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Safety of the Inactivated Japanese Encephalitis Virus Vaccine IXIARO in Children

An Open-label, Randomized, Active-controlled, Phase 3 Study

Dubischar, Katrin L. MSc*; Kadlecek, Vera MSc*; Sablan, Benjamin Jr MD; Borja-Tabora, Charissa Fay MD; Gatchalian, Salvacion MD§¶; Eder-Lingelbach, Susanne MSc*; Mueller, Zsuzsanna MSc*; Westritschnig, Kerstin MD*

Author Information
The Pediatric Infectious Disease Journal: September 2017 - Volume 36 - Issue 9 - p 889-897
doi: 10.1097/INF.0000000000001623

Abstract

Recurrent epidemics of Japanese encephalitis (JE) are of significant public health concern in most Asian countries and parts of the Western Pacific.1 The disease is contracted by bites from mosquitoes, mainly Culex species, infected with the JE virus (JEV), a member of the Flavivirus genus. Initial clinical manifestations of JE include nonspecific febrile illness such as fever, coryza, diarrhea and rigors.1 This may be followed by convulsions, aseptic meningitis, encephalitis or poliomyelitis-like illness.1,2 A recent analysis estimates that about 68,000 symptomatic JE infections occur annually in the 24 JE-endemic countries.3 Children are at particular risk, which is reflected in the annual incidence of 5.4 cases per 100,000 in the age stratum of 0–14-year-olds. While most infections are asymptomatic, the mortality rate in symptomatic cases is up to 30%, and neurologic sequelae are observed in about half of surviving patients.1,4 JE among travelers from nonendemic countries to Asia is rare. However, consequences can be devastating as 18% of the 55 published JE cases in travelers of all ages over the last 35 years resulted in death and 44% had mild to severe sequelae.5

Human immunization has proved to be highly effective in controlling JE. Routine immunization of children with first-generation mouse brain–derived vaccines has reduced JE incidence in endemic countries.6 Concerns over the safety of the mouse brain–derived vaccines however led to the development of newer vaccines. This includes, among others, a Vero-cell–derived JE vaccine IXIARO (Valneva Austria GmbH, Vienna, Austria), which was licensed in 2009 for active JE immunization in adults in Australia (trade name JESPECT, distributed by CSL, Parkville, Victoria), Europe and the United States, as well as several other countries. Based on data from the trial reported here and obtained in a trial in traveling children from western countries, IXIARO was approved for use in the pediatric population from 2 months of age and older in Europe and the United States in 2013, with 3 µg/0.25 mL doses used for children <3 years of age and 6 µg/0.5 mL for children 3 to <18 years of age.7 The primary immunization schedule for IXIARO consists of 2 doses administered 28 days apart.8

Given the elevated risk of children for JE, there is a need to protect both children native to endemic regions and children traveling from western, non-JEV–endemic regions. A phase 2 study with IXIARO in children in India 1 to <3 years of age supported using a half dose (two 3 µg/0.25 mL doses administered 28 days apart) in this age group.9 The objectives of the present study were to assess the safety profile of IXIARO at dose values of 0.25 and 0.5 mL compared with active controls in a pediatric population from endemic regions and to assess age-dependent differences in the safety profile of IXIARO. In addition, we also aimed to assess differences in the safety profile of IXIARO in subjects with or without baseline immunity against JEV and dengue virus (DENV).

MATERIALS AND METHODS

Study Population

Healthy children and adolescents ≥2 months to <18 years of age at the time of first vaccination were eligible. Subjects with a history of clinical JE, known JEV seropositivity (in case of prior testing) or vaccination against JEV or yellow fever were excluded. The study was conducted in accordance with the Declaration of Helsinki (2008). Study protocol and informed consent/assent form were approved by the institutional review board of each participating study site. Written informed consent was obtained from the subject’s legal representative, and depending on the study site, assent was sought from children 8 or 12 years of age and older.

Methodology

This was an open-label, randomized, active-controlled, phase 3 study in children with a dose-finding run-in phase, conducted at 3 study centers in the Philippines (IC51-323, NCT 01041573). Immunogenicity results including baseline seropositivity rates are reported elsewhere in this issue of PIDJ.10

Subjects were randomized according to their age as follows (Table 1): dose-finding run-in phase in subjects ≥3 to <12 years of age (performed in parallel to recruitment and study conduct for the other age groups): 201subjects received either 0.25 or 0.5 mL IXIARO in a 1:1 ratio. The appropriate dose was determined by the safety and immunogenicity results of an interim analysis at day 56 (see below). Subjects ≥2 months to <1 year of age received either IXIARO (0.25 mL) or Prevnar (0.5 mL; formerly Wyeth Pharmaceuticals Inc., now Pfizer Inc., Kent, United Kingdom) in a 2:1 ratio. Subjects ≥1 to <3 years of age and ≥12 to <18 years of age received either IXIARO (half dose, 0.25 mL, if <3 years of age and full dose, 0.5 mL, if ≥12 years of age) or HAVRIX 720 (0.5 mL; GlaxoSmithKline Biologicals, Rixensart, Belgium) in a 3:1 ratio. Subjects ≥3 to <12 years of age: after the appropriate dose was determined from the run-in phase, further subjects in this age group received either the appropriate IXIARO dose or HAVRIX 720 (0.5 mL) in a 2:1 ratio. Four in-person visits were conducted on study days 0, 28, 56 and 201 (month 7). Subjects in the IXIARO treatment groups were vaccinated on days 0 and 28, a 4-day interval around day 28 was allowed. The subjects in the comparator groups (Prevnar or HAVRIX 720) were vaccinated as follows: Prevnar on days 0, 28, 56 and month 7 to 13 (ie, on or after the last study visit; children <6 months of age) or days 0, 56 and month 7 (for children 6 to <12 months of age) and HAVRIX on days 0 and month 7 (children ≥12 months of age). Other vaccinations were deferred within 2 weeks before the first and up to 1 week after the second IXIARO vaccination. All subjects were offered the 2 control vaccines and for the control groups, 1 other vaccination with varicella, measles mumps rubella or meningococcal vaccine after the study.

TABLE 1
TABLE 1:
Vaccination Schedules and Vaccine Dose by Age Group

To study the impact of pre-existing Flavivirus antibodies on safety of the vaccine, all subjects were tested for JE (plaque reduction neutralization test) or dengue [using the Panbio Dengue Immunoglobulin G Indirect Enzyme-linked Immunosorbent Assay for the qualitative detection of immunoglobulin G antibodies to dengue antigen serotypes (1, 2, 3 and 4)] at baseline.

Vaccines

IXIARO, inactivated, alum-adjuvanted, Vero-cell–derived vaccine based on JEV strain SA14-14-2; Prevnar, pneumococcal 7-valent conjugate vaccine (diphtheria CRM197 protein) and HAVRIX 720, inactivated hepatitis A virus vaccine.

Safety Assessments

Local and systemic adverse events (AEs) were solicited using subject diaries covering 7 days after each vaccination separately, day 0 being the day of vaccination. For Prevnar, 7-day diaries were used after each dose of vaccine, except for injections administered on the last study day, when symptoms were only monitored for 60 minutes. Likewise, a 7-day diary was used after the first dose of HAVRIX, and symptoms were monitored for 60 minutes after the second dose at month 7. Solicited AEs were: (1) Local: injection site pain, itching, tenderness (ie, pain upon touching), induration, swelling and redness and (2) Systemic: headache, muscle pain, flu-like symptoms, excessive fatigue, rash, body temperature, nausea, vomiting, diarrhea, irritability and loss of appetite. One diary card was used for all ages, but parents could document if a child was too young to communicate certain events (such as pain). Solicited AEs were by definition considered to have a causal association with vaccination (ie, were related AEs). Severity was graded by the investigator using a modified version of the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events.11

Body temperature was measured in the subject’s ear, and fever was graded as follows: grade 1 = 37.7–38.6°C, grade 2 = 38.7–39.3°C, grade 3 = 39.4–40.5°C and grade 4 = >40.5°C. Measurable local reactions (redness, induration and swelling): grade 1 = <1 cm, grade 2 = 1 to ≤3 cm, grade 3 = >3 cm and grade 4 = necrosis. For other AEs, gradings ranged from grade 1 = generally describing nonlimiting, minimal symptoms to grade 4 = generally describing symptoms causing inability to perform usual activities or being life threatening.

All unsolicited AEs that occurred after the first vaccination up to month 7 were recorded and assessed for severity and causal association with the study vaccines by the investigator. At each visit, subjects underwent a physical examination, including hematology/clinical chemistry tests and urinalysis in older children. A Data Safety Monitoring Board (DSMB) oversaw safety during trial conduct and advised on the dose decision.

Statistics

Safety analyses were based on the safety population (all subjects who received at least 1 vaccination). The primary study endpoint was the rate of subjects with serious AEs (SAEs) or medically attended AEs up to day 56 after the first vaccination (ie, covering both doses of IXIARO, the first 2 or 3 doses of Prevnar or the first dose of HAVRIX). Secondary endpoints included the rate of subjects with SAEs or medically attended AEs up to month 7 after the first vaccination, the rate of subjects with solicited local and systemic AEs, the rate of subjects with unsolicited AEs up to day 56 and up to month 7 and the rate of subjects with abnormal laboratory parameters (hematology, biochemistry and urinalysis). For solicited AEs, percentages were based on subjects assessable for a given symptom. AE rates were compared between treatment groups using Fisher exact test. A P value of <0.05 was considered significant. Exact 95% confidence intervals (CIs) for the AE rates were calculated. Data were analyzed stratified by age group. The incidence of AEs, related AEs, SAEs and medically attended AEs up to day 56 was additionally analyzed using a logistic regression model with age, prevaccination serostatus against JEV and prevaccination serostatus against DENV (another Flavivirus) as categorical covariates. AEs of special interest (AESIs) were predefined AEs potentially associated with hypersensitivity/allergy and neurologic disorders, for which a combined rate was calculated. Medical Dictionary for Regulatory Activities was used for AE coding (version 13.0, ICH.), and all analyses were run in SAS version 9.2 (SAS Institute Inc., Cary, NC).

RESULTS

Subject Disposition and Demographics

A total of 1869 subjects were randomized from March to December 2010 and received at least 1 dose of study vaccine. Of these, 1842 subjects (98.6%) completed the study and 27 (1.4%) discontinued prematurely (Fig. 1). Two subjects in the Prevnar group, 5 subjects in the total IXIARO group and 7 subjects in the HAVRIX 720 group received only 1 dose of study vaccine. Demographic data are summarized in Table 2. Gender distribution was balanced in all age and treatment groups, and all subjects were of Asian ethnicity.

TABLE 2
TABLE 2:
Demographic Data by Age Group
FIGURE 1
FIGURE 1:
Study flow diagram.1One subject was randomized to IXIARO 0.5 mL but received HAVRIX 720. “Other” includes the following reasons for withdrawal: migration out from the study area (8/11), lost to follow-up (1/11), subject was positive to anti-Hepatitis C Virus (1/11) and blood extraction (1/11). Of those 11 subjects, 7 received IXIARO vaccine (6 received 2 doses; 1 received only 1 dose), 1 received 1 dose of Prevnar, and 3 received 1 dose of HAXRIX. One subject died from disseminated intravascular coagulation; bacterial meningitis and pneumonia 4 months after the second vaccination. N indicates total number of subjects randomized/completed per age/dose group; n, number of subjects with a specific major reason for discontinuation.

Dose Selection for the IXIARO Vaccine Group

Two hundred one subjects ≥3 to <12 years of age received either 0.25 or 0.5 mL IXIARO in the dose-finding, run-in phase. The safety analysis of this part of the study demonstrated that both IXIARO doses had a comparable safety profile. The dose of 0.5 mL had a numerically higher seroconversion rate (0.25 mL 95.9% vs. 0.5 mL 100%; P = 0.058) and a significantly higher geometric mean titer (0.25 mL 111 vs. 0.5 mL 214; P < 0.001). Based on these data, the 0.5 mL dose was used for the ≥3 to <12 years age group after the run-in phase. Details on the interim safety and immunogenicity analysis of the run-in phase are reported elsewhere in this Journal issue.10

Overview of AE Rates up to Day 56

A summary of AEs reported up to day 56 by age group is provided in Table 3. The AE rates (ie, rates of subjects with at least 1 solicited or unsolicited AE) of subjects ≥2 months to <1 year of age were 84.0% in the IXIARO 0.25 mL group and 87.5% in the Prevnar group. In the entire population of subjects ≥1 to <18 years of age, AE rates were 62.0% in the IXIARO group (both dose levels combined) and 59.6% in the HAVRIX 720 group. The rate of subjects with any related AEs (ie, any solicited AE or any unsolicited AE considered possibly or probably related to vaccination by the investigator) was higher in IXIARO 0.5 mL recipients ≥1 to <3 years of age (49.7%) compared with HAVRIX recipients of the same age (36.2%) and in IXIARO 0.5 mL recipients 3–11 years of age (0.25 mL dose: 38.0%; 0.5 mL dose: 31.7%) compared with HAVRIX recipients of the same age (15.8%; 95% CI: 9.3–24.4) (Table 3), likely reflecting the number of vaccine doses received up to day 56 (2 for IXIARO and 1 for HAVRIX). The rates of solicited local or systemic AEs, which constitute the vast majority of related AEs, were similar after the first dose of IXIARO and HAVRIX, while roughly 20% of subjects also reported solicited AE after the second dose of IXIARO: any solicited AE, 32.0% after IXIARO#1 versus 29.4% after HAVRIX versus 18.2% after IXIARO#2. The breakdown of AEs up to day 56 by age groups showed that AEs were less frequent in older age groups (Table 3).

TABLE 3
TABLE 3:
Summary of All Adverse Events (Solicited and Unsolicited) up to Day 56 by Age Group

SAEs and Medically Attended AEs

The primary study endpoint was the rate of subjects with either SAEs or medically attended AEs up to day 56 after the first vaccination. Across treatment groups and within each age group, these rates were generally similar without statistically significant differences (Table 3). The incidence of SAEs or medically attended AEs diminished with increasing age from approximately 40% in infants <1 year to less than 2% of adolescents. The majority of these were medically attended AEs, predominantly infectious diseases which were seen in high frequencies in all study groups especially in the younger age groups.

Eleven subjects in the trial experienced a total of 12 SAEs up to day 56, all were <3 years of age (Table, Supplemental Digital Content 1, http://links.lww.com/INF/C720). None of the SAEs was considered related to the study vaccine. The most frequently reported SAE was febrile convulsion followed by gastroenteritis (Table, Supplemental Digital Content 1, http://links.lww.com/INF/C720). Febrile convulsion (including cases not considered serious) was reported in 7 subjects up to day 56; 5 further cases were reported until month 7. Details of all cases of febrile convulsion are provided in Table (Supplemental Digital Content 2, http://links.lww.com/INF/C721).

Overall, 339 subjects experienced medically attended AEs up to day 56, mainly infectious diseases. Upper respiratory tract infections were most frequent. Gastroenteritis was significantly more common in the IXIARO group in children below 1 year of age, but was not more common compared with HAVRIX in older age groups. There were 2 cases of dengue fever, graded as severe by the investigator, 1 in a subject in the age group ≥1 to <3 years in the IXIARO 0.25 mL group, and 1 in a subject in the age group ≥3 to <12 years. Medically attended AEs with an incidence ≥3% are shown in Table (Supplemental Digital Content 1, http://links.lww.com/INF/C720).

During the 7-month follow-up, rates of subjects with SAEs were also similar across treatment groups and ranged from 1.5% to 2.5% (data not shown). There was 1 death in the study. A 12-year-old male subject died from disseminated intravascular coagulation 4 months after the second vaccination with IXIARO 0.5 mL. Central nervous system infection/probable bacterial meningitis and pneumonia were reported as antecedents and underlying causes of death. The investigator and DSMB considered the event unrelated to the study vaccine. Furthermore, there was an SAE of Kawasaki disease 2.8 months after the last vaccination with IXIARO 0.5 mL, considered possibly related to the study vaccine by the investigator but unrelated by the DSMB, in a 5-year-old male subject in the IXIARO 0.5 mL group. The subject recovered with sequelae.

AEs of Special Interest

AESIs were predefined AEs potentially associated with hypersensitivity/allergy or neurologic disorders. No potential neurologic AESI was reported during this study. None of the AESIs was serious. The incidence of AESIs up to day 56 did not differ significantly between treatment groups (data not shown). The incidence of AESIs with an onset within 14 days relative to any dose of vaccine was 1.8% (95% CI: 1.1–3.0) IXIARO 0.25 mL, 0.6% (0.1–1.6) IXIARO 0.5 mL, 6.3% (1.7–15.2) Prevnar and 1.5% (0.6–3.3) for HAVRIX; details are presented in Table (Supplemental Digital Content 3, http://links.lww.com/INF/C722). Two events, 1 rash and 1 papular rash, both mild in nature, were considered related to IXIARO. In 17 of 19 subjects with AESIs following IXIARO vaccination, the events were considered unrelated to vaccination by the investigator. Nine of 11 subjects who experienced an AESI after the first dose received a further dose of vaccine without reoccurrence of symptoms (Table, Supplemental Digital Content 3, http://links.lww.com/INF/C722). Causality assessments by the treating investigator for the other unrelated cases were based on suspected viral infections (urticaria after 13 days, maculopapular rash), delay between vaccination and onset [hypersensitivity after 7 days (in addition, absence of symptoms other than wheals and itchiness)] and food related (hypersensitivity after 11 days). One subject had a mild rash 9 days after first dose of HAVRIX 720. No cases of lymphedema, swelling of the head, neck lips, tongue or bronchospasm were observed.

Unsolicited AEs

Unsolicited AEs seen in >5% of subjects and related unsolicited AEs seen in >1% of subjects are summarized by system organ class and preferred term in Table (Supplemental Digital Content 4, http://links.lww.com/INF/C723). The proportions of subjects who experienced unsolicited AEs decreased with increasing age and did not differ significantly between groups. The majority of unsolicited AEs were infectious diseases, with upper respiratory tract infections as the most frequent event in all age groups.

The majority of unsolicited AEs were mild (grade 1) or moderate (grade 2) in intensity. There was 1 potentially life-threatening (grade 4) event of bronchopneumonia (serious, not related to the study vaccine) in the ≥1 to <3 years age group (IXIARO 0.25 mL). All related unsolicited AEs in children <3 years of age and most related unsolicited AEs in the ≥3 to <12 years age group were mild or moderate in intensity, no unsolicited AEs were judged as related in adolescents.

No marked changes in laboratory parameters and vital signs were reported during the study (data not shown).

Solicited AEs

The overall incidence of solicited local and systemic events did not differ statistically significantly between the treatment groups in any of the age groups.

Local AEs within 7 days after the first vaccination are shown in Figure 2. The most frequently reported AEs were redness and tenderness in the youngest age group (≥2 months to <1 years), redness and pain in the ≥1 to <3 years age group and pain and tenderness in the 2 older age groups. In comparison with Prevnar, local reactions were less common after IXIARO, reaching significance for tenderness and induration [3.1% vs. 12.7% (P < 0.021) and 0% vs. 7.9% (P = 0.003), respectively, in the ≥2 months to <1 years age group).

FIGURE 2
FIGURE 2:
Solicited local AEs within 7 days after first vaccination. *Statistically significant difference (P < 0.05) between treatment groups (Fisher exact test). The percentage of subjects who experienced a given symptom, all severity grades combined, is indicated above each bar. For induration, swelling and redness, the severity grades were grade 1 = <1 cm, grade 2 = 1 to <3 cm and grade 3 = >3 cm; for other symptoms, gradings ranged from grade 1 = generally describing nonlimiting, minimal symptoms to grade 4 = generally describing symptoms causing inability to perform usual activities or being life threatening. N indicates number of subjects with assessable symptoms.

The most frequently reported solicited systemic AEs within 7 days after the first vaccination are shown in Figure 3. Fever was the most frequent systemic AE up to the age of 12 years (23.7%, 20.2%, 15.0% and 3.8% in increasing age groups). Headache was the predominant symptom in adolescents (4.6%). There was no consistent pattern for the temporal onset of fever. Paracetamol use during the 7 days after the first vaccination was similar in all treatment groups and decreased with age, from about 18% in infants to approximately 2% in adolescents. Compared with the control vaccines, systemic AE rates were similar except for the ≥3 to <12 years age group where numerically lower AE rates for HAVRIX 720 were observed.

FIGURE 3
FIGURE 3:
Solicited systemic AEs within 7 days after first vaccination. A: Age group ≥2 months to <1 year. B: Age group ≥1 to <3 years. C: Age group ≥3 to <12 years. D: Age group ≥12 to <18 years. Fever grading: grade 1 = 37.7–38.6°C, grade 2 = 38.7–39.3°C, grade 3 = 39.4–40.5°C and grade 4 = >40.5°C. For other AEs, gradings ranged from grade 1 = generally describing nonlimiting, minimal symptoms to grade 4 = generally describing symptoms causing inability to perform usual activities or being life threatening. Only solicited systemic symptoms that were reported by ≥5% of subjects in at least 1 treatment group are shown. No grade 4 solicited systemic AEs were reported within 7 days after the first vaccination. Only the maximum severity experienced between day 0 and day 6 is presented for each subject. Percentages are based on the number of subjects in the treatment group in a given age group, with assessable data for that symptom. HAV indicates HAVRIX 720; Prev, Prevnar; IX, IXIARO.

Interestingly, fewer subjects reported solicited local and systemic AEs in the IXIARO groups after the second dose (28.2% postdose 2 vs. 45.8% postdose 1 in the ≥2 months to <1 years age group and 32.0% postdose 2 vs. 18.2% postdose 1 in the ≥1 to <18 years age group).

Impact of Age and Prevaccination Flavivirus Serostatus on AE and SAEs Rates

Covariate analyses with adjustment for the prespecified covariates age and prevaccination JEV and DENV serostatus were performed. In general, increasing age was the only factor consistently significantly associated with a decrease in AE rates. Evidence of pre-existing Flavivirus antibodies, which were detected by serologic assays for dengue and JEV (results published in this issue of PIDJ,10 did not show a significant impact on AE, SAE, medically attended AE or related AE rates.

DISCUSSION

We studied the safety profile of the JEV vaccine IXIARO in a pediatric population 2 months to 17 years of age compared with the age-specific control vaccines Prevnar (in subjects <1 year) and HAVRIX 720 (in subjects ≥1 year of age), during a period of 7 months after the first vaccination. The study was conducted in the Philippines, where JEV is endemic. The comparator vaccines were chosen for their well-established safety profile and because they have similar features compared with IXIARO (alum-adjuvanted, intramuscular route of administration).12,13 None of the study vaccines was included in the National Immunization Program in the Philippines; thus, children at all ages benefited from receiving the vaccines regardless of the treatment group, and we were not forced to limit recruitment to a narrow age band. However, this selection of control vaccines resulted in our study’s major limitation, the different schedule of IXIARO and the control vaccines used. This had particular impact on solicited AE rates, which naturally increase with the number of doses administered. We limited the comparison of solicited AE rates mostly to reactions after the first dose to have a “fair comparison.” For the total AE rate up to day 56 (ie, solicited and unsolicited), however, this was certainly a confounder in favor of HAVRIX.

A total of 1842 subjects (98.6%) completed the study, while 27 (1.4%) withdrew prematurely, with the most common reason being withdrawn consent. The reasons for drop-outs did not point to any safety issue.

As age is an obvious confounder of AE rates, safety data from this trial are presented broken down by age group. Across all treatment groups, rates for unsolicited AEs to day 56 were clearly associated with age group and highest in subjects younger than 3 years of age. Treatment groups had similar rates of unsolicited AEs within each age group. The most common unsolicited AEs were infectious diseases, notably upper respiratory tract infections, which is not surprising in the given population and setting, and pyrexia. The majority of AEs were classified as mild (grade 1), and the incidence of unsolicited AEs considered by the investigator to be related to study vaccine was low.

The primary study endpoint was the rate of subjects who experienced SAEs or medically attended AEs up to day 56 after the first vaccination. The incidence of SAEs or medically attended AEs was comparable between treatment groups within each of the age groups. The majority of medically attended AEs were infectious diseases, foremost upper respiratory tract infections and gastroenteritis commonly expected at younger ages. Parents also may have sought medical care more often as it was provided for free during the study. Gastroenteritis was significantly more common after IXIARO compared with Prevnar in children <12 months of age. However, in the absence of a plausible pathophysiologic pathway linking vaccination and gastroenteritis, and in the absence of differences in the rates of other gastrointestinal disorders or other infectious diseases, this is most likely a chance finding; not surprising given the high number of statistical comparisons. All of the 11 SAEs reported up to day 56 occurred in subjects younger than 3 years; 5 of these were febrile convulsions. A total of 12 febrile convulsions were reported overall until the end of the study at month 7, all in subjects younger than 3 years of age. None was considered related to the study vaccine, and most subjects had urinary tract infections or upper respiratory tract infections when the seizures occurred. The incidence of febrile convulsions was comparable in the treatment groups concerned (8/640 subjects in the IXIARO 0.25 mL/≥1 to <3 years group, 3/213 subjects in the HAVRIX 720/≥1 to <3 years group and 1/64 subjects in the Prevnar/≥2 months to <1 year group), with no temporal clustering shortly after the immunizations. It was therefore considered as normal background rate by the DSMB that reviewed the safety data.

During the follow-up to month 7, Kawasaki disease developed in 1 subject considered possibly related to the study vaccine by the investigator. However, in the absence of a pathophysiologic pathway linking an inactivated vaccine and the disease, together with the long latency after the last vaccination with IXIARO 0.5 mL (2.8 months) and the incidence of this disease in Asian populations, the DSMB concluded that the event was unrelated to the study vaccine. One subject died as a consequence of disseminated intravascular coagulation secondary to probable bacterial meningitis and pneumonia, 4 months after the second vaccination with IXIARO 0.5 mL. Neither the investigator nor the DSMB considered the event related to the study vaccine.

In such a diverse age cohort, we expected age to have an impact on AE rates, but pre-existing Flavivirus antibodies could have influenced reactogenicity, too. We thus performed an analysis of covariance to test if either of these was truly influencing safety and found that only age was significantly associated with a decrease in AEs, SAE and medically attended AE rates in the ≥1 to <3 years and ≥3 to ≤12 years age groups. Rare but serious neurologic AEs, including cases of severe or fatal acute disseminated encephalomyelitis, were reported for inactivated mouse-brain–derived JE vaccines in the past but have not been observed in any IXIARO study to date.14,15 Although no causal link between these events and the mouse-brain–derived JE vaccines was demonstrated, the World Health Organization recommended the gradual replacement of inactivated mouse-brain-–derived vaccines by new-generation JE vaccines.16 The incidence of AESIs did not reveal any safety concerns with respect to allergic or neurologic reactions in subjects who received IXIARO. Events potentially indicative of hypersensitivity/allergy were infrequent in the 14 days after vaccination with IXIARO 0.25 mL (1.8%) or 0.5 mL (0.6%), compared with 6.3% with Prevnar and 1.5% for HAVRIX 720. This is similar to the incidence of 3.5% reported in a pooled analysis of IXIARO safety data derived from 7 phase 3 studies in more than 3500 adults.13 None of the AESIs in our study was serious. The single most frequent AESI was conjunctivitis and not related to the study vaccine. Two events, 1 rash and 1 papular rash, both mild in nature, were considered related to IXIARO. For the other 17 AESIs in the IXIARO group, including 2 subjects (0.2% of the 0.25 mL dose group) with urticaria, no causal association with the study vaccine was assumed by the investigator, because other causes were seen as more likely (such as suspected viral infections or food-related symptoms), or because of the time interval between vaccination and event onset. Several of these subjects received a second dose of IXIARO which did not provoke a reaction, suggesting the lack of causal association with the vaccine for these hypersensitivity reactions. However, for 3 of 9 cutaneous AESIs, a causal association with vaccination—although not suspected by the investigator—cannot be excluded. It was previously suggested that the absence of gelatin in the IXIARO formulation may explain the low incidence of hypersensitivity events generally seen with IXIARO.14,15

In general, solicited local and systemic AEs were most common in infants, lower in the age groups between 1 and 12 years, and higher again in adolescents for local AEs. Most of these reactions were mild. Comparing AEs within 7 days after the first vaccination, local AEs were more prevalent with Prevnar than with IXIARO 0.25 mL in the ≥2 months to <1 year age group, in particular redness, tenderness and induration (the latter 2 events were statistically significantly more frequent in the Prevnar group). By and large, local AE rates were also comparable to HAVRIX 720 in the older age groups. The local AE profile varied with age, redness was seen in >15% of subjects below 1 year of age, no local AE was seen in >10% in the age groups between 1 and 12 years of age, while tenderness (10%) and pain (15%) were seen commonly in adolescents. Solicited systemic AEs were comparable between IXIARO, Prevnar and HAVRIX 720 and were less common in the older age groups; fever was the most common AE in all age groups except for the adolescents where headache was more prevalent. In a post hoc analysis when the lower cut-off for fever was shifted from 37.7°C to 38°C, fever rates were approximately 1/3 lower (data not shown).

In an analysis of IXIARO safety data from adults, tenderness and pain were the most frequent local AEs, and headache and myalgia were the the most common systemic AEs during the 7-day period after the first injection.14,15 The safety profile in adolescents in the present study was thus consistent with the profile seen in adults, although the incidence of these events was lower in adolescents (pain 15.0% and tenderness 10.0%, compared with >20% for both in adults; headache with 4.6% in the present study compared with 17.6% in adults).

Across all age groups, the incidence of both solicited local and systemic AEs was less after the second vaccination with IXIARO, similar to the observations in adults.14,15

In conclusion,

  • The safety profile of IXIARO was comparable to the control vaccines Prevnar and HAVRIX 720 in terms of overall AE rates, related AE rates, SAEs or medically_attended AEs, both with the 0.25 mL dose in children ≥2 months to < 3 years and the 0.5 mL dose in children from 3 years of age.
  • The most commonly observed AEs, upper respiratory tract infections, gastroenteritis and fever, were in line with the expected AE profile in a pediatric population, mostly mild in intensity and not causally linked to vaccination.
  • IXIARO appears to cause fewer local reactions in infants, and significantly less tenderness and induration, compared with Prevnar.
  • IXIARO appears to have a local reactogenicity profile comparable to that of HAVRIX 720 in children 1 to < 18 years of age.

The AE profile in the age group ≥12 years to <18 years resembles the AE profile seen in adults.

ACKNOWLEDGMENTS

The authors thank the following individuals for their valuable contributions at various stages of this trial: Christoph Klade and Vera Buerger for their contributions during the study planning phase; Evelyn Hatzenbichler and Astrid Kaltenboeck for their contributions during study setup and conduct (all formerly Intercell AG, Vienna, Austria).

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    Keywords:

    Japanese encephalitis vaccine; safety; children; IXIARO

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