Background <p>The SARS-CoV-2 virus has continuously evolved, with new variants like Delta, Omicron-BA.5, and XBB-EG.5 posing challenges to vaccine efficacy. mRNA vaccines have emerged as a promising tool due to their rapid development and adaptability. This study evaluates the protective efficacy of six novel mRNA vaccine candidates against these variants using a golden hamster model.</p> Methods <p>Six mRNA vaccines were designed, targeting the spike (S) and nucleocapsid (N) proteins of SARS-CoV-2. The vaccines were tested on golden hamsters, which were immunized and then challenged with Delta, Omicron-BA.5, and XBB-EG.5 variants. Key outcomes measured included body weight, viral RNA loads in various tissues, cytokine levels, and lung tissue pathology.</p> Results <p>Hamsters vaccinated with the novel mRNA vaccines showed reduced weight loss, lower viral RNA loads in throat swabs and lung tissues, and reduced levels of pro-inflammatory cytokines compared to control groups. Additionally, vaccinated animals exhibited significantly less lung damage as evidenced by both histological and immunofluorescence analyses, especially in groups vaccinated with RBD-Fe, RE-N, and COVID-19 epitope formulations.</p> Conclusions <p>These mRNA vaccines demonstrated broad protective efficacy against multiple SARS-CoV-2 variants. They elicited immune responses, reduced viral RNA loads, and mitigated inflammatory and pathological damage, highlighting their potential in combating rapidly evolving SARS-CoV-2 variants.</p>