An Integrative Approach to Rational Engineering of Dengue Virus-Like Particles

Virus-like particles (VLPs) are promising vaccine candidates due to their noninfectious and highly immunogenic nature. These particles lack a viral genomic core and display a robust host immune response. VLPs are typically highly unstable and heterogeneous in size. This motivates the characterization of the biophysical and structural properties of VLPs to facilitate the rational design of stable and highly immunogenic particles. We employed an integrative approach combining multiscale modeling, lipidomics, and in vitro experiments to gain molecular insights into the factors governing VLP stability and homogeneity. We focused on dengue virus VLPs, which are known to elicit neutralizing antibodies similar to infectious virions. Systematic introduction of mutations in the structurally crucial stem helix region of the chimeric E protein guided by molecular simulations allowed us to modulate the secretion efficiency of VLPs in vitro . Overall, this work highlights the role of protein□lipid envelope interactions in maintaining VLP stability with better yield, providing a framework for the future development of stable and immunogenic next-generation VLP-based vaccines.