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Vaccines ; 10(9):1427, 2022.
Article in English | MDPI | ID: covidwho-2006262


We conducted a nonrandomized, open-label phase I study to assess the safety and immunogenicity of an intradermal coronavirus disease 2019 (COVID-19) DNA vaccine (AG0302-COVID-19) administered using a pyro-drive jet injector at Osaka University Hospital between Yanagida November 2020 and December 2021. Twenty healthy volunteers, male or female, were enrolled in the low-dose (0.2 mg) or high-dose (0.4 mg) groups and administered AG0302-COVID19 twice at a 2-week interval. There were no adverse events that led to discontinuation of the study drug vaccination schedule. A serious adverse event (disc protrusion) was reported in one patient in the high-dose group, but the individual recovered, and the adverse event was not causally related to the study drug. In the analysis of the humoral immune response, the geometric mean titer (GMT) of serum anti-SARS-CoV-2 spike glycoprotein-specific antibody was low in both the low-dose and high-dose groups (246.2 (95% CI 176.2 to 344.1, 348.2 (95% CI 181.3 to 668.9)) at the 8 weeks after first vaccination. Regarding the analysis of the cellular immune, the number of IFN-γ-producing cells responsive to the SARS-CoV-2 spike glycoprotein increased with individual differences after the first dose and was sustained for several months. Overall, no notable safety issues were observed with the intradermal inoculations of AG0302-COVID19. Regarding immunogenicity, a cellular immune response was observed in some subjects after AG0302-COVID19 intradermal inoculation, but no significant antibody production was observed.

Int J Environ Res Public Health ; 19(10)2022 05 15.
Article in English | MEDLINE | ID: covidwho-1855628


Older adults face the concern of developing frailty and sarcopenia due to an inactive lifestyle during the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to reveal the preventive behaviors taken by older adults who perceived a decline in physical fitness during COVID-19 and analyze the background factors which promoted such behaviors using a qualitative study design in 2020. The participants were recruited through the cohort study of Japanese older adults who were aged 79-81 and had not been diagnosed with sarcopenia previously in 2019 and perceived their physical fitness to have declined during the pandemic. The interviews of 19 participants were analyzed using thematic analysis. The participants engaged in five types of preventive behaviors to counter declining physical fitness: "walking", "exercising at home", "improving daily diet", "maintaining a daily routine", and "taking a good rest". Four themes were extracted pertaining to backgrounds of such preventive behaviors: "feeling anxiety and mental pressure", "available networks with family and neighbors", "prior experiences of behaviors", and "access to information". Anxiety due to lifestyle changes during the pandemic was the primary reason for the behaviors. This study can be a useful guide for undertaking possible measures to prevent frailty during future pandemics.

COVID-19 , Frailty , Sarcopenia , Aged , COVID-19/epidemiology , COVID-19/prevention & control , Cohort Studies , Humans , Independent Living , Pandemics/prevention & control , Physical Fitness , Sarcopenia/epidemiology
Curr Res Transl Med ; 70(4): 103348, 2022 Apr 20.
Article in English | MEDLINE | ID: covidwho-1796171


To fight against the worldwide COVID-19 pandemic, the development of an effective and safe vaccine against SARS-CoV-2 is required. As potential pandemic vaccines, DNA/RNA vaccines, viral vector vaccines and protein-based vaccines have been rapidly developed to prevent pandemic spread worldwide. In this study, we designed plasmid DNA vaccine targeting the SARS-CoV-2 Spike glycoprotein (S protein) as pandemic vaccine, and the humoral, cellular, and functional immune responses were characterized to support proceeding to initial human clinical trials. After intramuscular injection of DNA vaccine encoding S protein with alum adjuvant (three times at 2-week intervals), the humoral immunoreaction, as assessed by anti-S protein or anti-receptor-binding domain (RBD) antibody titers, and the cellular immunoreaction, as assessed by antigen-induced IFNγ expression, were up-regulated. In IgG subclass analysis, IgG2b was induced as the main subclass. Based on these analyses, DNA vaccine with alum adjuvant preferentially induced Th1-type T cell polarization. We confirmed the neutralizing action of DNA vaccine-induced antibodies by a binding assay of RBD recombinant protein with angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, and neutralization assays using pseudo-virus, and live SARS-CoV-2. Further B cell epitope mapping analysis using a peptide array showed that most vaccine-induced antibodies recognized the S2 and RBD subunits. Finally, DNA vaccine protected hamsters from SARS-CoV-2 infection. In conclusion, DNA vaccine targeting the spike glycoprotein of SARS-CoV-2 might be an effective and safe approach to combat the COVID-19 pandemic.

Nihon Ronen Igakkai Zasshi ; 58(4): 591-601, 2021.
Article in Japanese | MEDLINE | ID: covidwho-1558993


AIM: To prevent the transmission of the novel coronavirus [COVID-19] and stop its spread, a state of emergency was declared from April to May 2020. People were encouraged to refrain from outings and reduce their contact with people. The purpose of this study was to examine the subjective changes in the amount of activity under COVID-19 crisis among the elderly and the factors related to this decrease in activity. METHODS: This study was part of the SONIC study, an ongoing prospective cohort study targeting community dwelling older people in their 70, 80, 90s, and over 100 years old in different regions (urban and suburban) of Japan. Subjective changes in the amount of activity during the state of emergency were assessed via a mail questionnaire. RESULTS: The percentage decrease in activity for the subjects in their 70s, 80s, and 90s were 68.1% (513/753), 65.3% (324/496), and 56.0% (164/293), respectively. By region, 69.4% in urban, while 57.7% in the suburbs. In the 70- and 80-year-old cohorts, the decrease in activity was more frequent among those in urban areas than in suburban areas. In the 90-year-old cohort, the differences between the regions were attenuated, while the economic status and walking speed were significantly associated with a decrease in activity. CONCLUSIONS: The decrease in activity varied by age group and region, suggesting that approaches to preventing the adverse health effects associated with inactivity due to the COVID-19 crisis are more important in urban areas than in suburban ones.

COVID-19 , Independent Living , Aged , Aged, 80 and over , Cohort Studies , Humans , Prospective Studies , SARS-CoV-2
Medicine (Baltimore) ; 100(13): e25265, 2021 Apr 02.
Article in English | MEDLINE | ID: covidwho-1455403


RATIONALE: Complement deficiency are known to be predisposed to disseminated gonococcal infection (DGI). We herein present a case of DGI involving a Japanese man who latently had a complement 7 deficiency with compound heterozygous variants. PATIENT CONCERNS: A previously healthy 51-year-old Japanese man complained of sudden-onset high fever. Physical examination revealed various skin lesions including red papules on his trunk and extremities, an impetigo-like pustule on left forearm, and tendinitis of his right forefinger. DIAGNOSIS: Blood culture testing detected gram-negative cocci, which was confirmed to be Neisseria gonorrhoeae based on mass spectrometry and a pathogen-specific PCR test. INTERVENTIONS: Screening tests for underlying immunocompromised factors uncovered that complement activities (CH50) was undetectable. With a suspicion of a congenital complement deficiency, genetic analysis revealed rare single nucleotide variants in complement 7 (C7), including c.281-1G>T and a novel variant c.1454C>T (p.A485V). CH50 was normally recovered by adding purified human C7 to the patient's serum, supporting that the patient has C7 deficiency with compound heterozygous variants. OUTCOMES: Under a diagnosis of DGI, the patient underwent an antibiotic treatment with cefotaxime for a week and was discharged without any sequela. LESSONS: DGI is a rare sexually-transmitted infection that potentially induces systemic complications. Complement immunity usually defeats N. gonorrhoeae and prevents the organism from causing DGI. This case highlighted the importance of suspecting a complement deficiency when a person develops DGI.

Complement C7/deficiency , Genetic Variation/genetics , Gonorrhea/genetics , Hereditary Complement Deficiency Diseases/genetics , Hereditary Complement Deficiency Diseases/microbiology , Neisseria gonorrhoeae , Complement C7/genetics , Female , Gonorrhea/microbiology , Humans , Japan , Male , Middle Aged
Hypertens Res ; 44(9): 1047-1053, 2021 09.
Article in English | MEDLINE | ID: covidwho-1260939


There is currently a respiratory disease outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After rapid development, RNA vaccines and adenoviral vector vaccines were approved within a year, which has demonstrated the strong impact of preventing infectious diseases using gene therapy technology. Furthermore, intensive immunological analysis has been performed to evaluate the efficiency and safety of these vaccines, potentially allowing for rapid progress in vaccine technology. After the coronavirus disease 2019 (COVID-19) era, the novel vaccine technology developed will expand to other vaccines. We have been developing vaccines for chronic diseases, such as hypertension, for >10 years. Regarding the development of vaccines against self-antigens (i.e., angiotensin II), the vaccine should efficiently induce a blocking antibody response against the self-antigen without activating cytotoxic T cells. Therefore, the epitope vaccine approach has been proposed to induce antibody production in response to a combination of a B cell epitope and exogenous T cell epitopes through major histocompatibility complex molecules. When these vaccines are established as therapeutic options for hypertension, their administration regimen, which might be a few times per year, will replace daily medication use. Thus, therapeutic vaccines for hypertension may be a novel option to control the progression of cerebrovascular diseases. Hopefully, the accumulation of immunological findings and vaccine technology advances due to COVID-19 will provide a novel concept for vaccines for chronic diseases.

Autoantigens/immunology , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Hypertension/therapy , SARS-CoV-2/immunology , Vaccines/therapeutic use , Chronic Disease , Humans
FASEB J ; 35(3): e21419, 2021 03.
Article in English | MEDLINE | ID: covidwho-1075599


In the early phase of the Coronavirus disease 2019 (COVID-19) pandemic, it was postulated that the renin-angiotensin-system inhibitors (RASi) increase the infection risk. This was primarily based on numerous reports, which stated that the RASi could increase the organ Angiotensin-converting enzyme 2 (ACE2), the receptor of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in rodents. RASi can theoretically antagonize the potential influence of angiotensin II (Ang II) on ACE2. However, while Ang II decreases the ACE2 levels in cultured cells, there is little evidence that supports this phenomenon in living animals. In this study, we tested whether Ang II or Ang II combined with its antagonist would alter the ACE2 and other molecules associated with the infection of SARS-CoV-2. Male C57BL6/J mice were administered vehicle, Ang II (400 ng/kg/min), or Ang II with losartan (10 mg/kg/min) for 2 weeks. ACE2 knockout mice were used as a negative control for the ACE2 assay. We found that both Ang II, which elevated blood pressure by 30 mm Hg, and Ang II with losartan, had no effect on the expression or protein activity of ACE2 in the lung, left ventricle, kidney, and ileum. Likewise, these interventions had no effect on the expression of Transmembrane Protease Serine 2 (TMPRSS2) and Furin, proteases that facilitate the virus-cell fusion, and the expression or activity of Tumor Necrosis Factor α-Convertase (TACE) that cleaves cell-surface ACE2. Collectively, physiological concentrations of Ang II do not modulate the molecules associated with SARS-CoV-2 infection. These results support the recent observational studies suggesting that the use of RASi is not a risk factor for COVID-19.

Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin II/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Losartan/pharmacology , SARS-CoV-2 , ADAM17 Protein/genetics , ADAM17 Protein/metabolism , Angiotensin II/administration & dosage , Angiotensin II Type 1 Receptor Blockers/administration & dosage , Angiotensin-Converting Enzyme 2/genetics , Animals , Furin/genetics , Furin/metabolism , Gene Expression Regulation, Enzymologic/drug effects , Losartan/administration & dosage , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Vasoconstrictor Agents/pharmacology
Clin Sci (Lond) ; 134(22): 3047-3062, 2020 11 27.
Article in English | MEDLINE | ID: covidwho-1030462


Angiotensin converting enzyme-2 (ACE2) is a multifunctional transmembrane protein recently recognised as the entry receptor of the virus causing COVID-19. In the renin-angiotensin system (RAS), ACE2 cleaves angiotensin II (Ang II) into angiotensin 1-7 (Ang 1-7), which is considered to exert cellular responses to counteract the activation of the RAS primarily through a receptor, Mas, in multiple organs including skeletal muscle. Previous studies have provided abundant evidence suggesting that Ang 1-7 modulates multiple signalling pathways leading to protection from pathological muscle remodelling and muscle insulin resistance. In contrast, there is relatively little evidence to support the protective role of ACE2 in skeletal muscle. The potential contribution of endogenous ACE2 to the regulation of Ang 1-7-mediated protection of these muscle pathologies is discussed in this review. Recent studies have suggested that ACE2 protects against ageing-associated muscle wasting (sarcopenia) through its function to modulate molecules outside of the RAS. Thus, the potential association of sarcopenia with ACE2 and the associated molecules outside of RAS is also presented herein. Further, we introduce the transcriptional regulation of muscle ACE2 by drugs or exercise, and briefly discuss the potential role of ACE2 in the development of COVID-19.

Angiotensin I/metabolism , COVID-19/metabolism , Muscle, Skeletal/enzymology , Peptide Fragments/metabolism , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/enzymology , COVID-19/genetics , Humans , SARS-CoV-2/physiology
JPRN; 12/11/2020; TrialID: JPRN-jRCT2051200085
Clinical Trial Register | ICTRP | ID: ictrp-JPRN-jRCT2051200085





Inoculate AG0302-COVID19 intracutaneously

Primary outcome:

1. Safety
Information such as the type, frequency and severity of adverse events that occurred from the time of the first inoculation of the investigational drug to 8 weeks after the first inoculation will be collected to evaluate the safety.
2. Immunogenicity
Rate of change from baseline in SARS-CoV-2 spike (S) glycoprotein-specific antibody titers 2 weeks after the first inoculation of the investigational drug (immediately before the second inoculation), 4 weeks, 6 weeks, and 8 weeks Analyze and assess immunogenicity.


Inclusion criteria: (1) Subjects who have obtained written consent voluntarily to participate in this clinical trial
(2) Subjects whose age at the time of obtaining consent is 20 years to 75 years
(3) Subjects who are negative for SARS-CoV-2 by PCR test
(4) Subjects who are negative for both SARS-CoV-2 IgM antibody and SARS-CoV-2 IgG antibody by antibody test

Exclusion criteria: (1) Subjects with symptoms of suspected COVID-19 infection (respiratory symptoms, headache, malaise, olfactory disorders, taste disorders, etc.)
(2) Subjects with a history of COVID-19 (hearing from subjects)
(3) History of participation (history of inoculation) for the unapproved vaccine clinical trials
(4) Subjects with axillary temperature of 37.0 degree or higher
(5) Subjects who have a history of anaphylaxis due to the food or the drugs etc.
(6) Medical history of serious cardiovascular system, haemal system, respiratory system, liver, kidney, digestive system and neuropsychiatric system, or subjects who has a current medical history
(7) Subjects with a history of convulsion or epilepsy
(8) Subjects with a history of diagnosis of immunodeficiency
(9) Subjects who have a close relative (within 3rd degree) of congenital immunodeficiency
(10) Subjects who have a history of bronchial asthma
(11) Subjects who had a fever of 39.0 degree or higher within 2 days after the last vaccination, and those who suspected allergy such as a systemic rash
(12) Females who wish to become pregnant from the date of study registration to 12 weeks after the first inoculation of the investigational drug, and pregnant females who are breast-feeding. In addition, females who may become pregnant and their male sexual partners should use appropriate contraceptives (pill), condoms, vasectomy, tubal ligation, diaphragm, intrauterine devices, spermicides, intrauterine hormone-releasing system, etc. from the study entry date until 12 weeks after vaccination
(13) Subjects who have participated in clinical trials of other unapproved drugs and received the investigational drug within 4 weeks before the start of this clinical trial (starting from vaccination day)
(14) Subjects who have been received a live vaccine, inactivated vaccine, or toxoid within 4 weeks before the start of this clinical trial (starting from vaccination day)
(15) Subjects who have been administered with drugs that affect the immune system (however, excluding external preparations) such as immunomodulators (DMARDs, etc.), immunosuppressants, biologics, etc. within 4 weeks from vaccination
(16) Subjects who received blood transfusion or gamma globulin therapy within 12 weeks before vaccination, or high-dose gamma globulin therapy (200 mg/kg or more) within 24 weeks before vaccination
(17) Subjects who have a history of overseas travel within 4 weeks before the start of the clinical trial (starting from vaccination day)
(18) Subjects who are unable to comply with the clinical trial protocol and follow up (for mental, family, social or geographical reasons)
(19) Subjects who are judged to be ineligible for this clinical trial by the investigator

Geriatr Gerontol Int ; 20(12): 1112-1119, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-901048


Since the end of 2019, a life-threatening infectious disease (coronavirus disease 2019: COVID-19) has spread globally, and numerous victims have been reported. In particular, older persons tend to suffer more severely when infected with a novel coronavirus (SARS-CoV-2) and have higher case mortality rates; additionally, outbreaks frequently occur in hospitals and long-term care facilities where most of the residents are older persons. Unfortunately, it has been stated that the COVID-19 pandemic has caused a medical collapse in some countries, resulting in the depletion of medical resources, such as ventilators, and triage based on chronological age. Furthermore, as some COVID-19 cases show a rapid deterioration of clinical symptoms and accordingly, the medical and long-term care staff cannot always confirm the patient's values and wishes in time, we are very concerned as to whether older patients are receiving the medical and long-term care services that they wish for. It was once again recognized that it is vital to implement advance care planning as early as possible before suffering from COVID-19. To this end, in August 2020, the Japan Geriatrics Society announced ethical recommendations for medical and long-term care for older persons and emphasized the importance of conducting advance care planning at earlier stages. Geriatr Gerontol Int 2020; 20: 1112-1119.

Advance Care Planning , COVID-19/therapy , Long-Term Care/ethics , Advance Care Planning/ethics , Aged , Aged, 80 and over , COVID-19/epidemiology , COVID-19/mortality , COVID-19/prevention & control , Consensus , Decision Making/ethics , Geriatrics/standards , Health Resources/economics , Humans , Japan , Pandemics/ethics , Triage/ethics