The use of gene-based Covid-19 vaccines containing the S protein gene has proven to be very effective in protection against infection by SARS-CoV-2. However, increasing numbers of variants with higher transmissibility and/or virulence have been reported. These variants raise concerns that immunization with gene-based vaccines containing only the S protein gene may allow for emergence of more virulent mutated variants by a Darwinian-like “natural-selection” process. Such variants may evade protective anti-S protein antibodies in immunized individuals. A concrete example for a virus acquiring mutations that facilitate immune evasion in humans (called “escape-mutations”) is that of HIV within infected patients. These mutations increase the number of N (asparagine)-linked carbohydrate chains (N-glycans) forming the “glycan-shield” on gp120 of HIV. Gp120 is the envelope glycoprotein that mediates HIV infection of host-cells, analogous to the role of S protein in SARS-CoV-2. The glycan-shield on gp120 masks many antigenic epitopes on this glycoprotein and the additional glycans on mutated HIV variants prevent binding of neutralizing-antibodies. The S protein of SARS-CoV-2 has a glycan-shield of 22 N-glycans, covering ~65% of its surface and thus masking various antigenic peptides from detection by host immune systems. N-glycans are synthesized on asparagine (Asn) within the Asn-X-Ser/Thr (N-X-S/T) sequon, where X is any amino acid other than proline. Thus, any substitution mutation that introduces Asn or Ser/Thr to form this sequon will result in synthesis of additional N-glycans that can further mask regions of the S protein recognized by neutralizing antibodies.
