Vaccine Information: IXIARO

IXIARO- japanese encephalitis virus strain sa 14-14-2 antigen (formaldehyde inactivated) injection, suspension
Valneva Scotland Ltd.

1 INDICATIONS AND USAGE

IXIARO is a vaccine indicated for the prevention of disease caused by Japanese encephalitis virus (JEV). IXIARO is approved for use in individuals 2 months of age and older.

2 DOSAGE AND ADMINISTRATION

For intramuscular administration only.

2.1 Dosage and Schedule

Primary Series:
Children 2 months to <3 years of age: Primary immunization with IXIARO consists of two (2) 0.25 mL doses, administered 28 days apart.
Individuals 3 years of age and older: Primary immunization with IXIARO consists of two (2) 0.5 mL doses, administered 28 days apart.
Complete the primary immunization series at least 1 week prior to potential exposure to JEV.

Booster Dose:
Individuals 17 years of age and older: If the primary series of two doses was completed more than 1 year previously, a booster dose may be given if ongoing exposure or re-exposure to JEV is expected.
Infants, children and adolescents 2 months to <17 years of age: The safety and immunogenicity of a booster dose has not been evaluated.

2.2 Administration

IXIARO is administered intramuscularly. The preferred sites for intramuscular injection are the anterolateral aspect of the thigh in infants 2 to 11 months of age, the anterolateral aspect of the thigh (or the deltoid muscle if muscle mass is adequate) in children 1 to <3 years of age, or the deltoid muscle in individuals 3 years of age and older.
Do not administer intravenously, intradermally, or subcutaneously.

2.3 Preparation for Administration

Prior to agitation, IXIARO is a clear liquid with a white precipitate. Before administration, shake the syringe well to obtain a white, opaque, homogeneous suspension.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If either of these conditions exists, do not administer.
Preparation of a 0.25 mL Dose of IXIARO for Administration to Children 2 Months to <3 Years of Age:
1. Shake the pre-filled syringe containing 0.5 mL to obtain a homogeneous suspension.
2. 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.
3. Attach a sterile safety needle to the pre-filled syringe (needle is not provided with IXIARO).
4. Hold the syringe in an upright position and uncap the needle.
5. Push the plunger stopper up to the edge of the red line on the syringe barrel, indicated by a red arrow (see Figure1)*, and discard expelled volume into a medical waste container.
6. Lock the needle safety shield and remove the needle.
7. Attach a new sterile needle prior to injection of the remaining volume.
*If the plunger stopper is pushed beyond the red line, do not administer the vaccine. Repeat the procedure using a new pre-filled syringe.

Preparation of a 0.5 mL Dose of IXIARO for Administration to Individuals 3 Years of Age and Above:
1. Shake the pre-filled syringe containing 0.5 mL to obtain a homogeneous suspension.
2. 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.3. Attach a sterile needle to the pre-filled syringe (needle is not provided with IXIARO).

3 DOSAGE FORMS AND STRENGTHS

IXIARO is a suspension for injection supplied in 0.5 mL single dose syringes. For children 2 months to <3 years of age, a single dose is 0.25 mL. For individuals 3 years of age and older, a single dose is 0.5 mL. [See Dosage and Administration (2.1)]

4 CONTRAINDICATIONS

Severe allergic reaction (e.g., anaphylaxis) after a previous dose of IXIARO, any other Japanese Encephalitis Virus vaccine, or any component of IXIARO, including protamine sulfate, is a contraindication to administration of IXIARO [See Description (11)]. Alternatively, because of uncertainty as to which component of the vaccine may be responsible, individuals with a history of severe allergic reaction to another Japanese Encephalitis vaccine may be referred to an allergist for evaluation if immunization with IXIARO is considered.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity 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

Vaccination with IXIARO may not protect all individuals.

5.3 Altered Immunocompetence

Immunocompromised individuals may have a diminished immune response to IXIARO.

6 ADVERSE REACTIONS

In infants 2 months to <1 year of age, the most common injection site reaction was redness (>15%); the most common solicited systemic adverse reactions were fever (>20%), irritability (>15%) and diarrhea (>10%). In children 1 to <3 years of age, the most common solicited systemic adverse reaction was fever (>20%). In children 3 to <12 years of age, the most common solicited systemic adverse reaction was fever (>10%). In adolescents 12 to <18 years of age, the most common solicited injection site reactions were pain (15%) and tenderness (10%). In adults 18 years of age and older, the most common injection site reactions were pain (>25%) and tenderness (>25%); the most common solicited systemic adverse reactions were headache (>20%) and myalgia (>10%).

6.1 Clinical Trials Experience

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.

Clinical Studies in Children 2 Months to <18 Years of Age:

Adverse Events in a Pediatric Trial Comparing IXIARO to U.S.-Licensed Control Vaccines HAVRIX and PREVNAR:

The safety of IXIARO was evaluated in a randomized, controlled, open-label clinical trial in healthy male and female subjects 2 months to <18 years of age, conducted in the Philippines, a country where Japanese Encephalitis is endemic (Study 1)¹. IXIARO was compared to two control vaccines: HAVRIX (Hepatitis A vaccine, pediatric 720 EL.U./0.5 mL formulation, GlaxoSmithKline Biologicals) and Prevnar (Pneumococcal 7-valent Conjugate Vaccine [Diphtheria CRM₁₉₇ protein], Pfizer). A total of 1,769 subjects were randomized in an age-stratified scheme in a 3:1 ratio (2:1 ratio for ages <1 year) to receive intramuscular injections of either IXIARO (two 0.25 mL doses on Days 0 and 28 for infants and children 2 months to <3 years of age or two 0.5 mL doses on Days 0 and 28 for children 3 to <18 years of age) or HAVRIX (children 1 year of age and older, 2 doses on Day 0 and at Month 7) or Prevnar (infants 2 to <6 months of age, 3 doses on Days 0, 28, 56 and an optional 4^th dose at Month 7 or later; infants 6 to <12 months of age, 3 doses on Days 0 and 56 and at Month 7). Subject numbers and dosing schemes by age group are displayed in Table 1.

Table 1. Subject Numbers and Dosing Schemes by Age Group (Safety Population, Study 1^§ ,Philippines)

Treatment Group	IXIARO* (N=1311)	HAVRIX (N=394)	PREVNAR (N=64)
Subjects in Age Group 2 months to <1 year	131	–	64
Subjects in Age Group 1 year to <3 years	640	213	–
Subjects in Age Group 3 to <12 years	300	101	–
Subjects in Age Group 12 to <18 years	240	80	–

^§ NCT01041573

*Infants and children 2 months to <3 years of age received two 0.25 mL doses administered on Days 0 and 28. Individuals 3 years of age and older received two 0.5 mL doses administered on Days 0 and 28.

Analysis of safety in children was carried out using the safety population including 1,311 subjects receiving at least one dose of IXIARO, 394 subjects receiving the first dose of HAVRIX on Day 0, and 64 subjects receiving at least one dose of Prevnar on Day 0 (all infants <1 year of age). The IXIARO and control groups were similar with regard to demographics (mean age 5.48 years, range 2 months to 17 years; 49.5% female; ethnicity: Asian: 100% for Study 1 overall). Parents or subjects recorded adverse events on a diary card for the first seven days after each vaccination. Only those events considered to be assessable based on the subjects developmental status were recorded. Parents or subjects were queried regarding the occurrence of any unsolicited AEs following the previous vaccination at in-person visits, which included a medical exam, on Day 28, Day 56, and at Month 7.

Solicited Adverse Events

For an overview of solicited local and systemic reactions for pediatric age groups see Table 2 (infants 2 months to <1 year of age), Table 3 (toddlers 1 to <3 years of age) Table 4 (children 3 to <12 years of age), and Table 5 (adolescents 12 to <18 years of age). As children 1 year of age and older received the second dose of HAVRIX at the final study visit at Month 7, rates of solicited AEs among these subjects after the second vaccination are only available for IXIARO.

Table 2.Rates of Solicited Adverse Reactions on Days 0-7 After Each Vaccination in Infants 2 Months to <1 Year of Age, by Dose and Treatment Group, Study 1^§ ,Philippines

	Post Dose 1 (% of subjects)	Post Dose 2 (% of subjects)
Injection Site Reactions	IXIARO* (N=131 ‡)	Prevnar (N=64 ‡)	IXIARO* (N=131 ‡)	Prevnar (N=64‡)
Tenderness	3.1	12.7	0.8	3.3
Hardening	0.0	7.9	0.0	1.6
Swelling	1.5	6.3	1.5	1.6
Redness	17.6	25.4	5.3	16.4
Solicited Systemic Reactions
Irritability	15.3	12.7	8.4	8.2
Vomiting	7.6	6.3	3.8	1.6
Diarrhea	11.5	6.3	8.4	4.9
Excessive fatigue	3.1	7.9	1.5	3.3
Rash	8.4	9.5	3.8	4.9
Loss of appetite	5.3	9.5	5.3	6.6
Fever ≥37.7°C (≥99.9°F)	23.7	25.4	14.5	23.3
37.7-38.6 °C (99.9-101.5°F)	17.6	22.2	12.2	15.0
38.7-39.3 °C (101.6-102.7°F)	6.1	1.6	1.5	6.7
39.4-40.5 °C (102.8-104.9°F)	0.0	1.6	0.8	1.7
>40.5°C (>104.9°F)	0.0	0.0	0.0	0.0

^§ NCT01041573

*IXIARO dose 0.25 mL.

‡N=number of subjects with available diary card data after each dose, used as the denominator to calculate percentages.

Table 3. Rates of Solicited Adverse Reactions on Days 0-7 After Each Vaccination in Children 1 Year to <3 Years of Age, by Dose and Treatment Group, Study 1^§ ,Philippines

	Post Dose 1 (% of subjects**)		Post Dose 2 (% of subjects**)
Injection Site Reactions	IXIARO* (N=640 ‡)		Havrix (N=213 ‡)	IXIARO* (N=637 ‡)
Pain	3.6 (6/165)		7.4 (4/54)	3.6 (6/166)
Itching	0.6 (1/180)		0.0 (0/63)	0.0 (0/184)
Tenderness	3.1		5.6	1.4
Hardening	0.9		0.5	0.3
Swelling	2.0		3.3	1.7
Redness	6.1		7.5	2.5
Solicited Systemic Reactions
Irritability	7.7		5.6	2.7
Nausea	2.2 (5/228)		1.3 (1/78)	0.9 (2/229)
Vomiting	4.2		5.6	2.8
Diarrhea	7.0		5.2	4.6
Flu-like symptoms	7.7 (13/169)		13.3 (8/60)	4.0 (7/176)
Excessive fatigue	2.5		0.9	1.1
Muscle pain	2.3 (3/130)		0.0 (0/42)	0.7 (1/136)
Rash	4.2		2.3	1.3
Headache	1.5 (2/135)		4.4 (2/45)	1.4 (2/143)
Loss of appetite	5.6		4.2	2.5
Fever ≥37.7°C (≥99.9°F)	20.2		15.5	12.7
37.7-38.6 °C (99.9-101.5°F)	15.6		12.2	8.5
38.7-39.3 °C (101.6-102.7°F)	3.0		1.4	2.5
39.4-40.5 °C (102.8-104.9°F)	1.6		1.9	1.6
>40.5°C (>104.9°F)	0.0		0.0	0.2

§NCT01041573
*IXIARO dose 0.25 mL.
‡N=number of subjects with available diary card data after each dose, used as the denominator to calculate percentages** Where the number of subjects with available data for a particular symptom differed from the overall number of subjects with available diary card data, the rate (n/N) is provided; n is the number of subjects who reported that symptom, and N is the number of subjects with available data for that symptom.

Table 4. Rates of Solicited Adverse Reactions on Days 0-7 After Each Vaccination in Children 3 Years to <12 Years of Age, by Dose and Treatment Group, Study 1^§ ,Philippines

	Post Dose 1 (% of subjects)	Post Dose 2 (% of subjects)
Injection Site Reactions	IXIARO* (N=291-300 ‡)	Havrix (N=99-101 ‡)	IXIARO* (N=293-300 ‡)
Pain	5.5	3.0	1.7
Itching	1.4	0.0	0.0
Tenderness	4.3	1.0	2.0
Hardening	1.3	0.0	0.0
Swelling	2.0	3.0	2.0
Redness	3.0	1.0	0.7
Solicited Systemic Reaction
Irritability	0.0	1.0	0.3
Nausea	0.3	0.0	0.3
Vomiting	1.7	1.0	0.7
Diarrhea	0.7	0.0	1.0
Flu-like symptoms	1.4	2.0	0.3
Excessive fatigue	1.0	1.0	0.7
Muscle pain	2.4	3.0	0.3
Rash	1.0	0.0	0.0
Headache	3.8	4.0	1.4
Loss of appetite	1.0	2.0	1.0
Fever ≥37.7°C (≥99.9°F)	10.7	8.9	4.7
37.7-38.6 °C (99.9-101.5°F)	7.7	6.9	3.3
38.7-39.3 °C (101.6-102.7°F)	2.0	2.0	0.7
39.4-40.5 °C (102.8-104.9°F)	1.0	0.0	0.7
>40.5°C (>104.9°F)	0.0	0.0	0.0

§NCT01041573
*IXIARO dose 0.5 mL.‡N=range of subjects with available diary card data after each dose, used as denominators to calculate percentages.

Table 5 . Rates of Solicited Adverse Reactions on Days 0-7 After Each Vaccination in Children 12 Years to <18 Years of Age, by Dose and Treatment Group, Study 1 ^§ , Philippines

	Post Dose 1 (% of subjects)	Post Dose 2 (% of subjects)
Injection Site Reactions	IXIARO* (N=240 ‡)	Havrix (N=80 ‡)	IXIARO* (N=238 ‡)
Pain	15.0	12.5	6.7
Itching	0.8	0.0	0.4
Tenderness	10.0	13.8	4.6
Hardening	1.3	0.0	0.4
Swelling	0.4	1.3	0.8
Redness	0.8	6.3	3.8
Solicited Systemic Reaction
Irritability	2.1	1.3	0.0
Nausea	2.1	1.3	0.0
Vomiting	1.3	0.0	0.0
Diarrhea	0.4	2.5	0.0
Flu-like symptoms	3.3	7.5	1.3
Excessive fatigue	2.5	1.3	0.4
Muscle pain	2.9	5.0	1.3
Rash	0.8	1.3	0.0
Headache	4.6	5.0	3.4
Loss of appetite	2.1	2.5	0.4
Fever ≥37.7°C (≥99.9°F)	3.8	6.3	5.0
37.7-38.6 °C (99.9-101.5°F)	3.3	3.8	3.8
38.7-39.3 °C (101.6-102.7°F)	0.4	1.3	1.3
39.4-40.5 °C (102.8-104.9°F)	0.0	1.3	0.0
>40.5°C (>104.9°F)	0.0	0.0	0.0

§NCT01041573
*IXIARO dose 0.5 mL.‡N=number of subjects with available diary card data after each dose, used as the denominator to calculate percentages.

Serious Adverse Events

There was one death due to disseminated intravascular coagulation following suspected bacterial meningitis in a 12 year old male 4 months after the second dose of IXIARO. Forty serious adverse events (SAEs) were reported during the 7 month study period. Twenty-three subjects (1.6%) who received IXIARO, 1 subject (1.6%) who received Prevnar and 10 subjects (2.5%) who received HAVRIX experienced an SAE. Some subjects experienced more than one SAE.

The SAEs occurring most frequently in all study groups were febrile convulsions. A total of 12 febrile convulsions were reported (9 of them as SAEs), in 8 subjects (1.0% of children below the age of 3 years) receiving IXIARO, 3 subjects (1.4% of children below the age of 3 years) receiving HAVRIX and 1 subject (1.6%) receiving Prevnar. All febrile convulsions occurred in children below the age of 3 years. Onset of febrile convulsions ranged from 2 days to >5 months after doses of IXIARO with no apparent temporal clustering, 4 weeks after Prevnar and 9 days to >16 weeks after HAVRIX.

Adverse Events in a Pediatric Trial² of IXIARO in Children Traveling from Western Countries:

The safety of IXIARO was evaluated in an ongoing, uncontrolled, open-label clinical trial conducted in the United States, Europe and Australiain healthy children with planned travel to JEV-endemic areas (Study 2)². IXIARO (0.25 mL dose for children 2 months to <3 years of age, 0.5 mL dose for children and adolescents 3 to <18 years of age) was administered by intramuscular injection on Day 0 and Day 28. An analysis of safety was carried out after enrolment of 60 subjects (mean age: 12.50 years, range 10 months to 17 years; 56.7% female; ethnicity: White: 83.3%, Asian: 13.3%, Black: 3.3%). Parents or subjects recorded adverse events on a diary card for the first seven days after each vaccination. Only those events considered to be assessable based on the subjects developmental status were recorded. Parents or subjects were queried about the occurrence of unsolicited AEs through 6 months after the last vaccination (Month 7).

At the time of the analysis, 40% (2/5) subjects 2 months to <3 years of age experienced injection site hardening, injection site redness, and diarrhea following the first or second dose of IXIARO. Solicited adverse reactions among subjects 3 to <18 years of age are summarized in Table 6.

Table 6. Rates of Solicited Adverse Reactions on Days 0-7 After Each IXIARO 0.5 mL Vaccination in Children 3 Years to <18 Years of Age Traveling From Western Countries, Study 2^§

	Post Dose 1 (N=55) % of subjects	Post Dose 2 (N=49) % of subjects
Injection Site Reactions
Pain	18.2	16.3
Itching	3.6	2.0
Tenderness	30.9	24.5
Hardening	0.0	2.0
Swelling	0.0	0.0
Redness	5.5	0.0
Solicited Systemic Reaction
Irritability	0.0	6.1
Nausea	1.8	2.0
Vomiting	0.0	2.0
Diarrhea	1.8	0.0
Flu-like symptoms	0.0	0.0
Excessive fatigue	12.7	0.0
Muscle pain	27.3	2.0
Rash	1.8	2.0
Headache	1.8	4.1
Loss of appetite	1.8	0.0
Fever 37.7°C (99.9°F)	5.5	2.0
37.7-38.6 °C (99.9-101.5°F)	3.6	2.0
38.7-39.3 °C (101.6-102.7°F)	1.8	0.0
39.4-40.5 °C (102.8-104.9°F)	0.0	0.0
>40.5°C (>104.9°F)	0.0	0.0

§NCT01047839‡N=number of subjects with available diary card data after each dose, used as the denominator to calculate percentages.

Clinical Studies in Adults 18 Years of Age and Older:

In five randomized, controlled clinical studies^{3 , 4, 5, 6, 7} conducted in North America, Europe, Australia and New Zealand, a total of 3,558 healthy adults 18 to 86 years of age received at least one dose of IXIARO and were followed-up for safety for 6 months after the first dose. 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% 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 in Adults:

The safety of IXIARO was evaluated in a randomized, controlled, double‑blind clinical trial in healthy male and female subjects 18 years of age (Study 3)³. 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; ethnicity: 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. Adverse events of any severity grade occurring with an incidence of 1% of subjects are shown in Table 7. Most adverse events (>90%) were mild to moderate.

Table 7 . Rates of Common Solicited and Unsolicited Systemic Adverse Events* in Adults Residing in Non-Endemic Areas After IXIARO or Control [ PBS + Al(OH)₃ ], Safety Population, Study 3 ^§

	Post Dose 1 (Day 0 to Day 28) % of subjects	Post Dose 2 (Day 28 to Day 56) % of subjects	Post Dose 1 or Dose 2 (Day 0 to Day 56) % of subjects
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
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
Fever†	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

§NCT00605085
*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 also 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

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. The rates of injection site reactions are shown in Table 8. Most injection site reactions (>90%) were mild to moderate.

Table 8. Rates of Injection Site Solicited Adverse Reactions* After IXIARO or Control [PBS + Al(OH)₃ ], Adults Residing in Non-Endemic Areas, Safety Population With Evaluable Diary Cards, Study 3^§

	Post Dose 1 (% of subjects†)	Post Dose 2 (% of subjects†)	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
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
Pruritus	2.6	3.3	1.6	1.9	3.8	4.5

§NCT00605085
* 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

Adverse Events in a Clinical Trial Comparing IXIARO to JE-VAX in Adults:

The safety of IXIARO compared to another U.S.-licensed inactivated JE vaccine (JE-VAX) was evaluated in a randomized, double-blind clinical trial in subjects 18 years of age (Study 4)⁴.

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 2^nd dose of IXIARO. The most common adverse events after immunization occurring in 1% of subjects were headache, myalgia, fatigue, influenza-like illness, nausea, nasopharyngitis, fever, 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 for 7 days after each vaccination 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 in Adults:

The safety of a booster dose of IXIARO administered 14 months after completion of the primary series was evaluated in an open-label, uncontrolled study in subjects 18 years of age (Study 8)⁸.

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).

The most common injection site reactions (>10% of subjects) were pain (12.8%) and tenderness (19.2%); the most common systemic adverse events (>10%) were nasopharyngitis (15.2%) and headache (11.1%).

Safety in Concomitant Use with the Hepatitis A Vaccine, HAVRIX in Adults (Study 6)⁶

The safety of IXIARO when administered concomitantly with inactivated Hepatitis A Virus vaccine (HAVRIX) was evaluated in a controlled trial in which subjects 18 years of age 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 2^nd 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.