——欧盟批准了乙型脑炎的新疫苗IXIARO Intercell AG公司宣布欧盟批准了其预防乙型脑炎的新疫苗Ixiaro上市。 本品是一种针对乙型脑炎病毒感染进行自动接种的纯化的灭活疫苗。Intercell公司在苏格兰有该疫苗专门的生产车间，本品通过组织培养进行制备而不采用活的生物体进行提取。 乙型脑炎是种通过蚊虫叮咬进行传播的感染性疾病，每年大约有3～5万人会感染上次病，其中有1～1.5万例患者会因此病丧生。（该评估数据因为未报道事件及其他因素的影响只能作为下限值。）此外，50%的幸存者存在长期的神经系统并发症。该疾病主要出现在亚洲发展中国家，包括印度和中国。目前对于乙型脑炎还无有效的治疗方案。 关于Ixiaro 本品是一种针对乙型脑炎病毒感染进行自动接种的纯化的灭活疫苗，整个开发过程超过了10年的时间。本品由Intercell公司与美国国防部的生物研究中心Walter Reed Army 实验室联合开发。 本品与美国上市的JE-VAX(R)免疫活性相当。整个临床研究中，本品的安全性与安慰剂相似。而且，本品与JE-VAX(R)在比较研究中，患者的耐受性良好。 IXIARO（乙脑灭活疫苗，吸附） 暂停肌内注射 美国首次批准：2009  生产商：Intercell公司生物医学有限公司 适应症及用法 IXIARO是表示主动免疫的疫苗，为17岁及以上的人口由日本脑炎病毒（JEV）引起的疾病的预防。 【用法用量】 原发性免疫由28天给药剂量。 每0.5毫升剂量肌肉注射。 免疫程序应完成至少1周前到JEV的潜在风险。 如果主系列管理1年多以前，一个助推器剂量可优先潜在的再次曝光。 剂型和优势 暂停提供单剂量0.5毫升注射器的注射。 禁忌 一前一后的IXIARO剂量是严重的过敏反应（如过敏性休克）管理IXIARO的禁忌症。 警告和注意事项 IXIARO含有硫酸鱼精蛋白，已知的化合物造成的过敏反应，在某些个人。 不良反应 最常见（≥10％），全身不良反应是头痛和肌肉痛。最常见（≥10％），注射部位反应，疼痛和压痛。 特殊人群中使用 安全性和有效性尚未确立，孕妇，哺乳期妇女，或在儿童和青少年（年龄超过17岁）。 更新日期：02/2012 Vaccine for Japanese encephalitis Novartis Vaccines has launched Ixiaro for active immunisation of adults against Japanese encephalitis. Vaccine for Japanese encephalitis Ixiaro, the only vaccine licensed for Japanese encephalitis, is a purified formalin-inactivated whole-virus, cultivated in Vero-cells. Ixiaro should be considered for use in individuals at risk of exposure to Japanese encephalitis through travel or in the course of their occupation. CLINICAL STUDIES A study looked at the seroconversion in three dosing schedules: 6 microgram injection on days 0 and 28; 6 microgram injection on day 0; and 12 microgram on day 0. Those who did not receive two doses of the vaccine received placebo on day 28. 97.3% of patients on the two-dose schedule reached seroconversion on day 56 compared to 25.6% in the single 6 microgram group and 41.2% in the single 12 microgram group.1 Another study compared the use of Ixiaro with a previously licensed vaccine to test its immunogenicity; 98% seroconversion was seen in patients who received Ixiario compared to 95% seen in the previously licensed vaccine group.2 There were no serious adverse effects seem in either group with the most common adverse effects including headache, flu-like illness, myalgia and fatigue.2 1 INDICATIONS AND USAGE IXIARO is a vaccine indicated for the prevention of disease caused by Japanese encephalitis virus (JEV) in persons 17 years of age and older. 2 DOSAGE AND ADMINISTRATION 2.1 Immunization Series Primary immunization with IXIARO consists of 2 doses administered 28 days apart. Immunization series should be completed at least 1 week prior to potential exposure to JEV. If the primary series was administered more than 1 year previously, a booster dose may be given prior to potential re-exposure. Data on the timing of, and the response to, a booster administered more than 2 years after receipt of the final dose of vaccine (primary series or booster) are not available. 2.2 Administration Before administration, shake the syringe well to obtain a white, opaque, homogeneous suspension. Do not administer if particulate matter remains following shaking or if discoloration is observed.  Each 0.5 mL dose of IXIARO is administered intramuscularly into the deltoid muscle.  Do not administer intravenously, intradermally, or subcutaneously. 3 DOSAGE FORMS AND STRENGTHS IXIARO is a suspension for injection supplied in 0.5 mL single dose syringes. [See Description (11)] 4 CONTRAINDICATIONS Severe allergic reaction (e.g., anaphylaxis) after a previous dose of IXIARO is a contraindication to administration of IXIARO [See Description (11)]. 5 WARNINGS AND PRECAUTIONS 5.1 Preventing and Managing Allergic Vaccine Reactions IXIARO contains protamine sulfate, a compound known to cause hypersensitivity reactions in some individuals [See Description (11)]. Appropriate medical care should be readily available in case of anaphylactic reaction. 5.2 Limitations of Vaccine Effectiveness Vaccinees who receive only one dose of IXIARO may have a suboptimal response and may therefore incur higher risk if exposed to JEV compared to vaccinees who receive both doses.  Vaccination with IXIARO may not result in protection in all cases. IXIARO will not protect against encephalitis caused by viruses/pathogens other than JEV. 5.3 Altered Immunocompetence There are no safety or efficacy data regarding the use of IXIARO in immunocompromised individuals. Immunocompromised individuals may have a diminished immune response to IXIARO. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. 6.1 Clinical Trials Experience The most common (≥ 10%) systemic adverse events observed in clinical trials with IXIARO were headache and myalgia. The most common (≥ 10%) local reactions after IXIARO administration were pain and tenderness. In seven randomized, controlled clinical studies and one uncontrolled clinical study1, 2, 3, 4, 5, 6, 7,8 conducted in North America, Europe, Australia and New Zealand, a total of 3,945 healthy adults aged 18 to 86 years received at least one dose of IXIARO, of which 3,558 were followed-up for safety for 6 to 36 months after the first dose and further 387 were followed-up for safety for two months. In this pooled dataset of subjects who received IXIARO, one death occurred in a subject with metastatic lung adenocarcinoma four months after completing the two-dose regimen. About 1.8% of subjects who received IXIARO experienced a serious adverse event, including one case of multiple sclerosis. Approximately 1% of subjects who received IXIARO discontinued due to adverse events. Adverse Events in a Clinical Trial Comparing IXIARO to a Control: The safety of IXIARO was evaluated in a randomized, controlled, double-blind clinical trial in healthy male and female subjects1. IXIARO was compared to a control: Phosphate Buffered Saline containing 0.1% aluminum hydroxide [PBS + Al(OH)3]. A total of 2,675 subjects were randomized in a 3:1 ratio to receive either an intramuscular injection of IXIARO (0.5 mL) each on Day 0 and Day 28, or an intramuscular injection of PBS + Al(OH)3 (0.5 mL) each on Day 0 and Day 28. Analysis of safety was carried out using the safety population including 1,993 subjects receiving at least one dose of IXIARO and 657 subjects receiving at least one dose of PBS + Al(OH)3 (mean age: 33.8 years, range 18 to 86 years; 55.3% female; race: White: 91.7%, Asian: 1.8%, Black: 3.4%, Other: 3.0%). The IXIARO and control groups were similar with regard to demographics. Subjects recorded adverse events on a diary card for the first seven days after each vaccination. In addition, the study investigator took a medical history and performed a physical exam to evaluate for adverse events on the day of each vaccination and at a visit 4 weeks after the second vaccination. Serious Adverse Events No deaths occurred during this trial. Sixteen serious adverse events (SAE) were reported during the study period. Ten subjects (0.5%) who received IXIARO and 6 subjects (0.9%) who received PBS + Al(OH)3 experienced a SAE. The serious adverse events occurring in the IXIARO group were as follows: dermatomyositis, appendicitis, rectal hemorrhage, limb abscess (contralateral to the injected arm), chest pain, ovarian torsion, ruptured corpus luteal cyst, and three orthopedic injuries. Systemic Adverse Events Overall, the percentage of subjects who experienced at least one adverse event during the study period was 58.9% in the IXIARO group compared to 56.6% in the PBS + Al(OH)3 group. The severity of adverse events was as follows: mild in 33.7% of subjects receiving IXIARO compared to 34.1% of subjects receiving PBS + Al(OH)3, moderate in 20.1% of subjects receiving IXIARO compared to 17.4% of subjects receiving PBS + Al(OH)3, and severe in 5.1% of subjects receiving IXIARO compared to 5.2% of subjects receiving PBS + Al(OH)3. Severity was defined as follows: Mild, awareness of signs or symptoms, but easily tolerated; Moderate, discomfort enough to interfere with usual activity; and Severe, incapable of work or usual activity. Adverse events of any severity grade occurring with an incidence of ≥1% of subjects are shown in Table 1. Table 1. Common Systemic Adverse Events* After IXIARO or Control [PBS + Al(OH)3], Safety Population   Incidence (% of subjects) in the First Vaccination Period (Day 0 to Day 28) Incidence (% of subjects) in the Second Vaccination Period (Day 28 to Day 56) Incidence (% of subjects) in the Total Vaccination Period (Day 0 to Day 56) Adverse Event IXIARO N=1993 PBS + Al(OH)3 N=657 IXIARO N=1968 PBS + Al(OH)3 N=645 IXIARO N =1993 PBS + Al(OH)3 N=657 *The adverse events in this table are those observed at an incidence of ≥ 1% in the IXIARO or PBS + Al(OH)3 groups. †These symptoms were solicited in a subject diary card. Percentages include unsolicited events that occurred after the 7 day period covered by the diary card. ‡N=number of subjects in the safety population (subjects treated with at least one dose) who received the respective dose Headache† 21.6 20.2 13.4 13.0 27.9 26.2 Myalgia† 13.3 12.9 5.6 5.3 15.6 15.5 Fatigue† 8.6 8.7 5.2 5.9 11.3 11.7 Influenza-like Illness† 8.2 8.5 5.8 4.3 12.3 11.7 Nausea† 4.7 5.3 2.6 3.7 6.6 7.5 Nasopharyngitis 2.3 1.8 2.6 2.3 4.7 4.0 Pyrexia† 1.9 2.1 1.5 1.7 3.2 3.0 Rhinitis 1.0 0.8 0.5 0.6 1.4 1.4 Upper Respiratory Tract Infection 0.9 0.9 0.8 0.9 1.7 2.0 Back Pain 0.8 0.9 0.6 0.2 1.3 1.1 Pharyngolaryngeal Pain 0.8 0.9 1.0 0.5 1.6 1.4 Rash† 0.8 0.9 0.7 0.8 1.3 1.5 Diarrhea 0.8 0.8 0.7 0.3 1.5 1.1 Cough 0.8 0.8 0.6 0.6 1.2 1.2 Vomiting† 0.6 0.8 0.8 0.9 1.4 1.7 Injection Site Reactions Injection site reactions after IXIARO were compared to reactions after PBS + Al(OH)3. Symptoms were recorded into a subject diary for the first seven days after each injection, and the injection site was assessed by the investigator at each visit. Pain, tenderness, and pruritis severity was assessed subjectively as absent, mild, moderate or severe by the subject. The amount of erythema, induration and edema was measured by the subject and/or the investigator and rated as absent, mild (≤1cm), moderate (>1 to <3cm), or severe (≥3cm). The severity of injection site reactions observed after either dose was as follows: mild in 41.6% of subjects receiving IXIARO compared to 44.2% of subjects receiving PBS + Al(OH)3, moderate in 9.5% of subjects receiving IXIARO compared to 7.7% of subjects receiving PBS + Al(OH)3, and severe in 3.2% of subjects receiving IXIARO compared to 3.1% of subjects receiving PBS + Al(OH)3. The frequency of injection site reactions of any severity grade is shown in Table 2. Table 2. Injection Site Solicited Adverse Reactions* After IXIARO or Control [PBS + Al(OH)3], Subjects in the Safety Population With Evaluable Diary Cards   Incidence Post Dose 1 (% of subjects†) Incidence Post Dose 2 (% of subjects†) Incidence Post Dose 1 or Dose 2 (% of subjects†) Adverse Reaction IXIARO N‡=1963 PBS + Al(OH)3 N‡=645 IXIARO N‡=1951 PBS + Al(OH)3 N‡=638 IXIARO N‡=1963 PBS + Al(OH)3 N‡=645 *Injection site reactions were assessed for 7 days after each dose. †Denominators used to calculate percentages are based on the number of evaluable diary card entries (defined as documented presence on any day [i.e., entry of “yes”] or absence on all days [i.e., entry of “no”]) for each individual symptom and observation period. ‡ N=number of subjects who returned diary cards after each dose Any Reaction 48.5 47.7 32.6 32.2 55.4 56.2 Pain 27.7 28.2 17.7 18.2 33.0 35.8 Tenderness 28.8 26.9 22.5 18.1 35.9 32.6 Erythema 6.8 5.4 4.6 4.1 9.6 7.4 Induration 4.8 5.3 4.0 3.0 7.5 7.4 Edema 2.4 3.3 2.3 1.6 4.2 4.6 Pruritis 2.6 3.3 1.6 1.9 3.8 4.5 Adverse Events in a Clinical Trial Comparing IXIARO to JE-VAX: The safety of IXIARO compared to another inactivated JE vaccine (JE-VAX) was evaluated in a randomized, double-blind clinical trial2. No deaths occurred during this trial. One serious adverse event occurred in this trial in a subject with a history of myocardial infarction (MI) who experienced a MI three weeks after receiving the 2nddose of IXIARO. The most common adverse events after immunization occurring in ≥1% of subjects were headache, myalgia, fatigue, influenza-like illness, nausea, nasopharyngitis, pyrexia, pharyngolaryngeal pain, cough, rash, diarrhea, sinusitis, upper respiratory tract infection, back pain, migraine, vomiting and influenza, which occurred with similar frequency in both treatment groups. Local injection site reactions solicited in diary cards were observed at a rate of 54% in the IXIARO group (N=428) compared to a rate of 69.1% in the JE-VAX group (N=435). Adverse Events in a Clinical Trial Investigating a Booster Dose of IXIARO: The safety of a IXIARO booster dose administered 15 months after the first dose of the primary series was evaluated in an open-label, uncontrolled trial3. Within 28 days of booster vaccination, adverse events were reported by 35.4% of subjects (N=198). Within 12 months of booster vaccination, subjects who experienced at least one adverse event were 56.1%. Injection site reactions were reported in the subject diary for 30.8% of subjects within 7 days of booster vaccination. Adverse events considered by the investigators to be treatment-related were recorded for 11.6% of subjects (these related events were all observed within one month after the booster dose administration). Pain and tenderness were the most common injection site reactions (>10% of subjects); nasopharyngitis and headache were the most common systemic adverse events (>10%). Safety in Concomitant Use with the Hepatitis A Vaccine, HAVRIX4 The safety of IXIARO when administered concomitantly with inactivated Hepatitis A Virus vaccine (HAVRIX) was evaluated in a controlled trial in which subjects were assigned randomly to one of three treatment groups: Group A (N=62) received IXIARO + HAVRIX; Group B (N=65) received IXIARO + control [PBS + Al(OH)3]; Group C (N=65) received HAVRIX + control [PBS + Al(OH)3]. One serious adverse event occurred in this trial in a subject with a history of alcoholism and seizure disorder who experienced a seizure three weeks after receiving the 2nd dose of IXIARO + control. The percentage of subjects who experienced at least one adverse event was as follows: Group A: 38.7%; Group B: 41.5%; Group C: 47.7%. The most frequently reported injection site reaction on the day of the first vaccination in all three groups was injection site pain in 59.0% of subjects in Group A, in 48.4% of subjects in Group B and in 48.4% of subjects in Group C. 6.2 Post-Marketing Experience The following additional adverse events have been reported during post-marketing use of IXIARO. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine. Nervous system disorders: Paraesthesia, Neuritis. 7 DRUG INTERACTIONS 7.1 Use with HAVRIX In one clinical trial4, IXIARO was administered concomitantly with HAVRIX (Hepatitis A Vaccine) [See Adverse Reactions (6) and Clinical Studies (14)]. In this trial, there was no evidence for interference with the immune response to IXIARO or to HAVRIX when HAVRIX was administered concomitantly with dose 1 of IXIARO [See Clinical Studies (14)]. Data are not available on concomitant administration of IXIARO with other US-licensed vaccines. When IXIARO is administered concomitantly with injectable vaccines, they should be given with separate syringes at different injection sites. IXIARO should not be mixed with any other vaccine in the same syringe or vial. 7.2 Use with Immunosuppressive Therapies There are no data regarding the use of IXIARO concomitantly with immunosuppressive therapies, e.g., irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses) [See Warnings and Precautions (5)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy category B. Reproduction studies have been performed in female rats at doses approximately 300-fold excess relative to the projected human dose (on a mg/kg basis) and have revealed no evidence of impaired fertility or harm to the fetus due to IXIARO. There are, however, no adequate and well‑controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, IXIARO should be used during pregnancy only if clearly needed. The effect of IXIARO vaccine on embryo-fetal and pre-weaning development was evaluated in a developmental toxicity study using pregnant rats. One group of rats was administered IXIARO twice prior to gestation and once during the period of organogenesis (gestation Day 6). A second group of pregnant rats was administered IXIARO once prior to gestation and once during the period of organogenesis (gestation Day 6).  IXIARO was administered at 0.5 mL/rat/occasion (approximately 300-fold excess relative to the projected human dose on a mg/kg basis), by intramuscular injection. No adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-fetal or pre-weaning development were observed. There was a statistically significant finding of incomplete ossification in a few fetuses derived from the second group of pregnant rats. However, there are no data to suggest that this finding is vaccine related. There were no vaccine-related fetal malformations or other evidence of teratogenesis noted in this study.  8.2 Nursing Mothers It is not known whether this vaccine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if IXIARO is administered to a nursing woman. 8.3 Pediatric Use Safety and effectiveness of IXIARO in a pediatric population (<17 years of age) has not been established.  8.4 Geriatric Use Clinical studies of IXIARO did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.  The limited dataset from the pivotal efficacy study2 is as follows: in subjects ≥65 years of age who received IXIARO per protocol (N=24), seroconversion rate was 95.8% and geometric mean titer was 255.2. In subjects ≥ 65 years of age who had been vaccinated in any of five trials1, 2, 4, 5 included in a pooled dataset (N=161), adverse events were reported in 61.9 % (73/118) of subjects in the IXIARO group, 57.7% (15/26) in the JE-VAX group, and 70.6% (12/17) in the control [PBS + Al(OH)3] group.  Five serious adverse events (SAE) were reported.  Four subjects (3.4%) who received IXIARO, no subjects who received JE-VAX, and one subject (5.9%) who received the control [PBS + Al(OH)3] experienced a SAE.  The serious adverse events occurring in the IXIARO group were as follows: one case each of rectal hemorrhage, pancreatic adenocarcinoma, breast cancer, and one death in a subject with metastatic lung adenocarcinoma, which occurred four months after the subject completed the two-dose regimen. 11 DESCRIPTION IXIARO, Japanese Encephalitis Vaccine, Inactivated, Adsorbed is a sterile suspension for intramuscular injection. Each dose of vaccine contains approximately 6 mcg of purified, inactivated JEV proteins and 250 mcg of aluminum hydroxide. The appearance of the liquid is a white, opaque, non-uniform suspension which becomes homogeneous upon shaking. As IXIARO is inactivated, it cannot cause Japanese Encephalitis. IXIARO is a vaccine prepared by propagating JEV strain SA14-14-2 in Vero cells. Multiple viral harvests are performed, which are pooled, clarified and concentrated. The virus suspension is treated with protamine sulfate to remove contaminating DNA and proteins. The resulting partially purified virus is processed through a sucrose density gradient centrifugation step and fractionated. Each fraction is analyzed for the presence of virus, and fractions with the highest virus activity are pooled to give a purified virus suspension. The purified virus is then inactivated by treatment with formaldehyde. The preparation is adjusted to a specified protein concentration and formulated by addition of aluminum hydroxide. The formulated bulk vaccine is filled into syringes, at a volume of 0.5 mL per syringe. From the manufacturing process, IXIARO also contains: formaldehyde (not more than 200 ppm), bovine serum albumin (not more than 100 ng/mL), host cell DNA (not more than 200 pg/mL), sodium metabisulphite (not more than 200 ppm), host cell proteins (not more than 300 ng/6µg of protein), and protamine sulfate (not more than 1µg/mL). No preservatives, stabilizers, or antibiotics are added to the formulation. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Japanese encephalitis is a disease caused by the mosquito-borne Japanese encephalitis virus (JEV). IXIARO acts by inducing antibodies that neutralize live JEV.  13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility IXIARO has not been evaluated for carcinogenic or mutagenic potential. IXIARO was found to have no effect on fertility of female rats at intramuscular doses of up to 300‑fold excess relative to the projected human dose (on a mg/kg basis) administered prior to and after mating [See Use in Specific Populations (8.1)]. The effect of IXIARO on male fertility has not been evaluated. 14 CLINICAL STUDIES Clinical efficacy trials of JE vaccines have found that neutralizing antibody, as measured by a Plaque Reduction Neutralization Test (PRNT) is protective against JEV infection9. Therefore, the evaluation of the efficacy of IXIARO was based on immunogenicity using PRNT as a serological correlate of protection. The World Health Organization consultation group recognizes a PRNT titer of ≥1:10 as being a reasonable correlate for protection10. Clinical Trial2 of Immunogenicity of IXIARO – Non-inferiority of IXIARO Compared to U.S.-Licensed JE Vaccine, JE-VAX Immunogenicity of the vaccine was evaluated in a randomized, active-controlled, observer-blinded clinical trial conducted in the U.S., Germany and Austria in 867 healthy male and female subjects 18 to 80 years of age (mean age: 41.3 years; 60.8% female; race: White 80.8%, Asian 0.8%, Black 13.1%, Other 5.3%). Subjects in the IXIARO treatment arm received the following schedule of three intramuscular doses: Day 0, 0.5 mL of IXIARO, Day 7, PBS + Al(OH)3 (0.5 mL phosphate buffered saline with 0.1% aluminum hydroxide), and on Day 28, 0.5 mL of IXIARO. Subjects in the comparator arm received a subcutaneous dose of 1.0 mL of the US‑licensed JEV vaccine, JE-VAX, on Days 0, 7 and 28. The co-primary endpoints were seroconversion rate (SCR), defined as anti-JEV antibody titer ≥1:10, and geometric mean titer (GMT) at Day 56 in the per protocol population. The immune responses elicited by IXIARO met predefined statistical criteria for non-inferiority compared to those induced by JE‑VAX. See Table 3. Table 3. Seroconversion Rates and Geometric Mean Titers After IXIARO or JE‑VAX, Per Protocol Population †Seroconversion Rates (SCRs): Non-inferiority of IXIARO compared to JE‑VAX for SCRs was demonstrated if the lower bound of the 2-sided 95% confidence interval (CI) for the SCR difference (IXIARO minus JE‑VAX) was >‑10% at Day 56. ‡Geometric Mean Titers (GMTs): Non-inferiority of IXIARO compared to JE‑VAX for GMTs was demonstrated if the lower bound of the 2-sided 95% CI for the GMT ratio (IXIARO /JE‑VAX) was >1/1.5 at Day 56. ◊Pre-Vaccination titers were negative by definition in the PP population and have been imputed to 5. Seroconversion Rates Time Point IXIARO SCR (n/N) [95% CI] JE‑VAX SCR (n/N) [95% CI] Rate difference [95% CI] Pre-Vaccination Screen 0 0 Day 56 (28 days after vaccine dose #2) 96.4% (352/365) [94.0, 97.9] 93.8% (347/370) [90.9, 95.8] 2.6% [-0.5,6.0]† Geometric Mean Titers Time Point IXIARO N=365 n (GMT) [95% CI’s] JE‑VAX N=370 n (GMT) [95% CI’s] GMT ratio estimator [95% CI] Pre-Vaccination Screen 365 (5.0)◊ 370 (5.0)◊ Day 56 (28 days after vaccine dose #2) 361 (243.6) [ 216.4, 274.1] 364 (102.0) [90.3, 115.2 ] 2.33 [1.97, 2.75]‡ Follow-up Study of Long Term Immunogenicity (6; 12, 24 and 36 months) The persistence of JE-neutralizing antibody was evaluated in a subgroup of subjects recruited for follow-up after participation in one of two clinical trials1, 2. In the Intent-to-Treat (ITT) population of subjects randomized to vaccination with IXIARO (N=181) and in the ITT36 population of subjects who intended to stay in the study until month 36 (N = 152), seroconversion rates (SCR) at 6; 12; 24 and 36 months after initiation of the two-dose series were 95% [95%CI 90.8,97.4] and 83.4% [95%CI 77.3,88.1] , 81.8% [95%CI 75.5,86.7] and 84.9% [95%CI 78.3,89.7], respectively. Geometric mean titers (GMT) at 6, 12, 24 and 36 months after initiation of the two-dose series were 83.5 [95%CI 70.9,98.4] and 41.2 [95%CI 34.4,49.3], 44.3; [95% CI 36.7,53.4] and 43.8 [95% CI 36.5,52.6] respectively. Clinical Trial3 on the Effect of a Booster Dose of IXIARO on Long-term Immunity A single 6 mcg booster dose of IXIARO was evaluated in 198 subjects in an uncontrolled, open-label phase 3 study at 15 months after the first IXIARO injection. At 1 month after the booster, GMT was 900.1 (a 40-fold increase from day 0 prior to the booster vaccination) and a SCR of 100% was observed. At 12 months after the booster, a GMT of 361.4 and a SCR of 98.5% (primary endpoint) were observed. The immune response (SCR and GMT) following a booster dose of IXIARO at various time points is summarized below. See Table 4. Table 4. SCR and GMT Before and at Months 1, 6 and 12 After a Booster Dose Administered to Subjects at 15 Months After Primary Immunization with IXIARO (ITT population) SCR (n/N) [95% CI] Geometric Mean Titers GMT ( n ) [95% CI’s] Pre-booster, Day 0 69.2% (137/198) [62.4%, 75.2%] 22.5 (198) [19.0, 26.7] Day 28 100.0% (198/198) [98.1%, 100.0%] 900.1 (198) [742.4, 1091.3] Month 6 98.5% (194/197) [95.6%, 99.5%] 487.4 (197) [390.7, 608.1] Month 12 98.5% (191/194) [95.6%, 99.5%] 361.4 (194) [294.5, 443.5] Temporal Evaluation of Immunogenicity of IXIARO During Vaccination Series In a randomized, dosing regimen, observer-blinded clinical trial4 in 374 healthy male and female subjects, aged 18-76 years, the immunogenicity of IXIARO was evaluated on days 10, 28, 35, and 56 during the vaccination period. Seroconversion rates (SCR) at each time point for the subjects randomized to the standard dosing regimen (IXIARO on days 0 and 28) are displayed in Table 5. Table 5. Seroconversion Rates (SCR) During the Vaccination Series (IXIARO on Days 0 and 28), Per Protocol Population Day 0 (Dose 1 administered) Day 10 (10 days post dose 1) SCR (n/N) [95% CI] Day 28 (28 days post dose 1) SCR (n/N) [95% CI] Day 28 (Dose 2 administered) Day 35 (7 days post dose 2) SCR (n/N) [95% CI] Day 56 (28 days post dose 2) SCR (n/N) [95% CI] 21.1%(24/114) [13.6%; 28.5%] 39.8%(45/113) [30.8%; 48.8%] 97.3%(110/113) [94.4%; 100.0%] 97.3%(110/113) [94.4%, 100%] Immunogenicity of IXIARO Booster Doses The immunogenicity of booster doses was assessed in seronegative subjects in a study7 investigating persistence of immunity following three different primary immunization regimens (2x6 mcg, 1x12mcg or 1x6 mcg). Booster doses were administered at 11 or 23 months after the first dose to subjects with JE-neutralizing antibody titers < 1:10. Results showed that the second injection can be given up to 11 months after the first one. When a second dose was given 11 months after the first dose, seroconversion rate was 99.0% (99/100) with a GMT of 504.3 [95% CI: 367.3, 692.3]) four weeks after vaccination, and by Month 24 was 88.5% (85/96; GMT 121.0 [95% CI: 87.4, 167.6]) without any further booster. In the group with two-dose primary immunization, the rates of subjects with persistent JE-neutralizing antibody titers ≥ 1:10 without a booster at months 12 and 24 were 58.3% [95% CI 49.1,66.9] and 48.3% [95%CI 39.4,57.3], respectively, and GMTs were 18.0 [95% CI 14.3,22.6] and 16.2 [95% CI 12.6,20.8]. After administration of a booster dose to subjects with JE-neutralizing antibody titers < 1:10 in the group with complete primary immunization, SCRs 4 weeks after the booster at months 11 and 23 were 100% [17/17, 95% CI 81.6,100.0] and 100% [27/27, 95% CI 87.5,100.0] respectively, and GMTs were 673.6 [95% CI 378.7,1198.2], and 2536.7 [95% CI 1467.7,4384.4], respectively. Clinical Trial4 of Immunogenicity of IXIARO and the Hepatitis A Vaccine, HAVRIX, When Used Concomitantly The concomitant use of IXIARO with inactivated Hepatitis A Virus vaccine (HAVRIX) was evaluated in a randomized, controlled, single‑blind clinical trial including 192 healthy male and female subjects aged 18 to 61 years. Subjects were divided into three treatment groups: Group A (N=62) received IXIARO + HAVRIX; Group B (N=65) received IXIARO + control [PBS + Al(OH)3] (0.5mL phosphate buffered saline with 0.1% aluminum hydroxide by intramuscular injection); Group C (N=65) received HAVRIX + control [PBS + Al(OH)3]. Anti-JEV GMT at Day 56 in Group A met non-inferiority criteria compared to anti-JEV GMT at Day 56 in Group B. In addition, anti-HAV GMT at Day 28 in Group A met non-inferiority criteria compared to anti-HAV GMT at Day 28 in Group C. Therefore, concomitant administration of IXIARO and HAVRIX did not adversely affect immunogenicity compared to administration of either vaccine individually. Safety results regarding co-administration of IXIARO with HAVRIX are summarized in Section 6.2, Clinical Trials Experience. 15 REFERENCES Clinical study referred to as NCT00605085 in the National Library of Medicine clinical trial database, also referred to as study IC51-302 in the Biologics License Application. Clinical study referred to as NCT00604708 in the National Library of Medicine clinical trial database, also referred to as study IC51-301 in the Biologics License Application. Clinical study referred to as NCT00595309 in the National Library of Medicine clinical trial database, also referred to as study IC51-311 in the Biologics License Application. Clinical study referred to as NCT00596271 in the National Library of Medicine clinical trial database, also referred to as study IC51-308 in the Biologics License Application. Clinical study referred to as NCT00595790 in the National Library of Medicine clinical trial database, also referred to as study IC51-304 in the Biologics License Application. Clinical study referred to as NCT00594958 in the National Library of Medicine clinical trial database, also referred to as study IC51-309 in the Biologics License Application.  Clinical study referred to as NCT00595270 in the National Library of Medicine clinical trial database, also referred to as study IC51-305 in the Biologics License Application. Clinical study referred to as NCT00595465 in the National Library of Medicine clinical trial database, also referred to as study IC51-310 in the Biologics License Application Hoke CH, Nisalak A, Sangawhipa N, Jatanasen S, Laorakapongse T, Innis BL, Kotchasenee S, Gingrich JB, Latendresse J, Fukai K, et al.  Protection against Japanese encephalitis by inactivated vaccines.  N Engl J Med. 1988 Sep 8;319(10):608-14.  Hombach J, Solomon T, Kurane I, Jacobson J, Wood D.  Report on a WHO consultation on immunological endpoints for evaluation of new Japanese encephalitis vaccines, WHO, Geneva, 2-3 September, 2004. Vaccine. 2005;23:5205-11. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied IXIARO is supplied as a sterile 0.5 mL suspension in a pre‑filled syringe (Type I glass) with a plunger stopper (chlorobutyl elastomer) in a pack size of 1 syringe with or without a separate needle. NDC 42515-001-01. None of the syringe or packaging materials contain latex. 16.2 Storage Conditions Store in a refrigerator at 2° to 8° C (35° to 46° F).  Do not freeze. Do not use the vaccine after the expiration date shown on the label. Store in the original package in order to protect from light. During storage, a clear liquid with a white precipitate can be observed. 16.3 Handling Prior to agitation, IXIARO may appear as a clear liquid with a white precipitate. After thorough agitation, it forms a white, cloudy liquid/suspension. The vaccine should be visually inspected for coarse particulate matter and discoloration prior to administration. Discard the product if particulates are present or if it appears discolored or if the syringe appears to be physically damaged. To attach Luer needle, remove the syringe tip cap by gently twisting it. Do not attempt to snap or pull the tip off as this may damage the syringe. Any unused product or waste material should be disposed of in accordance with local requirements. 17 PATIENT COUNSELING INFORMATION 17.1 Counseling by the Health Care Provider Question the vaccine recipient about reactions to previous vaccines, and inform the vaccine recipient of the benefits and risks of IXIARO. Current U.S. and international advisories should be consulted regarding prevalence of Japanese encephalitis in specific locations.  Counsel persons traveling to epidemic and endemic areas that IXIARO may not fully protect everyone who gets the vaccine and that personal precautions should be taken to reduce exposure to mosquito bites (adequate clothing, use of repellents, mosquito nets).  When educating vaccine recipients regarding the potential side effects, explain that IXIARO contains formalin-inactivated JEV particles and is, therefore, non‑infectious. Give the required vaccination information to the vaccine recipient, and provide an opportunity to discuss any questions or concerns. Instruct the vaccine recipient to report any adverse reactions to their health care provider.