Immune evasion of neutralizing antibodies by SARS-CoV-2 Omicron

Abstract

Since its emergence at the end of 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the infection of more than 600 million people worldwide and has significant damage to global medical, economic, and political structures. Currently, a highly mutated variant of concern, SARS-CoV-2 Omicron, has evolved into many different subvariants mainly including BA.1, BA.2, BA.3, BA.4/5, and the recently emerging BA.2.75.2, BA.2.76, BA.4.6, BA.4.7, BA.5.9, BF.7, BQ.1, BQ.1.1, XBB, XBB.1, etc. Mutations in the N-terminal domain (NTD) of the spike protein, such as A67V, G142D, and N212I, alter the antigenic structure of Omicron, while mutations in the spike receptor binding domain (RBD), such as R346K, Q493R, and N501Y, increase the affinity for angiotensin-converting enzyme 2 (ACE2). Both types of mutations greatly increase the capacity of Omicron to evade immunity from neutralizing antibodies, produced by natural infection and/or vaccination. In this review, we systematically assess the immune evasion capacity of SARS-CoV-2, with an emphasis on the neutralizing antibodies generated by different vaccination regimes. Understanding the host antibody response and the evasion strategies employed by SARS-CoV-2 variants will improve our capacity to combat newly emerging Omicron variants.

Keywords: Bivalent mRNA vaccine; Booster; Immune evasion; Mutations; Omicron; SARS-CoV-2.

Graphical abstract

Fig. 1

Classification of the Coronaviridae. The Coronaviridae family has been divided into Orthocoronavirnae and Torovirinae subfamilies. The subfamily Orthocoronavirnae is divided into 4 genera, Alpha-, Beta-, Gamma-, and Delta-coronavirus. Viruses in the Alpha-genus are represented in blue and the Beta-genus are represented in orange. Viruses in the Beta-genus are divided into 4 subgroups A, B, C, and D, with subgroup A, represented in light green, subgroup B in orange, subgroup C in lavender, and subgroup D in light yellow. SARS-CoV-2 belongs to subgroup B in the genus Beta-coronavirus. The Variants of concerns of SARS-CoV-2 are represented in yellow, and Omicron subvariants are represented in purple.

Fig. 2

Overview of the SARS-CoV-2 genome encoding nonstructural proteins, structural proteins, and accessory proteins. Nonstructural proteins include ORF1a (NSP 1–11) and ORF1b (NSP 12–16). Structural proteins include membrane (M), envelope (E), nucleocapsid (N), and spike (S). Accessory proteins include ORF3a, ORF3b, ORF6, ORF7a, ORF7b, ORF8, ORF9b, ORF9c, and ORF10.

Fig. 3

Comprehensive comparison of mutations between diverse Omicron subvariants. Mutations in the spike protein in Omicron subvariants wild type (WT), BA.1, BA.1.1, BA.2, BA.2.12.1, BA.2.13, BA.2.75, BA.2.75.2, BA.2.76, BA.3, BA.4/5, BA.4.6, BA.4.7, BF.7, BA.5.9, BQ.1, BQ.1.1, XBB, and XBB.1. All identical and different mutations on the receptor binding domain (RBD) between different Omicron subvariants are shown. “× ” represents a deletion. The spatial positions of mutations in BA.1, BA.2, BA.4/5, and BQ.1 are highlighted in structure models. The helix, loop, and sheet of S protein are colored in teal, grey, and yellow, respectively. Mutations are shown as red spheres (PDB 7EB4).

Fig. 4

The mechanisms of viral attachment to host cells. The S protein enters the human body by binding to the angiotensin-converting enzyme 2 (ACE2) in human cells. In the left picture, the neutralizing antibody binds the S protein so the S protein cannot bind ACE2, thus preventing SARS-CoV-2 from entering the cell. In the right picture, the neutralizing antibody is unable to bind effectively to the S protein, thus allowing the S protein to bind ACE2 and SARS-CoV-2 can enter the cell. The increase of mutations in the Omicron S protein causes a conformational change in the S protein, which allows the S protein to bind the RBD better and prevents most neutralizing antibodies from being effective against Omicron.

Fig. 5

Interaction of S protein with neutralizing antibodies. Mutations K417N, Q493R, G496S, and N501Y are indicated by cyan, red, blue, and yellow, respectively. Hydrogen bonds are indicated in violet. The interaction residues between mutations K417N, Q493R, G496S, and N501Y on the S protein of Omicron and neutralizing antibodies are colored orange (PDB 7ZFD).

Fig. 6

Neutralization ability of sera against Omicron by different vaccination and infection routines. Comparison of the neutralizing effect of respective sera from different groups. The number of antibodies represents the level of serum neutralization. A: SARS-CoV-2 infected but unvaccinated individuals, B: Vaccinated individuals without a history of SARS-CoV-2 infection, C: Individuals with SARS-CoV-2 breakthrough infection after vaccination, D: Individuals infected with SARS-CoV-2 before vaccination against Omicron.