RBD mRNA vaccine (Monash Institute of Pharmaceutical Sciences)

Multiple SARS-CoV-2 variants are identified with higher rates of transmissibility or greater disease severity. Particularly, recent emergence of Omicron variant with rapid human-to-human transmission posts new challenges to the current prevention strategies. In this study, following vaccination with an mRNA vaccine encoding SARS-CoV-2 receptor-binding domain (RBD-mRNA), we detected serum antibodies that neutralized pseudoviruses expressing spike (S) protein harboring single or multiple mutations, as well as authentic SARS-CoV-2 variants, and evaluated its protection against SARS-CoV-2 infection. The vaccine induced durable antibodies that potently neutralized prototypic strain and B.1.1.7 lineage variant pseudoviruses containing N501Y or D614G mutations alone or in combination with a N439K mutation (B.1.258 lineage), with a L452R mutation (B.1.427 or B.1.429 lineage), or a L452R-E484Q double mutation (B.1.617.1 variant), although neutralizing activity against B.1.1.7 lineage variant containing 10 amino acid changes in the S protein was slightly reduced. The RBD-mRNA-induced antibodies exerted moderate neutralization against authentic B.1.617.2 and B.1.1.529 variants, and pseudotyped B.1.351 and P.1 lineage variants containing K417N/T, E484K, and N501Y mutations, the B.1.617.2 lineage variant harboring L452R, T478K, and P681R mutations, and the B.1.1.529 lineage variant containing 38 mutations in the S protein. Particularly, RBD-mRNA vaccine completely protected mice from challenge with a virulent mouse-adapted SARS-CoV-2 variant. Among these lineages, B.1.1.7, B.1.351, P.1, B.1.617.2, and B.1.1.529 belong to Alpha, Beta, Gamma, Delta, and Omicron variants, respectively. Our observations reveal that RBD-mRNA vaccine is promising and highlights the need to design novel vaccines with improved neutralization against current and future pandemic SARS-CoV-2 variants.

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants threatens efforts to contain the coronavirus disease 2019 (COVID-19) pandemic.Micron (B.1.1.529), the fifth novel SARS-CoV-2 variant of concern (VOC), harbors 15 mutations in the receptor-binding domain (RBD) of the spike (S) protein, and these mutations include almost all the sites of existing VOCs (Alpha/B.1.1.7, Beta/B.1.351, Gamma/P.1, and Delta/B.1.617.2).To understand how SARS-CoV-2 variants, including Beta, Delta, and Omicron, evade RBD-targeting NAbs, we screened the binding affinities of monoclonal antibodies (mAbs) currently being evaluated in late clin. trials, NAbs with Emergency Use Authorization (EUA), and mAb hu33 to SARS-CoV-2 RBDs.We previously isolated a large panel of SARS-CoV-2 RBD-binding mAbs from RBD mRNA vaccine immunized mice using a 10xGenomics-based antibody discovery platform.To reveal the binding epitope of hu33, we investigated the complex formed by the fragment antigen-binding (Fab) regions of hu33 and a prefusion-stabilized Beta S trimer using single-particle cryo-electron microscopy (cryo-EM), and reconstructed a cryo-EM d. map for the one RBD open state at an overall resolution of 3.1 Å.RBD residues including Leu441, Val445, Tyr451, and Pro499 form hydrophobic and van der Waals interactions with hu33, whereas Asn343, Ala344, Thr345, Arg346, Asn440, Ser443, and Lys444 are targeted via polar interactions.In summary, this study showed that the Omicron variant escapes most EUA Class I/II NAbs, whereas the neutralization sensitivity of Class III mAbs, non-ACE2-blocking antibodies, was less affected by this variant.In the meantime, hu33 was a mutation-resistant and broadly neutralizing activity against Omicron-included SARS-CoV-2 variants.Structural and functional analyses support the idea that hu33 is a potential treatment option for treating the SARS-CoV-2 VOCs and combating the COVID-19 pandemic.