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Immune-focused RBD nanoparticles induce cross-reactive, RBS-directed responses capable of variant-resistant

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A novel nanoparticle vaccine targeting the SARS-CoV-2 receptor binding site effectively neutralizes Omicron variants. This engineered immunogen demonstrates durable, cross-reactive antibody responses, offering a promising strategy against evolving viruses.

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Area of Science:

  • Immunology
  • Virology
  • Vaccine Development

Background:

  • New SARS-CoV-2 variants continually emerge, posing threats due to immune evasion from prior infections or vaccinations.
  • The Omicron BA.1 variant caused significant antigenic shifts, reducing antibody effectiveness and leading to loss of Emergency Use Authorization (EUA) for some vaccines.
  • Concerns exist regarding the re-emergence of SARS-CoV-2 variants related to BA.1.

Purpose of the Study:

  • To engineer a self-assembling nanoparticle displaying an optimized immunogen (RBD 4mut g5.1) for broad SARS-CoV-2 neutralization.
  • To evaluate the immunogenicity and protective efficacy of the RBD 4mut g5.1 nanoparticle vaccine in preclinical models.
  • To demonstrate that a single, rationally designed component can elicit robust and cross-reactive immune responses.

Main Methods:

  • Structure-guided design was used to create the RBD 4mut g5.1 immunogen, incorporating four BA.1 mutations in the receptor binding site (RBS).
  • The immunogen was displayed on a self-assembling nanoparticle platform.
  • Immunogenicity and neutralization assays were performed in both naïve and antigen-experienced mouse models.

Main Results:

  • The RBD 4mut g5.1 nanoparticle induced durable and cross-reactive antibody responses in mice.
  • These antibodies demonstrated potent neutralization of ancestral SARS-CoV-2 and multiple Omicron variants.
  • The vaccine conferred heterologous protection at a memory timepoint, indicating long-term immune memory.

Conclusions:

  • A single, rationally designed immunogen on a nanoparticle platform is sufficient for generating broad immunity against SARS-CoV-2 variants.
  • The RBD 4mut g5.1 nanoparticle represents a promising vaccine candidate for combating immune-evasive SARS-CoV-2 variants.
  • This approach offers a potential strategy for developing vaccines against other pathogens with evolving epitopes.