Contemporaneous SARS-CoV-2-Neutralizing Antibodies Mediated by N-glycan Shields

Abstract

Mutations and the glycosylation of epitopes can convert immunogenic epitopes into non-immunogenic ones via natural selection or evolutionary pressure, thereby decreasing their sensitivity to neutralizing antibodies. Based on Thomas Francis's theory, memory B and T cells induced during primary infections or vaccination will freeze the new mutated epitopes specific to naïve B and T cells from the repertoire. On this basis, some researchers argue that the current vaccines derived from the previous strains of the SARS-CoV-2 virus do not increase immunity and may also prevent the immune response against new epitopes. However, evidence shows that even if the binding affinity is reduced, the previous antibodies or T cell receptors (TCRs) can still bind to this new epitope of the Beta, Gamma, and Delta variant if their concentration is high enough (from a booster injection) and neutralize the virus. This paper presents some convincing immunological reasons that may challenge this theory and argue for the continuation of universal vaccination to prevent further mutations of the SARS-CoV-2 virus. Simultaneously, the information presented can be used to develop vaccines that target novel epitopes or create new recombinant drugs that do not lose their effectiveness when the virus mutates.

Keywords: COVID-19; N-glycan; SARS-CoV-2; cross-reactive lymphocytes; original antigenic sin.

Figure 1

The various ways in which the immune system can still mount a response against mutated variants. (A) Despite the single mutation in the epitope of the second variant, the epitope-specific antibodies from the first variant can still bind and neutralize the new variant if the amount of antibodies is high enough from a booster injection. (B) The SARS-CoV-2 spike epitope may be converted into a non-immunogenic form after mutation, allowing the binding of the S protein to the ACE2 receptor. (C) The new epitope-specific B cell presents the prior epitope to the helper T cell with the aid of a co-stimulatory signal from the prior epitope-specific memory helper T cell. (D) Mutated variants may have increased affinity to bind to ACE2 due to conformational changes in the SPG through FcR-independent antibody-dependent enhancement (Fc-independent ADE).