A self-assembled nanoparticle vaccine displaying chimeric and trimeric RBD-HRC elicits broad-spectrum neutralizing antibodies against multiple coronaviruses.

Coronaviruses, known for their high mutation rates and character of cross-species transmission, continue to pose significant threats to global health, as demonstrated by outbreaks of SARS, MERS, and SARS-CoV-2. Vaccines remain the most effective means of preventing viral infection, transmission, and epidemic spread. However, traditional vaccine development faces significant challenges due to the rapid evolution of viruses and their ability to evade the immune system. In response, we present a novel vaccine design based on self-assembling nanoparticles that display multiple glycosylation-modified receptor-binding domain-heptad repeat C-domain (RBD-HRC) trimers, forming a multimerized, polyvalent chimeric RBD-HRC vaccine. This approach enhances immunogenicity by closely mimicking the native structure of the spike protein, thereby eliciting broad-spectrum neutralizing antibodies that can target coronavirus-derived pseudoviruses from different genera. Notably, it even demonstrates neutralizing activity against coronaviruses not included in the vaccine design. Additionally, this vaccine formulation induces a robust cellular immune response. The multivalent nature of the nanoparticle vaccine promotes stronger T-cell activation and exhibits enhanced broad-spectrum activity. Our strategy offers a scalable and versatile platform for the development of vaccines against a wide range of viral pathogens. IMPORTANCE: Broad-spectrum vaccines are urgently needed to control the rapid evolution of viruses and their cross-species transmission. The effective presentation of epitopes, especially conserved ones, plays a critical role in vaccine design. Moreover, the polymerization of epitopes has been shown to significantly enhance immunogenicity. In this study, we present a scalable platform for developing broad-spectrum vaccines against rapidly evolving pathogens. This vaccine platform, based on self-assembling nanoparticles, displays glycosylation-modified coronavirus spike receptor-binding domain-heptad repeat C-domain (RBD-HRC) trimers, enabling the formation of multimerized and polyvalent chimeric antigens. We found that the trivalent RBD-HRC nanoparticle vaccine elicits the broadest neutralizing antibody response, strongest T-cell activation, and highest neutralization potency compared to other formulations, offering valuable insights for future vaccine development.