Project 4: Protein nanoparticle vaccines

PROJECT SUMMARY - PROJECT 4: PROTEIN NANOPARTICLE VACCINES Project 4 focuses on developing generalizable approaches to the design, production, and evaluation of two-component protein nanoparticle vaccines for arenaviruses, phenuiviruses, and paramyxoviruses. These approaches will be enabled by powerful new machine learning-based tools for protein modeling and design. In Aim 1, we will develop generalizable approaches to designing de novo protein nanoparticle immunogens that display oligomeric antigens in specific geometrical arrangements with atomic-level accuracy. These methods and approaches will be used to design nanoparticle immunogens that present trimeric paramyxovirus fusion (F) and arenavirus glycoprotein complex (GPC) antigens, as well as tetrameric paramyxovirus receptor binding protein (RBP) antigens. The designed nanoparticle immunogens will present each antigen in various symmetries and valencies, with precisely varied antigen-antigen spacing and orientation, each an important structural determinant of immunogenicity. In Aim 2, we will develop generalizable approaches to designing de novo protein nanoparticle immunogens that display monomeric and heterodimeric antigens in specific geometric arrangements with atomic-level accuracy. The orientation of these antigens-each of which has the full set of 6 rotational and translational degrees of freedom since they lack internal symmetry-will be precisely controlled to maximize the accessibility of epitopes that are targeted by neutralizing antibodies. We will design nanoparticles in which the monomeric or heterodimeric antigens are presented in various symmetries and valencies, with precisely varied antigen-antigen spacing and orientation. In Aim 3, we will produce the designed vaccine candidates; intensively characterize their biochemical, biophysical, antigenic, and structural properties; and rigorously evaluate their performance in immunogenicity studies and challenge studies in small and large animal models. We will build on the Institute for Protein Design's extensive infrastructure for protein production and characterization to rapidly screen the large numbers of vaccine candidates we design using our machine learning-based methods. Structural characterization at UW and deep mutational scanning at the Fred Hutchinson Cancer Center will both inform and provide rigorous assessment of the accuracy of our design methods. Finally, we will leverage the deep expertise and new animal models developed at UTMB Galveston to rigorously evaluate our designed nanoparticle vaccines and identify lead candidates for further preclinical and clinical development.