Abstract
INTRODUCTION: The newly emerged Omicron subvariants demonstrate resistance to current therapeutic antibodies and an enhanced ability to evade the vaccine-induced immune responses. Among them, JN.1 sublineages are considered highly immune-evasive, underscoring the urgent need for broadly protective vaccines. Ferritin nanoparticles, with their unique hollow nanocage structure, provide an efficient antigen-display platform for next-generation vaccine development. METHODS: Based on the previously constructed Delta-6P-S recombinant protein vaccine with broad-spectrum protective effects, this study optimized the S protein structure displayed on the surface of ferritin nanoparticles by comparing the immune responses induced in C57BL/6J mice. RESULTS: Delta-4S1158 nanoparticles, containing a truncated S-6P structure with four additional mutation sites, elicited robust S-specific immunoglobulin G (IgG), potent neutralizing antibodies, and a Th2-biased T-cell response in C57BL/6J mice, demonstrating favorable immunogenicity and safety. The JN.1-4S1158 nanoparticles, based on this structural design, induced a strong cross-neutralizing antibody response in C57BL/6J mice and conferred effective protection against Omicron BA.5, XBB, and JN.1 variants. Vaccinated mice exhibited significantly reduced viral genomic loads in trachea and lung tissues compared to controls, with no infectious virus detected. Lung tissue pathology was minimal in vaccinated mice. CONCLUSION: The JN.1-4S1158 nanoparticle vaccine demonstrates broad-spectrum protective effects against Omicron subvariants and shows potential for further development. It also provides a basis for the development of a universal SARS-CoV-2 vaccine.