Twenty-Five Year Trend Change in the Etiology of Pediatric Invasive Bacterial Infections in Korea, 1996-2020.

BACKGROUND: The coronavirus disease-2019 (COVID-19) pandemic has contributed to the change in the epidemiology of many infectious diseases. This study aimed to establish the pre-pandemic epidemiology of pediatric invasive bacterial infection (IBI). METHODS: A retrospective multicenter-based surveillance for pediatric IBIs has been maintained from 1996 to 2020 in Korea. IBIs caused by eight bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pyogenes, Listeria monocytogenes, and Salmonella species) in immunocompetent children > 3 months of age were collected at 29 centers. The annual trend in the proportion of IBIs by each pathogen was analyzed. RESULTS: A total of 2,195 episodes were identified during the 25-year period between 1996 and 2020. S. pneumoniae (42.4%), S. aureus (22.1%), and Salmonella species (21.0%) were common in children 3 to 59 months of age. In children ≥ 5 years of age, S. aureus (58.1%), followed by Salmonella species (14.8%) and S. pneumoniae (12.2%) were common. Excluding the year 2020, there was a trend toward a decrease in the relative proportions of S. pneumoniae (rs = -0.430, P = 0.036), H. influenzae (rs = -0.922, P < 0.001), while trend toward an increase in the relative proportion of S. aureus (rs = 0.850, P < 0.001), S. agalactiae (rs = 0.615, P = 0.001), and S. pyogenes (rs = 0.554, P = 0.005). CONCLUSION: In the proportion of IBIs over a 24-year period between 1996 and 2019, we observed a decreasing trend for S. pneumoniae and H. influenzae and an increasing trend for S. aureus, S. agalactiae, and S. pyogenes in children > 3 months of age. These findings can be used as the baseline data to navigate the trend in the epidemiology of pediatric IBI in the post COVID-19 era.

The Prevalence of Symptomatic Congenital Cytomegalovirus Disease in Korea; A 15-Year Multicenter Study and Analysis of Big Data From National Health Insurance System.

The birth prevalence of symptomatic congenital cytomegalovirus (cCMV) disease among live birth in Korea from a multicenter study was 0.06% during 2001-2015 with increasing frequency. The administrative prevalence of cCMV infection by big-data analysis from the national health insurance system was 0.01% and the average healthcare cost was US$2010 per person.

Changes in Etiology of Invasive Bacterial Infections in Infants Under 3 Months of Age in Korea, 2006-2020.

OBJECTIVES: Invasive bacterial infection (IBI) causes a significant burden in infants. In this study, we analyzed changes in epidemiology of IBI among infants in Korea. METHODS: A retrospective multicenter-based surveillance for IBIs in infants <3 months of age was performed during 2006-2020. Cases were classified as an early-onset disease (EOD) (0-6 days) or late-onset disease (LOD) (7-89 days). The temporal trend change in proportion of pathogens was analyzed. RESULTS: Among 1545 cases, the median age was 28 days (IQR: 12, 53) and EOD accounted for 17.7%. Among pathogens, S. agalactiae (40.4%), E. coli (38.5%), and S. aureus (17.8%) were the most common and attributed for 96.7%. Among EOD (n = 274), S. agalactiae (45.6%), S. aureus (31.4%), E. coli (17.2%) and L. monocytogenes (2.9%) were most common. Among LOD (n = 1274), E. coli (43.1%), S. agalactiae (39.3%), S. aureus (14.9%) and S. pneumoniae (1.3%) were most common. In the trend analysis, the proportion of S. aureus (r s = -0.850, P < 0.01) decreased significantly, while that of S. agalactiae increased (r s = 0.781, P < 0.01). CONCLUSION: During 2006-2020, among IBI in infants <3 months of age, S. agalactiae, E. coli, and S. aureus were most common and an increasing trend of S. agalactiae was observed.

Differential Impact of Nonpharmaceutical Interventions on the Epidemiology of Invasive Bacterial Infections in Children During the Coronavirus Disease 2019 Pandemic.

BACKGROUND: Invasive bacterial infection (IBI) remains a major burden of mortality and morbidity in children. As coronavirus disease 2019 (COVID-19) emerged, stringent nonpharmaceutical interventions (NPIs) were applied worldwide. This study aimed to evaluate the impact of NPIs on pediatric IBI in Korea. METHODS: From January 2018 to December 2020, surveillance for pediatric IBIs caused by 9 pathogens (S. pneumoniae, H. influenzae, N. meningitidis, S. agalactiae, S. pyogenes, S. aureus, Salmonella species, L. monocytogenes and E. coli) was performed at 22 hospitals throughout Korea. Annual incidence rates were compared before and after the COVID-19 pandemic. RESULTS: A total of 651 cases were identified and the annual incidence was 194.0 cases per 100,000 in-patients in 2018, 170.0 in 2019 and 172.4 in 2020. Most common pathogen by age group was S. agalactiae in infants < 3 months (n = 129, 46.7%), S. aureus in 3 to < 24 months (n = 35, 37.2%), Salmonella spp. in 24 to < 60 months (n = 24, 34.8%) and S. aureus in children ≥ 5 years (n = 128, 60.7%). Compared with 2018 to 2019, the incidence rate in 2020 decreased by 57% for invasive pneumococcal disease (26.6 vs. 11.5 per 100,000 in-patients, P = 0.014) and 59% for Salmonella spp. infection (22.8 vs. 9.4 per 100,000 in-patients, P = 0.018). In contrast, no significant changes were observed in invasive infections due to S. aureus, S. agalactiae and E. coli. CONCLUSIONS: The NPIs implemented during the COVID-19 pandemic reduced invasive diseases caused by S. pneumoniae and Salmonella spp. but not S. aureus, S. agalactiae and E. coli in children.

Immunogenicity and Safety of a Newly Developed Tetanus-Diphtheria Toxoid (Td) in Healthy Korean Adolescents: a Multi-center, Randomized, Double-blind, Active-Controlled Phase 3 Trial.

BACKGROUND: Although the combination tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) is recommended at adolescence in developed countries, the tetanus and diphtheria toxoid vaccine (Td), which is less costly, is recommended instead in some parts of the world. A new Td, BR-TD-1001, was developed by a Korean manufacturer for distribution to endemic regions and for use in the initial step of novel Tdap development. METHODS: This phase 3, randomized, double-blind, multi-center trial, conducted in Korea, aimed to evaluate the immunogenicity and safety of BR-TD-1001. Healthy children aged 10 to 12 years were randomized 1:1 to receive either BR-TD-1001 or the control Td (Td-pur, GlaxoSmithKline). Antibodies were measured using enzyme-linked immunosorbent assay. RESULTS: A total of 218 subjects (BR-TD-1001, n = 108; control, n = 110) were enrolled and included in the safety analysis. Vaccine-mediated antibody responses were similar in both groups. We confirmed the non-inferiority of BR-TD-1001 against the control, Td; 100% of both groups achieved seroprotection against diphtheria and tetanus. Furthermore, there was no significant difference between groups in the proportion of participants who demonstrated boost responses against diphtheria and tetanus toxoids. The incidence of solicited local and systemic adverse events (AEs), unsolicited AEs, and serious AEs did not differ significantly between groups. CONCLUSION: The BR-TD-1001 satisfied the immunological non-inferiority criterion against diphtheria and tetanus, with a clinically acceptable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04618939.

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.

Active-controlled phase III study of an egg-cultivated quadrivalent inactivated split-virion influenza vaccine (GC3110A) in healthy Korean children aged 6-35 months.

The inactivated trivalent influenza vaccine (TIV) offers limited protection when two influenza B lineages co-circulate or when there is a vaccine mismatch (i.e., discordance in the predominant circulating B strain and WHO-recommended B strain). Inactivated quadrivalent influenza vaccine (QIV) may reduce the burden of influenza. Here, we report the results of a phase 3 clinical trial that evaluated the immunogenicity and safety of a novel QIV, GC3110A, in Korean children aged 6-35 months, which has been approved and is currently in use in Korea. The study involved two parts. In Part 1, the safety of GC3110A was evaluated in 10 subjects. After none of the subjects reported grade 3 adverse events (AEs), we proceeded to Part 2. Part 2 was a randomized, double-blind, multicenter phase 3 trial wherein we compared the immunogenicity and safety of GC3110A with those of a licensed control TIV. Immunogenicity was evaluated by measuring hemagglutination inhibition titers. The 200 participants enrolled in Part 2 were randomized in a 4:1 ratio to receive GC3110A or control TIV. The study vaccine group met both primary (i.e., the lower limit of 95% confidence interval [CI] of the seroconversion rate exceeds 40% for four strains) and secondary (i.e., the lower limit of 95% CI of the seroprotection rate exceeds 70% for four strains) immunogenicity endpoints. There was no significant between-group difference in the seroconversion rate, seroprotection rate, and geometric mean titer for the shared strains. However, the study vaccine group demonstrated significantly higher immunity for the additional strain B/Yamagata. In the safety analysis, there was no significant between-group difference in the proportion of participants with solicited local AEs, solicited systemic AEs, and unsolicited AEs. In conclusion, the results indicate that GC3110A has comparable immunogenicity and safety to those of TIV. Clinical Trial Registry Number: NCT03285997.

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.

Immunogenicity and safety profiles of a new MAV/06 strain varicella vaccine in healthy children: A multinational, multicenter, randomized, double-blinded, active-controlled phase III study.

Immunization is the most effective preventive strategy against varicella. While the Oka strain is commonly used for varicella vaccination worldwide, Korea widely uses the MAV/06 strain. A new live attenuated MAV/06 strain varicella vaccine (MG1111), which uses the new cell line Medical Research Council-5 for better viral propagation, was developed. MG1111 was approved by Korean health authorities. Here, we report the results of phase III, randomized, double-blind, multicenter study conducted in Korea and Thailand, which compared the immunogenicity and safety profiles of MG1111 versus the control vaccine, VarivaxTM. In total, 515 healthy children (12 month-12 years) were randomized 1:1 to receive either the MG1111 or control vaccine (MG1111: 258, Control: 257). The seroconversion rate (SCR) and geometric mean titer (GMT) were measured using the fluorescent antibody to membrane antigen (FAMA) test. The MG1111 group achieved a SCR of 97.9% (95% CI: 95.2-99.3) after vaccination. The lower limit of 95% CI for SCR difference (MG1111-VarivaxTM) was -4.0%, which was higher than the specified non-inferiority margin of -10%. Further, the GMT of the MG1111 increased from 2.0 to 74.2 (95% CI: 65.0-84.8) and the lower limits of the 95% CI for post-vaccination GMT ratios (MG1111/VarivaxTM) were 0.55 higher than the specified parameter of 0.5. Therefore, the MG1111 group was not statistically inferior to the control vaccine group in terms of SCR and GMT. Furthermore, the MG1111 and control vaccine groups were not significantly different in the percentage of participants showing adverse events-solicited, local, or systemic during 43-day period of observation and serious adverse events during 6 month of observation. The present results indicate that MG1111was not immunologically inferior to VarivaxTM, and safety profiles of MG1111 are similar to those of VarivaxTM.

A longitudinal hospital-based epidemiology study to assess acute otitis media incidence and nasopharyngeal carriage in Korean children up to 24 months.

This study was conducted to assess the nasopharyngeal (NP) carriage and acute otitis media (AOM) occurrence in Korean children who received pneumococcal conjugate vaccines (PCVs). The longitudinal study was conducted through four consecutive visits. At each visit, NP aspirates were obtained and subjects were asked to visit if AOM occurred. A total of 305 subjects were enrolled and received PCV13 (n = 182) or PCV10 (n = 123). In the PCV13 group, the NP carriage of Streptococcus pneumoniae at each visit was 2.7%, 14.8%, 18.7%, and 15.9%, respectively. Non-typeable Haemophilus influenzae (NTHi) was 3.3%, 2.7%, 2.7%, and 5.5%, and that of Moraxella catarrhalis was 1.1%, 9.3%, 4.9%, and 0.5%. In the PCV10 group, the NP carriage of S. pneumoniae at each visit was 3.3%, 7.3%, 6.5%, and 4.1%, respectively. That of NTHi was 2.4%, 4.1%, 1.6%, and 0.8%, and that of M. catarrhalis was 4.1%, 0.8%, 0.8%, and 0.0%. AOM occurrence in the PCV13 group observed after the primary dose and before booster dose was 20.9%, occurrence after booster dose was 11.0%, and the incidence of two or more AOM was 11.0%. In the PCV10 group, AOM occurrence was 9.8%, 7.3%, respectively, and the incidence of two or more AOM was 2.4%. The predominant S. pneumoniae isolated were non-vaccine type (10A, 15A, and 15B). In this study, AOM occurrence was lower in the PCV10 group than in the PCV13 group. This seems to be related to ecological changes that lead to differences in NP carriage, especially S. pneumoniae and NTHi.

Socioeconomic Impact of the Rotavirus Vaccine in Korea: Comparing the Epidemiologic and Economic Characteristics of Rotavirus Gastroenteritis Before and After the Introduction of Vaccines.

BACKGROUND: Since the introduction of 2 rotavirus (RV) vaccines in Korea, the vaccination rate has reached over 80% with out-of-pocket spending in the private market. We investigated the socioeconomic impact of RV vaccines in Korea to assess their value and public health contribution. METHODS: By using National Health Insurance Service claims data, we compared the epidemiologic and economic characteristics of rotavirus gastroenteritis (RVGE) before and after the introduction of RV vaccines. For each year of the study period, the annual prevalence and national costs of RVGE were estimated based on children under 5 years with at least 1 National Health Insurance Service claims record with a diagnosis of RVGE. RESULTS: Compared with the prevaccination period, the prevalence of RVGE decreased in the postvaccination period by 48.9% from 2097 per 100,000 children in 2006 to 1072 per 100,000 children in 2015, implying an increase in the vaccination rate and the prevention effect of the vaccines. The highest reduction was observed among those 12 to <24 months of age (-73.4%), presumably due to the benefit of full vaccination, while children under 2 months, ineligible for the RV vaccine, showed an increase (41.7%). The number of hospitalized RVGE cases per year decreased by 69.0%. The national economic burden of RVGE decreased by 28.6%. CONCLUSIONS: The substantial reduction in the socioeconomic burden of RVGE after the introduction of RV vaccines confirms their benefit to society. This study would help health policy makers make empirical decisions on incorporating the vaccination into national immunization programs.

Evaluation of Waning Immunity at 6 Months after Both Trivalent and Quadrivalent Influenza Vaccination in Korean Children Aged 6-35 Months.

BACKGROUND: The titer of influenza vaccine-induced antibodies declines over time, and younger children have lower immunogenicity and shorter duration of immunity. This study aimed to compare persistence of antibody at 6 months after influenza vaccination according to influenza virus strains, vaccine type, antigen dose, and primed status in children aged 6 to 35 months. METHODS: A total 124 healthy children aged 6 to 35 months were enrolled from September to December 2016 at 10 hospitals in Korea and randomly assigned to either a full dose of quadrivalent influenza vaccine or a half dose of trivalent influenza vaccine with Victoria B strain group. Hemagglutination inhibition antibody titers (that measure the seroprotection rates) were assessed for the recommended influenza strains at 6 months post vaccination. RESULTS: The seroprotection rates at 6 months for strains A (H1N1), A (H3N2), B/Yamagata, and B/Victoria were 88.7%, 97.4%, 36.6%, and 27.6%, respectively. The seroprotection rates for A (H1N1), A (H3N2) and B (Victoria) were 91.4%, 98.7% and 27.5% in a full dose of quadrivalent vaccine vs. 83.7%, 94.6% and 27.9% in a half dose trivalent vaccine, respectively. The seroprotection rate for the B (Yamagata) strain was 23.8% in the quadrivalent group and 14.0% in the trivalent group. CONCLUSION: Persistence of antibodies at 6 months was more favorable against the influenza A strains than against the B strains. Persistence of antibodies to additional B strain at 6 months was superior in the quadrivalent vaccine group. The immunity of primed children with different B strains was not superior to that of the unprimed group with another B strain.

Cost-effectiveness analysis of the implementation of a National Immunization Program for rotavirus vaccination in a country with a low rotavirus gastroenteritis-related mortality: A South Korean study.

Rotavirus is a leading cause of severe gastroenteritis among children younger than 5 years in South Korea. Two rotavirus vaccines (RVs), pentavalent human-bovine reassortant vaccine (Rotateq®; RV5) and attenuated human strain originated monovalent vaccine (Rotarix®; RV1), have been available for voluntary vaccination using out-of-pocket payment since 2007 and 2008, respectively. Yet, RVs are not included in the National Immunization Program (NIP), partly because of the low associated mortality rate. We assessed the cost-effectiveness of RVs to assist the evidence-based decision-making process for NIP implementation in South Korea. Using a transparent age-structured static cohort model, we simulated the experience of ten annual birth cohorts of South Korean children from 2018 to 2027. Model inputs included rotavirus gastroenteritis (RVGE) incidence and mortality rates, RVGE treatment costs, vaccine coverage and timeliness, and vaccine effectiveness and price. The incremental costs of including RVs in the NIP compared to no vaccination were 59,662,738 USD and 152,444,379 USD for RV1 and RV5, respectively. The introduction of RV1 and RV5 can prevent 4799 disability-adjusted life years (DALYs) and 5068 DALYs. From the societal perspective, the incremental cost-effectiveness ratios (ICERs) for adopting RV into the NIP versus no vaccination were 12,432 USD per DALY averted for RV1 and 30,081 USD per DALY averted for RV 5. The weighted average for the ICERs of the two vaccines computed using the market share of each vaccine in the current voluntary use as a weight, was 21,698 USD per DALY averted. The estimated ICER was below 1 × gross domestic product per capita (30,000 USD), which has been a commonly used willingness-to-pay threshold for health care technology assessment in South Korea, suggesting that introducing RVs into the NIP would be cost-effective.

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.

Risk Factor Analysis for Secondary Malignancy in Dexrazoxane-Treated Pediatric Cancer Patients.

PURPOSE: Dexrazoxane has been used as an effective cardioprotector against anthracycline cardiotoxicity. This study intended to analyze cardioprotective efficacy and secondary malignancy development, and elucidate risk factors for secondary malignancies in dexrazoxane-treated pediatric patients. MATERIALS AND METHODS: Data was collected from 15 hospitals in Korea. Patients who received any anthracyclines, and completed treatment without stem cell transplantation were included. For efficacy evaluation, the incidence of cardiac events and cardiac event-free survival rates were compared. Data about risk factors of secondary malignancies were collected. RESULTS: Data of total 1,453 cases were analyzed; dexrazoxane with every anthracyclines group (D group, 1,035 patients) and no dexrazoxane group (non-D group, 418 patients). Incidence of the reported cardiac events was not statistically different between two groups; however, the cardiac event-free survival rate of patients with more than 400 mg/m2 of anthracyclines was significantly higher in D group (91.2% vs. 80.1%, p=0.04). The 6-year cumulative incidence of secondary malignancy was not different between both groups after considering follow-up duration difference (non-D, 0.52%±0.37%; D, 0.60%±0.28%; p=0.55). The most influential risk factor for secondary malignancy was the duration of anthracycline administration according to multivariate analysis. CONCLUSION: Dexrazoxane had an efficacy in lowering cardiac event-free survival rates in patients with higher cumulative anthracyclines. As a result of multivariate analysis for assessing risk factors of secondary malignancy, the occurrence of secondary malignancy was not related to dexrazoxane administration.

Immunogenicity and safety of a combined DTPa-IPV/Hib vaccine administered as a three-dose primary vaccination course in healthy Korean infants: phase III, randomized study.

We assessed the immunogenicity and safety of a three-dose primary vaccination schedule with the combined diphtheria-tetanus-acellular pertussis-inactivated poliovirus/Haemophilus influenzae type b vaccine (DTPa-IPV/Hib) in Korean infants. In this phase III open-label, multicenter study (NCT01309646), healthy infants aged 42-69 days (randomized 1:1) received three doses of either pentavalent DTPa-IPV/Hib (DTPa-IPV/Hib group) or DTPa-IPV and Hib vaccines administered separately (DTPa-IPV+Hib group) at 2, 4, 6 months of age. The primary objective was to demonstrate non-inferiority of DTPa-IPV/Hib compared to DTPa-IPV+Hib vaccines in terms of immune responses to all vaccine antigens, 1 month post-dose 3. Solicited symptoms (local and general) were recorded during 4 days, and unsolicited adverse events (AEs) during 31 days, after each vaccination. Serious AEs (SAEs) were recorded throughout the study duration. The immunogenicity of the pentavalent DTPa-IPV/Hib vaccine was non-inferior compared to concomitant administration of DTPa-IPV+Hib vaccines. One month post-dose 3, nearly all infants had antibody levels above the seroprotective thresholds for anti-diphtheria toxoid, anti-tetanus toxoid, anti-polyribosyl-ribitol phosphate, and anti-poliovirus type 1, 2 and 3, and had antibody levels above the seropositive thresholds for anti-pertussis toxoid (PT), anti-filamentous hemagglutinin (FHA) and anti-pertactin (PRN) antibodies. A vaccine response for PT, FHA and PRN was observed in at least 96.7% of study participants. Anti-PRP geometric mean concentrations appeared lower for the DTPa-IPV/Hib group (8.456 µg/mL) than for the DTPa-IPV+Hib group (18.700 µg/mL). In both groups, the most common solicited symptoms were injection site redness and irritability. Fifty-seven SAEs were reported throughout the study; none were considered to be vaccination related.

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.

The antipyretic efficacy and safety of propacetamol compared with dexibuprofen in febrile children: a multicenter, randomized, double-blind, comparative, phase 3 clinical trial.

BACKGROUND: We aimed to compare the antipyretic efficacy, safety, and tolerability between oral dexibuprofen and intravenous propacetamol in children with upper respiratory tract infection (URTI) presenting with fever. METHODS: Patients aging from 6 months to 14 years admitted for URTI with axillary body temperature ≥ 38.0 °C were enrolled and randomized into the study or control group. Patients in the study group were intravenously infused with propacetamol and subsequently oral placebo medication was administered. Patients in the control group were intravenously infused with 100 mL of 0.9% sodium chloride solution without propacetamol and then oral dexibuprofen was administered. We checked the body temperature of all patients at 0.5 h (hr), 1 h, 1.5 h, 2 h, 3 h, 4 h, and 6 h after oral placebo or dexibuprofen had been applied. RESULTS: A total of 263 patients (125 in the study group) were finally enrolled. The body temperatures of patients in the study group were significantly lower until 2 h after administration (37.73 ± 0.58 vs 38.36 ± 0.69 °C (p < 0.001), 37.37 ± 0.53 vs 37.88 ± 0.69 °C (p < 0.001), 37.27 ± 0.60 vs 37.62 ± 0.66 °C (p < 0.001), 37.25 ± 0.62 vs 37.40 ± 0.60 °C (p = 0.0452), at 0.5 h, 1 h, 1.5 h, and 2 h, respectively). The two groups showed no significant differences in terms of the range of body temperature decrease, the Area Under the Curve of body temperature change for antipyretic administration-and-time relationship, the maximum value of body temperature decrease during the 6 h test period, the number of patients whose body temperature normalized (< 37.0 °C), the mean time when first normalization of body temperature, and the development of adverse events including gastrointestinal problem, elevated liver enzyme, and thrombocytopenia. CONCLUSIONS: Intravenous propacetamol may be a safe and effective choice for pediatric URTI patients presenting with fever who are not able to take oral medications or need faster fever control. TRIAL REGISTRATION: CRIS KCT0002888 . Date of registration: July 31st, 2013.

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.