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1.
SSRN; 2022.
Preprint in English | SSRN | ID: ppcovidwho-343254

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) caused global pandemics during last three years, the development of new therapeutics is urgently needed. Methods: We conducted a randomized, double-blind, placebo-controlled, single-dose, dose-escalation Phase Ⅰ study to evaluate the safety, tolerability, pharmacokinetics (PK) and cytokine responses after the administration of the recombinant TFF2-IFN proteins. Healthy volunteers were informed, enrolled and randomized into 4 groups with a dose escalation of 0.2, 1, 2, 4 mg/per dose, and then inhaled with the investigation product (IP) or placebo. 32 eligible participants were finally enrolled, 8 were assigned to placebo group and 24 to TFF2-IFN groups with 6 participants per group. Findings: All 32 participants completed the study. 41.7% (10/24) of participants who received recombinant TFF2-IFN protein reported 11 AEs during treatment, and 62.5% (5/8) of participants who received placebo reported 6 AEs. 16 out of total 17 AEs were Grade 1 in severity. Only one Grade 3 AE was occurred in placebo group, and no worse event happened as SAE. The PK were analyzed for the times and concentrations of investigation product in 0.2, 1, 2, 4mg groups in 24 TFF2-IFN recipients, the results showed that TFF2-IFN retains in the lung for at least 6-8 hours, only the highest dose group (4mg/per) has a transient detectable concentration in sera, whereas all other dose groups had a level below the lower limit of quantification (LLOQ). In addition, only IFN-gamma was detectable and none of inflammatory cytokines appeared in sera. Interpretation: In summary, the recombinant TFF2-IFN protein was a well-tolerated and safe therapeutics when administrated through nebulization, featured with prolonged retention in respiratory tract which will be greatly beneficial to combat against respiratory viral infection.

2.
Cell ; 185(19):3588-3588, 2022.
Article in English | Academic Search Complete | ID: covidwho-2027949

ABSTRACT

The current dogma of RNA-mediated innate immunity is that sensing of immunostimulatory RNA ligands is sufficient for the activation of intracellular sensors and induction of interferon (IFN) responses. Here, we report that actin cytoskeleton disturbance primes RIG-I-like receptor (RLR) activation. Actin cytoskeleton rearrangement induced by virus infection or commonly used reagents to intracellularly deliver RNA triggers the relocalization of PPP1R12C, a regulatory subunit of the protein phosphatase-1 (PP1), from filamentous actin to cytoplasmic RLRs. This allows dephosphorylation-mediated RLR priming and, together with the RNA agonist, induces effective RLR downstream signaling. Genetic ablation of PPP1R12C impairs antiviral responses and enhances susceptibility to infection with several RNA viruses including SARS-CoV-2, influenza virus, picornavirus, and vesicular stomatitis virus. Our work identifies actin cytoskeleton disturbance as a priming signal for RLR-mediated innate immunity, which may open avenues for antiviral or adjuvant design. [Display omitted] • Phosphatase-regulatory protein PPP1R12C promotes antiviral defense to RNA virus infection • PPP1R12C mediates RIG-I and MDA5 dephosphorylation and signaling • Actin cytoskeleton disturbance leads to PPP1R12C relocalization and RLR priming • Full RLR activation requires RNA agonist and actin cytoskeleton disturbance Disturbances to the actin cytoskeleton during infection of a cell by an RNA virus drive a specific phosphatase complex to prime RIG-I-like receptors to sense viral RNA, thus promoting effective antiviral responses. [ FROM AUTHOR] Copyright of Cell is the property of Cell Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

3.
Acta Microbiologica Sinica ; 7(23), 2022.
Article in Chinese | CAB Abstracts | ID: covidwho-2025659

ABSTRACT

Objective: The aim of this study is to screen an ideal adjuvant for an inactivated porcine deltacoronavirus(PDCoV) vaccine to induce mucosal immunity and reduce the side effect of the vaccine. We used different mucosal adjuvants to prepare the inactivated PDCoV vaccines. We then used mouse model to evaluate the humoral, cellular and mucosal immune responses induced by the inactivated vaccines via different immunization routes.

4.
Viruses ; 14(8):1806, 2022.
Article in English | ProQuest Central | ID: covidwho-2024292

ABSTRACT

Background and Aims: Sex hormones are widely recognised to act as protective factors against several viral infections. Specifically, females infected by the hepatitis C virus display higher clearance rates and reduced disease progression than those found in males. Through modulation of particle release and spread, 17β-oestradiol controls HCV’s life cycle. We investigated the mechanism(s) behind oestrogen’s antiviral effect. Methods: We used cell culture-derived hepatitis C virus in in vitro assays to evaluate the effect of 17β-oestradiol on the innate immune response. Host immune responses were evaluated by enumerating gene transcripts via RT-qPCR in cells exposed to oestrogen in the presence or absence of viral infection. Antiviral effects were determined by focus-forming unit assay or HCV RNA quantification. Results: Stimulation of 17β-oestradiol triggers a pre-activated antiviral state in hepatocytes, which can be maintained for several hours after the hormone is removed. This induction results in the elevation of several innate immune genes, such as interferon alpha and beta, tumour necrosis factor, toll-like receptor 3 and interferon regulatory factor 5. We demonstrated that this pre-activation of immune response signalling is not affected by a viral presence, and the antiviral state can be ablated using an interferon-alpha/beta receptor alpha inhibitor. Finally, we proved that the oestrogen-induced stimulation is essential to generate an antiviral microenvironment mediated by activation of type I interferons. Conclusion: Resulting in viral control and suppression, 17β-oestradiol induces an interferon-mediated antiviral state in hepatocytes. Oestrogen-stimulated cells modulate the immune response through secretion of type I interferon, which can be countered by blocking interferon-alpha/beta receptor alpha signalling.

5.
Molecules ; 27(16):5080, 2022.
Article in English | ProQuest Central | ID: covidwho-2023932

ABSTRACT

The discovery and the development of safe and efficient therapeutics against arthritogenic alphaviruses (e.g., chikungunya virus) remain a continuous challenge. Alkaloids are structurally diverse and naturally occurring compounds in plants, with a wide range of biological activities including beneficial effects against prominent pathogenic viruses and inflammation. In this short review, we discuss the effects of some alkaloids of three biologically relevant structural classes (isoquinolines, indoles and quinolizidines). Based on various experimental models (viral infections and chronic diseases), we highlight the immunomodulatory effects of these alkaloids. The data established the capacity of these alkaloids to interfere in host antiviral and inflammatory responses through key components (antiviral interferon response, ROS production, inflammatory signaling pathways and pro- and anti-inflammatory cytokines production) also involved in alphavirus infection and resulting inflammation. Thus, these data may provide a convincing perspective of research for the use of alkaloids as immunomodulators against arthritogenic alphavirus infection and induced inflammation.

6.
International Journal of Molecular Sciences ; 23(17):9914, 2022.
Article in English | ProQuest Central | ID: covidwho-2023752

ABSTRACT

Viral respiratory tract infections are associated with asthma development and exacerbation in children and adults. In the course of immune responses to viruses, airway epithelial cells are the initial platform of innate immunity against viral invasion. Patients with severe asthma are more vulnerable than those with mild to moderate asthma to viral infections. Furthermore, in most cases, asthmatic patients tend to produce lower levels of antiviral cytokines than healthy subjects, such as interferons produced from immune effector cells and airway epithelial cells. The epithelial inflammasome appears to contribute to asthma exacerbation through overactivation, leading to self-damage, despite its naturally protective role against infectious pathogens. Given the mixed and complex immune responses in viral-infection-induced asthma exacerbation, this review examines the diverse roles of airway epithelial immunity and related potential therapeutic targets and discusses the mechanisms underlying the heterogeneous manifestations of asthma exacerbations.

7.
International Journal of Molecular Sciences ; 23(17):9653, 2022.
Article in English | ProQuest Central | ID: covidwho-2023745

ABSTRACT

Discovery of the microbiota-gut–brain axis has led to proposed microbe-based therapeutic strategies in mental health, including the use of mood-altering bacterial species, termed psychobiotics. However, we still have limited understanding of the key signaling pathways engaged by specific organisms in modulating brain function, and evidence suggests that bacteria with broadly similar neuroactive and immunomodulatory actions can drive different behavioral outcomes. We sought to identify pathways distinguishing two psychoactive bacterial strains that seemingly engage similar gut–brain signaling pathways but have distinct effects on behaviour. We used RNAseq to identify mRNAs differentially expressed in the blood and hippocampus of mice following Lacticaseibacillus rhamnosus JB-1, and Limosilactobacillus reuteri 6475 treatment and performed Gene Set Enrichment Analysis (GSEA) to identify enrichment in pathway activity. L. rhamnosus, but not L. reuteri treatment altered several pathways in the blood and hippocampus, and the rhamnosus could be clearly distinguished based on mRNA profile. In particular, L. rhamnosus treatment modulated the activity of interferon signaling, JAK/STAT, and TNF-alpha via NF-KB pathways. Our results highlight that psychobiotics can induce complex changes in host gene expression, andin understanding these changes, we may help fine-tune selection of psychobiotics for treating mood disorders.

8.
Frontiers in Immunology ; 13, 2022.
Article in English | Scopus | ID: covidwho-2022745

ABSTRACT

Influenza vaccines remain the most effective tools to prevent flu and its complications. Trivalent or quadrivalent inactivated influenza vaccines primarily elicit antibodies towards haemagglutinin and neuraminidase. These vaccines fail to induce high protective efficacy, in particular in older adults and immunocompromised individuals and require annual updates to keep up with evolving influenza strains (antigenic drift). Vaccine efficacy declines when there is a mismatch between its content and circulating strains. Current correlates of protection are merely based on serological parameters determined by haemagglutination inhibition or single radial haemolysis assays. However, there is ample evidence showing that these serological correlates of protection can both over- or underestimate the protective efficacy of influenza vaccines. Next-generation universal influenza vaccines that induce cross-reactive cellular immune responses (CD4+ and/or CD8+ T-cell responses) against conserved epitopes may overcome some of the shortcomings of the current inactivated vaccines by eliciting broader protection that lasts for several influenza seasons and potentially enhances pandemic preparedness. Assessment of cellular immune responses in clinical trials that evaluate the immunogenicity of these new generation vaccines is thus of utmost importance. Moreover, studies are needed to examine whether these cross-reactive cellular immune responses can be considered as new or complementary correlates of protection in the evaluation of traditional and next-generation influenza vaccines. An overview of the assays that can be applied to measure cell-mediated immune responses to influenza with their strengths and weaknesses is provided here. Copyright © 2022 Janssens, Joye, Waerlop, Clement, Leroux-Roels and Leroux-Roels.

9.
European Journal of Dermatology ; 32(3):377-383, 2022.
Article in English | MEDLINE | ID: covidwho-2022182

ABSTRACT

Background: Type 1 interferon (IFN-I) response induced by SARS-CoV-2 has been hypothesized to explain the association between chilblain lesions (CL) and SARS-CoV-2 infection. Objective: To explore direct cytopathogenicity of SARS-CoV-2 in CL and to focus on IFN-I expression in patients with chilblains. Materials & Methods: A monocentric cohort of 43 patients presenting with CL from April 2020 to May 2021 were included. During this period, all CL were, a priori, considered to be SARS-CoV-2-related. RT-qPCR on nasopharyngeal swabs and measurements of anti-SARS-CoV-2 antibodies were performed. Anti-SARS-CoV-2 immunostainings as well as SARS-CoV-2 RT-qPCR were performed on biopsy specimens of CL and controls. Expression of MX1 and IRF7 was analysed on patients' biopsy specimens and/or PBMC and compared with controls and/or chilblains observed before the pandemic. Serum IFN-alpha was also measured. Results: RT-qPCR was negative in all patients and serological tests were positive in 11 patients. Immunostaining targeting viral proteins confirmed the lack of specificity. SARS-CoV-2 RNA remained undetected in all CL specimens. MX1 immunostaining was positive in CL and in pre-pandemic chilblains compared to controls. MX1 and IRF7 expression was significantly increased in CL specimens but not in PBMC. Serum IFN-alpha was undetected in CL patients. Conclusion: CL observed during the pandemic do not appear to be directly related to SARS-CoV-2 infection, either based on viral cytopathogenicity or high IFN-I response induced by the virus.

10.
Clin Infect Dis ; 2021 Dec 10.
Article in English | MEDLINE | ID: covidwho-2017796

ABSTRACT

BACKGROUND: We evaluated a standardized interferon-γ (IFN-γ) release assay (IGRA) for detection of T-cell immune response after SARS-CoV-2 infection or vaccination. METHODS: This prospective study included COVID-19 patients with different severity of illness and follow-up (FU), vaccinated subjects, and healthy unvaccinated persons. SARS-CoV-2 T-cell response was measured using a specific quantitative IGRA in whole blood (Euroimmun, Germany) and TrimericS-IgG and neutralizing antibodies with validated serological platforms. Positivity of RT-PCR or vaccination was considered as reference standard. RESULTS: Two hundred and thirty nine individuals were included (152 convalescent, 54 vaccinated and 33 uninfected unvaccinated). Overall sensitivity, specificity, positive (PPV) and negative (NPV) predictive values (95% CI) of the IGRA were 81.1% (74.9%-86%), 90.9% (74.5%-97.6%), 98.2% (94.5%-99.5%), and 43.5% (31.8%-55.9%), respectively. All vaccinated SARS-CoV-2-naïve subjects had positive IGRA at 3 months. In convalescent subjects the magnitude of IFN-γ responses and IGRA accuracy varied according to disease severity and duration of FU, with the best performance in patients with severe COVID-19 at 3-month and the worst in those with mild disease at 12-month. The greatest contribution of IGRA to serological tests was observed in patients with mild disease and long-term FU (incremental difference, 30.4%). CONCLUSION: The IGRA assessed was a reliable method of quantifying T-cell response after SARS-COV-2 infection or vaccination. In convalescent patients the sensitivity is largely dependent on disease severity and time since primary infection. The assay is more likely to add clinical value to serology in patients with mild infections.

11.
Clin Infect Dis ; 2022 Jan 17.
Article in English | MEDLINE | ID: covidwho-2017815

ABSTRACT

While SARS-CoV-2 vaccines prevent severe disease effectively, post-vaccination 'breakthrough' COVID-19 infections and transmission among vaccinated individuals remain ongoing concerns. We present an in-depth characterization of transmission and immunity among vaccinated individuals in a household, revealing complex dynamics and unappreciated comorbidities, including autoimmunity to type1 interferon in the presumptive index case.

12.
J Infect Dis ; 2022.
Article in English | PubMed | ID: covidwho-2017962

ABSTRACT

Interferon (IFN)-specific autoantibodies have been implicated in severe COVID-19 and have been proposed as a potential driver of the persistent symptoms characterizing Long COVID, a type of post-acute sequelae of SARS-CoV-2 infection (PASC). We report than only two of 215 SARS-CoV-2 convalescent participants tested over 394 timepoints, including 121 people experiencing Long COVID symptoms, had detectable IFN-α2 antibodies. Both had been hospitalized during the acute phase of the infection. These data suggest that persistent anti-IFN antibodies, although a potential driver of severe COVID-19, are unlikely to contribute to Long COVID symptoms in the post-acute phase of the infection.

13.
International Journal of Infectious Diseases ; 122:537-542, 2022.
Article in English | Web of Science | ID: covidwho-2015429

ABSTRACT

Objectives: Interferon- gamma release assays (IGRAs) are widely used in public health practice to diagnose latent tuberculosis. During the COVID-19 pandemic and rollout of COVID-19 vaccination, it has remained unclear whether COVID-19 vaccines interfere with IGRA readouts. Methods: We prospectively recruited healthcare workers during their annual occupational health examinations in 2021. Baseline IGRA readouts were compared with follow-up data after the participants had received two doses of COVID-19 vaccination. Results: A total of 134 baseline IGRA-negative cases (92 with ChAdOx1 vaccine, 27 with mRNA-1273 vaccine, and 15 with heterologous vaccination) and seven baseline IGRA-positive cases were analyzed. Among the baseline IGRA-negative cases, there were decreased interferon- gamma concentrations over the Nil ( P = 0.005) and increased Mitogen-Nil ( P < 0.001) values after vaccination. For TB2-Nil value, a similar trend ( P = 0.057) of increase was observed. Compared with the 0.35 IU/ml threshold, the baseline and follow-up readout differences were less than ;+/- 0.10;IU/ml over the TB1-Nil and TB2-Nil values in > 90% baseline IGRA-negative cases. No significant readout difference was observed among baseline IGRApositive cases. Conclusion: COVID-19 vaccination did not change IGRA interpretation in most cases. Cases showing conversion/borderline IGRA readouts should be given special consideration. (c) 2022 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

14.
International Journal of Pharmaceutical Sciences Review and Research ; 75(2):62-69, 2022.
Article in English | EMBASE | ID: covidwho-2010617

ABSTRACT

Diabetes is a chronic metabolic disorder emerging as a global burden. Diabetes serves as a risk factor for many complications inclusive of COVID-19. The SARS – 2 pathogens have led to Coronavirus disease. Coronaviruses are enveloped viruses with a single-stranded, positive-sense RNA genome recognized to cause respiratory infections in human beings. Diabetes patients being affected by coronavirus become more critical due to worsening hyperglycemia induces aggravation, endothelial dysfunction, and occlusion of blood vessels through the era of oxidative stress riding the down-regulation of glucose metabolism and hyperglycemia. Increased glucose level causes inflammation and tissue damage serves as a supportive factor for higher tissue damage in COVID patients. Sufferers with extreme COVID-19 have an exceptionally impaired interferon type 1 response with low IFN alpha activity in the blood, indicating excessive blood viral load, and an impaired inflammatory response. This can be alleviated by regular screening and appropriate therapy as like as metformin, camostat mesylate, chloroquine, and adjunctive therapy. Metformin is the desired preliminary drug to deal with T2DM. Camostat mesylate drug accelerated glycemia and insulin resistance and reduced fat buildup in mammalian models. Adjunctive treatment can be used to obviate the evolution of COVID-19.

15.
Mediterranean Journal of Rheumatology ; 33(2):268-270, 2022.
Article in English | EMBASE | ID: covidwho-2010602

ABSTRACT

Anti-MDA5 antibodies characterise a distinct phenotype of dermatomyositis in adults as well as children, with ethnic disparity in clinical presentation and severity. They often present as a diagnostic conundrum with rash, ulceration, and polyarthritis, but minimal muscle disease. Mechanic's hands are typically associated with anti-synthetase syndrome, but their presence in anti-MDA5 antibody positive patients, although reported, is not well known. We present the case of a boy in whom mechanic's hand heralded a relapse of juvenile dermatomyositis which was suspected based on remotely assessed patient-reported outcome measures on teleconsultation. This report suggests that mechanic's hands should also prompt testing for myositis antibodies including anti-MDA5 in Indian children with JDM. Diligent awareness of the condition, and timely use of patient reported outcome measures of muscle power and skin assessment may guide management while delivering remote care in challenging situations such as a global pandemic.

16.
Frontiers in Pharmacology ; 13, 2022.
Article in English | EMBASE | ID: covidwho-2009895

ABSTRACT

Podocytes form a key component of the glomerular filtration barrier. Damage to podocytes is referred to as “podocyte disease.” There are many causes of podocyte injury, including primary injury, secondary injury, and gene mutations. Primary podocytosis mostly manifests as nephrotic syndrome. At present, first-line treatment is based on glucocorticoid administration combined with immunosuppressive therapy, but some patients still progress to end-stage renal disease. In Asia, especially in China, traditional Chinese medicine (TCM) still plays an important role in the treatment of kidney diseases. This study summarizes the potential mechanism of TCM and its active components in protecting podocytes, such as repairing podocyte injury, inhibiting podocyte proliferation, reducing podocyte apoptosis and excretion, maintaining podocyte skeleton structure, and upregulating podocyte-related protein expression. At the same time, the clinical efficacy of TCM in the treatment of primary podocytosis (including idiopathic membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis) is summarized to support the development of new treatment strategies for primary podocytosis.

17.
Journal of Clinical Oncology ; 40(16), 2022.
Article in English | EMBASE | ID: covidwho-2009659

ABSTRACT

Background: Gal-3 is a protein that binds specifically to N-acetylglucosamine-expressing carbohydrates, which are upregulated on key tumorigenic cell surface proteins. Gal-3 is widely over-expressed in the tumor microenvironment and is generally linked to poor outcomes. Gal-3 regulates immune cell function of T cells and macrophages, and promotes neovascularization and fibrosis [Peng Cancer Res 2008;Markowska J Biol Chem 2011;Kouo Cancer Immunol Res 2015]. Gal-3 sequesters interferon gamma, reduces T-cell influx, and contributes to tumor cell evasion of the immune system via LAG-3 activation [Chen PNAS 2009;Gordon-Alonso Nat Commun 2017]. Gal-3 has been identified as a marker of resistance to checkpoint inhibitors (CPIs);patients with stage IV NSCLC with high Gal-3 levels (> 70% Gal-3 immunohistochemical staining) have been shown to be resistant to the CPI pembrolizumab [Capalbo Int J Mol Sci 2019]. Animal data indicate synergy between CPI therapy and Gal-3 inhibition [Vuong Cancer Res 2019;Zhang FEBS Open Bio 2021]. Thus, inhibiting Gal-3 together with CPI-based immunotherapy may enhance tumor-specific immune responses, and overcome CPI resistance. Methods: GALLANT-1 (NCT05240131) is a 3-part, placebo-controlled phase Ib/IIa trial that will investigate safety and efficacy of GB1211 (a Gal-3 inhibitor) + atezo vs placebo + atezo in patients with advanced NSCLC. Part A will include 8-12 patients and study safety and tolerability of 200 mg and 400 mg GB1211 twice-daily + atezo (open-label). Primary endpoint is number of adverse events (AEs) after 12 weeks' treatment and will determine the dosage for Part B. Part B will include 75-94 patients, and is a randomized, double-blind study of GB1211 + atezo or placebo + atezo. Primary endpoints are safety (number of AEs) and efficacy (percentage change from baseline in the sum of longest diameter of target lesions after 12 weeks' treatment). Part C is an expansion study including patients from Parts A and B, with safety and efficacy assessments. Eligibility criteria: advanced or metastatic stage IIIB or IV NSCLC adenocarcinoma;measurable disease per RECIST v1.1;expression of programmed death ligand-1 on ≥50% of tumor cells;eligible for 1200 mg atezo every 3 weeks. Exclusion criteria: symptomatic, untreated, or actively progressing central nervous system metastases;prior systemic chemotherapy for treatment of recurrent advanced or metastatic disease, except if part of neoadjuvant/ adjuvant therapy;prior treatment with immune CPIs and/or GB1211;presence of EGFR mutation and ALK, ROS1, and RET alterations;treatment with antineoplastic or systemic immunotherapeutic agents prior to first GB1211 dose;severe infectious disease < 4 weeks prior to first GB1211 dose;active hepatitis B or C, HIV, or COVID-19. The study is being initiated;updated enrollment status will be presented at the meeting.

18.
Journal of Clinical Oncology ; 40(16), 2022.
Article in English | EMBASE | ID: covidwho-2009627

ABSTRACT

Background: Vaccination remains the leading strategy against Covid-19 worldwide. BNT 162b2 (tozinameran) belongs among first licensed vaccines with good efficacy. However, the role of monitoring both, antibodies and cell immunity after vaccination remains unclear. Methods: We conducted a 6-month prospective study involving vaccinated workers of NCCC in Slovakia who were tested for the presence of neutralizing antibodies and cell immunity after second dose of tozinameran. SARS-CoV-2 IgG antibodies were detected by the Atellica IM sCOVG, a fully automated 2-step sandwich immunoassay using indirect chemiluminescent technology. Blood samples were tested by two IGRA tests (Quantiferon RUO and CoviFeron) to assess interferon-γ (IFN-γ) responses to SARS CoV-2 spike protein antigen and nucleocapsid protein antigen. Results were stratified by gender and body mass index. P values for categorical variables were calculated using χ2 or Fishers exact test. P values for continuous variables were calculated using T test and Wilcoxon-Mann-Whitney test. Value of statistical significance was set to 0.05. Data were analyzed using SAS 9.4 software. Results: Medical records of 94 respondents (71 females) were analyzed. Mean age was 40.2 years (23 - 62 years) and mean body mass index (BMI) ± standard error of mean (SEM) was 26.4±2.7 (21.3 - 31.7). Twenty-two (23.4 %) respondents had Covid-19 before first, 5 (5.3 %) before second, and 2 (2.15 %) after second dose of vaccine (P < 0.0001). IgG were tested 24.4±5.0, 50.2±12.1, and 187.9±12.8 days after second vaccination. IgG index progressively decline with corresponding values 126.81±40.34, 93.55±51.29, and 17.68±29.07 (P < 0.0001). Mean time from second vaccination to cell immunity testing was 157.2±101.3 days. Forty-eight (51.1 %) of respondents had negative, 6 (6.4 %) border line, and 40 (42.6 %) positive cell immunity (P < 0.0001). Conclusions: Our study confirmed the efficacy of tozinameran despite both, rapid decline of antibodies and absence of cell immunity in majority of subjects.

19.
American journal of physiology. Lung cellular and molecular physiology ; 2022.
Article in English | MEDLINE | ID: covidwho-2009235

ABSTRACT

INTRODUCTION: E-cigarette vaping is a major aspect of nicotine consumption, especially for children and young adults. An acute vaping model has not been demonstrated in the hamster, which has the unique benefit of becoming infected with and transmitting respiratory viruses, including SARS-CoV-2, without genetic alteration. METHODS: Using a two-day, whole-body vaping exposure protocol in male hamsters, we evaluated serum cotinine, bronchoalveolar lavage cells, lung and nasal histopathology, and gene expression in the nasopharynx and lung through RT-qPCR. RESULTS: In nasal tissue, RT-qPCR analysis revealed nicotine-dependent increases in genes associated with type 1 inflammation (CCL-5 and CXCL-10), fibrosis (TGF-b), a nicotine-independent increase oxidative stress response (SOD-2), and a nicotine-independent decrease in the vasculogenesis/angiogenesis (VEGF-A). In the lung, nicotine-dependent increases in the expression of genes involved in the renin-angiotensin pathway (ACE, ACE2), coagulation (tissue factor, Serpine-1), extracellular matrix remodeling (MMP-2, MMP-9), type 1 inflammation (IL-1b, TNF-a, and CXCL-10), fibrosis (TGF-b and Serpine-1), oxidative stress response (SOD-2), neutrophil extracellular traps release (ELANE), and vasculogenesis and angiogenesis (VEGF-A) were identified. CONCLUSION: To our knowledge, this is the first demonstration that the Syrian hamster is a viable model of e-cig vaping. In addition, this is the first report that e-cig vaping with nicotine can increase tissue factor gene expression in the lung. Our results show that even an acute exposure to e-cigarette vaping causes significant upregulation of mRNAs in the respiratory tract from pathways involving the renin-angiotensin system, coagulation, extracellular matrix remodeling, type 1 inflammation, fibrosis, oxidative stress response, NETosis, vasculogenesis, and angiogenesis.

20.
Annals of the Rheumatic Diseases ; 81:971-972, 2022.
Article in English | EMBASE | ID: covidwho-2009130

ABSTRACT

Background: Enpatoran is a selective and potent dual toll-like receptor (TLR) 7/8 inhibitor in development for the treatment of cutaneous and systemic lupus erythematosus (CLE/SLE). Enpatoran inhibits TLR7/8 activation in vitro and suppresses disease activity in lupus mouse models.1 Enpatoran was well tolerated and had linear pharmacokinetic (PK) parameters in healthy volunteers.2 As TLR7/8 mediate immune responses to single-stranded RNA viruses, including SARS-CoV-2, it was postulated that enpatoran may prevent hyperinfammation and cytokine storm in COVID-19. Objectives: In response to the COVID-19 pandemic, we conducted an exploratory Phase II trial to assess safety and determine whether enpatoran prevents clinical deterioration in patients (pts) hospitalized with COVID-19 pneumonia. PK and pharmacodynamics (PD) of enpatoran were also evaluated. Methods: ANEMONE was a randomized, double-blind, placebo (PBO)-con-trolled study conducted in Brazil, the Philippines, and the USA (NCT04448756). Pts aged 18-75 years, hospitalized with COVID-19 pneumonia (WHO 9-point scale score =4) but not mechanically ventilated, with SpO2 <94% and PaO2/FiO2 ≥150 (FiO2 maximum 0.4) were eligible. Those with a history of uncontrolled illness, active/unstable cardiovascular disease and SARS-CoV-2 vaccination were excluded. Pts received PBO or enpatoran (50 or 100 mg twice daily [BID]) for 14 days, with monitoring to Day 28 and safety follow-up to Day 60. Primary outcomes were safety and time to recovery (WHO 9-point scale ≤3). Clinical deterioration (time to clinical status >4, WHO 9-point scale) was a secondary outcome. Exploratory endpoints were enpatoran and biomarker concentrations (cytokines, C-reactive protein [CRP], D-dimer and interferon gene signature [IFN-GS] scores) assessed over time. Results: 149 pts received either PBO (n=49), or enpatoran 50 mg (n=54) or 100 mg (n=46) BID;88% completed treatment and 86% received concomitant steroids. Median age was 50 years (77% <60 years old), 66% were male, and 50% had ≥1 comorbidity (40% hypertension, 24% diabetes). Overall, 59% pts reported a treatment-emergent adverse event (TEAE) with three non-treatment-related deaths;11% reported a treatment-related TEAE. The proportion of pts in the enpatoran group reporting serious TEAEs was low (50 mg BID 9%;100 mg BID 2%) vs PBO (18%). Gastrointestinal disorders were most common (PBO 8%;50 mg BID 28%;100 mg BID 9%). The primary outcome of time to recovery with enpatoran vs PBO was not met;medians were 3.4-3.9 days. A positive signal in time to clinical deterioration from Day 1 through Day 28 was observed;hazard ratios [95% CI] for enpatoran vs PBO were 0.39 [0.13, 1.15] (50 mg BID) and 0.30 [0.08, 1.08] (100 mg BID). Mean enpatoran exposure was dose-proportional, and PK properties were within expectations. The median (quartile [Q]1-Q3) interleukin 6 (IL-6), CRP and D-dimer baseline concentration across the groups were 5.7 (4.0-13.5) pg/mL, 30.04 (11.40-98.02) and 0.62 (0.39-1.01) mg/L, respectively. Baseline IFN-GS scores were similar across groups. Conclusion: The ANEMONE trial was the frst to evaluate the safety and efficacy of a TLR7/8 inhibitor in an infectious disease for preventing cytokine storm. Enpa-toran up to 100 mg BID for 14 days was well tolerated by patients acutely ill with COVID-19 pneumonia. Time to recovery was not improved with enpatoran, perhaps due to the younger age of patients who had fewer comorbidities compared to those in similar COVID-19 trials. However, there was less likelihood for clinical deterioration with enpatoran than placebo. This trial provides important safety, tolerability, PK and PD data supporting continued development of enpatoran in SLE and CLE (NCT04647708, NCT05162586).

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