SARS-CoV-2 structural features may explain limited neutralizing-antibody responses

Abstract

Neutralizing antibody responses of SARS-CoV-2-infected patients may be low and of short duration. We propose here that coronaviruses employ a structural strategy to avoid strong and enduring antibody responses. Other viruses induce optimal and long-lived neutralizing antibody responses, thanks to 20 or more repetitive, rigid antigenic epitopes, spaced by 5–10 nm, present on the viral surface. Such arrays of repetitive and highly organized structures are recognized by the immune system as pathogen-associated structural patterns (PASPs), which are characteristic for pathogen surfaces. In contrast, coronaviruses are large particles with long spikes (S protein) embedded in a fluid membrane. Therefore, the neutralizing epitopes (which are on the S protein) are loosely “floating” and widely spaced by an average of about 25 nm. Consequently, recruitment of complement is poor and stimulation of B cells remains suboptimal, offering an explanation for the inefficient and short-lived neutralizing antibody responses.

Fig. 1. Structure of SARS-CoV-2.

Coronaviruses have their names from the typical spikes which are made of the spike (S) protein that is inserted in the lipid bilayer membrane of the virus. The receptor-binding domain (RBD) and its receptor-binding motif (RBM) enable interaction with the cell surface receptor ACE2 mediating entry of the virus into host cells. This can be blocked by neutralizing antibodies. Therefore, most neutralizing epitopes are located on RBD/RBM. Besides the S protein, SARS-CoV-2 has two further viral surface proteins (not shown): envelope (E) and matrix (M).

Fig. 2. Distances between neutralizing epitopes.

A An example of a classical RNA virus with a capsule made of multiple copies of only one protein that are rigidly structured, displaying highly immunogenic repetitive neutralizing epitopes spaced by 5–10 nm. This virus is built with 180 monomers and has a total viral diameter of 30 nm. B, C A coronavirus with its S proteins, showing the distance of the neutralizing epitopes of about 25 nm, which is large and unfavorable for triggering antibody responses. D, E A virus-like particle (VLP) built by a viral protein into which the RBM of SARS-CoV-2 is genetically inserted. This VLP displays the neutralizing epitopes with an optimized spacing of 5 nm.