The continuous emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants means there is a need to explore additional strategies to develop broad-spectrum vaccines or therapeutics for individuals remaining at risk of coronavirus disease 2019 (COVID-19). Neutralizing monoclonal antibody (mAb) that binds to the conserved S2 subunit of the SARS-CoV-2 spike (S) protein alone, or in combination with mAb that binds to the receptor-binding domain (RBD) of S protein, might be effective in eliciting protection from infection by a variety of SARS-CoV-2 variants. Using high-throughput single-cell immunoglobulin sequencing of B cells from COVID-19-convalescent donors, we identified a high-affinity S2-specific mAb-39, that could inhibit original SARS-CoV-2 strain, Omicron BA.1, BA.2.86, BA.4, BA.5, and EG.5.1 S protein-mediated membrane fusion, leading to the neutralization of these pseudoviral infections. Moreover, mAb-39 could also improve the neutralizing activity of anti-RBD antibody against the highly neutralization-resistant Omicron variants. Molecular docking and point mutation analyses revealed that mAb-39 recognized epitopes within the conserved upstream region of the heptad repeat 2 (HR2) motif of the S2 subunit. Collectively, these findings demonstrate that targeting the conserved upstream region of the HR2 motif (e.g., using mAbs) provides a novel strategy for preventing the infection of SARS-CoV-2 and its variants.

Hepatitis B is caused by hepatitis B virus (HBV), and persistent HBV infection is a global public health problem, with 257 million people as HBV chronic carriers. Viral covalently closed circular DNA (cccDNA) is a key factor to establish persistent infection in infected hepatocytes. Current antiviral therapies have no direct impact on pre-existing cccDNA reservoir, which can be assembled into minichromosome by hijacking host factors. Understanding the mechanisms of epigenetic regulation in cccDNA minichromosome is crucial to develop new therapy on cccDNA, an attractive target for HBV cure. This review summarizes the current advances in epigenetic regulation of cccDNA minichromosome, which might provide clues to novel druggable targets to cure hepatitis B by either silencing or eliminating cccDNA reservoir.