The SARS-CoV-2 pandemic necessitated effective vaccines that can endure antigenic mutations. Here we demonstrate highly immunogenic conjugate vaccines that elicit broad cross-neutralization to variants of concern (VOC) in animal studies. By utilizing protein-protein conjugation and Toll-Like Receptor (TLR) agonist adjuvants we achieve enhanced immunogenicity compared to unconjugated equivalents. These vaccine candidates induced broad cross-protection against several VOC, a characteristic lacking in early COVID-19 vaccines. Murine neutralizing antibody (nAb) titers from animals vaccinated with Beta-only conjugates were equivalent between Beta, Delta, Omicron BA.1, BA.2, and BA.4/BA.5 variants, which were circulating up to three years after the antigenic Beta strain. Additionally, Beta-Delta bivalent conjugate vaccines readily prevented disease in hamster challenge. Together this demonstrates a vaccine with remarkably broad cross-protection and potential to protect for extended periods despite mutations, without requiring modified boosters or antigen adaption. These techniques can be applied to more recent SARS-CoV-2 strains, and other viruses, highlighting the benefits of protein-protein conjugation coupled with TLR agonist secondary adjuvants.
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