SARS-CoV-2 variants are evolving new ways to evade antibodies and vaccines

By Nidhi Saha, BDSReviewed by Danielle Ellis, B.Sc.Dec 8 2021

Continued replication of severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2) under selective pressure from natural and vaccine-induced immunity has led to the emergence of variants of concern (VOCs) with increased transmissibility or virulence.

These variants acquire mutations in the spike protein receptor-binding domain (RBD) that binds the cellular receptor angiotensin-converting enzyme 2 (ACE2). The RBD and spike protein N-terminal domain (NTD) are targets of neutralizing antibodies.

VOCs elicit one to three RBD mutations, which may overlap. For instance, the B.1.617.2 (Delta) variant can acquire the K417NRBD mutation found in the B.1.351 (Beta) variant, generating the Delta AY.2 variant. However, variant monitoring efforts are still under-sampling viral evolution, and an undocumented combination of RBD mutations may have the potential for antibody escape.

The Study

A recent study published in the journal Science investigated the structural pliability of the SARS-CoV-2 spike protein RBD and its capacity to evade neutralizing antibodies.

In this study, monoclonal antibodies were isolated from the blood of a COVID-19 convalescent individual. Venous blood samples were derived from healthy mRNA-1273 and BNT162b2 vaccine recipients. 

Findings

The results showed that many RBD mutations occur in a persistently infected immunocompromised host. Furthermore, structural plasticity at the ACE2-RBD interface facilitates the accumulation of such mutations.

Thus, the phenotypes indicate that further evolved variants were likely to be more elusive to therapeutic antibody neutralization than currently circulating VOCs – and could prove to be resistant to two-component antibody cocktails.

It was observed that after two messenger ribonucleic acid (mRNA) vaccine immunizations and seven days after the second dose, all mRNA vaccine recipients had detectable neutralizing activity against pseudotypes containing an NTD supersite deletion and RBDs with six to seven mutations. However, precise epitopes targeted by this residual neutralizing activity are yet to be identified.

Antibodies targeting the RBD core is speculated to be responsible for the residual vaccine-elicited serum neutralizing activity. The receptor-binding motif (RBM) is a critical site of potent neutralizing antibody binding that is the most antibody accessible and the least masked by glycan and conformational shielding. Hence, continued RBM evolution may modulate antibody responses toward more conserved neutralizing epitopes on the RBD core.

Comparison of immune evasion revealed that variants with an NTD supersite deletion and an E484_RBD substitution are the most concerning with respect to resistance to polyclonal antibodies. In fact, E484_RBD acts as a significant driver in neutralization escape; furthermore, the pseudotype – Beta, more robustly escapes antibody neutralization than Gamma.

Here, D364N_RBD was identified as an additional mutation that would introduce a putative N-linked glycosylation site. This independent acquisition on the same surface of the RBD core suggests that this region may be a target of immune selective pressure.

It was stated that the addition of the N370_RBD glycan might be associated with reduced virulence, but chances of secondary mutations nevertheless, which may again restore the viral fitness. Such compensatory mutations would promote ACE2 binding and RBD opening.

In summary, viral replication in human hosts under antibody selective pressure will continue to cause further mutations and newer VOCs. Therefore, future strategies to tackle the ongoing pandemic must involve aggressive variant monitoring efforts, designing next-generation antibody-based therapeutics, updating mRNA- or DNA-based vaccines to rapidly adapt to new variants, and examining the consequences of further viral evolution prior to the emergence of the next highly antibody resistant strain.