Structure-selected RBM immunogens prime polyclonal memory responses that neutralize SARS-CoV-2 variants of concern.

Successful control of the COVID-19 pandemic depends on vaccines that prevent transmission. The full-length Spike protein is highly immunogenic but the majority of antibodies do not target the virus: ACE2 interface. In an effort to affect the quality of the antibody response focusing it to the receptor-binding motif (RBM) we generated a series of conformationally-constrained immunogens by inserting solvent-exposed RBM amino acid residues into hypervariable loops of an immunoglobulin molecule. Priming C57BL/6 mice with plasmid (p)DNA encoding these constructs yielded a rapid memory response to booster immunization with recombinant Spike protein. Immune sera antibodies bound strongly to the purified receptor-binding domain (RBD) and Spike proteins. pDNA primed for a consistent response with antibodies efficient at neutralizing authentic WA1 virus and three variants of concern (VOC), B.1.351, B.1.617.2, and BA.1. We demonstrate that immunogens built on structure selection can be used to influence the quality of the antibody response by focusing it to a conserved site of vulnerability shared between wildtype virus and VOCs, resulting in neutralizing antibodies across variants. Author summary: Next generation SARS-CoV-2 vaccines need to address the transmission of new virus variants that continue to threaten global health and recovery. This may require new perspectives in immunogen design as well as immune response engineering. Here we applied these ideas in a two-step proof of concept study. First, we designed conformationally-constrained immunogens expressing key residues at the RBM: ACE2 interface to mimic their stereochemical orientation in the native Spike protein. Second, we initiated the process of B cell immunity (priming) using plasmid DNA injected intra-spleen to exploit the spatial organization of a secondary lymphoid organ. Mice given a single booster immunization with intact Spike protein developed a rapid memory antibody response against RBD and Spike proteins. Importantly, immune sera neutralized authentic WA1 virus and the B.1.351/Beta, B.1.617.2/Delta, and BA.1/Omicron variants of concern. Our findings demonstrate that immunogens built on structure selection and lymphoid organ targeting are a powerful way to focus the antibody response to a conserved site of vulnerability shared between wildtype virus and variants of concern. [ABSTRACT FROM AUTHOR]