Infection-enhancing anti-SARS-CoV-2 antibodies recognize both the original Wuhan/D614G strain and Delta variants. A potential risk for mass vaccination ?
Nouara Yahi
Henri Chahinian
Jacques Fantini
Published:August 09, 2021
https://www.journalofinfection.com/article/S0163-4453(21)00392-3/fulltext
Abstract
Antibody dependent enhancement (ADE) of infection is a safety concern for vaccine strategies. In a recent publication, Li et al. (Cell 184 :1-17, 2021) have reported that infection-enhancing antibodies directed against the N-terminal domain (NTD) of the SARS-CoV-2 spike protein facilitate virus infection in vitro, but not in vivo. However, this study was performed with the original Wuhan/D614G strain. Since the Covid-19 pandemic is now dominated with Delta variants, we analyzed the interaction of facilitating antibodies with the NTD of these variants. Using molecular modelling approaches, we show that enhancing antibodies have a higher affinity for Delta variants than for Wuhan/D614G NTDs. We show that enhancing antibodies reinforce the binding of the spike trimer to the host cell membrane by clamping the NTD to lipid raft microdomains. This stabilizing mechanism may facilitate the conformational change that induces the demasking of the receptor binding domain. As the NTD is also targeted by neutralizing antibodies, our data suggest that the balance between neutralizing and facilitating antibodies in vaccinated individuals is in favor of neutralization for the original Wuhan/D614G strain. However, in the case of the Delta variant, neutralizing antibodies have a decreased affinity for the spike protein, whereas facilitating antibodies display a strikingly increased affinity. Thus, ADE may be a concern for people receiving vaccines based on the original Wuhan strain spike sequence (either mRNA or viral vectors). Under these circumstances, second generation vaccines with spike protein formulations lacking structurally-conserved ADE-related epitopes should be considered.
The aim of the present study was to evaluate the recognition of SARS-CoV-2 Delta variants by infection enhancing antibodies directed against the NTD. The antibody studied is 1054 (pdb file #7LAB) which has been isolated from a symptomatic Covid-19 patient1. Molecular modelling simulations were performed as previously described2. Two currently circulating Delta variants were investigated, with the following mutational patterns in the NTD :
Each mutational pattern was introduced in the original Wuhan/D614G strain, submitted to energy minimization, and then tested for antibody binding. The energy of interaction (ΔG) of the reference pdb file #7LAB (Wuhan/D614G strain) in the NTD region was estimated to -229 kJ/mol−1. In the case of Delta variants, the energy of interaction was raised to -272 kJ.mol−1 (B.1.617.1) and -246 kJ.mol−1 (B.1.617.2). Thus, these infection enhancing antibodies not only still recognize Delta variants but even display a higher affinity for those variants than for the original SARS-CoV-2 strain.
The global structure of the trimeric spike of the B.1.617.1 variant in the cell-facing view is shown in Figure 1A. As expected, the facilitating antibody bound to the NTD (in green) is located behind the contact surface so that it does not interfere with virus-cell attachment. Indeed, a preformed antibody-NTD complex could perfectly bind to the host cell membrane. The interaction between the NTD and a lipid raft is shown in Figure 1B, and a whole raft-spike-antibody complex in Figure 1C. Interestingly, a small part of the antibody was found to interact with the lipid raft, as further illustrated in Figures 1D-E. More precisely, two distinct loops of the heavy chain of the antibody encompassing amino acid residues 28-31 and 72-74, stabilize the complex through a direct interaction with the edge of lipid raft (Figure 1F). Overall, the energy of interaction of the NTD-raft complex was raised from -399 kJ.mol−1 in absence of the antibody to -457 kJ.mol−1 with the antibody. By clamping the NTD and the lipid raft, the antibody reinforces the attachment of the spike protein to the cell surface and thus facilitates the conformational change of the RBD which is the next step of the virus infection process2.
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