February 1-7 2021
Targeting certain stable regions of the spike protein
SARS-CoV-2, responsible for the COVID-19 outbreak, is a virus belonging to the coronavirus family. This family includes 4 species of virus causing benign endemics in humans (HCoVs). It also includes 2 other species (MERS-CoV and Sars-CoV-1) that have recently emerged and which can cause serious illness.
The SARS-CoV-2 proteins are relatively different from the proteins of other coronaviruses, but there are certain regions in common. This is why there is potential for cross reaction in the immune system: a component of the immune system (T lymphocytes, B lymphocytes or antibodies for example) produced during infection by a benign coronavirus may be effective against SARS-CoV-2 if they recognise an epitope conserved between the two viruses. An epitope, or antigen, is a region of the virus recognised by the immune system, such as, for example, the S protein in contact with the ACE2 cellular receptor that enables the viral particle to enter the cell.
This epitope is therefore the main target for vaccines since it has a high potential for neutralization. However, this region is one of those that co-exist less frequently between coronaviruses. The nucleocapsid protein that protects the viral genome is, however, constantly found within coronaviruses. But this region has weak potential for neutralization by antibodies.
So it is useful to analyse the viral epitopes to discover those at the origin of cross reactions in the immune system which may have some potential for neutralization, even if these epitopes usually correspond to stable regions. The advantage of these epitopes is that they can continue to be targeted despite successive virus mutations.
Amercian and Norwegian researchers have, for this reason, developed an approach to detection of those epitopes found in the spike and nucleocapsid proteins of SARS-CoV-2. To do this, they analyzed serum from 55 patients infected by SARS-CoV-2, and therefore containing antibodies, and serum from 69 non-infected patients.
In some non-infected individuals, there was, however, a reaction against certain SARS-CoV-2 epitopes. Data collected shows that there are in fact 2 classes of epitopes: those conserved between the coronaviruses and causing cross reactions, and those specific to SARS-CoV-2 that produce antibodies specific to this virus.
So these results confirmed the presence of epitopes that are stable between one virus and another. For example, the FP (Fusion Peptide) epitope that enables fusion between the viral and cellular membranes so the virion can enter the cell, has a high level of conservation within the coronavirus family.
Amongst these epitopes, 2 regions situated in the spike protein (the FP and HR2 regions) are subject to cross-reaction from antibodies targeting other species of coronaviruses, suggesting the production of antibodies at the time of infection by an older endemic coronavirus. These 2 sites have in addition high potential for neutralization.
This can be represented schematically as follows:
In conclusion, the identification of epitopes in domains conserved between coronaviruses is at the origin of cross-reaction immune responses. Amongst these epitopes the FP and HR2 regions may be important to the development of anti- SARS-CoV-2 vaccines. Scientists speculate that vaccines integrating these two regions will be more effective because they will be capable of rapidly recruiting B-memory lymphocytes already stimulated by an older HCoV infection. These vaccines would be less subject to evasion by the virus since these regions have less risk of carrying mutations.