SARS-CoV-2 spike conformation determines plasma neutralizing activity

Abstract

Numerous safe and effective COVID-19 vaccines have been developed that utilize various delivery technologies and engineering strategies. The influence of the SARS-CoV-2 spike (S) glycoprotein conformation on antibody responses induced by vaccination or infection in humans remains unknown. To address this question, we compared plasma antibodies elicited by six globally-distributed vaccines or infection and observed markedly higher binding titers for vaccines encoding a prefusion-stabilized S relative to other groups. Prefusion S binding titers positively correlated with plasma neutralizing activity, indicating that physical stabilization of the prefusion conformation enhances protection against SARS-CoV-2. We show that almost all plasma neutralizing activity is directed to prefusion S, in particular the S1 subunit, and that variant cross-neutralization is mediated solely by RBD-specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants and longer durability than current technologies.

Omicron BA.1 and BA.2 neutralizing activity elicited by a comprehensive panel of human vaccines

“…The receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein interacts with the receptor ACE2 (21)(22)(23)(24)(25), promoting S conformational changes that lead to membrane fusion and viral entry (26,27). S is the main target of neutralizing antibodies, which have been shown to be a correlate of protection against SARS-CoV-2 (28)(29)(30)(31)(32)(33)(34)(35)(36), with RBD-targeting antibodies accounting for nearly all cross-variant neutralizing activity (37). SARS-CoV-2 vaccines are thus based on the S glycoprotein (sometimes the RBD only (28,38,39)) or full virus (inactivated) and utilize a variety of delivery technologies.…”

Broad neutralization of SARS-CoV-2 variants by circular mRNA producing VFLIP-X spike in mice

“…The first-generation prefusion-stabilized spike engineered by two proline substitutions (S-2P) has served as an initial immunogen in current SARS-CoV-2 vaccines, presenting one or more RBDs "up" [1][2][3] . As serum neutralizing activity is primarily directed to the prefusion spike, structure-based engineering that better stabilizes the prefusion state could elicit more potent neutralizing antibody responses 4 . Importantly, immunodominant neutralizing epitopes are mainly located in the RBD [4][5][6] .…”

“…As serum neutralizing activity is primarily directed to the prefusion spike, structure-based engineering that better stabilizes the prefusion state could elicit more potent neutralizing antibody responses 4 . Importantly, immunodominant neutralizing epitopes are mainly located in the RBD [4][5][6] . However, multiple RBD mutations in emerging variants resulted in changes in immunodominance hierarchy and impaired neutralization potency of RBD-directed neutralizing antibodies 7,8 .…”

“…Specifically, common mutations, including substitutions at positions 417, 452, 484 and 501, have been identified as major drivers of antigenic differences 5,6 . Nonetheless, serum neutralizing activity has been demonstrated to be primarily directed to the prefusion spike, suggesting that the structure-based engineering paradigm aiming to stabilize the prefusion state could elicit potent neutralizing antibody responses 7 . Importantly, immunodominant neutralizing epitopes are mainly located in the RBD [7][8][9] .…”

“…Nonetheless, serum neutralizing activity has been demonstrated to be primarily directed to the prefusion spike, suggesting that the structure-based engineering paradigm aiming to stabilize the prefusion state could elicit potent neutralizing antibody responses 7 . Importantly, immunodominant neutralizing epitopes are mainly located in the RBD [7][8][9] . Promisingly, neutralization efficacy of multiple identified RBD-targeted neutralizing monoclonal antibodies is unaffected by mutations in the RBD of emerging variants [10][11][12] .…”