Precision vaccine design targeting the prefusion state of viral glycoproteins: advances in structural vaccinology

The prefusion conformation of viral glycoproteins is a key target for vaccine development because it can induce strong neutralizing antibody responses. Nevertheless, these structures are frequently metastable and susceptible to conformational alterations that diminish immunogenic efficacy. Progress in structural vaccinology has facilitated the meticulous design of viral proteins to maintain their prefusion conformation, thus improving vaccination effectiveness. This study emphasizes essential methodologies in precision vaccine design focused on preserving the structural integrity, solubility, and immunogenicity of viral glycoproteins. Methods include cavity-filling mutations, proline insertions, and disulfide bond engineering have demonstrated efficacy in enhancing structural stiffness and inhibiting unwanted post-fusion rearrangements. Hydrophobic surface residues are frequently substituted with polar or charged residues to boost solubility and minimize aggregation, while the development of salt bridges and helix-stabilizing substitutions further augment heat stability. The removal of proteolytic cleavage sites and the enhancement of hydrophobic core packing facilitate sustained conformational integrity. Alterations to the fusion peptide, an essential conserved area for viral entry, can inhibit early conformational changes, whereas charge-balancing alterations mitigate electrostatic stress. Glycan shielding conceals non-neutralizing or immunodominant epitopes, steering immune reactions towards conserved, protective areas. Collectively, these structure-guided interventions constitute a thorough molecular toolset, facilitating the creation of prefusion-stabilized immunogens for advanced vaccines. Successfully implemented in vaccine candidates for Respiratory Syncytial Virus (RSV), Human Immunodeficiency Virus (HIV), and Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), these methodologies establish a solid basis for the swift and logical generation of vaccines against emerging viral threats.