Japanese encephalitis virus (JEV), transmitted by mosquitoes,1 is the most common cause of viral encephalitis in Asia, with an estimated annual occurrence of 68,000 cases,2 a fatality rate of 30% and neurologic sequelae discerned in half of surviving patients.1,3 In endemic regions, children between 0 and 14 years of age constitute the majority of the cases (75%)2; in hyperendemic areas, half of the cases occur before the age of 4 years.4 In line with these observations, serologic surveys show that most infections occur before the age of 15 years in endemic areas,5 resulting in almost universal naturally acquired immunity by early adulthood in those regions. As travelers from western countries are usually naive to JEV,5 Japanese encephalitis (JE) vaccination may be indicated for pediatric and adult travelers to Asia. Here, we report on the immunogenicity results of a phase 3 clinical study of the JEV vaccine IXIARO (Valneva Austria GmbH, Vienna, Austria) in children6 to support pediatric licensure of IXIARO as traveler’s vaccine for western countries.
Although most unvaccinated travelers to Asia and endemic countries are at a very low risk of contracting JE,7 the consequences can be serious. Vaccination is recommended for long-term travelers during the transmission season and for expatriates and should be considered for those with shorter stays who might be at a higher risk because of travel destination, outdoor activities, rural exposure and season.5 The majority of infections with JEV are asymptomatic with only 1:25 to 1:1000 infections leading to disease.8 However, for approximately 4 decades until 2008, severe JE cases were observed in travelers ranging from young children to elderly adults with a variety of different risk profiles (location, duration of travel, activities, etc.).7 Among these, a fatality rate of 18% and mild to severe sequelae in 44% were reported. In 2010, 2 imported pediatric JE cases, one of them fatal, were reported in the United States.9 These cases underscore the unpredictability of the disease.
There are many different JE vaccines utilized in immunization programs in endemic countries, for example, mouse-brain–derived, or more recently, inactivated or live-attenuated JE vaccines produced in cell culture.10 However, only 2 JE vaccines are now licensed and available in western countries [IXIARO and IMOJEV (Sanofi Pasteur, Lyon)]. Until recently, no vaccine was available for pediatric use in the United States and Europe: before 2013, the only vaccine approved for use in children ≥1 year of age in the United States was JE-VAX (Sanofi Pasteur), an inactivated mouse-brain–derived vaccine, which has not been available since 2011.5 Another JE vaccine produced on mouse-brain substrate by a South Korean manufacturer (Jencevac, Korean Green Cross Vaccine Corporation, Yongin) has been used in Europe under special import permits, but its safety and immunogenicity data have never been evaluated by the European Medicines Agency. In Australia, the live-attenuated, chimeric JE-Yellow Fever vaccine, IMOJEV, was licensed for adults and children as young as 1 year of age and available since late 2012. The vaccine is administered as a single injection resulting in high seroconversion rates (SCRs), but it is not licensed in any other western country.
IXIARO is an inactivated Vero cell culture–derived JE vaccine first approved in 2009 for use in adults as two 6 µg/0.5 mL doses administered 28 days apart.11–13 Licensure of IXIARO in adults was obtained on the basis of noninferiority for immunogenicity10 compared with a field-efficacious JE mouse-brain vaccine.14,15 A first pediatric study with IXIARO, a phase 2 trial in children 1–2 years of age using the standard (6 µg/0.5 mL) and half (3 µg/0.25 mL) dose was conducted in India.16 Both doses demonstrated immunogenicity and safety profiles comparable with that of a mouse-brain–derived vaccine. The data presented here, together with clinical data in traveling children from a smaller study,17 led to pediatric licensure of IXIARO in the European Union and the United States in 2013 with half the adult dose (two 3 µg/0.25 mL doses) administered to children 2 months to under 3 years of age, and the full dose to children 3 to <18 years of age.18
JEV belongs to the family of Flaviviridae, genus Flavivirus, which shares antigenic epitopes that elicit cross-reactive and, if more closely related, cross-protective anti-Flavivirus antibodies.19 In the Philippines, both dengue virus (DENV, another Flavivirus) and JEV circulate,20 but data on JEV seroprevalence are scarce.21–23 JE vaccine was neither included in the national immunization program nor licensed; therefore, no vaccine-induced immunity was expected. Nonetheless, naturally acquired JEV or DENV antibodies might alter the immune response to JE vaccination compared with naive western populations. This may also be the case with maternal antibodies (in general, few JE cases are seen in children below 1 year and even fewer in children below 6 months of age24 in endemic regions, children born to JE naive mothers may be susceptible to infection at all ages).
The objectives of this study were to assess the immunogenicity of the JE vaccine IXIARO in terms of geometric mean titers (GMTs) and SCRs at day 56 in a pediatric population from endemic regions, to establish the appropriate IXIARO dose, 0.25 or 0.5 mL, for subjects ≥3 to <12 years of age, to assess age-dependent differences in the immunogenicity profile of IXIARO and to assess differences in the immunogenicity profile of the vaccine in subjects with no prevaccination antibodies and subjects with pre-existing antibodies against JEV and DENV. While not a protocol-defined objective, the study was also expected to provide seroprevalence data relevant for use of this vaccine in endemic areas or as a travel vaccine.
MATERIALS AND METHODS
The study cohort consisted of subjects randomized to the immunogenicity subgroup of the open-label, randomized, active-controlled, phase 3 clinical study of the JE vaccine IXIARO in children from a JEV-endemic region (Philippines, metropolitan Manila area) (IC51-323, NCT 01041573). The study was conducted to assess the safety and immunogenicity profile of IXIARO in a pediatric population ≥2 months to <18 years of age and to establish the appropriate IXIARO dose, 0.25 mL or 0.5 mL, in subjects ≥3 to <12 years of age. Safety results are reported elsewhere,6 together with a detailed description of study subjects, study design and procedures and the study vaccine IXIARO.
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. Approval of the study protocol and the informed consent/assent forms was obtained from the responsible institutional review board at each participating study site. The study was conducted in accordance with the Declaration of Helsinki (2008).
Children and adolescents ≥2 months to <18 years of age at the time of the first vaccination were recruited in an age-stratified manner. Subjects were randomly assigned to receive either the investigational vaccine (IXIARO) or a comparator vaccine [HAVRIX 720 (GlaxoSmithKline Biologicals, Rixensart, Belgium), inactivated hepatitis A virus vaccine, or Prevnar (formerly Wyeth Pharmaceuticals Inc., now Pfizer Inc., Kent, United Kingdom), pneumococcal 7-valent conjugate vaccine (diphtheria CRM197 protein), according to subject’s age]. The randomization process involved an interactive voice/web response system based on a predefined randomization list created electronically by a statistician. Using the same randomization list, about one-third of subjects randomized to IXIARO were randomly assigned to the immunogenicity subgroup. Subjects received the following vaccination doses depending on their age: ≥2 months to <1 year and ≥1 to <3 years, IXIARO 0.25 mL; ≥3 to <12 years, IXIARO 0.25 mL or 0.5 mL; and ≥12 to <18 years, IXIARO 0.5 mL. The 0.25 mL dose was prepared as follows: after thorough agitation, the required volume was drawn up into a tuberculin syringe from the prefilled syringe containing the 0.5 mL dose. The prefilled syringe was inspected by the study monitor to verify dosing. The vaccine was administered intramuscularly in the deltoid or thigh in 2 doses given approximately 28 days apart, the first dose on day 0 and the second dose on day 28. A 4 days interval around day 28 was allowed.
Dose-finding Run-in Phase
Parallel to recruitment and study conduct for the other age groups, 200 subjects ≥3 to <12 years of age were planned to be randomized (1:1 ratio) into a dose-finding run-in phase to receive either IXIARO 0.25 mL (half adult dose) or 0.5 mL (full adult dose). The appropriate dose was determined based on the safety and immunogenicity results of an interim analysis of data collected up to day 56. A Data Safety Monitoring Board reviewed blinded safety data [solicited systemic and local adverse events [AEs] and unsolicited AEs] and recommended if one of the 2 doses was deemed more appropriate based on the safety profile. An overview of the study groups is shown in Figure 1.
Baseline (ie, prevaccination) serologic testing for JEV was performed in the entire study cohort (ie, safety population, which included all patients who entered the study and received at least 1 vaccination). Immunogenicity analyses were performed on the Intent-to-treat (ITT) population. ITT was the main analysis population and was defined as all subjects randomized into the immunogenicity subgroup who received at least 1 vaccination. The immunogenicity endpoints were SCR [using the World Health Organization–accepted protective titer, defined as 50% plaque reduction neutralization test (PRNT50) titer ≥1025 as a cutoff to determine seroconversion; ie, SCR in this trial can be read as seroprotection rate] and GMT for JE neutralizing antibodies, assessed at day 56 and month 7 with a PRNT50. Additionally, the rate of subjects with a 4-fold increase in PRNT50 titers compared with prevaccination was assessed at day 56.
JEV Neutralizing Antibodies
A validated PRNT was used to measure GMTs for JEV neutralizing antibodies as described by Tauber et al.26 The neutralizing antibody titer is expressed as PRNT50 titer of each serum, that is, the reciprocal of the serum dilution giving a 50% plaque reduction compared with 100% plaque formation in the virus control without any neutralizing antibody.
Blood samples were analyzed using the Panbio Dengue Immunoglobulin G (IgG) Indirect Enzyme-linked Immunosorbent Assay (Panbio Diagnostics, Brisbane, Australia) for the qualitative detection of IgG antibodies to DENV antigens of serotypes (1, 2, 3 and 4).
The number and percentage of subjects achieving seroconversion at screening, day 56 and month 7 were calculated for each IXIARO dose group together with the 95% 2-sided confidence interval (CI) for the percentages, calculated according to Altman.27 The number and percentage of subjects with a 4-fold increase in PRNT50 titer at day 56 were calculated for each IXIARO dose group together with the 95% 2-sided CI for the percentages. All rates were calculated based on the number of subjects with available serum samples. Raw GMTs and the 95% CIs for the geometric mean were calculated using log10-transformed titers; negative sera were assigned the value of 5 for calculation of GMT. Negative prevaccination sera had to increase to a minimum PRNT50 titer of 40 to be considered a 4-fold increase. GMTs were summarized at screening, day 56 and month 7 by dose group. The GMT ratio between the 2 dose groups (IXIARO 0.5 mL to IXIARO 0.25 mL) and 95% CI of the GMT ratio were calculated at day 56 and month 7. Data were stratified by age group. The effects of covariates on immune response were analyzed at day 56 and month 7 by analysis of covariance (ANCOVA) on the log-transformed PRNT50 titers. Covariate analysis was performed by treatment group with prevaccination PRNT50 titers and center as covariates, and by pre-existing anti-JEV and anti-DENV serostatus with center as covariate. The anti-log of least square means and the estimated ratio between the IXIARO doses were calculated along with the 95% CI and the P value.
The analyses of SCRs, GMTs and 4-fold increase in PRNT50 titer described above were repeated stratified by pre-existing JEV serostatus (seropositive or seronegative at screening) and by pre-existing DENV serostatus (positive or negative at screening). Immunogenicity data in these subjects were contrasted to results in the subset that tested negative to both viruses.
Seroprevalence of JEV in the Entire Study Population
The seroprevalence of JEV was assessed at screening in the safety population of the study IC51-323 (ie, 1869 enrolled subjects). Seroprevalence at baseline was higher in subjects younger than 6 months of age (22.2%; 95% CI: 12.5–36.3) compared with those between 6 months and younger than 1 year of age (2.7 %; 95% CI: 1.0–6.7) and to those 1 to <3 years of age (2.9%; 95% CI: 2.0–4.3). Seroprevalence was highest in the adolescent age group (between 12 and younger than 18 years of age; 44.1%; 95% CI: 38.7–49.5). Based on the seroprevalence and mean age in the groups, the average annual infection rate was calculated to be about 3% in children above 1 year of age.28
Subject Disposition and Demographics
The immunogenicity subgroup of study IC51-323 comprised 496 subjects who received at least 1 dose of IXIARO (ITT population, Fig. 1). Only 3 subjects did not receive the second dose. Demographic data and the distribution of subjects into age groups are shown in Table (Supplemental Digital Content 1, http://links.lww.com/INF/C713). All subjects were of Asian ethnicity (data not shown), and gender distribution was similar in all age groups. The prevaccination seroprevalence for JEV and DENV varied with age.
Vaccine Dosage for Subjects ≥3 to <12 Years of Age
One hundred children ≥3 to <12 years of age received IXIARO 0.25 mL and 101 received IXIARO 0.5 mL. Demographic data and baseline JEV and DENV immunity were well balanced between these groups (Table, Supplemental Digital Content 1, http://links.lww.com/INF/C713). SCR at day 56 did not differ significantly between the 0.25 mL (95.9%) and 0.5 mL dose groups (100.0%; P = 0.058). GMT at day 56 was statistically significantly higher in the 0.5 mL dose group compared with the 0.25 mL dose group [least squares mean 214 vs. 111, respectively, GMT ratio 1.92 (95% CI: 1.44–2.57); P < 0.001, ANCOVA with baseline PRNT50 titer, age and center as covariates). No serious AEs considered related to vaccination were reported and the majority of AEs were mild. Local and systemic symptoms were reported by 16.0% and 25.0% of subjects, respectively, in the 0.25 mL group and by 22.8% and 20.8%, respectively, in the 0.5 mL group. The most common solicited systemic symptom was fever (21% and 14%, respectively). Based on the comparable safety profile of both doses and on the significantly higher GMT, it was decided that the full adult dose of IXIARO, that is, 0.5 mL, was appropriate for the age group of ≥3 to <12 years.
Immune Response at Day 56 and Month 7
At day 56, the SCR with the 0.25 mL dose of IXIARO in children <3 years of age was 99.3% (147/148) and with the 0.5 mL dose in children 3 to <18 years of age was 100% (237/237). GMTs were 288 and 191, respectively. At month 7, titers mostly remained in the protective range (PRNT50 ≥10) with the 0.25 mL dose (88.2%, 134/152) and 0.5 mL dose (94.5%, 224/237), with lower GMTs (45 and 65, respectively).
When stratified by age, SCRs in excess of 99% were seen in all groups with doses licensed for that age (Table 1). A 4-fold increase in titers at day 56 was found in at least 94.0% of subjects in the various age groups, with the exception of the ≥12 to <18 years age group (77.4%) with the highest rate of prevaccination JEV seropositivity. GMTs were highest in children below 6 months with gradually lower GMTs in the older age groups (Fig. 2).
At month 7, protective titers persisted in all subjects less than 1 year old and in at least 85.5% of subjects in the older age groups. GMT remained highest in the youngest age group.
Immune Response at Day 56 and Month 7 Stratified by Prevaccination JEV and DENV Serostatus
Immunogenicity assessments stratified by dose group and by prevaccination serostatus (JEV+, DENV+ and JEV−/DENV−), using nonmutually exclusive categories, are summarized in Table 2. This analysis included the entire ITT population, including subjects in the ≥3 to <12 years age group who received 0.25 mL IXIARO.
Covariance Analysis: Influence of Prevaccination JEV and Prevaccination DENV Serostatus and Age
An ANCOVA was performed on the entire immunogenicity dataset, including the 0.25 mL dose group in the age group ≥3 to <12 years, to determine the influence of various factors impacting immunogenicity (not shown). Prevaccination JEV serostatus did not have a statistically significant association with GMTs at day 56 but was significantly associated with higher GMTs in both dose groups at month 7 (P = 0.004).
A DENV seropositive prevaccination status was associated with a significantly (P < 0.001) lower GMT at day 56, but at month 7, there were no significant differences in GMT any longer.
When age was included in the ANCOVA model, younger age was significantly associated with a higher immune response to IXIARO vaccination, and the results for JEV and DENV serostatus remained essentially the same.
The present study reports the immunogenicity results of a randomized, active-controlled, open-label study, comprising 3 treatment groups [IXIARO (0.25 mL or 0.5 mL according to age), HAVRIX 720, hepatitis A vaccine, or Prevnar, 7-valent pneumococcal vaccine], performed in the Philippines, in a pediatric population that spanned ages from 2 months to 17 years. The study was the main pediatric trial for IXIARO, a JE vaccine primarily used to immunize travelers from western countries to JEV-endemic regions. The safety results of the entire population of 1869 randomized subjects who received at least 1 dose of IXIARO were favorable and showed a safety profile comparable to HAVRIX 720 and Prevnar.6 The substudy in 496 subjects described here sought to assess the immunogenicity of IXIARO in children and determine the appropriate IXIARO dose in children ≥3 to <12 years of age.
Immunogenicity and safety during the dose-finding run-in phase in 201 subjects ≥3 to <12 years of age showed that the 0.5 mL dose induced a numerically higher SCR and significantly higher GMT than the 0.25 mL dose, with a comparable safety profile. The 0.5 mL dose was thus confirmed for this age group. Using half the standard antigen dose for children <3 years of age is common practice for viral vaccines; half doses were also used for JE-VAX while available5 and are used for JenceVac (Korean Green Cross, Yongin),16 tick-borne encephalitis vaccines29 and influenza vaccines.30
In the ITT population, both IXIARO doses (0.25 mL and 0.5 mL) elicited a strong immune response, strongest in the younger age groups. Protective values of antibody titers (ie, PRNT50 ≥10) at day 56 were found in >99% of children receiving the age-appropriate IXIARO dose, that is, 0.25 mL for subjects younger than 3 years and 0.5 mL for older ones. SCRs declined after the primary vaccination series and ranged between 85.5% and 100% at month 7, depending on age and dose group. Similarly, GMTs were highest in the youngest age group at both time points. For the ≥3 to <12 years and the ≥12 to <18 years age groups, GMTs were comparable to concentrations typically seen in adults.11,16,31 The decline in GMTs after day 56 is expected after vaccination with an inactivated viral vaccine and is similar to the decline in antibody titers observed in adults following vaccination with IXIARO.12,13,32
The prevaccination serology of the present study provides a large cross-sectional serosurvey for JEV based on a PRNT assay specific for detecting only neutralizing antibodies against JEV. More importantly, a PRNT titer of greater than 1:10 is indicative of neutralizing antibody concentrations for conferring protection against JEV, in other words, the percentage of subjects with such protective values of antibodies is called seroprotection rate. Possibly, reflecting the presence of maternally derived antibodies in the present study even before vaccination, the seroprotection rate in infants younger than 6 months of age was 22.2%, and it was much lower (<3%) in those ≥6 months to <3 years of age. Further, in 44.1% of adolescent subjects, protective values of antibodies were detected before vaccination. Given the fact that there was no JE vaccination program in place, these rates can only reflect the natural exposure rate to JEV infection in the Philippines. Data from the Philippine Integrated Disease Surveillance and Response indicate that JEV is circulating in the Bicol region and in 10 additional provinces as well as Metro Manila where the present study was conducted.33 In addition, the observed seroprevalence and age pattern in this study are consistent with previous data from the Philippines where the majority of confirmed JE cases were children: 75% were under 15 years of age and 85% were under 19 years old.33 Data from other JEV-endemic areas estimate an annual infection rate of about 3%,28 which is similar to 2.6% reported for unvaccinated children in Japan.34 Given the high seroprevalence, introduction of JE into the national immunization schedule in the Philippines seems warranted. With respect to DENV serology, the indirect DENV IgG Indirect Enzyme-linked Immunosorbent Assay method used in this study has limited specificity for DENV and may have resulted in false-positive results because of cross reaction with other flaviviruses. However, restricted by the limited amount of blood that could be drawn in children, we were limited to a test that requires less volume. Only 11 subjects overall were JEV+ but tested DENV−. In contrast, there was a significant proportion of about 30% that tested positive for DENV but were negative for JEV, indicating that those subjects may truly have had exposure to DENV only, without exposure to JEV.
Investigation of the impact of previous JEV or DENV infection on the immune response to JE vaccination was done by stratifying subjects according to their prevaccination serostatus for JEV and DENV. There was no significant association with pre-existing JEV immunity on the response to vaccination when measured at day 56 (ie, 1 month after the second dose) although a lower GMT was observed in subjects with pre-existing antibodies against JEV. However, at month 7, a significantly higher GMT was observed in those subjects pre-exposed to JEV. In contrast, pre-existing antibodies against DENV already led to a significantly lower GMT at day 56 but had no significant impact on the titer at month 7. Of note, these differences on GMT did not translate into significantly different seroprotection rates neither at day 56 nor month 7, having therefore limited clinical implications.
Our finding that SCRs were high in all groups regardless of the JEV and DENV prevaccination serostatus is relevant, as travelers from nonendemic regions are most likely seronegative to both viruses and short-term immunity is most relevant to them. The lower GMTs 4 weeks after the second dose in children seropositive to JEV suggest that our study does not overestimate the immune response compared with what might be seen in naive children. Confirming these findings, a study performed in travelling children from nonendemic countries has been performed, and results are in line with the seroprotection rates seen in the present study.18
Of potential relevance to endemic regions, our data, while limited, provide no evidence of a negative interference of presumably maternal antibodies in children less than 6 months with the immune response to vaccination. The highest GMTs were observed in children less than 6 months of age, where the pre-existing JEV rate was 30.0%. With live vaccines, viral replication and thus immunogenicity might be affected by the presence of maternal antibodies. For inactivated vaccines, however, there seems to be no reason not to vaccinate at younger ages if necessary.
Recurrent seasonal or sporadic epidemics of JE remain a major public health concern in large parts of Asia and pose a low but unpredictable risk for travelers1; however, no vaccine was available for prevention of JE in travelling children. Thus, there was a clear medical need to develop IXIARO for pediatric use.
In conclusion, the present study demonstrated that IXIARO at a dose of 0.25 mL for children 2 months to 3 years of age and 0.5 mL for children 3 years of age and above, with 2 intramuscular injections 28 days apart, elicits protective neutralizing antibody levels in over 99% of subjects. Protective immunity lasts for at least 7 months in more than 85% of vaccinated children. Further studies were performed to collect immunogenicity data in traveling children from western countries to determine the duration of protection both in JEV endemic and nonendemic populations, and to investigate safety and immunogenicity of booster doses. Based on the results of our study and data from a cohort of traveling children, IXIARO was granted pediatric licensure in the EU and US, for use in children from the age of 2 months old and older.
We are grateful to the following individuals for their valuable contributions at various stages of this trial: Christoph Klade and Vera Buerger for their contribution during the study planning phase; Evelyn Hatzenbichler and Astrid Kaltenboeck for their contribution during study setup and conduct (all formerly Intercell AG, Vienna, Austria).
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Japanese encephalitis vaccine; immunogenicity; children; IXIARO
Supplemental Digital Content
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