Differential escape of neutralizing antibodies by SARS-CoV-2 Omicron and pre-emergent sarbecoviruses

Abstract

The SARS-CoV-2 B.1.1.529 lineage, Omicron variant, was first detected in November 2021 and carries 32 amino acid mutations in the spike protein (15 in RBD) and exhibits significant escape of neutralizing antibodies targeting the parental SARS-CoV-2 virus. Here, we performed a high-resolution multiplex (16-plex) surrogate virus neutralization assay covering all major SARS-CoV-2 variants and pre-emergent ACE2-binding sarbecoviruses against 20 different human serum panels from infected, vaccinated and hybrid immune individuals which had vaccine-breakthrough infections or infection followed by vaccination. Among all sarbecoviruses tested, we observed 1.1 to 4.7-, 2.3 to 10.3- and 0.7 to 33.3-fold reduction in neutralization activities to SARS-CoV-2 Beta, Omicron and SARS-CoV-1, respectively. Among the SARS-CoV-2 related sarbecoviruses, it is found that the genetically more distant bat RaTG13 and pangolin GX-P5L sarbecoviruses had less neutralization escape than Omicron. Our data suggest that the SARS-CoV-2 variants emerged from the changed immune landscape of human populations are more potent in escaping neutralizing antibodies, from infection or vaccination, than pre-emergent sarbecoviruses naturally evolved in animal populations with no or less immune selection pressure.

Figure 1

Mutations in Omicron Spike protein and RBDs of SARS-CoV-2 variants and other sarbecoviruses. a, Illustration of SARS-CoV-2 Omicron spike mutations. Mutations in the RBD region are highlighted in red. b, Phylogenetic tree based on the amino acid sequence of RBD was generated using PhyML with Blosum62 model with 1,000 bootstrap replicates. Numbers at the branches are percentage bootstrap values for the associated nodes. Scale bar indicates number of substitutions per site. c, RBD amino acid sequence identity (%) among different sarbecoviruses. Numbers in brackets indicates the total number of amino acid residue differences from the ancestral SARS-CoV-2 RBD. d, Multiple alignment of amino acid sequences of sarbecovirus RBDs used in this study. Mutations/deletions were highlighted in red.

Figure 2

Neutralization activity against SARS-CoV-2 variants and other sarbecoviruses. The geometric mean neutralization titer 50% (GMT) against 16 different sarbecoviruses derived from four different serum panels. a, Convalescent sera from individuals infected with Ancestral, VOCs Beta, Delta or SARS-CoV-1; b, Individuals who have received standard vaccination (BNT162b2 x2, mRNA-1273 x 2, CoronaVac x2, BBIBP-CorV x2 and AZD1222 x2); c, Individuals after receiving booster (BNT162b2 x3, mRNA-1273 x3, BNT162b2 x2/mRNA-1273, CoronaVac x3, CoronaVac x2/BNT162b2, CoronaVac x2/AZD1222, and CoronaVac x2/BBIBP-CorV); and d, Individuals with hybrid immunity (Delta-breakthrough, Omicron-breakthrough, COVID-19-vaccinated, and SARS-vaccinated). e, GMT fold reduction heat-map of different convalescent, vaccine and hybrid immunity panels against 16 different sarbecoviruses.

Figure 3

Neutralization escape in relation to number of RBD mutations. a, Neutralization titers derived from multiplex sVNT (n = 124). The effect of RBD mutations on NAb escape for different serum panels including those with b, two doses of mRNA vaccines, c, three doses of mRNA vaccine, d, vaccinated individuals with breakthrough infection, and e, BTN162b2-vaccinated SARS survivors. Paired two-tailed student’s t-tests were used in a. Line in a indicates median. Linear regression analysis in b-e were performed using GraphPad prism. Line and dotted line in b-e indicates linear regression plot on SARS-CoV-2 with pre-emergent sarbecoviruses and VOCs, respectively.