An integrative approach to rational engineering of dengue virus-like particles

<h2>Summary</h2> Virus-like particles (VLPs) are promising vaccine candidates due to their noninfectious and highly immunogenic nature. Enveloped VLPs are unstable and heterogeneous in size because they lack a viral genomic core, yet they can induce a robust immune response. This motivates the characterization of their biophysical and structural properties to enable rational design of stable, highly immunogenic particles. We employed an integrative approach combining multiscale modeling, structural analyses, and <i>in vitro</i> experiments to gain molecular insights into the factors governing VLP stability, homogeneity, secretion, and antibody binding. We focused on dengue virus VLPs, which elicit neutralizing antibodies similar to infectious virions. Systematic introduction of mutations facing lipid tails in the stem helix of the chimeric E protein, guided by molecular simulations, allowed modulation of secretion efficiency and immunogenicity. Overall, this work highlights the role of envelope protein-lipid interactions in maintaining VLP stability and yield, guiding engineering of improved VLP-based vaccines.