Chemo Sero Therapeutic Research Institute Kaketsuken

Kumamoto-shi, Japan

Chemo Sero Therapeutic Research Institute Kaketsuken

Kumamoto-shi, Japan

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Okada K.,Fukuoka National Hospital | Miyazaki C.,Fukuoka West Rehabilitation Center for Children | Kino Y.,Chemo Sero Therapeutic Research Institute Kaketsuken | Ozaki T.,Konan Kosei Hospital | And 2 more authors.
Journal of Infectious Diseases | Year: 2013

Background. Phase II and III clinical studies were conducted to evaluate immunogenicity and safety of a novel DTaP-IPV vaccine consisting of Sabin inactivated poliovirus vaccine (sIPV) and diphtheria-tetanus-acellular pertussis vaccine (DTaP).Methods. A Phase II study was conducted in 104 healthy infants using Formulation H of the DTaP-sIPV vaccine containing high-dose sIPV (3, 100, and 100 D-antigen units for types 1, 2, and 3, respectively), and Formulations M and L, containing half and one-fourth of the sIPV in Formulation H, respectively. Each formulation was administered 3 times for primary immunization and once for booster immunization. A Phase III study was conducted in 342 healthy infants who received either Formulation M + oral polio vaccine (OPV) placebo or DTaP + OPV. The OPV or OPV placebo was orally administered twice between primary and booster immunizations.Results. Formulation M was selected as the optimum dose. In the Phase III study, the seropositive rate was 100% for all Sabin strains after primary immunization, and the neutralizing antibody titer after booster immunization was higher than in the control group (DTaP + OPV). All adverse reactions were clinically acceptable.Conclusions. DTaP-sIPV was shown to be a safe and immunogenic vaccine.Clinical Trials Registration. JapicCTI-121902 for Phase II study, JapicCTI-101075 for Phase III study (http://www.clinicaltrials.jp/user/cte-main.jsp). © 2013 The Author 2013. All rights reserved.


Akaike N.,Kumamoto Health Science University | Akaike N.,Kumamoto Kinoh Hospital | Shin M.-C.,Kumamoto Health Science University | Wakita M.,Kumamoto Health Science University | And 6 more authors.
Journal of Physiology | Year: 2013

Type A botulinum toxin blocks not only ACh release from motor nerve terminals but also central synaptic transmission, including glutamate, noradrenaline, dopamine, ATP, GABA and glycine. Neurotoxins (NTXs) are transported by both antero- and retrogradely along either motor or sensory axons for bidirectional delivery between peripheral tissues or the CNS. A newly developed type A2 NTX (A2NTX) injected into one rat foreleg muscle was transported to the contralateral muscle. This finding was consistent with the NTX traveling retrogradely via spinal neurons and then transsynaptically through motor neurons to the contralateral motor neurons within the spinal cord and on to the soleus muscle. In the present study we found that toxin injection into the rat left soleus muscle clearly induced bilateral muscle relaxation in a dose-dependent fashion, although the contralateral muscle relaxation followed the complete inhibition of toxin-injected ipsilateral muscles. The toxin-injected ipsilateral muscle relaxation was faster and stronger in A2NTX-treated rats than A1LL (BOTOX). A1LL was transported almost equally to the contralateral muscle via neural pathways and the bloodstream. In contrast, A2NTX was mainly transported to contralateral muscles via the blood. A1LL was more successfully transported to contralateral spinal neurons than A2NTX. We also demonstrated that A1LL and A2NTX were carried from peripheral to CNS and vice versa by dual antero- and retrograde axonal transport through either motor or sensory neurons. © 2012 The Physiological Society.


Miyazaki C.,Fukuoka West Rehabilitation Center for Children | Okada K.,Fukuoka Dental College | Ozaki T.,Konan Kosei Hospital | Hirose M.,Hirose Pediatric Clinic | And 5 more authors.
Clinical and Vaccine Immunology | Year: 2014

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.) Copyright © 2014, American Society for Microbiology. All Rights Reserved.


Matsushita S.,Kumamoto University | Yoshimura K.,Kumamoto University | Yoshimura K.,Japan National Institute of Infectious Diseases | Ramirez K.P.,Kumamoto University | And 2 more authors.
AIDS | Year: 2015

OBJECTIVE:: Neutralizing antibodies against HIV-1 such as a humanized mAb KD-247 can mediate effector functions that attack infected cells in vitro. However, the clinical efficacy of neutralizing antibodies in infected individuals remains to be determined. We evaluated the safety, tolerability and pharmacokinetics of KD-247 infusion and its effect on plasma HIV-1 RNA load and CD4 T-cell count. DESIGN AND METHODS:: KD-1002 is a phase Ib, double-blind, placebo-controlled, dose-escalation study of KD-247 in asymptomatic HIV-1 seropositive individuals who did not need antiretroviral therapy. Individuals were randomized to 4, 8 or 16mg/kg KD-247 or placebo, and received three infusions over a 2-week period. RESULTS:: Patients were randomized to receive one of the three doses of KD-247 and the treatment was well tolerated. We observed a significant decrease in HIV RNA in the 8 and 16mg/kg KD-247 cohorts, with two individuals who achieved more than 1 log reduction of HIV RNA. Two patients in the 16mg/kg cohort had selections and/or mutations in the V3-tip region that suggested evasion of neutralization. Long-term suppression of viral load was observed in one patient despite a significant decrease in plasma concentration of KD-247, suggesting effects of the antibody other than neutralization or loss of fitness of the evading virus. CONCLUSION:: The results indicate that KD-247 reduces viral load in patients with chronic HIV-1 infection and further clinical trials are warranted.. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Yokote H.,Chemo Sero Therapeutic Research Institute Kaketsuken | Shinmura Y.,Chemo Sero Therapeutic Research Institute Kaketsuken | Kanehara T.,Chemo Sero Therapeutic Research Institute Kaketsuken | Maruno S.,Chemo Sero Therapeutic Research Institute Kaketsuken | And 3 more authors.
Clinical and Vaccine Immunology | Year: 2014

Freeze-dried live attenuated smallpox vaccine LC16m8 prepared in cell culture has been the sole smallpox vaccine licensed in Japan since 1975 and was recently recommended as aWHOstockpile vaccine. We evaluated the safety of recently remanufactured lots of LC16m8 using a series of immunodeficient mouse models. These models included suckling mice, severe combined immunodeficiency disease (SCID) mice, and wild-type mice treated with cyclosporine. LC16m8 showed extremely low virulence in each of the three mouse models compared with that of its parental strains, Lister and LC16mO. These results provide further evidence that LC16m8 is one of the safest replication-competent smallpox vaccines in the world and may be considered for use in immunodeficient patients. Copyright © 2014, American Society for Microbiology. All Rights Reserved.


Nagao M.,Mie National Hospital | Fujisawa T.,Mie National Hospital | Ihara T.,Mie National Hospital | Kino Y.,Chemo Sero Therapeutic Research Institute Kaketsuken
Journal of Allergy and Clinical Immunology | Year: 2016

Background Influenza vaccines produced in embryonated eggs might pose a risk to patients with egg allergy. However, patients experiencing influenza vaccine-associated anaphylaxis (IVA) do not always have egg allergy. In the 2011-2012 season, an unusually high incidence of IVA was reported in Japan. Objective We sought to identify the cause of the increase in anaphylactic events in 2011-2012 in Japan. Methods We collected blood specimens from patients with IVA from all areas of Japan. We analyzed 19 patients with confirmed IVA and 25 age-matched control subjects, including 10 with egg allergy who had no adverse events after corresponding vaccination. ELISA was used to measure specific IgE levels to the trivalent vaccines of several manufacturers and hemagglutinin proteins derived from both egg and cell cultures. Antigen-induced basophil activation was evaluated by measuring CD203c expression by means of flow cytometry. Vaccine excipients were also examined for effects on CD203c expression. Results None of the patients with IVA had severe egg allergy. Levels of specific IgE antibodies to influenza vaccine antigens, whole-vaccine products from different manufacturers, and hemagglutinin proteins (A H1, H3, and B) derived from both egg and cell cultures were significantly increased in patients with IVA compared with those in control subjects. Influenza vaccine-induced CD203c expression in basophils was also highly enhanced in patients with IVA but not in control subjects. Because IVA was most frequent in patients who received 2-phenoxyethanol (2-PE)-containing vaccine, the effect of this preservative on basophil activation was examined, and the activation was slightly enhanced by 2-PE but not thimerosal. Conclusions The 2011-2012 IVA spike in Japan was caused by specific IgE antibodies to influenza vaccine components. Excipients could not be implicated, except for a modest effect of 2-PE. © 2015 The Authors.


PubMed | Mie National Hospital and Chemo Sero Therapeutic Research Institute Kaketsuken
Type: Journal Article | Journal: The Journal of allergy and clinical immunology | Year: 2016

Influenza vaccines produced in embryonated eggs might pose a risk to patients with egg allergy. However, patients experiencing influenza vaccine-associated anaphylaxis (IVA) do not always have egg allergy. In the 2011-2012 season, an unusually high incidence of IVA was reported in Japan.We sought to identify the cause of the increase in anaphylactic events in 2011-2012 in Japan.We collected blood specimens from patients with IVA from all areas of Japan. We analyzed 19 patients with confirmed IVA and 25 age-matched control subjects, including 10 with egg allergy who had no adverse events after corresponding vaccination. ELISA was used to measure specific IgE levels to the trivalent vaccines of several manufacturers and hemagglutinin proteins derived from both egg and cell cultures. Antigen-induced basophil activation was evaluated by measuring CD203c expression by means of flow cytometry. Vaccine excipients were also examined for effects on CD203c expression.None of the patients with IVA had severe egg allergy. Levels of specific IgE antibodies to influenza vaccine antigens, whole-vaccine products from different manufacturers, and hemagglutinin proteins (A H1, H3, and B) derived from both egg and cell cultures were significantly increased in patients with IVA compared with those in control subjects. Influenza vaccine-induced CD203c expression in basophils was also highly enhanced in patients with IVA but not in control subjects. Because IVA was most frequent in patients who received 2-phenoxyethanol (2-PE)-containing vaccine, the effect of this preservative on basophil activation was examined, and the activation was slightly enhanced by 2-PE but not thimerosal.The 2011-2012 IVA spike in Japan was caused by specific IgE antibodies to influenza vaccine components. Excipients could not be implicated, except for a modest effect of 2-PE.


PubMed | Japan National Institute of Infectious Diseases, Chemo Sero Therapeutic Research Institute Kaketsuken and Japan National Institute of Public Health
Type: Journal Article | Journal: Vaccine | Year: 2015

LC16m8 is a live, attenuated, cell-cultured smallpox vaccine that was developed and licensed in Japan in the 1970s, but was not used in the campaign to eradicate smallpox. In the early 2000s, the potential threat of bioterrorism led to reconsideration of the need for a smallpox vaccine. Subsequently, LC16m8 production was restarted in Japan in 2002, requiring re-evaluation of its safety and efficacy. Approximately 50,000 children in the 1970s and about 3500 healthy adults in the 2000s were vaccinated with LC16m8 in Japan, and 153 adults have been vaccinated with LC16m8 or Dryvax in phase I/II clinical trials in the USA. These studies confirmed the safety and efficacy of LC16m8, while several studies in animal models have shown that LC16m8 protects the host against viral challenge. The World Health Organization Strategic Advisory Group of Experts on Immunization recommended LC16m8, together with ACAM2000, as a stockpile vaccine in 2013. In addition, LC16m8 is expected to be a viable alternative to first-generation smallpox vaccines to prevent human monkeypox.


PubMed | Kumamoto University, Kumamoto Saishunso National Hospital and Chemo Sero Therapeutic Research Institute KAKETSUKEN
Type: Journal Article | Journal: Pediatrics international : official journal of the Japan Pediatric Society | Year: 2016

In the prenatal diagnosis of Gaucher disease (GD), glucocerebrosidase (GBA) activity is measured with fetal cells, and gene analysis is performed when pathogenic mutations in GBA are identified in advance. Herein is described prenatal diagnosis in a family in which two children had GD. Although prior genetic information for this GD family was not obtained, next-generation sequencing (NGS) was carried out for this family because immediate prenatal diagnosis was necessary. Three mutations were identified in this GD family. The father had one mutation in intron 3 (IVS2+1), the mother had two mutations in exons 3 (I[-20]V) and 5 (M85T), and child 1 had all three of these mutations; child 3 had none of these mutations. On NGS the present fetus (child 3) was not a carrier of GD-related mutations. NGS may facilitate early detection and treatment before disease onset.


PubMed | Kumamoto University and Chemo Sero Therapeutic Research Institute Kaketsuken
Type: Journal Article | Journal: Microbiology and immunology | Year: 2015

Activated protein C (APC) has an anticoagulant action and plays an important role in blood coagulation homeostasis. In addition to its anticoagulant action, APC is known to have cytoprotective effects, such as anti-apoptotic action and endothelial barrier protection, on vascular endothelial cells and monocytes. However, the effects of APC on DCs have not been clarified. To investigate the effects of APC on human DCs, monocytes were isolated from peripheral blood and DC differentiation induced with LPS. APC significantly inhibited the production of inflammatory cytokines TNF- and IL-6 during differentiation of immature DCs to mature DCs, but did not inhibit the production of IL-12 and anti-inflammatory cytokine IL-10. Interestingly, treatment with 5g/mL, but not 25g/mL, of APC significantly enhanced production of IL-10. In addition, protein C, which is the zymogen of APC, did not affect production of these cytokines. On the other hand, flow cytometric analysis of DCs surface molecules indicated that APC does not significantly affect expression of CD83, a marker of mDC differentiation, and the co-stimulatory molecules CD40, CD80 and CD86. These results suggest that APC has anti-inflammatory effects on human DCs and may be effective against some inflammatory diseases in which the pathogenesis involves TNF- and/or IL-6 production.

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