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Delivery of self-amplifying mRNA (SAM) has high potential for infectious disease vaccination due to its self-adjuvanting and dose-sparing properties. Yet a challenge is the susceptibility of SAM to degradation and the need for SAM to reach the cytosol fully intact to enable self-amplification. Lipid nanoparticles are successfully deployed at incredible speed for mRNA vaccination, but aspects such as cold storage, manufacturing, efficiency of delivery, and the therapeutic window can benefit from further improvement. To investigate alternatives to lipid nanoparticles, a class of >200 biodegradable end-capped lipophilic poly(beta-amino ester)s (PBAEs) that enable efficient delivery of SAM in vitro and in vivo as assessed by measuring expression of SAM encoding reporter proteins is developed. The ability of these polymers to deliver SAM intramuscularly in mice is evaluated, and a polymer-based formulation that yields up to 37-fold higher intramuscular (IM) expression of SAM compared to injected naked SAM is identified. Using the same nanoparticle formulation to deliver a SAM encoding rabies virus glycoprotein, the vaccine elicits superior immunogenicity compared to naked SAM delivery, leading to seroconversion in mice at low RNA injection doses. These biodegradable nanomaterials may be useful in the development of next-generation RNA vaccines for infectious diseases.Copyright © 2023 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.
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Background: Coronavirus Disease 2019 (COVID-19) is a highly contagious disease that resulted in 4533645 deaths until September first, 2021. Multiple Sclerosis (MS) patients receive immunosuppressive drugs. Thus, there is a concern that these drugs will reduce the patient's immune system resistance against COVID19. Objective(s): This study aimed to evaluate the epidemiology of COVID19 and its impact on MS patients in our university hospital in Tehran City, Iran. Material(s) and Method(s): A cross-sectional study was conducted based on hospital-based registry data from May 2020 to March 2021. Among more than 500 registered MS patients in Imam Khomeini Hospital in Tehran City, Iran, referring within our study period, 84 patients reported SARS-COV2 infection. The diagnosis of MS was confirmed by the McDonald criteria. Moreover, the diagnosis of COVID-19 in MS patients was established by the real-time-PCR technique and chest computed tomography. Result(s): Out of 84 MS patients with SARS-COV2 infection, 55(65.5%) were women, and their mean age was 37.48 years. The most commonly used medications by MS patients were Rituximab 20 (26.3%) and Dimethyl Fumarate 14(18.4%). Totally, 9(10.8%) of the patients needed to be hospitalized due to COVID-19, with a mean hospitalization duration of 5.88 days. A total of 1 (1.2%) death was reported. Conclusion(s): Compared to the healthy population, COVID-19 is not more serious in MS patients. Most MS patients with COVID-19 infection were not hospitalized and continued their medication during the infection.Copyright © 2022 The Authors. This is an open access article under the CC-By-NC license. All Rights Reserved.
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Cumulative data regardingCOVID-19 infection during pregnancy have demonstrated the ability of SARS-CoV-2 to infect the placenta. However, the mechanisms of SARS-CoV-2 placental viral entry are yet to be defined. SARS-CoV-2 infects cells by binding to the ACE2 receptor. However, SARS-CoV-2 cell entry also requires co-localization of spike protein cleavage by the serine protease TMPRSS2. However, the co-expression of ACE2 and TMPRSS2 in placental cells is debated, raising the question of whether potential non-canonical molecular mechanismsmay be involved in SARS-CoV-2 placental cells' viral entry. Although published data regarding the ability of the SARS-CoV- 2 to infect the fetus are contradicting, the placenta appears to be an immunological barrier to active SARS-CoV-2 infection and vertical transmission;however, the mechanism is unclear. Our experiments demonstrated the ability of the SARS-CoV-2 virus to directly infect the placenta and induce transcriptomic responses in COVID-positive mothers. These transcriptomic responses were characterized by differential expression of specific mRNAs and miRNAs associated with SARS-CoV-2 infection, with induction of specific placental miRNAs that can inhibit viral replication. Failure in such mechanisms may be associated with vertical transmission. Since the start of the COVID-19 pandemic, the COVID-19 mRNA vaccines have been widely used to reduce the morbidity and mortality of SARS-CoV-2 infection. Historically, non-live vaccines have not caused any harm to pregnant mothers;however, it is unclear whether our current understanding of the effects of non-live vaccines serves as a reliable precedent owing to the novel technology used to create these mRNA vaccines. Since there are no definitive data on the possible biodistribution of mRNA vaccines to the placenta, the likelihood of vaccine mRNA reaching the fetus remains uncertain. Little has been reported on the tissue localization of the lipid nanoparticles (LNPs) after intramuscular (IM) administration of the mRNA vaccine. The biodistribution of LNPs containing the mRNA vaccine has been investigated in animal models but not humans. In the murine model, the vaccine LNPs were rapidly disseminated to several organs, including the heart, liver, kidney, lung, and spleen, following IM administration. However, no traditional pharmacokinetic or biodistribution studies have been performed with the mRNA vaccines, including possible biodistribution to breast milk or the placenta.
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Background: This study aimed to evaluate the outcomes of preclinical studies on the safety and immunogenicity of an inactivated COVID-19 vaccine candidate to warrant further clinical evaluation. Method(s): SARS-CoV-2 positive nasopharyngeal swab specimens were confirmed by real-time polymerase chain reaction and next-generation sequencing. The safety and immunogenicity tests of the COVID-19 vaccine were carried out in rats and Rhesus monkeys, and Balb/C mice and Rhesus monkeys, respectively. Result(s): The candidate vaccine was well tolerated and induced promising levels of SARS-CoV-2- specific IgG1, IgG2a, and Granzyme B in Balb/C mice, and anti-SARS-CoV-2 spike IgG and neutralizing antibodies in Rhesus monkeys. Based on cVNT results, the inactivated vaccine in 0.5 and 1 microg/100 microL doses was able to induce a neutralizing effect against the SARS-CoV-2 virus up to a dilution of 1:512 and 1:1000. The protective efficacy of the vaccine candidate was challenged with 2 x108 PFU of live viruses and confirmed by lung CT scan and histopathological evaluations compared to the control group. Repeated intramuscular injection of the candidate vaccine was generally well-tolerated in Rats and Rhesuses. No significant side effects were observed in rats injected with ten full human doses and in the Rhesus monkeys with three full human doses. Conclusion(s): Based on the findings presented in this study, it is recommended that this vaccine be moved into human testing commencing with a phase I clinical trial.Copyright © 2021 Muslim OT et al.
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The problem of prevention of coronavirus disease 2019 (COVID-19) in patients with immune-mediated inflammatory rheumatic diseases (IMRD) remains highly relevant. The presence of IRD is associated with a high risk of disease and severe course of COVID-19 during immunosuppressive treatment, primarily anti-B cell therapy with rituximab (RTX), and a low level of post-vaccination response in such patients. A new strategy for the prevention and treatment of COVID-19 are virus-neutralizing monoclonal antibodies to coronavirus;currently, combined long-acting monoclonal antibodies tixagevimab and cilgavimab (Evusheld) are registered for prevention in the world and the Russian Federation. . Tixagevimab and cilgavimab (TC) show neutralizing activity against SARS-CoV-2, including the Omicron strain, primarily its variants BA.4, BA.5, BA.2.75 ("Centaur"). Objective - to evaluate the efficacy and safety of TC for pre-exposure prophylaxis of COVID-19 in rheumatic patients receiving RTX, based on a prospective observational study. Materials and methods. The main group included 86 patients with various IMRD receiving RTX: 50 of them had ANCA-associated systemic vasculitis (AAV), 15 - rheumatoid arthritis, 9 - Sjogren's syndrome (SS), 4 - IgG4-related disease, 3 - systemic lupus erythematosus (SLE), 3 - dermatomyositis (DM), 2 - systemic scleroderma (SSD). Median age was 59 (19-82) years;male: female ratio - 1:1,8. From March 26 to August 30 2022, patients received a single intramuscular injection of TC in a total dose of 300 mg, mainly after RTX (in 52% of cases, in 28% on the next day after RTX). The control group included 42 patients with AAV (median age - 45 (35-71) years;male: female ratio - 1:1), also treated with RTX, who did not receive pre-exposure prophylaxis of TC. The duration of observation was 7 months, until November 1 2022. At this time, 98% of confirmed cases of coronavirus in the Russian Federation were Omicron. A telephone and/or online survey of patient has been conducted to detect cases of COVID-19 and adverse reactions. Results. In the TC group, confirmed coronavirus infection have been detected in 17 (20%) patients (AAV - 10, SS - 3, SSD - 2, SLE - 1, DM - 1), with fever in 7 (8%), only in one case hospitalization was required (lung damage was not detected in computed tomography), in two cases, according to CT mild lung damage (CT 1-2), there were no deaths. Good TC's tolerability was noted, signs not associated with COVID-19 or progression of IMRD after administration of TC were observed in 8 (9%) patients (GPA - 3 MPA - 1, RA - 2, SLE - 1, IgG4-related disease - 1), adverse reactions definitely associated with the use of TC were not found. The most serious event not associated with coronavirus infection was the progression of polyneuropathy in a patient with RA. In the control group, 3 (7%) patients were diagnosed with COVID-19, one with severe lung injury (CT 3, pulmonary embolism) and death. Conclusions. The data of clinical studies and our own clinical experience evidence the effectiveness of the use of a combination of long-acting monoclonal antibodies TC (Evusheld), registered for indications for pre-exposure prophylaxis and treatment of COVID-19. Patients with IMRD treated with RTX have a favorable safety profile of TC. The introduction of virus-neutralizing monoclonal antibodies, a new drug class for the prevention and treatment of infectious diseases, opens significant prospects for improving the prognosis of patients with IRD.Copyright © 2023 Ima-Press Publishing House. All rights reserved.
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(1) Background: As the COVID-19 pandemic enters its fourth year, it continues to cause significant morbidity and mortality worldwide. Although various vaccines have been approved and the use of homologous or heterologous boost doses is widely promoted, the impact of vaccine antigen basis, forms, dosages, and administration routes on the duration and spectrum of vaccine-induced immunity against variants remains incompletely understood. (2) Methods: In this study, we investigated the effects of combining a full-length spike mRNA vaccine with a recombinant S1 protein vaccine, using intradermal/intramuscular, homologous/heterologous, and high/low dosage immunization strategies. (3) Results: Over a period of seven months, vaccination with a mutant recombinant S1 protein vaccine based on the full-length spike mRNA vaccine maintained a broadly stable humoral immunity against the wild-type strain, a partially attenuated but broader-spectrum immunity against variant strains, and a comparable level of cellular immunity across all tested strains. Furthermore, intradermal vaccination enhanced the heterologous boosting of the protein vaccine based on the mRNA vaccine. (4) Conclusions: This study provides valuable insights into optimizing vaccination strategies to address the ongoing challenges posed by emerging SARS-CoV-2 variants.
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The efficacy of mefloquine has not been studied in the in vivo experiments and clinical trials involving COVID-19 patients. The study was aimed to assess the effects of mefloquine on the SARS-CoV-2 accumulation in the lungs of infected animals and to study the efficacy and safety of mefloquine compared to hydroxychloroquine in patients with COVID-19. During the experiment, a total of 96 Syrian hamsters were infected with SARS-CoV-2. Accumulation of the virus in lungs was compared in the groups of animals treated with mefloquine and ribavirin and in the control group. During the clinical trial, the mefloquine and hydroxychloroquine safety and efficacy in patients with mild and moderate COVID-19 (172 individuals) was assessed based on the symptom changes over time and the computed tomography results. The experiment showed that the SARS-CoV-2 accumulation in the lungs of Syrian hamsters 6 days after infection and mefloquine treatment was 2.2 +/- 0.18 lg PFU/g, which was lower (p < 0.05) than in the control group (3.5 +/- 0.21 lg PFU/g) and ribavirin group (5.2 +/- 0.05 lg PFU/g). During the clinical trial, it was found that 50.0% of patients in the mefloquine group and 32.4% in the hydroxychloroquine group (p < 0.05) developed a mild disease, and the completely resolved respiratory failure was registered in 76.5% and 44.6%, respectively (p < 0.001). Adverse events were observed in 86.7 % and 77% of patients in the mefloquine and hydroxychloroquine groups, respectively (p > 0.05). Thus, during the experiment, mefloquine contributed to the faster virus titer reduction in the lungs. During the clinical trial, the mefloquine efficacy was non-inferiority or, based on a number of indicators, higher compared to hydroxychloroquine, with comparable safety.Copyright © Extreme Medicine.All right reserved.
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This study clarifies the predicted subcutaneous shoulder depth and investigates the safety of the conventional (three-finger breadth method) and new (axillary method) intramuscular injection methods. The anatomical features of 245 volunteers who received the COVID-19 vaccination via the conventional method were investigated at the injection site (T point) and the hypothetical injection site using the new method (A point) via ultrasonography. The body mass index (BMI) and subcutaneous thickness at the T point (men: r = 0.75; women: r = 0.45) and the A point (men: r = 0.81; women: r = 0.55) were positively correlated. The upper arm circumference and subcutaneous thickness at the T point (r = 0.51) and the A point (r = 0.58) were correlated in women. Formulas to predict subcutaneous thickness using BMI and upper arm circumference were established: predicted subcutaneous thickness at the A point = 0.62 × BMI - 7.7 mm (R2 = 0.66) in men and 0.658 × BMI - 5.5 mm (R2 = 0.31) in women. This study demonstrates safe intramuscular injection sites and their depth.
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Background: Within the ACTIV-2/A5401 platform (NCT04518410), the safety and efficacy of tixagevimab/cilgavimab (T/C), an anti-SARS-CoV-2 monoclonal antibody combination, was studied in outpatients with COVID-19. Intravenous (IV) and intramuscular (IM) administration of T/C were assessed. Method(s): Non-hospitalized adults >=18 years enrolled within 10 days of positive SARS-CoV-2 test and symptom onset. Participants at higher risk of disease progression were eligible for IV T/C 300mg (150mg each component) or placebo;all were eligible for IM T/C 600mg (300mg each) administered to the lateral thigh or placebo. Co-primary outcomes were: time to symptom improvement through day 28;nasopharyngeal (NP) SARS-CoV-2 RNA below lower limit of quantification (LLoQ) on days 3, 7 or 14;and treatment emergent Grade >=3 adverse events. Result(s): Between February and May 2021, 223 participants (106 T/C, 117 placebo) initiated study intervention and were included in the IM analysis and 114 participants (58 T/C, 56 placebo) in the IV analysis;the IV study was stopped early for administrative reasons. Both studies enrolled 45% Latinx;the IM and IV populations included 12% and 19% Black participants, 49% and 59% female sex at birth, and median age was 39 and 44 years, respectively, all of which were balanced between active vs placebo for each. Median (IQR) days from symptom onset at enrollment was 6 (4, 7). There were no differences in time to symptom improvement comparing IM T/C to placebo (median 8 (IQR 7, 12) vs 10 (8, 13) days;p=0.35) or IV T/C to placebo (11 (9, 15) vs 10 (7, 15) days;p=0.71). A significantly greater proportion (80%) in the IM T/C arm had NP SARS-CoV-2 RNA below LLoQ at day 7 compared to placebo (65%), but not days 3 or 14, overall p=0.003 across visits. Secondary and post-hoc analyses revealed antiviral effects within the smaller IV study. There was no difference in Grade >=3 AEs with either administration route. Fewer participants were hospitalized who received T/C vs placebo (4 vs 7 in IM group;0 vs 4 in IV group), neither group reaching statistical significance. Conclusion(s): Tixagevimab/cilgavimab administered IM or IV was well-tolerated and demonstrated antiviral activity and a trend towards fewer hospitalizations, but did not change time to symptom improvement in mild-to-moderate COVID-19 compared to placebo. Monoclonal antibodies administered intramuscularly to the thigh may present a valuable alternative for early SARSCoV-2 infection. Virologic Outcomes of Tixagevimab/Cilgavimab treatment 600mg IM (panels A and B) or 300mg IV (panels C and D) versus placebo.
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We present a case report of an inadvertent administration of intravenous carboprost in a COVID-19-positive parturient who was taken up for an emergency caesarean section for meconi um-stained liquor. Unintentionally, the patient was administered intravenous carboprost instead of ondansetron. The patient developed breathlessness, uneasiness and hypertension. Despite the mishap, the patient fully recovered and was discharged after 15 days. Although the medical error in the present case was non-harmful, the treating doctor discussed the case with the patient. Conclusion: A case with inadvertent intravenous administration of carboprost in a COVID-19-positive parturient is reported with a good outcome.
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Background: Shoulder injury related to vaccine administration (SIRVA) is a recognized complication and possible source of morbidity associated with incorrectly administered intramuscular deltoid vaccinations. As this site is commonly used for intramuscular injection, both clinicians and vaccine administrators should be familiar with SIRVA to minimize risk and monitor for its clinical presentation. Case Report: A 49-year-old male presented with shoulder pain that began 1 day after intramuscular administration of an influenza vaccine and point tenderness near the site of injection. Magnetic resonance imaging of the shoulder demonstrated focal osseous edema in the humeral head related to suboptimal needle placement. Conclusion: Based on the combination of history, physical examination findings, and imaging findings, the diagnosis of SIRVA was made with confidence in this clinical scenario.
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Introduction: Vaccination is considered the most effective method of preventing diseases and their complications. Unfortunately, many people question their legitimacy and safety. At the beginning of 2021, a few months after the announcement of the SARS-CoV-2 pandemic by the World Health Organization (WHO), the first COVID-19 vaccines were granted a conditional marketing authorization. mRNA vaccines have attracted great interest due to the use of new technology and the content of polyethylene glycol (PEG 2000) in their composition, which may induce anaphylaxis. Due to vaccine tolerance concerns, some vaccination centres have refused to administer the vaccine to patients. Aim(s): Risk assessment of allergic reactions after administration of the COVID-19 vaccine. Material(s) and Method(s): 115 patients were admitted to the Department of Allergology and Clinical Immunology in Katowice, including 107 patients with a high risk of anaphylaxis after vaccination according to the referring physician and 8 patients with a history of hypersensitivity reactions after the first dose of COVID-19 vaccination. Patients were referred for diagnosis of hypersensitivity to components of the Pfizer/BioNTech COVID-19 vaccine and administration of the vaccine in a hospital setting. During hospitalization, all patients underwent skin prick and intradermal tests with the Pfizer/BioNTech COVID-19 vaccine components, with negative results. Patients were administered the Pfizer/BioNTech COVID-19 vaccine intramuscularly, followed by at least 60 minutes of observation in the Department. Result(s): No symptoms of early hypersensitivity were observed. One patient developed urticarial lesions on the skin of the neck approximately 4-5 hours after vaccination. Conclusion(s): The risk of anaphylaxis after COVID-19 vaccine administration is low, and only a small group of patients with an allergic history require a specialised diagnostics. Physicians authorised to administer the vaccine should be acquainted with the latest recommendations, assess the risk of anaphylaxis and avoid unnecessary delays in administering a vaccine that can protect against severe morbidity and death.Copyright © 2023, Termedia Publishing House Ltd.. All rights reserved.
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By September 2022, approximately 2. 88 million doses of COVID-19 mRNA vaccine had been administered in Japanese children, and 9 cases of vaccine-related anaphylaxis had been reported. Of these, 2 cases were determined to be definite anaphylaxis by expert review, for an incidence rate of 0. 7 cases per million doses. This is equivalent to the incidence of anaphylaxis from adverse reactions to existing vaccines. If anaphylaxis occurs, pediatricians should administer an intramuscular injection of adrenaline, the first choice of treatment for anaphylaxis. The allergen contained in mRNA vaccines is likely to be polyethylene glycolPEG. Therefore, we must be cau-tious in our decision to vaccinate individuals with a history of allergic reactions to PEG-containing agents. However, since no clinical test has been established to confirm allergic reactions to PEG prior to vaccination, efforts are being made to identify high-risk patients by questionnaire. It is necessary for each facility to clearly state how to respond to anaphylaxis and share information among staff so that treatment can be reliably administered in the event of anaphylaxis.Copyright © 2022, Dokkyo University School of Medicine. All rights reserved.
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By September 2022, approximately 2. 88 million doses of COVID-19 mRNA vaccine had been administered in Japanese children, and 9 cases of vaccine-related anaphylaxis had been reported. Of these, 2 cases were determined to be definite anaphylaxis by expert review, for an incidence rate of 0. 7 cases per million doses. This is equivalent to the incidence of anaphylaxis from adverse reactions to existing vaccines. If anaphylaxis occurs, pediatricians should administer an intramuscular injection of adrenaline, the first choice of treatment for anaphylaxis. The allergen contained in mRNA vaccines is likely to be polyethylene glycol(PEG). Therefore, we must be cau-tious in our decision to vaccinate individuals with a history of allergic reactions to PEG-containing agents. However, since no clinical test has been established to confirm allergic reactions to PEG prior to vaccination, efforts are being made to identify high-risk patients by questionnaire. It is necessary for each facility to clearly state how to respond to anaphylaxis and share information among staff so that treatment can be reliably administered in the event of anaphylaxis.Copyright © 2022, Dokkyo University School of Medicine. All rights reserved.
ABSTRACT
By September 2022, approximately 2. 88 million doses of COVID-19 mRNA vaccine had been administered in Japanese children, and 9 cases of vaccine-related anaphylaxis had been reported. Of these, 2 cases were determined to be definite anaphylaxis by expert review, for an incidence rate of 0. 7 cases per million doses. This is equivalent to the incidence of anaphylaxis from adverse reactions to existing vaccines. If anaphylaxis occurs, pediatricians should administer an intramuscular injection of adrenaline, the first choice of treatment for anaphylaxis. The allergen contained in mRNA vaccines is likely to be polyethylene glycol(PEG). Therefore, we must be cau-tious in our decision to vaccinate individuals with a history of allergic reactions to PEG-containing agents. However, since no clinical test has been established to confirm allergic reactions to PEG prior to vaccination, efforts are being made to identify high-risk patients by questionnaire. It is necessary for each facility to clearly state how to respond to anaphylaxis and share information among staff so that treatment can be reliably administered in the event of anaphylaxis.Copyright © 2022, Dokkyo University School of Medicine. All rights reserved.
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It has been proven that mRNA vaccines are highly effective against the COVID-19 outbreak, and low prevalence of side effects has been shown. However, there are still many gaps in our understanding of the biology and biosafety of nucleic acids as components of lipid nanoparticles (LNPs) most often used as a system for inctracellular delivery of mRNA-based vaccines. It is known that LNPs cause severe injection site inflammation, have broad biodistribution profiles, and are found in multiple tissues of the body, including the brain, after administration. The role of new medications with such pharmacokinetics in inflammation developing in inaccessible organs is poorly understood. The study was aimed to assess the effects of various doses of mRNA-LNP expressing the reporter protein (0, 5, 10, and 20 microg of mRNA encoding the firefly luciferase) on the expression of neuroinflammation markers (Tnfalpha, Il1beta, Gfap, Aif1) in the prefrontal cortex and hypothalamus of laboratory animals 4, 8, and 30 h after the intramuscular injection of LNP nanoemulsion. It was shown that mRNA-LNP vaccines in a dose of 10-20 microg of mRNA could enhance Aif1 expression in the hypothalamus 8 h after vaccination, however, no such differences were observed after 30 h. It was found that the Gfap, l11beta, Tnfalpha expression levels in the hypothalamus observed at different times in the experimental groups were different. According to the results, mRNA-LNPs administered by the parenteral route can stimulate temporary activation of microglia in certain time intervals in the dose-dependent and site specific manner.Copyright © 2022 Pirogov Russian National Research Medical University. All rights reserved.
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Seborrhoeic keratosis is a benign brownish-black skin lesion that is almost always seen in middle-aged and elderly populations. The sudden onset and rapid increase in size and/ or number of seborrhoeic keratoses is called the Leser-Trelat sign, suggesting a paraneoplastic manifestation of internal malignancy. However, eruptive seborrhoeic keratoses are also described in some nonmalignant conditions such as human papillomavirus infection and HIV infection. Herein, we report a case with Leser-Trelat sign in a patient following COVID-19 infection. A 50-year-old man presented to our dermatology clinic complaining of the sudden appearance of multiple warty-like lesions on his back, which had occurred 2 months after recovery from COVID-19 infection. According to his medical history, the patient presented with cough, fever and dyspnoea about 2 months prior to the appearance of his skin lesions. He was referred to a health centre, where a nasopharyngeal swab was taken, and his polymerase chain reaction test for COVID-19 was positive. In addition, bilateral patchy ground-glass infiltration was reported in his high-resolution computed tomography (HRCT) scan, all in favour of COVID- 19 infection. The patient was then treated with acetaminophen, dexamethasone (intramuscular injection), salmeterol and a fluticasone inhaler, and his symptoms improved. Two months after recovery from his mild COVID-19 infection, several small asymptomatic pigmented verrucous papules appeared on his back. Physical examination revealed multiple rough, oval-shaped, brownish papules of varying size. Dermatoscopy of the lesions was also performed. Both clinical and dermoscopic findings were in favour of seborrhoeic keratosis. In order to reach a final diagnosis, a skin biopsy was performed, and microscopic examination of the biopsy specimen showed hyperkeratosis and well-defined epidermal hyperplasia composed mainly of the proliferation of benignlooking basaloid cells and fewer squamoid cells and horn cysts and increased melanin, mostly at the dermoepidermal junction. The dermis showed no significant change. Based on the above findings, the patient was diagnosed with eruptive seborrhoeic keratosis. To determine the possible cause of this eruption, the patient was further evaluated. In his past medical history, he was generally healthy before his COVID-19 infection and had no history of comorbidities. The patient underwent a workup to rule out any internal malignancies. Laboratory tests revealed normal results and included a complete blood count, liver and kidney function tests, electrolytes, prostate-specific antigen and urine analysis. Gastrointestinal endoscopy and colonoscopy ruled out any gastrointestinal malignancy. Chest X-ray and HRCT revealed no malignant lesion. In addition, the patient's abdominopelvic sonography was normal. The patient had no family history of similar skin lesions and gave no history of any chronic inflammatory skin diseases or viral conditions. Therefore, the appearance of the Leser-Trelat sign after COVID- 19 infection was a possibility in this patient. The role of transforming growth factor-alpha and tumour necrosis-alpha in eruptive seborrhoeic keratoses, as well as in COVID-19 infection, can be a common area of interest to explore in the aetiology of this entity.
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BACKGROUND: Sotrovimab, a dual-action Fc-engineered human immunoglobulin G (IgG1) mAb, binds to a conserved epitope on the SARS-CoV- 2 receptor binding domain and was developed to treat mild to moderate COVID-19. A high concentration formulation is being evaluated to offer the potential for IM administration at lower volumes and at different injection sites. METHOD(S): COSMIC (NCT05280717) is a phase 1, open-label healthy volunteer study comprising three parts. Part A is an ongoing randomized, parallel group study investigating the relative bioavailability, safety, and tolerability of two concentrations of sotrovimab administered at different injection sites. A total of 215 subjects were randomized in a 2:2:1:1 ratio into 4 treatment arms: dorsogluteal injection (62.5 mg/mL), or 100 mg/mL administered as dorsogluteal, thigh, or deltoid injection(s). PK will be evaluated for 24 weeks post-dose. RESULT(S): Preliminary PK is available from 50 participants who received a 500 mg IM dose of sotrovimab of the higher concentration (100 mg/mL). Administration into thigh or deltoid resulted in higher geometric mean Cmax and AUCD1-15 and lower inter-subject variability compared to 100 mg/mL dorsogluteal. Following gluteal, thigh, or deltoid injections, the geometric mean (%CV) Cmax was 44.8 mug/mL (63.3), 70.9 mug/mL (35.5), and 65.1 mug/mL (27.1), respectively, and the geometric mean (%CV) AUCD1-15 was 534 day*mug/mL (67.5), 814 day*mug/mL (39.7), and 782 day*mug/mL (26.3), respectively. Median Tmax was earlier following thigh (4 days) and deltoid (5.5 days) injection than gluteal (7 days) injection. CONCLUSION(S): Administration of sotrovimab into thigh or deltoid muscles may improve exposure and reduce inter-subject variability compared to gluteal IM administration. These data may inform IM injection site selection for mAbs.