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Updated: May 29, 2025
Engineering Antiviral Agents via Surface Plasmon Resonance
Published on: June 14, 2022
Structural prediction of chimeric immunogen candidates to elicit targeted antibodies against betacoronaviruses
Jamel Simpson1, Peter M Kasson1,2,3
1Program in Biophysics and Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America.
Abstract:
Betacoronaviruses pose an ongoing pandemic threat. Antigenic evolution of the SARS-CoV-2 virus has shown that much of the spontaneous antibody response is narrowly focused rather than broadly neutralizing against even SARS-CoV-2 variants, let alone future threats. One way to overcome this is by focusing the antibody response against better-conserved regions of the viral spike protein. This has been demonstrated empirically in prior work, but we posit that systematic design tools will further potentiate antigenic focusing approaches. Here, we present a design approach to predict stable chimeras between SARS-CoV-2 and other coronaviruses, creating synthetic spike proteins that display a desired conserved region, in this case S2, and vary other regions. We leverage AlphaFold to predict chimeric structures and create a new metric for scoring chimera stability based on AlphaFold outputs. We evaluated 114 candidate spike chimeras using this approach. Top chimeras were further evaluated using molecular dynamics simulation as an intermediate validation technique, showing good stability compared to low-scoring controls. Experimental testing of five predicted-stable and two predicted-unstable chimeras confirmed 5/7 predictions, with one intermediate result. This demonstrates the feasibility of the underlying approach, which can be used to design custom immunogens to focus the immune response against a desired viral glycoprotein epitope.
Insights
Scientists developed a new method to design synthetic coronavirus spike proteins. This approach aims to focus the immune response against conserved viral regions, potentially improving vaccines against current and future pandemic threats.
Area of Science:
- Virology
- Immunology
- Computational Biology
Background:
- Betacoronaviruses, including SARS-CoV-2, present a continuous pandemic risk.
- Spontaneous antibody responses are often narrowly focused, limiting effectiveness against viral variants and future threats.
- Targeting conserved regions of the viral spike protein can elicit broader neutralizing antibodies.
Purpose of the Study:
- To present a systematic design approach for creating stable chimeric spike proteins.
- To engineer synthetic immunogens that focus antibody responses on conserved viral epitopes.
- To overcome limitations of natural antibody responses against evolving coronaviruses.
Main Methods:
- Utilized AlphaFold to predict the structural stability of chimeric spike proteins.
- Developed a novel chimera stability scoring metric based on AlphaFold predictions.
- Evaluated 114 candidate chimeras, with top candidates further assessed using molecular dynamics simulations.
- Experimentally tested seven selected chimeras (five predicted stable, two predicted unstable).
Main Results:
- The computational design approach successfully predicted chimeric spike protein stability.
- Molecular dynamics simulations supported the stability predictions for top candidates.
- Experimental validation confirmed the accuracy of the design approach, with 5 out of 7 tested chimeras showing predicted stability.
- One chimera showed intermediate stability, and one predicted-stable chimera was unstable.
Conclusions:
- The developed design strategy is feasible for creating custom immunogens.
- This approach can engineer synthetic spike proteins to focus immune responses on desired conserved epitopes.
- This method holds potential for developing next-generation vaccines against coronaviruses and other viral threats.
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