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

Autor: Almanza G; The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America., Clark AE; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, California, United States of America., Kouznetsova V; San Diego Supercomputer Center, University of California at San Diego, La Jolla, California, United States of America., Olmedillas E; Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, California, United States of America., Castro A; Biomedical Informatics Program, University of California San Diego, La Jolla, California, United States of America., Tsigelny IF; San Diego Supercomputer Center, University of California at San Diego, La Jolla, California, United States of America., Wu Y; Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, and School of Basic Medical Sciences, Capital Medical University, Beijing, China., Gao GF; Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China., Leibel SL; Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, United States of America., Bray W; Division of Genetics, Department of Pediatrics, Center for Drug Discovery Innovation, Program in Immunology, Institute for Genomic Medicine, La Jolla, California, United States of America., Ollmann Saphire E; Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, California, United States of America., Carlin AF; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, California, United States of America., Zanetti M; The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2022 Jul 21; Vol. 18 (7), pp. e1010686. Date of Electronic Publication: 2022 Jul 21 (Print Publication: 2022).
DOI: 10.1371/journal.ppat.1010686
Abstrakt: 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.
Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: MZ is named inventor in US patent 8,372,640 that relates to the protein engineering process and method of immunization used in this work. All other authors have declared that no competing interests exist.
Databáze: MEDLINE
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