Subdominant SARS-CoV-2 epitopes key to understanding emerging variants

Researchers in the UK have conducted a study showing the importance of considering subdominant epitopes within severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) when investigating neutralizing antibodies that target the virus.

The SARS-CoV-2 virus is the agent responsible for the coronavirus disease 2019 (COVID-19) pandemic that continues to threaten global public health and the worldwide economy.

The team from King's College London, The Francis Crick Institute, and University College London has identified potent neutralizing antibodies targeting epitopes beyond those found in the receptor-binding domain (RBD) of the spike protein – the structure the virus uses to bind to and infect cells.

The RBD is the dominant target of neutralizing antibodies and several neutralizing epitopes in the RBD that are targeted by monoclonal antibodies have been identified and characterized.

Katie Doores and colleagues have now characterized neutralizing antibodies that target epitopes in the spike protein's N-terminal domain.

Importantly, the team found that mutations present in the recently emerged B.1.1.7 viral variant confer resistance to neutralization by these NTD-specific antibodies.

"This work demonstrates that neutralizing antibodies targeting subdominant epitopes need to be considered when investigating antigenic drift in emerging variants," writes the team.

A pre-print version of the research paper is available on the bioRxiv* server, while the article undergoes peer review.

The importance of the RBD during the infection process

The first step in the SARS-CoV-2 infection process involves the binding of the spike glycoprotein to the host cell receptor angiotensin-converting enzyme 2 (ACE2).

The spike protein comprises two functional subunits. Subunit 1 (S1) contains the NTD and the RBD, which attaches to ACE2 using the receptor-binding motif (RBM). Subunit 2 (S2) contains the fusion peptide and is responsible for the fusion of the viral membrane to the host cell.

Antibodies targeting the RBD are thought to account for more than 90% of the neutralizing activity against SARS-CoV-2 in convalescent sera. Several RBD epitopes that are targeted by neutralizing monoclonal antibodies have been identified.  

Studies have recently indicated that mutations enabling escape from RBD-specific neutralization are arising in recently emerged variants SARS-CoV-2 such as B.1.1.7.

"This highlights the need to identify neutralizing antibodies that bind epitopes outside RBD and to understand the role these antibodies play in protection from re-infection or following vaccination," says Doores and the team.

What did the researchers do?

To understand how such mutations might affect the spike protein's antigenicity, Doores and colleagues isolated and characterized neutralizing antibodies that target epitopes lying beyond those already identified in RBD epitopes.

The team used a recombinant spike protein to isolate 107 neutralizing antibodies from three convalescent donors and identified neutralizing epitopes present on various regions of the spike.

Forty-seven (43.9%) of these antibodies exhibited neutralizing activity, the majority of which (34; 72.3%) targeted the RBD.

The antibodies targeted epitopes similar to those previously reported, including epitopes involved in ACE2 binding of the RBM. However, they also targeted epitopes found beyond the RBD - in the NTD and S2.

None of the antibodies targeting S2 showed neutralizing activity, but they were able to cross-react with spike protein expressed on the cell surface.

The team says it will be important to investigate whether these antibodies can facilitate effector functions and play a role in viral clearance.

More about antibodies targeting the NTD

Ten (21.3%) of the 47 neutralizing antibodies targeted the NTD. These antibodies fell into two distinct groups. One group contained antibodies that neutralized SARS-CoV-2 at a similar potency to RBD-specific antibodies. The other group exhibited less potent glycan-dependent neutralization.

Importantly, the team found that while the dominant neutralizing response targeted the RBD, the B.1.1.7 variant contained mutations that conferred resistance to NTD-specific neutralization.

"As RBD is the predominant target for neutralizing antibodies following infection, this would suggest RBD-specific nAbs [neutralizing antibodies] had a limited contribution to any immune escape contributing to the selection of the B.1.1.7 variant," writes Doores and colleagues.

The team says this demonstrates the importance of considering neutralizing antibodies targeting subdominant epitopes beyond the RBD when identifying newly emerging SARS-CoV-2 variants of concern.

"We show that the B.1.1.7 variant is resistant to neutralization by the NTD nAbs, demonstrating the importance of considering both dominant and sub-dominant neutralizing epitopes on Spike when studying viral evolution and antigenic drift," concludes the team.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Sally Robertson

Written by

Sally Robertson

Sally first developed an interest in medical communications when she took on the role of Journal Development Editor for BioMed Central (BMC), after having graduated with a degree in biomedical science from Greenwich University.

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