The ongoing COVID-19 pandemic, caused by SARS-CoV-2, necessitates the development of effective antiviral treatments. While several monoclonal antibodies (mAbs) have been approved for clinical use, the emergence of variants like Delta and Omicron poses a significant challenge due to their ability to evade neutralization. These variants, particularly Omicron, harbor numerous mutations in the spike protein, reducing the efficacy of many existing mAbs. This necessitates the identification of broad-spectrum antivirals with activity against these variants and potential future mutants. The research focuses on a previously identified human antibody, 586G, to assess its potential as a potent and broadly neutralizing therapeutic.

The introduction notes that a panel of mAbs has been authorized for clinical use, but the rapid mutation of the SARS-CoV-2 spike protein has led to variants that escape these treatments. The Omicron variant, with over 30 mutations in the spike protein, particularly affects the efficacy of many identified mAbs. This highlights the pressing need for new broad-spectrum antivirals.

The study used various methods to characterize the antibody 586G. ELISA was used to assess the binding affinity of 586G to receptor-binding domains (RBDs) from various SARS-CoV-2 variants (WT, Delta, Omicron BA.1, and BA.2). A luciferase-based neutralization assay and a live viral plaque reduction assay were used to evaluate the neutralizing activity of 586G against pseudo-typed and authentic SARS-CoV-2 viruses. Biolayer interferometry (BLI) was employed to measure the affinity of 586G for spike proteins from different SARS-CoV-2 variants. In vivo studies in Syrian golden hamsters were conducted to evaluate the prophylactic and therapeutic efficacy of intranasally delivered 586G against both Delta and Omicron variants. Viral RNA levels in nasal washes, tissues, and plasma were measured by RT-PCR. A plaque assay determined virus titers. Histological analysis of lung tissues assessed lung injury. Statistical analyses used unpaired t-tests and GraphPad Prism 9.

586G exhibited potent and broad neutralizing activity against SARS-CoV-2 WT, Delta, and Omicron variants in both pseudovirus and live virus assays. The IC50 values were significantly lower than those of approved nAbs against Omicron. In vivo studies in hamsters showed that intranasal delivery of 586G provided protection against both Delta and Omicron variants. A low dose (2 mg/kg daily) effectively prevented viral replication in the lungs. Prophylactic administration of 586G significantly reduced viral RNA levels in nasal washes, tissues, and reduced lung pathology. The antibody demonstrated efficacy in both prophylactic and therapeutic settings.

The findings demonstrate that 586G is a highly potent neutralizing antibody with broad activity against circulating SARS-CoV-2 variants, including Omicron, which significantly reduces efficacy of other approved mAbs. The successful nasal delivery and the low effective dose are advantages that could translate to cost-effective and user-friendly treatment. The study's in vivo results in hamsters strongly support the potential of 586G as a prophylactic and therapeutic agent against current and future SARS-CoV-2 variants. Further research could explore the development of nebulized 586G therapy to enhance clinical outcomes.

The study identified 586G as a potent neutralizing antibody effective against SARS-CoV-2 Delta and Omicron variants, even at a low dose via nasal administration. Its broad spectrum and ease of administration make it a promising candidate for future COVID-19 therapeutics. Future research should focus on clinical trials and optimization of delivery methods like nebulization.

The study was conducted in a hamster model. While hamsters are a widely accepted model for SARS-CoV-2 research, the results may not perfectly translate to human responses. Further research is needed to fully assess the safety and efficacy of 586G in human clinical trials.