ABSTRACT
Background/Aims: The global pandemic of COVID-19 has caused tremendous loss of human life since 2019. Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the best policies to control the pandemic. The vaccination efficacy in Taiwanese patients with different comorbidities is elusive and to be explored. Method(s): Uninfected subjects who received 3-doses of mRNA vaccines (Moderna, BioNTech), non-replicating viral vector-based vaccines (AstraZeneca, AZ) or protein subunit vaccines (Medigen COVID-19 vaccine, MVC) were prospectively enrolled. SARSCoV2- IgG spike antibody level was determined (Abbott [SARS-CoV- 2 IgG II]) within 3 months after the last dose of vaccination. Charlson Comorbidity Index (CCI) was applied to disclose the association of vaccine titer and underlying comorbidities. Result(s): A total of 824 subjects were enrolled in the current study. The mean age was 58.9 years and males accounted for 48.7% of the population. The proportion of CCI with 0-1, 2-3 and>4 was 52.8% (n = 435), 31.3% (n = 258) and 15.9% (n = 131), respectively. The most commonly used vaccination combination was AZ-AZ-Moderna (39.2%), followed by Moderna-Moderna-Moderna (27.8%) and AZAZ- BioNTech (14.7%), respectively. The mean vaccination titer was 3.11 log BAU/mL after a median 48 days of the 3rd dose. Subjects of male gender, lower body mass index, chronic kidney disease, higher CCI, and receiving AZ-AZ based vaccination were likely to have a lower titer of antibody. There was a decreasing trend of antibody titer with the increase of CCT (trend P<0.001). Linear regression analysis revealed that AZ-AZ-based vaccination (beta: 0.341, 95% confidence intervals [CI]: 0.144, 0.21, P<0.001) and higher CCI (beta: - 0.055, CI: - 0.096, - 0.014, P = 0.009) independently correlated with low IgG spike antibody levels. Conclusion(s): Patients with more comorbidities had a poor response to 3 doses of COVID-19 vaccination. Further studies are warranted to clarify the efficacy of booster vaccination in the population. The vaccine titer did not differ between patient with or without chronic liver disease.
ABSTRACT
Transmembrane serine protease (TMPRSS2) plays an oncogenic role in prostate cancer as the fusion gene with ERG, and has also been demonstrated to be essential for the cellular entry of severe acute respiratory syndrome coronaviruses (SARS-CoV). Thus, targeting TMPRSS2 is a promising strategy for therapies against both prostate cancer and coronavirus infection. Although Nafamostat and Camostat have been identified as TMPRSS2 inhibitors, severe side effects such as cerebral hemorrhage, anaphylactoid reaction, and cardiac arrest shock greatly hamper their clinical use. Therefore, more potent and safer drugs against this serine protease should be further developed. In this study, we developed a fluorescence resonance energy transfer (FRET)-based platform for effectively screening of inhibitors against TMPRSS2 protease activity. The disruption of FRET between green and red fluorescent proteins conjugated with the substrate peptide, which corresponds to the cleavage site of SARS-CoV-2 Spike protein, was measured to determine the enzymatic activity of TMPRSS2. Through an initiate pilot screening with around 100 compounds, Flupirtine, a selective neuronal potassium channel opener, was identified as a potential TMPRSS2 inhibitor from an FDA-approved drug library by using this screening platform, and showed inhibitory effect on the TMPRSS-dependent infection of SARS-CoV-2 Spike-pseudotyped lentiviral particles. This study describes a platform proven effective for rapidly screening of TMPRSS2 inhibitors, and suggests that Flupirtine may be worthy of further consideration of repurposing to treat COVID-19 patients.