Reactogenicity and immunogenicity of measles-rubella combined vaccine in school-entry-aged subjects with naturally acquired measles immunity.

BACKGROUND: The reintroduction of measles-rubella combined (MR) vaccination to Japan raised concerns about adverse events as well as immunogenicity related to booster immunization in subjects with naturally acquired immunity to measles or rubella. METHODS: The time course of reactogenicity and antibody responses in recipients with pre-existing immunity to measles through natural infection was observed. Eighteen children aged 80-104 months received MR booster vaccination; 16 of them had had previous rubella vaccination. RESULTS: There were virtually no clinical reactions related to booster vaccination, and a highly significant antibody response to rubella antigen, whereas the antibody rise to measles was statistically significant but poor. CONCLUSIONS: Vaccination of individuals already immune is not harmful. Booster immunization to rubella for Japanese children is vitally important.

Characteristics of group B Streptococcus isolated from infants with invasive infections: a population-based study in Japan.

Group B Streptococcus (GBS) is one of the leading causes of neonatal bacterial infections. Population-based surveillance of GBS-related invasive diseases among newborns and infants from 10 prefectures in Japan was performed between 2007 and 2012. The characteristics of cases and isolated GBS are described in this study. The incidence rate of GBS-related invasive diseases was 0.13 per 1,000 live births. Analysis of GBS samples obtained from 60 invasive cases showed that the most frequent serotypes were III (48.3%), Ia (30.0%), and Ib (10.0%). All isolates were susceptible to penicillin G, ampicillin, cefotaxime, imipenem, and panipenem. However, 14, 2, and 7 isolates were resistant to erythromycin, clindamycin, and both erythromycin and clindamycin, respectively. Multilocus sequence typing revealed that GBS sequence type (ST) 23, ST17, and ST335 caused higher incidences of meningitis. These data show that serotypes III, Ia, and Ib together caused more than 80% of invasive infections in Japanese infants, and that GBS strains are still susceptible to ß-lactam antibiotics.

[A study on the HA amount of HA influenza vaccination on efficacy and safety in infants].

We examined the efficacy and safety of inactivated influenza vaccine when the amount of HA influenza vaccination in children was increased to the dose recommended by the WHO. The purpose of this study was to obtain basic evidence to review the vaccination dose in Japanese children. HA influenza vaccine produced by the Research Foundation for Microbial Diseases of Osaka University (Biken) licenced in Japan was administered through vaccination at the international dose, and split HA influenza vaccine produced by Sanofi Pasteur corp. (Sanofi) was used as control. Children from 6 months to less than 13 years of age were registered, and vaccinated with doses of 0.25 mL or 0.5 mL. Clinical symptoms during the influenza season were monitored to investigate vaccine efficacy, and information on adverse reactions was collected to evaluate safety profile. Paired serum HI and NT antibody titers were measured at pre first dose and post second dose of vaccination. Both HI and NT antibody titers for H1N1 subtype were satisfactory elevated after administration of both vaccines. Elevation of the NT antibody titer for the H3N2 subtype was observed for both vaccines, but the H3N2 HI antibody titer for the Biken vaccine was not so high. For the subtype B virus, the NT titer had a better response than the HI titer for both vaccines. As only the H1N1 virus was prevalent in the area during the study period, we performed factor analysis concerning influenza contraction only for the H1N1 antibody titer. An HI titer of 1 : 40 or more at post-vaccination was a significant factor to lower the risk of influenza contraction. The relative risk for fever among children with an HI titer of 1 : 20 or less was significantly higher than those with an HI titer of 1 : 40 or more. Children with a higher HI titer had better prevention against fever, so that both vaccines were considered to be effective. As for the appearance of adverse reactions, both vaccines were considered to be safe. From the above-mentioned results, vaccination with the Japanese Biken vaccine at an international dose was thought to be an effective and safe procedure.

Rotavirus-associated acute gastroenteritis hospitalizations among Japanese children aged <5 years: active rotavirus surveillance in Mie Prefecture, Japan.

Two effective vaccines for rotavirus infection will be available near future in Japan and data on the burden of rotavirus disease and the circulating rotavirus strains are urgently needed. To obtain these data, we set up active rotavirus hospitalization surveillance in three cities, Tsu, Matsusaka, and Ise in Mie Prefecture, Japan. From November 1, 2007 through October 31, 2009, we enrolled children <5 years of age who were hospitalized with a diagnosis of acute gastroenteritis (AGE) and collected information on age, sex, month of admission, city of residence, and symptoms at the time of hospitalization. Stool samples were also obtained for rotavirus testing and genotype investigation. Rotavirus infection accounted for approximately 40% to 50% of hospitalized AGE cases in each city, and approximately 63% of those hospitalized were 2 years of age or younger. Matsusaka had the highest incidence rate at 4.7 rotavirus hospitalizations per 1,000 children <5 years of age (95% confidence interval [CI]: 3.6-5.9), followed by Tsu City (4.4 per 1,000; 95% CI: 3.6-5.3), and Ise City (2.8 per 1,000; 95% CI: 2.0-4.0). The most dominant rotavirus genotype was G3P[8], which accounted for 73.1% of cases. Our findings confirm the substantial health burden of rotavirus AGE hospitalization among Japanese children <5 years of age.

[Varicella vaccine potency and stability during transport and delivery].

Oka varicella vaccine was developed to confer active immunity to varicella-zoster virus (VZV) in immunocompromized and immunocompetent children. It is now used to prevent varicella in about 20 million people worldwide. Although VZV infectivion is relatively unstable compared to other viruses, cell-free virus is stabilized and lyophilized vaccine has been developed. Virus titers were evaluated in vaccine distributed to six clinics in 5 years. Yearly mean virus titers at the vaccine producer were 42,000-67,000 plaque-forming units per dose, corresponding to Oka varicella vaccine (Zostavax) used to prevent zoster and postherpetic neuralgia by Oxman et al. Virus titer was found to be stable during delivery to clinics. Virus titers of varicella vaccine were equivalent to Zostavax and vaccine delivered to clinics had enough virus titer to confer active immunity to VZV in this study.

Safe and effective booster immunization using DTaP in teenagers.

The incidence of reported cases with pertussis has increased in young adults in Japan and the lack of additional booster immunizations containing pertussis components is suspected to be one of the causal reasons. Instead of DT immunization at 11-12 years of age, safety and immunogenicity were investigated using 0.2 ml and 0.5 ml of DTaP. 176 subjects in DTaP 0.5ml, 178 in DTaP 0.2 ml, and 197 in DT 0.1 ml groups were enrolled in clinical trial. The relative risk of local reactions in the DTaP 0.2 ml group compared to the DT 0.1 ml group was 1.13 (95% CI: 0.97-1.30), and that of the DTaP 0.5 ml to the DT 0.1 ml group was 1.34 (95% CI: 1.18-1.53). The relative risks of local pain and heat were 1.62 (95% CI: 1.33-1.98) and 1.59 (95% CI: 1.19-2.13), respectively, in the DTaP 0.5 ml group compared to the DT 0.1 ml group. Sero-positive rates against PT and FHA were 54% and 82% before immunization and increased to >95% for both after vaccination with no significant difference in GMT. Instead of the scheduled DT program, 0.2 ml of DTaP was acceptable and demonstrated efficient immunogenicity.

Multiple cutaneous squamous cell carcinomas in a patient with interferon gamma receptor 2 (IFN gamma R2) deficiency.

Disseminated squamous cell carcinoma (SCC) of the skin is exceedingly rare in children. SCC occurs after immunodeficiency from immunosuppression in organ transplant recipients or patients with HIV infection or leukaemia, but has not been reported in primary immunodeficiencies other than epidermodysplasia verruciformis. Interferon gamma receptor 2 (IFN gamma R2) deficiency is an exceedingly rare primary immunodeficiency, conferring almost selective predisposition to mycobacterial diseases. A disseminated, cutaneous SCC is described that occurred in a patient homozygous for a novel frameshift deletion at positions 949 and 950 (949delTG) in the IFNGR2 gene. The patient first presented at 1 year of age with disseminated Mycobacterium avium infection, with later infections of atypical mycobacteria (Mycobacterium fortuitum and Mycobacterium porcium). At 17 years of age, the patient developed multifocal SCC lesions on the face and both hands. Histopathological examination revealed well differentiated SCC. Despite local tumour excision, multiple lesions occurred and a large SCC on the right arm required amputation. The patient died at 20 years of age of disseminated SCC. Inherited disorders of IFN gamma mediated immunity may predispose patients to SCC.

[Herpes zoster and its prevention].

The mean herpes zoster incidence in Japan was 4.15/1,000 person-years and was 5.23-7.84/1,000 person-years among those 50 years old and older. One in three persons experiences herpes zoster before age 80, indicating how common it is. The Oka varicella vaccine was developed to prevent varicella in healthy and immunocompromized children and is now used to prevent varicella in 20 million people worldwide. Contact with varicella patients and Oka varicella vaccine are reported to augment varicella-zoster virus immunity in adults and the elderly. Oxman et al. have shown that Oka varicella vaccine prevents herpes zoster and postherpetic neuralgia (PHN) in the elderly. Oka varicella vaccine is approved to prevent herpes zoster and PHN in the elderly in USA and Europe. We review the relationship between varicella/Oka varicella vaccine and herpes zoster, the study by Oxman et al., and the need to introduce this new application of Oka varicella vaccine in Japan.

A retrospective evaluation of hospitalizations for acute gastroenteritis at 2 sentinel hospitals in central Japan to estimate the health burden of rotavirus.

BACKGROUND: Two rotavirus vaccines have recently been licensed for use in >80 countries worldwide but not in Japan. To assess the value of introducing rotavirus vaccination in Japan, data on the burden of rotavirus disease are needed. METHODS: To describe the epidemiology of severe rotavirus disease among Japanese children aged <5 years, we examined retrospective demographic, clinical, and laboratory data from the period 2003-2007 for children hospitalized with acute gastroenteritis (AGE) at 2 sentinel hospitals in Japan. RESULTS: At each of the 2 hospitals, 17%-21% of all pediatric hospitalizations were for AGE. Three-fourths of all AGE-related admissions occurred during the winter (December-May). Rotavirus testing was performed for approximately three-fourths of patients admitted with AGE in the winter, of which 55% at one hospital and 59% at the other tested positive. By extrapolating the test results to those patients with AGE admitted in the winter who were not tested, we estimated that 39%-44% of year-round and 52%-57% of winter hospitalizations were attributable to rotavirus. The annual incidence of hospitalization for rotavirus AGE in the 2 cities served by the hospitals was estimated to be 3.8 and 4.9 per 1000 person-years. CONCLUSIONS: The burden of severe rotavirus disease among Japanese children is substantial and warrants consideration of vaccination as a prevention strategy.

Inactivated influenza vaccine effectiveness against influenza-like illness among young children in Japan--with special reference to minimizing outcome misclassification.

The aim of the present study was to investigate the influenza vaccine effectiveness among young children in Japan. Study subjects were recruited from 43 pediatric clinics. Influenza-like illness (ILI) was defined as an acute febrile illness with respiratory symptoms; ILI with a fever of > or =39 degrees C was considered to be severe ILI (SILI). The adjusted OR of vaccination significantly decreased to 0.75 for SILI. Influenza vaccination for young children had a protective effect on the occurrences of SILI. This study also indicated that three key tools (case surveillance with equal scrutiny, confining observation to the peak epidemic period, and adoption of strict criteria for ILI) could minimize outcome misclassification and thus provide adequate methodology for monitoring vaccine effectiveness without laboratory confirmation.

[Microbiological properties of M. porcinum isolated from a patient with impairments in IL-12/IFN-gamma pathway].

PURPOSE: Mycobacterium porcinum has been successfully isolated from the patient with abnormal signal transduction pathway of IL12/IFN-gamma. The properties of each bacterium were determined by conventional identification methods, DNA sequencing analysis and MIC assay. MATERIALS AND METHODS: M. porcinum was isolated 7 times from 1996 to 2007 from cervical lymph node, axillary lymph nodes, inguinal lymph node, brachial lymph node and site of a tumor of the patient. In another occasion, mycobacteria were isolated from lavage fluid of the endoscope in routine inspection. Using these mycobacteria, M. porcinum (ATCC33776) and M. fortuitum (ATCC6841), the conventional identification method and MIC assay were carried out. For analyses of the DNA sequencing (rpoB, dnaJ and hsp65), the ATCC type strain of mycobacteria (11 strains) which are closely related to M. porcinum were also used. RESULTS AND DISCUSSION: DNA sequencing analyses of the 7 samples isolated from the patient, were concurrently identical in 3 different genes. Drug susceptibility test showed that 7 isolates had no marked change. In conventional identification analyses, M. porcinum (ATCC33776), M. fortuitum (ATCC6841), and M. porcinum that were isolated in 1996, were able to grow at 42 degrees C. However, 6 isolates that were isolated after 1999, did not grow at 42 degrees C. The colony detectable days of these 7 strains changed from 3 to 7. Over the time, the morphology of each colony changed from smooth to rough. Though the initial isolate had the ability to utilize mannitol, the later 4 isolates had no such ability.

[Learning from the US immunization administration].

The US federal government has been providing support to state and local health departments for immunization program since 1920' s. Many government and nongovernment organizations, groups and personnel are involved in the process of the US immunization program. These organizations and groups are moving towards the same direction under the policy of "reducing the incidence of vaccine preventable diseases and to increase the safe usage of vaccines and related biological products". Thus every organization keeps step with the others, which will make states and other local government easier to follow the recommendations. In this review, we will introduce the system and structure of the US immunization administration and indicate why the US has succeeded to decrease vaccine preventable disease with immunization.

Development of varicella vaccine.

The Oka strain of varicella-zoster virus (VZV) was first isolated from vesicles of an otherwise healthy 3-year-old boy with typical varicella. The virus was passaged 11 times in human embryonic lung fibroblasts at 34 degrees C and 12 times in guinea pig embryo fibroblasts (GPEFs) at 37 degrees C. GPEFs were the only nonprimate cells tested in which some degree of viral replication occurred. The resultant virus was temperature sensitive and showed host dependency, measured as better replication in GPEFs than that shown by the parental virus. The passaged virus was used as a candidate varicella vaccine and proved safe and effective for healthy and immunocompromised children. During the follow-up of vaccinated children with acute lymphocytic leukemia, the incidence of herpes zoster (HZ) was significantly lower among children who did not have a rash after vaccination, compared with those who had a rash caused by VZV (6 [2.3%] of 260 vs. 12 [17.1%] of 70, respectively). Because of the pathogenesis of VZV, the incidence of latency and of HZ is predicted to be lower among vaccine recipients than among individuals who have experienced varicella.

[Cost-effectiveness analysis of routine mumps immunization in Japan].

OBJECTIVE: Mumps immunization is not included in routine immunization in Japan. We measured the cost-effectiveness of routine immunization. METHODS: We surveyed outpatients prospectively from June 15, 2004, for 19 months in an area with a population of 100,000. Almost all of the 11 pediatric clinics and hospitals in this area cooperated. In 2006, we retrospectively surveyed all inpatients hospitalized for more than 24 hours and dying of mumps. RESULTS: We collected data from 189 doctors who rated outpatients and 112 families. The disease burden for outpatients including family nursing was estimated to be 47.1 billion yen nationwide. We estimated the total number of inpatients as 4,596. The disease burden of inpatients including the cost of family nursing was estimated to be 1.35 billion yen. Adding cases of sequelae and death, the total disease burden was estimated to be 52.5 billion yen. The incremental benefit cost ratio for routine immunization is higher than 1 even in the lower bounds of the 95% confidence interval. DISCUSSION AND CONCLUSIONS: The incremental benefit cost ratio shows that the additional benefit due to routine immunization exceeds additional cost, emphasizing the benefits of routine mumps immunization.

[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%).

High CD4/CD45RO+ and CD8/CD45RO+ frequencies in children with vaccine-modified measles.

BACKGROUND: Despite availability and wide vaccine coverage, measles infections still occur especially in developing countries. An outbreak of measles occurred among previously immunized older Ghanaian children who had milder clinical symptoms with measles-specific IgG antibodies that could have been attributed to secondary vaccine failure, suggesting that the infection was vaccine-modified measles (VMM). METHODS: Two-color immunophenotyping of the peripheral blood mononuclear cells was performed at acute, recovery and convalescence phases for 19 VMM patients (mean age 6.2 +/- 3.5 years) using flow cytometry, and compared with that of 20 healthy, sex- and age-matched controls. RESULTS: The results showed a significantly higher memory helper (CD4(+)/CD45RO(+)) cell frequency and increased suppressor cell (CD8(+)/CD45R0(+)) frequency in VMM patients compared to healthy controls. There were no complications and all the patients recovered completely. CONCLUSIONS: These findings show that the mild symptoms in patients with VMM may have correlated with the increase of memory T cells, which is in sharp contrast with previous reports on acute measles infection. This may suggest that the intact immunologic memory cells could have been crucial for the resolution of VMM.

Antipyretics and delirious behavior during febrile illness.

BACKGROUND: The purpose of the present paper was to study the use of antipyretics in children with delirium associated with fever in order to clarify their possible adverse effects. METHODS: The use of antipyretics was investigated in 26 children with delirious behavior associated with fever. Temporal relation between delirious behavior and the use of antipyretics was recognized in six children. RESULTS: In four children, delirious behavior was observed soon after administration of antipyretics. The antipyretics used were acetaminophen in two children, mephenamate in one, and diclofenac in one. In the other two children, delirious behavior was observed when body temperature began to fall 1-2 h after administration of antipyretics. The antipyretics used were acetaminophen in one child and mephenamate in one. CONCLUSION: A temporal relationship between antipyretics and delirious behavior was observed in some patients with febrile delirium. This suggests that antipyretics can be a trigger of delirium.

Leukotriene D4 induces production of transforming growth factor-beta1 by eosinophils.

Eosinophils may play an important role in the pathogenesis of airway remodeling in asthma through the production of various fibrogenic cytokines such as transforming growth factor-beta1 (TGF-beta1). Cysteinyl leukotrienes are also suggested to be involved in remodeling with their potential to induce proliferation of airway smooth muscle cells. Since massive eosinophil infiltration and the release of cysteinyl leukotrienes in airway secretions are often seen in asthma, we hypothesized that cysteinyl leukotrienes may be involved in airway remodeling through induction of TGF-beta1 from eosinophils. Peripheral blood eosinophils were cultured with leukotriene D(4) (LTD(4)) and/or interleukin-5 (IL-5) or granulocyte colony-stimulating factor (GM-CSF) for 16 h and gene expression of TGF-beta1 was quantified with real-time PCR. A combination of LTD(4) and IL-5 or LTD(4) and GM-CSF synergistically induced TGF-beta1 expression in eosinophils although stimulation with single factor, LTD(4), IL-5 or GM-CSF did not induce the gene expression. LTD(4) also induced significant gene expression in eosinophils cultured in an intercellular adhesion molecule-1-coated plate. The results suggested that CysLTs stimulate eosinophils to induce TGF-beta1 production in allergic inflammation where IL-5 and GM-CSF are abundant and may be involved in the pathogenesis of airway remodeling.