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[Preprint]. 2022 Mar 28:2022.03.25.485875. [Version 1] doi: 10.1101/2022.03.25.485875

Figure 1.

Figure 1.

Mosaic nanoparticles may preferentially induce cross-reactive antibodies through avidity effects. (A) Left: Structure of SARS-2 S trimer (PDB 6VYB) showing one “up” RBD (dashed circle). Right: Sequence conservation of the 16 sarbecovirus RBDs in panel D calculated by the ConSurf Database (79) shown on two views of an RBD surface (PDB 7BZ5). The ACE2 binding footprint (PDB 6M0J) is outlined by a yellow dotted line. Locations of residues that are substituted in SARS-2 variants of concern (VOCs) and variants of interest (VOIs) as of March 2022 (https://viralzone.expasy.org/9556) are indicated as black dots. Class 1, 2, 3, 4, and 1/4 epitopes are outlined in different colored dotted lines using information from structures of representative monoclonal antibodies bound to RBD or S trimer (C102: PDB 7K8M; C002: PDB 7K8T, S309: PDB 7JX3; CR3022: PDB 7LOP; C022: PDB 7RKU). The N-linked glycan attached to RBD residue 343 is indicated by teal spheres, and the potential N-linked glycosylation site at position 370 in RBDs derived from sarbecoviruses other than SARS-2 is indicated by a teal circle. (B) Schematic showing hypothesis for how mosaic RBD-nanoparticles could induce production of cross-reactive antibodies. Left: Clustered membrane-bound B cell receptors bind with avidity to a strain-specific epitope (dark pink triangle) on dark pink antigens attached to a homotypic particle. Middle: B-cell receptors cannot bind with avidity to strain-specific epitope (triangle) on dark pink antigen attached to a mosaic particle. Right: B-cell receptors can bind with avidity to common epitope (green circle) presented on different antigens attached to a mosaic particle, but not to strain-specific epitopes (triangles). (C) Sarbecoviruses from which the RBDs in mosaic-8b RBD-mi3 were derived (matched) and sarbecoviruses from which RBDs were not included in mosaic-8b (mismatched). Clades are defined as in (13). The Wuhan-Hu-1 SARS-2 RBD was used in mosaic-8gm instead of the SARS-2 Beta RBD. (D) Phylogenetic tree of selected sarbecoviruses calculated using PhyML 3.0 (80) based on amino acid sequences of RBDs aligned using Clustal Omega (81). Viruses with RBDs included in mosaic-8b are highlighted in gray rectangles.