Intersection of Biophysical and Structural Approaches in Vaccine Design

Developments in vaccine technologies continue to enhance our capabilities in providing pre-emptive population-wide protection against devastating infectious diseases. Modern vaccinology has just recently begun to exploit the information available through detailed analysis of antigen structures. However, the three-dimensional antigen structures by themselves only provide a snapshot of these proteins. In order to provide practical value, interpretation of antigen structures often requires the integration of diverse biochemical properties. In combination, spatial, biophysical and functional characteristics provide a multi-dimensional framework for engineering vaccines and exploiting antigens to combat the pathogens that display them.

From a medical perspective, surface antigens are high-level targets that are often a key feature of a pathogen’s arsenal. The detailed atomic maps of these targets can reveal their exploitable weaknesses. The challenge in utilizing a 3D image of an antigen for vaccine development lies in teasing out the key properties to create a vaccine supportive of eliciting a strong immune response. Residue characteristics relating to binding and stability have been extremely powerful in antigen engineering efforts. For example, the rapid development of the Covid-19 vaccine can be credited to a deep structural and biophysical characterization of related Coronavirus spike glycoproteins. The dynamic states of the surface antigen are intimately tied to its function as a fusion mediator. A detailed understanding of the mechanism revealed the vulnerable conformational state as well as which epitopes would be presented. Residue changes can lock the conformational state but also enhance thermostability. While the majority of successful structure-based design stories have focused on viral pathogens, bacterial pathogens are also highly important as vaccine targets. Modern vaccine formulations themselves have moved beyond simple recombinant antigens to now include biomolecular packages for delivering antigen mRNA. Expanding the strategies for utilizing biophysical and biochemical properties will push forward and broaden the reach of future vaccine.

The aim of this Research Topic is to highlight biophysical and biochemical studies and methods that bridge the gap between the molecular-level details of a native antigen afforded by a structure and the final engineered vaccine.

Original Research Articles, Reviews, Mini Reviews and Perspective Articles are welcome. Antigenic targets from all microbial (viral, bacterial, and eukaryotic) pathogens will be considered. This Research Topic will cover, but is not limited to, the following areas:

• Structural studies and/or structural analysis of antigens
• Integration of broad experimental data onto antigen structures
• Residue-level mapping of biophysical properties (e.g., thermostability)
• Functional dynamics and surface accessibility
• Structural determinants of antibody-binding
• Chimeric and multivalent approaches
• Biophysical characterization of mRNA delivery systems