Location: Biologics Development Module
Project Number: 3022-32000-026-022-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: Feb 27, 2026
End Date: Feb 26, 2027
Objective:
Objective 1: Selective Disruption of Yeast Envelope: Cooperator will simulate vesicles in silico exposed to classes of detergents spanning nonionic, zwitterionic, cationic, and anionic head groups and varying tail lengths. Outcomes such as bilayer thinning, area dilation, pore nucleation, rupture, and mixed micelle formation will be quantified versus detergent concentration and chemistry to map regimes of reversible permeabilization versus catastrophic solubilization.
Objective 2: Virus Like Particle (VLP) Integrity and Adjuvant Function: Coarse-grained VLP capsid models will be exposed to detergents identified in Objective 1. Cooperator will track capsid radius, shape fluctuations, inter-subunit contacts, and hydrophobic surface exposure, identifying formulations that preserve overall architecture while potentially enhancing antigen presentation. Interactions of detergent-decorated VLPs with model membranes will be used as proxies for adjuvant-relevant membrane engagement.
Objective 3: Separation of Yeast Proteins from VLPs: Generic yeast proteins will be modeled as coarse-grained chains with different hydrophobic and electrostatic patterns and their partitioning between aqueous, micellar, and VLP-associated states examined in the presence of candidate detergents. Binding free energies and micelle size distributions will be used to predict conditions where yeast proteins are preferentially solubilized into small micelles, while VLPs remain in larger, separable assemblies.
Objective 4: Integrated Optimization of Detergent Formulations: Lysis efficiency, VLP compatibility, protein solubilization selectivity, and practical parameters such as chemistry, manufacturing and controls (CMC) and likely toxicity will be combined into a multi-criteria scoring framework. Single-component and mixed detergent systems will be screened to identify Pareto-optimal formulations that best satisfy the competing demands of selective yeast lysis, VLP preservation, and adjuvant function.
Approach:
Most virus-like-particle (VLP) vaccines depend on adjuvants to boost and shape the immune response. Classical and modern adjuvants act through mechanisms including depot formation, enhanced antigen uptake, and innate immune receptor activation. Detergent-like molecules are involved both as processing aids and as functional components that perturb cell membranes and can influence immunogenicity. Yeast cell wall architecture is dynamic and responsive to environmental cues, which makes yeast highly resilient to physical and chemical disruption. Chemical permeabilization using detergents and organic solvents has been explored for creating leaky but viable cells and for complete lysis to recover intracellular products. Empirical work indicates that milder nonionic detergents and carefully tuned solvent conditions can disrupt membranes while avoiding widespread protein denaturation, yet a mechanistic mapping between detergent structure and disruption pathways is still missing. Cooperator will use in silico modeling to identify and test conditions of "ideal" adjuvant for yeast-produced VLPs, while working to identify real-world adjuvant candidates that display "ideal" parameters.