Tailored Design of Protein Nanoparticle Scaffolds for Multivalent Presentation of Viral Glycoprotein Antigens
Copyright policy )Tailored Design of Protein Nanoparticle Scaffolds for Multivalent Presentation of Viral Glycoprotein Antigens
AbstractThe adaptive immune system is highly sensitive to arrayed antigens, and multivalent display of viral glycoproteins on symmetric scaffolds has been found to substantially increase the elicitation of antigen-specific antibodies. Motivated by the considerable promise of this strategy for next-generation anti-viral vaccines, we set out to design new self-assembling protein nanoparticles with geometries specifically tailored to scaffold ectodomains of different viral glycoproteins. We first designed and characterized homo-trimers from designed repeat proteins with N-terminal helices positioned to match the C termini of several viral glycoprotein trimers. Oligomers found to experimentally adopt the designed configuration were then used to generate nanoparticles with tetrahedral, octahedral, or icosahedral symmetry. Examples of all three target symmetries were experimentally validated by cryo-electron microscopy and several were assessed for their ability to display viral glycoproteins via genetic fusion. Electron microscopy and antibody binding experiments demonstrated that the designed nanoparticles display conformationally intact native-like HIV-1 Env, influenza hemagglutinin, and prefusion RSV F trimers in the predicted geometries. This work demonstrates that novel nanoparticle immunogens can be designed from the bottom up with atomic-level accuracy and provides a general strategy for precisely controlling epitope presentation and accessibility.
- California Institute of Technology United States
- University of Mary United States
- Vaccine Research Center
- National Institute of Health Pakistan
- National Cancer Institute United States
Prevention (rcdc), immunology, computational biology, Pneumonia & Influenza (rcdc), 31 Biological sciences (for-2020), Nanotechnology, Viral, Immunization (rcdc), Biology (General), 32 Biomedical and Clinical Sciences (for-2020), Antigens, Viral, Cryoelectron Microscopy (mesh), Humans (mesh), 3 Good Health and Well Being (sdg), Bioengineering (rcdc), Q, Vaccination, R, Humoral, 600, systems biology, Biological sciences, Infection (hrcs-hc), Infectious Diseases, Medical Microbiology, Vaccine Related (rcdc), Influenza Vaccines, Nanoparticles (mesh), Influenza Vaccines (mesh), Pneumonia & Influenza, HIV/AIDS, Medicine, Glycoproteins (mesh), Infection, Biotechnology, Computational and Systems Biology, QH301-705.5, Science, Immunology, 0601 Biochemistry and Cell Biology (for), Bioengineering, Lemo21, virus, Biotechnology (rcdc), Emerging Infectious Diseases (rcdc), Vaccination (mesh), Vaccine Related, Viral (mesh), Humoral (mesh), 42 Health sciences (for-2020), Humans, 3207 Medical Microbiology (for-2020), human, Antigens, 3204 Immunology (for-2020), Glycoproteins, HIV/AIDS (rcdc), Influenza (rcdc), Biomedical and Clinical Sciences, BL21, Prevention, Inflammatory and immune system, Cryoelectron Microscopy, Immunity, E. coli, Health sciences, 500, Influenza, Inflammatory and immune system (hrcs-hc), Immunity, Humoral, Emerging Infectious Diseases, Good Health and Well Being, 32 Biomedical and clinical sciences (for-2020), Infectious Diseases (rcdc), inflammation, HEK293F, Nanotechnology (rcdc), Sexually Transmitted Infections, Nanoparticles, Immunization, Biochemistry and Cell Biology, Sexually Transmitted Infections (rcdc), B lymphocytes
Prevention (rcdc), immunology, computational biology, Pneumonia & Influenza (rcdc), 31 Biological sciences (for-2020), Nanotechnology, Viral, Immunization (rcdc), Biology (General), 32 Biomedical and Clinical Sciences (for-2020), Antigens, Viral, Cryoelectron Microscopy (mesh), Humans (mesh), 3 Good Health and Well Being (sdg), Bioengineering (rcdc), Q, Vaccination, R, Humoral, 600, systems biology, Biological sciences, Infection (hrcs-hc), Infectious Diseases, Medical Microbiology, Vaccine Related (rcdc), Influenza Vaccines, Nanoparticles (mesh), Influenza Vaccines (mesh), Pneumonia & Influenza, HIV/AIDS, Medicine, Glycoproteins (mesh), Infection, Biotechnology, Computational and Systems Biology, QH301-705.5, Science, Immunology, 0601 Biochemistry and Cell Biology (for), Bioengineering, Lemo21, virus, Biotechnology (rcdc), Emerging Infectious Diseases (rcdc), Vaccination (mesh), Vaccine Related, Viral (mesh), Humoral (mesh), 42 Health sciences (for-2020), Humans, 3207 Medical Microbiology (for-2020), human, Antigens, 3204 Immunology (for-2020), Glycoproteins, HIV/AIDS (rcdc), Influenza (rcdc), Biomedical and Clinical Sciences, BL21, Prevention, Inflammatory and immune system, Cryoelectron Microscopy, Immunity, E. coli, Health sciences, 500, Influenza, Inflammatory and immune system (hrcs-hc), Immunity, Humoral, Emerging Infectious Diseases, Good Health and Well Being, 32 Biomedical and clinical sciences (for-2020), Infectious Diseases (rcdc), inflammation, HEK293F, Nanotechnology (rcdc), Sexually Transmitted Infections, Nanoparticles, Immunization, Biochemistry and Cell Biology, Sexually Transmitted Infections (rcdc), B lymphocytes
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