Why is COVID virus now so infectious? Evidence that VAX antibodies can/may bind to N-terminal domain on spike & induces open conformation of RBD & enhances the binding capacity of the spike to ACE2

by Paul Alexander

and thus infectivity of SARS-CoV-2; additional mutational analysis revealed that all of the infectivity-enhancing antibodies recognized a specific site on the NTD; Liu & Arase et al. CELL publication

A reader pointed out a key question and I have edited the title for we are strongly inferring that the vaccinal antibodies operate similarly (the antigenic-specific non-neutralizing vaccinal antibodies)…see also Yahi et al. that helps with this picture: Infection-enhancing anti-SARS-CoV-2 antibodies recognize both the original Wuhan/D614G strain and Delta variants. A potential risk for mass vaccination?

A key passage:

‘Using molecular modeling 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).’

Key finding of Liu et al.’s study:

“In this study, we found a non-canonical, Fc-receptor-independent ADE mechanism. The antibodies against a specific site on the NTD of the SARS-CoV-2 spike protein were found to directly augment the binding of ACE2 to the spike protein, consequently increasing SARS-CoV-2 infectivity.”


An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies

Antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein prevent SARS-CoV-2 infection. However, the effects of antibodies against other spike protein domains are largely unknown. Here, we screened a series of anti-spike monoclonal antibodies from coronavirus disease 2019 (COVID-19) patients and found that some of antibodies against the N-terminal domain (NTD) induced the open conformation of RBD and thus enhanced the binding capacity of the spike protein to ACE2 and infectivity of SARS-CoV-2. Mutational analysis revealed that all of the infectivity-enhancing antibodies recognized a specific site on the NTD. Structural analysis demonstrated that all infectivity-enhancing antibodies bound to NTD in a similar manner. The antibodies against this infectivity-enhancing site were detected at high levels in severe patients. Moreover, we identified antibodies against the infectivity-enhancing site in uninfected donors, albeit at a lower frequency. These findings demonstrate that not only neutralizing antibodies but also enhancing antibodies are produced during SARS-CoV-2 infection.