ABSTRACT
The emerging SARS-CoV-2 variants of concern (VOC) increasingly threaten the effectiveness of current first-generation COVID-19 vaccines that are administered intramuscularly and are designed to only target the spike protein. There is thus a pressing need to develop next-generation vaccine strategies to provide more broad and long-lasting protection. By using adenoviral vectors (Ad) of human and chimpanzee origin, we developed Ad-vectored trivalent COVID-19 vaccines expressing Spike-1, Nucleocapsid and RdRp antigens and evaluated them following single-dose intramuscular or intranasal immunization in murine models. We show that respiratory mucosal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the three-arm immunity, consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells, and mucosal trained innate immunity. We further show that single-dose intranasal immunization provides robust protection against not only the ancestral strain of SARS-CoV-2, but also two emerging VOC, B.1.1.7 and B.1.351. Our findings indicate that single-dose respiratory mucosal delivery of an Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy against current and future VOC. This strategy has great potential to be used not only to boost first-generation vaccine-induced immunity but also to expand the breadth of protective T cell immunity at the respiratory mucosa.
Subject(s)
COVID-19ABSTRACT
BACKGROUND: COVID-19 is a pandemic respiratory contagious viral (SARS-CoV-2) disease associated with high morbidity and mortality worldwide. Currently, there are no effective preventive or treatment strategies for COVID-19 and it has been declared as a global health emergency by WHO. In silico molecular docking studies can be useful to predict the binding affinity between the phytocompound and the target protein and play a vital role in finding an inhibitor through structure-based drug design. OBJECTIVE: In this aspect, our objective was to screen essential flavonoids against possible protein targets such as SARS-CoV-2 spike glycoprotein receptor binding domain (RBD-S) and host Angiotensin Converting Enzyme-2 protease domain (PD-ACE-2) using in silico molecular docking studies. METHODS: Approximately 49 flavonoids were identified and were evaluated for their drug-likeness based on Lipinski rule, bioactivity scores, antiviral and toxicity profiles using SwissADME, Molinspiration, PASS and GUSAR online tools. The flavonoids that passed Lipinski rule were subjected to in silico analysis through molecular docking on RBD-S and PD-ACE-2 using Molegro Virtual Docker v6.0. RESULTS: The bioactive flavonoids that showed NIL violations and were found in compliance with Lipinski rule were selected for docking studies. In silico analysis reported that biochanin A and silymarin bind significantly at the active sites of RBD-S and PD-ACE-2 with a MolDock score of -78.41and -121.28 kcal/mol respectively. Bioactivity scores, antiviral potential and toxicity profiles were predicted for the top interacting phytocompounds and substantial relevant data was reported. CONCLUSION: The current outcomes created a new paradigm for understanding biochanin A and silymarin bioflavonoids as potent inhibitors of RBD-S and PD-ACE-2 targets respectively. Further work can be extended to confirm their therapeutic potential for COVID-19.