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SARS-CoV-2 has infected more than 600 million people worldwide over the last 2.5 years. So far, there efficacy of many antiviral drugs against COVID-19 has been evaluated only in small studies conducted in different countries. Objective. To assess the efficacy of umifenovir in patients with COVID-19. Materials and methods. We performed systematic search of publications in the PubMed and Google Scholar databases. Sixteen studies with a total of 1,843 patients were included in the analysis. The following endpoints were evaluated: frequencies of negative PCR test on days 7 and 14;mortality in patients with mild, moderate, and severe disease;and frequency of fever resolution on day 7. Results. We found that patients receiving umifenovir demonstrated a significantly higher frequency of negative PCR test on day 7 than patients who received no causal therapy or other antiviral drugs (odds ratio (OR) 1.69, 95% confidence interval (CI): 1.09-2.62, p = 0.02, I2 = 13%). This difference was even more significant among patients with mild to moderate COVID-19 (OR: 2.03, 95% CI: 1.24-3.32, p = 0.005, I2 = 0%), as well as on day 14 (OR: 2.02, 95% CI: 1.35-3.94, p = 0.0007, I2 = 50%). We also observed a reduced risk of death in the studies that included only patients with mild and moderate disease (JR: 0.53, 95% CI: 0.33-0.83, p = 0.006, I2 = 0). Umifenovir therapy did not affect the frequency of fever resolution by day 7 (OR: 0.87, 95% CI: 0.49-1.56, p = 0.64, I2 = 0%). Conclusion. Umifenovir significantly accelerated virus elimination by days 7 and 14 among patients with mild to moderate COVID-19. Umifenovir also reduced the risk of death compared to other antiviral drugs.Copyright © 2022, Dynasty Publishing House. All rights reserved.
ABSTRACT
SARS-CoV-2 has infected more than 600 million people worldwide over the last 2.5 years. So far, there efficacy of many antiviral drugs against COVID-19 has been evaluated only in small studies conducted in different countries. Objective. To assess the efficacy of umifenovir in patients with COVID-19. Materials and methods. We performed systematic search of publications in the PubMed and Google Scholar databases. Sixteen studies with a total of 1,843 patients were included in the analysis. The following endpoints were evaluated: frequencies of negative PCR test on days 7 and 14;mortality in patients with mild, moderate, and severe disease;and frequency of fever resolution on day 7. Results. We found that patients receiving umifenovir demonstrated a significantly higher frequency of negative PCR test on day 7 than patients who received no causal therapy or other antiviral drugs (odds ratio (OR) 1.69, 95% confidence interval (CI): 1.09-2.62, p = 0.02, I2 = 13%). This difference was even more significant among patients with mild to moderate COVID-19 (OR: 2.03, 95% CI: 1.24-3.32, p = 0.005, I2 = 0%), as well as on day 14 (OR: 2.02, 95% CI: 1.35-3.94, p = 0.0007, I2 = 50%). We also observed a reduced risk of death in the studies that included only patients with mild and moderate disease (JR: 0.53, 95% CI: 0.33-0.83, p = 0.006, I2 = 0). Umifenovir therapy did not affect the frequency of fever resolution by day 7 (OR: 0.87, 95% CI: 0.49-1.56, p = 0.64, I2 = 0%). Conclusion. Umifenovir significantly accelerated virus elimination by days 7 and 14 among patients with mild to moderate COVID-19. Umifenovir also reduced the risk of death compared to other antiviral drugs.Copyright © 2022, Dynasty Publishing House. All rights reserved.
ABSTRACT
Interferons (IFN) have antiviral activity against many viruses, including SARS-CoV-2. A combination of IFN-a2b and the antioxidant taurine is widely used in the Russian Federation, and its antiviral activity has not been studied before. The aim of this study was to determine the antiviral activity of interferon drugs, in combination with taurine and without it. The study included cytotoxicity and antiviral activity assays of IFN-a2b preparations, when stored according to the instructions at 2-8degreeC, and after 1 month storage at the temperature of 20-26degreeC in a pre-opened state. The combination of IFN alpha-2b with taurine has a higher antiviral activity compared to IFN alpha-2b mono-preparation by more than 25% at a <<low>> and 85% at a <<high>> multiplicity of infection. Selectivity index for combinations of IFN-a2b (50,000 IU/dose) + taurine (1 mg/ml) and IFN-a2b (10,000 IU/ml) + taurine (0.8 mg/ml) was more than 600 units, whereas for the IFN-a2b (10,000 IU/ml) it was 200 units. Antiviral activity does not change after one month at room temperature. The combination of interferon with taurine at high concentrations was less toxic than interferon. The results obtained demonstrate practicability of interferon alpha-2b and taurine combination use for treatment and prevention of COVID-19.Copyright © Team of Authors, 2022.
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Lactoferrin, artemisinin, and azithromycin exhibit a broad spectrum of antiviral, immunomodulatory, and anti-inflammatory effects. The experiments show that these drugs partially inhibit the infection caused by SARS-CoV-2 in vitro. This allows us to conclude that the effects on the entry of virions into cells mediated by each of these substances taken separately are insufficient for complete inhibition of the SARS-CoV-2 infection. The study was aimed to perform in vitro assessment of cytotoxicity and antiviral activity against the laboratory SARS-CoV-2 strain of the mixture of active ingredients: lactoferrin, artemisinin, and azithromycin. We used the Vero CCL81 (ATСС) cell line and the Dubrovka laboratory strain of SARS-CoV-2 (GenBank ID: MW161041.1), isolated in the Vero CCL81 cell culture from the nasopharyngeal swab of patient with СOVID-19. Cytotoxic effects and antiviral activity against SARS-CoV-2 of the drug mixture were assessed based on the cytopathic effects using the MTT (methylthiazolyldiphenyl-tetrazolium bromide) assay. Hydroxychloroquine was used as a reference drug. It has been shown that at high (MOI 100) and low (MOI 20) multiplicity of infection used in the Vero CCL 81 cell culture, the mixture of artemisinin, lactoferrin and azithromycin has a significant effect on the SARS-CoV-2 reproduction, and IC50 (half maximal inhibitory concentration) is estimated as the 1: 2 dilution in both cases. The findings make it possible to conclude that the studied mixture is low toxic and shows significant antiviral effects in vitro. © 2022 Group of Companies Med Expert, LLC. All rights reserved.
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INTRODUCTION: The variability of SARS-CoV-2 appeared to be higher than expected, the emergence of new variants raises concerns. The aim of the work was to compare the pathogenicity of the Wuhan and BA.1.1/Omicron variants in BALB/c mice and Syrian hamsters. MATERIALS AND METHODS: The study used strains of SARS-CoV-2: Dubrovka phylogenetically close to Wuhan-Hu-1, and LIA phylogenetically close to Omicron, BALB/c mice, transgenic mice B6.Cg-Tg(K18-ACE2)2Prlmn/HEMI Hemizygous for Tg(K18-ACE2)2Prlmn, Syrian golden hamsters. Animals were infected intranasally, pathogenicity was estimated by a complex of clinical, pathomorphological and virological methods. RESULTS: Comparative studies of SARS-CoV-2 Dubrovka and LIA strains on animal models demonstrated their heterogeneous pathogenicity. In parallel infection of BALB/c mice with Dubrovka and LIA variants, the infection proceeded without serious clinical signs and lung damage. Infection with the LIA strain resulted to a systemic disease with a high concentration of viral RNA in the lungs and brain tissues of animals. The presence of viral RNA in mice infected with the Dubrovka strain was transient and undetectable in the lungs by day 7 post-infection. Unlike the mouse model, in hamsters, the Dubrovka strain had a greater pathogenicity than the LIA strain. In hamsters infected with the Dubrovka strain lung lesions were more significant, and the virus spread through organs, in particular in brain tissue, was observed. In hamsters infected with the LIA strain virus was not detected in brain tissue. CONCLUSION: The study of various variants of SARS-CoV-2 in species initially unsusceptible to SARS-CoV-2 infection is important for monitoring zoonotic reservoirs that increase the risk of spread of new variants in humans.
Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Cricetinae , Mice , Angiotensin-Converting Enzyme 2 , Disease Models, Animal , Mice, Inbred BALB C , RNA, Viral/genetics , SARS-CoV-2/geneticsABSTRACT
Interferons (IFN) have antiviral activity against many viruses, including SARS-CoV-2. A combination of IFN-a2b and the antioxidant taurine is widely used in the Russian Federation, and its antiviral activity has not been studied before. The aim of this study was to determine the antiviral activity of interferon drugs, in combination with taurine and without it. The study included cytotoxicity and antiviral activity assays of IFN-a2b preparations, when stored according to the instructions at 2-8°C, and after 1 month storage at the temperature of 20-26°C in a pre-opened state. The combination of IFN alpha-2b with taurine has a higher antiviral activity compared to IFN alpha-2b mono-preparation by more than 25% at a «low» and 85% at a «high» multiplicity of infection. Selectivity index for combinations of IFN-a2b (50,000 IU/dose) + taurine (1 mg/ml) and IFN-a2b (10,000 IU/ml) + taurine (0.8 mg/ml) was more than 600 units, whereas for the IFN-a2b (10,000 IU/ml) it was 200 units. Antiviral activity does not change after one month at room temperature. The combination of interferon with taurine at high concentrations was less toxic than interferon. The results obtained demonstrate practicability of interferon alpha-2b and taurine combination use for treatment and prevention of COVID-19.
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Introduction. The emergence of new epidemiologically significant variants of SARS-CoV-2 has shifted emphasis to development of a live vaccine, which would be able to provide protection against a wide range of antigenic variants of the virus. The aim of the study was to obtain SARS-CoV-2 variants attenuated through cold adaptation and to provide their biological characterization. Materials and methods. The Dubrovka laboratory strain of SARS-CoV-2 and its variants were cultured on Vero and Calu-3 cells. The virus quantification was performed by virus titration in Vero cells and by real-time reverse transcription-polymerase chain reaction. SARS-CoV-2 virions were analyzed using transmission electron microscopy. Genome sequences of the virus were identified by nanopore sequencing. The attenuation (att) phenotype of SARS-CoV-2 variants was identified using Syrian hamsters as an animal model for COVID-19. Results. Cold-adapted (ca) SARS-CoV-2 variants – Dubrovka-ca-B4 and Dubrovka-ca-D2 were produced by continued passaging of the Dubrovka strain in the Vero cell culture at the temperature being gradually decreased to 23ºC and by subsequent cloning. Up to 20 nucleotide substitutions and 18 amino acid substitutions were detected in genomes of ca-variants. Ca-variants, as distinct from the parent Dubrovka strain, actively replicated at 23ºC, while the Dubrovka-ca-D2 variant had a temperature-sensitive (ts) phenotype (did not replicate at 39ºC). Ca-variants of the virus replicated poorly at 37ºC in the Calu-3 human lung cell culture, which, along with the ts-phenotype, can be a marker of virus attenuation for humans. In the intranasally infected Syrian hamsters, ca-variants of the virus demonstrated an attenuation phenotype: they did not cause loss of appetite, fatigue, drowsiness, did not slow down weight gain, replicating much more slowly in the lungs and brain compared to the virulent Dubrovka strain. Conclusion. The obtained attenuated SARS-CoV-2 ca-variants, Dubrovka-ca-B4 and Dubrovka-ca-D2, should be studied further as candidate vaccine strains for a live attenuated vaccine against COVID-19. © Team of authors, 2022.
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One of the most important steps in the development of drugs and vaccines against a new coronavirus infection is their testing on a relevant animal model. The laboratory mouse, with well-studied immunology, is the preferred mammalian model in experimental medicine. However, mice are not susceptible to infection with SARS-CoV-2 due to the lack of human angiotensin-converting enzyme (hACE2), which is the cell receptor of SARS-CoV-2 and necessary for the entry of the virus into the cell. In present work, it was shown that intranasal administration of the adeno-associated vectors AAV9 and AAV-DJ encoding the hACE2 provided a high level of expression of ACE2 gene in the lungs of mice. In contrast, the introduction of the AAV6 vector led to a low level ACE2 expression. Infection with SARS-CoV-2 of mice expressing hACE2 in the lungs led to virus replication and development of bronchopneumonia on the 7th day after infection. Thus, a simple method for delivering the human ACE2 gene to mouse lungs by intranasal administration of the AAV vector has been proposed. This approach enabled rapid generation of mouse model for studying coronavirus infection.
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Vaccination against COVID-19 is the most effective method of controlling the spread of SARS-CoV-2 and reducing mortality from this disease. The development of vaccines with high protective activity against a wide range of SARS-CoV-2 antigenic variants remains relevant. In this regard, evaluation of the effectiveness of physical methods of virus inactivation, such as ultraviolet irradiation (UV) of the virus stock, remains relevant. This study demonstrates that the UV treatment of SARS-CoV-2 completely inactivates its infectivity while preserving its morphology, antigenic properties, and ability to induce the production of virus-neutralizing antibodies in mice through immunization. Thus, the UV inactivation of SARS-CoV-2 makes it possible to obtain viral material similar in its antigenic and immunogenic properties to the native antigen, which can be used both for the development of diagnostic test systems and for the development of an inactivated vaccine against COVID-19.
Subject(s)
COVID-19 , Viral Vaccines , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Mice , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Ultraviolet Rays , Vaccines, InactivatedABSTRACT
Introduction.The COVID-19 pandcmic has stimulated the search for drugs with specific antiviral activity against the new pathogenic strain of the SARS-CoV-2 coronavirus. First of all, scientific search was aimed at studying drugs with already proven efficacy against influenza and ARVI. The aim of this worfc was to study the antiviral activity of Cytovir∗-3 in vitro in relation to the cytopathogenic effect of the SARS-CoV-2 virus. Material and methods. The antiviral activity of the drug Cy- tovir∗-3 against the SABS-CoV-2 virus was studied in experimental models in vitro on Vero CCL81 cell culture (ATCC).The maximum tolerated concentration and the 50% cytotoxic dose were determined using a quantitative microculture tetra- zolium test assay to calculate the working range of the concentrations of the test drug. Results and discussion. As a result of the study, it was shown that the greatest activity of the drug was manifested when it was added to the cells 24 hours before and 1 hour and 24 hours after viral infection, the inhibition level reached 53% (>IC50) at the drug concentrations of 105,55, and 85 fig/ml, respectively. Cytovir∗-3 suppressed the viral activity of SARS-CoV-2 in the dose range from 10 pg/ml to 105 pg/ml under the indicated infection conditions. It was found that the drug did not exhibit cytotoxic effects on the Vero cell culture in the range of antiviral doses. Conclusion. The antiviral activity of Cytovir∗-3 against the SARS-CoV-2 virus has been proven due to the achievement of IC50, which is below the maximum tolerated dose of 149 pg/ml.
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On account of the COVID-19 pandemic, the global pharmaceutical industry has achieved impressive results in the development and introduction of various types of vaccines causing the formation of acquired immunityagainst the SARS-CoV-2 coronavirus Into clinical practice. However, none of them currently show the declared one hundred percent guarantee of protection. In the case of the COVID-19 disease, patients with concomitant pathologies are the most vulnerable to the occurrence of severe complications. The aerosol route of transmission of SARS-CoV-2 contributes to the emergence of outbreaks of the new coronavirus infection in crowded places and closed rooms with poor ventilation. In this regard, an urgent problem is the search for drugs with local antiviral activity, which, together with restrictive measures and mask wearing policy, can potentially reduce the likelihood of contracting coronavirus. In this experimental in vitro study on Vero CCL81 cell culture (ATCC), the local anti¬viral activity of the drugThymogen∗ spray against the SARS-CoV-2 virus was studied in comparison with the antiseptic Miramistin® solution. As a result of the experiment, no toxic effects on Vero ceils were detected in the drugs in the studied concentrations. In a series of experiments, Thymogen∗ spray showed local antiviral activity against SARS-CoV-2 when the virus titer was 5,2 lg TCID50. Therefore, the drugThymogen® dosed nasal spray has high potential as a topical drug for prevention and treatment of COVID-19 disease, which requires additional confirmation in relevant clinical studies. © 2021 Media Sphera Publishing Group. All rights reserved.
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AIM: An analysis of coronavirus infection in Russia and evaluation of different AVT regimens effectiveness. MATERIALS AND METHODS: The study involved a retrospective analysis of 1082 patient records with laboratory-confirmed COVID-19 in 17 regions of Russia. The number of men and women was equal, mean age 48.718.1 (median 50). Patients with moderate COVID-19 (85%) versus mild COVID-19 (15%) were characterized by higher age (median 54 vs 21 years; p0.001), higher body mass index (27.8 vs 23.4; p0.001), prevalence of chronic diseases (75.3% vs 8.5%; p0.001), including circulatory system diseases (37.8%). Moderate COVID-19 characterized higher intoxication (10.86.1 vs 4.22.7 days; p0.001) and catarrhal symptoms duration (10.25.4 vs 6.14.1 days; p0.001). RESULTS: During hospitalization 92% of the patients received AVT, 77% antibiotics, and 16% corticosteroids. Umifenovir therapy resulted in a significant reduction of intoxication (8.75.5 vs 11.75.5 days; p0.001) and catarrhal symptoms duration (8.85.1 vs 12.04.9 days; p0.001) compared to the group without AVT. The usage of INF reduced intoxication symptoms compared with the group without AVT (8.97.5 vs 11.75.5; p0.05). Therapy with hydroxychloroquine, imidazolylethanamide pentandioic acid, and lopinavir + ritonavir combination did not affect the course of COVID-19. Most of adverse reactions were related to antibiotics. CONCLUSION: Umifenovir therapy and inclusion of interferon in AVT regimens was associated improvement in the clinical manifestation of the disease among patients.
Subject(s)
COVID-19 , Male , Humans , Female , Middle Aged , Young Adult , Adult , Lopinavir/therapeutic use , COVID-19/epidemiology , Ritonavir/therapeutic use , Hydroxychloroquine/therapeutic use , SARS-CoV-2 , Retrospective Studies , Antiviral Agents/therapeutic use , Interferons , Anti-Bacterial Agents/therapeutic useABSTRACT
Introduction. In clinical practice, the differential diagnosis of COVID-19 can be challenging during the flu season, entailing serious consequences such as delays in appropriate control measures against the SARS-CoV-2 pandemic. Another problem is posed by co-infection of SARS-CoV-2 and influenza virus (IV), which significantly contributes to the severity of the COVID-19 disease. This study was aimed to explore the cross-impact of co-administration of Russian influenza and COVID-19 vaccines on development of specific immunity in laboratory animals. Materials and methods. The study was conducted on BALB/c mice. The animals were inoculated intramuscularly with the vaccine for COVID-19 prevention (CoviVac) and the vaccine for influenza prevention (Flu-M). The sera from the immunized animals were examined separately. Three IV strains were used in the hemagglutination inhibition assay. Antibodies (Abs) against SARS-CoV-2 were detected by an enzyme-linked immunosorbent assay (ELISA). The neutralization test was performed to detect virus neutralizing antibodies against SARS-CoV-2 and IV. Results. Relatively high titers of specific Abs were found in the groups of animals inoculated with one vaccine and with two vaccines concurrently. In the groups of animals inoculated with CoviVac and with two vaccines concurrently, both in the ELISA test and in the neutralization test, the average titers of specific Abs against SARSCoV-2 did not demonstrate any statistical difference. The group of animals inoculated concurrently with two vaccines demonstrated statistically higher titers of Abs against IV after the second immunization compared to the group of animals inoculated with Flu-M. Discussion. The study has shown that post-vaccination immunity both to IV and to SARS-CoV-2 develops after co-vaccination with two vaccines. The observed enhanced post-vaccination immune response to IV in the coimmunized laboratory animals needs further research. Conclusion. The performed studies suggest the possibility of co-administration of two vaccines to prevent influenza and COVID-19. © 2021, Central Research Institute for Epidemiology. All rights reserved.
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Coronaviruses are known to cause acute respiratory infections. Antiviral therapy, including for COVID-19, is based on clinical practice, experimental data and trial results. The purpose of this review is to: provide and systematize actual preclinical data, clinical trials results and clinical practice for antiviral agent umifenovir (Arbidol). Databases Scopus, Web of Science, RSCI and medRxiv were used for publication searching from 2004. A meta-analysis of clinical trials results was performed. Umifenovir is antiviral agent, it belongs to fusion inhibitors, interacts with SARS-CoV-2 spike protein. Umifenovir the impede the trimerization of spike glycoprotein and inhibit host cell adhesion, at the level of the coronaviruses S-protein of interaction with ACE2 receptor. Preclinical studies in vitro and on animals show umifenovir activity against a number of coronaviruses, including SARS-CoV, MERS-CoV, SARS-CoV-2, and others. Umifenovir, in combination with other antiviral drugs, symptomatic or traditional medicine, was used in China to treat patients with COVID-19, resulting in reduced mortality, virus elimination, the frequency of more severe course and complications in middle severity. However, antiviral therapy for the treatment of severe patients, with ARDS, did not lead to improved outcomes. In comparative clinical studies, umifenovir showed similar effectiveness with other antiviral drugs, and lower frequency of adverse reactions. Therapy with umifenovir, led to an increase percentage of patients with negative results of PCR tests on days 714 (I2=69.8%, RR 0.48, 95% CI 0.190.76; p=0.001). The efficacy and safety of antivirals against SARS-CoV-2 still requires clinical investigation. Moderate forms of COVID-19 could be effectively treated by antivirals, but severe forms of COVID-19, characterized by pulmonary immunopathology, require different approaches to treatment.