Updated on 2022/09/20

写真a

 
MAEDA Kenji
 
Organization
Research Field in ? Professor
Title
Professor
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Degree

  • 博士(医学) ( 2003.3   熊本大学 )

  • 医師 ( 1995.4   熊本大学 )

Research Interests

  • SARS-CoV-2

  • HIV-1

  • HBV

  • CMV

  • Antiviral therapy

  • SARS-CoV-2

  • HBV

  • HIV

Research Areas

  • Life Science / Infectious disease medicine

  • Life Science / Virology

  • Life Science / Infectious disease medicine

  • Life Science / Virology  / HIV

Education

  • Kumamoto University

    1999.4 - 2003.3

  • Kumamoto University

    1989.4 - 1995.3

Research History

  • Kagoshima University   Division of Antiviral Therapy, Joint Research Center for Human Retrovirus Infection   Professor

    2022.4

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  • 国立研究開発法人 国立国際医療研究センター   研究所   レトロウイルス感染症研究室長

    2015.4 - 2022.3

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Papers

  • Takeuchi JS, Fukunaga A, Yamamoto S, Tanaka A, Matsuda K, Kimura M, Kamikawa A, Kito Y, Maeda K, Ueda G, Mizoue T, Ujiie M, Mitsuya H, Ohmagari N, Sugiura W .  SARS-CoV-2 specific T cell and humoral immune responses upon vaccination with BNT162b2: a 9 months longitudinal study. .  Scientific reports12 ( 1 ) 15447   2022.9SARS-CoV-2 specific T cell and humoral immune responses upon vaccination with BNT162b2: a 9 months longitudinal study.

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    DOI: 10.1038/s41598-022-19581-y

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  • Nobumasa Okumura, Sho Saito, Yuki Takamatsu, Junko S Takeuchi, Yusuke Asai, Mio Sanada, Noriko Iwamoto, Maeda Kenji, Hiroaki Mitsuya, Norio Ohmagari .  Antibody titers and neutralizing activity in cases of COVID-19 after a single dose of vaccination. .  Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   2022.9Antibody titers and neutralizing activity in cases of COVID-19 after a single dose of vaccination.International journal

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    Vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have shown high efficacy in preventing the onset of disease. However, the immune response to infection immediately after the first vaccination remains unknown. We examined the anti-SARS-CoV-2-binding-antibody titers and neutralizing activity in patients who developed coronavirus disease 2019 after the first vaccination. The anti-SARS-CoV-2-binding-antibody titers and neutralizing activity drastically increased from the first to the second collection. Our results may provide important data on the course of immune response following vaccination.

    DOI: 10.1016/j.jiac.2022.08.026

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  • Kamimura G., Ueda K., Takeda A., Maeda K., Aoki M., Sato M. .  A case of schwannoma at the origin of the right recurrent laryngeal nerve resected under uniportal video-assisted thoracic surgery .  Respirology Case Reports10 ( 9 )   2022.9

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    Language:Japanese   Publisher:Respirology Case Reports  

    Mediastinal neurogenic tumours are mostly derived from sympathetic nerves and intercostal nerves, and vagus nerve-derived schwannomas are rare. We encountered a tumour originating from the origin of the recurrent laryngeal nerve that was accompanied by the azygos lobe, which made it difficult to approach; it was ultimately able to be removed via uniportal video-assisted thoracic surgery. This case involved a 63-year-old female patient. There were no particular symptoms, but an abnormal chest shadow was noted on an imaging examination. Chest imaging revealed a smooth-surfaced mass in the upper right mediastinum with the azygos lobe. A diagnosis of schwannoma was made by imaging, and the patient underwent resection via uniportal video-assisted thoracic surgery. The tumour, which originated from the origin of the right recurrent laryngeal nerve, was sharply removed without causing recurrent laryngeal nerve palsy.

    DOI: 10.1002/rcr2.1023

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  • Masayuki Amano, Sachiko Otsu, Kenji Maeda, Yukari Uemura, Yosuke Shimizu, Kazumi Omata, Masao Matsuoka, Shinya Shimada, Hiroaki Mitsuya .  Neutralization activity of sera/IgG preparations from fully BNT162b2 vaccinated individuals against SARS-CoV-2 Alpha, Beta, Gamma, Delta, and Kappa variants. .  Scientific reports12 ( 1 ) 13524 - 13524   2022.8Neutralization activity of sera/IgG preparations from fully BNT162b2 vaccinated individuals against SARS-CoV-2 Alpha, Beta, Gamma, Delta, and Kappa variants.International journal

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    In the present prospective study, 225 individuals in Kumamoto General Hospital, Japan, who received two-doses of BNT162b2 vaccine were enrolled/followed up over 150 days and neutralizing activity (NT50) of their sera and antiviral activity (EC50) of IgG purified from sera on day-60 post-1st-dose were determined against wild-type SARS-CoV-2 (SARS-CoV-2Wuhan) (n = 211) and 9 variants (Alpha, Beta, Gamma, Delta, and Kappa) (n = 45). Time-dependent changes of IgG-activity (n = 25) against SARS-CoV-2Wuhan and variants were also examined. Day-60 sera showed reduced NT50 by more than 50% against all variants examined, and greatest reduction was seen with Beta. IgG fractions of high-responders and moderate-responders showed similar fold-changes in EC50 against each variant compared to SARS-CoV-2Wuhan. Evaluation of EC50 of IgG obtained at different time-points (day-28 to -150) revealed time-dependent reduction of activity against all variants. However, against Delta, relatively long-lasting favorable antiviral activity (at least 150 days) was observed. Our data strongly suggest that the successful antecedent scale-up of mRNA-based vaccine administrations in Japan was the primary contributor to the lessening of the otherwise more devastating SARS-CoV-2 pandemic wave caused by the Delta variant. The present data that the effectiveness of vaccine against the then-dominant SARS-CoV-2 variant was likely associated with the moderation of the COVID-19 pandemic wave suggest that as in the case of influenza vaccines, the development of multivalent mRNA-based vaccines represent a generalizable approach to pre-emptively respond pandemic with mutable pathogens.

    DOI: 10.1038/s41598-022-17071-9

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  • Miyazato Yusuke, Yamamoto Kei, Nakaya Yuichiro, Morioka Shinichiro, Takeuchi Junko S., Takamatsu Yuki, Maeda Kenji, Kimura Moto, Sugiura Wataru, Mitsuya Hiroaki, Yano Masao, Ohmagari Norio .  Successful use of casirivimab/imdevimab anti-spike monoclonal antibodies to enhance neutralizing antibodies in a woman on anti-CD20 treatment with refractory COVID-19(和訳中) .  Journal of Infection and Chemotherapy28 ( 7 ) 991 - 994   2022.7Successful use of casirivimab/imdevimab anti-spike monoclonal antibodies to enhance neutralizing antibodies in a woman on anti-CD20 treatment with refractory COVID-19(和訳中)

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  • Yusuke Miyazato, Kei Yamamoto, Yuichiro Nakaya, Shinichiro Morioka, Junko S Takeuchi, Yuki Takamatsu, Kenji Maeda, Moto Kimura, Wataru Sugiura, Hiroaki Mitsuya, Masao Yano, Norio Ohmagari .  Successful use of casirivimab/imdevimab anti-spike monoclonal antibodies to enhance neutralizing antibodies in a woman on anti-CD20 treatment with refractory COVID-19. .  Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy28 ( 7 ) 991 - 994   2022.7Successful use of casirivimab/imdevimab anti-spike monoclonal antibodies to enhance neutralizing antibodies in a woman on anti-CD20 treatment with refractory COVID-19.International journal

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    Management of COVID-19 patients with humoral immunodeficiency is challenging. We describe a woman with COVID-19 with multiple relapses due to anti-CD20 monoclonal antibody treatment. She was successfully treated with casirivimab/imdevimab and confirmed to have neutralizing antibodies. This case suggests that monoclonal antibodies have therapeutic and prophylactic value in patients with humoral immunodeficiency.

    DOI: 10.1016/j.jiac.2022.03.002

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  • Yuriko Terayama, Noriko Tomita, Junko Terada-Hirashima, Yukari Uemura, Yosuke Shimizu, Junko S. Takeuchi, Yuki Takamatsu, Kenji Maeda, Ayako Mikami, Mugen Ujiie, Wataru Sugiura .  Protocol of an Exploratory Single-Arm Study to Evaluate the Safety and Immunogenicity of KD-414 as a Booster Vaccine for SARS-CoV-2 in Healthy Adults (KAPIVARA) .  Life12 ( 7 ) 966 - 966   2022.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:MDPI AG  

    Background: The coronavirus disease 2019 (COVID-19) pandemic is currently ongoing, and there have been significant efforts in the development of COVID-19 vaccines. However, the neutralizing antibody titers in vaccinated individuals are reported to progressively decrease over time. Japanese pharmaceutical companies have published the results of Phase I and II studies on the safety and efficacy of different vaccines. Final clinical trials will be conducted with the aim of practical application by March 2023. To effectively utilize vaccines developed by Japanese companies, the efficacy and safety of a booster dose (i.e., third vaccination) must be evaluated among individuals who have received three doses of different vaccines. Methods: This protocol describes a study that aims to examine the effect of a booster dose of “KD-414”, a novel Japanese inactivated vaccine, on antibody titers among participants involved in a previous study. Volunteers in this protocol will be recruited from participants in the previous study and immunized with KD-414 after obtaining consent. The antibody titers, before and after immunization with KD-414, among participants who previously received two doses of the BNT162b2 mRNA vaccine, will be comparatively analyzed. Discussion: The reactogenicity and immunogenicity of seven different COVID-19 vaccines including an inactivated vaccine as a third dose after two doses of ChAdOx1 nCov-19 or BNT162b2, has been tested previously, and found to be superior to control (quadrivalent meningococcal conjugate vaccine) regardless of which vaccine had been received during the initial course. This suggests that many types of third booster doses are efficacious. It is anticipated that this study will provide evidence of the safety and immunogenicity of KD-414 as a booster vaccine, which will have profound public health implications.

    DOI: 10.3390/life12070966

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  • Yuki Takamatsu, Kazumi Omata, Yosuke Shimizu, Noriko Kinoshita-Iwamoto, Mari Terada, Tetsuya Suzuki, Shinichiro Morioka, Yukari Uemura, Norio Ohmagari, Kenji Maeda, Hiroaki Mitsuya .  SARS-CoV-2-neutralizing humoral IgA response occurs earlier but modest and diminishes faster compared to IgG response. .  bioRxiv : the preprint server for biology   2022.6SARS-CoV-2-neutralizing humoral IgA response occurs earlier but modest and diminishes faster compared to IgG response.International journal

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    Secretory immunoglobulin A (IgA) plays a crucial role in the mucosal immunity for preventing the invasion of the exogenous antigens, however, little has been understood about the neutralizing activity of serum IgA. Here, to examine the role of IgA antibodies against COVID-19 illnesses, we determined the neutralizing activity of serum/plasma IgG and IgA purified from previously SARS-CoV-2-infected and COVID-19 mRNA-vaccine-receiving individuals. We found that serum/plasma IgA possesses substantial but rather modest neutralizing activity against SARS-CoV-2 compared to IgG with no significant correlation with the disease severity. Neutralizing IgA and IgG antibodies achieved the greatest activity at approximately 25 and 35 days after symptom onset, respectively. However, neutralizing IgA activity quickly diminished and went down below the detection limit approximately 70 days after onset, while substantial IgG activity was observed till 200 days after onset. The total neutralizing activity in sera/plasmas of those with COVID-19 largely correlated with that in purified-IgG and purified-IgA and levels of anti-SARS-CoV-2-S1-binding IgG and anti-SARS-CoV-2-S1-binding IgA. In individuals who were previously infected with SARS-CoV-2 but had no detectable neutralizing IgA activity, a single dose of BNT162b2 or mRNA-1273 elicited potent serum/plasma neutralizing IgA activity but the second dose did not further strengthen the neutralization antibody response. The present data show that the systemic immune stimulation with natural infection and COVID-19 mRNA-vaccines elicit both SARS-CoV-2-specific neutralizing IgG and IgA response in serum, but the IgA response is modest and diminishes faster compared to IgG response. Author Summary: Immunoglobulin A (IgA) is the most abundant type of antibody in the body mostly located on mucosal surfaces as a dimeric secretory IgA. Such secretory IgA plays an important role in preventing the adherence and invasions of foreign objects by its neutralizing activity, while monomeric serum IgA is thought to relate to the phagocytic immune system activation. Here, we report that individuals with the novel coronavirus disease (COVID-19) developed both systemic neutralizing IgG and IgA active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the neutralizing IgA response was quick and reached the highest activity 25 days post-symptom-onset, compared to 35 days for IgG response, neutralizing IgA activity was modest and diminished faster than neutralizing IgG response. In individuals, who recovered from COVID-19 but had no detectable neutralizing IgA activity, a single dose of COVID-19 mRNA-vaccine elicited potent neutralizing IgA activity but the second dose did not further strengthen the antibody response. Our study provides novel insights into the role and the kinetics of serum IgA against the viral pathogen both in naturally-infected and COVID-19 mRNA-vaccine-receiving COVID-19-convalescent individuals.

    DOI: 10.1101/2022.06.09.495422

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  • Noriko Tomita, Sho Saito, Junko Terada-Hirashima, Ayako Mikami, Yukari Uemura, Satoshi Kutsuna, Hidetoshi Nomoto, Kyoko Fujisawa, Maki Nagashima, Mari Terada, Shinobu Ashida, Shinichiro Morioka, Masahiro Satake, Akira Hangaishi, Tomiteru Togano, Katsuyuki Shiratori, Yuki Takamatsu, Kenji Maeda, Norio Ohmagari, Wataru Sugiura, Hiroaki Mitsuya .  A Multi-Center, Open-Label, Randomized Controlled Trial to Evaluate the Efficacy of Convalescent Plasma Therapy for Coronavirus Disease 2019: A Trial Protocol (COVIPLA-RCT). .  Life (Basel, Switzerland)12 ( 6 )   2022.6A Multi-Center, Open-Label, Randomized Controlled Trial to Evaluate the Efficacy of Convalescent Plasma Therapy for Coronavirus Disease 2019: A Trial Protocol (COVIPLA-RCT).International journal

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    BACKGROUND: Coronavirus disease 2019 is a global public health concern. As of December 2020, the therapeutic agents approved for coronavirus disease 2019 in Japan were limited to two drugs: remdesivir, an antiviral drug, granted a Special Approval for Emergency on 7 May 2020, and dexamethasone, which has an anti-inflammatory effect. The aim of this study is to evaluate the efficacy of convalescent plasma collected from donors who recovered from coronavirus disease 2019. METHODS: This is an open-label, randomized controlled trial comprising two groups: a convalescent plasma and a standard-of-care group. Plasma administered to patients with coronavirus disease 2019 randomized in the convalescent plasma group of this trial will be plasma that has been collected and stored in an associated study. Patients with a diagnosis of mild coronavirus disease 2019 will be included in this trial. The efficacy of convalescent plasma transfusion will be evaluated by comparing the convalescent plasma group to the standard-of-care group (without convalescent plasma transfusion) with respect to changes in the viral load and other measures. The primary endpoint will be time-weighted average changes in the SARS-CoV-2 virus load in nasopharyngeal swabs from day 0 to days 3 and 5. It is hypothesized that the intervention should result in a decrease in the viral load in the convalescent plasma group until day 5. This endpoint has been used as a change in viral load has and been used as an index of therapeutic effect in several previous studies. DISCUSSION: The proposed trial has the potential to prevent patients with mild COVID-19 from developing a more severe illness. Several RCTs of convalescent plasma therapy have already been conducted in countries outside of Japan, but no conclusion has been reached with respect to the efficacy of convalescent plasma therapy, which is likely in part because of the heterogeneity of the types of target patients, interventions, and endpoints among trials. Actually, previous clinical trials on plasma therapy have shown inconsistent efficacy and are sometimes ineffective in COVID-19 patients with severe disease, which is due to unmeasured neutralizing antibody titer in the COVID-19 convalescent plasma. To improve this issue, in this study, we measure neutralizing activity of convalescent plasma before administration and provide the plasma with high neutralizing activity to the subjects. It is hoped that this study will further evidence to support the role of convalescent plasma therapy in COVID-19.

    DOI: 10.3390/life12060856

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  • Makoto Inada, Masahiro Ishikane, Mari Terada, Akihiro Matsunaga, Kenji Maeda, Noriko Iwamoto, Mugen Ujiie, Satoshi Kutsuna, Shinichiro Morioka, Yukihito Ishizaka, Hiroaki Mitsuya, Norio Ohmagari .  Antibody responses after two doses of SARS-CoV-2 mRNA-1273 vaccine in an individual with history of COVID-19 re-infection. .  International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases119   18 - 20   2022.6Antibody responses after two doses of SARS-CoV-2 mRNA-1273 vaccine in an individual with history of COVID-19 re-infection.International journal

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    We present a case of a 58-year-old Japanese man with a history of 2 previous COVID-19 infections, who received 2 doses of mRNA-1273 vaccine. We are not aware of any previous study regarding antibody tendency after 2 infections and 2 vaccinations. We evaluated his IgG titer of antispike protein and neutralizing activity from the first infection before and after 2 doses of vaccine. Both antispike IgG titer and neutralizing activity showed a tendency to decline almost 1 year after initial infection; they rapidly increased after the first vaccination, and they remained high after the second vaccination. Although this is a single case report, it seems to have generalizability because the findings are consistent with previous reports regarding single infections or 3 doses of vaccination. Our findings suggest that a single booster shot may provide sufficient protection and aid the understanding of immunologic responses of vaccination in patients with COVID-19 with history of re-infection.

    DOI: 10.1016/j.ijid.2022.03.017

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  • Masayuki Amano, Kenji Maeda, Kiyoto Tsuchiya, Shinya Shimada, Hiroaki Mitsuya .  Third-dose BNT162b2 vaccination elicits markedly high-level SARS-CoV-2-neutralizing antibodies in vaccinees who poorly responded to second dose in Japan. .  The Journal of infectious diseases   2022.5Third-dose BNT162b2 vaccination elicits markedly high-level SARS-CoV-2-neutralizing antibodies in vaccinees who poorly responded to second dose in Japan.International journal

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    DOI: 10.1093/infdis/jiac209

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  • Ryuta Uraki, Maki Kiso, Shun Iida, Masaki Imai, Emi Takashita, Makoto Kuroda, Peter J Halfmann, Samantha Loeber, Tadashi Maemura, Seiya Yamayoshi, Seiichiro Fujisaki, Zhongde Wang, Mutsumi Ito, Michiko Ujie, Kiyoko Iwatsuki-Horimoto, Yuri Furusawa, Ryan Wright, Zhenlu Chong, Seiya Ozono, Atsuhiro Yasuhara, Hiroshi Ueki, Yuko Sakai-Tagawa, Rong Li, Yanan Liu, Deanna Larson, Michiko Koga, Takeya Tsutsumi, Eisuke Adachi, Makoto Saito, Shinya Yamamoto, Masao Hagihara, Keiko Mitamura, Tetsuro Sato, Masayuki Hojo, Shin-Ichiro Hattori, Kenji Maeda, Riccardo Valdez, Moe Okuda, Jurika Murakami, Calvin Duong, Sucheta Godbole, Daniel C Douek, Ken Maeda, Shinji Watanabe, Aubree Gordon, Norio Ohmagari, Hiroshi Yotsuyanagi, Michael S Diamond, Hideki Hasegawa, Hiroaki Mitsuya, Tadaki Suzuki, Yoshihiro Kawaoka .  Characterization and antiviral susceptibility of SARS-CoV-2 Omicron/BA.2. .  Nature607 ( 7917 ) 119 - 127   2022.5Characterization and antiviral susceptibility of SARS-CoV-2 Omicron/BA.2.International journal

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    The recent emergence of SARS-CoV-2 Omicron variants possessing numerous mutations has raised concerns of decreased effectiveness of current vaccines, therapeutic monoclonal antibodies, and antiviral drugs for COVID-19 against these variants1,2. The original Omicron lineage, BA.1, prevailed in many countries, but more recently, BA.2 has become dominant in at least 68 countries3. Here, we evaluated the replicative ability and pathogenicity of authentic infectious BA.2 isolates in immunocompetent and human ACE2 (hACE2)-expressing mice and hamsters. In contrast to recent data with chimeric, recombinant SARS-CoV-2 strains expressing the spike proteins of BA.1 and BA.2 on an ancestral WK-521 backbone4, we observed similar infectivity and pathogenicity in mice and hamsters between BA.2 and BA.1, and less pathogenicity compared to early SARS-CoV-2 strains. We also observed a marked and significant reduction in the neutralizing activity of plasma from COVID-19 convalescent individuals and vaccine recipients against BA.2 compared to ancestral and Delta variant strains. In addition, we found that some therapeutic monoclonal antibodies (REGN10987/REGN10933, COV2-2196/COV2-2130, and S309) and antiviral drugs (molnupiravir, nirmatrelvir, and S-217622) can restrict viral infection in the respiratory organs of BA.2-infected hamsters. These findings suggest that the replication and pathogenicity of BA.2 is comparable to that of BA.1 in rodents and that several therapeutic monoclonal antibodies and antiviral compounds are effective against Omicron/BA.2 variants.

    DOI: 10.1038/s41586-022-04856-1

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  • Kohei Kamegai, Noriko Iwamoto, Tomiteru Togano, Kenji Maeda, Yuki Takamatsu, Yusuke Miyazato, Masahiro Ishikane, Masashi Mizokami, Masaya Sugiyama, Shun Iida, Sho Miyamoto, Tadaki Suzuki, Norio Ohmagari .  A Fatal Breakthrough COVID-19 Case Following Bendamustine-Rituximab Therapy. .  International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases121   85 - 88   2022.4A Fatal Breakthrough COVID-19 Case Following Bendamustine-Rituximab Therapy.International journal

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    Although messenger ribonucleic acid vaccines are substantially effective toward SARS-CoV-2 infection, patients with hematologic malignancies are still prone to the virus. Herein, we report a fatal case of breakthrough SARS-CoV-2 Delta variant infection in a patient with mucosa-associated lymphoid tissue lymphoma with remission by bendamustine-rituximab (BR) therapy completed a year ago. The serologic study revealed impaired responsiveness toward vaccines and prolonged high viral load after infection. BR therapy seemingly induced an immune escape. Prevention and treatment strategies for such vulnerable patients should be clarified immediately.

    DOI: 10.1016/j.ijid.2022.04.058

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  • Emi Takashita, Noriko Kinoshita, Seiya Yamayoshi, Yuko Sakai-Tagawa, Seiichiro Fujisaki, Mutsumi Ito, Kiyoko Iwatsuki-Horimoto, Peter Halfmann, Shinji Watanabe, Kenji Maeda, Masaki Imai, Hiroaki Mitsuya, Norio Ohmagari, Makoto Takeda, Hideki Hasegawa, Yoshihiro Kawaoka .  Efficacy of Antiviral Agents against the SARS-CoV-2 Omicron Subvariant BA.2. .  The New England journal of medicine386 ( 15 ) 1475 - 1477   2022.4Efficacy of Antiviral Agents against the SARS-CoV-2 Omicron Subvariant BA.2.International journal

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  • Seik-Soon Khor, Yosuke Omae, Junko S Takeuchi, Ami Fukunaga, Shohei Yamamoto, Akihito Tanaka, Kouki Matsuda, Moto Kimura, Kenji Maeda, Gohzoh Ueda, Tetsuya Mizoue, Mugen Ujiie, Hiroaki Mitsuya, Norio Ohmagari, Wataru Sugiura, Katsushi Tokunaga .  An Association Study of HLA with the Kinetics of SARS-CoV-2 Spike Specific IgG Antibody Responses to BNT162b2 mRNA Vaccine. .  Vaccines10 ( 4 )   2022.4An Association Study of HLA with the Kinetics of SARS-CoV-2 Spike Specific IgG Antibody Responses to BNT162b2 mRNA Vaccine.International journal

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    BNT162b2, an mRNA-based SARS-CoV-2 vaccine (Pfizer-BioNTech, New York, NY, USA), is one of the most effective COVID-19 vaccines and has been approved by more than 130 countries worldwide. However, several studies have reported that the COVID-19 vaccine shows high interpersonal variability in terms of humoral and cellular responses, such as those with respect to SARS-CoV-2 spike protein immunoglobulin (Ig)G, IgA, IgM, neutralizing antibodies, and CD4+ and CD8+ T cells. The objective of this study is to investigate the kinetic changes in anti-SARS-CoV-2 spike IgG (IgG-S) profiles and adverse reactions and their associations with HLA profiles (HLA-A, -C, -B, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1) among 100 hospital workers from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan. DQA1*03:03:01 (p = 0.017; Odd ratio (OR) 2.80, 95%confidence interval (CI) 1.05-7.25) was significantly associated with higher IgG-S production after two doses of BNT162b2, while DQB1*06:01:01:01 (p = 0.028, OR 0.27, 95%CI 0.05-0.94) was significantly associated with IgG-S declines after two doses of BNT162b2. No HLA alleles were significantly associated with either local symptoms or fever. However, C*12:02:02 (p = 0.058; OR 0.42, 95%CI 0.15-1.16), B*52:01:01 (p = 0.031; OR 0.38, 95%CI 0.14-1.03), DQA1*03:02:01 (p = 0.028; OR 0.39, 95%CI 0.15-1.00) and DPB1*02:01:02 (p = 0.024; OR 0.45, 95%CI 0.21-0.97) appeared significantly associated with protection against systemic symptoms after two doses of BNT162b2 vaccination. Further studies with larger sample sizes are clearly warranted to determine HLA allele associations with the production and long-term sustainability of IgG-S after COVID-19 vaccination.

    DOI: 10.3390/vaccines10040563

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  • Shohei Yamamoto, Ami Fukunaga, Akihito Tanaka, Junko S Takeuchi, Yosuke Inoue, Moto Kimura, Kenji Maeda, Gohzoh Ueda, Tetsuya Mizoue, Mugen Ujiie, Wataru Sugiura, Norio Ohmagari .  Association between reactogenicity and SARS-CoV-2 antibodies after the second dose of the BNT162b2 COVID-19 vaccine. .  Vaccine40 ( 13 ) 1924 - 1927   2022.3Association between reactogenicity and SARS-CoV-2 antibodies after the second dose of the BNT162b2 COVID-19 vaccine.International journal

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    High vaccine reactogenicities may reflect stronger immune responses, but the epidemiological evidence for coronavirus disease 2019 (COVID-19) vaccines is sparse and inconsistent. We observed that a fever of ≥38℃ after two doses of the BNT162b2 vaccine was associated with higher severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike IgG titers.

    DOI: 10.1016/j.vaccine.2022.02.052

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  • Emi Takashita, Noriko Kinoshita, Seiya Yamayoshi, Yuko Sakai-Tagawa, Seiichiro Fujisaki, Mutsumi Ito, Kiyoko Iwatsuki-Horimoto, Shiho Chiba, Peter Halfmann, Hiroyuki Nagai, Makoto Saito, Eisuke Adachi, David Sullivan, Andrew Pekosz, Shinji Watanabe, Kenji Maeda, Masaki Imai, Hiroshi Yotsuyanagi, Hiroaki Mitsuya, Norio Ohmagari, Makoto Takeda, Hideki Hasegawa, Yoshihiro Kawaoka .  Efficacy of Antibodies and Antiviral Drugs against Covid-19 Omicron Variant. .  The New England journal of medicine386 ( 10 ) 995 - 998   2022.3Efficacy of Antibodies and Antiviral Drugs against Covid-19 Omicron Variant.International journal

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  • Hiroko Beppu, Toshie Ogawa, Masahiro Ishikane, Tomoko Kawanishi, Tatsuya Fukuda, Lubuna Sato, Akihiro Matsunaga, Kenji Maeda, Daisuke Katagiri, Yukihito Ishizaka, Hiroaki Mitsuya, Norio Ohmagari, Fumihiko Yasui, Michinori Kohara, Kan Kikuchi, Sachiko Wakai .  A case of COVID-19 reinfection in a hemodialysis patient: the role of antibody in SARS-CoV-2 infection. .  CEN case reports   2022.3A case of COVID-19 reinfection in a hemodialysis patient: the role of antibody in SARS-CoV-2 infection.

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    Hemodialysis patients are vulnerable to severe and lethal COVID-19, and their protective immunity against COVID-19 is not yet fully understood. Therefore, we report a case of COVID-19 reinfection in a hemodialysis patient 81 days after the first episode and discuss the role of antibodies in SARS-CoV-2 infection. A hemodialysis patient developed asymptomatic COVID-19 due to an outbreak in a hospital on October 29th, 2020. As he was hospitalized and did not develop any symptoms, he was discharged on November 9th. On January 18th, he presented with symptomatic COVID-19 due to close household contact. Then, he developed respiratory failure and was transferred to National Center for Global Health and Medicine if he would need intensive care. He recovered with oxygen inhalation, favipiravir, and steroid treatment, and was discharged on February 12th. To evaluate anti-SARS-CoV-2 antibodies during two hospital stays, we measured immunoglobulin (Ig) G specific for S1 subunit of Spike (S) protein of SARS-CoV-2 (IgG-S1) , IgG specific for the full-length S protein (anti-Spike IgG) and neutralizing antibodies. No seroconversion occurred 5 days after initial infection, the seroconversion of IgG-S1 was observed 10 days after the second infection. Similar to IgG-S1 antibody titer results, anti-Spike IgG and neutralizing antibodies increased from 12 days after the second infection. In conclusion, we experienced a case of COVID-19 reinfection in a hemodialysis patient 81 days after the first episode and showed the kinetics and role of antibodies in SARS-CoV-2 infection. Further studies are needed to understand SARS-CoV-2 reinfection risk in hemodialysis patients and its clinical significance.

    DOI: 10.1007/s13730-022-00697-z

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  • Yoshihiro Kawaoka, Ryuta Uraki, Maki Kiso, Shun Iida, Masaki Imai, Emi Takashita, Makoto Kuroda, Peter Halfmann, Samantha Loeber, Tadashi Maemura, Seiya Yamayoshi, Seiichiro Fujisaki, Zhongde Wang, Mutsumi Ito, Michiko Ujie, Kiyoko Iwatsuki-Horimoto, Yuri Furusawa, Ryan Wright, Zhenlu Chong, Seiya Ozono, Atsuhiro Yasuhara, Hiroshi Ueki, Yuko Sakai, Rong Li, Yanan Liu, Deanna Larson, Michiko Koga, Takeya Tsutsumi, Eisuke Adachi, Makoto Saito, Shinya Yamamoto, Shohei Matsubara, Masao Hagihara, Keiko Mitamura, Tetsuro Sato, Masayuki Hojo, Shin-Ichiro Hattori, Kenji Maeda, Moe Okuda, Jurika Murakami, Calvin Duong, Sucheta Godbole, Daniel Douek, Shinji Watanabe, Norio Ohmagari, Hiroshi Yotsuyanagi, Michael Diamond, Hideki Hasegawa, Hiroaki Mitsuya, Tadaki Suzuki .  Characterization and antiviral susceptibility of SARS-CoV-2 Omicron/BA.2. .  Research square   2022.2Characterization and antiviral susceptibility of SARS-CoV-2 Omicron/BA.2.International journal

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    The recent emergence of SARS-CoV-2 Omicron variants possessing large numbers of mutations has raised concerns of decreased effectiveness of current vaccines, therapeutic monoclonal antibodies, and antiviral drugs for COVID-19 against these variants1,2. While the original Omicron lineage, BA.1, has become dominant in many countries, BA.2 has been detected in at least 67 countries and has become dominant in the Philippines, India, and Denmark. Here, we evaluated the replicative ability and pathogenicity of an authentic infectious BA.2 isolate in immunocompetent and human ACE2 (hACE2)-expressing mice and hamsters. In contrast to recent data with chimeric, recombinant SARS-CoV-2 strains expressing the spike proteins of BA.1 and BA.2 on an ancestral WK-521 backbone3, we observed similar infectivity and pathogenicity in mice and hamsters between BA.2 and BA.1, and less pathogenicity compared to early SARS-CoV-2 strains. We also observed a marked and significant reduction in the neutralizing activity of plasma from COVID-19 convalescent individuals and vaccine recipients against BA.2 compared to ancestral and Delta variant strains. In addition, we found that some therapeutic monoclonal antibodies (REGN10987/REGN10933, COV2-2196/COV2-2130, and S309) and antiviral drugs (molnupiravir, nirmatrelvir, and S-217622) can restrict viral infection in the respiratory organs of hamsters infected with BA.2. These findings suggest that the replication and pathogenicity of BA.2 is comparable to that of BA.1 in rodents and that several therapeutic monoclonal antibodies and antiviral compounds are effective against Omicron/BA.2 variants.

    DOI: 10.21203/rs.3.rs-1375091/v1

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  • Yuki Takamatsu, Masaki Imai, Kenji Maeda, Noriko Nakajima, Nobuyo Higashi-Kuwata, Kiyoko Iwatsuki-Horimoto, Mutsumi Ito, Maki Kiso, Tadashi Maemura, Yuichiro Takeda, Kazumi Omata, Tadaki Suzuki, Yoshihiro Kawaoka, Hiroaki Mitsuya .  Highly Neutralizing COVID-19 Convalescent Plasmas Potently Block SARS-CoV-2 Replication and Pneumonia in Syrian Hamsters. .  Journal of virology96 ( 4 ) e0155121   2022.2Highly Neutralizing COVID-19 Convalescent Plasmas Potently Block SARS-CoV-2 Replication and Pneumonia in Syrian Hamsters.International journal

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    Despite various attempts to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients with COVID-19 convalescent plasmas, neither appropriate approach nor clinical utility has been established. We examined the efficacy of administration of highly neutralizing COVID-19 convalescent plasma (hn-plasmas) and such plasma-derived IgG administration using the Syrian hamster COVID-19 model. Two hn-plasmas, which were in the best 1% of 340 neutralizing activity-determined convalescent plasmas, were intraperitoneally administered to SARS-CoV-2-infected hamsters, resulting in a significant reduction of viral titers in lungs by up to 32-fold compared to the viral titers in hamsters receiving control nonneutralizing plasma, while with two moderately neutralizing plasmas (mn-plasmas) administered, viral titer reduction was by up to 6-fold. IgG fractions purified from the two hn-plasmas also reduced viral titers in lungs more than those from the two mn-plasmas. The severity of lung lesions seen in hamsters receiving hn-plasmas was minimal to moderate as assessed using microcomputerized tomography, which histological examination confirmed. Western blotting revealed that all four COVID-19 convalescent plasmas variably contained antibodies against SARS-CoV-2 components, including the receptor-binding domain and S1 domain. The present data strongly suggest that administering potent neutralizing activity-confirmed COVID-19 convalescent plasmas would be efficacious in treating patients with COVID-19. IMPORTANCE Convalescent plasmas obtained from patients who recovered from a specific infection have been used as agents to treat other patients infected with the very pathogen. To treat using convalescent plasmas, despite that more than 10 randomized controlled clinical trials have been conducted and more than 100 studies are currently ongoing, the effects of convalescent plasma against COVID-19 remained uncertain. On the other hand, certain COVID-19 vaccines have been shown to reduce the clinical COVID-19 onset by 94 to 95%, for which the elicited SARS-CoV-2-neutralizing antibodies are apparently directly responsible. Here, we demonstrate that highly neutralizing effect-confirmed convalescent plasmas significantly reduce the viral titers in the lung of SARS-CoV-2-infected Syrian hamsters and block the development of virally induced lung lesions. The present data provide a proof of concept that the presence of highly neutralizing antibody in COVID-19 convalescent plasmas is directly responsible for the reduction of viral replication and support the use of highly neutralizing antibody-containing plasmas in COVID-19 therapy with convalescent plasmas.

    DOI: 10.1128/JVI.01551-21

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  • Satoshi Kutsuna, Sho Saito, Yuki Takamatsu, Mari Terada, Tomiteru Togano, Noriko Kinoshita, Kenji Maeda, Akihiro Matsunaga, Masahiro Satake, Keiji Matsubayashi, Nelson Hirokazu Tsuno, Makiko Kojima, Madoka Kuramitsu, Kenta Tezuka, Emi Ikebe, Kazu Okuma, Isao Hamaguchi, Yumiko Shimanishi, Akira Hangaishi, Yukihito Ishizaka, Norio Ohmagari, Hiroaki Mitsuya .  Safety of convalescent plasma therapy for COVID-19 patients and analysis of viral kinetics: a single-center, open-label, single-arm, interventional study in Japan .  GHM Open   2022

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    DOI: 10.35772/ghmo.2022.01002

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  • Shohei Yamamoto, Kenji Maeda, Kouki Matsuda, Akihito Tanaka, Kumi Horii, Kaori Okudera, Junko S Takeuchi, Tetsuya Mizoue, Maki Konishi, Mitsuru Ozeki, Haruhito Sugiyama, Nobuyoshi Aoyanagi, Hiroaki Mitsuya, Wataru Sugiura, Norio Ohmagari .  COVID-19 breakthrough infection and post-vaccination neutralizing antibody among healthcare workers in a referral hospital in Tokyo: a case-control matching study. .  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America75 ( 1 ) e683 - e691   2021.12COVID-19 breakthrough infection and post-vaccination neutralizing antibody among healthcare workers in a referral hospital in Tokyo: a case-control matching study.International journal

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    BACKGROUND: While increasing coverage of effective vaccines against coronavirus disease 2019 (COVID-19), emergent variants raise concerns about breakthrough infection. Data are limited, however, whether breakthrough infection during the epidemic of the variant is ascribed to insufficient vaccine-induced immunogenicity. METHODS: We described incident COVID-19 in relation to the vaccination program among workers of a referral hospital in Tokyo. During the predominantly Delta epidemic, we followed 2,415 fully vaccinated staff (BNT162b2) for breakthrough infection and selected three matched controls. We measured post-vaccination neutralizing antibodies against the wild-type, Alpha (B.1.1.7), and Delta (B.1.617.2) strains using live viruses and anti-spike antibodies using quantitative assays, and compared them using the generalized estimating equation model between the two groups. RESULTS: No COVID-19 cases occurred 1-2 months after the vaccination program during the fourth epidemic wave in Japan, dominated by the Alpha variant, while 22 cases emerged 2-4 months after the vaccination program during the fifth wave, dominated by the Delta variant. In the vaccinated cohort, all 17 cases of breakthrough infection were mild or asymptomatic and had returned to work early. There was no measurable difference between cases and controls in post-vaccination neutralizing antibody titers against the wild-type, Alpha, and Delta, and anti-spike antibody titers, while neutralizing titers against the variants were considerably lower than those against the wild-type. CONCLUSIONS: Post-vaccination neutralizing antibody titers were not decreased among patients with breakthrough infection relative to their controls under the Delta variant rampage. The result points to the importance of infection control measures in the post-vaccination era, irrespective of immunogenicity profile.

    DOI: 10.1093/cid/ciab1048

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  • Matsuda K, Islam S, Takada T, Tsuchiya K, Yang Tan BJ, Hattori SI, Katsuya H, Kitagawa K, Kim KS, Matsuo M, Sugata K, Delino NS, Gatanaga H, Yoshimura K, Matsushita S, Mitsuya H, Iwami S, Satou Y, Maeda K .  A widely distributed HIV-1 provirus elimination assay to evaluate latency-reversing agents <i>in vitro</i>. .  Cell reports methods1 ( 8 ) 100122   2021.12A widely distributed HIV-1 provirus elimination assay to evaluate latency-reversing agents <i>in vitro</i>.

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    DOI: 10.1016/j.crmeth.2021.100122

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  • Matsuda K, Islam S, Takada T, Tsuchiya K, Yang BTJ, Shin-ichiro Hattori SI, Katsuya H, Kitagawa K, Kim KS, Matsuo M, Sugata K, Delino NS, Gatanaga H, Yoshimura K, Matsushita S, Mitsuya H, Iwami S, Satou Y, Maeda K .  A widely-distributed HIV-1 provirus elimination assay to evaluate latency-reversing agents in vitro .  Cell Rep. Methods   2021.12A widely-distributed HIV-1 provirus elimination assay to evaluate latency-reversing agents in vitroReviewed

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  • Kenji Maeda, Masayuki Amano, Yukari Uemura, Kiyoto Tsuchiya, Tomoko Matsushima, Kenta Noda, Yosuke Shimizu, Asuka Fujiwara, Yuki Takamatsu, Yasuko Ichikawa, Hidehiro Nishimura, Mari Kinoshita, Shota Matsumoto, Hiroyuki Gatanaga, Kazuhisa Yoshimura, Shin-Ichi Oka, Ayako Mikami, Wataru Sugiura, Toshiyuki Sato, Tomokazu Yoshida, Shinya Shimada, Hiroaki Mitsuya .  Correlates of neutralizing/SARS-CoV-2-S1-binding antibody response with adverse effects and immune kinetics in BNT162b2-vaccinated individuals. .  Scientific reports11 ( 1 ) 22848 - 22848   2021.11Correlates of neutralizing/SARS-CoV-2-S1-binding antibody response with adverse effects and immune kinetics in BNT162b2-vaccinated individuals.International journal

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    While mRNA vaccines against SARS-CoV-2 are exceedingly effective in preventing symptomatic infection, their immune response features remain to be clarified. In the present prospective study, 225 healthy individuals in Japan, who received two BNT162b2 doses, were enrolled. Correlates of BNT162b2-elicited SARS-CoV-2-neutralizing activity (50% neutralization titer: NT50; assessed using infectious virions) with various determinants were examined and the potency of sera against variants of concerns was determined. Significant rise in NT50s was seen in sera on day 28 post-1st dose. A moderate inverse correlation was seen between NT50s and ages, but no correlation seen between NT50s and adverse effects. NT50s and SARS-CoV-2-S1-binding-IgG levels on day 28 post-1st dose and pain scores following the 2nd dose were greater in women than in men. The average half-life of NT50s was ~ 68 days, and 23.6% (49 out of 208 individuals) failed to show detectable neutralizing activity on day 150. While sera from elite-responders (NT50s > 1,500: the top 4% among the participants) potently to moderately blocked all variants of concerns examined, some sera with low NT50s failed to block the B.1.351-beta strain. Since BNT162b2-elicited immunity against SARS-CoV-2 is short, an additional vaccine or other protective measures are needed.

    DOI: 10.1038/s41598-021-01930-y

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  • Junko S Takeuchi, Ami Fukunaga, Shohei Yamamoto, Akihito Tanaka, Kouki Matsuda, Moto Kimura, Azusa Kamikawa, Yumiko Kito, Kenji Maeda, Gohzoh Ueda, Tetsuya Mizoue, Mugen Ujiie, Hiroaki Mitsuya, Norio Ohmagari, Wataru Sugiura .  SARS-CoV-2 specific T cell and humoral immune responses upon vaccination with BNT162b2 .      2021.11

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    <bold>Background.</bold> The humoral and cellular immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) upon coronavirus disease 2019 (COVID-19) vaccination remain to be clarified. Hence, we aimed to investigate the chronological changes in SARS-CoV-2 specific IgG antibody, neutralizing antibody, and T cell responses during and after receiving the BNT162b2 vaccine.
    <bold>Methods.</bold> We performed serological, neutralization, and T cell assays among 100 hospital workers aged 22-73 years who received the vaccine. We conducted five surveys on day 1, day 15, day 29 (seven days after the second dose), day 61, and days 82-96 following the first dose.
    <bold>Results.</bold> SARS-CoV-2 spike protein-specific IgG (IgG-S) titers and T cell responses increased significantly following the first vaccination dose. The highest titers were observed on day 29 and decreased gradually until the end of the follow-up period. There was no correlation between IgG-S and T cell responses. Notably, T cell responses were detected on day 15, earlier than the onset of neutralizing activity.
    <bold>Conclusions.</bold> This study demonstrated that both IgG-S and T cell responses were detected before acquiring sufficient levels of SARS-CoV-2 neutralizing antibodies. These early immune responses are sustained for approximately six-ten weeks following the second vaccination dose.

    DOI: 10.1101/2021.11.06.21265632

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  • Hidetoshi Nomoto, Kei Yamamoto, Gen Yamada, Michiyo Suzuki, Noriko Kinoshita, Jin Takasaki, Ataru Moriya, Kenji Maeda, Motoi Kimura, Norio Ohmagari .  Time-course evaluation of the quantitative antigen test for severe acute respiratory syndrome coronavirus 2: The potential contribution to alleviating isolation of COVID-19 patients. .  Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy27 ( 11 ) 1669 - 1673   2021.11Time-course evaluation of the quantitative antigen test for severe acute respiratory syndrome coronavirus 2: The potential contribution to alleviating isolation of COVID-19 patients.International journal

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    INTRODUCTION: The automated quantitative antigen test (QAT), which detects severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is suitable for mass screening. However, its diagnostic capability differentiated by time from onset and potential contribution to infectivity assessment have not been fully investigated. METHODS: A retrospective, observational study using nasopharyngeal swab specimens from coronavirus disease (COVID-19) inpatients was conducted using LumipulseⓇ SARS-CoV-2 antigen test. Diagnostic accuracy was examined for the early (up to 10 days after onset) and late (over 10 days after onset) stages. Time-course QAT changes and reverse-transcription quantitative polymerase chain reaction tests results were displayed as locally estimated scatterplot smoothing curve, and receiver operating characteristic curve (ROC) analysis was used to determine the appropriate cutoff value for differentiating the early and late stages. RESULTS: We obtained 100 specimens from 68 COVID-19 patients, including 51 early-stage and 49 late-stage specimens. QAT sensitivity and specificity were 0.82 (0.72-0.90) and 0.95 (0.75-0.99) for all periods, 0.93 (0.82-0.98) and 1.00 (0.39-1.00) for the early stage, and 0.66 (0.48-0.82) and 0.93 (0.69-0.99) for the late stage, respectively. The ROC analysis indicated an ideal cutoff value of 6.93 pg/mL for distinguishing early-from late-stage specimens. The sensitivity, specificity, positive predictive value, and negative predictive value for predicting the late stage were 0.76 (0.61-0.87), 0.76 (0.63-0.87), 0.76 (0.61-0.87), and 0.76 (0.63-0.87). CONCLUSIONS: QAT has favorable diagnostic accuracy in the early COVID-19 stages. In addition, an appropriate cutoff point can potentially facilitate rapid identification of noncontagious patients.

    DOI: 10.1016/j.jiac.2021.08.015

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  • Nomoto Hidetoshi, Yamamoto Kei, Yamada Gen, Suzuki Michiyo, Kinoshita Noriko, Takasaki Jin, Moriya Ataru, Maeda Kenji, Kimura Motoi, Ohmagari Norio .  重症急性呼吸器症候群コロナウイルス2型に対する定量抗原検査の経時的評価 COVID-19患者の隔離緩和に貢献する可能性(Time-course evaluation of the quantitative antigen test for severe acute respiratory syndrome coronavirus 2: The potential contribution to alleviating isolation of COVID-19 patients) .  Journal of Infection and Chemotherapy27 ( 11 ) 1669 - 1673   2021.11重症急性呼吸器症候群コロナウイルス2型に対する定量抗原検査の経時的評価 COVID-19患者の隔離緩和に貢献する可能性(Time-course evaluation of the quantitative antigen test for severe acute respiratory syndrome coronavirus 2: The potential contribution to alleviating isolation of COVID-19 patients)

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    Language:English   Publisher:エルゼビア・ジャパン(株)  

    SARS-CoV-2に対する化学発光酵素免疫測定法に基づく自動定量抗原検査法(QAT)の診断能の経時変化や感染性評価への寄与についての後方視的観察研究を実施した。COVID-19入院患者68名から鼻咽頭ぬぐい液100検体を採取した。51検体は初期(発症後10日以内)、49検体は後期(発症後10日以上)に得た。QATの感度と特異度は、それぞれ全期間で0.82(0.72〜0.90)と0.95(0.75〜0.99)、初期で0.93(0.82〜0.98)と1.00(0.39〜1.00)、後期で0.66(0.48〜0.82)と0.93(0.69〜0.99)であった。ROC解析により、初期検体と後期検体を区別する理想的なカットオフ値は6.93pg/mLであった。その新しいカットオフ値を用いた場合、後期を予測する感度、特異度、陽性的中率、陰性的中率はそれぞれ0.75(0.61〜0.86)、0.76(0.62〜0.87)、0.75(0.61〜0.86)、0.76(0.62〜0.87)であった。以上より、QATはCOVID-19の初期段階において良好な診断精度を有していた。また、適切なカットオフポイントを設定することで、非伝染性患者を迅速に特定できる可能性があった。

  • Shohei Yamamoto, Kenji Maeda, Kouki Matsuda, Akihito Tanaka, Kumi Horii, Kaori Okudera, Junko S. Takeuchi, Tetsuya Mizoue, Maki Konishi, Mitsuru Ozeki, Haruhito Sugiyama, Nobuyoshi Aoyanagi, Hiroaki Mitsuya, Wataru Sugiura, Norio Ohmagari .  COVID-19 breakthrough infections and pre-infection neutralizing antibody .      2021.10

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    <title>Abstract</title><sec><title>Background</title>While increasing coverage of effective vaccines against coronavirus disease 2019 (COVID-19), emergent variants raise concerns about breakthrough infections. Data are limited, however, whether breakthrough infection during the epidemic of the variant is ascribed to insufficient vaccine-induced immunogenicity.

    </sec><sec><title>Methods</title>We described incident COVID-19 in relation to the vaccination program among workers of a referral hospital in Tokyo. During the predominantly Delta epidemic, we followed 2,473 fully vaccinated staff (BNT162b2) for breakthrough infection and selected three matched controls. We measured pre-infection neutralizing antibodies against the wild-type, Alpha (B.1.1.7), and Delta (B.1.617.2) strains using live viruses and anti-spike antibodies using quantitative assays, and compared them using the generalized estimating equation model between the two groups.

    </sec><sec><title>Results</title>No COVID-19 cases occurred 1–2 months after the vaccination program during the fourth epidemic wave in Japan, dominated by the Alpha variant, while 22 cases emerged 2–4 months after the vaccination program during the fifth wave, dominated by the Delta variant. In the vaccinated cohort, all 17 cases of breakthrough infection were mild or asymptomatic and had returned to work early. There was no measurable difference between cases and controls in pre-infection neutralizing antibody titers against the wild-type, Alpha, and Delta, and anti-spike antibody titers, while neutralizing titers against the variants were considerably lower than those against the wild-type.

    </sec><sec><title>Conclusions</title>Pre-infection neutralizing antibody titers were not decreased among patients with breakthrough infection under the Delta variant rampage. The result points to the importance of infection control measures in the post-vaccination era, irrespective of immunogenicity profile.

    </sec>

    DOI: 10.1101/2021.10.20.21265301

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  • Nomoto H, Yamamoto K, Yamada G, Suzuki M, Kinoshita N, Takasaki J, Moriya A, Maeda K, Kimura M, Ohmagari N .  Time-series evaluation of the quantitative antigen test for coronavirus disease 2019: the potential usefulness in infectivity assessment. .  Journal of Infection and Chemotherapy   2021.9Time-series evaluation of the quantitative antigen test for coronavirus disease 2019: the potential usefulness in infectivity assessment.Reviewed

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  • Yasuhiro Hayashi, Kiyoto Tsuchiya, Mizuki Yamamoto, Yoko Nemoto-Sasaki, Kazunari Tanigawa, Kotaro Hama, Yusuke Ueda, Takashi Tanikawa, Jin Gohda, Kenji Maeda, Jun-Ichiro Inoue, Atsushi Yamashita .  N-(4-Hydroxyphenyl) Retinamide Suppresses SARS-CoV-2 Spike Protein-Mediated Cell-Cell Fusion by a Dihydroceramide Δ4-Desaturase 1-Independent Mechanism. .  Journal of virology95 ( 17 ) e0080721   2021.8Reviewed International journal

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:American Society for Microbiology  

    Sphingolipids could play an important role in SARS-CoV-2 S-mediated membrane fusion with host cells. We studied the cell-cell fusion using SARS-CoV-2 S-expressing cells and sphingolipid-manipulated target cells, with an inhibitor of the sphingolipid metabolism. 4-HPR (also known as fenretinide) is an inhibitor of DES1, and it exhibits antitumor activity and suppresses cell-cell fusion and viral infection. 4-HPR suppresses membrane fusion through a decrease in membrane fluidity, which could possibly be the cause for the inhibition of SARS-CoV-2 infection.

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  • Kei Yamamoto, Michiyo Suzuki, Gen Yamada, Tsutomu Sudo, Hidetoshi Nomoto, Noriko Kinoshita, Keiji Nakamura, Yoshie Tsujimoto, Yusaku Kusaba, Chie Morita, Ataru Moriya, Kenji Maeda, Shintaro Yagi, Motoi Kimura, Norio Ohmagari .  Corrigendum to "Utility of the antigen test for coronavirus disease 2019: factors influencing the prediction of the possibility of disease transmission" [Int J Infect Dis 104 (2021) 65-72]. .  International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases109   323 - 323   2021.8Corrigendum to "Utility of the antigen test for coronavirus disease 2019: factors influencing the prediction of the possibility of disease transmission" [Int J Infect Dis 104 (2021) 65-72].International journal

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  • Yamamoto Kei, Nagashima Mami, Yoshida Isao, Sadamasu Kenji, Kurokawa Masami, Nagashima Maki, Kinoshita Noriko, Maeda Kenji, Takasaki Jin, Teruya Katsuji, Ohmagari Norio .  新型コロナウイルス(SARS-CoV-2)抗原迅速検査の結果はウイルス培養の結果と相関するか(Does the SARS-CoV-2 rapid antigen test result correlate with the viral culture result?) .  Journal of Infection and Chemotherapy27 ( 8 ) 1273 - 1275   2021.8新型コロナウイルス(SARS-CoV-2)抗原迅速検査の結果はウイルス培養の結果と相関するか(Does the SARS-CoV-2 rapid antigen test result correlate with the viral culture result?)

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    Language:English   Publisher:エルゼビア・ジャパン(株)  

    新型コロナウイルス感染症患者21例を対象に、抗原迅速検査とウイルス培養の結果が相関するかどうかを検討した。対象は新型コロナウイルス感染症患者から採取した鼻腔スワブ検体26例で、そのうち25例は患者が発熱、咳嗽等の呼吸器症状、胸痛、味覚障害、嗅覚障害を発現している期間に採取したものであった。増幅に必要なサイクル数(CT値)を30以下としてリアルタイム定量PCR法を実施し、抗原迅速検査とウイルス培養を実施した。抗原迅速検査ではウイルス量が多いほど陽性率が高かったが、ウイルス培養では発症から10日以内で陽性率が高かった。抗原迅速検査の陽性20例のうち9例(45%)、陰性6例のうち1例(17%)から培養検査でウイルスが検出された。ウイルス量は抗原迅速検査とウイルス培養の結果と関連していた。ROC解析でウイルス量の最適カットオフ値を2.1×10^5copies/mLとした場合、抗原迅速検査の陽性を予測する感度は75%、特異度は100%であった。またウイルス量のカットオフ値を5.4×10^5copies/mLとした場合、ウイルス培養の陽性を予測する感度は90%、特異度は81%であった。

  • Shohei Yamamoto, Akihito Tanaka, Yusuke Oshiro, Masamichi Ishii, Hironori Ishiwari, Maki Konishi, Kouki Matsuda, Mitsuru Ozeki, Kengo Miyo, Kenji Maeda, Tetsuya Mizoue, Wataru Sugiura, Hiroaki Mitsuya, Haruhito Sugiyama, Norio Ohmagari .  Seroprevalence of SARS-CoV-2 antibodies in a national hospital and affiliated facility after the second epidemic wave of Japan. .  The Journal of infection83 ( 2 ) 237 - 279   2021.8Seroprevalence of SARS-CoV-2 antibodies in a national hospital and affiliated facility after the second epidemic wave of Japan.Reviewed International journal

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    DOI: 10.1016/j.jinf.2021.05.017

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  • Kei Yamamoto, Mami Nagashima, Isao Yoshida, Kenji Sadamasu, Masami Kurokawa, Maki Nagashima, Noriko Kinoshita, Kenji Maeda, Jin Takasaki, Katsuji Teruya, Norio Ohmagari .  Does the SARS-CoV-2 rapid antigen test result correlate with the viral culture result? .  Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy27 ( 8 ) 1273 - 1275   2021.8Does the SARS-CoV-2 rapid antigen test result correlate with the viral culture result?Reviewed International journal

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    Rapid antigen tests (RATs) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have advantages over viral culture in terms of cost and rapidity of testing, but they have low sensitivity. In addition, RATs tend to be negative from approximately 11 days after symptom onset. To determine whether the antigen-negative state indicates a lack of infectiousness, we assessed the association between viral culture and RAT results. Viral culture, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and rapid antigen testing were performed on stored nasopharyngeal samples with threshold cycle values < 30, based on previous RT-qPCR testing. SARS-CoV-2 was isolated by viral culture from nine samples (45%) and one sample (17%) with positive and negative RAT results, respectively. The RAT and viral culture results were both associated with the viral load level and their cutoffs were similar, but the associations were not statistically significant. RAT might be a useful indicator of infectiousness, which can be helpful to control infection. However, further studies with larger sample size are warranted to confirm this observation.

    DOI: 10.1016/j.jiac.2021.05.006

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  • Kenji Maeda, Masayuki Amano, Yukari Uemura, Kiyoto Tsuchiya, Tomoko Matsushima, Kenta Noda, Yosuke Shimizu, Asuka Fujiwara, Yuki Takamatsu, Yasuko Ichikawa, Hidehiro Nishimura, Mari Kinoshita, Shota Matsumoto, Hiroyuki Gatanaga, Kazuhisa Yoshimura, Shin-Ichi Oka, Ayako Mikami, Wataru Sugiura, Toshiyuki Sato, Tomokazu Yoshida, Shinya Shimada, Hiroaki Mitsuya .  Correlates of Neutralizing/SARS-CoV-2-S1-binding Antibody Response with Adverse Effects and Immune Kinetics in BNT162b2-Vaccinated Individuals. .  medRxiv : the preprint server for health sciences11 ( 1 ) 22848 - 22848   2021.7Correlates of Neutralizing/SARS-CoV-2-S1-binding Antibody Response with Adverse Effects and Immune Kinetics in BNT162b2-Vaccinated Individuals.Reviewed International journal

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    While mRNA vaccines against SARS-CoV-2 are exceedingly effective in preventing symptomatic infection, their immune response features remain to be clarified. In the present prospective study, 225 healthy individuals in Japan, who received two BNT162b2 doses, were enrolled. Correlates of BNT162b2-elicited SARS-CoV-2-neutralizing activity (50% neutralization titer: NT50; assessed using infectious virions) with various determinants were examined and the potency of sera against variants of concerns was determined. Significant rise in NT50s was seen in sera on day 28 post-1st dose. A moderate inverse correlation was seen between NT50s and ages, but no correlation seen between NT50s and adverse effects. NT50s and SARS-CoV-2-S1-binding-IgG levels on day 28 post-1st dose and pain scores following the 2nd dose were greater in women than in men. The average half-life of NT50s was ~ 68 days, and 23.6% (49 out of 208 individuals) failed to show detectable neutralizing activity on day 150. While sera from elite-responders (NT50s > 1,500: the top 4% among the participants) potently to moderately blocked all variants of concerns examined, some sera with low NT50s failed to block the B.1.351-beta strain. Since BNT162b2-elicited immunity against SARS-CoV-2 is short, an additional vaccine or other protective measures are needed.

    DOI: 10.1101/2021.07.27.21261237

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  • Shogo Nakajima, Koichi Watashi, Takanobu Kato, Masamichi Muramatsu, Takaji Wakita, Noriko Tamura, Shin-Ichiro Hattori, Kenji Maeda, Hiroaki Mitsuya, Yoshiaki Yasutake, Tetsuya Toyoda .  Biochemical and Structural Properties of Entecavir-Resistant Hepatitis B Virus Polymerase with L180M/M204V Mutations. .  Journal of virology95 ( 16 ) e0240120   2021.7Biochemical and Structural Properties of Entecavir-Resistant Hepatitis B Virus Polymerase with L180M/M204V Mutations.Reviewed International journal

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    Entecavir (ETV) is a widely used anti-hepatitis B virus (HBV) drug. However, the emergence of resistant mutations in HBV reverse transcriptase (RT) results in treatment failure. To understand the mechanism underlying the development of ETV-resistance by HBV RT, we analyzed the L180M, M204V, and L180M/M204V mutants using a combination of biochemical and structural techniques. ETV-triphosphate (ETV-TP) exhibited competitive inhibition with dGTP both in wild type (wt) and M204V RT, as observed using Lineweaver-Burk Plot. By contrast, RT L180M or L180M/M204V did not fit either competitive, uncompetitive, non-competitive, or typical mixed inhibition, although ETV-TP was a competitive inhibitor of dGTP. Crystallography of HIV RTY115F/F116Y/Q151M/F160M/M184V mimicking HBV RT L180M/M204V showed that the F115 bulge (F88 in HBV RT) caused by F160M mutation induces the deviated binding of dCTP from its normal tight binding position. Modeling of ETV-TP on the deviated dCTP indicates that a steric clash could occur between ETV-TP methylene and the 3'-end nucleoside ribose. ETV-TP is likely to primarily interact with HBV RT M171 prior to final accommodation at the dNTP-binding site (Yasutake et al. Scientific Rep. (2018)8:1624/DOI:10.1038/s41598-018-19602-9). Therefore, in HBV RT L180M/M204V, ETV-TP may be stuck at M171, a residue which is conserved in almost all HBV isolates, thereby leading to the strange inhibition pattern observed in the kinetic analysis. Collectively, our results provide novel insights into the mechanism of ETV resistance of HBV RT caused by L180M/M204V mutations. IMPORTANCE HBV infects 257 million people in the world, who suffer from elevated risk of liver cirrhosis and cancer. ETV is one of the most potent anti-HBV drugs and its resistant mutations in HBV RT have been extensively studied. Nevertheless, the mechanisms underlying ETV-resistance have remained elusive. We propose an attractive hypothesis to explain ETV resistance and its effectiveness using a combination of kinetic and structural analysis. ETV is likely to have an additional interaction site, M171, besides the dNTP pocket of HBV RT; this finding indicates that nucleos(t)ide analogues (NAs) recognizing multiple interaction sites within RT may effectively inhibit the enzyme. Modification of ETV may render it more effective and enable the rational design of efficient NA inhibitors.

    DOI: 10.1128/JVI.02401-20

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  • Masaki Imai, Peter J Halfmann, Seiya Yamayoshi, Kiyoko Iwatsuki-Horimoto, Shiho Chiba, Tokiko Watanabe, Noriko Nakajima, Mutsumi Ito, Makoto Kuroda, Maki Kiso, Tadashi Maemura, Kenta Takahashi, Samantha Loeber, Masato Hatta, Michiko Koga, Hiroyuki Nagai, Shinya Yamamoto, Makoto Saito, Eisuke Adachi, Osamu Akasaka, Morio Nakamura, Ichiro Nakachi, Takayuki Ogura, Rie Baba, Kensuke Fujita, Junichi Ochi, Keiko Mitamura, Hideaki Kato, Hideaki Nakajima, Kazuma Yagi, Shin-Ichiro Hattori, Kenji Maeda, Tetsuya Suzuki, Yusuke Miyazato, Riccardo Valdez, Carmen Gherasim, Yuri Furusawa, Moe Okuda, Michiko Ujie, Tiago J S Lopes, Atsuhiro Yasuhara, Hiroshi Ueki, Yuko Sakai-Tagawa, Amie J Eisfeld, John J Baczenas, David A Baker, Shelby L O'Connor, David H O'Connor, Shuetsu Fukushi, Tsuguto Fujimoto, Yudai Kuroda, Aubree Gordon, Ken Maeda, Norio Ohmagari, Norio Sugaya, Hiroshi Yotsuyanagi, Hiroaki Mitsuya, Tadaki Suzuki, Yoshihiro Kawaoka .  Characterization of a new SARS-CoV-2 variant that emerged in Brazil. .  Proceedings of the National Academy of Sciences of the United States of America118 ( 27 ) e2106535118 - e2106535118   2021.7Reviewed International journal

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    The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a key role in viral infectivity. It is also the major antigen stimulating the host's protective immune response, specifically, the production of neutralizing antibodies. Recently, a new variant of SARS-CoV-2 possessing multiple mutations in the S protein, designated P.1, emerged in Brazil. Here, we characterized a P.1 variant isolated in Japan by using Syrian hamsters, a well-established small animal model for the study of SARS-CoV-2 disease (COVID-19). In hamsters, the variant showed replicative abilities and pathogenicity similar to those of early and contemporary strains (i.e., SARS-CoV-2 bearing aspartic acid [D] or glycine [G] at position 614 of the S protein). Sera and/or plasma from convalescent patients and BNT162b2 messenger RNA vaccinees showed comparable neutralization titers across the P.1 variant, S-614D, and S-614G strains. In contrast, the S-614D and S-614G strains were less well recognized than the P.1 variant by serum from a P.1-infected patient. Prior infection with S-614D or S-614G strains efficiently prevented the replication of the P.1 variant in the lower respiratory tract of hamsters upon reinfection. In addition, passive transfer of neutralizing antibodies to hamsters infected with the P.1 variant or the S-614G strain led to reduced virus replication in the lower respiratory tract. However, the effect was less pronounced against the P.1 variant than the S-614G strain. These findings suggest that the P.1 variant may be somewhat antigenically different from the early and contemporary strains of SARS-CoV-2.

    DOI: 10.1073/pnas.2106535118

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  • Makoto Inada, Masahiro Ishikane, Mari Terada, Akihiro Matsunaga, Kenji Maeda, Kiyoto Tsuchiya, Kenji Miura, Yu Sairenji, Noriko Kinoshita, Mugen Ujiie, Satoshi Kutsuna, Yukihito Ishizaka, Hiroaki Mitsuya, Norio Ohmagari .  Asymptomatic COVID-19 re-infection in a Japanese male by elevated half-maximal inhibitory concentration (IC50) of neutralizing antibodies. .  Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy27 ( 7 ) 1063 - 1067   2021.7Asymptomatic COVID-19 re-infection in a Japanese male by elevated half-maximal inhibitory concentration (IC50) of neutralizing antibodies.Reviewed International journal

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    INTRODUCTION: "Re-infection" with COVID-19 is a growing concern; re-infection cases have reported worldwide. However, the clinical characteristics of SARS-CoV-2 re-infection, including the levels and role of anti-SARS-CoV-2 Spike protein IgG antibodies and the half-maximal concentration (IC50) of neutralizing antibodies remain unknown. METHODS: Both the epidemiological and clinical information has been collected during two episodes of COVID-19 in a patient. Laboratory results, including RT-PCR, Ct values, anti-SARS-CoV-2 Spike protein IgG antibodies, and the IC50 of neutralizing antibodies levels were analyzed on the patient. RESULTS: The patient was a 58-year-old man who developed moderate COVID-19 pneumonia with oxygen demand (cannula 2 L/min) in the first episode. By day 30, he recuperated and was discharged after testing negative for SARS-CoV-2. After two and a half months, his three family members showed COVID-19 symptoms and tested positive for SARS-CoV-2. He tested positive for SARS-CoV-2 once again and was asymptomatic (the second episode). The IC50 of neutralizing antibodies against SARS-CoV-2 greatly increased from 50.0 μg/mL (after the first episode) to 14.8 μg/mL (after the second episode), and remained strongly reactive (20.1 μl/mL) after 47 days of the second episode. CONCLUSIONS: Epidemiological, clinical, and serological analyses confirmed that the patient had re-infection instead of persistent viral shedding from first infection. Our results suggest that SARS-CoV-2 re-infection may manifest as asymptomatic with increased neutralizing antibody levels. Further studies such as the virus characteristics, immunology, and epidemiology on SARS-CoV-2 re-infection are needed.

    DOI: 10.1016/j.jiac.2021.04.017

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  • Inada Makoto, Ishikane Masahiro, Terada Mari, Matsunaga Akihiro, Maeda Kenji, Tsuchiya Kiyoto, Miura Kenji, Sairenji Yu, Kinoshita Noriko, Ujiie Mugen, Kutsuna Satoshi, Ishizaka Yukihito, Mitsuya Hiroaki, Ohmagari Norio .  日本人男性における中和抗体の中和活性(IC50)上昇による無症候性COVID-19再感染(Asymptomatic COVID-19 re-infection in a Japanese male by elevated half-maximal inhibitory concentration(IC50) of neutralizing antibodies) .  Journal of Infection and Chemotherapy27 ( 7 ) 1063 - 1067   2021.7日本人男性における中和抗体の中和活性(IC50)上昇による無症候性COVID-19再感染(Asymptomatic COVID-19 re-infection in a Japanese male by elevated half-maximal inhibitory concentration(IC50) of neutralizing antibodies)

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    SARS-CoV-19の初回感染から105日後に無症候性再感染となった症例からの疫学的、臨床的、血清学的データを評価した。SARS-CoV-19のスパイクタンパク質をエンコードするDNAを保有するプラスミドをトランスフェクトされた293細胞から組換えスパイクタンパク質を調整し、IgG抗体検出ELISA用抗原とした。回復期の症例の血漿/血清からIgG分画を分離し、SARS-CoV-2と混合後、VeroE6/TMPRSS2細胞に接種培養して細胞変性効果の有無を認めた。症例は58歳男性で初感染時には胸部CT検査で両肺に多発するすりガラス陰影が認められた。酸素療法を要する中等症のCOVID-19肺炎を発症した。ファビピラビル治療を受けて症状が改善し、qRT-PCRが2回連続で陰性となり30日目に退院した。約2ヵ月半後、症例の家族3名が発症し本人もPCR陽性となったが無症候であった。初回感染から94、126、152日後の症例の抗SARS-CoV-2スパイクタンパク質IgG抗体のOD値は15.6、13.6、11.8と依然高い水準にあった。初回感染から94日後の中和抗体のIC50は50μg/mLを示した。初回感染から126日後(再感染から21日後)には14.8μg/mLと強い反応性を示し、初回発症から152日後(再感染から47日後)も20.1μg/mLと高い中和活性を示した。

  • Mari Terada, Satoshi Kutsuna, Tomiteru Togano, Sho Saito, Noriko Kinoshita, Yumiko Shimanishi, Tetsuya Suzuki, Yusuke Miyazato, Makoto Inada, Takahito Nakamoto, Hidetoshi Nomoto, Satoshi Ide, Mitsuhiro Sato, Kenji Maeda, Akihiro Matsunaga, Masahiro Satake, Keiji Matsubayashi, Hirokazu Tsuno, Makiko Kojima, Madoka Kuramistu, Kenta Tezuka, Emi Ikebe, Kazu Okuma, Isao Hamaguchi, Katsuyuki Shiratori, Motohiko Sato, Yuiko Kawakami, Kumi Inaba, Saori Igarashi, Reina Yamauchi, Mina Matsumura, Keiko Ishimaru, Bijuan Zhang, Chika Kuge, Maiko Ishihara, Miho Gouda, Keiko Tanaka, Yukihito Ishizaka, Norio Ohmagari .  How we secured a COVID-19 convalescent plasma procurement scheme in Japan. .  Transfusion61 ( 7 ) 1998 - 2007   2021.7How we secured a COVID-19 convalescent plasma procurement scheme in Japan.Reviewed International journal

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    BACKGROUND: In order to tackle the COVID-19 pandemic, a COVID-19 convalescent plasma (CCP) procurement program was initiated in Japan in April 2020. The program was a collaboration between a government-managed national hospital, an infectious disease research institute, and a blood banking organization. Each party assumed different responsibilities: recruitment, SARS-CoV-2 antibody profiling, and plasmapheresis; conduction of screening tests; and SARS-CoV-2 blood testing, respectively. METHODS: We adopted a two-point screening approach before the collected CCP was labeled as a CCP product for investigational use, for which we mainly tested anti-SARS-CoV-2 antibody eligibility and blood product eligibility. Anti-SARS-CoV-2 spike protein titer was measured using enzyme-linked immunosorbent assay, and the IC50 value was denoted as the neutralizing activity. Blood donor eligibility was extended beyond the normal blood donation guidelines to include a broader range of participants. After both eligibility criteria were confirmed, participants were asked to revisit the hospital for blood donation, which is a unique aspect of the Japanese CCP program, as most donations are taking place in normal blood donation venues in other countries. Some donors were re-scheduled for repeat plasma donations. As public interest in anti-SARS-CoV-2 antibodies increased, test results were given to the participants. RESULTS: As of September 17, 2020, our collection of CCP products was sufficient to treat more than 100 patients. As a result, projects for administration and distribution are also being conducted. CONCLUSIONS: We successfully implemented a CCP procurement scheme with the goal to expand to other parts of the country to improve treatment options for COVID-19.

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  • Kutsuna Satoshi, Asai Yusuke, Matsunaga Akihiro, Kinoshita Noriko, Terada Mari, Miyazato Yusuke, Nakamoto Takato, Suzuki Tetsuya, Saito Sho, Endo Mio, Kanda Kohei, Maeda Kenji, Takasaki Jin, Hojo Masayuki, Ishizaka Yukihito, Ohmagari Norio .  COVID-19の回復期にある患者における抗SARS-CoV-2 IgG抗体産生の関連因子(Factors associated with anti-SARS-CoV-2 IgG antibody production in patients convalescing from COVID-19) .  Journal of Infection and Chemotherapy27 ( 6 ) 808 - 813   2021.6COVID-19の回復期にある患者における抗SARS-CoV-2 IgG抗体産生の関連因子(Factors associated with anti-SARS-CoV-2 IgG antibody production in patients convalescing from COVID-19)

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    COVID-19の回復期にある患者における十分な抗SARS-CoV-2抗体産生に影響を及ぼす可能性のある因子を調べた。2020年1〜6月にCOVID-19と診断された患者84例(男性59例、年齢中央値50歳)を登録した。発症日と血液採取日を記録し、抗体価を測定した各検体について発症からの日数を算出した。SARS-CoV-2スパイクタンパク質全長をエンコードするプラスミドDNAをExpi293細胞にトランスフェクトし、発現した組換えタンパク質を精製してELISA用の抗原とした。96ウェルに抗原をコーティングし患者血清と反応後HRP標識抗ヒトIgGを添加し発色基質TMB溶液を加えて発色させ吸光度を測定した。84例中19例は回復期のみに抗体が検出された。65例は急性期と回復期の両方で抗体が検出された。多変量対数正規分析により、男性、糖尿病、急性期の最大CRP値がIgG抗体上昇と有意に関連していた。グルココルチコイドの使用は抗体価とは関連していなかった。抗体価は発症から5〜6週間でピークに達した。本調査では重症COVID-19の危険因子と特定されている糖尿病が高い抗体価をもたらした。疾患重症度よりCRP高値の方が高い抗体価に関連していた。

  • Shohei Yamamoto, Akihito Tanaka, Shinji Kobayashi, Yusuke Oshiro, Mitsuru Ozeki, Kenji Maeda, Kouki Matsuda, Kengo Miyo, Tetsuya Mizoue, Wataru Sugiura, Hiroaki Mitsuya, Haruhito Sugiyama, Norio Ohmagari .  Consistency of the results of rapid serological tests for SARS-CoV-2 among healthcare workers in a large national hospital in Tokyo, Japan. .  Global health & medicine3 ( 2 ) 90 - 94   2021.4Consistency of the results of rapid serological tests for SARS-CoV-2 among healthcare workers in a large national hospital in Tokyo, Japan.Reviewed

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    We assessed the consistency of seropositive results of three rapid immunoassays (Kits A, B, and C) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared to highly accurate serological tests (Abbott and Roche) among healthcare workers in a hospital in Tokyo. The seroprevalence of SARS-CoV-2 immunoglobulin G was 0.41%, 2.36%, and 0.08% using Kits A, B, and C, respectively. Of the 51 samples that were seropositive on any rapid test, all were seronegative on both the Abbott and the Roche assays. Given that the seroprevalence of SARS-CoV-2 immunoglobulin G varied widely according to the choice of rapid test and the rapid test results were inconsistent with the results of highly accurate tests, the diagnostic accuracy of rapid serological tests for SARS-CoV-2 should be assessed before introducing these tests for point-of-care testing or surveillance.

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  • Akihito Tanaka, Shohei Yamamoto, Kengo Miyo, Tetsuya Mizoue, Kenji Maeda, Wataru Sugiura, Hiroaki Mitsuya, Haruhito Sugiyama, Norio Ohmagari .  Seroprevalence of antibodies against SARS-CoV-2 in a large national hospital and affiliated facility in Tokyo, Japan .  Journal of Infection82 ( 4 ) e1 - e3   2021.4Seroprevalence of antibodies against SARS-CoV-2 in a large national hospital and affiliated facility in Tokyo, JapanReviewed International journal

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    DOI: 10.1016/j.jinf.2021.01.010

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  • Yamamoto Shohei, Tanaka Akihito, Kobayashi Shinji, Oshiro Yusuke, Ozeki Mitsuru, Maeda Kenji, Matsuda Kouki, Miyo Kengo, Mizoue Tetsuya, Sugiura Wataru, Mitsuya Hiroaki, Sugiyama Haruhito, Ohmagari Norio .  東京の大規模国立病院の医療従事者におけるSARS-CoV-2に対する迅速血清検査の結果の一貫性(Consistency of the results of rapid serological tests for SARS-CoV-2 among healthcare workers in a large national hospital in Tokyo, Japan) .  Global Health & Medicine3 ( 2 ) 90 - 94   2021.4東京の大規模国立病院の医療従事者におけるSARS-CoV-2に対する迅速血清検査の結果の一貫性(Consistency of the results of rapid serological tests for SARS-CoV-2 among healthcare workers in a large national hospital in Tokyo, Japan)

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    Language:English   Publisher:(国研)国立国際医療研究センター  

    大規模病院の医療従事者におけるSARS-CoV-2感染の血清有病率評価において、3種類の迅速ラテラルフロー・イムノアッセイ(LFIA)が2種類の高精度実験室ベース検査の結果と一致するかを調査する横断研究を実施した。迅速LFIAはキットA、キットB、キットC、高精度血清検査はAbbottおよびRocheを用いた。SARS-CoV-2免疫グロブリンGの血清有病率はキットAで0.41%、キットBで2.36%、キットCで0.08%であった。迅速検査で血清陽性であった標本51体のうち、全標本がAbbottおよびRocheアッセイの両方で血清陰性であった。SARS-CoV-2免疫グロブリンGの血清有病率は迅速検査の選択により大きく異なり、迅速検査の結果と高精度検査の結果が一致しないことから、診療現場での検査または調査に導入する前にSARS-CoV-2に対する迅速血清検査の診断精度を評価すべきであることが示された。

  • Kenji Maeda, Nobuyo Higashi-Kuwata, Noriko Kinoshita, Satoshi Kutsuna, Kiyoto Tsuchiya, Shin-Ichiro Hattori, Kouki Matsuda, Yuki Takamatsu, Hiroyuki Gatanaga, Shinichi Oka, Haruhito Sugiyama, Norio Ohmagari, Hiroaki Mitsuya .  Neutralization of SARS-CoV-2 with IgG from COVID-19-convalescent plasma. .  Scientific reports11 ( 1 ) 5563 - 5563   2021.3Reviewed International journal

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    <title>Abstract</title>While there are various attempts to administer COVID-19-convalescent plasmas to SARS-CoV-2-infected patients, neither appropriate approach nor clinical utility has been established. We examined the presence and temporal changes of the neutralizing activity of IgG fractions from 43 COVID-19-convalescent plasmas using cell-based assays with multiple endpoints. IgG fractions from 27 cases (62.8%) had significant neutralizing activity and moderately to potently inhibited SARS-CoV-2 infection in cell-based assays; however, no detectable neutralizing activity was found in 16 cases (37.2%). Approximately half of the patients (~ 41%), who had significant neutralizing activity, lost the neutralization activity within ~ 1 month. Despite the rapid decline of neutralizing activity in plasmas, good amounts of SARS-CoV-2-S1-binding antibodies were persistently seen. The longer exposure of COVID-19 patients to greater amounts of SARS-CoV-2 elicits potent immune response to SARS-CoV-2, producing greater neutralization activity and SARS-CoV-2-S1-binding antibody amounts. The dilution of highly-neutralizing plasmas with poorly-neutralizing plasmas relatively readily reduced neutralizing activity. The presence of good amounts of SARS-CoV-2-S1-binding antibodies does not serve as a surrogate ensuring the presence of good neutralizing activity. In selecting good COVID-19-convalescent plasmas, quantification of neutralizing activity in each plasma sample before collection and use is required.

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  • Kenta Noda, Kouki Matsuda, Shigehiro Yagishita, Kenji Maeda, Yutaro Akiyama, Junko Terada-Hirashima, Hiromichi Matsushita, Satoshi Iwata, Kazuto Yamashita, Yusuke Atarashi, Shunsuke Watanabe, Nobuyuki Ide, Tomokazu Yoshida, Norio Ohmagari, Hiroaki Mitsuya, Akinobu Hamada .  A novel highly quantitative and reproducible assay for the detection of anti-SARS-CoV-2 IgG and IgM antibodies. .  Scientific reports11 ( 1 ) 5198 - 5198   2021.3Reviewed International journal

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    <title>Abstract</title>The quantitative range and reproducibility of current serological tests for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are not optimized. Herein, we developed a diagnostic test that detects SARS-CoV-2 IgG and IgM with high quantitativeness and reproducibility and low interference. The system was based on the high-sensitivity chemiluminescence enzyme immunoassay (HISCL) platform and detects IgG and IgM specific to SARS-CoV-2 spike and nucleocapsid proteins. Quantification accuracy and reproducibility were evaluated using serially diluted samples from 60 SARS-CoV-2-infected patients. Assay performance was evaluated using serum samples from the SARS-CoV-2-infected patients and 500 SARS-CoV-2-negative serum samples collected before the emergence of SARS-CoV-2. The system showed high quantification accuracy (range, 10<sup>2</sup>), high reproducibility (within 5%), and no cross-reaction between SARS1- and MERS-S proteins. Detection accuracy was 98.3% and 93.3% for IgG and IgM against spike proteins and 100% and 71.7% for IgG and IgM against nucleocapsid proteins, respectively. Mean antibody levels were &gt; 10 times that in negative samples upon admission and &gt; 100 times that at convalescent periods. Clinical severity upon admission was not correlated with IgG or IgM levels. This highly quantitative, reproducible assay system with high clinical performance may help analyze temporal serological/immunological profiles of SARS-CoV-2 infection and SARS-CoV-2 vaccine effectiveness.

    DOI: 10.1038/s41598-021-84387-3

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  • Yamayoshi S, Yasuhara A, Ito M, Akasaka O, Nakamura M, Nakachi I, Koga M, Mitamura K, Yagi K, Maeda K, Kato H, Nojima M, Pattinson D, Ogura T, Baba R, Fujita K, Nagai H, Yamamoto S, Saito M, Adachi E, Ochi J, Hattori SI, Suzuki T, Miyazato Y, Chiba S, Okuda M, Murakami J, Hamabata T, Iwatsuki-Horimoto K, Nakajima H, Mitsuya H, Omagari N, Sugaya N, Yotsuyanagi H, Kawaoka Y .  Antibody titers against SARS-CoV-2 decline, but do not disappear for several months. .  EClinialMedicine32   100734 - 100734   2021Antibody titers against SARS-CoV-2 decline, but do not disappear for several months.Reviewed International journal

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    Background: To develop an effective vaccine against a novel viral pathogen, it is important to understand the longitudinal antibody responses against its first infection. Here we performed a longitudinal study of antibody responses against SARS-CoV-2 in symptomatic patients. Methods: Sequential blood samples were collected from 39 individuals at various timepoints between 0 and 154 days after onset. IgG or IgM titers to the receptor binding domain (RBD) of the S protein, the ectodomain of the S protein, and the N protein were determined by using an ELISA. Neutralizing antibody titers were measured by using a plaque reduction assay. Findings: The IgG titers to the RBD of the S protein, the ectodomain of the S protein, and the N protein peaked at about 20 days after onset, gradually decreased thereafter, and were maintained for several months after onset. Extrapolation modeling analysis suggested that the IgG antibodies were maintained for this amount of time because the rate of reduction slowed after 30 days post-onset. IgM titers to the RBD decreased rapidly and disappeared in some individuals after 90 days post-onset. All patients, except one, possessed neutralizing antibodies against authentic SARS-CoV-2, which they retained at 90 days after onset. The highest antibody titers in patients with severe infections were higher than those in patients with mild or moderate infections, but the decrease in antibody titer in the severe infection cohort was more remarkable than that in the mild or moderate infection cohort. Interpretation: Although the number of patients is limited, our results show that the antibody response against the first SARS-CoV-2 infection in symptomatic patients is typical of that observed in an acute viral infection. Funding: The Japan Agency for Medical Research and Development and the National Institutes of Allergy and Infectious Diseases.

    DOI: 10.1016/j.eclinm.2021.100734

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  • Kouki Matsuda, Takuya Kobayakawa, Ryusho Kariya, Kiyoto Tsuchiya, Shoraku Ryu, Kohei Tsuji, Takahiro Ishii, Hiroyuki Gatanaga, Kazuhisa Yoshimura, Seiji Okada, Akinobu Hamada, Hiroaki Mitsuya, Hirokazu Tamamura, Kenji Maeda .  A Therapeutic Strategy to Combat HIV-1 Latently Infected Cells With a Combination of Latency-Reversing Agents Containing DAG-Lactone PKC Activators. .  Frontiers in microbiology12   636276 - 636276   2021A Therapeutic Strategy to Combat HIV-1 Latently Infected Cells With a Combination of Latency-Reversing Agents Containing DAG-Lactone PKC Activators.Reviewed International journal

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    Advances in antiviral therapy have dramatically improved the therapeutic effects on HIV type 1 (HIV-1) infection. However, even with potent combined antiretroviral therapy, HIV-1 latently infected cells cannot be fully eradicated. Latency-reversing agents (LRAs) are considered a potential tool for eliminating such cells; however, recent in vitro and in vivo studies have raised serious concerns regarding the efficacy and safety of the "shock and kill" strategy using LRAs. In the present study, we examined the activity and safety of a panel of protein kinase C (PKC) activators with a diacylglycerol (DAG)-lactone structure that mimics DAG, an endogenous ligand for PKC isozymes. YSE028, a DAG-lactone derivative, reversed HIV-1 latency in vitro when tested using HIV-1 latently infected cells (e.g., ACH2 and J-Lat cells) and primary cells from HIV-1-infected individuals. The activity of YSE028 in reversing HIV-1 latency was synergistically enhanced when combined with JQ1, a bromodomain and extra-terminal inhibitor LRA. DAG-lactone PKC activators also induced caspase-mediated apoptosis, specifically in HIV-1 latently infected cells. In addition, these DAG-lactone PKC activators showed minimal toxicity in vitro and in vivo. These data suggest that DAG-lactone PKC activators may serve as potential candidates for combination therapy against HIV-1 latently infected cells, especially when combined with other LRAs with a different mechanism, to minimize side effects and achieve maximum efficacy in various reservoir cells of the whole body.

    DOI: 10.3389/fmicb.2021.636276

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  • Kutsuna S, Asai Y, Matsunaga A, Kinoshita N, Terada M, Miyazato Y, Nakamoto T, Suzuki T, Saito S, Endo M, Kanda K, Maeda K, Takasaki J, Hojo M, shizaka Y, Ohmagari N .  Factors associated with anti-SARS-CoV-2 IgG antibody production in patients convalescing from COVID-19. .  Journal of Infection and Chemotherapy27 ( 6 ) 808 - 813   2021Factors associated with anti-SARS-CoV-2 IgG antibody production in patients convalescing from COVID-19.Reviewed International journal

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    INTRODUCTION: Among patients with coronavirus disease 2019 (COVID-19), the factors that affect anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody production remain unclear. This study aimed to identify such factors among patients convalescing from COVID-19. METHODS: This study comprised patients who had been diagnosed with COVID-19 between January 1 and June 30, 2020 and gave consent for anti-SARS-CoV-2 spike protein antibody measurement using enzyme-linked immunosorbent assay during their acute and/or convalescent phases. Factors related to elevated antibody titers and the relationship between the days from disease onset and the development of antibody titers were assessed. RESULTS: A total of 84 participants enrolled in the study. Nineteen participants had antibody titers measured during the convalescent phase only, and 65 participants had antibody titers measured during the acute and convalescent phases. The antibody titers peaked in weeks 5 and 6. The stepwise multivariate log-normal analysis revealed that male sex (P = 0.04), diabetes mellitus (P = 0.03), and high C-reactive protein levels during the disease course (P < 0.001) were associated with elevated IgG antibodies. Glucocorticoid use was not associated with antibody titers. CONCLUSION: The study found that high values of maximum CRP levels during the acute phase, male sex, and diabetes mellitus were associated with elevated antibody titers. Antibody titers tended to be highest in the first 5 or 6 weeks after the onset of symptoms.

    DOI: 10.1016/j.jiac.2021.01.006

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  • Yamamoto K, Suzuki M, Yamada G, Sudo T, Nomoto H, Kinoshita N, Nakamura K, Tsujimoto Y, Kusaba Y, Morita C, Moriya A, Maeda K, Yagi S, Kimura M, Ohmagari N .  Utility of the antigen test for coronavirus disease 2019: Factors influencing the prediction of the possibility of disease transmission. .  Int. J. Infect. Dis.104   65 - 72   2021Utility of the antigen test for coronavirus disease 2019: Factors influencing the prediction of the possibility of disease transmission.Reviewed International journal

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    OBJECTIVES: Rapid antigen testing (RAT) for coronavirus disease 2019 (COVID-19) has lower sensitivity but high accuracy during the early stage when compared to reverse transcription quantitative polymerase chain reaction (RT-qPCR). The aim of this study was to investigate the concordance between RAT and RT-qPCR results, and their prediction of disease transmission. METHODS: This single-center retrospective observational study of inpatients with COVID-19 was conducted from March 6 to June 14, 2020. Nasopharyngeal swabs were used to perform RAT and RT-qPCR. The primary endpoint was concordance between RAT and RT-qPCR results. The secondary endpoints were the factors causing disagreement in the results and the estimated transmissibility in RT-qPCR-positive patients with mild symptoms. RESULTS: Overall, 229 samples in viral transport medium (VTM) were obtained from 105 patients. The positive and negative concordance rates for VTM were 41% vs 99% (κ = 0.37) and 72% vs 100% (κ = 0.50) for samples collected on disease days 2-9. An increased body temperature (odds ratio 0.54) and absence of drugs with potential antiviral effect (odds ratio 0.48) yielded conflicting results. RAT was associated with the ability to end isolation (OR 0.11, 95% confidence interval 0.20-0.61). CONCLUSIONS: RAT and RT-qPCR results were highly consistent for samples collected at the appropriate time and could be useful for inferring the possibility of transmissibility.

    DOI: 10.1016/j.ijid.2020.12.079

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MISC

  • HIV潜伏感染細胞に対する新規治療法開発に向けた研究

    松田 幸樹, 前田 賢次

    Cytometry Research   31 ( 2 )   7 - 13   2022.3

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    HIV-1は宿主のゲノムにウイルス自身のゲノムを組み込むことで感染を成立させ、患者体内に長期間潜伏する。この潜伏感染細胞(リザーバー)の存在がHIV感染症根治の妨げになっている。HIVリザーバー細胞を排除するため、Latency-reversing-agents(LRA)を用いたshock and kill薬が開発された。蛋白質キナーゼC活性化剤がHIV潜伏感染細胞株およびHIV患者由来CD4+T細胞において強力なLRA活性を有することも報告された。

Presentations

  • 林 康広, 土屋 亮人, 山本 瑞生, 佐々木 洋子, 谷川 和也, 濱 弘太郎, 上田 裕介, 合田 仁, 前田 賢次, 井上 純一郎, 山下 純   新型コロナウイルスの感染効率は宿主細胞のスフィンゴイド塩基の質に影響する  

    脂質生化学研究  2021.5  日本脂質生化学会

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  • 前田 賢次   抗ウイルス薬の現状と未来 抗HIV薬開発研究の進展と今後の展望  

    臨床とウイルス  2021.5  日本臨床ウイルス学会

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  • 前田 賢次   抗ウイルス感染症研究のフロンティア-ウイルス感染症克服に向けた薬学専門分野での挑戦- ウイルス関連分子標的アプローチによる抗ウイルス薬の創製 HIV-1からSARS-CoV-2まで  

    日本薬学会年会要旨集  2022.3  (公社)日本薬学会

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  • 松田 幸樹, 前田 賢次   HIV潜伏感染細胞に対する新規治療法開発に向けた研究  

    Cytometry Research  2021.6  (一社)日本サイトメトリー学会

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  • 石井 貴大, 小早川 拓也, 松田 幸樹, 辻 耕平, 吉村 和久, 満屋 裕明, 前田 賢次, 玉村 啓和   HIV感染症の根治を指向したDAG-ラクトン誘導体の合成  

    日本薬学会年会要旨集  2022.3  (公社)日本薬学会

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  • 石井 貴大, 小早川 拓也, 松田 幸樹, 辻 耕平, 吉村 和久, 満屋 裕明, 前田 賢次, 玉村 啓和   HIV感染症の根治へ向けたDAG-ラクトン誘導体の構造活性相関研究  

    日本薬学会年会要旨集  2021.3  (公社)日本薬学会

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  • 北村 春樹, 松田 幸樹, 助川 明香, 高橋 一帆, 小早川 拓也, 玉村 啓和, 山岡 昇司, 前田 賢次, 武内 寛明   HIV-1潜伏感染細胞排除戦略に有用な新規低分子化合物や既存医薬品の探索および評価  

    日本エイズ学会誌  2021.11  (一社)日本エイズ学会

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  • 助川 明香, 松田 幸樹, 北村 春樹, 月谷 知也, 芳野 広起, 小早川 拓也, 玉村 啓和, 山岡 昇司, 前田 賢次, 武内 寛明   HIV-1潜伏感染細胞を再活性化する新規低分子化合物の探索  

    日本エイズ学会誌  2021.11  (一社)日本エイズ学会

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  • 松田 幸樹, 小早川 拓也, 刈谷 龍昇, 土屋 亮人, 劉 晶楽, 辻 耕平, 石井 貴大, 潟永 博之, 吉村 和久, 岡田 誠治, 濱田 哲暢, 満屋 裕明, 玉村 啓和, 前田 賢次   DAG-lactone骨格を有するPKC活性化剤を含むLRAの併用によるHIV-1潜伏感染細胞治療戦略  

    日本エイズ学会誌  2021.11  (一社)日本エイズ学会

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  • 前田 賢次   COVID-19 & HIV感染症-I/II〜「みえない感染拡大」の脅威と制御〜 新型コロナウイルスに対する中和抗体の産生・活性解析と治療への応用  

    日本エイズ学会誌  2021.11  (一社)日本エイズ学会

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Research Projects

  • HIV残存ウイルスリザーバーの評価を可能とする新規バイオマーカー探索と治療法開発

    2020 - 2022

    国立研究開発法人国立国際医療研究センター  国際医療研究開発費 

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  • COVID-19治療としての回復者血漿療法の基盤整備

    2020 - 2021.3

    国立研究開発法人日本医療研究開発機構 (AMED)  新興再興感染症に対する革新的医薬品等開発推進研究事業 

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  • 新型コロナウイルス感染症(COVID-19)の治療法を確立するための研究

    2020 - 2021.3

    厚生労働省  新興・再興感染症及び予防接種政策推進研究事業 

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  • 病態に即した個別化医療へ向けた抗HIV薬の薬物動態解析

    2018.4 - 2021.3

    国立研究開発法人国立国際医療研究センター  国際医療研究開発費 

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    Authorship:Coinvestigator(s)  Grant type:Competitive

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  • HIV Cureを目指した新規作用機序を有する抗HIV薬開発研究

    2018.4 - 2021.3

    AMED  エイズ対策実用化研究事業 

    Kenji Maeda

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    Authorship:Principal investigator  Grant type:Competitive

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  • 野生型と薬剤耐性B型肝炎ウイルスに強力な活性を発揮する新規治療薬の研究・開発

    2017.4 - 2022.3

    AMED  肝炎等克服実用化研究事業 B型肝炎創薬実用化等研究事業 

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