Stabilized coronavirus spike proteins for enhanced vaccine efficacy

Engineered proteins with stabilized coronavirus spike protein ectodomains enhance immune response and are useful in diagnostics, screening, and vaccines against coronaviruses like SARS-CoV-2 by maintaining prefusion conformation, potentially producing cross-reactive antibodies.

Background

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has highlighted the urgent need for effective vaccines and therapeutics to combat coronavirus infections. The spike (S) protein of coronaviruses, particularly its receptor-binding domain (RBD), is a key target for neutralizing antibodies and vaccine development due to its role in mediating virus entry into host cells.

However, the S protein is highly dynamic and prone to conformational changes, which can complicate the development of stable vaccine antigens and therapeutics. Existing approaches, such as mRNA vaccines and recombinant protein subunit vaccines, have shown promise but face challenges related to stability, immunogenicity, and the emergence of viral variants that may evade immune responses.

Stabilizing the S protein in its prefusion conformation is crucial for maintaining its antigenic properties and eliciting a robust immune response. However, achieving this stabilization while retaining the protein’s immunogenicity and ensuring broad protection against diverse coronavirus strains remains a significant scientific and technical challenge.

Technology description

Engineered proteins featuring stabilized coronavirus spike (S) protein ectodomains have been developed to enhance antigenicity, particularly for beta-coronaviruses like SARS-CoV-2. These proteins are designed for use in diagnostics, screening platforms, and vaccine compositions. Stabilization is achieved through modifications such as disulfide bonds, cavity-filling substitutions, proline substitutions, and electrostatic interaction substitutions. These modifications maintain the protein in a prefusion conformation, essential for eliciting an effective immune response.

The engineered proteins can stimulate an immune response against the coronavirus S protein, potentially leading to the production of cross-reactive antibodies. Additionally, nucleic acid molecules encoding these engineered proteins can be used in pharmaceutical compositions to prevent coronavirus infections. The proteins can also be used in trimeric forms and fused with trimerization domains to enhance stability and functionality.

This technology is differentiated by its focus on maintaining the S protein in a prefusion conformation, which is crucial for effective immune response stimulation. The use of multiple stabilization strategies, including disulfide bonds and proline substitutions, ensures that the engineered proteins remain stable and functional. This approach not only enhances the antigenicity of the proteins but also allows to produce cross-reactive antibodies, offering potential protection against different coronavirus strains.

The inclusion of nucleic acid molecules encoding these proteins further broadens the application scope, enabling their use in a variety of pharmaceutical compositions. The ability to produce these proteins in trimeric forms with enhanced stability and functionality sets this technology apart, providing a robust platform for developing diagnostics and vaccines against coronavirus infections.