Analysis of Immune Escape Variants from Antibody-Based Therapeutics against COVID-19: A Systematic Review

Abstract

The accelerated SARS-CoV-2 evolution under selective pressure by massive deployment of neutralizing antibody-based therapeutics is a concern with potentially severe implications for public health. We review here reports of documented immune escape after treatment with monoclonal antibodies and COVID-19-convalescent plasma (CCP). While the former is mainly associated with specific single amino acid mutations at residues within the receptor-binding domain (e.g., E484K/Q, Q493R, and S494P), a few cases of immune evasion after CCP were associated with recurrent deletions within the N-terminal domain of the spike protein (e.g., ΔHV69-70, ΔLGVY141-144 and ΔAL243-244). The continuous genomic monitoring of non-responders is needed to better understand immune escape frequencies and the fitness of emerging variants.

Keywords: COVID-19; SARS-CoV-2; convalescent plasma; viral clearance.

Figure 1

PRISMA flow diagram of study selection.

Figure 2

(Top panel) The full SARS-CoV-2 S (spike) glycoprotein homotrimer (PDBID 6VXX) [16] in the prefusion conformation is shown in surface representation, with each spike monomer colored a different shade of green. N-linked glycosylations which were resolved in the cryo-EM map in this structure (16/22 sequons per protomer) are displayed as magenta sticks. The receptor binding domains (RBDs), in the closed state, are highlighted in 3 shades of blue corresponding to the shade of the corresponding trimer. Escape mutations from case reports of patients treated with CCP are highlighted in orange. Spike mutations associated with immune escape from clinically approved mAb treatments in vitro or from case reports are highlighted in red, while escape mutations identified in both patients who received clinically approved mAb treatments and CCP treatment are colored yellow. The full spike is shown oriented along the long axis (left) and rotated 90 degrees to display mutations concentrated in the RBDs. Note that mutations located on unresolved loops on the cryo-EM map of the full spike are not visualized (L18, V70, Y144, Y145, D146, R246, W258, G446, N460, I472, V483, E484, G485, F486, R682, N1178 and C1250). (Bottom panel) A table summarizing escape mutations localized to the RBD resulting from mAb treatments in vitro and case reports, as well as from CCP treatment. The crystal structure of single RBD domain (PBDID: 7BWJ) [17] from a more complete model (no missing loops) is displayed in surface view with the secondary structure superimposed in cartoon representation. Each escape mutation residue is highlighted by coloration according to the legend to right, and sidechains shown as sticks. In cases where a certain position corresponds to escape mutations from multiple treatments, the position is colored white and the label includes asterisks with the colors corresponding to each treatment where the escape mutation was identified. All figures were generated in PyMOL [18].