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1.
Lancet Infect Dis ; 21(10): 1383-1394, 2021 10.
Article in English | MEDLINE | ID: covidwho-1621119

ABSTRACT

BACKGROUND: Given the scale of the ongoing COVID-19 pandemic, the development of vaccines based on different platforms is essential, particularly in light of emerging viral variants, the absence of information on vaccine-induced immune durability, and potential paediatric use. We aimed to assess the safety and immunogenicity of an MF59-adjuvanted subunit vaccine for COVID-19 based on recombinant SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a novel molecular clamp (spike glycoprotein-clamp [sclamp]). METHODS: We did a phase 1, double-blind, placebo-controlled, block-randomised trial of the sclamp subunit vaccine in a single clinical trial site in Brisbane, QLD, Australia. Healthy adults (aged ≥18 to ≤55 years) who had tested negative for SARS-CoV-2, reported no close contact with anyone with active or previous SARS-CoV-2 infection, and tested negative for pre-existing SARS-CoV-2 immunity were included. Participants were randomly assigned to one of five treatment groups and received two doses via intramuscular injection 28 days apart of either placebo, sclamp vaccine at 5 µg, 15 µg, or 45 µg, or one dose of sclamp vaccine at 45 µg followed by placebo. Participants and study personnel, except the dose administration personnel, were masked to treatment. The primary safety endpoints included solicited local and systemic adverse events in the 7 days after each dose and unsolicited adverse events up to 12 months after dosing. Here, data are reported up until day 57. Primary immunogenicity endpoints were antigen-specific IgG ELISA and SARS-CoV-2 microneutralisation assays assessed at 28 days after each dose. The study is ongoing and registered with ClinicalTrials.gov, NCT04495933. FINDINGS: Between June 23, 2020, and Aug 17, 2020, of 314 healthy volunteers screened, 120 were randomly assigned (n=24 per group), and 114 (95%) completed the study up to day 57 (mean age 32·5 years [SD 10·4], 65 [54%] male, 55 [46%] female). Severe solicited reactions were infrequent and occurred at similar rates in participants receiving placebo (two [8%] of 24) and the SARS-CoV-2 sclamp vaccine at any dose (three [3%] of 96). Both solicited reactions and unsolicited adverse events occurred at a similar frequency in participants receiving placebo and the SARS-CoV-2 sclamp vaccine. Solicited reactions occurred in 19 (79%) of 24 participants receiving placebo and 86 (90%) of 96 receiving the SARS-CoV-2 sclamp vaccine at any dose. Unsolicited adverse events occurred in seven (29%) of 24 participants receiving placebo and 35 (36%) of 96 participants receiving the SARS-CoV-2 sclamp vaccine at any dose. Vaccination with SARS-CoV-2 sclamp elicited a similar antigen-specific response irrespective of dose: 4 weeks after the initial dose (day 29) with 5 µg dose (geometric mean titre [GMT] 6400, 95% CI 3683-11 122), with 15 µg dose (7492, 4959-11 319), and the two 45 µg dose cohorts (8770, 5526-13 920 in the two-dose 45 µg cohort; 8793, 5570-13 881 in the single-dose 45 µg cohort); 4 weeks after the second dose (day 57) with two 5 µg doses (102 400, 64 857-161 676), with two 15 µg doses (74 725, 51 300-108 847), with two 45 µg doses (79 586, 55 430-114 268), only a single 45 µg dose (4795, 2858-8043). At day 57, 67 (99%) of 68 participants who received two doses of sclamp vaccine at any concentration produced a neutralising immune response, compared with six (25%) of 24 who received a single 45 µg dose and none of 22 who received placebo. Participants receiving two doses of sclamp vaccine elicited similar neutralisation titres, irrespective of dose: two 5 µg doses (GMT 228, 95% CI 146-356), two 15 µg doses (230, 170-312), and two 45 µg doses (239, 187-307). INTERPRETATION: This first-in-human trial shows that a subunit vaccine comprising mammalian cell culture-derived, MF59-adjuvanted, molecular clamp-stabilised recombinant spike protein elicits strong immune responses with a promising safety profile. However, the glycoprotein 41 peptide present in the clamp created HIV diagnostic assay interference, a possible barrier to widespread use highlighting the criticality of potential non-spike directed immunogenicity during vaccine development. Studies are ongoing with alternative molecular clamp trimerisation domains to ameliorate this response. FUNDING: Coalition for Epidemic Preparedness Innovations, National Health and Medical Research Council, Queensland Government, and further philanthropic sources listed in the acknowledgments.


Subject(s)
Adjuvants, Immunologic/pharmacology , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Spike Glycoprotein, Coronavirus/immunology , Squalene/immunology , Adult , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Australia , Female , Healthy Volunteers , Humans , Male , Pandemics/prevention & control , Polysorbates , Vaccination/adverse effects , Young Adult
2.
Front Cell Infect Microbiol ; 11: 791660, 2021.
Article in English | MEDLINE | ID: covidwho-1599571

ABSTRACT

The appearance and magnitude of the immune response and the related factors correlated with SARS-CoV-2 vaccination need to be defined. Here, we enrolled a prospective cohort of 52 participants who received two doses of inactivated vaccines (BBIBP-CorV). Their serial plasma samples (n = 260) over 2 months were collected at five timepoints. We measured antibody responses (NAb, S-IgG and S-IgM) and routine blood parameter. NAb seroconversion occurred in 90.7% of vaccinated individuals and four typical NAb kinetic curves were observed. All of the participants who seroconverted after the first dose were females and had relatively high prevaccine estradiol levels. Moreover, those without seroconversion tended to have lower lymphocyte counts and higher serum SAA levels than those who experienced seroconversion. The NAb titers in young vaccine recipients had a significantly higher peak than those in elderly recipients. S-IgG and S-IgM dynamics were accompanied by similar trends in NAb. Here, we gained insight into the dynamic changes in NAbs and preliminarily explored the prevaccine blood parameters related to the kinetic subclasses, providing a reference for vaccination strategies.


Subject(s)
COVID-19 Vaccines , COVID-19 , Aged , Antibodies, Neutralizing , Antibodies, Viral , Antibody Formation , Female , Healthy Volunteers , Humans , Prospective Studies , SARS-CoV-2 , Vaccines, Inactivated
3.
Trials ; 22(1): 831, 2021 Nov 23.
Article in English | MEDLINE | ID: covidwho-1529943

ABSTRACT

BACKGROUND: Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir. METHODS: This is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion. DISCUSSION: This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir. TRIAL REGISTRATION: ClinicalTrials.gov NCT04385719 . Registered 13 May 2020.


Subject(s)
Anti-HIV Agents , Lamivudine , Adenosine Monophosphate/analogs & derivatives , Adult , Alanine/analogs & derivatives , Atazanavir Sulfate , Healthy Volunteers , Humans , Oligopeptides , Pyridines , Ritonavir , Tenofovir , Uganda
4.
Clin Transl Sci ; 14(6): 2556-2565, 2021 11.
Article in English | MEDLINE | ID: covidwho-1526359

ABSTRACT

Nezulcitinib (TD-0903), a lung-selective pan-Janus-associated kinase (JAK) inhibitor designed for inhaled delivery, is under development for treatment of acute lung injury associated with coronavirus disease 2019 (COVID-19). This two-part, double-blind, randomized, placebo-controlled, single ascending dose (part A) and multiple ascending dose (part B) phase I study evaluated the safety, tolerability, and pharmacokinetics (PK) of nezulcitinib in healthy participants. Part A included three cohorts randomized 6:2 to receive a single inhaled dose of nezulcitinib (1, 3, or 10 mg) or matching placebo. Part B included three cohorts randomized 8:2 to receive inhaled nezulcitinib (1, 3, or 10 mg) or matching placebo for 7 days. The primary outcome was nezulcitinib safety and tolerability assessed from treatment-emergent adverse events (TEAEs). The secondary outcome was nezulcitinib PK. All participants completed the study. All TEAEs were mild or moderate in severity, and none led to treatment discontinuation. Overall (area under the plasma concentration-time curve) and peak (maximal plasma concentration) plasma exposures of nezulcitinib were low and increased in a dose-proportional manner from 1 to 10 mg in both parts, with no suggestion of clinically meaningful drug accumulation. Maximal plasma exposures were below levels expected to result in systemic target engagement, consistent with a lung-selective profile. No reductions in natural killer cell counts were observed, consistent with the lack of a systemic pharmacological effect and the observed PK. In summary, single and multiple doses of inhaled nezulcitinib at 1, 3, and 10 mg were well-tolerated in healthy participants, with dose-proportional PK supporting once-daily administration.


Subject(s)
Azetidines/adverse effects , COVID-19/drug therapy , Imidazoles/adverse effects , Indazoles/adverse effects , Piperidines/adverse effects , Administration, Inhalation , Adult , Area Under Curve , Azetidines/administration & dosage , Azetidines/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Healthy Volunteers , Humans , Imidazoles/administration & dosage , Imidazoles/pharmacokinetics , Indazoles/administration & dosage , Indazoles/pharmacokinetics , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Lymphocyte Count , Male , Middle Aged , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Young Adult
5.
Front Immunol ; 12: 739757, 2021.
Article in English | MEDLINE | ID: covidwho-1505515

ABSTRACT

Coronavirus disease 2019 (COVID-19) exhibits a sex bias with males showing signs of more severe disease and hospitalizations compared with females. The mechanisms are not clear but differential immune responses, particularly the initial innate immune response, between sexes may be playing a role. The early innate immune responses to SARS-CoV-2 have not been studied because of the gap in timing between the patient becoming infected, showing symptoms, and getting the treatment. The primary objective of the present study was to compare the response of dendritic cells (DCs) and monocytes from males and females to SARS-CoV-2, 24 h after infection. To investigate this, peripheral blood mononuclear cells (PBMCs) from healthy young individuals were stimulated in vitro with the virus. Our results indicate that PBMCs from females upregulated the expression of HLA-DR and CD86 on pDCs and mDCs after stimulation with the virus, while the activation of these cells was not significant in males. Monocytes from females also displayed increased activation than males. In addition, females secreted significantly higher levels of IFN-α and IL-29 compared with males at 24 h. However, the situation was reversed at 1 week post stimulation and males displayed high levels of IFN-α production compared with females. Further investigations revealed that the secretion of CXCL-10, a chemokine associated with lung complications, was higher in males than females at 24 h. The PBMCs from females also displayed increased induction of CTLs. Altogether, our results suggest that decreased activation of pDCs, mDCs, and monocytes and the delayed and prolonged IFN-α secretion along with increased CXCL-10 secretion may be responsible for the increased morbidity and mortality of males to COVID-19.


Subject(s)
COVID-19/immunology , Dendritic Cells/immunology , Leukocytes, Mononuclear/immunology , SARS-CoV-2/physiology , Adaptive Immunity , Adult , Chemokine CXCL1/metabolism , Female , HLA-DR Antigens/metabolism , Healthy Volunteers , Humans , Immunity, Innate , Interferon-gamma/metabolism , Male , Middle Aged , Sex Characteristics , Up-Regulation , Young Adult
6.
Front Immunol ; 12: 752397, 2021.
Article in English | MEDLINE | ID: covidwho-1497081

ABSTRACT

Covaxin/BBV152 is a whole virion inactivated SARS-CoV-2 vaccine. The effect of prime-boost vaccination with Covaxin on systemic immune responses is not known. We investigated the effect of Covaxin on the plasma levels of a wide panel of cytokines and chemokines at baseline (M0) and at months 1 (M1), 2 (M2) and 3 (M3) following prime-boost vaccination in healthy volunteers. Our results demonstrate that Covaxin induces enhanced plasma levels of Type 1 cytokines (IFNγ, IL-2, TNFα), Type 2/regulatory cytokines (IL-4, IL-5, IL-10 and IL-13), Type 17 cytokine (IL-17A), other pro-inflammatory cytokines (IL-6, IL-12, IL-1α, IL-1ß) and other cytokines (IL-3 and IL-7) but diminished plasma levels of IL-25, IL-33, GM-CSF and Type 1 IFNs. Covaxin also induced enhanced plasma levels of CC chemokine (CCL4) and CXC chemokines (CXCL1, CXCL2 and CX3CL1) but diminished levels of CXCL10. Covaxin vaccination induces enhanced cytokine and chemokine responses as early as month 1, following prime-boost vaccination, indicating robust activation of innate and adaptive immune responses in vaccine recipients.


Subject(s)
COVID-19 Vaccines/immunology , SARS-CoV-2/physiology , Vaccines, Inactivated/immunology , Adaptive Immunity , Adult , Chemokines/blood , Cytokines/blood , Female , Healthy Volunteers , Humans , Immunity, Innate , Immunization , Immunization, Secondary , Male , Middle Aged , Vaccination , Young Adult
7.
Proc Natl Acad Sci U S A ; 118(41)2021 10 12.
Article in English | MEDLINE | ID: covidwho-1486398

ABSTRACT

The COVID-19 pandemic led to widespread mandates requiring the wearing of face masks, which led to debates on their benefits and possible adverse effects. To that end, the physiological effects at the systemic and at the brain level are of interest. We have investigated the effect of commonly available face masks (FFP2 and surgical) on cerebral hemodynamics and oxygenation, particularly microvascular cerebral blood flow (CBF) and blood/tissue oxygen saturation (StO2), measured by transcranial hybrid near-infrared spectroscopies and on systemic physiology in 13 healthy adults (ages: 23 to 33 y). The results indicate small but significant changes in cerebral hemodynamics while wearing a mask. However, these changes are comparable to those of daily life activities. This platform and the protocol provides the basis for large or targeted studies of the effects of mask wearing in different populations and while performing critical tasks.


Subject(s)
Brain/physiology , Masks , Activities of Daily Living , Adult , Brain/blood supply , Brain/metabolism , COVID-19/prevention & control , Female , Healthy Volunteers , Hemodynamics , Humans , Male , Microcirculation , Monitoring, Physiologic , Oxygen/metabolism , SARS-CoV-2 , Spectroscopy, Near-Infrared , Young Adult
8.
J Immunol ; 207(10): 2405-2410, 2021 11 15.
Article in English | MEDLINE | ID: covidwho-1471046

ABSTRACT

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) causes severe acute respiratory syndrome. mRNA vaccines directed at the SARS-CoV-2 spike protein resulted in development of Abs and protective immunity. To determine the mechanism, we analyzed the kinetics of induction of circulating exosomes with SARS-CoV-2 spike protein and Ab following vaccination of healthy individuals. Results demonstrated induction of circulating exosomes expressing spike protein on day 14 after vaccination followed by Abs 14 d after the second dose. Exosomes with spike protein, Abs to SARS-CoV-2 spike, and T cells secreting IFN-γ and TNF-α increased following the booster dose. Transmission electron microscopy of exosomes also demonstrated spike protein Ags on their surface. Exosomes with spike protein and Abs decreased in parallel after four months. These results demonstrate an important role of circulating exosomes with spike protein for effective immunization following mRNA-based vaccination. This is further documented by induction of humoral and cellular immune responses in mice immunized with exosomes carrying spike protein.


Subject(s)
Antibodies, Viral/metabolism , COVID-19 Vaccines/immunology , COVID-19/immunology , Exosomes/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocytes/metabolism , Animals , Blood Circulation , Cells, Cultured , Exosomes/immunology , Healthy Volunteers , Humans , Immunization , Interferon-gamma/metabolism , Mice , Mice, Inbred C57BL , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , Tumor Necrosis Factor-alpha/metabolism , Vaccination
9.
Sci Rep ; 11(1): 20144, 2021 10 11.
Article in English | MEDLINE | ID: covidwho-1462037

ABSTRACT

Pulmonary function testing (PFT) allows for quantitative analysis of lung function. However, as a result of the coronavirus disease 2019 (COVID-19) pandemic, a majority of international medical societies have postponed PFTs in an effort to mitigate disease transmission, complicating the continuity of care in high-risk patients diagnosed with COVID-19 or preexisting lung pathologies. Here, we describe the development of a non-contact wearable pulmonary sensor for pulmonary waveform analysis, pulmonary volume quantification, and crude thoracic imaging using the eddy current (EC) phenomenon. Statistical regression analysis is performed to confirm the predictive validity of the sensor, and all data are continuously and digitally stored with a sampling rate of 6,660 samples/second. Wearable pulmonary function sensors may facilitate rapid point-of-care monitoring for high-risk individuals, especially during the COVID-19 pandemic, and easily interface with patient hospital records or telehealth services.


Subject(s)
COVID-19/diagnosis , Monitoring, Physiologic/instrumentation , Point-of-Care Systems , Respiratory Function Tests/instrumentation , Wearable Electronic Devices , COVID-19/epidemiology , COVID-19/transmission , COVID-19/virology , Feasibility Studies , Healthy Volunteers , Humans , Infection Control , Infectious Disease Transmission, Patient-to-Professional/prevention & control , Monitoring, Physiologic/methods , Pandemics/prevention & control , Respiratory Function Tests/methods , Respiratory Physiological Phenomena
10.
Proc Natl Acad Sci U S A ; 118(41)2021 10 12.
Article in English | MEDLINE | ID: covidwho-1450314

ABSTRACT

The COVID-19 pandemic led to widespread mandates requiring the wearing of face masks, which led to debates on their benefits and possible adverse effects. To that end, the physiological effects at the systemic and at the brain level are of interest. We have investigated the effect of commonly available face masks (FFP2 and surgical) on cerebral hemodynamics and oxygenation, particularly microvascular cerebral blood flow (CBF) and blood/tissue oxygen saturation (StO2), measured by transcranial hybrid near-infrared spectroscopies and on systemic physiology in 13 healthy adults (ages: 23 to 33 y). The results indicate small but significant changes in cerebral hemodynamics while wearing a mask. However, these changes are comparable to those of daily life activities. This platform and the protocol provides the basis for large or targeted studies of the effects of mask wearing in different populations and while performing critical tasks.


Subject(s)
Brain/physiology , Masks , Activities of Daily Living , Adult , Brain/blood supply , Brain/metabolism , COVID-19/prevention & control , Female , Healthy Volunteers , Hemodynamics , Humans , Male , Microcirculation , Monitoring, Physiologic , Oxygen/metabolism , SARS-CoV-2 , Spectroscopy, Near-Infrared , Young Adult
11.
PLoS One ; 16(9): e0258104, 2021.
Article in English | MEDLINE | ID: covidwho-1443857

ABSTRACT

Due to the currently ongoing pandemic of coronavirus disease 2019 (COVID-19), it is strongly recommended to wear facemasks to minimize transmission risk. Wearing a facemask may have the potential to increase dyspnea and worsen cardiopulmonary parameters during exercise; however, research-based evidence is lacking. We investigated the hypothesis that wearing facemasks affects the sensation of dyspnea, pulse rate, and percutaneous arterial oxygen saturation during exercise. Healthy adults (15 men, 9 women) underwent a progressive treadmill test under 3 conditions in randomized order: wearing a surgical facemask, cloth facemask, or no facemask. Experiment was carried out once daily under each condition, for a total of 3 days. Each subject first sat on a chair for 30 minutes, then walked on a treadmill according to a Bruce protocol that was modified by us. The experiment was discontinued when the subject's pulse rate exceeded 174 beats/min. After discontinuation, the subject immediately sat on a chair and was allowed to rest for 10 minutes. Subjects were required to rate their levels of dyspnea perception on a numerical scale. Pulse rate and percutaneous arterial oxygen saturation were continuously monitored with a pulse oximeter. These parameters were recorded in each trial every 3 minutes after the start of the exercise; the point of discontinuation; and 5 and 10 minutes after discontinuation. The following findings were obtained. Wearing a facemask does not worsen dyspnea during light to moderate exercise but worsens dyspnea during vigorous exercise. Wearing a cloth facemask increases dyspnea more than wearing a surgical facemask during exercise and increases pulse rate during vigorous exercise, but it does not increase pulse rate during less vigorous exercise. Wearing a surgical facemask does not increase pulse rate at any load level. Lastly, wearing a facemask does not affect percutaneous arterial oxygen saturation during exercise at any load level regardless of facemask type.


Subject(s)
COVID-19/prevention & control , Dyspnea/etiology , Exercise Tolerance , Heart Rate , Masks , Adult , Exercise , Exercise Test , Female , Healthy Volunteers , Humans , Male , Masks/adverse effects , Young Adult
12.
Cell Rep ; 37(3): 109839, 2021 10 19.
Article in English | MEDLINE | ID: covidwho-1439921

ABSTRACT

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provide an exciting avenue toward antiviral therapeutics. From patient transcriptomic data, we determined that a circulating miRNA, miR-2392, is directly involved with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia, as well as promoting many symptoms associated with coronavirus disease 2019 (COVID-19) infection. We demonstrate that miR-2392 is present in the blood and urine of patients positive for COVID-19 but is not present in patients negative for COVID-19. These findings indicate the potential for developing a minimally invasive COVID-19 detection method. Lastly, using in vitro human and in vivo hamster models, we design a miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters, and may potentially inhibit a COVID-19 disease state in humans.


Subject(s)
COVID-19/genetics , COVID-19/immunology , MicroRNAs/genetics , SARS-CoV-2/genetics , Adult , Aged , Aged, 80 and over , Animals , Antiviral Agents/pharmacology , Biomarkers/metabolism , COVID-19/drug therapy , Cricetinae , Female , Ferrets , Gene Expression Regulation , Glycolysis , Healthy Volunteers , Humans , Hypoxia , Inflammation , Male , Mice , Middle Aged , Proteomics/methods , ROC Curve , Rats
13.
Curr Issues Mol Biol ; 43(3): 1212-1225, 2021 Sep 22.
Article in English | MEDLINE | ID: covidwho-1438531

ABSTRACT

The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Most SARS-CoV-2 infections are mild or even asymptomatic. However, a small fraction of infected individuals develops severe, life-threatening disease, which is caused by an uncontrolled immune response resulting in hyperinflammation. However, the factors predisposing individuals to severe disease remain poorly understood. Here, we show that levels of CD47, which is known to mediate immune escape in cancer and virus-infected cells, are elevated in SARS-CoV-2-infected Caco-2 cells, Calu-3 cells, and air-liquid interface cultures of primary human bronchial epithelial cells. Moreover, SARS-CoV-2 infection increases SIRPalpha levels, the binding partner of CD47, on primary human monocytes. Systematic literature searches further indicated that known risk factors such as older age and diabetes are associated with increased CD47 levels. High CD47 levels contribute to vascular disease, vasoconstriction, and hypertension, conditions that may predispose SARS-CoV-2-infected individuals to COVID-19-related complications such as pulmonary hypertension, lung fibrosis, myocardial injury, stroke, and acute kidney injury. Hence, age-related and virus-induced CD47 expression is a candidate mechanism potentially contributing to severe COVID-19, as well as a therapeutic target, which may be addressed by antibodies and small molecules. Further research will be needed to investigate the potential involvement of CD47 and SIRPalpha in COVID-19 pathology. Our data should encourage other research groups to consider the potential relevance of the CD47/ SIRPalpha axis in their COVID-19 research.


Subject(s)
Antigens, Differentiation/metabolism , CD47 Antigen/metabolism , COVID-19/epidemiology , COVID-19/metabolism , Pandemics , Receptors, Immunologic/metabolism , SARS-CoV-2/metabolism , Severity of Illness Index , Signal Transduction/immunology , Blood Donors , Blotting, Western/methods , Bronchi/cytology , COVID-19/pathology , COVID-19/virology , Caco-2 Cells , Epithelial Cells/metabolism , Epithelial Cells/virology , Healthy Volunteers , Humans , Monocytes/metabolism , Monocytes/virology , Polymerase Chain Reaction/methods , RNA, Viral/genetics , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification
14.
Cells ; 10(10)2021 09 26.
Article in English | MEDLINE | ID: covidwho-1438528

ABSTRACT

The coronavirus disease 2019 (COVID-19) is related to enhanced production of NETs, and autoimmune/autoinflammatory phenomena. We evaluated the proportion of low-density granulocytes (LDG) by flow cytometry, and their capacity to produce NETs was compared with that of conventional neutrophils. NETs and their protein cargo were quantified by confocal microscopy and ELISA. Antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA) and the degradation capacity of NETs were addressed in serum. MILLIPLEX assay was used to assess the cytokine levels in macrophages' supernatant and serum. We found a higher proportion of LDG in severe and critical COVID-19 which correlated with severity and inflammatory markers. Severe/critical COVID-19 patients had higher plasmatic NE, LL-37 and HMGB1-DNA complexes, whilst ISG-15-DNA complexes were lower in severe patients. Sera from severe/critical COVID-19 patients had lower degradation capacity of NETs, which was reverted after adding hrDNase. Anti-NET antibodies were found in COVID-19, which correlated with ANA and ANCA positivity. NET stimuli enhanced the secretion of cytokines in macrophages. This study unveils the role of COVID-19 NETs as inducers of pro-inflammatory and autoimmune responses. The deficient degradation capacity of NETs may contribute to the accumulation of these structures and anti-NET antibodies are related to the presence of autoantibodies.


Subject(s)
Autoimmunity , COVID-19/blood , COVID-19/immunology , Extracellular Traps/immunology , Immunity, Humoral , Inflammation , Neutrophils/immunology , Antibodies, Antinuclear , Antimicrobial Cationic Peptides/blood , Autoantibodies/metabolism , Cross-Sectional Studies , Cytokines/metabolism , Cytokines/pharmacology , Flow Cytometry , Granulocytes/metabolism , HMGB1 Protein/blood , Healthy Volunteers , Humans , Microscopy, Confocal , Monocytes/cytology , Neutrophils/cytology , SARS-CoV-2 , Ubiquitins/pharmacology
15.
Cells ; 10(10)2021 09 26.
Article in English | MEDLINE | ID: covidwho-1438527

ABSTRACT

Specific memory B cells and antibodies are a reliable read-out of vaccine efficacy. We analysed these biomarkers after one and two doses of BNT162b2 vaccine. The second dose significantly increases the level of highly specific memory B cells and antibodies. Two months after the second dose, specific antibody levels decline, but highly specific memory B cells continue to increase, thus predicting a sustained protection from COVID-19. We show that although mucosal IgA is not induced by the vaccination, memory B cells migrate in response to inflammation and secrete IgA at mucosal sites. We show that the first vaccine dose may lead to an insufficient number of highly specific memory B cells and low concentration of serum antibodies, thus leaving vaccinees without the immune robustness needed to ensure viral elimination and herd immunity. We also clarify that the reduction of serum antibodies does not diminish the force and duration of the immune protection induced by vaccination. The vaccine does not induce sterilizing immunity. Infection after vaccination may be caused by the lack of local preventive immunity because of the absence of mucosal IgA.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/cytology , COVID-19 Vaccines/therapeutic use , COVID-19/immunology , COVID-19/prevention & control , Immunoglobulin A/immunology , Immunologic Memory , Adult , Antibodies, Neutralizing/blood , Antigens, Viral/immunology , B-Lymphocytes/immunology , Cryopreservation , Female , Health Personnel , Healthy Volunteers , Hospitals, Pediatric , Humans , Immunoglobulin G , Immunoglobulin M/immunology , Lactation , Male , Middle Aged , Mucous Membrane/immunology , Patient Safety , SARS-CoV-2 , Vaccination
16.
BMJ Case Rep ; 14(9)2021 Sep 14.
Article in English | MEDLINE | ID: covidwho-1408507

ABSTRACT

In Thailand, 40 000 subdistrict health centre (SDHC) personnel and >1 million village health volunteers (VHVs) are responsible for primary healthcare of 23 million households in 75 032 villages. They were trained, made household visits, gave hygiene advice, participated in the 'Big Cleaning Day' campaign, produced cloth face masks, proactively identified high-risk visitors and monitored quarantined cases. 7.4 million Thais received basic education on hygiene, 1.3 million villagers joined the campaign and 3.6 million handmade cloth face masks were produced. In March 2020, 3.9 million households were visited, and 40 000 high-risk cases were detected. The intensity of proactive case findings increased to 12.6 million home visits and 834 000 cases were detected in April 2020. Almost 800 000 cases complied with the 14-day mandatory home quarantine, of which 3.6% developed symptoms suspected of respiratory tract infection. VHVs and SDHC personnel could efficiently contribute to the prevention and control of COVID-19 in Thailand.


Subject(s)
COVID-19 , Pandemics , Health Personnel , Healthy Volunteers , Humans , SARS-CoV-2 , Thailand/epidemiology
17.
Front Public Health ; 9: 657804, 2021.
Article in English | MEDLINE | ID: covidwho-1399184

ABSTRACT

Objective: Our objective is to explore the effect of applying cloud video conferencing methods to the informed consent process in an early-phase clinical trial during the COVID-19 pandemic. Methods: All participants who intended to participate in the trial were informed via a cloud video conference before signing the informed consent forms (ICF). Then, the attitudes of the participants with the cloud video conference and their understanding of the trial were evaluated using a questionnaire when they visited to sign the ICF onsite. Results: A total of 165 subjects participated in the cloud video conference process, and 142 visited the site to sign and date the ICFs at the center during the appointment time. The survey showed that nearly 100% of the subjects evaluated the video-based informed consent process as very good or good and gave correct answers to questions about the trial. Furthermore, 136 (95.8%) subjects believed that the knowledge about the trial derived via the video-based informed consent process was consistent with the onsite reality, and 139 (97.9%) subjects expressed their willingness to participate in an informed consent procedure undertaken through an online video conference. Conclusions: The video-based informed consent process achieved the same effects as an onsite informed consent process. The former saves time and cost of transportation for the subject and exhibits good public acceptance; especially in light of the COVID-19 pandemic, this process is conducive for reducing the risk of subject infection due to travel and would also help avoid crowding on site.


Subject(s)
COVID-19 , Pandemics , Healthy Volunteers , Humans , SARS-CoV-2 , Videoconferencing
18.
PLoS One ; 16(9): e0256621, 2021.
Article in English | MEDLINE | ID: covidwho-1394545

ABSTRACT

This paper describes a detailed study of spectral and time-resolved photoprocesses in human platelets and their complexes with platinum (Pt) nanoparticles (NPs). Fluorescence, quantum yield, and platelet amino acid lifetime changes in the presence and without femtosecond ablated platinum NPs have been studied. Fluorescence spectroscopy analysis of main fluorescent amino acids and their residues (tyrosine (Tyr), tryptophan (Trp), and phenylalanine (Phe)) belonging to the platelet membrane have been performed. The possibility of energy transfer between Pt NPs and the platelet membrane has been revealed. Förster Resonance Energy Transfer (FRET) model was used to perform the quantitative evaluation of energy transfer parameters. The prospects of Pt NPs usage deals with quenching-based sensing for pathology's based on platelet conformations as cardiovascular diseases have been demonstrated.


Subject(s)
Blood Platelets/chemistry , Fluorescence Resonance Energy Transfer/methods , Metal Nanoparticles/chemistry , Platinum/chemistry , Adult , Energy Transfer , Healthy Volunteers , Humans , Spectrometry, Fluorescence/methods
19.
Oxid Med Cell Longev ; 2021: 5520059, 2021.
Article in English | MEDLINE | ID: covidwho-1394271

ABSTRACT

Due to the increase of stress-related memory impairment accompanying with the COVID-19 pandemic and financial crisis, the prevention of cognitive decline induced by stress has gained much attention. Based on the evidence that an anthocyanin-rich mulberry milk demonstrated the cognitive enhancing effect, we hypothesized that it should be able to enhance memory in working-age volunteers who are exposed to working stress. This study is an open-label, two-arm randomized study. Both men and women volunteers at age between 18 and 60 years old were randomly assigned to consume the tested product either 1 or 2 servings daily for 6 weeks. All subjects were assessed for cortisol, acetylcholinesterase (AChE), monoamine oxidase (MAO), monoamine oxidase type A (MAO-A), and monoamine oxidase type B (MAO-B) in saliva, and their working memory was determined both at baseline and at a 6-week period. The results showed that the working memory of subjects in both groups was enhanced at the end of the study period together with the reduction of saliva cortisol. The suppression of AChE, MAO, and MAO-A was also observed in subjects who consumed the tested product 2 servings daily. Therefore, we suggest the memory enhancing effect of an anthocyanin-rich mulberry milk. The possible mechanism may occur primarily via the suppression of cortisol. In addition, the high dose of mulberry milk also suppresses AChE, MAO, and MAO-A.


Subject(s)
Anthocyanins/pharmacology , Memory, Short-Term/drug effects , Morus , Occupational Stress , Plant Extracts/pharmacology , Acetylcholinesterase/drug effects , Acetylcholinesterase/metabolism , Adult , Female , Healthy Volunteers , Humans , Male , Middle Aged , Monoamine Oxidase/drug effects , Monoamine Oxidase/metabolism , Morus/chemistry
20.
Respir Care ; 66(1): 113-119, 2021 01.
Article in English | MEDLINE | ID: covidwho-1389654

ABSTRACT

BACKGROUND: Low airway surface pH is associated with many airway diseases, impairs antimicrobial host defense, and worsens airway inflammation. Inhaled Optate is designed to safely raise airway surface pH and is well tolerated in humans. Raising intracellular pH partially prevents activation of SARS-CoV-2 in primary normal human airway epithelial (NHAE) cells, decreasing viral replication by several mechanisms. METHODS: We grew primary NHAE cells from healthy subjects, infected them with SARS-CoV-2 (isolate USA-WA1/2020), and used clinical Optate at concentrations used in humans in vivo to determine whether Optate would prevent viral infection and replication. Cells were pretreated with Optate or placebo prior to infection (multiplicity of infection = 1), and viral replication was determined with plaque assay and nucleocapsid (N) protein levels. Healthy human subjects also inhaled Optate as part of a Phase 2a safety trial. RESULTS: Optate almost completely prevented viral replication at each time point between 24 h and 120 h, relative to placebo, on both plaque assay and N protein expression (P < .001). Mechanistically, Optate inhibited expression of major endosomal trafficking genes and raised NHAE intracellular pH. Optate had no effect on NHAE cell viability at any time point. Inhaled Optate was well tolerated in 10 normal subjects, with no change in lung function, vital signs, or oxygenation. CONCLUSIONS: Inhaled Optate may be well suited for a clinical trial in patients with pulmonary SARS-CoV-2 infection. However, it is vitally important for patient safety that formulations designed for inhalation with regard to pH, isotonicity, and osmolality be used. An inhalational treatment that safely prevents SARS-CoV-2 viral replication could be helpful for treating patients with pulmonary SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Epithelial Cells/drug effects , Glycine/pharmacology , Isotonic Solutions/pharmacology , Lung/drug effects , SARS-CoV-2 , Virus Replication/drug effects , Administration, Inhalation , Antiviral Agents/administration & dosage , Cells, Cultured/drug effects , Glycine/administration & dosage , Healthy Volunteers , Humans , Hydrogen-Ion Concentration/drug effects , Isotonic Solutions/administration & dosage
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