An Engineered Spike Immunogen Drives Broad Protection of a Bivalent Recombinant Protein COVID-19 Vaccine in Animal Models.

The continued evolution of SARS-CoV-2 has reduced the protective effectiveness of first-generation vaccines and underscores the need for broadly reactive next-generation vaccine candidates. Here, we evaluated STFKB, an alum-adjuvanted bivalent recombinant protein vaccine composed of the monomeric Spike (STFKprototype) and the engineered Spike (STFK1628X). We assessed the immunogenicity, tolerability, and protective efficacy of STFKB in mice, rats, guinea pigs, rhesus macaques, and Syrian hamsters. STFKB induced robust STFK- and STFK1628X-specific antibody responses and broadly reactive neutralizing antibodies against multiple SARS-CoV-2 variants in the tested animal models. In hamster challenge studies, STFKB vaccination protected animals from Omicron BA.1 and BA.5 challenge, as shown by reduced body-weight loss, lower viral RNA loads in respiratory tissues, and improved gross lung pathology. Across the tested preclinical models, STFKB was well tolerated, with no vaccine-related overt toxicity observed under the study conditions. These findings support the rationale and translational potential of the bivalent vaccine strategy proposed in this study.