This study presents a simulation-driven approach to design stabilized S2-only immunogens for COVID-19 vaccines. The SARS-CoV-2 spike (S) protein, which is the primary antigen in most COVID-19 vaccines, consists of two subunits, S1 and S2. While S1 is immunodominant and targets the host's humoral immune response, S2 is highly conserved and less prone to accumulate mutations, making it a promising target for broader protection against different variants. However, S2 is metastable and transitions to a stable, postfusion conformation when S1 is removed. To address this, the researchers used molecular dynamics simulations to characterize the opening mechanism of the S2 trimer and designed tryptophan substitutions to stabilize the closed prefusion conformation. These substitutions improved thermostability, cellular expression, and immunogenicity, as evidenced by cryo-EM structural characterization and neutralization assays in mice. The engineered S2 immunogen, HexaPro-SS-2W, showed increased expression yield, superior thermostability, and preserved immunogenicity against various SARS-CoV-2 variants. This work highlights the potential of simulation-driven design in vaccine development and suggests that stabilized S2 immunogens could serve as a foundation for pan-coronavirus vaccines.This study presents a simulation-driven approach to design stabilized S2-only immunogens for COVID-19 vaccines. The SARS-CoV-2 spike (S) protein, which is the primary antigen in most COVID-19 vaccines, consists of two subunits, S1 and S2. While S1 is immunodominant and targets the host's humoral immune response, S2 is highly conserved and less prone to accumulate mutations, making it a promising target for broader protection against different variants. However, S2 is metastable and transitions to a stable, postfusion conformation when S1 is removed. To address this, the researchers used molecular dynamics simulations to characterize the opening mechanism of the S2 trimer and designed tryptophan substitutions to stabilize the closed prefusion conformation. These substitutions improved thermostability, cellular expression, and immunogenicity, as evidenced by cryo-EM structural characterization and neutralization assays in mice. The engineered S2 immunogen, HexaPro-SS-2W, showed increased expression yield, superior thermostability, and preserved immunogenicity against various SARS-CoV-2 variants. This work highlights the potential of simulation-driven design in vaccine development and suggests that stabilized S2 immunogens could serve as a foundation for pan-coronavirus vaccines.