Japanese encephalitis (JE) virus is the most common

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1 225 ORIGINAL ARTICLE Short-Term Immunogenicity and Safety of an Accelerated Pre-Exposure Prophylaxis Regimen With Japanese Encephalitis Vaccine in Combination With a Rabies Vaccine: A Phase III, Multicenter, Observer-Blind Study Tomas Jelinek, MD, Gerd D. Burchard, MD, Sebastian Dieckmann, MD, Silja Bühler, MD, MSc, Maria Paulke-Korinek, PhD, Hans D. Nothdurft, MD, Emil Reisinger, MD, MBA, # Khaleel Ahmed, MPharm, Dietrich Bosse, MD, Seetha Meyer, MD, Marco Costantini, MSc, MBA, and Michele Pellegrini, MD, PhD The Berlin Center for Travel and Tropical Medicine, Berlin, Germany; Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany; Institute of Tropical Medicine and International Health, Charité, Berlin, Germany; Institute of Social and Preventive Medicine, University of Zurich, Zurich, Switzerland; Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Vienna, Austria; Department of Infectious Diseases and Tropical Medicine, University of Munich, Munich, Germany; # Department of Tropical Medicine and Infectious Diseases, Rostock University Medical Center, Rostock, Germany; Novartis Healthcare Pvt. Ltd., Hyderabad, India; Novartis Vaccines and Diagnostics, GmbH, Marburg, Germany; Novartis Vaccines and Diagnostics, S.r.l., Siena, Italy DOI: /jtm See the Editorial by David O. Freedman, pp of this issue. Background. The current Japanese encephalitis (JE) vaccination regimen requires two doses and 4 weeks to complete, which may not always be feasible for travelers on short notice. One of the primary endpoints of this phase III study was to demonstrate noninferiority of immune responses to a JE vaccine following an accelerated 1-week JE vaccination regimen administered concomitantly with a rabies vaccine as compared to a standard 4-week JE regimen alone. In addition, the immunogenicity of concomitant administration of JE and rabies vaccines following standard regimens was evaluated, as well as the tolerability and safety profile of each regimen under study. Methods. Healthy adults aged 18 to 65 years were randomized to regimens with an accelerated or standard schedule: JE+rabies-standard (n = 167), JE+rabies-accelerated (n = 217) or (n = 56). Immunogenicity against JE antigen was assessed by a 50% plaque reduction neutralization test (PRNT 50 )titerof 1 : 10, measured 28 days after last active vaccine (LAV) administration. Solicited reactions were collected 7 days after each vaccination; spontaneously reported adverse events (AEs) and serious AEs were monitored up to day 57. This paper reports results until day 57. Results. Noninferiority of immune responses was established for JE+rabies-accelerated compared to the regimen 28 days after LAV administration. Overall, 99% and 100% of subjects in the JE+rabies-accelerated and groups, respectively, achieved PRNT 50 titers of 1 : 10 at 28 days after LAV administration. No impact of concomitant rabies vaccination was observed either on immune responses or on the safety profile of the JE vaccine. Conclusions. This was the first randomized, controlled trial that demonstrated the strong short-term immunogenicity of a new, accelerated, 1-week JE-regimen, which was noninferior to that of the standard regimen, with a satisfactory tolerability and safety profile and no impact of concomitant rabies vaccination. This accelerated regimen, if licensed, could potentially be a valid alternative for individuals requiring a primary series of JE vaccination and rabies pre-exposure prophylaxis on short notice. Corresponding Author: Michele Pellegrini, MD, PhD, Global Vaccines Development, Novartis Vaccines & Diagnostics S.r.l, Via Fiorentina, 1, Siena, Italy. michele.pellegrini@novartis.com Japanese encephalitis (JE) virus is the most common vaccine-preventable cause of viral encephalitis in Asia. 1 JE vaccination is generally recommended for those who expect to spend a month or more in endemic areas during JE transmission season, and for short-term travelers who may engage in extensive outdoor activities 2015 International Society of Travel Medicine, Journal of Travel Medicine 2015; Volume 22 (Issue 4):

2 226 Jelinek et al. in endemic areas, especially during JE transmission season. 2 However, uptake of JE vaccines in travelers for which vaccination should have been considered is low 3,4 and a number of JE cases have been reported in travelers who spent both long- and short-term trips in JE-endemic areas. 4 7 Primary immunization with inactivated, Vero cell-derived JE vaccine generally consists of two intramuscular (IM) doses, 4 weeks apart, 8 which may not always be feasible for individuals who require vaccination on short notice, including tourists, business travelers, diplomats, emergency aid workers, and military personnel. Therefore, an accelerated immunization regimen may be beneficial to improve compliance with vaccination regimens and to confer adequate immune responses against JE virus. Convenience of such an accelerated regimen, especially for travelers, may also be enhanced by the concomitant administration of other vaccines. Among others, rabies vaccination for pre-exposure prophylaxis (PrEP) is recommended for travelers to high-risk areas in rabies-affected countries, and for people in certain high-risk occupations 9,10 ; some, especially travelers on short notice, might benefit from concomitant JE and rabies vaccination. PrEP rabies vaccination, as recommended by the World Health Organization (WHO), consists of three full IM doses of purified cell-cultureor embryonated-egg-based vaccines, and similarly to the JE vaccine is given over a period of 3 to 4 weeks. 8 This study was designed to achieve two independent immunogenicity primary objectives, and this paper reports on one of these: to demonstrate noninferiority of the immune response to a JE vaccine, administered concomitantly with a purified chick embryo cell-culture (PCEC) rabies vaccine following a new accelerated regimen compared to the standard two-dose 4-week JE vaccine regimen alone. Data on the immunogenicity of the PCEC rabies vaccine administered according to the accelerated and the standard regimens ie, the other primary immunogenicity objective will be reported in a separate article. The overall study duration was 12 months; the focus of the present article is on short-term immunogenicity and safety of the JE vaccine from day 1 to day 57. Short-term immunogenicity and safety of the rabies vaccine, as well as long-term immunogenicity and safety of the both the JE and rabies vaccines are being reported separately. Methods Study Design This was a Phase 3 randomized, observer-blind, multicenter trial conducted at seven study centers located in Austria, Germany, and Switzerland (Clinicaltrials.gov identifier: NCT ). The protocol was approved by the appropriate Ethics Review Committees, and the study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. Before enrolment, written informed consent was obtained from each participant. Study Participants Overall, 661 healthy adults (N = 440 reported in this paper) of both sexes, aged 18 to 65 years were enrolled in the study. Subjects were assigned randomly in a 3 : 4 :1 : 4 ratio to one of four vaccine groups: JE + PCEC rabies vaccines following the standard PrEP regimens (JE + rabies-standard), JE + PCEC rabies vaccines following a new accelerated 1-week regimen (), a standard regimen with JE vaccine alone () or a standard regimen with PCEC rabies vaccine alone (rabies-standard; not reported in this article) (Table 1). The main exclusion criteria were known allergy or hypersensitivity to any vaccine components; history of previous rabies/rabies immunoglobulin and/or JE immunization; a body temperature 38 C within 3 days of intended vaccination; receipt of any other vaccines within 2 weeks prior to enrollment or intent to receive any vaccine within 4 weeks from the study vaccines; receipt or intent to receive anti-malaria drugs up to 14 days prior to vaccination through day 43, because of the potential interference with rabies antibody responses; and pregnancy or breast-feeding. Vaccines For the JE immunization, the commercially available IXIARO [Valneva (formerly Intercell AG), Vienna, Austria] vaccine was given as a two-dose IM regimen [single 0.5 ml dose on days 1 and 8 or on days 1 and 29 (corresponding to days 0 and 28 on the product label) following the accelerated or the standard regimen, respectively; Table 1]. IXIARO is an inactivated Vero cell-derived JE vaccine using the SA strain, which has been licensed among others in Australia, Europe, and the United States for active immunization against JE in adults (since 2009), and in children aged 2 months (since 2013). 11 For the rabies vaccination, the commercially available PCEC rabies vaccine, Rabipur (Novartis Vaccines and Diagnostics GmbH, Marburg, Germany; strain: Flury-LEP), was given as a three-dose IM PrEP regimen [a single 1.0 ml dose on days 1, 4, and 8 or on days 1, 8, and 29 (corresponding to days 0, 7, and 28 on the product label) following the accelerated or the standard regimen, respectively; Table 1]. Rabipur is indicated for both pre- and post-exposure prophylaxis of rabies in all age groups. 12 Placebo treatment consisted of normal saline solution (0.9% w/v sodium chloride) and was used to keep the observer-blind design. Vaccines were administered as IM injections preferably into the deltoid region of either the left arm (JE vaccine or placebo, depending on the visit) or the right arm (PCEC rabies vaccine or placebo) in an observer-blind fashion by designated unblinded site staff. The investigator and all other study staff, including those evaluating adverse events (AEs), remained blinded.

3 Accelerated JE and Rabies Vaccination Regimen 227 Table 1 Vaccine schedules Vaccines administered* Groups Number of subjects enrolled Schedules Day 1 Day 4 Day 8 Day 29 JE + rabies-standard N = 167 Standard (JE + rabies vaccines) JE, rabies Placebo Rabies, placebo JE, rabies N = 217 Accelerated (JE + rabies vaccines) JE, rabies Rabies JE, rabies Placebo, placebo N = 56 Standard (JE vaccine alone) JE, placebo Placebo Placebo, placebo JE, placebo Rabies-standard N = 221 Standard (rabies vaccine alone) Rabies, placebo Placebo Rabies, placebo Rabies, placebo JE = Japanese encephalitis. *To keep the observer blind design, placebo was matched with rabies or JE vaccination according to study group. Corresponding vaccination days 0, 7, and 28 according to official label use. Data on the immunogenicity and safety of subjects exposed to the rabies vaccine accelerated and the standard regimens (including the rabies-standard group not included in this article) will be reported in a separate article. Immunogenicity Objectives The primary objective related to JE vaccination was to establish noninferiority of the immune response to the compared to the regimens based on the percentage of subjects with 50% plaque reduction neutralization test (PRNT 50 ) titers 1 : 10 (considered as the minimum protective level 13 ), measured 28 days after the last active vaccine (LAV) administration, with a noninferiority margin set at 10%. Secondary objectives included: establishing noninferiority of the immune response of the JE + rabies-standard compared to the regimen [based on PRNT 50 geometric mean titers (GMTs) at 28 days after LAV administration] and establishing noninferiority of the immune response of the regimen compared to the JE + rabies-standard and compared to the regimen (based on the percentage of subjects with PRNT 50 titers 1:10 measured at 7 days after LAV administration). In addition, the kinetics of PRNT 50 GMTs and the percentages of subjects with adequate titers were evaluated up to day 57. Immunogenicity Assessment Venous blood samples (approximately 7 ml) were drawn prior to vaccination (day 1) and on days 15, 22, 36, and 57 and sera were stored at 18 C until analyzed. Determination of antibodies directed against JE virus was performed by a neutralization test using PRNT 50 assays (target JE strain SA ) conducted at the Valneva Laboratory, Vienna, Austria. Antibody titers were expressed as GMTs and seroprotection rate was defined as the percentage of subjects with anti-je neutralizing antibody (PRNT 50 )titers 1: 10. Serology assays were performed in a blinded fashion for vaccine groups and visits. Safety Assessment After each vaccination, subjects were observed for at least 30 minutes at the study site to monitor for immediate adverse reactions. The incidence and severity of solicited local and systemic AEs were recorded Table 2 Demographics and baseline characteristics of subjects in the JE vaccine groups JE + rabiesstandard JE + rabiesaccelerated N = 167 N = 217 N = 56 Age, years (mean ± SD) 37.3 ± ± ± 13.3 Male, n (%) 91 (54) 89 (41) 26 (46) Female, n (%) 76 (46) 128 (59) 30 (54) Weight, kg (mean ± SD) 75.7 ± ± ± 16.0 Height, cm (mean ± SD) ± ± ± 8.3 Ethnicity, n (%) White 166 (99) 213 (98) 54 (96) Black/African American 0 2 (<1) 1 (2) Asian 1 (<1) 0 0 Other 0 2 (<1) 1 (2) JE = Japanese encephalitis; SD = standard deviation. by the participants on a diary card for 7 days after vaccination. Reports of unsolicited AEs, including serious AEs (SAEs) and AEs leading to subject withdrawal were collected up to day 57. The investigators assessed the AEs for severity (categorized as mild, moderate, or severe), seriousness, and causal relationship to the study vaccines (classified as not related, possibly related, or probably related). Statistical Analyses With a sample size of 200 evaluable subjects in the group and 50 in the group, the study had approximately 99% power to show noninferiority between rabies + JE-accelerated and groups. Noninferiority of immunogenicity was based on the lower limit of the two-sided 97.5% confidence intervals (CIs) of the difference in the percentage of subjects (rabies + JE-accelerated ) with PRNT 50 titers 1 : 10, measured 28 days after LAV administration. The noninferiority margin was set at 10%. Noninferiority tests for the secondary objectives were based on the lower limit of the two-sided 95% CIs of the ratio of the GMTs (JE + rabies vs ) measured 28 days after LAV administration with a noninferiority

4 228 Jelinek et al. Table 3 sets) Overview of noninferiority analyses for primary and secondary JE vaccine immunogenicity endpoints (per protocol Immunogenicity endpoint Vaccine group Noninferiority analyses Primary Percentages of subjects with PRNT 50 titer 1 : 10, 28 days after LAV (97.5% CI) N = 206 n = (96 100) N = 49 n = (93 100) Vaccine group difference versus * Difference (97.5% CI) 1 ( ) Noninferiority criterion met? Yes Secondary Percentages of subjects with PRNT 50 titer 1 : 10, 7 days after LAV (95% CI) Secondary Percentages of subjects with PRNT 50 titer 1 : 10, 7 days after LAV (95% CI) Secondary PRNT 50 GMTs 28 days after LAV N = 209 n = (96 100) N = 209 n = (96 100) JE + rabies-standard N = 157 JE + rabies-standard N = 157 n = (97 100) N = 47 n = (92 100) N = 49 Vaccine group difference versus JE + rabies-standard Difference (95% CI) Yes 1 ( ) Vaccine group difference versus Difference (95% CI) 1 ( ) Ratio of GMTs JE + rabiesstandard : 291 ( ) 331 ( ) Ratio of GMTs (95% CI) 0.88 ( ) JE = Japanese encephalitis; N = number of subjects with evaluable serum samples at the relevant timepoints (7 or 28 days after LAV); PRNT 50 = 50% Plaque reduction neutralization test; LAV = last active vaccination; CI = confidence interval; GMT = geometric mean titers. *Noninferiority tests were based on the lower limit of the two-sided 97.5% CI of the difference in the percentages of subjects ( ) with PRNT 50 titer 1 : 10, measured 28 days after LAV, with a noninferiority margin set at 10%. Noninferiority tests were based on the lower limit of the two-sided 95% CI of the difference in the percentages of subjects ( JE + rabies-standard) with PRNT 50 titer 1 : 10, measured 7 days after LAV, with a noninferiority margin set at 10%. Noninferiority tests were based on the lower limit of the two-sided 95% CI of the difference in the percentages of subjects with ( ) with PRNT 50 titer 1 : 10, measured 7 days after LAV, with a noninferiority margin set at 10%. Noninferiority tests were based on the lower limit of the two-sided 95% CI of the ratio of the GMT (JE + rabies-standard : ) measured 28 days after LAV, with a noninferiority margin set at margin set at 0.5; and the lower limit of the two-sided 95% CIs of the difference in the percentage of subjects ( JE + rabies-standard; and ) with PRNT 50 titers 1 : 10, measured 7 days after LAV administration with a noninferiority margin set at 10%. The percentages of subjects with PRNT 50 titers 1 : 10 together with their associated 95% Clopper-Pearson CIs were calculated by randomization group. PRNT 50 GMTs and associated 95% CIs for each group, and time points were computed by taking the exponential of the corresponding log-transformed (least squares) means, and their 95% CIs were obtained from an anova model, with group and center as fixed factors. Safety data were evaluated descriptively, and summarized by the percentage and number of subjects with events in each group. Immunogenicity analyses were run on the per-protocol set (PPS), defined as all trial participants who received all the relevant doses of the study vaccines correctly, provided evaluable serum samples at the relevant time points and within the study-specified visit windows through day 57, and had no major protocol violations. Safety was analyzed for subjects exposed, ie, subjects who had at least one study vaccination, and who provided safety data. Results Disposition and Demographics Overall, 440 subjects were randomized to the three JE vaccine groups included in this paper, and all subjects but one (in the JE + rabies-standard group) were exposed to at least one dose of the vaccine(s) assigned (Table 1). The most frequent reasons for exclusion from the PPS were missing blood draws or blood draws taken outside of visit windows. Demographics and other baseline characteristics of the subjects are reported in Table 2. Groups were similar with respect to age, weight, height, and race (Table 2). The majority of subjects were of white ethnic origin (96% 99% across the JE vaccine groups). Females ranged from 46% of subjects in the JE + rabies-standard group to 59% in the group. Yes Yes

5 Accelerated JE and Rabies Vaccination Regimen 229 Figure 1 Kinetics of antibody responses to JE vaccine measured by (A) PRNT 50 GMTs and (B) the percentage of subjects with PRNT 50 titers 1 : 10 on days 1, 15, 22, 36, and 57 in the group, and on days 1, 36, and 57 in the JE + rabies-standard and groups (per protocol sets). GMTs and the percentage of subjects with PRNT 50 titers 1:10 were not evaluated at days 15 and 22 in the and JE + rabies-standard groups due to the vaccination schedule (days 1 and 29 for the standard schedule). N = number of subjects with evaluable serum samples at the different timepoints. JE = Japanese encephalitis; PRNT 50 = 50% plaque reduction neutralization test; GMT = geometric mean titers. Immunogenicity Noninferiority of the immune response of the as compared to the regimen, at 28 days after LAV was established; the lower limit of the two-sided 97.5% CI for the group differences (rabies + JE-accelerated vs rabies-standard) in the percentages of subjects with PRNT 50 titers 1:10 was 4.8%, which was above the pre-specified noninferiority margin of 10% (Table 3). Noninferiority was also established for the other secondary JE vaccine immunogenicity endpoints (Table 3). Figure 1A shows the kinetics of PRNT 50 GMTs in the JE vaccine groups. At day 36 PRNT 50 GMTs were higher in the group compared

6 230 Jelinek et al. to the and JE + rabies-standard groups; at day 57 the GMTs were similar in all groups. Irrespective of concomitant administration of PCEC rabies vaccine, PRNT 50 titers were similar for the two standard JE groups at all time points. At day 57 all subjects had immune responses above the antibody level considered adequate (PRNT 50 titers 1 : 10) in the two standard regimen groups and 98% were above that level in the accelerated 1-week regimen group (Figure 1B). Safety All subjects except one (in the JE + rabies-standard group) were exposed to at least one study vaccination and contributed to the safety analyses. The percentages of subjects experiencing at least one solicited AE after any vaccination were similar across all groups and ranged from 79% ( group) to 85% ( group) (Table 4). The most frequently reported local reaction after any vaccination was injection site pain, reported by 54% to 60% across JE vaccine groups, while the most commonly reported systemic reactions after any vaccination were fatigue (33% to 43% across groups), followed by headache (30% 41% across groups). Severe reactions were rare and occurred in 1% (local) and 4% (systemic) of subjects across groups. Unsolicited AEs were reported by 42% of subjects in the JE + rabies-standard group, and in 50% and 52% of subjects in the and groups, respectively (Table 4). The most frequent unsolicited AEs were nasopharyngitis (from 13% to 15% across JE vaccine groups) and headache (occurring more than 7 days after vaccination; 7% 10% across JE vaccine groups). Possibly or probably related AEs were reported by 11% to 23% of subjects across JE vaccine groups; nasopharyngitis was again the most frequently related AE reported: 4% in the and groups and 2% in the JE + rabies-standard group. Eight subjects reported SAEs. For one subject, a 23-year old female in the group, two SAEs were reported a few hours after the first JE vaccination (eyelid edema and generalized pruritus; considered SAEs because of medical relevance, not life-threatening nor leading to hospitalization), which were judged by the investigator as probably related to the vaccine. The subject completely recovered on the same day. No mortality was reported. Discussion The primary endpoint of this study was met by demonstrating noninferiority of antibody responses to JE vaccination given concomitantly with a PCEC rabies vaccine according to a new accelerated 1-week regimen compared to the standard 4-week regimen administered alone. At day 36, JE GMTs were higher in the accelerated group than in the standard regimen groups, and at day 57, PRNT 50 titers were similar Table 4 Percentage of subjects reporting adverse events (solicited and unsolicited safety sets) JE + rabiesstandard N = 166 JE + rabiesaccelerated N = 217 N = 56 Solicited AEs reported from day 1 to day 7 (%) Any solicited AEs Local Systemic Other Unsolicited AEs reported from day 1 to day 57 after any vaccination (%) Any unsolicited AEs Possibly or probably related AEs AEs leading to premature withdrawal Any SAEs Possibly or probably related SAEs JE = Japanese encephalitis; AE = adverse event; SAE = serious adverse event. across all JE vaccine groups. Percentages of subjects with PRNT 50 titers 1 : 10 at 7 days after LAV were 99% (day 15, JE+ rabies-accelerated), 99% (day 36, JE + rabies-standard), and 100% (day 36, ), remaining at stable levels for all vaccination regimens up to day 57 post-vaccination. The good response seen to the accelerated regimen in this trial is in line with preliminary findings from a Phase 2 study of IXIARO that showed 95% of subjects developed PRNT 50 titers 1 : 10 in response to the second dose of an experimental day 0, 14, 28 three-dose regimen. 14 Vaccine tolerability and safety profiles were generally similar across the study groups. No impact of concomitant rabies vaccination was observed either on immune responses or on the safety profile of the JE vaccine. This is in line with previous observations which demonstrated that the immunogenicity and safety of IXIARO JE vaccine was not compromised by concomitant administration of other vaccines, such as a hepatitis A vaccine (Havrix 1440, GlaxoSmithKline, Rixensart, Belgium). 15 In addition, administration of a quadrivalent meningococcal glycoconjugate ACWY-CRM vaccine [MenACWY-CRM (Menveo, Novartis Vaccines and Diagnostics S.r.l., Siena, Italy)] with IXIARO and Rabipur did not compromise the immunogenicity or safety of the individual vaccines. 16 The short-term results of the present study provide relevant information for individuals traveling at short notice and for limited periods (approximately 2 months). Long-term immunogenicity and safety data (up to 1 year following first vaccine dose) from this study will complement the evidence for subjects planning extended

7 Accelerated JE and Rabies Vaccination Regimen 231 or repeated travels to JE-endemic countries. The overall study design did not include the evaluation of the requirement for and the timing of booster vaccination following a primary series. Until consolidated evidence are available on the booster requirements following accelerated regimen, the current vaccine-specific indications for booster dose and timing are to be followed. In conclusion, this was the first randomized, controlled clinical trial demonstrating the short-term immunogenicity and safety of a JE vaccine following a newly proposed accelerated 1-week regimen in combination with a PCEC rabies vaccine. The results shown up to day 57, once confirmed by those at 1 year, are expected to support the adoption, if licensed, of the new accelerated JE vaccine regimen and could potentially be a valid alternative for individuals requiring a primary series of JE and rabies PrEP on short notice. The JE vaccine is highly immunogenic with a good tolerability and safety profile and under an accelerated administration regimen may provide the potential benefits of improving compliance to JE and rabies vaccination. Acknowledgments The authors would like to thank all the study participants and investigators: Kelly Lindert and Ahmed Abdul Mateen for their contribution to study design; Dr Hari Sai Priya Baddela, PhD (Novartis Healthcare Pvt. Ltd., Hyderabad, India) and Dr Amanda Prowse, PhD (CHC-Europe) for their editorial assistance in the preparation of the manuscript. This study was sponsored by Novartis Vaccines and Diagnostics GmbH, Germany. Declaration of Interests K. A., S. M., M. C., and M. P. are full-time employees of Novartis Vaccines. D. B. was a full-time employee of Novartis Vaccines at time of the study. M. P. K. accepted fees for speaking, serving on advisory boards and received funding to attend conferences from Baxter, GlaxoSmithKline, Valneva (formerly Intercell), Novartis, and Pfizer. H. D. N. accepted fees for speaking and serving on advisory boards from Baxter, GlaxoSmithKline, Novartis, and Takeda. S. B. received compensation as study investigator from Novartis Vaccines. T. J. received speaker honoraria and compensation as study investigator from Novartis Vaccines. References 1. World Health Organization. International travel and health. Japanese encephalitis. Available at: Who.Int/ith/diseases/japanese_encephalitis/en/ (Accessed 2014 Apr 10). 2. Burchard GD, Caumes E, Connor BA, et al. Expert opinion on vaccination of travelers against Japanese encephalitis. J Travel Med 2009; 16: Duffy MR, Reed C, Edelson PJ, et al. A survey of US travelers to Asia to assess compliance with recommendations for the use of Japanese encephalitis vaccine. J Travel Med 2013; 20: Hatz C, Werlein J, Mutsch M, et al. Japanese encephalitis: defining risk incidence for travelers to endemic countries and vaccine prescribing from the UK and Switzerland. J Travel Med 2009; 16: Hills SL, Griggs AC, Fischer M. Japanese encephalitis in travelers from non-endemic countries, Am J Trop Med Hyg 2010; 82: Lagarde S, Lagier JC, Charrel R, et al. Japanese encephalitis in a French traveler to Nepal. J Neurovirol 2014; 20: Tappe D, Nemecek A, Zipp F, et al. Two laboratoryconfirmed cases of Japanese encephalitis imported to Germany by travelers returning from Southeast Asia. J Clin Virol 2012; 54: World Health Organization. International travel and health. Chapter 6. Vaccine-preventable diseases and vaccines 2013 update. Available at: ith/chapters/ith2012en_chap6.pdf?ua=1 (Accessed 2014 Mar 7). 9. Malerczyk C, Detora L, Gniel D. Imported human rabies cases in Europe, the United States, and Japan, 1990 to J Travel Med 2011; 18: World Health Organization. International travel and health. Rabies. Available at: Int/ith/vaccines/rabies/en/ (Accessed 2014 Mar 7). 11. Ixiaro. Summary of product characteristics. Available at: library/epar_-_product_information/human/000963/wc Pdf (Accessed 2014 Mar 7). 12. Rabipur. Summary of product characteristics. Available at: spc.pdf (Accessed 2014 Mar 7). 13. Hombach J, Solomon T, Kurane I, et al. Report on a WHO consultation on immunological endpoints for evaluation of new Japanese encephalitis vaccines, WHO, Geneva, 2 3 September, Vaccine 2005; 23: Lyons A, Kanesa-thasan N, Kuschner RA, et al. A phase 2 study of a purified, inactivated virus vaccine to prevent Japanese encephalitis. Vaccine 2007; 25: Kaltenbock A, Dubischar-Kastner K, Eder G, et al. Safety and immunogenicity of concomitant vaccination with the cell-culture based Japanese encephalitis vaccine IC51 and the hepatitis A vaccine Havrix1440 in healthy subjects: a single-blind, randomized, controlled phase 3 study. Vaccine 2009; 27: Alberer M, Burchard G, Jelinek T, et al. Coadministration of a meningococcal glycoconjugate ACWY vaccine with travel vaccines: a randomized, open-label, multi-center study. Travel Med Infect Dis 2014; 12: