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Topics in Antiviral Medicine ; 30(1 SUPPL):329, 2022.
Article in English | EMBASE | ID: covidwho-1879985


Background: Seroprevalence studies of antibodies to SARS-CoV-2 are important for public health surveillance. Recent studies have shown that antibodies to SARS-CoV-2, both from natural infection and vaccination, decrease with time from exposure. Variation in the performance of antibody assays will impact the estimates of SARS-CoV-2 exposure and vaccination levels in a population. Using standardized serial dilutions, we evaluated 17 SARS-CoV-2 assays to establish an approximate limit of detection for each assay. Methods: The evaluated assays consisted of three chemiluminescent immunoassays (CLIAs), eight standard enzyme-linked immunosorbent assays (ELISAs), and six lateral flow assays (LFAs). All assays either evaluated IgG antibodies or total antibodies to SARS-CoV-2. The target antigen of 14 assays was the spike protein (S) or receptor binding domain (RBD);three assays evaluated antibodies to the nucleocapsid protein (N). A human SARS-CoV-2 serology standard with a WHO SARS-CoV-2 Serology International Standard binding antibody units (BAU) value of 764 BAU/mL to spike IgG and 681 BAU/mL to nucleocapsid IgG was obtained from the Frederick National Laboratory for Cancer Research. Half-logarithmic serial dilutions of the standard were then run in triplicate on each assay. Results: The MSD V-Plex chemiluminescent immunoassays (CLIAs) were the most sensitive by three logs, with positive results at a dilution greater than 1:106 (Figure). Standard ELISAs were less sensitive, with limits of detection ranging from dilutions of 1:20 (Euroimmun NeutraLISA) to 1:1620 (Euroimmun SARS-CoV-2 IgG and Euroimmun QuantiVac). Lateral flow assays (LFAs) were the least sensitive, with only one assay (Wondfo Colloidal Gold) having at least one positive result with a dilution greater than 1:180. Conclusion: As population seroprevalence to SARS-CoV-2 continues to rise, tests with a high limit of detection will be crucial for surveillance studies. As antibody levels decline after vaccination or infection, our data indicate that CLIAs like the MSD assay may provide the best opportunity to capture asymptomatic cases and individuals with low antibody titers.

Preprint in English | MEDLINE | ID: ppcovidwho-326666


Several vaccines have been introduced to combat the coronavirus infectious disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current SARS-CoV-2 vaccines include mRNA-containing lipid nanoparticles or adenoviral vectors that encode the SARS-CoV-2 Spike (S) protein of SARS-CoV-2, inactivated virus, or protein subunits. Despite growing success in worldwide vaccination efforts, additional capabilities may be needed in the future to address issues such as stability and storage requirements, need for vaccine boosters, desirability of different routes of administration, and emergence of SARS-CoV-2 variants such as the Delta variant. Here, we present a novel, well-characterized SARS-CoV-2 vaccine candidate based on extracellular vesicles (EVs) of Salmonella typhimurium that are decorated with the mammalian cell culture-derived Spike receptor-binding domain (RBD). RBD-conjugated outer membrane vesicles (RBD-OMVs) were used to immunize the golden Syrian hamster ( Mesocricetus auratus ) model of COVID-19. Intranasal immunization resulted in high titers of blood anti-RBD IgG as well as detectable mucosal responses. Neutralizing antibody activity against wild-type and Delta variants was evident in all vaccinated subjects. Upon challenge with live virus, hamsters immunized with RBD-OMV, but not animals immunized with unconjugated OMVs or a vehicle control, avoided body mass loss, had lower virus titers in bronchoalveolar lavage fluid, and experienced less severe lung pathology. Our results emphasize the value and versatility of OMV-based vaccine approaches.

Topics in Antiviral Medicine ; 29(1):137-138, 2021.
Article in English | EMBASE | ID: covidwho-1249968


Background: SARS-CoV-2 enters host cells via an interaction between viral spike protein and cellular ACE2. However, in common with other enveloped viruses, apoptotic mimicry may also assist cell entry: phosphatidylserine (PS) exposed on the viral envelope interacts with cellular PS receptors leading to efferocytosis. The PS receptor, GAS6 bound to AXL, has also been shown to suppress type I interferon (IFN) responses. AXL is the predominant cellular PS receptor expressed on airway-derived cell lines. We hypothesized that the clinical-stage, AXL kinase-specific inhibitor, bemcentinib, inhibits SARS-CoV-2 infection and represents a potential therapy for COVID-19. Methods: Viral infection and host transcriptional responses to infection with SARS-CoV-2 or a VSV pseudovirion bearing SARS-CoV-2 spike were measured in human airway epithelial cell lines, engineered hACE2-expressing A549 lung cancer cells, and Vero E6 cells treated with bemcentinib or protease inhibitors. Studies also measured the effect of bemcentinib on SARS-CoV-2 binding and internalization into cells. The in vivo effect of bemcentinib (50mg/ kg, orally, twice daily) was assessed in C57BL6/J mice infected with the murine coronavirus, mouse hepatitis virus (MHV, 500 or 5x104 infectious units intraperitoneally). Viral titers and loads in liver were evaluated at day 5 postinfection. Spleen and liver were harvested to evaluate type 1 IFN-related gene expression changes. Results: Bemcentinib prevented infection by SARS-CoV-2 as assessed by viral transcripts in RNAseq studies as well as viral load in qRT-PCR analysis of human lung epithelial, A549-hACE2 and Vero E6 cells. Bemcentinib reduced virus internalization without affecting virus binding. Further, bemcentinib inhibition correlated well with inhibitors that block endosomal acidification and cathepsin activity, consistent with AXL-mediated SARS-CoV-2 uptake into endosomes. In vivo, bemcentinib significantly inhibited murine MHV liver titers and virus load and significantly enhanced signatures of type I IFN response. Conclusion: The orally bioavailable AXL inhibitor bemcentinib demonstrated potent antiviral effects in pre-clinical SARS-CoV-2 and other coronavirus models. These data support two ongoing phase 2 studies (EudraCT 2020-001736-95 [UK] & CTRI/2020/10/028602 [India] and DOH-27-092020-6170 [South Africa]) of bemcentinib for the treatment of COVID-19 in hospitalized patients, including those requiring supplemental oxygen and/or non-invasive ventilation, but not intubation.

Microbiology Australia ; : 5, 2021.
Article in English | Web of Science | ID: covidwho-1243345


The extensive and on-going epidemiology studies of the SARS-CoV-2 pandemic have raised interesting observations on statins reducing COVID-19 severity. In this review, literature is analysed to examine how statins affect COVID-19 and influenza A, another pandemic respiratory virus. This information could be useful to prevent or reduce disease severity caused by respiratory viruses.

Microbiology Australia ; 42(1):10-12, 2021.
Article in English | EMBASE | ID: covidwho-1223135


The pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is distinctly different from outbreaks caused by other coronaviruses: SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). The differences in the rapid transmission and severity of human coronaviruses are due to the genetic composition of the virus. SARS-CoV-2 contains genes encoding non-structural proteins (NSPs), structural proteins, and accessory proteins. The NSPs are mainly involved in replication of the virus within the host and inhibition of the host defence system. Structural proteins are involved in viral entry and attachment to host cells, preservation of the core virion and elicit the majority of the immune response. The functions of the accessory proteins are largely unknown. Most focus has been given to structural proteins, especially the spike protein as the strongest vaccine candidate. However, the recent emergence of spike variants and their ability to rapidly transmit and escape neutralisation by vaccine-induced antibodies has threatened the global community. Meanwhile, recent studies of accessory proteins reveal their importance in viral pathogenesis. Hence, proper understanding of the functions of all unknown viral proteins is crucial to devise alternate antiviral strategies.