A simulation-driven approach was used to design S2-only immunogens stabilized in a closed prefusion conformation for SARS-CoV-2. The S2 subunit of the spike protein is highly conserved and can elicit broadly neutralizing and protective antibodies, but its instability limits its use as a vaccine strategy. By using molecular simulations, researchers identified tryptophan substitutions (V991W and T998W) that stabilize the S2 trimer in the closed prefusion state. Structural characterization via cryo-EM confirmed the molecular basis of this stabilization. The engineered S2 immunogen showed increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses. The study highlights the importance of understanding the conformational dynamics of the S2 trimer, which is crucial for designing effective vaccines. The simulations revealed that the S2 trimer transitions from a closed to an open conformation through an asymmetric protomer-protomer separation. The tryptophan substitutions were found to slow down this transition, enhancing the stability of the closed prefusion conformation. The results show that the engineered S2 immunogen can neutralize different SARS-CoV-2 variants, including Wuhan-1 and Omicron BA.1, indicating its potential as a broad-spectrum vaccine. The study also demonstrates the value of integrating computational methods with experimental validation to design stable and immunogenic antigens. The findings suggest that the S2 trimer can be stabilized in the closed prefusion conformation, which could lead to the development of pan-coronavirus vaccines. The approach used here provides a framework for designing vaccines that are effective against a wide range of coronaviruses, including emerging variants. The results underscore the importance of dynamic information from molecular simulations in informing immunogen design and highlight the potential of computational methods in vaccine development.A simulation-driven approach was used to design S2-only immunogens stabilized in a closed prefusion conformation for SARS-CoV-2. The S2 subunit of the spike protein is highly conserved and can elicit broadly neutralizing and protective antibodies, but its instability limits its use as a vaccine strategy. By using molecular simulations, researchers identified tryptophan substitutions (V991W and T998W) that stabilize the S2 trimer in the closed prefusion state. Structural characterization via cryo-EM confirmed the molecular basis of this stabilization. The engineered S2 immunogen showed increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses. The study highlights the importance of understanding the conformational dynamics of the S2 trimer, which is crucial for designing effective vaccines. The simulations revealed that the S2 trimer transitions from a closed to an open conformation through an asymmetric protomer-protomer separation. The tryptophan substitutions were found to slow down this transition, enhancing the stability of the closed prefusion conformation. The results show that the engineered S2 immunogen can neutralize different SARS-CoV-2 variants, including Wuhan-1 and Omicron BA.1, indicating its potential as a broad-spectrum vaccine. The study also demonstrates the value of integrating computational methods with experimental validation to design stable and immunogenic antigens. The findings suggest that the S2 trimer can be stabilized in the closed prefusion conformation, which could lead to the development of pan-coronavirus vaccines. The approach used here provides a framework for designing vaccines that are effective against a wide range of coronaviruses, including emerging variants. The results underscore the importance of dynamic information from molecular simulations in informing immunogen design and highlight the potential of computational methods in vaccine development.