記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1128/jvi.01823-23

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Molecular Sciences  

Combination antiretroviral therapy (cART) has significantly improved the prognosis of individuals living with human immunodeficiency virus (HIV). Acquired immunodeficiency syndrome has transformed from a fatal disease to a treatable chronic infection. Currently, effective and safe anti-HIV drugs are available. Although cART can reduce viral production in the body of the patient to below the detection limit, it cannot eliminate the HIV provirus integrated into the host cell genome; hence, the virus will be produced again after cART discontinuation. Therefore, research into a cure (or remission) for HIV has been widely conducted. In this review, we focus on drug development targeting cells latently infected with HIV and assess the progress including our current studies, particularly in terms of the “Shock and Kill”, and “Block and Lock” strategies.

DOI： 10.3390/ijms25052621

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.heliyon.2024.e24513

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Life  

Convalescent plasma therapy, which involves administering plasma from recovered coronavirus disease 2019 (COVID-19) patients to infected individuals, is being explored as a potential treatment for severe cases of COVID-19. This study aims to evaluate the efficacy and safety of convalescent plasma therapy in COVID-19 patients with moderate to severe illness. An open-label, single-arm intervention study was conducted without a control group. Plasma collected from recovered COVID-19 patients was administered to eligible participants. The primary endpoint was the proportion of patients who were placed on artificial ventilation or died within 14 days of transfusion. Secondary endpoints included clinical improvement, viral load measurements, and adverse event monitoring. A total of 59 cases were included in the study. The primary endpoint was evaluated by comparing the rate obtained in the study to an existing rate of 25%. The study also assessed clinical improvement, viral load changes, and safety endpoints through adverse event monitoring. Convalescent plasma therapy shows potential as a treatment option for COVID-19. This study aimed to provide evidence for the efficacy and safety of this therapy and may contribute to its future use in treating severe cases of COVID-19.

DOI： 10.3390/life13112184

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.heliyon.2023.e20568

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Infectious Diseases  

Background. Data are limited on the role of preinfection humoral immunity protection against Omicron BA.5 infection and long coronavirus disease (COVID) development. Methods. We conducted nested case-control analysis among tertiary hospital staff in Tokyo who donated blood samples in June 2022 (1 month before Omicron BA.5 wave), approximately 6 months after receiving a third dose of COVID-19 mRNA vaccine. We measured live virus-neutralizing antibody titers against wild type and Omicron BA.5, and anti–receptor-binding domain (RBD) antibody titers at preinfection, and compared them between cases and propensity-matched controls. Among the breakthrough cases, we examined association between preinfection antibody titers and incidence of long COVID. Results. Preinfection anti-RBD and neutralizing antibody titers were lower in cases than controls. Neutralizing titers against wild type and Omicron BA.5 were 64% (95% confidence interval [CI], 42%–77%) and 72% (95% CI, 53%–83%) lower, respectively, in cases than controls. Individuals with previous Omicron BA.1/BA.2 infections were more frequent among controls than cases (10.3% vs 0.8%), and their Omicron BA.5 neutralizing titers were 12.8-fold higher than infection-naive individuals. Among cases, preinfection antibody titers were not associated with incidence of long COVID. Conclusions. Preinfection immunogenicity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may play a role in protecting against the Omicron BA.5 infection but not preventing long COVID.

DOI： 10.1093/infdis/jiad317

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：STAR Protocols  

Eradication of HIV-1 latently infected cells is an important issue in HIV treatment. However, there are limited models available to assess therapeutic efficacy in vitro. Here, we present a protocol for establishing a variety of HIV-infected Jurkat cells, including productive and latent status, evaluating the efficacy of antiviral agents, followed by PCR/sequencing-based detection of replication competent HIV provirus. This protocol is useful for optimization of treatment of HIV-1 and provides insights into the mechanisms of clonal selection of heterogeneous HIV-1-infected cells. For complete details on the use and execution of this protocol, please refer to Matsuda et al. (2021).1

DOI： 10.1016/j.xpro.2023.102547

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記述言語：英語   出版者・発行元：エルゼビア・ジャパン(株)  

SARS-CoV-2に対する高い中和活性をもつ回復期血漿を用いた血漿療法を、高リスクCOVID-19患者に施行した。COVID-19症状出現から5日以内に血漿療法を始め、day 0～day 5の鼻咽頭拭い液のウイルス量の時間加重平均変化を主要評価項目とした。患者25名が無作為に回復期血漿療法群(n=14(うち4名は血漿療法を中止))と標準的治療群(n=11)に割り付けられた。症状出現から血漿投与までの日数の中央値は4.5日であった。day 0～day 5までのウイルス量の時間加重平均変化は血漿療法群で1.2log copies/mL、標準的治療群で1.2log copies/mLで、有意差はなかった。いずれの群にも死亡例はなかった。早期の回復期血漿投与はウイルス量低下に寄与しないと考えられた。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Medicinal Chemistry  

Cells latently infected with human immunodeficiency virus type 1 (HIV-1) prevent people living with HIV-1 from obtaining a cure to the infectious disease. Latency reversing agents (LRAs) such as protein kinase C (PKC) activators and histone deacetylase (HDAC) inhibitors can reactivate cells latently infected with HIV-1. Several trials based on treatment with HDAC inhibitors alone, however, failed to reduce the number of latent HIV-1 reservoirs. Herein, we have focused on a diacylglycerol (DAG)-lactone derivative, YSE028 (1), which is a PKC activator with latency reversing activity and no significant cytotoxicity. Caspase-3 activation of YSE028 (1) led to cell apoptosis, specifically in HIV-1 latently infected cells. Structure-activity relationship studies of YSE028 (1) have produced several useful derivatives. Among these, compound 2 is approximately ten times more potent than YSE028 (1) in reactivation of cells latently infected with HIV-1. The activity of DAG-lactone derivatives was correlated with the binding affinity for PKC and the stability against esterase-mediated hydrolysis.

DOI： 10.1016/j.ejmech.2023.115449

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19). Despite its use for treating several viral infections, we lack comprehensive data on its efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We conducted a multicenter, open-label, randomized controlled trial of convalescent plasma therapy with high neutralizing activity against SARS-CoV-2 in high-risk patients within five days after the onset of COVID-19 symptoms. The primary endpoint was the time-weighted average change in the SARS-CoV-2 viral load in nasopharyngeal swabs from days 0-5. RESULTS: Between February 24, 2021, and November 30, 2021, 25 patients were randomly assigned to either convalescent plasma (n = 14) or standard of care (n = 11) groups. Four patients discontinued their allocated convalescent plasma, and 21 were included in the modified intention-to-treat analysis. The median interval between the symptom onset and plasma administration was 4.5 days (interquartile range, 3-5 days). The primary outcome of the time-weighted average change in the SARS-CoV-2 viral load in nasopharyngeal swabs did not significantly differ between days 0-5 (1.2 log10 copies/mL in the convalescent plasma vs. 1.2 log10 copies/mL in the standard of care (effect estimate, 0.0 [95% confidence interval, -0.8-0.7]; P = 0.94)). No deaths were observed in either group. CONCLUSIONS: The early administration of convalescent plasma with high neutralizing activity did not contribute to a decrease in the viral load within five days compared with the standard of care alone.

DOI： 10.1016/j.jiac.2023.05.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMC Infectious Diseases  

Background: Longitudinal data are lacking to compare booster effects of Delta breakthrough infection versus third vaccine dose on neutralizing antibodies (NAb) against Omicron. Methods: Participants were the staff of a national research and medical institution in Tokyo who attended serological surveys on June 2021 (baseline) and December 2021 (follow-up); in between, the Delta-dominant epidemic occurred. Of 844 participants who were infection-naïve and had received two doses of BNT162b2 at baseline, we identified 11 breakthrough infections during follow-up. One control matched to each case was selected from boosted and unboosted individuals. We compared live-virus NAb against Wild-type, Delta, and Omicron BA.1 across groups. Results: Breakthrough infection cases showed marked increases in NAb titers against Wild-type (4.1-fold) and Delta (5.5-fold), and 64% had detectable NAb against Omicron BA.1 at follow-up, although the NAb against Omicron after breakthrough infection was 6.7- and 5.2-fold lower than Wild-type and Delta, respectively. The increase was apparent only in symptomatic cases and as high as in the third vaccine recipients. Conclusions: Symptomatic Delta breakthrough infection increased NAb against Wild-type, Delta, and Omicron BA.1, similar to the third vaccine. Given the much lower NAb against Omicron BA.1, infection prevention measures must be continued irrespective of vaccine and infection history while the immune evasive variants are circulating.

DOI： 10.1186/s12879-023-08272-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) induce effective immune responses, vaccination with booster doses is necessary because of waning immunity. We conducted an open-label, non-randomized, single-arm study in adults in Japan to assess the immunogenicity and safety of a single booster dose of the KD-414 purified whole-SARS-CoV-2-virion inactivated vaccine candidate after vaccination with a primary series of BNT162b2. The primary endpoint was serum neutralizing activity at 7 days after booster injection compared with the primary series of BNT162b2. The SARS-CoV-2-structural protein-binding antibody level and T cell response against SARS-CoV-2-Spike (S) peptides were also examined as secondary endpoints, and safety profile assessments were conducted. Twenty subjects who participated in a previous study declined an injection of KD-414 (non-KD-414 group) and received a booster dose of BNT162b2 instead. The non-KD-414 group was compared to the KD-414 group as a secondary outcome. A single dose of KD-414 induced lower serum neutralizing activity against the wild-type virus within 7 days compared to after the primary series of BNT162b2 but significantly induced anti-SARS-CoV-2-S1-receptor-binding domain-binding immunoglobulin G (IgG) antibodies and SARS-CoV-2-S peptide-specific CD4+ and CD8+ T cell responses. Local or systemic symptoms were significantly lower in the participants who received KD-414 than in those who received BNT162b2 as the third COVID-19 vaccine dose. The present data indicate that a single booster dose of KD-414 induces a substantial immune response in BNT162b2-primed individuals and has a good safety profile, thereby supporting further clinical trials to identify rational targets.

DOI： 10.1080/21645515.2023.2193074

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出版者・発行元：医歯薬出版  

DOI： 10.32118/ayu28409726

記述言語：英語   掲載種別：研究論文（学術雑誌）  

COVID-19 caused by SARS-CoV-2 has continually been serious threat to public health worldwide. While a few anti-SARS-CoV-2 therapeutics are currently available, their antiviral potency is not sufficient. Here, we identify two orally available 4-fluoro-benzothiazole-containing small molecules, TKB245 and TKB248, which specifically inhibit the enzymatic activity of main protease (Mpro) of SARS-CoV-2 and significantly more potently block the infectivity and replication of various SARS-CoV-2 strains than nirmatrelvir, molnupiravir, and ensitrelvir in cell-based assays employing various target cells. Both compounds also block the replication of Delta and Omicron variants in human-ACE2-knocked-in mice. Native mass spectrometric analysis reveals that both compounds bind to dimer Mpro, apparently promoting Mpro dimerization. X-ray crystallographic analysis shows that both compounds bind to Mpro's active-site cavity, forming a covalent bond with the catalytic amino acid Cys-145 with the 4-fluorine of the benzothiazole moiety pointed to solvent. The data suggest that TKB245 and TKB248 might serve as potential therapeutics for COVID-19 and shed light upon further optimization to develop more potent and safer anti-SARS-CoV-2 therapeutics.

DOI： 10.1038/s41467-023-36729-0

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記述言語：英語  

DOI： 10.1016/j.jinf.2023.01.038

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the anti-SARS-CoV-2 antibody levels, anti-spike (S)-immunoglobulin G (IgG) and anti-nucleocapsid (N)-IgG, and the neutralization activity of IgG antibody in COVID‑19‑convalescent plasma against variants of SARS-CoV-2, alpha, beta, gamma, delta, kappa, omicron and R.1 strains. The study included 30 patients with clinically diagnosed COVID-19. The anti-S-IgG and anti-N-IgG levels ranged from 30.0 to 555.1 and from 10.1 to 752.6, respectively. The neutralization activity (50% inhibition concentration: IC50) for the wild-type Wuhan strain ranged from < 6.3 to 81.5 µg/ml. IgG antibodies were > 100 µg/ml in 18 of 30 (60%) subjects infected with the beta variant. The IC50 values for wild-type and beta variants correlated inversely with anti-S-IgG levels (p < 0.05), but no such correlation was noted with anti-N-IgG. IgG antibodies prevented infectivity and cytopathic effects of six different variants of concern in the cell-based assays of wild-type, alpha, gamma, delta, kappa and R.1 strains, but not that of the beta and omicron strains. IgG is considered the main neutralizing activity in the blood, although other factors may be important in other body tissues.

DOI： 10.1038/s41598-023-28591-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Infectious Diseases  

Objectives: To investigate the role of immunogenicity after the third vaccine dose against Omicron infection and COVID-19-compatible symptoms of infection. Methods: First, we examined vaccine effectiveness (VE) of the third dose against the second dose during the Omicron wave among the staff at a tertiary hospital in Tokyo. In a case-control study of third vaccine recipients, we compared the preinfection live-virus neutralizing antibodies (NAb) against Omicron between breakthrough cases and their controls who had close contact with patients with COVID-19. Among these cases, we examined the association between NAb levels and the number of COVID-19-compatible symptoms. Results: Among the 1456 participants for VE analysis, 60 breakthrough infections occurred during the Omicron wave. The third dose VE for infection was 54.6%. Among the third dose recipients, NAb levels against Omicron did not differ between the cases (n = 22) and controls (n = 21). Among the cases, those who experienced COVID-19-compatible symptoms had lower NAb levels against Omicron than those who did not. Conclusion: The third vaccine dose was effective in decreasing the risk of SARS-CoV-2 infection during Omicron wave compared with the second dose. Among third dose recipients, higher preinfection NAb levels may not be associated with a lower risk of Omicron infection. Contrarily, they may be associated with fewer symptoms of infection.

DOI： 10.1016/j.ijid.2023.01.023

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Biochemical and Biophysical Research Communications  

Combinational antiretroviral therapy (cART) dramatically suppresses the viral load to undetectable levels in human immunodeficiency virus (HIV)-infected patients. However, HIV-1 reservoirs in CD4+T cells and myeloid cells, which can evade cART and host antiviral immune systems, are still significant obstacles to HIV-1 eradication. The “Shock and Kill” approach using latently-reversing agents (LRAs) is therefore currently developing strategies for effective HIV-1 reactivation from latency and inducing cell death. Here, we performed small-molecular chemical library screening with monocytic HIV-1 latently-infected model cells, THP-1 Nluc #225, and identified 4-phenylquinoline-8-amine (PQA) as a novel LRA candidate. PQA induced efficient HIV-1 reactivation in combination with PKC agonists including Prostratin and showed a similar tendency for HIV-1 activation in primary HIV-1 reservoirs. Furthermore, PQA induced killing of HIV-1 latently-infected cells. RNA-sequencing analysis revealed PQA had different functional mechanisms from PKC agonists, and oxidative stress-inducible genes including DDIT3 or CTSD were only involved in PQA-mediated cell death. In summary, PQA is a potential LRA lead compound that exerts novel functions related to HIV-1 activation and apoptosis-mediated cell death to eliminate HIV-1 reservoirs.

DOI： 10.1016/j.bbrc.2022.12.024

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記述言語：英語   出版者・発行元：エルゼビア・ジャパン(株)  

2021年5月～2021年8月に第1回目のワクチン接種を受け、その後に新型コロナウイルス感染症を発症した患者9名を対象に、抗新型コロナウイルス(SARS-CoV-2)結合抗体価と中和活性について後向き観察研究で調査した。調査項目は患者背景(年齢・性別、背景状態と併発状態、ワクチン型と接種時期、試料収集時期、ウイルス株、転帰)と臨床分離SARS-CoV-2株に対する血清の中和活性、および抗SARS-CoV-2結合抗体(S-IgG、S-IgM、N-IgG)量とした。その結果、SARS-CoV-2結合抗体と中和活性は、第1回目試料収集(中央値はワクチン接種後13.5日)から第2回目にかけて大幅に増加していた。

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Transfusion and Apheresis Science  

Purpose: In the current study, we aimed to evaluate the neutralizing IgG activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as the coagulation factors of convalescent plasmas which we manufactured in-house without a fast-freezing technique. Methods: We collected plasmas from eligible participants who had confirmed certain titers of neutralizing antibodies. The plasmas were frozen and stored in the ordinary biofreezer without a fast-freezing function. The purified-IgG neutralizing activity of 20 samples from 19 participants and the coagulation factors of 49 samples from 40 participants were evaluated before and after freezing. Results: Purified-IgG maintained its neutralizing activities, with the median 50 % inhibitory concentration (IC50) of 10.11 mg/ml (IQR 6.53–18.19) before freezing and 8.90 m g/ml (IQR 6.92–28.27) after thawing (p = 0.956). On the contrary, fibrinogen and factor Ⅷ decreased significantly after freezing and thawing in our environment. No significant temperature deviation was observed during the storage period. Conclusion: Neutralizing IgG activity, which largely contributes to the antiviral activity of convalescent plasma, did not change through our in-house manufacturing, without fastfreezing and storage conditions for more than 200 days. Ordinary freezers without the fast-freezing function are suitable enough to manufacture and store convalescent plasmas. Hospitals or facilities without specified resources could easily collect and store convalescent plasmas in case of upcoming emerging or re-emerging infectious diseases on-demand with appropriate neutralizing antibody levels measurements.

DOI： 10.1016/j.transci.2022.103638

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記述言語：日本語   出版者・発行元：(一社)日本エイズ学会  

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記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

症例は62歳男性で、2型糖尿病と末期腎不全のため5年間にわたり維持血液透析を行っており、C型肝炎とステージ2肝細胞癌のため他院で治療を受けていたが、無症候性のCOVID-19が判明したため当院に入院となった。在院期間を通じて症状は認められず、翌月に退院した。その数ヵ月後、家族の感染が判明して濃厚接触者となり、発熱、咳嗽などの症状が出現し、COVID-19と診断、入院となった。その後、呼吸不全をきたし、高度専門医療機関へ搬送転院となった。酸素吸入、ファビピラビル、ステロイドにより回復し、退院した。抗SARS-CoV-2抗体産生のキネティクスを評価するため、SARS-CoV-2スパイクタンパク質S1サブユニットに対するIgG抗体(IgG-S1)、full-lengthスパイクタンパク質に対するIgG抗体(anti-Spike IgG)、中和抗体を測定した。その結果、初回感染後5日目までセロコンバージョンを認めなかったのに対し、再感染後は10日目にIgG-S1のセロコンバージョンを認めた。同様にanti-Spike IgGおよび中和抗体は再感染後12日目から増加を示した。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Secretory immunoglobulin A (IgA) plays a crucial role in mucosal immunity for preventing the invasion of exogenous antigens; however, little is 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 to below the detection limit approximately 70 days after onset, while substantial IgG activity was observed until 200 days after onset. The total neutralizing activity in sera/plasmas of those with COVID-19 largely correlated with those 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 elicits both SARS-CoV-2-specific neutralizing IgG and IgA responses in serum, but the IgA response is modest and diminishes faster than the IgG response. IMPORTANCE Secretory dimeric immunoglobulin A (IgA) plays an important role in preventing the invasion of foreign objects by its neutralizing activity on mucosal surfaces, 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 (nIgG) and IgA (nIgA) active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the nIgA response was quick and reached the highest activity earlier than the nIgG response, nIgA activity was modest and diminished faster than nIgG activity. In individuals who recovered from COVID-19 but had no detectable nIgA activity, a single dose of COVID-19 mRNA vaccine elicited potent nIgA 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 nIgA against the pathogen in both naturally infected and COVID-19 mRNA vaccine-receiving COVID-19-convalescent individuals.

DOI： 10.1128/spectrum.02716-22

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：公益社団法人 日本薬学会  

Dihydroceramide Δ4-desaturase 1 (DEGS1) enzymatic activity is inhibited with N-(4-hydroxyphenyl)retinamide (4-HPR). We reported previously that 4-HPR suppresses severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry through a DEGS1-independent mechanism. However, it remains unclear whether DEGS1 is involved in other SARS-CoV-2 infection processes, such as virus replication and release. Here we established DEGS1 knockout (KO) in VeroE6TMPRSS2 cells. No significant difference was observed in virus production in the culture supernatant between wild-type (WT) cells and DEGS1-KO cells, although the levels of dihydroceramide (DHCer), a DEGS1 substrate, were significantly higher in DEGS1-KO cells than WT cells. Furthermore, the virus-induced cytopathic effect was also observed in DEGS1-KO cells. Importantly, the EC50 value of 4-HPR in DEGS1-KO cells was almost identical to the value reported previously in WT cells. Our results indicated the lack of involvement of DEGS1 in SARS-CoV-2 infection.

DOI： 10.1248/bpb.b22-00503

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記述言語：英語   出版者・発行元：(公社)日本薬学会  

VeroE6/TMPRSS2細胞からジヒドロセラミドΔ4-デサチュラーゼ1(DEGS1)をノックアウトした細胞(DEGS1-KO細胞)を樹立し、SARS-CoV-2感染への影響を調べた。DEGS1の基質であるジヒドロセラミド(DHCer)のレベルは野生型(WT)よりDEGS1-KO細胞で有意に高かったが、培養上清中のウイルス産生量に有意差はなかった。DEGS1-KO細胞でもWT細胞と同様にウイルスによる細胞変性効果がみられた。ウイルス感染による細胞毒性に対する4-HPRの抑制作用のEC50値は、WT細胞とDEGS1-KO細胞の間で差がみられなかった。以上の結果から、SARS-CoV-2感染にDEGS1は関与しないと考えられた。

記述言語：英語   出版者・発行元：Scientific Reports  

The humoral and cellular immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) upon the coronavirus disease 2019 (COVID-19) vaccination remain to be clarified. Hence, we aimed to investigate the long-term chronological changes in SARS-CoV-2 specific IgG antibody, neutralizing antibody, and T cell responses during and after receiving the BNT162b2 vaccine. We performed serological, neutralization, and T cell assays among 100 hospital workers aged 22–73 years who received the vaccine. We conducted seven surveys up to 8 months after the second vaccination dose. 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. This study demonstrated that both IgG-S and T cell responses were detected before acquiring sufficient levels of SARS-CoV-2 neutralizing antibodies. These immune responses are sustained for approximately 6 to 10 weeks but not for 7 months or later following the second vaccination, indicating the need for the booster dose (i.e., third vaccination).

DOI： 10.1038/s41598-022-19581-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jiac.2022.08.026

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記述言語：日本語   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-022-17071-9

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記述言語：英語   出版者・発行元：(国研)国立国際医療研究センター  

回復期血漿療法は重篤なCOVID-19患者に対する重要な治療法なので、その安全性を確認する試験を行った。高い抗SARS-CoV-2スパイクIgG価と強い中和活性を持つCOVID-19患者から血液を採取し、当院で保存した。回復期血漿を、入院後3日以内に酸素吸入を必要とする重篤なCOVID-19患者11名に投与した。1名は輸血後3時間以内に静注部位の周囲の皮膚に、発赤のような有害事象を経験した。10名は28日以内に臨床的に改善したが、1名は血漿療法と無関係の原因で死亡した。本研究のCOVID-19患者は厳しい有害事象なしに回復期血漿を受け入れたことを示唆していた。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jiac.2022.03.002

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記述言語：英語   出版者・発行元：エルゼビア・ジャパン(株)  

症例は58歳女性で、濾胞性リンパ腫の再発予防のため、2ヵ月ごとにリツキシマブを6ヵ月間投与されていた。リツキシマブ投与2日後に咳と咽頭痛が出現し、発症4日後にSARS-CoV-2陽性となり、他院に入院したが、入院後6日目に症状は自然に改善し、退院した。退院後8日目に咳嗽と発熱が再発した。再入院し、レムデシビル投与を5日間とデキサメタゾン6mg/日投与を受けた。発熱は急速に回復したが、再入院16日目にデキサメタゾンからプレドニゾロン10mg/日へ変更したところ再燃した。低酸素血症を発症し、胸部CTスキャンで肺浸潤が確認された。バリシティニブ4mg/日投与が開始され、デキサメタゾン6mg/日への変更とレムデシビル5日間投与が行われた。入院後55日目にCOVID-19治療が奏効しないため当院へ転院した。デキサメタゾン6mg/日の経口投与を継続した。レムデシビルを5日間投与し、入院6日目に中和モノクローナル抗体カシリビマブ/イムデビマブを投与し、経過を観察した。8日目に低酸素血症が改善し、12日目と13日目にSARS-CoV-2陰性化を確認し、16日目に退院した。副腎皮質ステロイドは1ヵ月かけて漸減し、発熱や呼吸困難の再発はなかった。退院後37日目の胸部CT所見では、浸潤はほぼ消失していた。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/life12070966

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記述言語：英語  

DOI： 10.1101/2022.06.09.495422

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/life12060856

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記述言語：英語  

DOI： 10.1016/j.ijid.2022.03.017

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/infdis/jiac209

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41586-022-04856-1

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記述言語：英語  

DOI： 10.1016/j.ijid.2022.04.058

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記述言語：英語  

DOI： 10.1056/NEJMc2201933

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/vaccines10040563

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.vaccine.2022.02.052

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記述言語：英語  

DOI： 10.1056/NEJMc2119407

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s13730-022-00697-z

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掲載種別：研究論文（学術雑誌）  

DOI： 10.21203/rs.3.rs-1463966/v1

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記述言語：英語  

DOI： 10.21203/rs.3.rs-1375091/v1

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1128/JVI.01551-21

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掲載種別：研究論文（学術雑誌）   出版者・発行元：National Center for Global Health and Medicine (JST)  

DOI： 10.35772/ghmo.2022.01002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/cid/ciab1048

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記述言語：英語  

DOI： 10.1016/j.crmeth.2021.100122

PubMed

担当区分：最終著者,　責任著者  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-021-01930-y

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出版者・発行元：Cold Spring Harbor Laboratory  

<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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記述言語：英語   出版者・発行元：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。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jiac.2021.08.015

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出版者・発行元：Cold Spring Harbor Laboratory  

<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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1128/JVI.00807-21

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記述言語：英語   出版者・発行元：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。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jinf.2021.05.017

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jiac.2021.05.006

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記述言語：英語  

DOI： 10.1016/j.ijid.2021.06.009

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1101/2021.07.27.21261237

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1128/JVI.02401-20

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1073/pnas.2106535118

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記述言語：英語   出版者・発行元：エルゼビア・ジャパン(株)  

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。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/trf.16541

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jiac.2021.04.017

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記述言語：英語   出版者・発行元：エルゼビア・ジャパン(株)  

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。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.35772/ghm.2021.01022

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jinf.2021.01.010

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記述言語：英語   出版者・発行元：(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。

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-021-84733-5

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その他リンク： http://www.nature.com/articles/s41598-021-84733-5

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-021-84387-3

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その他リンク： http://www.nature.com/articles/s41598-021-84387-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ijid.2020.12.079

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jiac.2021.01.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.eclinm.2021.100734

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fmicb.2021.636276

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