Exposure to BA.4/5 S protein drives neutralization of Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5 in vaccine-experienced humans and mice

Abstract

The SARS-CoV-2 Omicron variant and its sublineages show pronounced viral escape from neutralizing antibodies elicited by vaccination or prior SARS-CoV-2 variant infection owing to over 30 amino acid alterations within the spike (S) glycoprotein. Breakthrough infection of vaccinated individuals with Omicron sublineages BA.1 and BA.2 is associated with distinct patterns of cross-neutralizing activity against SARS-CoV-2 variants of concern (VOCs). In continuation of our previous work, we characterized the effect of Omicron BA.4/BA.5 S glycoprotein exposure on the neutralizing antibody response upon breakthrough infection in vaccinated individuals and upon variant-adapted booster vaccination in mice. We found that immune sera from triple mRNA-vaccinated individuals with subsequent breakthrough infection during the Omicron BA.4/BA.5 wave showed cross-neutralizing activity against previous Omicron variants BA.1, BA.2, BA.2.12.1, and BA.4/BA.5 itself. Administration of a prototypic BA.4/BA.5-adapted mRNA booster vaccine to mice following SARS-CoV-2 wild-type strain-based primary immunization is associated with broader cross-neutralizing activity than a BA.1-adapted booster. While the Omicron BA-1-adapted mRNA vaccine in a bivalent format (wild-type + BA.1) broadens cross-neutralizing activity relative to the BA.1 monovalent booster, cross-neutralization of BA.2 and descendants is more effective in mice boosted with a bivalent wild-type + BA.4/BA.5 vaccine. In naïve mice primary immunization with the bivalent wild-type + Omicron BA.4/BA.5 vaccine induces strong cross-neutralizing activity against Omicron VOCs and previous variants. These findings suggest that when administered as boosters, mono- and bivalent Omicron BA.4/BA.5-adapted vaccines enhance neutralization breadth, and that the bivalent version also has the potential to confer protection to individuals with no pre-existing immunity against SARS-CoV-2.

Assessment of Immunogenicity and Efficacy of CV0501 mRNA-based Omicron COVID-19 Vaccination in Small Animal Models

“…Similarly, previous mRNA vaccine studies in mice on an ancestral primed background demonstrated a broadening of immune responses upon boosting with ancestral/BA.1 bivalent vaccines compared with monovalent preparations [32,33].…”

“…The objective of this study was to assess the immunogenicity and efficacy of vaccine candidate, CV0501, which encodes the S protein of the Omicron variant BA. [32,33].…”

Assessment of Immunogenicity and Efficacy of CV0501 mRNA-Based Omicron COVID-19 Vaccination in Small Animal Models

“…Overall, our data point towards a potential benefit of bivalent vaccination for inducing a broad immune response. Similarly, previous mRNA vaccine studies in mice on an ancestral primed background demonstrated a broadening of immune responses upon boosting with ancestral/BA.1 bivalent vaccines compared with monovalent preparations [ 32 , 33 ].…”

Heterologous boost with mRNA vaccines against SARS-CoV-2 Delta/Omicron variants following an inactivated whole-virus vaccine

“…Omi BA.1). Both bivalent mRNA and BBIBP-CorV/ZSVG-02-O prime-boost show improved response against VOCs absent in the vaccines ( Scheaffer et al, 2023 ; Muik et al, 2022 ). To understand the reason underlying the broadened cross-activity by the ZSVG-02-O boost, we analyzed the composition of total IgG in the sera from animals received the single dose ZSVG-02-O following the BBIBP-CorV prime.…”

“…Those studies show a single Omicron-specific boost also induce similar antibody titers across the multiple strains. Compared with Omicron-specific mRNA vaccines from Moderna (mRNA-1273.529) ( Scheaffer et al, 2023 ) and BioNtech (Omi BA.1) ( Muik et al, 2022 ), ZSVG-02-O produced almost identical Nab responses in naïve animals against WT, Delta and BA.1 VOCs. However, a heterologous BBIBP-CorV/ZSVG-02-O prime-boost strategy produced a broadened immune response more similar to the bivalent mRNA-1273.214 from Moderna ( Scheaffer et al, 2023 ) and BioNtech (BNT162b2 +.…”