The ongoing evolution of SARS-CoV-2 variants emphasizes the need for vaccines providing broad cross-protective immunity. This study was undertaken to assess the ability of Advax-CpG55.2 adjuvanted monovalent recombinant spike protein (Wuhan, Beta, Gamma) vaccines or a trivalent formulation to protect hamsters againstBeta or Delta virus infection. The ability of vaccines to block virus transmission to naïve co-housed animals was also assessed. In naïve hosts, the Beta variant induced higher virus loads than the Delta variant, and conversely the Delta variant caused more severe disease and was more likely to be associated with virus transmission. The trivalent vaccine formulation provided the best protection against both Beta and Delta infection and also completely prevented virus transmission. The next best performing vaccine was the original monovalent Wuhan-based vaccine. Notably, hamsters that received the monovalent Gamma spike vaccine had the highest viral loads and clinical disease of all the vaccine groups, a potential signal of antibody dependent-enhancement (ADE). These hamsters were also the most likely to transmit Delta virus to naïve recipients. In murine studies, the Gamma spike vaccine induced the highest total spike protein to RBD IgG ratio and the lowest levels of neutralizing antibody, a context that could predispose to ADE. Overall, the study results confirmed that the current SpikoGen® vaccine based on Wuhan spike protein was still able to protect against clinical disease caused by either the Beta or Delta virus variants but suggested additional protection may be obtained by combining it with extra variant spike proteins to make a multivalent formulation. This study highlights the complexity of optimizing vaccine protection against multiple SARS-CoV-2 variants and stresses the need to continue to pursue new and improved COVID-19 vaccines able to provide robust, long-lasting, and broadly cross-protective immunity against constantly evolving SARS-CoV-2 variants.