Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus

• Published in: Cell Vol. 176; no. 6; pp. 1420 - 1431.e17
• Main Authors: Marcandalli, Jessica, Fiala, Brooke, Ols, Sebastian, Perotti, Michela, de van der Schueren, Willem, Snijder, Joost, Hodge, Edgar, Benhaim, Mark, Ravichandran, Rashmi, Carter, Lauren, Sheffler, Will, Brunner, Livia, Lawrenz, Maria, Dubois, Patrice, Lanzavecchia, Antonio, Sallusto, Federica, Lee, Kelly K., Veesler, David, Correnti, Colin E., Stewart, Lance J., Baker, David, Loré, Karin, Perez, Laurent, King, Neil P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.03.2019; Cell Press
• Subjects: Animals; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - metabolism; Antibodies, Viral - immunology; Caveolin 1; Cell Line; computational protein design; HEK293 Cells; Humans; Medicin och hälsovetenskap; Mice; Mice, Inbred BALB C; nanoparticles; Nanoparticles - therapeutic use; neutralizing antibodies; Primary Cell Culture; respiratory syncytial virus; Respiratory Syncytial Viruses - immunology; Respiratory Syncytial Viruses - pathogenicity; self-assembly; Vaccination - methods; vaccines; Vaccines - immunology; Viral Fusion Proteins - immunology; Viral Fusion Proteins - metabolism; Viral Fusion Proteins - physiology; self-assembly; neutralizing antibodies; computational protein design; nanoparticles; vaccines; respiratory syncytial virus
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2019.01.046

Respiratory syncytial virus (RSV) is a worldwide public health concern for which no vaccine is available. Elucidation of the prefusion structure of the RSV F glycoprotein and its identification as the main target of neutralizing antibodies have provided new opportunities for development of an effective vaccine. Here, we describe the structure-based design of a self-assembling protein nanoparticle presenting a prefusion-stabilized variant of the F glycoprotein trimer (DS-Cav1) in a repetitive array on the nanoparticle exterior. The two-component nature of the nanoparticle scaffold enabled the production of highly ordered, monodisperse immunogens that display DS-Cav1 at controllable density. In mice and nonhuman primates, the full-valency nanoparticle immunogen displaying 20 DS-Cav1 trimers induced neutralizing antibody responses ∼10-fold higher than trimeric DS-Cav1. These results motivate continued development of this promising nanoparticle RSV vaccine candidate and establish computationally designed two-component nanoparticles as a robust and customizable platform for structure-based vaccine design. [Display omitted] •Design of a self-assembling protein immunogen displaying 20 copies of prefusion RSV F•In vitro assembly yields highly ordered immunogens with tunable antigen density•The nanoparticle immunogens induce potent neutralizing antibody responses•Fusion of DS-Cav1 to the trimeric nanoparticle subunit stabilizes the antigen A computationally designed self-assembling nanoparticle that displays 20 copies of a trimeric viral protein induces potent neutralizing antibody responses.