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.

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

“…Understanding antibody responses elicited by and directed towards Omicron sublineages is key to inform public health policies and the design of SARS-CoV-2 and sarbecovirus vaccines ( 63, 64, 70–72 ). Our data show that Omicron breakthrough infections did not elicit high titers of pan-sarbecovirus neutralizing antibodies (e.g., directed against SARS-CoV), in agreement with recent data ( 73 ). These findings contrast with the observation that pre-existing immunity to SARS- CoV followed by SARS-CoV-2 vaccination was associated with elicitation of pan-sarbecovirus neutralizing antibodies ( 26 ).…”

“…For instance, Omicron BA.1 and BA.2 harbor variations of the RBD antigenic site II, which is the target of pan-sarbecovirus neutralizing antibodies such as S2X259 ( 31 ) and ADG2 ( 74 ), that lead to resistance to neutralization mediated by some of the mAbs recognizing this site ( 3, 16 ). This suggests that conservation of RBD sites across sarbecoviruses may have resulted (at least partially) from limited immune pressure rather than from functional or structural constraints (i.e., some mutations at these conserved sites may remain compatible with viral fitness) ( 73 ).…”

Priming conditions shape breadth of neutralizing antibody responses to sarbecoviruses

“…This diversity is further enhanced by those who survived SARS-CoV-1 in 2003 who are now being immunized with SARS-CoV-2 vaccines. A recently described multiplex bead surrogate neutralization assay provides the opportunity to investigate neutralizing antibody responses to a range of SARS-CoV-2 variants and sarbecoviruses 21,23 . We assembled a panel of plasma samples from individuals with a variety of conditions of priming, boosting and infection histories to investigate how these impact on the breadth and magnitude of neutralizing antibody responses to this broad panel of SARS-CoV-2 VoCs and sarbecoviruses.…”

“…Since Omicron appears to be the most antigenically divergent RBD 23 , one may speculate that individuals primed with an ancestral SARS-CoV-2 antigen (e.g. BNT162b2) boosted with an effective Omicron-spike vaccine or a bivalent Omicron and SARS-CoV-1 vaccine may lead to comparable or superior breadth of immunity.…”

“…However, these 2 vaccines represent distinct platforms known to induce neutralizing antibodies at the high and low ends of the antibody response range, respectively, and are most widely used vaccines globally. Recently, a related study has investigated booster vaccines, including viral vectored AZD1222 23 , with a similar reporting of mRNA vaccine advantage for antibody breadth.…”