Evaluation of a Novel Immunochromatographic Assay Using Monoclonal Antibodies against the Matrix Protein of Human Metapneumovirus.

BACKGROUND: The aim of this study was to determine the sensitivity and specificity of a novel immunochromatographic (IC) assay (APD1806) using monoclonal antibodies against the matrix (M) protein of human metapneumovirus (hMPV) for detection of hMPV from nasopharyngeal swab samples based on the results of real-time RT-PCR. METHODS: Nasopharyngeal swab samples taken from 189 patients aged 0 - 5 years who were suspected of having respiratory tract infections associated with hMPV were used in this study. The samples were tested both by the IC assay and by real-time RT-PCR for detection of hMPV. RESULTS: The sensitivity and specificity of the IC assay for detection of hMPV were 88.8% (95/107) and 92.7% (76/82), respectively. CONCLUSIONS: The IC assay using monoclonal antibodies against the M protein of hMPV is an accurate and fast assay that is suitable as a diagnostic tool for hMPV infection. The optimal timing of the IC assay is 12 hours or more after the onset of fever due to hMPV infection.

P1 gene of Mycoplasma pneumoniae isolated from 2016 to 2019 and relationship between genotyping and macrolide resistance in Hokkaido, Japan.

We characterized 515 Mycoplasma pneumoniae specimens in Hokkaido. In 2013 and 2014, the p1 gene type 1 strain, mostly macrolide-resistant, was dominant and the prevalence of macrolide resistance was over 50 %. After 2017, the p1 gene type 2 lineage, mostly macrolide-sensitive, increased and the prevalence of macrolide resistance became 31.0 % in 2017, 5.3 % in 2018 and 16.3 % in 2019.

Evaluation of a Novel Immunochromatographic Assay for Detection of Human Adenoviruses from Throat Swab Samples Compared with Real-time PCR.

BACKGROUND: The aim of this study was to determine the sensitivity and specificity of a novel immunochromatographic assay (ICA) kit, ALSONIC® Adeno (Alfresa Pharma Co., Osaka, Japan), for the detection of human adenovirus (HAdV) from throat swab samples based on the results of real-time PCR. The incubation time required for the novel assay kit (5 minutes) is shorter than that required for other ICA kits that are available in Japan. METHODS: Throat swab samples were taken from 151 patients aged 6 months to 15 years who were suspected of having respiratory tract infections caused by HAdV. RESULTS: The sensitivity and specificity of the ICA for detection of HAdV were 92.2% (83/90) and 95.1% (58/61), respectively, and the assay showed positive and negative predictive values of 96.5% (83/86) and 89.2% (58/65), respectively. CONCLUSIONS: ALSONIC® Adeno is suitable as a diagnostic tool in the acute phase of HAdV infection.

A nationwide population-based surveillance of invasive Haemophilus influenzae diseases in children after the introduction of the Haemophilus influenzae type b vaccine in Japan.

BACKGROUND: Haemophilus influenzae type b (Hib) vaccine was introduced as a voluntary vaccine in December 2008 and was included in the national routine immunization program in April 2013 in Japan. Currently, no nationwide data are available to evaluate the effectiveness of Hib vaccine in Japan. METHODS: To evaluate the effectiveness of Hib vaccine in Japan, nationwide active population-based surveillance of culture-proven invasive infections caused by H. influenzae in children was performed in 2008-2017 in 10 prefectures in Japan (covering approximately 23% of the total Japanese population). Clinical data were recorded on a standardized case report form. Capsular type and antimicrobial susceptibility of the H. influenzae isolates were examined. The incidence rate ratio (IRR) and its confidence interval (CI) were calculated to compare data from 5 years before and that from after the introduction of the national routine Hib vaccine immunization program. RESULTS: During the 10-year study period, 566 invasive H. influenzae disease cases including 336 meningitis cases were identified. The average number of invasive H. influenzae disease cases among children <5 years of age during 2013-2017 decreased by 93% (IRR: 0.07, 95%CI 0.05-0.10, p < 0.001) compared with those occurring during 2008-2012. Hib strains have not been isolated from invasive H. influenzae disease cases since 2014; however, non-typeable H. influenzae and H. influenzae type f isolates have been noted as causes of invasive H. influenzae diseases among children <5 years in the post-Hib vaccine era. CONCLUSIONS: After the governmental subsidization of the Hib vaccine, invasive Hib disease cases decreased dramatically in the study population, as per our surveillance. Continuous surveillance is necessary to monitor the effectiveness of Hib vaccine and for detecting any emerging invasive capsular types.

Safety, tolerability and immunogenicity of intramuscular administration of PRP-CRM197 Hib vaccine to healthy Japanese children: An open-label trial.

BACKGROUND: Japan licensed the conjugate Haemophilus influenzae type b vaccine, Vaxem™ Hib, based on clinical studies using subcutaneous injection. The present study was performed to ensure this vaccine is suitable for intramuscular injection in Japanese children. METHODS: Thirty-one healthy 2-6-month-old infants received three doses of Vaxem™ Hib by intramuscular injection at 4-week intervals and a booster dose 1 year later, concomitant with routine infant (DTaP-IPV and pneumococcal) and toddler (measles-rubella) vaccines. Immunogenicity was assessed before and after the primary series and booster dose by enzyme-linked immunosorbent assay for anti-polyribosyl-ribitol-phosphate (PRP) antibodies. Safety was assessed by medical examination and diary cards completed by the subjects' parents/legal guardians. RESULTS: There were no vaccine-related serious adverse events or withdrawals; all children completed the study. Four weeks after the primary series, the geometric mean anti-PRP titer (GMT) was 19.68 µg/mL, and all children had seroprotective titers (≥0.15 µg/mL) that persisted until the booster dose. Proportions of titers indicative of long-term protection (≥1.0 µg/mL) were 100% after the primary series and 77.4% before the booster. Anamnestic responses to the booster had a GMT of 51.33 µg/mL, and 100% had titers ≥1.0 µg/mL. All but one subject reported injection site reactions as resolved within 3 days of vaccination; systemic reactions due to Hib and routine vaccines were also resolved within this period. CONCLUSIONS: Vaxem™ Hib was generally well tolerated and immunogenic in Japanese children when administered by intramuscular injection in a three-dose primary series and as a booster with concomitant routine vaccines. Clinical trial registry: Registered on Clinical Trials.gov: NCT02074345.

Clinical effectiveness of four neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir) for children with influenza A and B in the 2014-2015 to 2016-2017 influenza seasons in Japan.

The clinical effectiveness of four neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir, and peramivir) for children aged 0 months to 18 years with influenza A and B were investigated in the 2014-2015 to 2016-2017 influenza seasons in Japan. A total of 1207 patients (747 with influenza A and 460 with influenza B) were enrolled. The Cox proportional-hazards model using all of the patients showed that the duration of fever after administration of the first dose of the NAI was shorter in older patients (hazard ratio = 1.06 per 1 year of age, p < 0.001) and that the duration of fever after administration of the first dose of the NAI was shorter in patients with influenza A infection than in patients with influenza B infection (hazard ratio = 2.21, p < 0.001). A logistic regression model showed that the number of biphasic fever episodes was 2.99-times greater for influenza B-infected patients than for influenza A-infected patients (p < 0.001). The number of biphasic fever episodes in influenza A- or B-infected patients aged 0-4 years was 2.89-times greater than that in patients aged 10-18 years (p = 0.010), and the number of episodes in influenza A- or B-infected patients aged 5-9 years was 2.13-times greater than that in patients aged 10-18 years (p = 0.012).

Therapeutic efficacy of azithromycin, clarithromycin, minocycline and tosufloxacin against macrolide-resistant and macrolide-sensitive Mycoplasma pneumoniae pneumonia in pediatric patients.

OBJECTIVE: To clarify therapeutic effects of azithromycin, clarithromycin, minocycline and tosufloxacin against macrolide-resistant Mycoplasma pneumoniae (MRMP) pneumonia and against macrolide-sensitive Mycoplasma pneumoniae (MSMP) pneumonia in pediatric patients. METHODS: A prospective, multicenter observational study was conducted from July 2013 to August 2015. The therapeutic effects of azithromycin, clarithromycin, minocycline and tosufloxacin were evaluated in 59 patients with pneumonia caused by MRMP and in 50 patients with pneumonia caused by MSMP. In vitro activities of antimicrobial agents against isolates of Mycoplasma pneumoniae were also measured. RESULTS: Mean durations of fever following commencement of treatment in patients infected with MRMP and MSMP were 5.2 and 1.9 days, respectively (log-rank test, P < 0.0001). Among patients infected with MRMP, mean durations of fever were 4.6, 5.5, 1.0 and 7.5 days for patients treated with azithromycin, clarithromycin, minocycline and tosufloxacin, respectively (log-rank test, P < 0.0001). Among patients infected with MSMP, mean durations of fever were 2.5, 1.7, 0.9 and 4.3 days for patients treated with azithromycin, clarithromycin, minocycline and tosufloxacin, respectively (log-rank test, P = 0.0162). The MIC90s of azithromycin and clarithromycin among the 27 isolates of MRMP were 64 and 256 µg/ml, respectively, and those among the 23 isolates of MSMP were <0.000125 and 0.001 µg/ml, respectively. The MIC90s of minocycline and tosufloxacin among the 27 isolates of MRMP were 1.0 and 0.25 µg/ml, respectively, and those among the 23 isolates of MSMP were 1.0 and 0.5 µg/ml, respectively. CONCLUSION: Both minocycline and tosufloxacin showed good in vitro activities against MRMP. Minocycline, but not tosufloxacin, shortened the duration of fever in pediatric patients infected with MRMP compared to the duration of fever in patients treated with macrolides.

Immunogenicity and safety of a fully liquid aluminum phosphate adjuvanted Haemophilus influenzae type b PRP-CRM197-conjugate vaccine in healthy Japanese children: A phase III, randomized, observer-blind, multicenter, parallel-group study.

BACKGROUND: Broad use of monovalent Haemophilus influenzae type b (Hib) conjugate vaccines based on the capsular polysaccharide polyribosyl-ribitol phosphate (PRP), has significantly reduced invasive Hib disease burden in children worldwide, particularly in children aged <1year. In Japan, PRP conjugated to tetanus toxoid (PRP-T) vaccine has been widely used since the initiation of public funding programs followed by a routine vaccination designation in 2013. METHODS: We compared the immunogenicity and safety of PRP conjugated to a non-toxic diphtheria toxin mutant (PRP-CRM197) vaccine with the PRP-T vaccine when administered subcutaneously to healthy Japanese children in a phase III study. Additionally, we evaluated the immunogenicity and safety profiles of a diphtheria-tetanus acellular pertussis (DTaP) combination vaccine when concomitantly administered with either PRP-CRM197 or PRP-T vaccines. The primary endpoint was the "long-term seroprotection rate", defined as the group proportion with anti-PRP antibody titers ⩾1.0µg/mL, after the primary series. RESULTS: Long-term seroprotection rates were 99.3% in the PRP-CRM197 group and 95.6% in the PRP-T group. The intergroup difference (PRP-CRM197 group - PRP-T group) was 3.7% (95% confidence interval: 0.099-7.336), demonstrating that PRP-CRM197 vaccine was non-inferior to PRP-T vaccine (p<0.0001). Furthermore, the "short-term seroprotection rate" (anti-PRP antibody titer ⩾0.15µg/mL) before booster vaccination was higher in the PRP-CRM197 group than in PRP-T. Concomitant administration of PRP-CRM197 vaccine with DTaP vaccine showed no differences in terms of immunogenicity compared with concomitant vaccination with PRP-T vaccine and DTaP vaccine. Although CRM197 vaccine had higher local reactogenicity, overall, both Hib vaccines had acceptable safety and tolerability profiles. CONCLUSION: The immunogenicity of PRP-CRM197 vaccine administered subcutaneously as a three-dose primary series in children followed by a booster vaccination 1year after the primary series induced protective levels of Hib antibodies with no safety or tolerability concerns. CLINICAL TRIAL REGISTRY: Registered on ClinicalTrials.gov: NCT01379846.

Regional Differences in Prevalence of Macrolide Resistance among Pediatric Mycoplasma pneumoniae Infections in Hokkaido, Japan.

Recently, macrolide-resistant (MR) Mycoplasma pneumonia appeared, and prevalence of macrolide resistance among M. pneumoniae infections varies by country. However, reports on regional differences in the prevalence of MR M. pneumonia within a country are scarce. In this study, 617 nasopharyngeal swab samples were collected from 617 pediatric patients, and DNA of M. pneumoniae was identified in 95 samples. In 51 of the 95 M. pneumonia positive samples, we detected the presence of mutation A2063G mutation (conferring macrolide resistance) in the 23S rRNA gene. The overall macrolide resistance rate was 53.7%, but there were regional differences: 0.0% in Muroran, 5.3% in Asahikawa, 55.3% in Sapporo, and 100.0% in Kushiro. Statistically significant pairwise differences in the prevalence of MR M. pneumoniae were observed among these cities except for the pair of Muroran and Asahikawa. After exclusion (in order to avoid the influence of macrolides) of patients who were prescribed macrolides before collection of nasopharyngeal swab samples, statistically significant differences persisted: 0.0% in Muroran, 5.6% in Asahikawa, 38.5% in Sapporo, and 100.0% in Kushiro.

Nationwide population-based surveillance of invasive pneumococcal disease in Japanese children: Effects of the seven-valent pneumococcal conjugate vaccine.

BACKGROUND: In Japan, the seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2010. PCV13 has replaced PCV7 since November 2013. METHODS: The effectiveness of PCV7 in protecting against invasive pneumococcal disease (IPD) in children aged <5 years was evaluated in a nationwide active population-based surveillance of IPD in 2008-2013 in 10 prefectures in Japan. RESULTS: 1181 cases were identified; 711 pneumococcal strains were analyzed for serotyping and antimicrobial resistance. Compared with the baseline IPD incidence (25.0 per 100,000), a 98% decline in IPD caused by PCV7 serotypes was found after the introduction of PCV7. This was partially offset by an increased incidence of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes, resulting in a 57% decline in overall IPD incidence. Absolute increases in the incidence rates of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes were 2.1 and 2.8 per 100,000 during the study period, respectively. The proportion of meropenem-nonsusceptible strains, especially with serotypes 19A and 15A, increased significantly after PCV7 introduction. CONCLUSIONS: Our data confirmed a 98% decline in IPD incidence caused by PCV7 serotypes in children aged <5 years and serotype replacement after PCV7 introduction. This shows the importance of continuing surveillance of serotypes responsible for IPD and their antimicrobial resistance in Japan.

Sensitivity and Specificity of a Loop-Mediated Isothermal Amplification Assay for the Detection of Mycoplasma Pneumonia from Nasopharyngeal Swab Samples Compared with those of Real-time PCR.

BACKGROUND: The aim of this study was to determine the sensitivity and specificity of a loop-mediated isothermal amplification (LAMP) assay kit for the detection of Mycoplasma pneumonia (Eiken Chemical Co., Ltd, Tokyo, Japan) from nasopharyngeal swab samples compared with those of real-time PCR. METHODS: Nasopharyngeal swab samples taken from 223 patients aged 3 - 18 years who were suspected of having respiratory tract infections associated with Mycoplasma pneumonia were used in this study. The samples were tested both by the LAMP assay and by real-time PCR for detection of Mycoplasma pneumonia. RESULTS: The sensitivity and specificity of the LAMP assay for the detection of Mycoplasma pneumonia were 99.1% (105/106) and 100.0% (117/117), respectively. CONCLUSIONS: The LAMP assay for the detection of Mycoplasma pneumonia is an accurate and fast assay that is suitable as a diagnostic tool in the acute phase of Mycoplasma pneumonia infection.

Immunogenicity and Safety of a 13-Valent Pneumococcal Conjugate Vaccine Given With DTaP Vaccine in Healthy Infants in Japan.

BACKGROUND: 13-Valent pneumococcal conjugate vaccine (PCV13) provides broader protection against pneumococcal disease than 7-valent pneumococcal conjugate vaccine (PCV7). This study performed in Japan compared the safety and immunogenicity of PCV13 with PCV7. METHODS: Healthy Japanese infants received PCV13 and diphtheria, tetanus and acellular pertussis vaccine (DTaP), PCV7 and DTaP or DTaP alone subcutaneously as a 3-dose infant series, with a fourth dose at 12 months of age. Antigen-specific immunoglobulin G (IgG) serum concentrations and opsonophagocytic activity and DTaP antibodies were measured 1 month after doses 3 and 4. RESULTS: After 3 and 4 doses, the proportion of subjects in the PCV13 + DTaP group achieving IgG concentrations ≥0.35 µg/mL to the 7 serotypes common to PCV13 and PCV7 was noninferior to that of the PCV7 + DTaP group. IgG geometric mean concentrations (GMCs) in the PCV13 + DTaP group were lower than but noninferior to the PCV7 + DTaP group GMCs. For the 6 additional pneumococcal serotypes, the proportion of PCV13 + DTaP group responders achieving IgG concentrations ≥0.35 µg/mL and IgG GMCs (except serotype 3 after dose 4) was noninferior to the lowest PCV7 + DTaP group pneumococcal response in PCV7 recipients, and responses to the 6 additional antigens were significantly higher. The majority of the subjects achieved prespecified antibody levels to DTaP antigens. GMCs to DTaP antigens were comparable among groups, except filamentous hemagglutinin (numerically higher in the DTaP alone group after dose 4). CONCLUSIONS: PCV13 + DTaP was as immunogenic as PCV7 for the 7 common pneumococcal antigens and elicited significantly higher responses to the 6 additional antigens. DTaP responses were comparable across groups. PCV13 given with DTaP was safe and well tolerated.

Prevalence of human T-lymphotropic virus type 1 carriers among pregnant women in Hokkaido, Japan.

As there is a risk of MTCT of HTLV-1, the HSGP HTLV-1 MTCT was organized in 2011. To determine how many pregnant women are infected with HTLV-1 in Hokkaido, which is the northernmost and the second largest island in Japan with a population of 5,467,000 and 39,392 newborns in 2011, the HSGP HTLV-1 MTCT asked all facilities that may care for pregnant women in Hokkaido in July 2013 to provide information on the number of pregnant women who underwent screening for anti-HTLV-1 antibody using particle agglutination or chemiluminescent enzyme immunoassay, and the numbers of those with positive, equivocal, and negative test results in the screening and confirmation tests using western blotting or PCR methods in 2012, respectively. A total of 111 facilities participated in this study and provided information on 33,617 pregnant women who underwent screening in 2012, corresponding to approximately 85% of all pregnant women who gave birth in Hokkaido in 2012. Of 81 candidates for a confirmation test because of positive (n = 77) or equivocal (n = 4) results on screening, 63 (78%) underwent the confirmation test and, finally, 34 (0.1%) and 33,563 (99.8%) women were judged to be HTLV-1 carriers and non-carriers, respectively. It was concluded that the prevalence rate of HTLV-1 carriers was low, one per 1000 pregnant women in Hokkaido. Approximately 40 infants are born yearly to mothers infected with HTLV-1 in Hokkaido.

Phase III clinical trials comparing the immunogenicity and safety of the vero cell-derived Japanese encephalitis vaccine Encevac with those of mouse brain-derived vaccine by using the Beijing-1 strain.

The immunogenicity and safety of an inactivated cell culture Japanese encephalitis vaccine (CC-JEV) were compared with those of an inactivated mouse brain-derived Japanese encephalitis vaccine (MB-JEV) in phase III clinical multicenter trials conducted in children. The vaccines contain the same Japanese encephalitis virus strain, the Beijing-1 strain. Two independent clinical trials (trials 1 and 2) were conducted. Trial 1 was conducted in 468 healthy children. Each subject was injected with 17 µg per dose of either CC-JEV or MB-JEV, and the immunogenicity and safety of the vaccines were investigated. Trial 1 showed that CC-JEV was more immunogenic and reactive than MB-JEV at the same dose. Therefore, to adjust the immunogenicity of CC-JEV to that of MB-JEV, a vaccine that has had a good track record regarding its efficacy for a long time, trial 2 was conducted in 484 healthy children. To improve the stability, CC-JEV was converted from a liquid type to a freeze-dried type of vaccine. Each subject was injected subcutaneously with either 4 µg per dose of CC-JEV, 8 µg per dose of CC-JEV, or 17 µg per dose of MB-JEV twice, at an interval of 2 to 4 weeks, followed by an additional booster immunization 1 to 15 months after the primary immunization. Based on the results of trial 2, 4 µg per dose of the freeze-dried CC-JEV (under the label Encevac) was selected as a substitute for the MB-JEV. Encevac was approved and launched in 2011 and has since been in use as a 2nd-generation Japanese encephalitis vaccine in Japan. (These studies have been registered at the JapicCTI under registration no. JapicCTI-132063 and JapicCTI-080586 for trials 1 and 2, respectively).

Comparison of the clinical effectiveness of zanamivir and laninamivir octanoate for children with influenza A(H3N2) and B in the 2011-2012 season.

OBJECTIVES: To evaluate the clinical effectiveness of the two inhaled neuraminidase inhibitors (NAIs), zanamivir (ZN) and laninamivir octate (LO), for influenza A(H3N2) and B virus infections. DESIGN: A prospective, multicenter observational study was conducted from January to April in 2012. SETTING: Outpatients aged 5-18 years who had a temperature of 37.5°C or higher and were diagnosed as having influenza based on an immunochromatographic assay were enrolled. SAMPLE: A total of 338 patients treated with ZN and 314 patients treated with LO were compared. MAIN OUTCOME MEASURES: The duration of fever after administration of the first dose of each NAI was evaluated as a primary endpoint. The secondary endpoint was episodes of biphasic fever. RESULTS: No statistically significant difference in the duration of fever was found between the ZN and LO groups (log-rank test, P = 0.117). A logistic regression model showed that episodes of biphasic fever increased by 1.19 times for every decrease of 1 year of age (P = 0.016) and that the number of biphasic fever episodes in patients treated with LO was 5.80-times greater than that in patients treated with ZN (P < 0.001). CONCLUSIONS: Although the duration of fever in the LO group was comparable to that in the ZN group, episodes of biphasic fever were more frequent in younger children and in the LO group than in the ZN group.

Population-based incidence of invasive haemophilus influenzae and pneumococcal diseases before the introduction of vaccines in Japan.

Before the introduction of vaccines, the incidence of bacterial meningitis among children aged 28 days to 5 years was 8.48, Haemophilus influenzae type-b meningitis was 5.65 and Streptococcus pneumoniae meningitis was 1.85 per 100,000 person-years in Hokkaido, Japan. The incidence of bacteremia caused by S. pneumoniae was 60.15 and H. influenzae was 18.80.

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in healthy infants in Japan.

BACKGROUND: A 13-valent pneumococcal conjugate vaccine (PCV13) containing 6 additional serotypes not included in the 7-valent PCV has been developed to broaden protection against Streptococcus pneumoniae, which is responsible for over 500,000 deaths annually worldwide in children <5 years of age. This study in Japanese infants evaluated the immunogenicity and safety of PCV13 given subcutaneously, the standard route for infant vaccination in Japan. METHODS: This phase 3, single-arm, open-label study was conducted at 25 sites. Subjects received PCV13 as a 3-dose infant series and a toddler dose. Parents/legal guardians recorded local reactions and systemic events after each vaccination. The proportion of subjects with serotype-specific antipneumococcal polysaccharide immunoglobulin (Ig)G antibody concentrations ≥0.35 µg/mL was calculated before and 1 month after the infant series and toddler dose. RESULTS: A total of 193 subjects enrolled. The proportion of subjects achieving pneumococcal IgG antibody concentrations ≥0.35 µg/mL was ≥97.2% for all 13 pneumococcal serotypes 1 month after the infant series and 98.9-100% after the toddler dose. IgG geometric mean concentrations were 2.57-14.69 µg/mL after the infant series and 2.06-16.33 µg/mL after the toddler dose. IgG geometric mean concentrations increased from pre- to posttoddler dose by ≥2.8-fold, demonstrating a booster effect. Local reactions and fever were generally mild or moderate in severity. CONCLUSIONS: PCV13 was immunogenic for all serotypes and had a favorable safety profile when administered subcutaneously to Japanese infants. PCV13 should offer broader serotype protection than 7-valent PCV in preventing pneumococcal disease in Japanese children.

My continuing efforts toward the eradication of the vaccine-preventable diseases from Japan.

When compared to the Western countries, unfortunately, the progress toward the eradication of vaccine-preventable diseases in Japan has been relatively slow and hampered by some problems inherent to Japan. Concerning this, I have been working on the vaccine-preventable diseases, that is, measles, influenza, Haemophilus influenzae, and Streptcoccus pneumoniae infections. My first work was to produce monoclonal antibodies against measles virus proteins, and by using these antibodies, I established the immunofluorescent measles virus detection system in tissue samples. I constructed the 'Hokkaido measles-zero strategy' to eliminate measles from Hokkaido prefecture, the northernmost island of Japan, within 5 years since 2001 with very kind efforts of pediatricians in Hokkaido and those who are engaged in political activities. Coworkers and I established the disease entity of influenza-associated encephalopathy. And finally, I worked as a member of some groups that accumulated the basic data on the occurrence of bacterial meningitis in Japan and urged the government to introduce the H. influenzae type b conjugate vaccine and the pediatric 7-valent pneumococcal conjugate vaccine in Japan. I would like to express many thanks to all of my colleagues for their contributions to these achievements.

[Heptavalent pneumococcal conjugate vaccine immunogenicity and safety in Japanese infants: primary and booster immunization results].

A phase II clinical trial designed as a multicenter open study with 30 participating institutions in Japan was conducted in 167 of 181 infants aged 2 to 6 months to evaluate heptavalent pneumococcal conjugate vaccine (7vPnCV) immunogenicity and safety. From September 22, 2004, to September 16, 2006, of 181 infants registered 167 meeting inclusion criteria were include in the immunogenicity analysis. Among the subjects include in the immunogenicity analysis after primary immunization (3 doses), the percentage with IgG antibody levels of at least 0.5 g/mL--a primary endpoint of this study--was 94.6% or higher. In the same cohort after the booster immunization (dose 4), the percentage was 96.0% or higher. Serious adverse event whose causal relationship to 7vPnCV vaccination could not be ruled out were fever of 38 degrees C and urticaria in 1 each subject, in whom the study was thus discontinued prematurely. Major adverse systemic postvaccination events were fever, irritability and somnolence. Major local adverse events were redness, swelling or induration, and pain. All adverse events were transient and recovered spontaneously. The vaccine's immunogenicity and safety profile are therefore favorable following primary and booster immunization and compatible with those reported in overseas studies. 7vPnCV is expected to show the safety and efficacy similar to that in other countries and to reduce pneumococcal disease in Japan.

[Epidemiological survey of pneumococcus serotypes in pediatric patients with acute suppurative otitis media].

To determine the distribution of Streptococcus pneumoniae serotypes isolated from patients under 6 years of age with acute suppurative otitis media, to calculate the serotype coverage of 7-valent pneumococcal conjugate vaccine, and to clarify trends in PCG-resistant Streptococcus pneumoniae, we conducted a one-year prospective study from April 2005 to March 2006 at 10 medical institutions in Hokkaido, Miyagi, Chiba, Tokyo, Kanagawa, and Mie, Japan. Specimens collected by tympanotomy or myringotomy numbered 856, and 691 strains were isolated from 599 specimens. Of these, 219 isolates (31.7%) were identified as Streptococcus pneumoniae and 201 met study requirements. The most common serotype was 19F (52 isolates, 25.9%), followed by 6B (30 isolates, 14.9%) and 23F (24 isolates, 11.9%). Seven-valent vaccine serotype coverage was 62.7%. The percentage of PSSP was 40.3%, PISP 42.8%, and PRSP 16.9%, resistant strains (PISP and PRSP) combined accounted for 59.7%. Seven-valent vaccine serotype coverage for PISP was 80.2% and PRSP 82.4%. PBP gene mutation was observed in 175 isolates (87.1%), including 70 of gPISP (34.8%) and 105 of gPRSP (52.2%). Gene mutation induced by macrolides was found in 176 isolates (87.6%).