This study was conducted at 112 government and Juntendo University hospitals in February 2021 for the primary series of SARS-CoV-2 vaccinations. We compared the timing of solicited adverse event (AE) onset and prevalence of unsolicited AEs for Pfizer, Moderna, and AstraZeneca vaccines in a nationwide, large-scale prospective cohort study. The Pfizer and Moderna mRNA vaccines were associated with a higher frequency of fever after the second dose than after the first dose. The AstraZeneca viral vector vaccine resulted in more frequent side effects after the first dose. The side effects of mRNA vaccines were the most common on the day after vaccination and almost subsided by the fourth day. The incidence of systemic AEs, including fever of ≥37.5 °C, was the highest for Moderna, followed by AstraZeneca and Pfizer. Local reactions were less frequent with the AstraZeneca vaccine than with the Pfizer and Moderna vaccines but tended to last longer. The frequency of AEs was higher in women than in men. The odds ratio for age per year regarding systemic reactions (adjusted for sex) was the least for AstraZeneca, followed by Pfizer and Moderna (< 1), indicating a more pronounced decrease in the frequency of fever and systemic reactions with increasing age. Age effects varied among vaccines. Delayed skin reactions, appearing around the seventh day after the first dose (Day 8), were observed as itchy redness, particularly in women aged ≥30 with the Moderna vaccine and less often with the Pfizer vaccine. Over half of the delayed skin reactions involved local erythema immediately after the second dose, but these reactions mostly disappeared within approximately 10 days. Despite differences in the incidence of AEs among the three vaccines by age and sex, all vaccines were well-tolerated. These findings provide crucial safety information, supporting informed vaccination decisions and ongoing surveillance efforts.

INTRODUCTION:To control the spread of severe disease caused by mutant strains of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), it is necessary to determine whether continued vaccination enhances humoral and cellular immunity. AIM:In this study, we examined the changes in humoral and cellular immunity to SARS-CoV-2 after administration of the third vaccination in Japanese adults who had received the second dose of messenger ribonucleic acid (mRNA)-1273 vaccine and the third vaccination (BNT162b2 or mRNA-1273). METHODS:We measured anti-spike antibodies in immunoglobulin G (IgG) and anti-nucleocapsid IgG titers in the serum of the vaccinated subjects. To evaluate cellular immunity, the peripheral blood mononuclear cells of inoculated individuals were cultured with spiked proteins, including those of the SARS-CoV-2 conventional strain and Omicron strain, and then subjected to enzyme-linked immunospot (ELISPOT). RESULTS:The results revealed that the anti-SARS-CoV-2 spike protein antibody titer increased after the third vaccination and was maintained; however, a decrease was observed at 6 months after vaccination. SARS-CoV-2 antigen-specific T helper (Th)1 and Th2 cell responses were also induced after the third vaccination and were maintained for 6 months after vaccination. Furthermore, induction of cellular immunity against Omicron strains by the omicron non-compliant vaccines, BNT162b2 or mRNA-1273, was observed. CONCLUSION:These findings demonstrate the effectiveness of vaccination against unknown mutant strains that may occur in the future and provide important insights into vaccination strategies.

mRNA vaccines emerged as a new therapeutic modality during the COVID-19 pandemic. Individuals with allergies often experience anxiety about potential adverse reactions to these vaccines. This study aims to elucidate the relationship between adverse reactions and various allergies, asthma, or atopic disorders. Data from approximately 20,000 Japanese healthcare workers participating in a prospective cohort study were analyzed. The number of vaccinated individuals was 19,792 (first dose), with systemic reactions occurring in 35.8% after the first dose and 75.3% after the second dose. Participants with allergies were categorized into groups: food and/or drug allergies ( n = 806), asthma and/or atopic disorders ( n = 2,370), asthma (both past medical history [PMH] and present illness [PI]) ( n = 1,983), and atopic disorders (PI) ( n = 567). Most systemic reactions in those with food and/or drug allergies occurred within the first three days of vaccination. Logistic regression analysis showed that food and/or drug allergies, asthma (PMH and PI), and asthma and/or atopic disorders were significantly associated with systemic reactions (odds ratios [95% confidence interval]: 1.65 [1.43-1.91], 1.36 [1.23-1.49], and 1.32 [1.21-1.45], respectively, for the first dose). These findings suggest the risk of systemic reactions after COVID-19 vaccination in individuals with the specified allergies, potentially contributing to vaccine hesitancy. Medical professionals should clearly communicate the risks and benefits of vaccination to those with allergies to alleviate their concerns. Additionally, our study's data may be useful for making decisions whether or not to get vaccinated in those with allergies and inform the development of future mRNA vaccines.

BackgroundDisease-specific induced pluripotent stem cells (iPSCs) are useful tools for pathological analysis and diagnosis of rare diseases. Given the limited available resources, banking such disease-derived iPSCs and promoting their widespread use would be a promising approach for untangling the mysteries of rare diseases. Herein, we comprehensively established iPSCs from patients with designated intractable diseases in Japan and evaluated their properties to enrich rare disease iPSC resources.MethodsPatients with designated intractable diseases were recruited for the study and blood samples were collected after written informed consent was obtained from the patients or their guardians. From the obtained samples, iPSCs were established using the episomal method. The established iPSCs were deposited in a cell bank.ResultsWe established 1,532 iPSC clones from 259 patients with 139 designated intractable diseases. The efficiency of iPSC establishment did not vary based on age and sex. Most iPSC clones originated from non-T and non-B hematopoietic cells. All iPSC clones expressed key transcription factors, OCT3/4 (range 0.27-1.51; mean 0.79) and NANOG (range 0.15-3.03; mean 1.00), relative to the reference 201B7 iPSC clone.ConclusionsThese newly established iPSCs are readily available to the researchers and can prove to be a useful resource for research on rare intractable diseases.

わが国の新型コロナワクチン臨時接種に係る安全性情報などを厚生労働省の審議会で迅速に公開することを目的として，行政推進調査事業として「新型コロナワクチンの接種開始初期の重点的調査（コホート調査）」が計画され，2021年2月からファイザー社コミナティ筋注，モデルナ社スパイクバックス筋注およびアストラゼネカ社バキスゼブリア筋注の初回シリーズについて実施された．人を対象とする医学系研究に関する倫理指針に適合した観察研究として迅速に実施するために，コマーシャル IRB の利用，実績のあるEDCを含む研究プラットフォームの準備，体温計などの資材管理を含んだマネージメント業務体制の構築，実施医療機関の管理をお願いした国立病院機構，地域医療機能推進機構，労働者健康安全機構病院各本部の協力が重要であった．その結果，9日間で約2万人の医療従事者を接種し，接種直後の安全性情報を3 月に公開した．2021年5月からモデルナ社（自衛隊職員対象），2021年8月からはアストラゼネカ社（一般人）の初回シリーズについての調査を実施した．さらに2021年12月からは3回目追加接種，2022年3月からは5～11歳の小児用ワクチン，2022年5月からは武田/ノババックス社ワクチンの調査および4 回目追加接種については安全性調査に加え，対象者の一部で抗体価の推移を検討し，副反応検討部会/安全対策調査会に23回（2022年7月8日現在）にわたって報告した．本調査結果は発熱，局所疼痛，倦怠感，頭痛などの特定有害事象に加えて，MedDRA コード化した自由記載欄，病休数，副反応使用薬剤数，抗体価推移および，PMDA 報告も含めた重篤な有害事象についても捕捉した医薬品安全性データベースとなっている．

BACKGROUND:This study evaluates the immunogenicity and reactogenicity of BNT162b2 and mRNA-1273 booster doses after the primary two-dose BNT162b2 series in Japan and is the first report from Western Pacific region.RESEARCH DESIGN AND METHODS:Healthcare workers receiving the two-dose BNT162b2 series and eligible for booster vaccination were enrolled. Self-reported adverse reactions were recorded for 8 days. Antibody titer was measured at baseline and on day 28.RESULTS:A total of 2,931 and 890 subjects received BNT162b2 (homologous) and mRNA-1273 (heterologous) booster vaccinations, respectively. The anti-SARS-CoV-2 spike protein IgG titer increased by 50.9- and 64.3-fold in the homologous and heterologous groups, respectively. Immunogenicity was greater with increasing age, regardless of sex. Adverse reactions were mild to moderate and decreased with age. The most common adverse reactions were injection-site pain (92.2%), fatigue (71.8%), headache (58.3%), and fever ≥37.5°C (46.5%). Two cases of non-severe myocarditis occurred in the heterologous group and resolved without clinical sequelae.CONCLUSION:Homologous booster schedules had fewer reported adverse reactions; heterologous boosters elicited greater immunogenicity. Among different age groups, subjects aged 60 or over had the lowest immunogenicity before the booster, and both homologous and heterologous boosters restored vaccine immunogenicity level comparable to those of younger age groups.

BACKGROUND:ELA-Max, an external liposomal preparation of lidocaine (4%) available without prescription in United States, has a recommended application time of 15 to 45 min without occlusive dressing, and the side effect has been reported to be rare. To investigate external anesthetic preparations to reduce neuropathic pain, we evaluated sensory nerve anesthesia by ELA-Max in comparison with placebo and other lidocaine topical preparations by double blind method.METHODS:We measured the neuroselective current perception threshold (N-CPT) 30 min after the application of ELA-Max on 30 healthy Japanese volunteers. Evaluation of anesthetic effect was performed by change in N-CPT rate before and after the application of 0.025 g x cm(-2) to the skin where stimulation was performed.RESULTS:ELA-Max increased N-CPT ratio in 4 out of 9 subjects stimulated at 5 Hz. However these CPT values were within normal ranges, and the change in N-CPT ratio was not statistically significant throughout all stimulation frequencies.CONCLUSIONS:The application of 0.025 g x cm(-2) ELA-Max for 30 min was not effective to induce therapeutic level of anesthesia. Extended application times as well as occlusive dressing may be needed for this preparation to be used clinically.

AIMS:Approximately 80% of uracil is excreted as beta-alanine, ammonia and CO2 via three sequential reactions. The activity of the first enzyme in this scheme, dihydropyrimidine dehydrogenase (DPD), is reported to be the key determinant of the cytotoxicity and side-effects of 5-fluorouracil. The aim of the present study was to re-evaluate the pharmacokinetics of uracil and its metabolites using a sensitive assay and based on a newly developed, physiologically based pharmacokinetic (PBPK) model.METHODS:[2-(13)C]Uracil was orally administrated to 12 healthy males at escalating doses of 50, 100 and 200 mg, and the concentrations of [2-(13)C]uracil, [2-(13)C]5,6-dihydrouracil and beta-ureidopropionic acid (ureido-(13)C) in plasma and urine and (13)CO2 in breath were measured by liquid chromatography-tandem mass spectrometry and gas chromatograph-isotope ratio mass spectrometry, respectively.RESULTS:The pharmacokinetics of [2-(13)C]uracil were nonlinear. The elimination half-life of [2-(13)C]5,6-dihydrouracil was 0.9-1.4 h, whereas that of [2-(13)C]uracil was 0.2-0.3 h. The AUC of [2-(13)C]5,6-dihydrouracil was 1.9-3.1 times greater than that of [2-(13)C]uracil, whereas that of ureido-(13)C was 0.13-0.23 times smaller. The pharmacokinetics of (13)CO2 in expired air were linear and the recovery of (13)CO2 was approximately 80% of the dose. The renal clearance of [2-(13)C]uracil was negligible.CONCLUSION:A PBPK model to describe (13)CO2 exhalation after orally administered [2-(13)C]uracil was successfully developed. Using [2-(13)C]uracil as a probe, this model could be useful in identifying DPD-deficient patients at risk of 5-fluorouracil toxicity.