 782 mg/l (< 450); glucose and lactate were within normal limits. Treatment and course Initially we tried to treat a broad range of organisms potentially causing meningitis or encephalitis. Typical bacteria and viruses endemic to Switzerland were not found, thus anti-infective treatment was stopped. Also the search for malaria, HIV, Chikungunya and Dengue infections yielded negative results. After 10 days we received a positive serologic test for Japanese encephalitis virus (JEV). Conclusions The Japanese encephalitis virus is transmitted by mosquitoes and is epidemiologically one of the most important transmissible neurologic diseases in Asia. Although only a minority of infected patients are gravely ill, their sequelae and death toll are considerable. Since 2009 a well-tolerated vaccine is available.

Coverage & missed opportunity for Japanese encephalitis vaccine, Gorakhpur division, Uttar Pradesh, India, 2015: Implications for Japanese encephalitis control.

BACKGROUND & OBJECTIVES: Japanese encephalitis (JE) is an important aetiology of acute encephalitis syndrome in Gorakhpur division, Uttar Pradesh, India. Two doses of JE vaccine ( first during 9-12 months and second during 16-24 months of age) are administered under the Universal Immunization Programme. We conducted surveys to estimate the coverage of JE vaccine and magnitude of missed opportunity for vaccination (MoV) for JE in Gorakhpur division. METHODS: To estimate the JE vaccine coverage, cluster surveys were conducted in four districts of Gorakhpur division by selecting 30 clusters by probability proportional to size method in each district, seven children aged 25-36 months were selected from each cluster and their mothers were interviewed about JE vaccination. To estimate the magnitude of MoV, exit surveys were conducted in vaccination clinics in selected health facilities, mothers were interviewed about the vaccination status of their children and vaccines administered to the child on the day of interview. RESULTS: A total of 840 children were surveyed, 210 from each district. The coverages of one and two doses of JE vaccine in Gorakhpur division were 75 per cent [95% confidence interval (CI): 71.0-78.9] and 42.3 per cent (95% CI: 37.8-46.8), respectively. Facility-based exit survey indicated that 32.7 per cent of the eligible children missed JE vaccine. INTERPRETATION & CONCLUSIONS: The survey results showed that three of the four children aged 25-36 months in Gorakhpur division had received at least one dose of JE vaccine. The coverage of second dose of JE vaccine, however, was low. Failure to administer vaccination simultaneously was the most common reason for MoV for JE vaccine. Training vaccinators about correct vaccination schedule and removing their misconception about administering vaccines simultaneously would substantially improve JE vaccine coverage in Gorakhpur.

Cellular Immune Responses to Live Attenuated Japanese Encephalitis (JE) Vaccine SA14-14-2 in Adults in a JE/Dengue Co-Endemic Area.

BACKGROUND: Japanese encephalitis (JE) virus (JEV) causes severe epidemic encephalitis across Asia, for which the live attenuated vaccine SA14-14-2 is being used increasingly. JEV is a flavivirus, and is closely related to dengue virus (DENV), which is co-endemic in many parts of Asia, with clinically relevant interactions. There is no information on the human T cell response to SA14-14-2, or whether responses to SA14-14-2 cross-react with DENV. We used live attenuated JE vaccine SA14-14-2 as a model for studying T cell responses to JEV infection in adults, and to determine whether these T cell responses are cross-reactive with DENV, and other flaviviruses. METHODS: We conducted a single arm, open label clinical trial (registration: clinicaltrials.gov NCT01656200) to study T cell responses to SA14-14-2 in adults in South India, an area endemic for JE and dengue. RESULTS: Ten out of 16 (62.5%) participants seroconverted to JEV SA14-14-2, and geometric mean neutralising antibody (NAb) titre was 18.5. Proliferation responses were commonly present before vaccination in the absence of NAb, indicating a likely high degree of previous flavivirus exposure. Thirteen of 15 (87%) participants made T cell interferon-gamma (IFNγ) responses against JEV proteins. In four subjects tested, at least some T cell epitopes mapped cross-reacted with DENV and other flaviviruses. CONCLUSIONS: JEV SA14-14-2 was more immunogenic for T cell IFNγ than for NAb in adults in this JE/DENV co-endemic area. The proliferation positive, NAb negative combination may represent a new marker of long term immunity/exposure to JE. T cell responses can cross-react between JE vaccine and DENV in a co-endemic area, illustrating a need for greater knowledge on such responses to inform the development of next-generation vaccines effective against both diseases. TRIAL REGISTRATION: clinicaltrials.gov (NCT01656200).