Search

The devastating impact of COVID-19 on global health shows the need to increase our pandemic preparedness. Recombinant therapeutic antibodies were successfully used to treat and protect at-risk patients from COVID-19. However, the currently circulating Omicron subvariants of SARS-CoV-2 are largely resistant to therapeutic antibodies, and novel approaches to generate broadly neutralizing antibodies are urgently needed. Here, we describe a tetravalent bispecific antibody, A7A9 TVB, which actively neutralized many SARS-CoV-2 variants of concern, including early Omicron subvariants. Interestingly, A7A9 TVB neutralized more variants at lower concentration as compared to the combination of its parental monoclonal antibodies, A7K and A9L. A7A9 also reduced the viral load of authentic Omicron BA.1 virus in infected pseudostratified primary human nasal epithelial cells. Overall, A7A9 displayed the characteristics of a potent broadly neutralizing antibody, which may be suitable for prophylactic and therapeutic applications in the clinics, thus highlighting the usefulness of an effective antibody-designing approach. • Efficient modular antibody-designing and delivery with gene therapy tools. • Retrovirus-based pseudoparticles of 12 SAR-CoV-2 variants of concern tested. • Tetravalent bispecific neutralizing antibody overcomes viral evasion. • Tetravalent design outperforms the combination of monoclonal antibodies. • Early neutralizing antibody clones benefit with new design. [ABSTRACT FROM AUTHOR]

BA.2.86, a recently identified descendant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 sublineage, contains ∼35 mutations in the spike (S) protein and spreads in multiple countries. Here, we investigated whether the virus exhibits altered biological traits, focusing on S protein-driven viral entry. Employing pseudotyped particles, we show that BA.2.86, unlike other Omicron sublineages, enters Calu-3 lung cells with high efficiency and in a serine- but not cysteine-protease-dependent manner. Robust lung cell infection was confirmed with authentic BA.2.86, but the virus exhibited low specific infectivity. Further, BA.2.86 was highly resistant against all therapeutic antibodies tested, efficiently evading neutralization by antibodies induced by non-adapted vaccines. In contrast, BA.2.86 and the currently circulating EG.5.1 sublineage were appreciably neutralized by antibodies induced by the XBB.1.5-adapted vaccine. Collectively, BA.2.86 has regained a trait characteristic of early SARS-CoV-2 lineages, robust lung cell entry, and evades neutralizing antibodies. However, BA.2.86 exhibits low specific infectivity, which might limit transmissibility. [Display omitted] • BA.2.86 efficiently enters lung cells and uses TMPRSS2 for lung cell entry • Mutations S50L and K356T are responsible for efficient lung cell entry of BA.2.86 • BA.2.86 is highly resistant against therapeutic antibodies • BA.2.86 evades antibodies induced upon infection and vaccination BA.2.86 is a recently emerged, highly mutated SARS-CoV-2 variant that spreads in many countries and threatens human health. This study shows that BA.2.86, unlike closely related variants, can enter lung cells with high efficiency and in a TMPRSS2-dependent fashion and is resistant against therapeutic antibodies. [ABSTRACT FROM AUTHOR]