Therapeutic and vaccine-induced cross-reactive antibodies with effector function against emerging Omicron variants

Abstract

Currently circulating SARS-CoV-2 variants acquired convergent mutations at receptor-binding domain (RBD) hot spots. Their impact on viral infection, transmission, and efficacy of vaccines and therapeutics remains poorly understood. Here, we demonstrate that recently emerged BQ.1.1. and XBB.1 variants bind ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1 and XBB.1 RBDs bound to human ACE2 and S309 Fab (sotrovimab parent) explain the altered ACE2 recognition and preserved antibody binding through conformational selection. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1, the variant displaying the greatest loss of neutralization. Moreover, in several donors vaccine-elicited plasma antibodies cross-react with and trigger effector functions against Omicron variants despite reduced neutralizing activity. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring persistent immune imprinting. Our findings suggest that this previously overlooked class of cross-reactive antibodies, exemplified by S309, may contribute to protection against disease caused by emerging variants through elicitation of effector functions.

Sotrovimab retains activity against SARS-CoV-2 Omicron variant BQ.1.1 in a non-human primate model

“…2 mg/kg) in mice or with Sotrovimab (7 or 14 mg/kg) in hamsters provided protection from a BQ.1.1 challenge (1,2). However, further data are needed to confirm Sotrovimab in vivo activity and determine whether it should remain, in addition to Nirmatrelvir-Ritonavir in the list of available treatments for patients at risk (3).…”

Safety, Virology, Pharmacokinetics, and Clinical Experience of High-dose Intravenous Sotrovimab for the Treatment of Mild to Moderate COVID-19: An Open-label Clinical Trial

“…Sotrovimab has demonstrated neutralization activity in vitro against the recent Omicron XBB.1.5, BQ.1, and BQ.1.1 variants with a range in potency that is similar or reduced relative to BA.2 [21]. This clinical experience with sotrovimab 2000 mg and the virology data reported, All rights reserved.…”

Rapid screening methods for universal binding peptide aptamers against SARS-CoV-2 variant spikes, including omicron variants, and their application to diagnostic and therapeutic agents.

“…While BA.5 has been the dominant strain since the end of 2022, variants such as BQ.1.1, strain derived from BA.5 and XBB strain derived from BA.2 have been emerging (119)(120)(121)(122)(123)(124)(125).…”

“…In particular, XBB.1.5 has immune escape ability against neutralizing antibodies produced by omicrontype bivalent vaccines [(conventional strain (strain of origin)/Omicron strain BA.1) or (conventional strain (strain of origin)/Omicron strain BA.4-5)]. There are currently no antibody drugs that exhibit effective neutralizing antibody activity against XBB.1.5 (99,121,(125)(126)(127)(128)(129)(130)(131)(132)(133)(134)(135)(136)(137)(138)(139)(140)(141)(142)(143)(144). This is because mutations in the Spike molecule change the conformation of the Spike, and the neutralizing activity of the antibody is easily lost.…”