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Author Spotlight: A Pseudotype Virus System for Assessing Omicron Subvariants and Neutralizing Antibodies in SARS-CoV-2 Research
Published on: September 8, 2023
Pan-beta-coronavirus subunit vaccine prevents SARS-CoV-2 Omicron, SARS-CoV, and MERS-CoV challenge
Gang Wang1, Abhishek K Verma2, Xiaoqing Guan1
1Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
Abstract:
Three highly pathogenic coronaviruses (CoVs), SARS-CoV-2, SARS-CoV, and MERS-CoV, belonging to the genus beta-CoV, have caused outbreaks or pandemics. SARS-CoV-2 has evolved into many variants with increased resistance to the current vaccines. Spike (S) protein and its receptor-binding domain (RBD) fragment of these CoVs are important vaccine targets; however, the RBD of the SARS-CoV-2 Omicron variant is highly mutated, rending neutralizing antibodies elicited by ancestral-based vaccines targeting this region ineffective, emphasizing the need for effective vaccines with broad-spectrum efficacy against SARS-CoV-2 variants and other CoVs with pandemic potential. This study describes a pan-beta-CoV subunit vaccine, Om-S-MERS-RBD, by fusing the conserved and highly potent RBD of MERS-CoV into an RBD-truncated SARS-CoV-2 Omicron S protein, and evaluates its neutralizing immunogenicity and protective efficacy in mouse models. Om-S-MERS-RBD formed a conformational structure, maintained effective functionality and antigenicity, and bind efficiently to MERS-CoV receptor, human dipeptidyl peptidase 4, and MERS-CoV RBD or SARS-CoV-2 S-specific antibodies. Immunization of mice with Om-S-MERS-RBD and adjuvants (Alum plus monophosphoryl lipid A) induced broadly neutralizing antibodies against pseudotyped MERS-CoV, SARS-CoV, and SARS-CoV-2 original strain, as well as T-cell responses specific to RBD-truncated Omicron S protein. Moreover, the neutralizing activity against SARS-CoV-2 Omicron subvariants was effectively improved after priming with an Omicron-S-RBD protein. Adjuvanted Om-S-MERS-RBD protein protected mice against challenge with SARS-CoV-2 Omicron variant, MERS-CoV, and SARS-CoV, significantly reducing viral titers in the lungs. Overall, these findings indicated that Om-S-MERS-RBD protein could develop as an effective universal subunit vaccine to prevent infections with MERS-CoV, SARS-CoV, SARS-CoV-2, and its variants.
Importance:
Coronaviruses (CoVs), SARS-CoV-2, SARS-CoV, and MERS-CoV, the respective causative agents of coronavirus disease 2019, SARS, and MERS, continually threaten human health. The spike (S) protein and its receptor-binding domain (RBD) fragment of these CoVs are critical vaccine targets. Nevertheless, the highly mutated RBD of SARS-CoV-2 variants, especially Omicron, significantly reduces the efficacy of current vaccines against SARS-CoV-2 variants. Here a protein-based pan-beta-CoV subunit vaccine is designed by fusing the potent and conserved RBD of MERS-CoV into an RBD-truncated Omicron S protein. The resulting vaccine maintained effective functionality and antigenicity, induced broadly neutralizing antibodies against all of these highly pathogenic human CoVs, and elicited Omicron S-specific cellular immune responses, protecting immunized mice from SARS-CoV-2 Omicron, SARS-CoV, and MERS-CoV infections. Taken together, this study rationally designed a pan-beta-CoV subunit vaccine with broad-spectrum efficacy, which has the potential for development as an effective universal vaccine against SARS-CoV-2 variants and other CoVs with pandemic potential.
Insights
A novel pan-beta-coronavirus vaccine, Om-S-MERS-RBD, was developed by combining MERS-CoV and Omicron S proteins. This universal vaccine shows broad-spectrum efficacy against SARS-CoV-2 variants, MERS-CoV, and SARS-CoV in mouse models.
Area of Science:
- Virology
- Immunology
- Vaccine Development
Background:
- Highly pathogenic coronaviruses (CoVs) like SARS-CoV-2, SARS-CoV, and MERS-CoV pose significant global health threats.
- Current vaccines face challenges due to rapid evolution of SARS-CoV-2 variants, particularly Omicron, with mutations in the spike protein's receptor-binding domain (RBD).
- There is a critical need for broad-spectrum vaccines effective against multiple beta-CoVs and their emerging variants.
Purpose of the Study:
- To design and evaluate a pan-beta-CoV subunit vaccine, Om-S-MERS-RBD, for broad-spectrum protection.
- To assess the neutralizing immunogenicity and protective efficacy of Om-S-MERS-RBD in preclinical mouse models.
- To address the limitations of current vaccines against rapidly evolving SARS-CoV-2 variants and other pandemic-potential CoVs.
Main Methods:
- A novel subunit vaccine, Om-S-MERS-RBD, was constructed by fusing the MERS-CoV RBD to an RBD-truncated SARS-CoV-2 Omicron S protein.
- The vaccine's structural integrity, functionality, and antigenicity were confirmed through binding assays.
- Immunogenicity and protective efficacy were evaluated in mouse models, including antibody and T-cell responses, and challenge studies against MERS-CoV, SARS-CoV, and SARS-CoV-2 variants.
Main Results:
- Om-S-MERS-RBD maintained its conformational structure, functionality, and antigenicity, binding effectively to relevant receptors and antibodies.
- Immunization induced broadly neutralizing antibodies against MERS-CoV, SARS-CoV, and the original SARS-CoV-2 strain, alongside Omicron S-specific T-cell responses.
- The vaccine demonstrated significant protection against SARS-CoV-2 Omicron variants, MERS-CoV, and SARS-CoV challenge, with reduced viral loads in lungs.
Conclusions:
- The Om-S-MERS-RBD subunit vaccine exhibits promising broad-spectrum efficacy against multiple pathogenic beta-CoVs.
- This rationally designed vaccine has the potential to be developed into an effective universal vaccine against current and future coronavirus threats.
- The study highlights a viable strategy for developing vaccines that can overcome viral mutations and variants of concern.
