Details of a Researcher - Wakui, Masatoshi

Papers - Wakui, Masatoshi

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全領域をコンプリート！超進化！AI時代の臨床検査：血液学検査 [凝固]

涌井昌俊

検査と技術印刷中 2025

Research paper (scientific journal), Single Work, Lead author, Last author, Corresponding author

Germline variants and mosaic chromosomal alterations affect COVID-19 vaccine immunogenicity

Sonehara K, Uwamino Y, Saiki R, Takeshita M, Namba S, Uno S, Nakanishi T, Nishimura T, Naito T, Sato G, Kanai M, Liu A, Uchida S, Kurafuji T, Tanabe A, Arai T, Ohno A, Shibata A, Tanaka S, Wakui M, Kashimura S, Tomi C, Hara A, Yoshikawa S, Gotanda K, Misawa K, Tanaka H, Azekawa S, Wang QS, Edahiro R, Shirai Y, Yamamoto K, Nagao G, Suzuki T, Kiyoshi M, Ishii-Watabe A, Higashiue S, Kobayashi S, Yamaguchi H, Okazaki Y, Matsumoto N, Masumoto A, Koga H, Kanai A; Japan COVID-19 Task Force; Biobank Japan Project; Oda Y, Suzuki Y, Matsuda K, Kitagawa Y, Koike R, Kimura A, Kumanogoh A, Yoshimura A, Imoto S, Miyano S, Kanai T, Fukunaga K, Hasegawa N, Murata M, Matsushita H, Ogawa S, Okada Y, Namkoong H

Cell Genomics 5 ( 3 ) 100783 2025

Research paper (scientific journal), Joint Work, Accepted

Vaccine immunogenicity is influenced by the vaccinee's genetic background. Here, we perform a genome-wide association study of vaccine-induced SARS-CoV-2-specific immunoglobulin G (IgG) antibody titers and T cell immune responses in 1,559 mRNA-1273 and 537 BNT162b2 vaccinees of Japanese ancestry. SARS-CoV-2-specific antibody titers are associated with the immunoglobulin heavy chain (IGH) and major histocompatibility complex (MHC) locus, and T cell responses are associated with MHC. The lead variants at IGH contain a population-specific missense variant (rs1043109-C; p.Leu192Val) in the immunoglobulin heavy constant gamma 1 gene (IGHG1), with a strong decreasing effect (β = −0.54). Antibody-titer-associated variants modulate circulating immune regulatory proteins (e.g., LILRB4 and FCRL6). Age-related hematopoietic expanded mosaic chromosomal alterations (mCAs) affecting MHC and IGH also impair antibody production. MHC-/IGH-affecting mCAs confer infectious and immune disease risk, including sepsis and Graves’ disease. Impacts of expanded mosaic loss of chromosomes X/Y on these phenotypes were examined. Altogether, both germline and somatic mutations contribute to adaptive immunity functions.

LC-MS/MS in Clinical Diagnostics: Opportunities, Technical Hurdles, and Implementation Challenges

Nakagawa T, Wakui M

Medical Mass Spectrometry 8 ( 2 ) 65 - 73 2024.11

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted

CWAの基礎

涌井昌俊

Thrombosis Medicine 14 ( 3 ) 61 - 65 2024.09

Research paper (scientific journal), Single Work, Lead author, Last author, Corresponding author

Modeling and predicting individual variation in COVID-19 vaccine-elicited antibody response in the general population

Nakamura N, Kobashi Y, Kim KS, Park H, Shimazu Y, Zhao T, Nishikawa Y, Omata F, Yoshida M, Abe T, Saito Y, Senoo Y, Takita M, Yamamoto C, Kawamura T, Sugiyama A, Nakayama A, Kaneko Y, eong YD, Tatematsu D, Sato Y, Iwanami S, Fujita Y, Wakui M, Aihara K, Kodama T, Shibuya K, Tani Y, Kawashima M, Nonaka S, Akao M, Iwami S*, Tsubokura M*

PLOS Digit Health 3 ( 5 ) e0000497 2024.05

Research paper (scientific journal), Joint Work, Accepted

As we learned during the COVID-19 pandemic, vaccines are one of the most important tools in infectious disease control. To date, an unprecedentedly large volume of high-quality data on COVID-19 vaccinations have been accumulated. For preparedness in future pandemics beyond COVID-19, these valuable datasets should be analyzed to best shape an effective vaccination strategy. We are collecting longitudinal data from a community-based cohort in Fukushima, Japan, that consists of 2,407 individuals who underwent serum sampling two or three times after a two-dose vaccination with either BNT162b2 or mRNA-1273. Using the individually reconstructed time courses of the vaccine-elicited antibody response based on mathematical modeling, we first identified basic demographic and health information that contributed to the main features of the antibody dynamics, i.e., the peak, the duration, and the area under the curve. We showed that these three features of antibody dynamics were partially explained by underlying medical conditions, adverse reactions to vaccinations, and medications, consistent with the findings of previous studies. We then applied to these factors a recently proposed computational method to optimally fit an “antibody score”, which resulted in an integer-based score that can be used as a basis for identifying individuals with higher or lower antibody titers from basic demographic and health information. The score can be easily calculated by individuals themselves or by medical practitioners. Although the sensitivity of this score is currently not very high, in the future, as more data become available, it has the potential to identify vulnerable populations and encourage them to get booster vaccinations. Our mathematical model can be extended to any kind of vaccination and therefore can form a basis for policy decisions regarding the distribution of booster vaccines to strengthen immunity in future pandemics.

Diminished neutralizing activity against the XBB1.5 strain in 55.9% of individuals post 6 months COVID-19 mRNA booster vaccination: Insights from a pseudovirus assay on 1,353 participants in the Fukushima Vaccination Community Survey, Japan

Zhao T, Tani Y, Makino-Okamura C, Takita M, Yamamoto C, Kawahara E, Abe T, Sugiura S, Yoshimura H, Uchiyama T, Yamazaki I, Ishigame H, Wakui M, Fukuyama H, Tsubokura M

Front Immunol (Frontiers in Immunology) 15 1337520 2024.03

Research paper (scientific journal), Joint Work, Accepted

This study investigates the neutralizing activity against the XBB1.5 variant and the ancestral strain in a population post-bivalent vaccination using a pseudo virus assay validated with authentic virus assay. While bivalent booster vaccination and past infections enhanced neutralization against the XBB 1.5 strain, individuals with comorbidities showed reduced responses. The study suggests the need for continuous vaccine updates to address emerging SARS-CoV-2 variants and highlights the importance of monitoring real-world immune responses.

特集：血栓・塞栓症の臨床　血液検査

涌井昌俊

日本臨床 (日本臨床社) 82 ( 2 ) 148 - 154 2024.02

Research paper (scientific journal), Single Work, Lead author, Corresponding author

ホットトピックス：凝固（出血）分野

涌井昌俊、長江千愛、武山雅博

血栓止血誌 35 ( 1 ) 印刷中 2024

Research paper (scientific journal), Lead author, Corresponding author

PRMT1 methylates PHGDH to sustain de novo fatty acid synthesis for the acquisition of chemoresistance in triple-negative breast cancer cells

Yamamoto T *, Hayashida T#, Masugi Y, Oshikawa K, Hayakawa N, Itoh M, Nishime C, Suzuki M, Nagayama A, Kawai Y, Hishiki T, Matsuura T, Naito Y, Kubo A, Yamamoto A, Yoshioka Y, Kurahori T, Nagasaka M, Takizawa M, Takano N, Kawakami K, Sakamoto M, Wakui M, Yamamoto T, Kitagawa Y, Kabe Y, Horisawa K, Suzuki A, Matsumoto M, Suematsu M *

Cancer Res (Cancer Research) 84 ( 7 ) 1065 - 1083 2024

Research paper (scientific journal), Joint Work, Accepted, ISSN 00085472

Triple-negative breast cancer (TNBC) chemoresistance hampers the ability to effectively treat patients. Identification of mechanisms driving chemoresistance can lead to strategies to improve treatment. Here, we revealed that protein arginine methyltransferase-1 (PRMT1) simultaneously methylates D-3-phosphoglycerate dehydrogenase (PHGDH), a critical enzyme in serine synthesis, and the glycolytic enzymes PFKFB3 and PKM2 in TNBC cells. 13C metabolic flux analyses showed that PRMT1-dependent methylation of these three enzymes diverts glucose toward intermediates in the serine-synthesizing and serine/glycine cleavage pathways, thereby accelerating the production of methyl donors in TNBC cells. Mechanistically, PRMT1-dependent methylation of PHGDH at R54 or R20 activated its enzymatic activity by stabilizing 3-phos-phoglycerate binding and suppressing polyubiquitination. PRMT1-mediated PHGDH methylation drove chemoresistance independently of glutathione synthesis. Rather, activation of the serine synthesis pathway supplied a-ketoglutarate and citrate to increase palmitate levels through activation of fatty acid synthase (FASN). Increased palmitate induced protein S-palmitoylation of PHGDH and FASN to further enhance fatty acid synthesis in a PRMT1-dependent manner. Loss of PRMT1 or pharmacologic inhibition of FASN or protein S-palmitoyltransferase reversed chemoresistance in TNBC. Furthermore, IHC coupled with imaging MS in clinical TNBC specimens substantiated that PRMT1-mediated methylation of PHGDH, PFKFB3, and PKM2 correlates with chemoresistance and that metabolites required for methylation and fatty acid synthesis are enriched in TNBC. Together, these results suggest that enhanced de novo fatty acid synthesis mediated by coordinated protein arginine methylation and protein S-palmitoylation is a therapeutic target for overcoming chemoresistance in TNBC. Significance: PRMT1 promotes chemoresistance in TNBC by methylating metabolic enzymes PFKFB3, PKM2, and PHGDH to augment de novo fatty acid synthesis, indicating that targeting this axis is a potential treatment strategy.

古くて新しい包括的凝固関連検査〜凝固波形解析の現状と展望〜

涌井昌俊

日本臨床検査医学会誌（旧・臨床病理） 72 ( 1 ) 29 - 34 2024

Research paper (scientific journal), Single Work, Lead author, Corresponding author

MMP-3測定用改良試薬「マトリックスメタロプロテイナーゼ-3キット LZ’栄研’ MMP-3」の基礎的検討

豊田咲希、青木絵美、中川央充、酒井昭子、野口昌代、大野明美、横田浩充、涌井昌俊、松下弘道

医療検査と自動化（日本医療検査科学会雑誌） 49 ( 1 ) 48 - 53 2024

Research paper (scientific journal), Joint Work, Accepted

Comparison of clot waveform analysis with or without adjustment between prothrombin time and activated partial thromboplastin time assays to assess in vitro effects of direct oral anticoagulants

Wakui M, Fujimori Y, Ozaki Y, Oka S, Ziparo M, Osada E, Kondo Y, Nakagawa T, Nakamura S, Matsushita H

Clin Chim Acta 562 119887 2024

Research paper (scientific journal), Joint Work, Lead author, Corresponding author, Accepted, ISSN 00098981

Background: Clot waveform analysis (CWA) reportedly enhances the interpretation of clotting time measurement. This study aimed to compare CWA between prothrombin time (PT) and activated partial thromboplastin time (APTT) assays for better understanding how to apply CWA for assessing effects of direct oral anticoagulants (DOACs). Methods: Samples were prepared by spiking plasma with rivaroxaban, apixaban, edoxaban, or dabigatran. To compensate the influence of fibrinogen, CWA parameters were adjusted by unifying maximum changes in transmittance in clotting reaction curves detected by the optical system. Results: Non-adjusted PT-CWA parameters unexpectedly rose at low drug concentrations but declined at high drug concentrations while adjusted PT-CWA parameters exhibited dose-dependent decrease. Both non-adjusted and adjusted APTT-CWA parameters showed dose-dependent decrease. Adjusted CWA parameters were applicable to Hill plot analysis. All DOACs exhibited Hill coefficients indicating positively cooperative effects regarding most adjusted PT-CWA parameters. Regarding adjusted APTT-CWA parameters, rivaroxaban, apixaban, and edoxaban exhibited Hill coefficients indicating no or negatively cooperative effects. The observed differences between PT-CWA and APTT-CWA suggested the implication of thrombin positive feedback in DOAC effects. Conclusion: The results revealed distinct features of DOAC effects in extrinsic and intrinsic pathways. To ascertain the clinical implication, further studies using clinical samples are needed.

Group of longitudinal adverse event patterns after the fourth dose of COVID-19 vaccination with a latent class analysis

Yamamoto C, Kobashi Y, Kawamura T, Nishikawa Y, Saito H, Oguro F, Zhao T, Takita M, Sawano T, Ozaki A, Abe T, Ito N, Kaneko Y, Nakayama A, Wakui M, Kodama T, Tsubokura M

Frontiers in Public Health in press 2024

Research paper (scientific journal), Joint Work, Accepted

Introduction: Vaccination has been implemented as a useful measure to combat the COVID-19 pandemic. However, there is a tendency for individuals to avoid vaccination due to the possibility of adverse events, making it important to investigate the relationship between COVID-19 vaccines and their adverse events. This study explored longitudinal adverse event patterns and factors that influence adverse events following the second to fourth doses of the COVID-19 vaccine through a latent class analysis. Methods: Participants were recruited from the Fukushima Prefecture and included individuals who had completed four doses of the COVID-19 mRNA vaccine. This study utilized data from questionnaire surveys and blood collection conducted between September 2021 and November 2022. In the questionnaire, factors such as sex, age, medical history, medication, type of vaccine administered, and adverse events following vaccination were recorded. Additionally, in the blood data, serological tests [IgG(S)] and cellular immune responses (T-spot) were measured. Descriptive statistics, latent class analysis, multivariable logistic regression, and multiple regression analyses were performed to identify the longitudinal adverse event patterns and influencing factors. By analyzing adverse events over time, we identified two distinct groups: those less prone to experiencing adverse events (Group 1) and those more susceptible (Group 2) to latent class analysis. Results: A total of 1,175 participants were included after excluding those without any adverse events. The median age of the participants in Group 1 was 70 years, and in Group 2 it was 51 years. The proportion of female participants was 298 in Group 1 and 353 in Group 2. Patients in Group 2 were significantly younger (p < 0.001) and more likely to be female (p < 0.001) than those in Group 1. Furthermore, the median IgG(S) value after the fourth vaccination was 3,233 AU/mL in Group 1 and 4,059.39 AU/mL in Group 2. The median T-spot value was 15.4 in Group 1 and 28.5 in Group 2. Group 2 showed significantly higher IgG(S) and T-spot values after the fourth vaccination (p < 0.001). Discussion: Our findings suggest that factors other than age, particularly sex and a history of allergies, significantly influence the likelihood of experiencing adverse events. Groups categorized by latent class analysis for longitudinal adverse events are expected to be valuable for optimizing vaccination strategies and formulating public health measures.

SARS-CoV-2 spike protein antibody titers after the fourth dose of BNT162b2 vaccine among Japanese patients undergoing hemodialysis: a single-center study

Watanabe S, Sawano T, Saito H, Ozaki A, Wakui M, Zhao T, YamamotoC, Kobashi Y, Kawamura T, Sugiyama A, Nakayama A, Kaneko Y, Shimmura H, Tsubokura M

Front Immuno in press 2024

Research paper (scientific journal), Joint Work, Accepted

Kinetics of Humoral and Cellular Immune Responses 5 Months Post-COVID-19 Booster Dose by Immune Response Groups at the Peak Immunity Phase: An Observational Historical Cohort Study Using the Fukushima Vaccination Community Survey

Kobashi Y, Kawamura T, Shimazu Y, Kaneko Y, Nishikawa Y, SugiyamaA, Tani Y, Nakayama A, Yoshida M, Zho T, Yamamoto C, Saito H, Takita M, Wakui M, Kodama T, Tsubokura M

Vaccine X in press 2024

Research paper (scientific journal), Joint Work, Accepted

Background: Understanding the waning of immunity after booster vaccinations is important to identify which immune-low populations should be prioritized. Methods: We investigated longitudinal cellular and humoral immunity after the third vaccine dose in both high- and low-cellular and humoral immunity groups at the peak immunity phase after the booster vaccination in a large community-based cohort. Blood samples were collected from 1045 participants at peak (T1: median 54 days post-third dose) and decay (T2: median 145 days post-third dose) phases to assess IgG(S), neutralizing activity, and ELISpot responses. Participants were categorized into high/low ELISpot/IgG(S) groups at T1. Cellular and humoral responses were tracked for approximately five months after the third vaccination. Results: In total, 983 participants were included in the cohort. IgG(S) geometric mean fold change between timepoints revealed greater waning in the >79 years age group (T2/T1 fold change: 0.27) and higher IgG(S) fold change in the low-ELISpot group at T1 (T2/T1 fold change: 0.32–0.33) than in the other groups, although ELISpot geometric mean remained stable. Conclusions: Antibody level of those who did not respond well to third dose vaccination waned rapidly than those who responded well. Evidence-based vaccine strategies are essential in preventing potential health issues caused by vaccines, including side-effects.

Access to Document (DOI)

Amino acid catabolite markers for early prognostication of pneumonia in patients with COVID-19

Maeda R, Seki Kimizuka N, Uwamino Y, Wakui M, Nakagama Y, Kido Y, Sasai M, Matsuura Y, Uchiyama J, Kim Y-Gi, Mishima M, Suematsu M, Sugiura Y

Nat Commun (Nature Communications) 14 ( 1 ) 8469 2023.12

Research paper (scientific journal), Joint Work, Accepted

Effective early-stage markers for predicting which patients are at risk of developing SARS-CoV-2 infection have not been fully investigated. Here, we performed comprehensive serum metabolome analysis of a total of 83 patients from two cohorts to determine that the acceleration of amino acid catabolism within 5 days from disease onset correlated with future disease severity. Increased levels of de-aminated amino acid catabolites involved in the de novo nucleotide synthesis pathway were identified as early prognostic markers that correlated with the initial viral load. We further employed mice models of SARS-CoV2-MA10 and influenza infection to demonstrate that such de-amination of amino acids and de novo synthesis of nucleotides were associated with the abnormal proliferation of airway and vascular tissue cells in the lungs during the early stages of infection. Consequently, it can be concluded that lung parenchymal tissue remodeling in the early stages of respiratory viral infections induces systemic metabolic remodeling and that the associated key amino acid catabolites are valid predictors for excessive inflammatory response in later disease stages.

Effects of DOAC-Stop on clot waveform analysis of plasma spiked with antithrombin-dependent and antithrombin-independent anticoagulants

Ozaki Y, Wakui M*#, Oka S, Fujimori Y, Kondo Y, Nakamura S, Osada E, Nakagawa T, Katagiri H, Matsushita H

Int J Lab Hematol (International Journal of Laboratory Hematology) 45 ( 6 ) 979 - 983 2023.12

Research paper (scientific journal), Joint Work, Lead author, Corresponding author, Accepted, ISSN 17515521

Antibody profiling of microbial antigens in the blood of COVID-19 mRNA vaccine recipients using microbial protein microarrays

Saito H, Yoshimura H, Yshida M, Tani Y, Kawashima M, Uchiyama T, Tianchen Z, Yamamoto C, Kobashi Y, Wakui M, Tianchen Z, Yamamoto C, Kawashima M, Sawano T, Kawamura T, Imoto S, Pak H, Nakamura N Iwami S, Kaneko Y, Nakayama A, , Kodama T, Wakui M, Kawamura T, Tsubokura M

Vaccines (Vaccines) 11 ( 11 ) 1694 2023.11

Research paper (scientific journal), Joint Work, Accepted

Although studies have demonstrated that infections with various viruses, bacteria, and parasites can modulate the immune system, no study has investigated changes in antibodies against microbial antigens after the COVID-19 mRNA vaccination. IgG antibodies against microbial antigens in the blood of vaccinees were comprehensively analyzed using microbial protein microarrays that carried approximately 5000 microbe-derived proteins. Changes in antibodies against microbial antigens were scrutinized in healthy participants enrolled in the Fukushima Vaccination Community Survey conducted in Fukushima Prefecture, Japan, after their second and third COVID-19 mRNA vaccinations. Antibody profiling of six groups stratified by antibody titer and the remaining neutralizing antibodies was also performed to study the dynamics of neutralizing antibodies against SARS-CoV-2 and the changes in antibodies against microbial antigens. The results showed that changes in antibodies against microbial antigens other than SARS-CoV-2 antigens were extremely limited after COVID-19 vaccination. In addition, antibodies against a staphylococcal complement inhibitor have been identified as microbial antigens that are associated with increased levels of neutralizing antibodies against SARS-CoV-2. These antibodies may be a predictor of the maintenance of neutralizing antibodies following the administration of a COVID-19 mRNA vaccine.

Association of systemic adverse reaction patterns with long-term dynamics of humoral and cellular immunity after coronavirus disease 2019 third vaccination

Yoshida M, Kobashi Y, Kawamura T, Shimazu Y, Nishikawa Y, Omata F, Saito H, Yamamoto C, Zhao T, Takita M, Ito N, Tatsuno K, Kaneko Y, Nakayama A, Kodama T, Wakui M, Takahashi K, Tsubokura M

Sci Rep (Scientific Reports) 13 ( 1 ) 9264 2023.06

Research paper (scientific journal), Joint Work, Accepted

The objective of this study was to clarify the impact of adverse reactions on immune dynamics. We investigated the pattern of systemic adverse reactions after the second and third coronavirus disease 2019 (COVID-19) vaccinations and their relationship with immunoglobulin G against severe acute respiratory syndrome coronavirus 2 spike 1 protein titers, neutralizing antibody levels, peak cellular responses, and the rate of decrease after the third vaccination in a large-scale community-based cohort in Japan. Participants who received a third vaccination with BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna), had two blood samples, had not had COVID-19, and had information on adverse reactions after the second and third vaccinations (n = 2198) were enrolled. We collected data on sex, age, adverse reactions, comorbidities, and daily medicine using a questionnaire survey. Participants with many systemic adverse reactions after the second and third vaccinations had significantly higher humoral and cellular immunity in the peak phase. Participants with multiple systemic adverse reactions after the third vaccination had small changes in the geometric values of humoral immunity and had the largest geometric mean of cellar immunity in the decay phase. Systemic adverse reactions after the third vaccination helped achieve high peak values and maintain humoral and cellular immunity. This information may help promote uptake of a third vaccination, even among those who hesitate due to adverse reactions.

Varying cellular immune response against SARS-CoV-2 after the booster vaccination: A cohort study from Fukushima Vaccination Community Survey, Japan

Tani Y, Takita M, Kobashi Y, Wakui M, Tianchen Z, Yamamoto C, Saito H, Kawashima M, Sugiura S, Nishikawa Y, Omata F, Shimazu Y, Kawamura T, Sugiyama A, Nakayama A, Kaneko Y, Kodama T, Kami M, Tsubokura M

Vaccines (Vaccines) 11 ( 5 ) 920 2023.04

Research paper (scientific journal), Joint Work, Accepted

Booster vaccination reduces the incidence of severe cases and mortality related to COVID-19, with cellular immunity playing an important role. However, little is known about the proportion of the population that has achieved cellular immunity after booster vaccination. Thus, we conducted a Fukushima cohort database and assessed humoral and cellular immunity in 2526 residents and healthcare workers in Fukushima Prefecture in Japan through continuous blood collection every 3 months from September 2021. We identified the proportion of people with induced cellular immunity after booster vaccination using the T-SPOT.COVID test, and analyzed their background characteristics. Among 1089 participants, 64.3% (700/1089) had reactive cellular immunity after booster vaccination. Multivariable analysis revealed the following independent predictors of reactive cellular immunity: age < 40 years (adjusted odds ratio: 1.81; 95% confidence interval: 1.19–2.75; p-value: 0.005) and adverse reactions after vaccination (1.92, 1.19–3.09, 0.007). Notably, despite IgG(S) and neutralizing antibody titers of ≥500 AU/mL, 33.9% (349/1031) and 33.5% (341/1017) of participants, respectively, did not have reactive cellular immunity. In summary, this is the first study to evaluate cellular immunity at the population level after booster vaccination using the T-SPOT.COVID test, albeit with several limitations. Future studies will need to evaluate previously infected subjects and their T-cell subsets.

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