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

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.
Cell 2019 v.176 no.6 pp. 1420-1431.e17
Primates, Respiratory syncytial virus, antigens, glycoproteins, mice, nanoparticles, neutralization, neutralizing antibodies, public health, vaccines
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.