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RBD-SD1 Nanoparticle Vaccines From DPP4-Using Merbecoviruses Elicit a Cross-Reactive Antibody Response but Limited
Peter J Halfmann1, Jeong Soo Lee2, Tong Wang1
1Department of Pathobiological Sciences, School of Veterinary Medicine, Influenza Research Institute, University of Wisconsin, Madison, Wisconsin, USA.
Abstract:
Coronaviruses within the Merbecovirus subgenus, including Middle East respiratory syndrome coronavirus (MERS-CoV) and its dipeptidyl peptidase 4 (DPP4)-using relatives, pose a persistent zoonotic threat. Efforts to prepare for future Merbecovirus spillover events require vaccines that protect beyond a single virus strain. To evaluate antigenic conservation and cross-protective potential, SpyCatcher-mi3 nanoparticles displaying the receptor-binding domain and subdomain 1 (RBD-SD1) from three DPP4-using merbecoviruses, MERS-CoV, NL140422, and HKU4, were generated. Female mice immunized with these nanoparticle vaccines elicited robust IgG antibody endpoint binding titers and cross-reactive antibody responses against the three merbecoviruses. Only the MERS-CoV RBD-SD1 vaccine, however, elicited neutralizing antibodies against MERS-CoV. While vaccination with MERS-CoV RBD-SD1 reduced lung viral titers in MERS-CoV-challenged human DPP4 mice below the limit of detection, no significant reduction in virus titers was seen in NL140422- and HKU4-RBD-SD1-vaccine-immunized mice. These findings indicate that while the RBD-SD1 interface presents conserved antigenic features sufficient for serological cross-recognition, these epitopes may not be functionally immunodominant for cross-neutralization.
Insights
Merbecovirus nanoparticle vaccines show conserved antigenic features for cross-recognition but limited cross-neutralization. MERS-CoV vaccines reduced viral load, but others did not, highlighting epitope immunodominance challenges.
Area of Science:
- Virology
- Immunology
- Vaccine Development
Background:
- Merbecoviruses, including MERS-CoV, represent a significant zoonotic threat requiring broad-spectrum vaccines.
- Current vaccine strategies need to address cross-protection against multiple Merbecovirus strains.
Purpose of the Study:
- To assess the antigenic conservation and cross-protective potential of Merbecovirus receptor-binding domain and subdomain 1 (RBD-SD1) nanoparticle vaccines.
- To evaluate the immunogenicity and efficacy of vaccines derived from MERS-CoV, NL140422, and HKU4.
Main Methods:
- Generation of SpyCatcher-mi3 nanoparticle vaccines displaying RBD-SD1 from three DPP4-using merbecoviruses.
- Immunization of female mice with nanoparticle vaccines and assessment of antibody responses.
- Challenge studies in human DPP4 mice to evaluate vaccine-induced protection against MERS-CoV, NL140422, and HKU4.
Main Results:
- Nanoparticle vaccines elicited robust IgG antibody titers and cross-reactive responses against all three viruses.
- Only the MERS-CoV RBD-SD1 vaccine induced neutralizing antibodies against MERS-CoV.
- MERS-CoV RBD-SD1 vaccination significantly reduced MERS-CoV lung viral titers, while other vaccines showed no significant reduction.
Conclusions:
- The RBD-SD1 interface possesses conserved epitopes for serological cross-recognition among merbecoviruses.
- These conserved epitopes are not consistently immunodominant for achieving functional cross-neutralization.
- Further research is needed to develop Merbecovirus vaccines that induce broad cross-protective immunity.
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