The pandemic outbreak of coronavirus disease 2019 (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ongoing evolution of the SARS-CoV-2 virus has induced significant challenges for vaccine efficacy, particularly in inducing broad and durable immunity against emerging variants while minimizing adverse effects. In chapter one, I tested the hypothesis of whether a strategy of multivalent and sequential heterologous spike protein vaccinations would induce a broader range and higher levels of neutralizing antibodies against SARS-CoV-2 variants and more effective protection than homologous spike protein vaccination. In the first approach, trivalent (Wuhan + Delta + Omicron) and sequential heterologous spike protein prime boost vaccination strategy demonstrated superior induction of neutralizing antibodies and receptor-binding inhibition across variants, as well as enhanced protective efficacy against SARS-CoV-2 challenge in mice, compared to homologous prime boost vaccination. In chapter two, I found that multivalent SARS-CoV-2 spike (Delta + Omicron variants)-encoding mRNA-based vaccines elicited stronger IgG responses and higher neutralizing antibody titers than high-dose monovalent spike mRNA vaccines. Lipid nanoparticles (LNPs) used to encapsulate mRNA vaccines exhibited adjuvant effects on enhancing the immunogenicity of homologous protein or foreign vaccine antigens when co-administered with inactivated split influenza or spike protein subunit vaccines. Together, these findings highlight the advantages of multivalent and heterologous vaccination strategies in broadening immune responses and improving protection against SARS-CoV-2 variants. The immunologic outcomes of combination vaccines suggest potential synergy between mRNA and protein-based platforms. My experimental results support the development of next-generation vaccines and a strategy of mRNA and protein combined vaccinations against COVID-19 and other pathogens.