Japanese encephalitis (JE) is an important mosquito-borne viral disease that is endemic in Asia, Western Pacific countries and Northern Australia.1 It belongs to the Flavivirus genus and is a small RNA virus.2 JE is a febrile illness mainly associated with central nervous system inflammation.2 Symptoms include high-grade fever, nausea, vomiting, altered sensorium, convulsions, neck stiffness, muscular rigidity and abnormal movements.3 The majority of infections are asymptomatic, with only 1 out of approximately 250 infections leading to clinical illness.4 The fatality rate in JE cases is 20%–30%, with neurologic sequelae present in 30%–50% of survivors.5 The largest burden of the disease is in children, but it can affect all age groups.5
Typically 68,000 cases of JE occur per annum; however, as reporting is highly variable and often incomplete, only around 10% of cases are reported to the World Health Organization (WHO).5 Most cases occur in subjects who have never been vaccinated against JE, underlining the importance of accessible, safe and convenient vaccines.
Epidemiologic data collected between 2003 and 2005 found JE to be a leading cause of encephalitis and meningo encephalitis in Thailand.6 Since the introduction of a national vaccine program in Thailand in 1990 including mouse-brain inactivated JE vaccine (produced locally at the Thai Government Pharmaceutical Organization), the incidence of JE has declined from up to 2400 cases/annum with 400 deaths/annum in the early 1970s to approximately 500 cases/annum with 50 deaths/annum.7 Reported incidence rates in the pre-vaccination era were as high as 8.5/100,000 in some northern provinces, which dropped to lower than 0.5/100,000 with JE vaccination.7–9 Although there is limited information available on the incidence of JE in the Philippines, hospital-based studies identified JE to be the cause of up to 50% of hospitalized encephalitis cases, indicating endemic transmission.7
There is no antiviral treatment for JE. Vaccination has been shown to be effective in preventing the disease,10 and WHO has recommended that JE vaccination should be integrated into national immunization schedules. A live, attenuated JE chimeric virus vaccine (JE-CV; IMOJEV, Sanofi Pasteur, Mérieux Biological Products Co., Ltd, Thailand) has shown to be safe and to elicit a protective immune response in infants and children in a number of clinical studies.11–14 JE-CV was first registered in Australia in 2010 and is currently licensed in many other countries for the prevention of JE in adults and children.
Here, we present the persistence of antibodies in a 5-year follow-up after primary immunization with JE-CV in a previously reported phase III study (JEC02 trial; ClinicalTrials.gov NCT00735644)13 conducted in Thailand and the Philippines in which a single primary dose of JE-CV was administered to JE vaccine-naïve children aged 12–18 months. The immune response to a booster dose of JE-CV administered 5 years after the primary dose was also assessed in a subset of participants.
This study (JEC05; ClinicalTrials.gov NCT01001988) is a multicenter, open-label, 5-year follow-up of antibody persistence in a cohort of approximately 600 children who had received a single primary immunization against JE with JE-CV at 12–18 months of age. Primary vaccination was done as part of a randomized, controlled phase III trial (JEC02; ClinicalTrials.gov NCT00735644) that has been previously reported, involving 3 sites in Thailand and 5 sites in the Philippines (N = 1097).13 All of the followed JE-CV primary recipients were offered a second JE-CV vaccination (booster dose at year 5), of whom a subset of 85 were invited to participate in the immune response study after a booster dose (JEC24; ClinicalTrials.gov NCT01954810). These 85 subjects were arbitrarily defined as those enrolled in 1 site in Thailand who did not receive any JE booster vaccination.
The 5-year follow-up study was conducted at all 3 sites in Thailand (Srinagarind Hospital, Khon Kaen; Phramongkutklao Hospital, Bangkok and King Chulalongkorn Memorial Hospital, Bangkok) and 2 of the 5 JEC02 sites in the Philippines (Bayanan Main Health Center, San Guillermo, Bayanan and Sucat Health Center, Sucat) between August 07, 2009 and October 16, 2013. Eligible participants were required to have been vaccinated with JE-CV in JEC02. Participants were excluded if they had received a JE vaccine other than JE-CV during JEC02 or during the period between the end of JEC02 and the start of this study.
The decision to involve the 3 Thailand sites was to inform them of any potential need for booster vaccination, if JE neutralizing-antibody titers dropped below the threshold of protection. As JE-CV was an investigational vaccine at the time of study initiation in JEC02, designed using data from a clinical study performed in adults,15 it was expected that a booster dose would not be required for at least 5 years. Nevertheless, any participant in Thailand with a neutralizing antibody titer below the threshold for protection (<10 1/dil) at any visit during the 5-year follow-up was offered an extra JE vaccination with a licensed mouse brain-derived JE vaccine (MBDV), administered according to the national immunization schedule recommending 2 doses of JE vaccine (at 18–24 months of age) and a booster dose (at 2.5–3 years of age),7,8 and they were withdrawn from the trial. In the Philippines, vaccination against JE is not included in the national immunization program, and as no licensed JE vaccine was available, seronegative participants were not discontinued from the study.
Studies were conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization-Good Clinical Practice guideline. Each study was approved by each study site’s institutional review board and local ethics committee, and written informed consent was obtained from all participants’ parents/guardians before entry into each study.
For the booster study, JE-CV vaccine commercial lots were supplied as powder and diluent for suspension for injection. Each 0.5 mL dose of reconstituted vaccine contained ≥4.0 and ≤5.8 log10 plaque-forming units of virus. The diluent for reconstitution consisted of 0.4% NaCl. The booster dose was administered subcutaneously into the upper arm.
Participants provided blood samples for determination of anti-JE antibodies at 1, 2, 3, 4 and 5 years after primary vaccination and 28 days after the booster vaccination. Antibody measurements before and 28 days after primary JE-CV administration have been published previously.13 JE-CV neutralizing antibody titers were measured using a 50% plaque reduction neutralization test (PRNT50) by Focus Diagnostics Inc. (Cypress, CA).16 Seroprotection status for antibody levels against JE virus was defined as JE-CV neutralizing antibody titer ≥10 1/dil, which is the threshold recommended by a group of experts assembled by WHO and accepted as evidence of protection.17,18 Seroconversion after vaccination was defined by JE-CV neutralizing antibody titers ≥10 1/dil in participants who were seronegative at the previous visit (titers <10 1/dil) or by a ≥4-fold rise in neutralizing antibody titers in participants who were seropositive (titers ≥10 1/dil) at previous visits.
Serious adverse events (AEs) related to the JE-CV vaccine and confirmed breakthrough cases of JE were recorded during the 5-year follow-up (JEC05) and up to 28 days after receipt of the booster dose (JEC24). Cases of JE were to be detected through interviews conducted during the yearly visits or during regular phone calls/home visits during the study. Laboratory confirmation of JE was based on a number of methods including: measurement of immunoglobulin M (IgM) antibodies in cerebrospinal fluid (CSF) or serum as detected by an IgM-capture enzyme-linked immunosor bent assay specifically for JE virus; detection of JE virus antigens in tissue by immunohistochemistry; detection of JE virus genome in serum, plasma, blood, CSF or tissue by reverse transcriptase polymerase chain reaction or an equally sensitive and specific nucleic acid amplification test; isolation of JE virus in serum, plasma, blood, CSF or tissue; detection of a ≥4-fold rise in antibodies specific to JE virus as measured by hemagglutination inhibition; or PRNT in serum collected during the acute and convalescent phase of illness (collected at least 14 days apart).
The full analysis set (FAS) included all available data from participants in the long-term follow-up with a blood sample taken at visit 1. The FAS was used for early immunogenicity analyses, for demographic analysis and for the description of detected JE cases. Confidence intervals (CIs) for seroprotection rates were calculated using the exact binomial method.19 For JE-CV neutralizing antibody titers, it was assumed that log10 transformation of these titers followed a normal distribution. The mean and the 95% CI were first calculated on log10 scale using the usual calculation for normal distribution and converted to antilog to provide geometric mean titers (GMTs) and their 95% CIs.
The Kaplan–Meier method was used to estimate the proportion of participants who remained seropositive over time during the 5-year long-term follow-up. Time to maintain seroprotection was calculated for participants with a 28-day post-vaccination titer ≥10 1/dil and was defined as the last time point when the titer was ≥10 1/dil (ie, years 1, 2, 3 or 4). Participants were excluded from the analysis if they left the study. If a titer value was missing for 1 or more visit and the participant was seropositive at the next visit, the participant was assumed to have been seropositive at the time of the missing visit(s)/titer(s). If a titer value was missing for a visit and the participant was seronegative at the next visit, the participant was assumed to have been seronegative at the time of the missing visit(s). Participants who remained seroprotected but who were subsequently withdrawn, had no blood sample taken or who were lost to follow-up were censored at the time of their last visit, in which JE-CV antibody levels were measured.
Two sensitivity analyses were performed to account for the withdrawal and subsequent re-vaccination (with a licensed JE vaccine) of participants found to be seronegative. In sensitivity analysis 1, if a subject was withdrawn at a visit (whatever the reason), missed a visit or had no blood sample taken at a visit and he/she was seronegative at the previous visit, the subject was assumed to be seronegative at the next subsequent visits if no antibody titer was available. In case a subject had positive titer values later (ie, ≥10 1/dil) for any reason after a visit where he/she was found to be “negative,” he/she was considered as positive and observed antibody titer was used in the computation. In sensitivity analysis 2, if a subject withdrew at a visit (whatever the reason) or missed a visit/blood sample and he/she was seronegative (ie, <10 1/dil, homologous virus strain) at the previous visit, the subject was assumed to be seronegative at all the following visits up to the year 5 visit; in case a subject had positive titer values later (ie, ≥10 1/dil) for any reason (ie, exposure to a JE virus in JE endemic countries) after a visit where he/she was found to be “negative,” he/she was still considered as negative, which was not the case in sensitivity analysis 1.
A total of 596 participants who received a single dose of JE-CV in JEC02 attended the year 1 visit in JEC05: 366 participants from Thailand and 230 participants from the Philippines (Fig. 1). By year 5, in Thailand, 14 of these participants were discontinued because of noncompliance with the protocol; 69 participants with antibody titers below the threshold considered for protection and administered a licensed JE vaccine were also discontinued; 17 participants voluntarily withdrew (not AE-related); and 14 participants were lost to follow-up. In the Philippines, 1 participant was lost to follow-up, 1 participant voluntarily withdrew (not AE-related) and 1 participant was discontinued because of noncompliance with the protocol (participant was unable to attend further visits). A total of 85 participants were enrolled into JEC24 and received a JE-CV booster dose; of these, 83 could be analyzed. One participant was unable to attend the follow-up visit, and in the other participant, the immunogenicity result was unavailable because of technical problems. Participant characteristics at baseline are summarized in Table 1.
A total of 580 participants had data available on day 28 post-JE-CV administration in JEC02; all 580 were seroprotected (titer ≥10 1/dil). The total number of participants included in the immunogenicity analysis (FAS) was 586 (ie, patients with year 1 data regardless of whether day 28 data were available), 547, 504, 484 and 478 at years 1, 2, 3, 4 and 5, respectively (Table 2). In the FAS, the GMT 28 days after vaccination was 253 1/dil decreasing to 77.2 1/dil 1 year after vaccination (Fig. 2). From 2 to 5 years after vaccination, the GMTs persisted at similar levels to year 1, with the exception of a peak at year 3 (132 1/dil). The GMT at year 5 was 63.4 1/dil (Fig. 2).
A total of 88.2%, 90.1%, 93.1%, 87.6% and 85.4% of participants (FAS) showed persistence of seroprotection (titer ≥10 1/dil) at years 1, 2, 3, 4 and 5 after vaccination (Table 2). However, these seroprotection rates did not account for the participants in Thailand excluded because they became seronegative (titer <10 1/dil); overall, 34, 19 and 16 participants were excluded at years 2, 3 and 4, respectively. Kaplan–Meier analyses (FAS) censoring participants who became seronegative estimated that 88.5%, 82.9%, 78.2%, 74.0% and 68.6% of participants remained seroprotected at 1, 2, 3, 4 and 5 years after vaccination. In sensitivity analyses 1 and 2 (FAS), seroprotection rates at year 5 were 74.7% and 67.2%, respectively (Table 2).
For the duration of the 5-year follow-up, seroprotection rates estimated from the Kaplan–Meier analyses were similar in participants from Thailand (dataset excluded those who were seronegative and discontinued the study) and the Philippines; 68.6% and 68.4% of seroprotected participants on day 28 maintained a seropositivity level at year 5 in Thailand and the Philippines, respectively (Fig, Supplemental Digital Content 1, http://links.lww.com/INF/C699).
The immunogenicity results for the subset of participants who received a booster dose of JE-CV (n = 83) are given in Table 3. Most participants (88.0%) were seroprotected at year 5 before booster vaccination. Twenty-eight days after a booster dose, the seroprotection rate increased to 100%, with 95.2% of participants seroconverted. The GMT after the booster dose increased from 61.2 1/dil (95% CI: 43.8–85.7 1/dil) to 4951 1/dil (95% CI: 3928–6241 1/dil).
No confirmed JE cases were reported from 6 months to 5 years after JE-CV administration.
No related serious AEs were reported from 6 months to 5 years after JE-CV administration or during the 28 days after booster.
A protective immune response persisted in the majority of participants for 5 years after a single dose of JE-CV as primary immunization, with GMTs remaining above the threshold considered as protective in the majority of participants. There were no concerns regarding to safety, and no JE cases were observed during the long-term follow-up. An initial decline in GMTs was observed between day 28 to year 1, after which GMTs remained relatively stable up to 5 years after vaccination, with the exception of a slight peak at year 3, declining very slowly over time afterwards. This GMT profile was in keeping with other studies of subjects naïve to JE vaccine in which GMT increased within 28 days of vaccination, then decreased between day 28 and month 12 and subsequently remained fairly stable and plateau-like with only a slow decrease over time from month 12 until year 5.20 The ongoing gradual decline in seroprotection rates may be masked and appear to plateau as a result of the withdrawal of those subjects who developed titers below the threshold for protection (who then received an additional JE vaccination). Data gathered in long-term follow-ups in other JE-CV studies in JE vaccine-naïve children support the recommendation of a JE-CV booster dose, given preferably 12 months after primary vaccination but can be given up to 24 months after primary vaccination.20
The day 28 seroprotection rate in the original study (JEC02), for subjects who were included in JEC05 and with available data on day 28 post-JE-CV administration, was 100.0% (95% CI: 99.4–100.0), while that in the whole population enrolled in JEC02 was 95.3% (95% CI: 93.9–96.5). This might be explained by the enrollment and selection criteria for JEC05, which excluded subjects with antibody titers below the threshold of protection at enrollment (because it was considered unethical to follow-up and take blood from subjects with negative titers), as well as subjects from Thailand with antibody titers below the threshold considered for protection (10 1/dil; who instead received a marketed MBDV JE vaccine boost and were withdrawn from the study). Therefore, the persistence was assessed mainly in subjects who were seroprotected 28 days after a single dose of JE-CV.
In this study, there was a difference in the booster JE vaccination between Thailand and the Philippines for participants whose neutralizing JE antibody titers fell below the threshold considered for protection during the follow-up period. The former were permitted to receive a licensed JE vaccine as a booster dose according to the national immunization schedule and were consequently withdrawn from the trial, unlike the latter who could not be offered a licensed JE vaccine as no JE vaccines were licensed or recommended by National Authorities in the Philippines at the time of the study; therefore, those subjects continued to participate in the long-term follow-up. This mostly explains the higher number of discontinuations in Thailand compared with the Philippines.
The withdrawal of seronegative participants in Thailand artificially increased the apparent seroprotection rate. Kaplan–Meier and sensitivity analyses, which took into account the discontinuation of seronegative participants, estimated lower immunogenicity rates (67%–75%) at year 5 compared with the main analysis (85%). Despite the differences in the 2 populations described above, Kaplan–Meier analyses estimated that a similar proportion of patients in Thailand and in the Philippines were seroprotected throughout the duration of the study. In both countries, it was estimated that approximately 68% of participants who were seroprotected at day 28 would remain seroprotected at year 5. It should be noted that participants may have had natural exposure to JE or other flaviviruses during their participation in the long-term follow-up, which could potentially impact on JE antibody titers—an effect that was accounted for in sensitivity analysis 2. During the long-term follow-up assessment, some subjects with low titers in prior years presented with increased antibody titers at the next year of follow-up, suggesting that either natural boosting with JE virus, or cross-reactivity with another circulating flavivirus, may have occurred. Even if natural exposure is assumed in these cases, no subjects in the long-term follow-up period of several trials presented with signs or symptoms constitutive of a JE infection, particularly those subjects with low titers over time or titers below the threshold of protection (10 1/dil).
In the subset of participants followed after receipt of a booster JE-CV dose, 5 years after the primary dose, almost all (95.2%) had at least a 4-fold rise in JE antibodies (seroconversion). The remainder (4.8%) had a less than 4-fold rise in antibody titers because their baseline antibody titer was already high before receiving the booster. The JE-CV booster resulted in a mean GMT of 4951 1/dil, which was well above the seroprotective threshold titer and far beyond the initial response (mean GMT 258 1/dil on day 28). Given the dramatic increase in JE antibody titers after the booster dose and that JE antibody levels were observed to decline only gradually with time in the long-term follow-up study, it is anticipated that a single primary dose of JE-CV followed by a booster dose will ensure long-term protection against JE. There were no safety concerns after administration of the booster dose in this study.
The immune response 28 days after the JE-CV booster dose in the current study (seroprotection, 100%; seroconversion 95.2%) is comparable with that observed in a study previously reported by Feroldi et al21 in which children, aged 36–42 months, received a JE-CV booster 2 years after a primary dose of JE-CV (seroprotection, 100%; seroconversion 95.3%). In another report by Chokephaibulkit et al,11 JE-CV was administered as the JE booster vaccination in children aged 2–5 years previously primed with MBDV; all children (100%) had seroprotective neutralizing JE antibody titers 28 days after the JE-CV booster dose.
Data for maintenance over time of the immune response elicited by different JE vaccines are limited, as are published long-term follow-up data with IXIARO (an inactivated JE vaccine that appears to have not more than 3 years of follow-up),22 making any comparisons with JE-CV difficult.
To conclude, a single primary dose of JE-CV administered to JE vaccine-naïve children, 12–18 months of age, provides a protective immune response that persists in the majority of participants for 5 years. A booster JE-CV dose, given 5 years after the primary dose, resulted in GMT levels far higher than the seroprotective threshold, with 100% of participants seroprotected 28 days after administration of the booster. No safety concerns were highlighted during the study. A booster JE-CV dose at 5 years, which is delayed compared with the recommended booster at 12–24 months post-primary vaccination in children, can still induce a robust immune response.
The authors thank the study participants and their parents in Bangkok, Khon Kaen (Thailand) and in Muntinlupa City (The Philippines). The authors acknowledge with thanks the contribution of investigational staff at King Chulalongkorn Memorial Hospital (Bangkok), Tropical Medicine Hospital (Bangkok), Phramongkutklao Hospital (Bangkok), Srinagarind Hospital (Khon Kaen), Research Institute for Tropical Medicine and at the Health Centers in Alabang, Bayanan, Buli, Cupang and Sucat in Muntinlupa City. The authors also thank Dr. Sutee Yoksan at the Center for Vaccine Development, Mahidol University, Thailand. The authors acknowledge with thanks the contribution of Dr. Pensri Kosuwon, Dr. Surapon Wiangnon, Dr. Chanyut Suphakunpinyo, Ms. Piangjit Tharnprisan, Ms. Paiporn Sripraya, Ms. Chanasda Sopharak, Ms. Darunee Sangsahachart, Research Affairs, Faculty of Medicine, Khon Kaen University, and the JE-CV Clinical Team at Sanofi Pasteur (Celine Monfredo, Claire Vigne, Marie-Caroline Guichard, Suree Satayavisit, Yuvadee Yaiprayoun, Karen Privat, Christel Guillaume, Nicolas Corde and Agnes Machmer), as well as the research staff and technicians at Global Clinical Immunology at Sanofi Pasteur. Editorial assistance with the preparation of the manuscript was provided by a medical writer, Lorraine Ralph, inScience Communications (Springer Healthcare, Chester, UK), funded by Sanofi Pasteur.
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Japanese encephalitis; vaccine; toddlers; long-term follow-up; booster
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