Cross-reactivity of eight SARS-CoV-2 variants rationally predicts immunogenicity clustering in sarbecoviruses

Abstract

A steep rise in Omicron reinfection cases suggests that this variant has increased immune evasion ability. To evaluate its antigenicity relationship with other variants, antisera from guinea pigs immunized with spike protein of SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs) were cross-tested against pseudotyped variants. The neutralization activity against Omicron was markedly reduced when other VOCs or VOIs were used as immunogens, and Omicron (BA.1)-elicited sera did not efficiently neutralize the other variants. However, a Beta or Omicron booster, when administered as the 4th dose 3-months after the 3rd dose of any of the variants, could elicit broad neutralizing antibodies against all of the current variants including Omicron BA.1. Further analysis with 280 available antigen–antibody structures and quantification of immune escape from 715 reported neutralizing antibodies provide explanations for the observed differential immunogenicity. Three distinct clades predicted using an in silico algorithm for clustering of sarbecoviruses based on immune escape provide key information for rational design of vaccines.

Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine

“…Taken together, these studies demonstrate that RBD-based protein vaccines are immunogenic in humans. This supports our view that our uniquely formulated beta-variant RBD-Fc dimer/MF59® adjuvanted vaccine will work well as a heterologous booster subsequent to S-based vaccination in humans, particularly considering the increased breadth of immune responses that appear to be promoted by the beta variant 19,20,27,28 .…”

“…While this is no longer a circulating VOC, having since been replaced by others and most recently omicron VOCs, our findings are that the beta RBD-hFc boost drives a broad nAb response that spans all of the SARS-CoV-2 VOCs we tested. Furthermore, studies with human samples have shown that exposure to the beta VOC was superior to the ancestral strain at driving broadly cross-reactive nAb, including those that can target omicron 19,20,27,28 .…”

“…Emerging evidence suggests that this same problem limits the boosting effect of whole S-based booster vaccines that incorporate VOC S protein sequences, presumably because the immune system prefers to target common epitopes shared between the mutant spike vaccine and the ancestral strain to which all approved vaccines are aligned 24, 25 (reviewed in 26 ). Interestingly, some studies have suggested that exposure to the beta VOC, either by infection or vaccination, provides broader neutralising antibodies against a range of VOC including omicron 19, 20, 27, 28 .…”

“…Furthermore, this vaccine is highly adaptable to incorporate RBD sequence changes, and we have engineered versions corresponding to several VOC RBDs. For clinical testing, we engineered a beta variant version of our RBD human IgG1-Fc vaccine, which based on recent studies, may yield broader immune responses to VOCs including omicron 19, 20, 27, 28 . Indeed, this beta RBD vaccine induced a potent nAb response against the beta SARS-CoV-2 virus, and protected mice against infection with this strain, as well as a mouse-tropic version of the ancestral SARS-CoV-2 strain, and generated strong nAb against other VOC.…”

Pathogenicity of SARS-CoV-2 Omicron BA.5 and BE.1 Variants in Syrian Hamsters and hACE2-transgenic Mmice

“…Phylogenetic analysis of genome-wide sequences, as well as amino acid sequences of the S-protein and RBD-domain, shows that the Omicron variant is genetically significantly removed both from the original SARS-CoV-2 variant and from all previous VOCs [2]. Moreover, a lot of studies confirm the weak cross-reactivity of the immune response formed to the variants of the virus from Alpha to Delta, in relation to the Omicron variant, as well as cross-reactivity in the opposite direction [3,4]. The Omicron variant shows sufficient genetic and structural distance from other SARS-CoV-2 variants, that suggests the possibility of separating the Omicron variant and its sub-lineages into a separate SARS-CoV-2 serotype [5].…”