Assessment of Safety and Prophylactic Efficacy of the EpiVacCorona Peptide Vaccine for COVID-19 Prevention (Phase III).

The State Research Center of Virology and Biotechnology "VECTOR" of the Federal Service for the Oversight of Consumer Protection and Welfare (Rospotrebnadzor) has developed the peptide-based EpiVacCorona vaccine, which is the first synthetic peptide-based antiviral vaccine for mass immunization in international vaccinology. An early clinical trial (Phase I-II) demonstrated that the EpiVacCorona vaccine is a safe product. The "Multicenter double-blind, placebo-controlled, comparative, randomized trial to assess the tolerability, safety, immunogenicity and prophylactic efficacy of the EpiVacCorona COVID-19 vaccine based on peptide antigens in 3000 volunteers aged 18 years and older" was performed regarding vaccine safety. The key objectives of the study were to evaluate the safety and prophylactic efficacy of the two-dose EpiVacCorona vaccine administered via the intramuscular route. The results of the clinical study (Phase III) demonstrated the safety of the EpiVacCorona vaccine. Vaccine administration was accompanied by mild local reactions in ≤27% of cases and mild systemic reactions in ≤14% of cases. The prophylactic efficacy of the EpiVacCorona COVID-19 vaccine after the completion of the vaccination series was 82.5% (CI95 = 75.3-87.6%). The high safety and efficacy of the vaccine give grounds for recommending this vaccine for regular seasonal prevention of COVID-19 as a safe and effective medicinal product.

Effect of Sulodexide on Circulating Blood Cells in Patients with Mild COVID-19.

Background. Despite the fact that COVID-19 usually manifests with severe pneumonia, there is a growing body of evidence that life-threatening multiorgan damage is caused by vascular and hemostatic abnormalities. Since there is no established therapy, assessing antithrombotics is indeed important. Sulodexide, a compound derived from porcine intestinal mucosa is a mixture of fast-moving heparin fraction (80%) and dermatan sulfate (20%), is approved in Europe and currently in trials for COVID-19 indication. Methods. This single-center, prospective, observational study included 28 patients with mild COVID-19 hospitalized in the Central Clinical Hospital of the Presidential Administration of the Russian Federation. Patients in the control group (n = 14) were treated using routine therapy according to current guidelines, while patients in the experimental group (n = 14) had the routine treatment supplemented with daily intravenous injections of sulodexide in 600-unit doses. Scanning electron microscopy was utilized to examine the blood specimens derived from the cubital vein at admission and at 10 days after hospitalization, which was approximately the average duration of patients' treatment in the hospital (11.6 ± 0.4 days). Results. Sulodexide significantly (by 40%) diminished the score of circulating endothelial cells, potentially indicating its antiviral endothelium-protective properties. It also prevented the extra activation of the platelets and the formation of erythrocytic sludges. Among patients in the control group, the share of activated platelets rose from 37 ± 5% to 45 ± 6% (p = 0.04) over the course of the study period, whereas among patients in the experimental group, the share of activated platelets remained practically unchanged (43 ± 6% vs. 38 ± 4%, p = 0.22). The score of erythrocytic sludges in the control group remained practically the same (4.8 ± 1.1 at admission vs. 3.9 ± 0.9 after 10 days, p = 0.67), whereas in the experimental group, it significantly decreased (from 5.7 ± 1.7 to 2.4 ± 0.9, p = 0.03). Conclusions. Sulodexide is able to defend endothelium, normalize blood, and, seemingly, prevent thrombosis. Therefore, it may be considered as a promising and effective agent for the treatment of patients with mild COVID-19. Broader randomized trials are needed to assess whether the observed findings will transform into sustained long-term clinical benefit.

Mild COVID-19 and Impaired Blood Cell-Endothelial Crosstalk: Considering Long-Term Use of Antithrombotics?

BACKGROUND: Current coronavirus disease 2019 (COVID-19) pandemic reveals thrombotic, vascular, and endothelial dysfunctions at peak disease. However, the duration, degree of damage, and appropriate long-term use of antithrombotic strategies are unclear. Most COVID data are yielded from random clinical observations or autopsy of postmortem samples, while precise blood cellular data in survivors are insufficient. METHODS: We analyzed erythrocytes, circulating endothelial cells, and echinocytes by electron microscopy and flow cytometry in patients with confirmed COVID-19 (n = 31) and matched healthy controls (n = 32) on admission and at hospital discharge. RESULTS: All patients experienced mild disease, none required pulmonary support, and all survived. Admission number of circulating endothelial cells was significantly (40-100 times) higher in COVID-19 patients. Cells were massively damaged by multiple fenestrae in membranes with diameter comparable to the size of supercapsid in SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus. COVID-19 also provoked formation of stacked aggregated erythrocytes capable of clogging microvascular bed and of diminishing oxygen supply. In some patients, such abnormalities persisted at hospital discharge revealing remaining intracellular penetration of SARS-CoV-2 where it may be replicated and returned to circulation. CONCLUSION: These observational and descriptive data suggest that persistent viral cell injury may cause blood vessel damage; their increased permeability resulted in tissue edema, inflammation, platelet activation, and augmented thrombosis. There is a residual blood cell damage following the acute phase in some COVID-19 survivors. Controlled outcome-driven trials are urgently needed for exploring optimal use of long-term antithrombotics and vascular protection strategies even after mild COVID-19.

Enoxaparin dose impacts blood cell phenotypes during mild SARS-CoV-2 infection: the observational single-center study.

Coronavirus disease 2019 (COVID-19) is associated with various hemostatic abnormalities requiring constant search for better delicate antithrombotic management in these high-risk patients. The choice and the optimal dose of anticoagulant is important, but unclear, especially for mild COVID-19. Enoxaparin has been tested in several COVID trials with mixed results regarding hard clinical outcomes including mortality. We analyzed clinical, laboratory data and changes in platelets, erythrocytes and leukocytes by scanning electron microscopy on admission and at hospital discharge in patients with confirmed COVID-19 treated with enoxaparin (n = 31) and matched healthy controls (n = 32) in a retrospective observational study. The data were triaged by enoxaparin dose comparing 40 mg/daily prophylactic enoxaparin dose (PED) with 80 mg/daily therapeutic (TED) regimens. All patients experienced mild disease, none required pulmonary support, and all survived. The impact of enoxaparin dose was prominent for platelets and erythrocytes, but less evident for leukocytes. PED was associated with significant platelet activation, diminished numbers of silent nonactive discoid cells, and increased number and size of platelet microaggregates with leukocyte involvement. In contrast, TED did not cause extra platelet activation, while circulating platelet microaggregates were smaller and lacking leukocytes in their construction. PED caused significant increase of erythrocyte-platelet aggregates formation, and numerically higher proportion of circulating echinocytes. TED was associated with significant decrease of rouleaux sludge formation compared to only some trend after PED. Changes in leukocytes were less dependent on enoxaparin dose. However, PED has been associated with enhanced aggregate formation in 7 out of 10 patients, while trap net formation has been decreased in 17 out of 21 TED patients. We conclude that over hospital stay TED was superior to PED in patients with mild COVID-19. The inability of PED to adequately protect major circulating blood cells is probably due to enhanced clearance or/and diminished bioavailability of enoxaparin during COVID. These retrospective observational small sample size data may be relevant to better understanding of the mixed results in controlled outcome-driven trials exploring optimal COVID-19 anticoagulant strategies.

The efficacy and safety of levilimab in severely ill COVID-19 patients not requiring mechanical ventilation: results of a multicenter randomized double-blind placebo-controlled phase III CORONA clinical study.

OBJECTIVE AND DESIGN: The aim of this double-blind, placebo-controlled, phase III CORONA clinical trial was to evaluate the efficacy and safety of IL-6 receptor inhibitor levilimab (LVL) in subjects with severe COVID-19. SUBJECTS: The study included 217 patients. The eligible were men and non-pregnant women aged 18 years or older, hospitalized for severe COVID-19 pneumonia. TREATMENT: 206 subjects were randomized (1:1) to receive single subcutaneous administration of LVL 324 mg or placebo, both in combination with standard of care (SOC). 204 patients received allocated therapy. After the LVL/placebo administration in case of deterioration of symptoms, the investigator could perform a single open-label LVL 324 mg administration as the rescue therapy. METHODS: The primary efficacy endpoint was the proportion of patients with sustained clinical improvement on the 7-category ordinal scale on Day 14. All efficacy data obtained after rescue therapy administration were considered missing. For primary efficacy analysis, all subjects with missing data were considered non-responders. RESULTS: 63.1% and 42.7% of patients in the LVL and in the placebo groups, respectively, achieved sustained clinical improvement on Day 14 (P = .0017). The frequency of adverse drug reactions was comparable between the groups. CONCLUSION: In patients with radiologically confirmed SARS-CoV-2 pneumonia, requiring or not oxygen therapy (but not ventilation) with no signs of other active infection administration of LVL + SOC results in an increase of sustained clinical improvement rate. TRAIL REGISTRATION: The trial is registered at the US National Institutes of Health (ClinicalTrials.gov; NCT04397562).

Impact of olokizumab on platelets, leukocytes and erythrocytes during mild COVID-19.

No abstract present.

AVIFAVIR for Treatment of Patients With Moderate Coronavirus Disease 2019 (COVID-19): Interim Results of a Phase II/III Multicenter Randomized Clinical Trial.

In May 2020 the Russian Ministry of Health granted fast-track marketing authorization to RNA polymerase inhibitor AVIFAVIR (favipiravir) for the treatment of COVID-19 patients. In the pilot stage of Phase II/III clinical trial, AVIFAVIR enabled SARS-CoV-2 viral clearance in 62.5% of patients within 4 days, and was safe and well-tolerated. Clinical Trials Registration. NCT04434248.

Cost-effectiveness of Platelet Function-Guided Strategy with Clopidogrel or Ticagrelor.

Some patients treated with dual antiplatelet therapy (DAPT) following acute coronary syndrome (ACS) can still exhibit heightened residual platelet reactivity (HRPR), which is potentially linked to adverse vascular outcomes. Better tailored DAPT strategies are needed to address this medical need. AIM: To assess the cost-effectiveness of guided DAPT with clopidogrel or ticagrelor in addition to aspirin when using VerifyNow P2Y12 testing in post-ACS patients. METHODS: The costs were calculated per 1,000 patients aged >55 years. It was assumed that all patients received either generic clopidogrel or ticagrelor for 1 year, and underwent VerifyNow P2Y12 assay testing before DAPT maintenance. RESULTS: Guided DAPT will prevent five more MIs and six more deaths per 1,000 patients than a standard prescription of generic clopidogrel. The total predictive value of costs per patient is 32% lower if a guided strategy is used than if ticagrelor is given to all patients. CONCLUSION: Assessment of heightened residual platelet reactivity with P2Y12 assay in triaging DAPT post-ACS patients for 1 year is a cost-effective strategy that would reduce financial burden compared to routine administration of more expensive antiplatelet agents.

Mortality and adverse events with brand and generic clopidogrel in the US Food and Drug Administration Adverse Event Reporting System.

AIMS: Clopidogrel is commonly used even after expiring patents. The brand clopidogrel (BC) was dealt by single company, while numerous manufacturers produce generic clopidogrel (GC). There are no convincing data to compare the safety of different formulations. Therefore, the data yielded from international, uniform, government-mandated registries may be useful. METHODS AND RESULTS: We assessed primary causative adverse events (PCAE) after BC and GC in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The outcomes were divided into death, cardiac, thrombotic/embolic, haemorrhagic, and rash/dermal complications. These primary endpoints were then examined by proportional reporting ratios (PRR) and chi-square (χ2). Among total FAERS (n = 9 466 679) reports, overall BC (n = 88 863) cases were more common than after GC (n = 36 559). When triaged by PCAE role, BC (n = 18 328) was also more abundant than GC (n = 3987). The reported death rates were more than doubled after BC [18.4% vs. 7.0%; PRR = 0.38; 95% confidence interval (95% CI) 0.32-0.43; χ2=369.7; P<0.0001] for total FAERS, and consistent for late 2010-2017 (17.6% vs. 7.0% PRR = 0.40; 95% CI 0.37-0.45; χ2=286.2; P<0.004) PCAE cases. In contrast, GC trended to co-report more cardiac (14.6% vs. 13.3%; PRR = 1.12; 95% CI 1.0-1.25; χ2=3.5; P<0.06). The haemorrhagic (40.9% vs. 32.3%; PRR = 1.45; 95% CI 1.33-1.57; χ2=75.8; P<0.0001), and rash/dermal (5.4% vs. 4.6%; PRR = 1.20; 95% CI 1.0-1.44; χ2=3.75; P<0.05) events were also more common for GC. Thrombotic/embolic events were reported equally (at 7.0%) after each formulation. CONCLUSION: The PCAE profiles differ with BC and GC in FAERS. While deaths reports were higher, the rates of cardiac, haemorrhagic, and skin complications were less common for BC. Despite expected reporting bias, this may indicate that the manufacturers of GC are reluctant to report deaths to the FDA. However, the overall adverse event profile suggests potentially better safety of BC over GC formulations.

Impact of CYP2C19 Polymorphism on Antiplatelet Potency of Prasugrel 5 and 10 mg Daily Maintenance.

BACKGROUND: Whether genetic polymorphisms (GP) impact residual platelet aggregation (RPA) following prasugrel is unclear, especially during maintenance phase. We assessed the influence of CYP2C19 GP carriers on RPA in the prospective observational cohort study. METHODS AND RESULTS: All post-stent patients (n = 206) received prasugrel 60 mg loading and either 5 or 10 mg daily maintenance with aspirin100 mg. RPA levels by light transmission aggregometry (LTA), multiplate electrode aggregometry (MEA), and VerifyNow (P2Y12 reaction units, PRU) with CYP2C19 GP were measured simultaneously. Demographics and clinical characteristics were not useful for predicting response after prasugrel. GP carriers exhibited higher RPA (PRU: p = 0.001, LTA: p = 0.001, MEA: p = 0.023) than noncarriers. CYP2C19 carriers had higher RPA for 5 mg (n = 35; LTA: p = 0.043, MEA: p = 0.023) and reached significance for 10 mg (n = 27; LTA: p = 0.001, PRU: p = 0.001) prasugrel. When divided into extensive, intermediate, and poor metabolizers, all exhibited statistical differences among the 3 groups (LTA: 14.9 ± 12.3%, 22.6 ± 14.9%, 22.9 ± 15.6%, p = 0.002; PRU: 104.1 ± 70.8%, 141.8 ± 78.0%, 151.0 ± 84.8%, p = 0.003; MEA: 19.7 ± 8.9%, 24.4 ± 12.2%, 28.1 ± 14.7%, p = 0.002). CONCLUSION: CYP2C19 GP impacts RPA during maintenance phase prasugrel in Korean outpatients. This effect is consistent for both of the approved prasugrel doses potentially affecting long-term outcomes including bleeding risks. However, the clinical utility of these findings is still uncertain, and requires more evidence from larger randomized trials beyond East Asians.

Historical overview of studies on inflammation in Russia.

INTRODUCTION: Historical overview of development investigations on inflammation in Russia up to date is presented. MATERIAL AND METHODS: Analysis of modern Russian language literature (1950-2010) on history of medicine and researchers' activity on inflammation, as well as Russian language content of internet on this theme, was made. Many names of Russian researchers are still little known to the English-speaking Western readers. RESULTS: Starting in the eighteenth century, the mystery of the inner workings of the inflammation process attracted the interest of physicians and biologists of the Russian Empire. Accumulated knowledge focused mainly on the etiological factors of inflammation. In the nineteenth century, scientific schools emerged for studying inflammation and established close contacts with leading scientists in other countries. At this time, Ilya Mechnikov formulated his famous biological theory of inflammation, according to which inflammation is a protective adaptation response to an injury. He also developed his teaching on phagocytosis and was awarded the Nobel Prize. In the twentieth century, Russian scientists participated in the discovery of viruses and new bacterial pathogens, and in the investigation of the mechanics of the genesis and development of inflammatory processes. CONCLUSION: Today interest in studies of inflammation in Russia is on the increase; scientists united by the Russian Inflammation Society continue their quest to investigate inflammatory mediators, and study molecular and cellular mechanisms and approaches in the treatment of complications associated with inflammation.