研究者詳細 - 涌井　昌俊

論文 - 涌井　昌俊

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Clot waveform analysis for perioperative hemostatic monitoring in a hemophilia A patient on emicizumab undergoing liver transplantation

Awane M, Wakui M, Ozaki Y, KondoY, Oka S, Fujimori Y, Yatabe Y, Arai T, Yamada Y, Hori S, Obara H, Hasegawa Y, Matsushita H

Clin Chim Acta （Clinica Chimica Acta） 544 117339 2023年04月

研究論文（学術雑誌）, 共著, 筆頭著者, 責任著者, 査読有り, ISSN 00098981

How to optimize perioperative factor VIII (FVIII) replacement through hemostatic monitoring is critically important to manage hemophilia A patients. The bispecific antibody emicizumab binds activated FIX (FIXa) and FX to functionally mimic FVIIIa. While being used for hemostatic control in hemophilia A, this therapeutic antibody inconveniently interferes with coagulation tests using human FIXa and FX, such as activated partial thromboplastin time (APTT) and FVIII activity measurement based on one-stage clotting assays. Clot waveform analysis (CWA) extends the interpretation of measurement curves for coagulation time to provide global information. We performed APTT-CWA to monitor perioperative hemostasis in a hemophilia A patient on emicizumab undergoing liver transplantation. Plasma samples were treated with anti-idiotype monoclonal antibodies against emicizumab to enable accurate coagulation assays. Kinetics of maximum coagulation velocity and acceleration mimicked that of FVIII activity. These CWA parameters better correlated with FVIII activity than APTT. The plateaus of them were observed at FVIII activity of 100% or more, supporting the protocol for perioperative FVIII replacement. Thus, CWA may measure coagulation potential in hemophilia A patients undergoing liver transplantation, aiding in optimizing perioperative hemostasis.

凝固カスケード反応の本質に迫る！　凝固波形解析

涌井昌俊

臨床検査専門医会誌（Laboratory and Clinical Practice; Lab Clin Pract） 40 （ 2 ） 36 - 41 2023年03月

研究論文（学術雑誌）, 単著

COVID-19のAPTT凝固波形解析

蔵野信、志村拓也、涌井昌俊、矢冨裕

血栓止血誌 34 （ 1 ） 29 - 35 2023年02月

研究論文（学術雑誌）, 共著

Antibody and T cell responses against SARS-CoV-2 after booster vaccination in patients on dialysis: a prospective observational study

Kawashima M, Saito H, Nishiuchi T, Yoshimura H, Wakui M, Tani Y, Nishikawa Y, Omata F, Takita M, Zhao T, Yamamoto C, Kobashi Y, Kawamura T, Sugiyama A, Nakayama A, Kaneko Y, Sawano T, Shibuya K, Kazama JJ, Shineha R, Tsubokura M

Vaccines （Vaccines） 11 （ 2 ） 260 2023年01月

研究論文（学術雑誌）, 共著, 査読有り

Intensive vaccination is recommended for populations more vulnerable to COVID-19 infection, although data regarding the built of immunity after vaccination for dialysis patients are lacking. This prospective, observational cohort study of maintenance hemodialysis patients examined IgG antibody levels against the SARS-CoV-2 spike (S1) protein, neutralizing activity, and interferon gamma levels after the third dose of the BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) vaccine. Humoral immunity was repeatedly measured for up to two months. The study includes 58 patients on hemodialysis. Median neutralizing antibodies reached a maximum at 56 and 9 days after booster vaccination with BNT162b2 and mRNA-1273, respectively. The median IgG antibody titer reached a maximum of 3104.38 and 7209.13 AU/mL after 16 days of booster dose, and cellular immunity was positive in 61.9% and 100% of patients with BNT162b2 and mRNA-1273 vaccination, respectively. By repeating the measurements over a period of two months, we clarified the chronological aspects of the acquisition of humoral immunity in dialysis patients after a booster COVID-19 vaccination; most dialysis patients acquired not only humoral immunity, but also cellular immunity against SARS-CoV-2. Future research should investigate the continued long-term dynamics of antibody titers and cellular immunity after the third or further vaccinations, evaluating the need for additional vaccinations for hemodialysis patients.

Polysulfide serves as a hallmark of desmoplastic reaction to differentially diagnose ductal carcinoma in situ and invasive breast cancer by SERS imaging

Kubo A, Masugi Y, Hase T, Nagashima K, Kawai Y, Takizawa M, Hishiki T, Shiota M, Wakui M, Kitagawa Y, Kabe Y, Sakamoto M, Yachie A, Hayashida T, Suematsu M

Antioxidant （Antioxidants） 12 （ 2 ） 240 2023年01月

研究論文（学術雑誌）, 共著, 査読有り

Pathological examination of formalin-fixed paraffin-embedded (FFPE) needle-biopsied samples by certified pathologists represents the gold standard for differential diagnosis between ductal carcinoma in situ (DCIS) and invasive breast cancers (IBC), while information of marker metabolites in the samples is lost in the samples. Infrared laser-scanning large-area surface-enhanced Raman spectroscopy (SERS) equipped with gold-nanoparticle-based SERS substrate enables us to visualize metabolites in fresh-frozen needle-biopsied samples with spatial matching between SERS and HE staining images with pathological annotations. DCIS (n = 14) and IBC (n = 32) samples generated many different SERS peaks in finger-print regions of SERS spectra among pathologically annotated lesions including cancer cell nests and the surrounding stroma. The results showed that SERS peaks in IBC stroma exhibit significantly increased polysulfide that coincides with decreased hypotaurine as compared with DCIS, suggesting that alterations of these redox metabolites account for fingerprints of desmoplastic reactions to distinguish IBC from DCIS. Furthermore, the application of supervised machine learning to the stroma-specific multiple SERS signals enables us to support automated differential diagnosis with high accuracy. The results suggest that SERS-derived biochemical fingerprints derived from redox metabolites account for a hallmark of desmoplastic reaction of IBC that is absent in DCIS, and thus, they serve as a useful method for precision diagnosis in breast cancer.

Time course of adverse reactions following BNT162b2 vaccination in healthy and allergic disease individuals aged 5–11 years and comparison with individuals aged 12–15 years: an observational and historical cohort study

Yoshida M, Kobashi Y, Shimazu Y, Saito H, Yamamoto C, Kawamura T, Wakui M, Takahashi K, Ito N, Nishikawa Y, Zhao T, Tsubokura M

Eur J Pediatr （European Journal of Pediatrics） 182 （ 1 ） 123 - 133 2023年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03406199

We aimed to investigate the type and frequency of adverse events over 7 days following the first and second BNT162b2 vaccination. This observational and historical cohort study included patients aged 5–11 years who received two doses of BNT162b2 and provided consent along with their guardians. We collected data on sex, age, height, weight, blood type, history of Bacille Calmette-Guerin vaccination, allergic disease, medication, history of coronavirus disease 2019 (COVID-19), and adverse reactions 7 days following the first and second BNT162b2 vaccination using a questionnaire. Our results were compared with previously reported results for individuals aged 12–15 years. A total of 421 participants were eligible for this study. Among the 216 patients with allergic disease, 48 (22.2%) had experienced worsening of their chronic diseases, and the frequency of fatigue and dizziness after the second dose was higher than that of healthy individuals. The experience of systemic adverse reactions was associated with asthma. The frequency of headache, diarrhea, fatigue, muscle/joint pain, and fever after the second BNT162b2 vaccination was lower in individuals aged 5–11 years than in those aged 12–15 years. Fever was the only systemic adverse reaction that lasted longer than 5 days (1.0% of participants). Conclusions: Individuals with allergic diseases, who are potentially susceptible to COVID-19, may experience worsening of their chronic diseases and more frequent adverse reactions after BNT162b2 vaccination than healthy individuals. To ensure that children with allergic diseases receive the vaccine safely, further information needs to be collected.What is Known:• Adverse reactions afterBNT162b2 vaccination among individuals aged 5–11 years are generallynonserious, more common after second vaccination, and substantially less commoncompared to those observed among individuals aged 12–15 years.What is New:• Individuals with allergic diseasesexperienced worsening of their chronic diseases and more frequent adversereactions after BNT162b2 vaccination than healthy individuals.• Systemic adverse reactions were associatedwith asthma. Fever was the only systemic adversereaction that lasted longer than 5 days.

Humoral and cellular immune response dynamics in Japanese healthcare workers up to six months after receiving a third dose of BNT162b2 monovalent vaccine

Uwamino Y, Yokoyama T, Sato Y, Shibata A, Kurafuji T, Tanabe A, Noguchi M, Arai T, Ohno A, Yokota H, Namkoong H, Nishimura T, Kosaki K, Hasegawa N, Wakui M, Murata M, Matsushita H

Vaccine （Vaccine） 41 （ 9 ） 1545 - 1549 2023年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0264410X

Longitudinal data on the immune response from the first dose to several months after the third dose of COVID-19 vaccine are limited. We analyzed the immune response in 406 Japanese healthcare workers who received at least three doses of vaccine. The geometric mean anti-receptor binding domain IgG antibody titers and antigen-stimulated T-cell interferon-gamma levels after 6 months after receiving a third dose were similar to those 8 weeks after receiving a second dose. Humoral and cellular immunity induced by the third dose was more durable than that induced by the second dose. UMIN Clinical Trials Registry ID: UMIN000043340.

APTT

涌井昌俊

検査と技術（医学書院） 51 （ 9 ） 956 - 960 2023年

研究論文（学術雑誌）, 単著, 筆頭著者, 責任著者

涌井昌俊

検査と技術（医学書院） 51 （ 9 ） 951 - 955 2023年

研究論文（学術雑誌）, 単著, 筆頭著者, 責任著者

Estimating immunity with mathematical models for SARS-CoV-2 after COVID-19 vaccination

Uwamino Y, Nagashima K, Yoshifuji A, Suga S, Nagao M, Fujisawa T, Ryuzaki M, Takemoto Y, Namkoong H, Wakui M, Matsushita H, Hasegawa N, Sato Y, Murata M

NPJ Vaccines （npj Vaccines） 8 （ 1 ） 33 2023年

研究論文（学術雑誌）, 共著, 査読有り

Tools that can be used to estimate antibody waning following COVID-19 vaccinations can facilitate an understanding of the current immune status of the population. In this study, a two-compartment-based mathematical model is formulated to describe the dynamics of the anti-SARS-CoV-2 antibody in healthy adults using serially measured waning antibody concentration data obtained in a prospective cohort study of 673 healthcare providers vaccinated with two doses of BNT162b2 vaccine. The datasets of 165 healthcare providers and 292 elderly patients with or without hemodialysis were used for external validation. Internal validation of the model demonstrated 97.0% accuracy, and external validation of the datasets of healthcare workers, hemodialysis patients, and nondialysis patients demonstrated 98.2%, 83.3%, and 83.8% accuracy, respectively. The internal and external validations demonstrated that this model also fits the data of various populations with or without underlying illnesses. Furthermore, using this model, we developed a smart device application that can rapidly calculate the timing of negative seroconversion.

Five doses of the mRNA vaccination potentially suppress ancestralstrain stimulated SARS-CoV2-specific cellular immunity: A cohort study from the Fukushima Vaccination Community Survey, Japan

Tani Y, Takita M, Wakui M, Saito H, Tianchen Z, Yamamoto C, Kawamura T, Sugiyama A, Nakayama A, Kaneko Y, Kodama T, Tsubokura M

Front Immunol （Frontiers in Immunology） 14 10.3389/fimmu.2023 2023年

研究論文（学術雑誌）, 共著, 査読有り

The bivalent mRNA vaccine is recommended to address coronavirus disease variants, with additional doses suggested for high-risk groups. However, the effectiveness, optimal frequency, and number of doses remain uncertain. In this study, we examined the long-term cellular and humoral immune responses following the fifth administration of the mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in patients undergoing hemodialysis. To our knowledge, this is the first study to monitor long-term data on humoral and cellular immunity dynamics in high-risk populations after five doses of mRNA vaccination, including the bivalent mRNA vaccine. Whereas most patients maintained humoral immunity throughout the observation period, we observed reduced cellular immune reactivity as measured by the ancestral-strain-stimulated ELISpot assay in a subset of patients. Half of the individuals (50%; 14/28) maintained cellular immunity three months after the fifth dose, despite acquiring humoral immunity. The absence of a relationship between positive controls and T-Spot reactivity suggests that these immune alterations were specific to SARS-CoV-2. In multivariable analysis, participants aged ≥70 years showed a marginally significant lower likelihood of having reactive results. Notably, among the 14 individuals who received heterologous vaccines, 13 successfully acquired cellular immunity, supporting the effectiveness of this administration strategy. These findings provide valuable insights for future vaccination strategies in vulnerable populations. However, further research is needed to evaluate the involvement of immune tolerance and exhaustion through repeated vaccination to optimize immunization strategies.

Assessing anti-SARS-CoV-2 cellular immunity in 571 vaccinees by using an interferon-gamma release assay

Wakui M, Uwamino Y, Yatabe Y, Nakagawa T, Sakai A, Kurafuji T, Shibata A, Tomita Y, Noguchi M, Tanabe A, Arai T, Ohno A, Yokota H, Uno S, Yamasawa W, Sato Y, Ikeda M, Yoshimura A, Hasegawa N, Saya H, Murata M

Eur J Immunol （European Journal of Immunology） 52 （ 12 ） 1961 - 1971 2022年12月

研究論文（学術雑誌）, 共著, 筆頭著者, 責任著者, 査読有り, ISSN 00142980

Memory T cell responses have been analyzed only in small cohorts of COVID-19 vaccines. Herein, we aimed to assess anti-SARS-CoV-2 cellular immunity in a large cohort using QuantiFERON assays, which are IFN-γ release assays (IGRAs) based on short-term whole blood culture. The study included 571 individuals receiving the viral spike (S) protein-expressing BNT162b2 mRNA vaccine. QuantiFERON assays revealed antigen-specific IFN-γ production in most individuals 8 weeks after the second dose. Simultaneous flow cytometric assays to detect T cells expressing activation-induced markers (AIMs) performed for 28 randomly selected individuals provided data correlating with the QuantiFERON data. Simultaneous IFN-γ enzyme-linked immunospot and AIM assays for another subset of 31 individuals, based on short-term peripheral blood mononuclear cell culture, also indicated a correlation between IFN-γ production and AIM positivity. These observations indicated the acquisition of T cell memory responses and supported the usability of IGRAs to assess cellular immunity. The QuantiFERON results were weakly correlated with serum IgG titers against the receptor-binding domain of the S protein and were associated with pre-vaccination infection and adverse reactions after the second dose. The present study revealed cellular immunity after COVID-19 vaccination, providing insights into the effects and adverse reactions of vaccination.

Memory B cells and memory T cells induced by SARS-CoV-2 booster vaccination or infection show different dynamics and responsiveness to the omicron variant

Mise-Omata S, Ikeda M, Takeshita M, Uwamino Y, Wakui M, Arai T, Yoshifuji A, Murano K, Siomi H, Nakagawara K, Ohyagi M, Ando M, Hasegawa N, Saya H, Murata M, Fukunaga K, Namkoong H, Lu X, Yamasaki S, Yoshimura A.

J Immunol （Journal of immunology (Baltimore, Md. : 1950)） 209 （ 11 ） 2104 - 2113 2022年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00221767

Although the immunological memory produced by BNT162b2 vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been well studied and established, further information using different racial cohorts is necessary to understand the overall immunological response to vaccination. We evaluated memory B and T cell responses to the severe acute respiratory syndrome coronavirus 2 spike protein before and after the third booster using a Japanese cohort. Although the Ab titer against the spike receptor-binding domain (RBD) decreased significantly 8 mo after the second vaccination, the number of memory B cells continued to increase, whereas the number of memory T cells decreased slowly. Memory B and T cells from unvaccinated infected patients showed similar kinetics. After the third vaccination, the Ab titer increased to the level of the second vaccination, and memory B cells increased at significantly higher levels before the booster, whereas memory T cells recovered close to the second vaccination levels. In memory T cells, the frequency of CXCR5+CXCR3+CCR6- circulating follicular Th1 was positively correlated with RBD-specific Ab-secreting B cells. For the response to variant RBDs, although 60-80% of memory B cells could bind to the omicron RBD, their avidity was low, whereas memory T cells show an equal response to the omicron spike. Thus, the persistent presence of memory B and T cells will quickly upregulate Ab production and T cell responses after omicron strain infection, which prevents severe illness and death due to coronavirus disease 2019.

Clot waveform analysis for perioperative hemostatic monitoring in a hemophilia A patient on emicizumab undergoing liver transplantation (preprint)

Awane M, Wakui M, Ozaki Y, KondoY, Oka S, Fujimori Y, Yatabe Y, Arai T, Yamada Y, Hori S, Obara H, Hasegawa Y, Matsushita H

Research Square preprint 2022年12月

研究論文（学術雑誌）, 共著, 筆頭著者, 責任著者

プロトロンビン時間（PT）の試薬特性

涌井昌俊

検査と技術（医学書院） 50 （ 7 ） 728 - 734 2022年07月

研究論文（学術雑誌）, 単著

メタクロマジー核酸染色によるRNP法TMを用いたCelltac G+TM試作機.の網赤血球算定の基礎的性能

荒井智子、片桐尚子、近藤直美、谷田部陽子、横田浩充、永井豊、三ツ橋雄之、涌井昌俊、村田満

日本検査血液学会雑誌 23 （ 2 ） 265 - 273 2022年07月

研究論文（学術雑誌）, 共著, 査読有り

COVID-19の免疫とワクチン

涌井昌俊

The Lipid 33 （ 1 ） 14 - 22 2022年04月

研究論文（学術雑誌）, 単著

Response kinetics of different classes of antibodies to SARS-CoV2 infection in the Japanese population: the IgA and IgG titers increased earlier than the IgM titers

KuranoM, Morita Y, Nakano Y, Yokoyama R, Shimura T, Qian C, Xia F, He F, Zheng L, Ohmiya H, Kishi Y, Okada J, Yoshikawa N, Nakajima K, Nagura Y, Okazaki H, Jubishi D, Moriya K, Seto Y, Yasui F, Kohara M, Wakui M, Kawamura T, Kodama T, Yatomi Y

Int Immunopharmacol （International Immunopharmacology） 103 1089491 2022年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 15675769

To better understand the immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with COVID-19, it is important to investigate the kinetics of the antibody responses and their associations with the clinical course in different populations, since there seem to be considerable differences between Western and Asian populations in the clinical features and spread of COVID-19. In this study, we serially measured the serum titers of IgM, IgG and IgA antibodies generated against the nucleocapsid protein (NCP), S1 subunit of the spike protein (S1), and receptor-binding domain in the S1 subunit (RBD) of SARS-CoV-2 in Japanese individuals with COVID-19. Among the IgM, IgG, and IgA antibodies, IgA antibodies against all of the aforementioned viral proteins were the first to appear after the infection, and IgG and/or IgA seroconversion often preceded IgM seroconversion. In regard to the timeline of the antibody responses to the different viral proteins (NCP, S1 and RBD), IgA against NCP appeared than IgA against S1 or RBD, while IgM and IgG against S1 appeared earlier than IgM/IgG against NCP or RBD. The IgG responses to all three viral proteins and responses of all three antibody classes to S1 and RBD were sustained for longer durations than the IgA/IgM responses to all three viral proteins and responses of all three antibody classes to NCP, respectively. The seroconversion of IgA against NCP occurred later and less frequently in patients with mild COVID-19. These results suggest possible differences in the antibody responses to SARS-CoV-2 antigens between the Japanese and Western populations.

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Young age, female sex, and presence of systemic adverse reactions are associated with high post-vaccination antibody titer after two doses of BNT162b2 mRNA SARS-CoV-2 vaccination: An observational study of 646 Japanese healthcare workers and university staff

Uwamino Y, Kurafuji T, Sato Y, Tomita Y, Shibata A, Tanabe A, Yatabe Y, Noguchi M, Sakai A, Noguchi M, Arai T, Ohno A, Yokota H, Yamasawa W, Uno S, Nishimura T, Hasegawa N, Saya H, Wakui M*, Murata M

Vaccine （Vaccine） 40 （ 7 ） 1019 - 1025 2022年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0264410X

Background: SARS-CoV-2 vaccination has started worldwide, including Japan. Although high rates of vaccine response and adverse reactions of BNT162b2 vaccine have been reported, knowledge about the relationship between sex differences and antibody response is limited. Furthermore, it is uncertain whether adverse reactions are associated with the vaccine response. Methods: This prospective observational study included 673 Japanese participants working in a medical school and its affiliated hospital in Tokyo, Japan (UMIN000043340). Serum samples were collected before the first dose and three weeks after the second dose of BNT162b2 vaccine, and antibody titers against the receptor-binding domain of the spike protein of SARS-CoV-2 were measured. Answers to questionnaires about background characteristics and adverse reactions were obtained at the time of sample collection, and the relationship between antibody titers was analyzed. Results: After excluding participants who did not complete receiving two doses of vaccination or two series of serum sample collection, 646 participants were analyzed. Although all participants became sero-positive after vaccination, antibody titers were highly variable among individuals (260.9–57,399.7A U/mL), with a median titer of 13478.0AU/mL. Mean titer was higher in females than in males and higher in young (≤45 years old) participants than in aged (>45 years old) participants. Participants who experienced adverse reactions demonstrated a higher antibody titer after vaccination than those without adverse reactions. Multivariable analysis demonstrated that young age, female sex, and adverse reactions after the second dose were independently related to higher antibody titers after the second dose. Discussion: A favorable antibody response was observed after two doses of BNT162b2 vaccination among mostly healthy Japanese participants, especially among female and young participants. Although further investigation is essential, our results imply that the systemic adverse reactions (i.e., fever and general fatigue) are associated with a higher antibody response that indicates the acquisition of humoral immunity.

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凝固波形解析

涌井昌俊

血栓止血誌 33 （ 1 ） 69 - 74 2022年02月

研究論文（学術雑誌）, 単著

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