The Synergy between Zinc and Antimicrobial Peptides: An Insight into Unique Bioinorganic Interactions.

Antimicrobial peptides (AMPs) are essential components of innate immunity across all species. AMPs have become the focus of attention in recent years, as scientists are addressing antibiotic resistance, a public health crisis that has reached epidemic proportions. This family of peptides represents a promising alternative to current antibiotics due to their broad-spectrum antimicrobial activity and tendency to avoid resistance development. A subfamily of AMPs interacts with metal ions to potentiate antimicrobial effectiveness, and, as such, they have been termed metalloAMPs. In this work, we review the scientific literature on metalloAMPs that enhance their antimicrobial efficacy when combined with the essential metal ion zinc(II). Beyond the role played by Zn(II) as a cofactor in different systems, it is well-known that this metal ion plays an important role in innate immunity. Here, we classify the different types of synergistic interactions between AMPs and Zn(II) into three distinct classes. By better understanding how each class of metalloAMPs uses Zn(II) to potentiate its activity, researchers can begin to exploit these interactions in the development of new antimicrobial agents and accelerate their use as therapeutics.

Changes in age-specific seroprevalence of Japanese encephalitis virus and impact of Japanese encephalitis vaccine in Korea.

The Japanese encephalitis (JE) virus is the leading cause of vaccine-preventable encephalitis in Asia. Since the introduction of a universal JE vaccination program and urbanization of Korea, the incidence of JE has dramatically decreased in Korea. However, recent JE cases have occurred, predominantly among unvaccinated adults and with a shift in age distribution. Here we aimed to review the changes in age-specific JE seroprevalence over time and discuss the implications of JE vaccination programs in Korea. Following the last epidemic in 1982-1983, mandatory vaccination for all children aged 3-15 years was conducted annually until 1994. However, JE has reemerged, predominantly affecting unvaccinated adults aged 40 years or older and demonstrating a shift in age distribution toward older populations. The age-specific seroprevalence of the JE virus in Korea has changed noticeably over time. Seropositivity in children and adolescents increased from 10%-59% in the 1970s to 90%-92% in the 1980s after the implementation of the JE vaccination program and increased further to 98% in 2012. No age-specific difference in the seroprevalence of JE was found, and appropriate levels of immunity to JE were maintained for all age groups. Continuous surveillance of the seroprevalence of JE is essential to establish a proper immunization policy in Korea.

Emergence of serotype 10A-ST11189 among pediatric invasive pneumococcal diseases, South Korea, 2014-2019.

Replacement with nonvaccine serotypes (NVTs) among invasive pneumococcal diseases (IPDs) after the introduction of extended-valency pneumococcal conjugate vaccines varies in predominant serotypes across countries. This study analyzed changes in serotype distribution through serotyping, multilocus sequence typing, and antimicrobial susceptibility testing of 168 pediatric IPD isolates obtained from a multihospital-based surveillance system during 2014-2019 in South Korea. Vaccine serotypes (VTs) accounted for 16.1% (19A, 10.1%; 6A, 1.8%; and 19F 1.8%), 82.1% were NVTs (10A, 23.8%; 15A, 8.3%; 12F, 6.5%; 15C, 6.5%; and 15B, 6.0%), and three (1.8%) were nontypeable. Serotype 10A was the most common serotype, with a significant increase from 11.5% in 2014 to 33.3% in 2019 (p < 0.05 for the trend). Other NVTs decreased from 70.4% to 41.7% between 2015 and 2019, most notably in serotype 12F (from 14.8% to 0%). Almost all (95.0%) serotype 10A isolates were ST11189, which were multidrug resistant.

Immunogenicity and safety of the third booster dose of the inactivated Japanese encephalitis vaccine in Korean children: A prospective multicenter study.

The immunization schedule for the inactivated Japanese encephalitis (JE) vaccine in Korea is a two-dose primary series at 12-24 months of age and three booster doses at 12 months after primary schedule and at 6 and 12 years of age. The aim of this study was to investigate immunogenicity and safety of the third booster dose of the inactivated JE vaccine, as well as the long-term immunogenicity of the second booster dose in Korean children. Healthy children aged 11-13 years, primed and given four doses of inactivated JE vaccines were included. All subjects received the third booster dose of the JE vaccine. Neutralizing antibody (NTAb) titers were assessed before and 4-6 weeks after vaccination using plaque reduction neutralization test (PRNT), and were considered to be protective at ≥ 1:10. Local and systemic adverse events were monitored for 4 weeks after vaccination. Before and after booster vaccination, all seroprotection rates were 100%. Geometric mean titer (GMT) showed a 6.05-fold increase, from 139.11 (95% CI: 110.76, 174.71) to 841.53 (95% CI, 714.25, 991.50). The local tolerability and systemic safety profiles were favorable, with no serious adverse events. In conclusion, the third booster dose of the inactivated JE vaccine was demonstrated to be safe and immunogenic in Korean children when administered according to the current immunization schedule.

Retention of neutralizing antibodies to Japanese encephalitis vaccine in age groups above fifteen years in Korea.

BACKGROUND: The incidence of Japanese encephalitis (JE) has markedly decreased after the national immunization program in Korea, but still reported intermittently in adults. Prospective studies are required to determine whether JE virus (JEV)-neutralizing antibody (NAb) levels decline with age after the final JE vaccination. In this study, we evaluated the titers of NAbs against JEV in Korean adolescents and adults. METHODS: Specimens were collected from normal, healthy individuals aged 1 to >70 years (a total of 1,605 cases) from five regional hospitals in Korea. Neutralizing antibody (NAb) titers were determined using a pseudotyped JEV NAb assay. RESULTS: The JEV NAb-positive population was >95% in the 15-29 year age group, 89.42% in the 30-44 year age group, 75.24% in the 55-59 years age group, and 59.77% in the ≥70 year age group. NAb titers from the 20 to 70 year age groups showed a progressive decrease in proportion to age (P < 0.0001). CONCLUSIONS: The retention of NAbs after the final JE vaccination in childhood is a key indicator of the vaccination program and will have a significant impact on future JE prevention strategies.

Seroprevalence of Neutralizing Antibodies against Japanese Encephalitis Virus among Adolescents and Adults in Korea: A Prospective Multicenter Study.

The immunization schedule for the Japanese encephalitis (JE) vaccine in Korea is a two-dose primary series at 12-24 months of age, followed by booster doses 12 months after the second dose and at the ages of 6 and 12 years. Although the number of JE cases has markedly decreased after the universal vaccination program, JE predominantly occurs in adults. The aim of this study was to assess the age-specific prevalence of the JE-neutralizing antibody (NTAb) among adolescents and adults in Korea. A total of 1603 specimens were collected from a healthy Korean population above 15 years old in five provinces. The JE-NTAb titers were measured with the pseudotyped virus assay and considered to be positive at ≥ 1:50. The seropositivity of JE-NTAb was the highest in the 15-29 years category (>95%) and gradually began to decrease in the age group of 30-44 years (89.42%). The lowest and second lowest JE-NTAb seropositive rates were observed among those aged 70 years or older (59.77%) and those aged 55-59 years (75.24%), respectively. Subjects from Seoul exhibited the highest JE-NTAb titer in all age groups compared to other provinces. In conclusion, the JE-NTAb seropositive rates and titers have maintained appropriate levels in the general Korean population. We propose that adult immunization and boosters at 12 years of age against JE are not strongly recommended in Korea.

Comparison of the Immunogenicity and Safety of Three Enhanced Inactivated Poliovirus Vaccines from Different Manufacturers in Healthy Korean Infants: A Prospective Multicenter Study.

The enhanced inactivated poliovirus vaccine was first introduced in 2002, and several inactivated poliovirus vaccines are licensed in Korea. Reliable data by a prospective study on the immunogenicity and safety of the inactivated poliovirus vaccines in Korean infants are required. Normal healthy infants aged 6-12 weeks received three doses of the vaccine (IPVAX™, Imovax Polio™ or Poliorix™) in intervals of 2 months. Neutralizing antibody (NTAb) titers were measured before and 4-6 weeks after three-dose primary vaccination. Immunogenicity was evaluated by seroconversion rates and geometric mean titers obtained by analyzing NTAb titers. Local and systemic adverse events were recorded during 7 days after each vaccination. A total of 150 infants were included: 40 in IPVAX™, 52 in Imovax Polio™, and 58 in Poliorix™. The seroconversion rates for the group vaccinated with IPVAX™ were 100% in types 1, 2 and 3, while those of Imovax Polio™ were 98.1%, 96.2%, 96.2% and those of Poliorix™ were 98.3%, 100%, 100%, respectively. In all groups, injection site redness and irritability were the most common local and systemic adverse events. Neither serious adverse events nor adverse events above grade 2 were reported throughout the study. The currently used inactivated poliovirus vaccines was demonstrated to be safe and immunogenic in healthy Korean infants.

Erratum: Addition of a Co-Author: Etiology of Invasive Bacterial Infections in Immunocompetent Children in Korea (2006-2010): a Retrospective Multicenter Study.

This corrects the article on e45 in vol. 33, PMID: 29349940.

Genetic structures of invasive Streptococcus pneumoniae isolates from Korean children obtained between 1995 and 2013.

BACKGROUND: Understanding the population genetics of pneumococci will allow detection of changes in the prevalence of circulating genotypes and evidence for capsular switching. We aimed to analyze the genetic structure of invasive pneumococcal isolates obtained from children before and after the use of pneumococcal conjugate vaccines (PCVs) in Korea. METHODS: A total of 285 invasive pneumococcal isolates were analyzed using serotyping, multilocus sequence typing, and antimicrobial susceptibility testing. We classified the isolation year to pre-PCV7 (1995-2003; n = 70), post-PCV7 (2004-2010; n = 142), and post-PCV13 (2011-2013; n = 73) periods. RESULTS: Of the 10 clonal complexes (CCs), antibiotic-resistant international clones, CC320 (31.6%), CC81 (14.7%), and CC166 (6.7%) were the main complexes. Serotype 19A was the main serotype of CC320 throughout the periods. Serotypes of CC81 mainly comprised of 23F (53.3%) in pre-PCV7 period and replaced by non-vaccine types (NVTs; 6C [10%], 13 [30%], 15A [40%], and 15B/C [20%]) in post-PCV13 period. The main serotype responsible for CC166 also changed from 9 V (80%) in pre-PCV7 to NVT 11A (50%) in post-PCV13 periods. Non-susceptibility to penicillin (42.3%) was the highest in CC320, increasing from 0 to 76%. CONCLUSION: The genetic structures of invasive pneumococcal isolates in Korean children have changed concomitantly with serotype after the implementation of PCVs.

Safety and Immunogenicity of an Egg-Cultivated Quadrivalent Inactivated Split-virion Influenza Vaccine (GC3110A) in Healthy Korean Children: a Randomized, Double-blinded, Active-controlled Phase III Study.

BACKGROUND: The frequency with which the 2 B lineages have been found to cocirculate in a season has been on the rise, which has spurred the need for a quadrivalent influenza vaccine (QIV) to protect against both B lineages. The World Health Organization (WHO) recommended that QIV include both B lineages beginning in the 2013-2014 flu season. This study was conducted to evaluate the immunogenicity and safety of an egg-cultivated QIV in healthy Korean children and adolescents aged ≥ 6 months to < 19 years. METHODS: A total of 528 subjects were randomized 4:1 to receive either a QIV (GC3110A) or a trivalent influenza vaccine. Hemagglutination inhibition antibody responses were assessed 28 days after the last dose. Safety was also evaluated. RESULTS: The proportion of subjects in the GC3110A group who achieved seroconversion was confirmed to exceed 40% across all age groups. The proportion of subjects aged ≥ 6 months to < 3 years in the GC3110A group who achieved seroprotection failed to meet the Ministry of Food and Drug Safety (MFDS) standard of 70%. Potential causes may include the small number of subjects, as well as the small dosage. However, results pertaining to the other age groups satisfied the MFDS standard. The safety profile was also comparable to that of the control. CONCLUSION: The new quadrivalent split influenza vaccine may offer broader protection to children and adolescents aged ≥ 3 years to < 19 years of age against both influenza B lineages than the existing trivalent influenza vaccines (Registered at the ClinicalTrials.gov NCT02541253).

Long-term immunogenicity of an initial booster dose of an inactivated, Vero cell culture-derived Japanese encephalitis vaccine (JE-VC) and the safety and immunogenicity of a second JE-VC booster dose in children previously vaccinated with an inactivated, mouse brain-derived Japanese encephalitis vaccine.

BACKGROUND: This study was performed with the aim of determining the long-term immunogenicity of an inactivated, Vero cell culture-derived Japanese encephalitis (JE) vaccine (JE-VC) and an inactivated, mouse brain-derived JE vaccine (JE-MB) after the 1st booster dose at 2 years of age, as well as the safety and immunogenicity of the 2nd booster dose of JE-VC at 6 years of age, in children primed and given a 1st booster dose of either JE-VC or JE-MB. METHOD: In this multicenter, open-label clinical trial, the study population consisted of healthy Korean children (aged 6 years) who participated in the previous JE vaccine trial. All subjects were subcutaneously vaccinated once for the booster immunization with Boryung Cell Culture Japanese Encephalitis Vaccine® (JE-VC). RESULT: Approximately 4 years after the 1st booster dose of JE-VC, the seroprotection rate (SPR) and geometric mean titer (GMT) of the neutralizing antibody were 100% and 1113.8, respectively. In children primed and given a 1st booster dose of JE-MB, the SPR and GMT were 88.5% and 56.3, respectively. After the 2nd booster dose of JE-VC, all participants primed and given a 1st booster dose of either JE-MB or JE-VC were seroprotective against JE virus. The GMT of the neutralizing antibody was higher in children primed and given a 1st booster dose of JE-VC (8144.1) than in those primed and given a 1st booster dose of JE-MB (942.5) after the vaccination (p < 0.001). In addition, the 2nd booster dose of JE-VC showed a good safety profile with no serious vaccine-related adverse events. CONCLUSION: The 1st booster dose of JE-VC and JE-MB showed long-term immunogenicity of at least 4 years, and the 2nd booster dose of JE-VC showed a good safety and immunogenicity profile in children primed and given a 1st booster dose of either JE-VC or JE-MB. ClinicalTtrials.gov Identifier: NCT02532569.

Etiology of Invasive Bacterial Infections in Immunocompetent Children in Korea (2006-2010): a Retrospective Multicenter Study.

BACKGROUND: Invasive bacterial infections in apparently immunocompetent children were retrospectively analyzed to figure causative bacterial organisms in Korea. METHODS: A total of 947 cases from 25 university hospitals were identified from 2006 to 2010 as a continuance of a previous 10-year period study from 1996 to 2005. RESULTS: Escherichia coli (41.3%), Streptococcus agalactiae (27.7%), and Staphylococcus aureus (27.1%) were the most common pathogens in infants < 3 months of age. S. agalactiae was the most prevalent cause of meningitis and pneumonia and E. coli was the major cause of bacteremia without localizing signs in this group. In children 3 to 59 months of age, Streptococcus pneumoniae (54.2%), S. aureus (20.5%), and Salmonella spp. (14.4%) were the most common pathogens. S. pneumoniae was the leading cause of pneumonia (86.0%), meningitis (65.0%), and bacteremia without localizing signs (49.0%) in this group. In children ≥ 5 years of age, S. aureus (62.8%) was the predominant pathogen, followed by Salmonella species (12.4%) and S. pneumoniae (11.5%). Salmonella species (43.0%) was the most common cause of bacteremia without localizing signs in this group. The relative proportion of S. aureus increased significantly over the 15-year period (1996-2010) in children ≥ 3 months of age (P < 0.001), while that of Haemophilus influenzae decreased significantly in both < 3 months of age group (P = 0.036) and ≥ 3 months of age groups (P < 0.001). CONCLUSION: S. agalactiae, E. coli, S. pneumoniae, and S. aureus are common etiologic agents of invasive bacterial infections in Korean children.

The Immunogenicity and Safety of a Combined DTaP-IPV//Hib Vaccine Compared with Individual DTaP-IPV and Hib (PRP~T) Vaccines: a Randomized Clinical Trial in South Korean Infants.

Recommended infant vaccination in Korea includes DTaP-IPV and Hib vaccines administered as separate injections. In this randomized, open, controlled study we assessed the non-inferiority of immunogenicity of DTaP-IPV//Hib pentavalent combination vaccine (Pentaxim™) compared with licensed DTaP-IPV and Hib (PRP~T) vaccines. We enrolled 418 healthy Korean infants to receive either separate DTaP-IPV and Hib vaccines (n = 206) or the pentavalent DTaP-IPV//Hib (n = 208) vaccine at 2, 4, 6 months of age. Antibodies to all components were measured before the first vaccination and one month after the third, and safety was assessed after each vaccination including recording of reactions by parents. We confirmed the non-inferiority of DTaP-IPV//Hib compared with DTaP-IPV and Hib vaccines; 100% of both groups achieved seroprotection against D, T, IPV and PRP~T, and 97.5%-99.0% demonstrated seroresponses to pertussis antigens. Antibody levels were similar in both groups, except for those to the Hib component, PRP~T. In separate and combined groups geometric mean concentrations of anti-PRP~T antibodies were 23.9 and 11.0 µg/mL, respectively, but 98.3% and 97.4% had titers ≥ 1 µg/mL, indicative of long-term protection. All vaccines were well tolerated, with no vaccine-related serious adverse event. Both groups had similar safety profiles, but the combined vaccine group had fewer injection site reactions. The immunological non-inferiority and similar safety profile of DTaP-IPV//Hib vaccine to separate DTaP-IPV and Hib vaccines, with the advantage of fewer injections and injection site reactions, supports the licensure and incorporation of DTaP-IPV//Hib into the Korean national vaccination schedule (Clinical trial registry, NCT01214889).

Early Changes in the Serotype Distribution of Invasive Pneumococcal Isolates from Children after the Introduction of Extended-valent Pneumococcal Conjugate Vaccines in Korea, 2011-2013.

This study was performed to measure early changes in the serotype distribution of pneumococci isolated from children with invasive disease during the 3-year period following the introduction of 10- and 13-valent pneumococcal conjugate vaccines (PCVs) in Korea. From January 2011 to December 2013 at 25 hospitals located throughout Korea, pneumococci were isolated among children who had invasive pneumococcal disease (IPD). Serotypes were determined using the Quellung reaction, and the change in serotype distribution was analyzed. Seventy-five cases of IPD were included. Eighty percent of patients were aged 3-59 months, and 32% had a comorbidity that increased the risk of pneumococcal infection. The most common serotypes were 19A (32.0%), 10A (8.0%), and 15C (6.7%). The PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, 23F, and 6A) accounted for 14.7% of the total isolates and the PCV13 minus PCV7 types (1, 3, 5, 7F and 19A) accounted for 32.0% of the total isolates. Serotype 19A was the only serotype in the PCV13 minus PCV7 group. The proportion of serotype 19A showed decreasing tendency from 37.5% in 2011 to 22.2% in 2013 (P = 0.309), while the proportion of non-PCV13 types showed increasing tendency from 45.8% in 2011 to 72.2% in 2013 (P = 0.108). Shortly after the introduction of extended-valent PCVs in Korea, serotype 19A continued to be the most common serotype causing IPD in children. Subsequently, the proportion of 19A decreased, and non-vaccine serotypes emerged as an important cause of IPD. The impact of extended-valent vaccines must be continuously monitored.

Complete occlusion of the right middle cerebral artery associated with Mycoplasma pneumoniae pneumonia.

We report a case of a 5-year-old girl who developed left hemiparesis and left facial palsy, 6 days after the initiation of fever and respiratory symptoms due to pneumonia. Chest radiography, conducted upon admission, showed pneumonic infiltration and pleural effusion in the left lung field. Brain magnetic resonance imaging showed acute ischemic infarction in the right middle cerebral artery territory. Brain magnetic resonance angiography and transfemoral cerebral angiography revealed complete occlusion of the right middle cerebral artery. Mycoplasma pneumoniae infection was identified by a 4-fold increase in IgG antibodies to M. pneumoniae between acute and convalescent sera by enzyme-linked immunosorbent assay. Fibrinogen and D-dimer levels were elevated, while laboratory exams in order to identify other predisposing factors of pediatric stroke were all negative. This is the first reported pediatric case in English literature of a M. pneumoniae-associated cerebral infarction involving complete occlusion of the right middle cerebral artery.

Immunogenicity and safety of a multicomponent meningococcal serogroup B vaccine in healthy adolescents in Korea--A randomised trial.

BACKGROUND: Neisseria meningitidis serogroup B is a significant cause of septicaemia and meningitis worldwide. This phase 3 randomised, controlled study assessed the immunogenicity and safety of a multicomponent meningococcal serogroup B vaccine, 4CMenB, in healthy Korean adolescents. METHODS: 264 adolescents (11-17 years old) were randomised to receive two doses, one month apart, of 4CMenB or control vaccines [placebo followed by one dose of a quadrivalent meningococcal ACWY glycoconjugate vaccine (MenACWY-CRM)]. Immunogenicity was evaluated by serum bactericidal assay with human complement (hSBA) against three serogroup B test strains specific for individual vaccine antigens (fHbp, NadA or PorA P1.4), and by enzyme-linked immunosorbent assay (ELISA) against the NHBA antigen. Solicited reactions and adverse events (AEs) were assessed. RESULTS: One month post-second vaccination, 98%, 97%, and 97% of subjects in the 4CMenB group achieved hSBA titres ≥ 4 against the fHbp, NadA and PorA test strains, respectively, while percentages in the Control group were comparable to baseline (27%, 16%, and 17%, respectively). Geometric mean ELISA concentrations (GMCs) against NHBA increased 52-fold relative to baseline in the 4CMenB group, while there was no substantial increase in GMCs in the Control group (1.05-fold). Frequencies of solicited reactions after any vaccination were higher in the 4CMenB group than in the Control group, although most reactions were of short duration and mild to moderate intensity. There were no vaccine-related serious AEs. CONCLUSIONS: Two doses of 4CMenB induced robust immune responses against the vaccine antigens and were well tolerated, with no safety concerns identified, in Korean adolescents (NCT01973218).

Erratum: Revised Adult Immunization Guideline Recommended by the Korean Society of Infectious Diseases, 2014.

[This corrects the article on p. 68 in vol. 47, PMID: 25844267.].

Immunogenicity and safety assessment of a trivalent, inactivated split influenza vaccine in Korean children: Double-blind, randomized, active-controlled multicenter phase III clinical trial.

A multicenter, double-blind, randomized, active-control phase III clinical trial was performed to assess the immunogenicity and safety of a trivalent, inactivated split influenza vaccine. Korean children between the ages of 6 months and 18 y were enrolled and randomized into a study (study vaccine) or a control vaccine group (commercially available trivalent, inactivated split influenza vaccine) in a 5:1 ratio. Antibody responses were determined using hemagglutination inhibition assay, and post-vaccination immunogenicity was assessed based on seroconversion and seroprotection rates. For safety assessment, solicited local and systemic adverse events up to 28 d after vaccination and unsolicited adverse events up to 6 months after vaccination were evaluated. Immunogenicity was assessed in 337 and 68 children of the study and control groups. In the study vaccine group, seroconversion rates against influenza A/H1N1, A/H3N2, and B strains were 62.0% (95% CI: 56.8-67.2), 53.4% (95% CI: 48.1-58.7), and 54.9% (95% CI: 48.1-60.2), respectively. The corresponding seroprotection rates were 95.0% (95% CI: 92.6-97.3), 93.8% (95% CI: 91.2-96.4), and 95.3% (95% CI: 93.0-97.5). The lower 95% CI limits of the seroconversion and seroprotection rates were over 40% and 70%, respectively, against all strains. Seroconversion and seroprotection rates were not significantly different between the study and control vaccine groups. Furthermore, the frequencies of adverse events were not significantly different between the 2 vaccine groups, and no serious vaccination-related adverse events were noted. In conclusion, the study vaccine exhibited substantial immunogenicity and safety in Korean children and is expected to be clinically effective.

Safety and immunogenicity of a freeze-dried, Vero cell culture-derived, inactivated Japanese encephalitis vaccine (KD-287, ENCEVAC®) versus a mouse brain-derived inactivated Japanese encephalitis vaccine in children: a phase III, multicenter, double-blinded, randomized trial.

BACKGROUND: Although mouse brain-derived, inactivated Japanese encephalitis vaccines (JE-MBs) have been successfully used for a long time, potential rare neurological complications have prompted the development of a Vero cell culture-derived inactivated vaccine (JE-VC). In a phase III clinical study, we aimed to compare the safety and immunogenicity of a JE-VC, KD-287 with a JE-MB, JEV-GCC, in children. METHODS: In this multicenter, double-blinded, randomized controlled trial, the study population consisted of 205 healthy Korean children aged 12-23 months. Each subject was subcutaneously vaccinated with either KD-287 or JEV-GCC twice at an interval of 2 weeks and then vaccinated once 12 months after the second vaccination. Neutralizing antibodies were measured by the plaque reduction neutralization test using the homologous and heterologous, as a post hoc analysis, challenge virus strains. RESULTS: The three-dose regimen of KD-287 showed a comparable safety profile with JEV-GCC except higher incidence of fever after the first dose (30.4% and 14.7%, respectively). Most of the fever was mild degree (61.3% and 66.7%, respectively). KD-287 fulfilled the non-inferiority criteria for seroconversion rate (SCR) and geometric mean titer (GMT) of the neutralizing antibody, which were the primary endpoints, at 4 weeks after the third vaccination (95% CI: -1.00, 3.10 for the SCR difference and 10.8, 17.6 for the GMT ratio). The SCRs of KD-287 were all 100% and the GMTs were higher in the KD-287 group than in the JEV-GCC group after the second vaccination and before and after the third vaccination (GMT ratio: 5.59, 20.13, and 13.79, respectively, p < 0.001 in all). GMTs were higher in the KD-287 group in the heterologous analysis also (GMT ratio: 4.05, 5.15, and 4.19, respectively, p < 0.001 in all). CONCLUSIONS: This study suggests that the KD-287, a JE-VC is as safe as and may be more effective than the licensed MB-derived vaccine. KD-287 could thus be useful as a second-generation vaccine and substitute for the current JE-MB vaccine in Korean children. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01150942.