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HIV-1 potent human broadly SARS-CoV-2 neutralizing IgA and IgG antibodies effective against omicron BA.1 and BA.2
Memory B-cell and antibody responses to the SARS-CoV-2 spike protein contribute to long-term immune protection against severe COVID-19, which can also be prevented by antibody-based interventions. We performed a wide SARS-CoV-2 immunoprofiling in Wuhan COVID-19 convalescents combining serological, cellular and monoclonal antibody explorations, which revealed humoral immunity coordination. We further report on the detailed molecular and functional characterization of 102 human SARS-CoV-2 spike mAbs cloned from IgG and IgA memory B cells of ten convalescent COVID-19 individuals. These antibodies are encoded by a diverse set of immunoglobulin genes, can be shared between individuals, recognize various conformational spike protein epitopes, and predominantly bind the S2 subunit. No anti-S2 mAbs were neutralizing but many harbored Fc-dependent effector functions (Fig.1A). A third of the RBD-targeting antibodies potently neutralized SARS-CoV-2 in vitro. The most potent, Cv2.1169 IgA and Cv2.3194 IgG, were fully active against α, β, γ, and δ variants, and still strongly blocked Omicron BA.1 and BA.2 infection in vitro. J-chain dimerization of Cv2.1169 IgA greatly improved its neutralization potency against BA.1 and BA.2 viruses. Structural analyses by cryo-EM and X-ray crystallography revealed the mode of binding of Cv2.1169 and its contacts with the RBD at atomic level (Fig.1B). Cv2.1169 produced as IgGs showed therapeutic efficacy in mouse and hamster SARS-CoV-2 infection models (Fig.1C). Collectively, this study allowed gaining insights into fundamental aspects of the SARS-CoV-2-specific humoral response, and identified potent and broad neutralizers with prophylactic and therapeutic potential. | Planchais et al, J Exp Med 2022 |.
Figure 1. Human memory B-cell antibodies to SARS-CoV-2 spike protein. (A) Principal component analysis 2D-plot showing the antiviral-related variables discriminating anti-S mAbs (n=101) color-coded by specificities. (B) Crystal structure of the complex formed by the Receptor Binding Domain (RBD) and Cv2.1169 (PDB ID: 7QEV). (C) Schematic diagram showing the in vivo experiments of Cv2.1169 antibody therapy in SARS-CoV-2-infected K18-hACE2 mice (top). Graphs showing the evolution of initial body weight (% Δ weight, bottom left) and survival rate (bottom right) in animal groups.
Broad sarbecovirus neutralization by combined memory B-cell antibodies to ancestral SARS-CoV-2
Antibodies play a pivotal role in protecting from SARS-CoV-2 infection, but their efficacy is challenged by the continuous emergence of viral variants. We previously cloned two class 1 anti-RBD antibodies from memory B cells elicited in response to infection with ancestral SARS-CoV-2 and harboring potent neutralizing activities up to BA.226. In this follow up study (Fig.4), we examined the antiviral activities of those SARS-CoV-2 neutralizers, Cv2.1169 and Cv2.3194, against post-BA.2 VOCs. We found that epistatic F486 mutations fixed in Omicron variants from BA.4/BA.5 completely shut down Cv2.1169 neutralization capacity. In contrast, Cv2.3194 still neutralized in vitro all VOCs up to BA.2.86 and showed prophylactic activity against SARS-CoV-2 and BA.5 infection in mice. Strikingly, Cv2.3194-derived donor also developed a broadly neutralizing antibody targeting the heptad repeat 2 (HR2) S2 region, Cv2.3132, which when associated with Cv2.3134 in an antibody cocktail led to a cooperative neutralizing effect. Thus, remarkably robust neutralizing memory B-cell antibodies elicited in response to ancestral SARS-CoV-2 infection can withstand viral evolution and immune escape. The cooperative effect of such antibody combination may confer a certain level of protection against the latest SARS-CoV-2 variants. | Planchais et al, iScience 2024 |.
