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Hiroaki Takahashi,
Takuya Yano,
Miwa Fukuta,
Akinori Yamauchi,
Kazuyuki Okuma, Toshiaki Ihara,
Takashi Nakano,
Tadashi Matsuda,
Sadayoshi Torigoe,
Ritsue Nii,
Machiko Isaji,
Masahiro Watanabe,
Hitoshi Ochiai,
Hiroyuki Sakatoku,
Takashi Kato,
Kazuhiro Maeda,
Yoshinobu Okuno,
Hitoshi Kamiya
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ABSTRACT: 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.
Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases 03/2013; 87(2):195-206.
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ABSTRACT: IgG subclass antibody responses are not fully understood. Alum-adjuvanted H5N1whole virion inactivated vaccine (WIV), a genetically reassortant vaccine seed strain originating from H5N1/A/Vietnam/1194/2004 and PR-8, induced significantly stronger antibody responses in neutralizing antibodies in children. In this report, IgG subclass antibody responses were investigated, and most serum samples were positive for IgG1 antibody before immunization. A significant response (more than 4-fold increase) of IgG1 antibody was observed in 67/193 (34.7%) and that of gG4 antibodies in 42/193(21.8%). Children <4 years of age showed a significant increase in IgG subclass antibodies but those ≥4 years showed lower responses. Alum- adjuvanted H5N1WIV induced an efficient immune response in young children especially <4 years.
Vaccine 10/2012; · 3.77 Impact Factor
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Pediatrics International 08/2012; · 0.63 Impact Factor
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ABSTRACT: Alum-adjuvanted H5 whole virion inactivated vaccine (WIV) was licensed for adults in Japan but induced marked febrile reactions with significantly stronger antibody responses in children. In this study, the mechanisms behind the different responses were investigated. Lymphocytes were obtained from 25 healthy subjects who were not immunized with H5 vaccine, to examine the innate immune impact of the various vaccine formulations, analyzing the cytokine production profile stimulated with alum adjuvant alone, alum-adjuvanted H5 WIIV, plain H5 WIV, and H5 split vaccine. Alum adjuvant did not induce cytokine production, but H5 split induced IFN-γ and TNF-α. H5 WIV induced IL-6, IL-17, TNF-α, MCP-1, IFN-γ, and IFN-α. An extremely low level of IL-1β was produced in response to H5 WIV, and alum-adjuvanted H5 WIV enhanced IL-1β production, with similar levels of other cytokines stimulated with H5 WIV. Enhanced production of cytokines induced by alum-adjuvanted H5 WIV may be related to the higher incidence of febrile reactions with stronger immune responses in children but it should be further investigated why efficient immune responses with febrile illness were observed only in young children.
Vaccine 04/2012; 30(26):3885-90. · 3.77 Impact Factor
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Pediatrics International 12/2011; 53(6):1097-9. · 0.63 Impact Factor
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ABSTRACT: The Schwarz FF-8 (FF-8) and AIK-C measles virus vaccine strains are currently used for vaccination in Japan. Here, the complete genome nucleotide sequence of the FF-8 strain has been determined and its genome sequence found to be remarkably similar to that of the AIK-C strain. These two strains are differentiated only by two nucleotide differences in the phosphoprotein gene. Since the FF-8 strain does not possess the amino acid substitutions in the phospho- and fusion proteins which are responsible for the temperature-sensitivity and small syncytium formation phenotypes of the AIK-C strain, respectively, other unidentified common mechanisms likely attenuate both the FF-8 and AIK-C strains.
Microbiology and Immunology 03/2011; 55(7):518-24. · 1.30 Impact Factor
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ABSTRACT: Hydrogen peroxide (H2O2) generation by human polymorphonuclear leukocytes (PMN) incubated with varicella zoster virus (VZV) antigen was studied by cytofluorography. Hydrogen peroxide generation was detected in the presence of VZV-seropositive sera. When seropositive sera were heat-inactivated, H2O2 generation was reduced. When PMN were pre-incubated with Leu-1 1b, a monoclonal antibody to the Fc receptor on PMN, H2O2 generation was also reduced. These results suggest that VZV antigen-antibody-complement complexes induce H2O2 generation by PMN after these complexes attach to Fc receptors on PMN.
Pediatrics International 01/2011; 36(4):341 - 346. · 0.63 Impact Factor
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ABSTRACT: Background: Wild-type measles virus (MV) is isolated in B95a but not in Vero cells. Through an adaptation process of wild-type MV to Vero cells, several amino acid substitutions were reported. Methods: Six strains were adapted to Vero cells and membrane (M), fusion (F) and hemagglutinin (H) genes were sequenced. Cell fusion was assessed and recombinant MVs were constructed, having wild-type H or M gene with or without mutations. Results: No F gene substitution was noted. Amino-acid substitutions at positions 481 from Asn to Tyr (N481Y) and 546 from Ser to Gly (S546G) were observed in the H protein. Glu at position 89 of the M protein was substituted for Gly (E89G) and two mutations were noted at positions 62 (S62R) and 83 (S83P) in M protein. Recombinant viruses with mutation(s) detected in Vero-adapted strains induced a cytopathic effect and grew well in Vero cells, but those with the wild type did not. Recombinant viruses with mutation(s) demonstrated lower viral growth in B95a cells. Conclusions: Substitutions of E89G, S62R and S83P of the M protein were newly observed through adaptation to Vero cells, besides the mutations described in previous reports, with varying adaptation for each strain.
Intervirology 01/2011; 54(4):217-28. · 2.34 Impact Factor
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ABSTRACT: The purpose of this study is to reevaluate the sensitivities of different methods used in the diagnosis of measles including virus isolation, RT-PCR, and measurement of IgM. Sixty-three throat swabs, 84 peripheral blood mononuclear cell (PBMC) samples, and 85 plasma samples were collected from 85 cases of suspected measles. The sensitivity of virus isolation using throat swabs and PBMC in comparison with RT-PCR was 58.1 and 93.5%, respectively. We defined laboratory-confirmed cases as those in which at least one of the methods was positive. The percentage of positive results by the different methods was compared among 49 laboratory-confirmed cases. The percentage of positive results from PBMC by RT-PCR and virus isolation was 100 and 91.7%, respectively. The percentage of positive results from throat swabs by RT-PCR and virus isolation was 91.2 and 52.8%, respectively. The percentage of IgM positive (79.6%) was significantly lower than that of PBMC by RT-PCR. Ten of 27 plasma samples collected within 5 days of the onset of fever were IgM negative. In contrast, all of the 21 plasma samples collected 6 days after the onset of fever were IgM positive. In conclusion, the detection of measles virus RNA in PBMC by RT-PCR was the most effective method for diagnosis of measles.
Japanese journal of infectious diseases. 07/2010; 63(4):225-8.
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ABSTRACT: As the coverage rate of the measles vaccine increases, not all patients present the typical symptoms of measles after exposure to the measles virus (MV). The virus loads in clinical specimens from patients with vaccine-modified non-typical measles are expected to be low compared with those of primary MV infection. A rapid and sensitive laboratory procedure is required for diagnosis of measles.
SYBR Green (TaKaRa) and TaqMan (ABI) real-time reverse transcription-polymerase chain reaction (RT-PCR) assays were developed to detect MV-RNA. For the real-time RT-PCR, primer sets were designed from a region of the MV H gene of the Edmonston strain (genotype A). A TaqMan probe specific for the H gene of genotype D MV was used. The minimum detectable level of MV-RNA in the SYBR Green and TaqMan real-time RT-PCR assays was evaluated using synthetic MV-RNA. The sensitivity of real-time RT-PCR was compared with that of nested RT-PCR and the virus isolation method using throat swabs and peripheral blood samples from patients with measles.
The minimum detectable level of RNA was 10 and 10(2) copies for SYBR Green RT-PCR and TaqMan RT-PCR, respectively. Ten-10(6) copies of standard RNA were linearly detected on SYBR Green RT-PCR. The sensitivity of SYBR Green RT-PCR was equal to that of nested RT-PCR. MV-RNA was detected in virus isolation-negative throat swabs on SYBR Green RT-PCR.
SYBR Green RT-PCR is a highly sensitive, rapid, and useful diagnostic procedure for the detection of MV.
Pediatrics International 03/2010; 52(4):611-5. · 0.63 Impact Factor
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ABSTRACT: Attenuated live vaccines of measles virus (MV) have been developed from clinical isolates by serial propagation in heterologous cells, mainly chicken embryonic cells. The safety and effectiveness of these vaccines have been well established. However, the molecular mechanism of their attenuation remains a subject of investigation. The CAM-70 MV vaccine strain was developed from the Tanabe strain by serial propagation in chicken embryonic cells. In the present study, we assessed the contribution of each gene in the CAM-70 strain to efficient growth in chicken embryonic fibroblasts (CEF). We used a cloned MV IC323 based on the wild-type IC-B strain and generated a series of IC323s that possess one or more of the CAM-70 genes. Then, we examined the infection of CEF and CEF expressing human signaling lymphocyte activation molecule with the recombinant MVs. Our results demonstrated that MV needs to adapt to CEF at both the entry and postentry steps and that the CAM-70 matrix protein gene plays an important role in adaptation to CEF at the early stage of the virus replication cycle. The CAM-70 large protein gene was responsible for the efficient transcription and replication in CEF, and the CAM-70 hemagglutinin and fusion protein genes were responsible for efficient entry. Investigations focusing on these genes might elucidate unknown molecular mechanisms underlying the attenuation of MV.
Journal of Virology 10/2009; 83(22):11645-54. · 5.40 Impact Factor
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ABSTRACT: The CAM-70 measles virus (MV) vaccine strain is currently used for vaccination against measles. We examined the fusion-inducing ability of the CAM-70 hemagglutinin (H) protein and found that it was impaired in both CD46- and signaling lymphocyte activation molecule (SLAM)-expressing cells. We also generated recombinant MVs possessing H genes derived from the CAM-70 strain. The CAM-70 H protein impaired viral growth in both CD46- and SLAM-expressing cells. In peripheral blood lymphocytes (PBL) and monocyte-derived dendritic cells (Mo-DC), the CAM-70 strain did not grow efficiently. Infection with recombinant MVs revealed that impaired growth of the CAM-70 strain was attributed to the H gene only partly in PBL and largely in Mo-DC. Thus, impaired fusion-inducing ability of the H protein may be one of the underlying molecular mechanisms resulting in the attenuation of the CAM-70 strain.
Vaccine 07/2009; 27(29):3838-48. · 3.77 Impact Factor
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ABSTRACT: Different genotypes of C1, D3, D5, and H1 were isolated in outbreaks of 1984, 1987-1988, 1991-1993, and 2001, respectively, when the previous circulating genotype was replaced successively by a new genotype, through molecular studies of measles since 1984 in Japan. In March 2007, several patients with measles were observed in outpatient clinics, who were all young adolescents in high school and university students. The outbreak expanded subsequently throughout Japanese districts in May and is still ongoing in 2008. Reverse transcription loop-mediated isothermal amplification (RT-LAMP) was used to detect the measles genome from 18 clinical samples obtained from patients suspected of modified measles infection with a very mild febrile illness. The measles genome was detected in nine patients by reverse transcription polymerase chain reaction (RT-PCR) and in 12 patients by RT-LAMP. Six measles strains were isolated in the 2007-2008 outbreak and identified as the D5 genotype (MVi/Bangkok.THA/93 type) different from the D5 sub-cluster (MVi/Palau.BLA/93 type) isolated in 1990-2005. Similar Bangkok type D5 strains were isolated in Phnom Penh in 2002 and in Taiwan in 2003, suggesting that the D5 strains might have been introduced via South East Asia, rather than resulting from the accumulation of mutations in the D5 strains of 1990-2005. One D9 strain was isolated from a sporadic case in Aichi in 2006. There was no difference in the antigenicity of the D9 and D5 strains in comparison with the vaccine strain. Infrastructure of systematic laboratory-based surveillance system should be established in order to confirm measles virus infection in Japan.
Journal of Medical Virology 05/2009; 81(6):1094-101. · 2.82 Impact Factor
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ABSTRACT: Immunochromatography (IC) tests are often used for the rapid diagnosis of influenza. Once influenza is diagnosed, an anti-influenza drug can be administered. Physicians claim, however, that they are not sufficiently sensitive, especially in the early phase of the disease. The aim of the present study was therefore to analyze the sensitivity of the IC test from the standpoint of virology.
To evaluate the sensitivity of the IC test statistically, 736 nasopharyngeal specimens were subjected to the IC test and virus isolation (VI). The IC test (+) specimens were compared with VI (+) specimens in the early phase after fever onset. Amounts of the virus in IC(-)VI(+) specimens were compared with those in IC(+)VI(+) specimens on real-time reverse transcriptase-polymerase chain reaction. The isolated viruses from these specimens were subjected to the IC test at the same dose. The nucleotide sequences of NP genes were compared.
The IC test was less sensitive for diagnosis in the early phase of the disease. Amounts of virus were significantly lower in IC(-)VI(+) specimens than in IC(+)VI(+) specimens. No variations were observed in the isolated viruses.
The IC test is not sufficiently sensitive owing to the low amount of virus in the nasopharyngeal tract in the early phase of the disease. Influenza should be diagnosed on the basis of clinical symptoms within 1 day after the fever onset.
Pediatrics International 05/2009; 51(2):211-5. · 0.63 Impact Factor
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ABSTRACT: The role of breast milk in viral transmission has not been fully studied. To determine the effect of breast milk on the establishment of primary human cytomegalovirus (HCMV) infection in term infants, HCMV-DNA was measured in breast milk and infant saliva.
The study population consisted of 48 healthy term infants and their mothers. The copy number of HCMV-DNA in the infants' saliva and mothers' milk was measured on quantitative real-time polymerase chain reaction (PCR).
HCMV-DNA was detected in both saliva and breast milk from 21 infant-mother pairs, in milk only from four pairs, in saliva only from 12 pairs, and in neither from 11 pairs. HCMV-DNA was first detected in the saliva of 10 infants at age 4 months, seven infants at 7 months, 13 infants at 10 months, and three infants at 12 months. The viral loads peaked 4-10 months after birth, and thereafter decreased or became negative. The peak copy number and rate of HCMV-DNA detection in saliva were significantly related to peak copy number and rate of detection in the corresponding breast milk.
Thus, HCMV passed through breast milk 1-7 months after delivery affects the persistence and level of HCMV-DNA in infant saliva and is the most important route of primary infection.
Pediatrics International 04/2009; 51(4):530-4. · 0.63 Impact Factor
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Naoko Yoshida,
Motoko Fujino,
Akiko Miyata,
Takao Nagai,
Makoto Kamada,
Hiroshi Sakiyama, Toshiaki Ihara,
Takuji Kumagai,
Teruo Okafuji,
Takao Okafuji,
Tetsuo Nakayama
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ABSTRACT: Clinically apparent mumps reinfection is considered extremely rare, but several cases have been suspected of reinfection in an out-patient clinic. In this study, virological examination, virus isolation, the reverse transcription loop-mediated isothermal amplification (RT-LAMP), and IgG and IgM EIA antibodies, were examined in order to identify mumps reinfection. Patients were divided into three categories; the reinfection group comprised 29 patients with a history of natural infection, the vaccine-failure group consisted of 37 patients with an immunization history, and two patients had histories of both immunization and mumps infection. Another 25 patients were enrolled as a primary infection group. Mumps virus was isolated in 5 (17%) and the genome was detected in 12 (41%) of 29 in the reinfection group. Reinfection was confirmed in 21/28, demonstrating high avidity of IgG EIA. Mumps virus was isolated in 15 (41%) and there was a higher positivity of genome amplification in 25 (68%) of 37 patients in the vaccine-failure group. Among these, 23 were confirmed as secondary vaccine failure by high avidity IgG EIA serology. In the primary infection group, the isolation rate and genome detection rate was higher in 16 (64%) and in 18 (72%) of 25 patients, respectively. There was no significant difference in virus load among the three groups but high mumps virus load was suspected in the IgM EIA-positive group based on the shorter amplification time on RT-LAMP. Mumps virus reinfection was confirmed by RT-LAMP and an IgG avidity test and was not a rare event.
Journal of Medical Virology 04/2008; 80(3):517-23. · 2.82 Impact Factor
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Tamie Sugawara,
Yasushi Ohkusa,
Keiko Taya,
Kaoru Oikawa,
Noriyuki Haneda,
Kiyoshi Kikuchi,
Fumihide Kato,
Seiji Yamaguchi,
Tetuji Yoshikawa,
Takashi Nakano, Toshiaki Ihara,
Hiroyuki Tutumi,
Yoshizo Asano,
Hitoshi Kamiya,
Nobuhiko Okabe
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ABSTRACT: Mumps immunization is not included in routine immunization in Japan. We measured the cost-effectiveness of routine immunization.
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.
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.
The incremental benefit cost ratio shows that the additional benefit due to routine immunization exceeds additional cost, emphasizing the benefits of routine mumps immunization.
Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases 10/2007; 81(5):555-61.
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Takao Nagai,
Teruo Okafuji,
Chiaki Miyazaki,
Yuhei Ito,
Makoto Kamada,
Takuji Kumagai,
Kenji Yuri,
Hiroshi Sakiyama,
Akiko Miyata, Toshiaki Ihara,
Hitoshi Ochiai,
Kunihisa Shimomura,
Eitaro Suzuki,
Sadayoshi Torigoe,
Masahiro Igarashi,
Tetsuo Kase,
Yoshinobu Okuno,
Tetsuo Nakayama
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ABSTRACT: To compare the incidence of aseptic meningitis associated with symptomatic natural mumps infection and in mumps vaccine recipients, we conducted a prospective comparative study. Consecutive samples of 1051 children with mumps were enrolled by 10 pediatricians and 21,465 vaccine recipients by 143 pediatric primary care practitioners, from January 1, 2000 to January 1, 2003. Parents used a daily diary to record symptoms during the period of illness (15 days) or 30-day period following immunization. Mumps infection was confirmed by virus isolation and/or detection of mumps virus genome in salivary and CSF samples. The incidence of aseptic meningitis was 13/1051 (1.24%) in patients with symptomatic natural mumps infection and was estimated to be 0.7-1.1% of overall infection in considering asymptomatic infection, and 10/21,465 (0.05%) in vaccine recipients. Although aseptic meningitis is a clear side effect of the mumps vaccine, the incidence is considerably lower than among those with symptomatic natural infection. Our results provide an informative data for consideration to resume mumps vaccine as a part of routine immunization schedule for Japanese children.
Vaccine 04/2007; 25(14):2742-7. · 3.77 Impact Factor
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ABSTRACT: Macrophages (Mø) and dendritic cells (DC) are thought to be targets of measles virus (MeV) at the early stage of infection. We compared the growth of Edmonston-derived vaccine strains and fresh clinical isolates of MeV in monocytes, monocyte-derived granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced Mø (GM-Mø) and in monocyte-derived DC (Mo-DC). Neither vaccine strains nor fresh isolates thrived in monocytes and GM-Mø and no differences were evident among them. On the other hand, infectious virus production was robust in Mo-DC infected with fresh isolates, but below the limits of detection in those infected with vaccine strains. Although the vaccine strains infected Mo-DC and replicated comparably with the fresh isolates, they accumulated far less matrix (M) protein. This was attributed to a difference in the stability of M protein produced in Mo-DC between the strains. Impaired production of infectious viruses in DC may be one cause of vaccine strain attenuation.
Virus Research 02/2007; 123(1):1-8. · 2.94 Impact Factor
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Yuji Nashida,
Tadashi Kumamoto,
Eiichi Azuma,
Masahiro Hirayama,
Mariko Araki,
Hiroshi Yamada,
Francis Dida,
Shotaro Iwamoto,
Shigehisa Tamaki,
Masaru Ido, Toshiaki Ihara,
Yoshihiro Komada
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ABSTRACT: Most patients who have undergone hematopoietic cell transplantation (HCT) lose specific immunity to measles. However, due to its immunosuppressive potential, it has been recommended that a live attenuated measles vaccination be administered two years following HCT. Measles virus (MV) glycoproteins including hemagglutinin (HA) are expressed on MV-infected dendritic cells (DCs), and they impair efficient antigen presentation between the DC and T cell. We produced a DC-based vaccine against MV by loading DCs with MV-infected autologous DCs. MV in the infected DCs was inactivated using ultraviolet-B. The DC-based vaccine neither expressed HA nor inhibited allogeneic T cell proliferation, while it induced the production of interferon-gamma (IFN-gamma) by autologous CD4 and CD8 naive T cells ex vivo. Importantly, the vaccine derived from patients who had undergone HCT also efficiently induced IFN-gamma producing cells. These findings indicate that our DC-based MV vaccine induces MV-specific immunity even in post-HCT patients without causing immunosuppression.
Transplantation 11/2006; 82(8):1104-7. · 4.00 Impact Factor
