The global COVID-19 pandemic has resulted in millions of deaths worldwide and the fastest approval of newly developed SARS-CoV-2 vaccines ever. Based on the TM-anchored S protein in its native, trimeric conformation, they typically elicited potent immune responses across young and middle-aged individuals. However, the mass-vaccination also showed that especially older individuals developed reduced and shorter lasting antibody responses. Due to the lack of age-adapted vaccines, strategies to improve S-specific antibody levels in the elderly were largely limited to increased injection frequencies. Therefore, the primary aim of this thesis was to systematically determine if and how different trimeric or monomeric S antigens delivered through DNA- or protein-based vaccination affect the priming of functional antibody responses particularly in old mice. It could be shown that the TM domain of S was crucial for trimer formation since the TM- antigen S 6-PΔTM lost its ability to form higher molecular structures. As compared to membrane-bound trimeric TM+ antigens (S and S 2-P), the secreted monomeric TM- S 6-PΔTM antigen could be produced in high amounts in transiently transfected HEK-293T cells. Interestingly, the trimeric (S and S 2-P) and monomeric (S 6-PΔTM) antigens elicited comparable S- and RBD-specific antibody titers, also with comparable pseudovirus neutralization activity in young mice through DNA- or protein-based vaccination. This demonstrated that the monomeric S 6-PΔTM presented epitopes that were sufficient for the induction of neutralizing antibodies. Furthermore, only the monomeric TM- S1-based S-596 but not S-300/450 antigens elicited measurable RBD-specific antibodies with neutralizing activity. This suggested that the neutralizing epitopes on monomeric S antigens are restricted to the RBD residues 451 to 541. The monomeric S 6-PΔTM and trimeric S 2-P antigens were further used to establish vaccination strategies in old mice. It could be demonstrated that the old immune system remained responsive to the trimeric S 2-P but not to the S 6-PΔTM and efficiently induced S- and RBD-specific antibodies when delivered as DNA-prime/DNA-boost (D x D) immunization. Similarly, a homologous protein-prime/protein-boost (P x P) immunization with monomeric S 6-PΔTM very inefficiently induced S- and RBD-specific antibodies in old mice. However, a heterologous DNA-prime/protein-boost (D x P) immunization with S 6-PΔTM efficiently induced high S- and RBD-specific antibodies in old mice, which even reached similar levels as in young mice and also conferred a comparable pseudovirus neutralization activity. In contrast, the reversed protein-prime/DNA-boost vaccination could not rescue the impaired antibody response in old mice. Although the immune stimulatory mechanism(s) of the heterologous D x P immunization are not completely understood, there was first evidence that this vaccination regimen might activate pDCs and cDC2s, which could interact with CD4+ T helper cells to induce an age-adapted microenvironment with elevated levels of IL-2, IL-4, IL-6, TNFα and IFNγ. These findings show that especially the delivery platform and also the structure are important to efficiently prime humoral immune responses in old mice and might therefore be relevant for designing age-adapted vaccines.