Animal efficacy study of a plant extract complex (BEN815) as a potential treatment for COVID-19.

In a short time, several types of injectable and oral therapeutics have been developed and used to effectively manage patients with coronavirus disease 2019 (COVID-19). BEN815 is an improved mixture of three extracts (Psidium guajava, Camellia sinensis, and Rosa hybrida) recognized by the Ministry of Food and Drug Safety of Korea as a health food ingredient that alleviates allergic rhinitis. The current animal efficacy study was performed to assess its probability of improving COVID-19 symptoms. BEN815 treatment significantly increased the survival of K18-hACE2 transgenic mice and reduced viral titers in the lungs at 5 days post infection (DPI). Furthermore, the lungs of the treated mice showed mild tissue damage at 5 DPI and nearly complete recovery from COVID-19 at 14 DPI. BEN815 appears to be an effective and minimally toxic anti-SARS-CoV-2 agent in mice and has potential for clinical applications.

Evaluation of the Antiviral Efficacy of Subcutaneous Nafamostat Formulated with Glycyrrhizic Acid against SARS-CoV-2 in a Murine Model.

The ongoing COVID-19 pandemic highlights the urgent need for effective antiviral agents and vaccines. Drug repositioning, which involves modifying existing drugs, offers a promising approach for expediting the development of novel therapeutics. In this study, we developed a new drug, MDB-MDB-601a-NM, by modifying the existing drug nafamostat (NM) with the incorporation of glycyrrhizic acid (GA). We assessed the pharmacokinetic profiles of MDB-601a-NM and nafamostat in Sprague-Dawley rats, revealing rapid clearance of nafamostat and sustained drug concentration of MDB-601a-NM after subcutaneous administration. Single-dose toxicity studies showed potential toxicity and persistent swelling at the injection site with high-dose administration of MDB-601a-NM. Furthermore, we evaluated the efficacy of MDB-601a-NM in protecting against SARS-CoV-2 infection using the K18 hACE-2 transgenic mouse model. Mice treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM exhibited improved protectivity in terms of weight loss and survival rates compared to the nafamostat-treated group. Histopathological analysis revealed dose-dependent improvements in histopathological changes and enhanced inhibitory efficacy in MDB-601a-NM-treated groups. Notably, no viral replication was detected in the brain tissue when mice were treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM. Our developed MDB-601a-NM, a modified Nafamostat with glycyrrhizic acid, shows improved protectivity against SARS-CoV-2 infection. Its sustained drug concentration after subcutaneous administration and dose-dependent improvements makes it a promising therapeutic option.

Baloxavir-oseltamivir combination therapy inhibits the emergence of resistant substitutions in influenza A virus PA gene in a mouse model.

Baloxavir marboxil (BXM) treatment-emergent polymerase acid (PA) I38X amino acid substitution (AAS) in the resistant variants of influenza viruses raise concerns regarding their emergence and spread. This study investigated the impact of 1 or 5 mg/kg BXM and 25 mg/kg oseltamivir phosphate (OS) (single or combination therapy) on the occurrence of resistance-related substitutions during the sequential lung-to-lung passages of AH1N1)pdm09 virus in mice. Deep sequencing analysis revealed that 67% (n = 4/6) of the population treated with BXM single therapy (1 or 5 mg/kg) possessed the treatment-emergent PA-I38X AAS variants (I38T, I38S, and I38V). Notably, BXM-OS combination therapy impeded PA-I38X AAS emergence. Although the doses utilized in the mouse model may not be directly translated into the clinically equivalent doses of each drugs, these findings offer insights toward alternative therapies to mitigate the emergence of influenza antiviral resistance.

Preclinical evaluation of the efficacy of an H5N8 vaccine candidate (IDCDC-RG43A) in mouse and ferret models for pandemic preparedness.

Because H5N1 influenza viruses continuously threaten the public health, the WHO has prepared various clades of H5N1 mock-up vaccines as one of the measures for pandemic preparedness. The recent worldwide outbreak of H5Nx virus which belongs to clade 2.3.4.4 and of which H5N6 subtype belongs and already caused human infection also increases the need of pandemic vaccine for such novel emerging viruses. In this study, we evaluated the protective efficacy and immunogenicity of an egg-based and inactivated whole-virus H5N8 (IDCDC-RG43A) developed by CDC containing HA and NA gene of the parent virus A/gyrfalcon/Washington/41088-6/2014. Mice vaccinated two times elicited low to moderate antibody titer in varying amount of antigen doses against the homologous H5N8 vaccine virus and heterologous intra-clade 2.3.4.4 H5N6 (A/Sichuan/26221/2014) virus. Mice immunized with at least 3.0 µg/dose of IDCDC-RG43A with aluminum hydroxide adjuvant were completely protected from lethal challenge with the mouse-adapted H5N8 (A/Environment/Korea/ma468/2015, maH5N8) as well as cleared the viral replication in tissues including lung, brain, spleen, and kidney. Vaccinated ferrets induced high antibody titers against clade 2.3.4.4 H5N8/H5N6 viruses and the antibody showed high cross-reactivity to clade 2.2 H5N1 but not to clade 1 and 2.3.4 viruses as measured by hemagglutinin inhibition and serum neutralization assays. Furthermore, administration of the vaccine in ferrets resulted in attenuation of clinical disease signs and virus spread to peripheral organs including lung, spleen, and kidney from high dose challenge with maH5N8 virus. The protective and immunogenic characteristic of the candidate vaccine are essential attributes to be considered for further clinical trials as a pre-pandemic vaccine for a potential pandemic virus.