A new study by French researchers from Aix-Marseille Université has alarmingly found that ADE or antibody dependent enhancement is indeed occurring in infections with the SARS-CoV-2 Delta variant.
The study findings were peer reviewed and published in the Journal of Infections. https://www.journalofinfection.com/article/S0163-4453(21)00392-3/fulltext
ADE or antibody dependent enhancement (ADE) of infection is a safety concern for vaccine strategies.
A misleading earlier study 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. https://www.sciencedirect.com/science/article/pii/S009286742100756X
This study however was performed with the original Wuhan/D614G strain.
Importantly since the COVID-19 pandemic is now dominated with Delta variants, the study team analyzed the interaction of facilitating antibodies with the NTD of these variants.
Utilizing molecular modeling approaches, the team showed that enhancing antibodies have a higher affinity for Delta variants than for Wuhan/D614G NTDs.
The study team demonstrated 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 de-masking of the receptor binding domain. As the NTD is also targeted by neutralizing antibodies, the study data suggest that the balance between neutralizing and facilitating antibodies in vaccinated individuals is in favor of neutralization for the original Wuhan/D614G strain.
Alarmingly, 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.
Hence antibody dependent enhancement or 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.
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