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Powerful neutralizing antibodies may target the N-terminal of the spike protein

The absence of pre-existing immunity against SARS-CoV-2 coupled with its high interhuman transmissibility led to the COVID-19 pandemic that we are currently experiencing. Several vaccines are now available, but it will still be some time before we have adequate vaccine coverage due to the time scales of production and distribution. In addition, the protection the vaccines will give when confronted with new variants is still unknown. It is therefore very important to develop effective prophylactic and therapeutic solutions so as to be able to keep the severe forms of COVID-19 in check.

We can count therapeutic antibodies amongst these possible solutions. The majority of the antibodies developed by infected patients are directed against the RBD (Receptor Binding Domain) of the spike (S) surface protein. The RBD is the region of the virus in contact with the ACE2 cellular receptor, enabling the viral particle to enter the cell. Another region of the S protein is the NTD (N-Terminal Domain). The antibodies directed against this domain have not been so extensively studied but they seem to play a role in neutralizing the virus, as has been observed in vitro. American and Swiss researchers have recently identified a specific site (a “supersite”) recognized by powerful neutralizing antibodies in the NTD.

These researchers first selected antibodies directed against SARS-CoV-2 in order to identify those targeting the NTD region. To do so, they isolated the antibodies produced by 3 patients having been infected by SARS-CoV-2. They then identified 278 antibodies directed against the virus (1.1 to 1.3% of the total antibodies). Amongst those, 65 to 77% recognized the RBD and, as expected, only a small fraction (41 antibodies, 6 to 20%) recognized the NTD.

This can be schematically represented as:

The scientists then tested the neutralizing capacity of these antibodies against pseudoviruses (non-replicating model viruses carrying the SARS-CoV-2 S protein). They were able to show that 9 of these antibodies are highly neutralizing, while 6 are moderately so, and 25 not at all.

How can these differences be explained? By studying the structure of the S protein, they were able to draw up a map of the epitopes, that is, the sites in the NTD recognized by the antibodies. They identified 6 epitopes, and one in particular, that they labelled supersites, recognized by all the neutralizing antibodies targeting this region. In other words, this supersite is a kind of Achilles heel of the virus. These antibodies appear to have neutralizing capacities thanks to their ability to activate immune effectors (see the February 22-28 2021 letter).

The researchers then investigated whether these antibodies were also effective against new variants of the virus, since these variants include changes in the NTD. After neutralization tests, they were able to show that the UK, South African and Brazilian variants escape neutralization by these antibodies either wholly or partially.

Finally, the researchers tested protection levels against SARS-CoV-2 infection on hamsters. They injected these antibodies 48 hours before intranasal infection of the hamsters, and found that the animals were protected. However, in some cases this immune pressure resulted in the selection of escape mutants.

This can be schematically represented as:

It is clear then that the supersite gives useful information regarding the functioning of certain neutralizing antibodies. These could be an interesting treatment option since their action complements that of antibodies targeting the RBD.

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