TY - JOUR T1 - Structure-selected RBM immunogens prime polyclonal memory responses that neutralize SARS-CoV-2 variants of concern JF - bioRxiv DO - 10.1101/2021.10.01.462840 SP - 2021.10.01.462840 AU - Gonzalo Almanza AU - Valentina Kouznetsova AU - Alex E. Clark AU - Eduardo Olmedillas AU - Andrea Castro AU - Igor F. Tsigelny AU - Yan Wu AU - George F. Gao AU - Erica Ollmann Saphire AU - Aaron F. Carlin AU - Maurizio Zanetti Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/10/04/2021.10.01.462840.abstract N2 - 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 concentrate the antibody response 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 two variants of concern (VOC), B.1.351 and B.1.617.2. These findings demonstrate that immunogens built on structure selection can focus the response to conserved sites of vulnerability shared between wildtype virus and VOCs and induce neutralizing antibodies across variants. ER -