Study: Novel monoclonal antibodies showing broad neutralizing activity against SARS-CoV-2 variants including Omicrons BA.5 and BA.2.75. Image credit: vipman/Shutterstock
Record
SARS-CoV-2 Omicron has caused a widespread increase in cases of coronavirus disease 2019 (COVID-19). Several studies have reported that three doses of mRNA vaccine confer protective immunity against the Omicron BA.1 and BA.2 subvariants of SARS-CoV-2.
The study and findings
The current study identified three mAbs broadly effective against multiple SARS-CoV-2 variants. Previously, the authors identified sera from patients infected with SARS-CoV-2 between July and November 2020, who later received a double-dose mRNA vaccine, which exhibited excellent neutralizing activity against SARS-CoV-2. First, they investigated antibody genes from peripheral blood mononuclear cells (PBMCs) collected from these patients. Ten antibody genes were identified from B cells isolated from PBMCs. Ten mAbs were tested for neutralizing activity. three were selected (MO1, MO2 and MO3). Antibody MO1 recognized spike proteins from D614G, Delta and Omicron variants BA.1, BA.2 and BA.5. MO2 recognized peaks from D614G, Delta, BA.1 and BA.2 variants, while MO3 recognized D614G and Omicron BA.1 and BA.2 variants. The researchers then found that MO1 neutralized the five SARS-CoV-2 variants along with the BA.1.1 variant. MO2 neutralized four SARS-CoV-2 variants (D614G, Delta, BA.1 and BA.5). Similarly, MO3 demonstrated neutralizing activity against three SARS-CoV-2 variants (D614G, BA.1 and BA.2). In addition, the three mAbs were able to neutralize the SARS-CoV-2 BA.2.75 variant. Further, the authors assessed the affinity of the antibodies to the Omicron spike proteins using biolayer interferometry (BLI). mAbs MO1 and MO2 had a substantial affinity for binding to the receptor binding domain (RBD) of the BA.2 tripartite spike. Antibody MO1 showed high affinity for the RBD of the BA.5 spike, whereas MO2 did not bind to it.
conclusions
The MO1 antibody effectively neutralized the major variants of SARS-CoV-2, including Omicron BA.2.75 and BA.5. BA.1 and BA.2 variants evade several known nAbs, and immune evasion of BA.5 is enhanced by additional substitutions such as F486V and L452R. Although MO2 neutralized BA.1 and BA.2, it failed to neutralize BA.5. MO1 retained neutralizing activity against BA.5, perhaps due to a conserved epitope outside the defined BA.5 spike mutation sites. The team reported that a structural analysis of MO1 was underway. However, preliminary findings from cryo-electron microscopy indicate that MO1 approaches the RBD spike similarly to the therapeutic mAbs cilgavimab and bebtelovimab, despite binding at a different site. That MO1 neutralizes early and more recent SARS-CoV-2 variants suggests that immunity against the ancestral SARS-CoV-2 RBD could protect individuals against Omicron variants by eliciting nAbs targeting conserved epitopes. The authors argue that multiple exposures to the spike protein could elicit broadly acting nAbs, independent of spike sequence variation. They hypothesize that a triple- or quadruple-dose vaccine based on wild-type SARS-CoV-2 could stimulate memory B cells to elicit antibodies with broad-spectrum activity.
*Important note
bioRxiv publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered definitive, guide clinical practice/health-related behavior, or be treated as established information.
