Vaccines are one of the most significant scientific discoveries allowing reduction and almost complete eradication of deadly diseases such as smallpox and polio. As diseases continue to emerge, we must develop ways to produce effective vaccines faster. The quality and magnitude of most vaccines can be modulated by targeting the innate immune system. To do this, we need a better understanding of the pathways regulating innate immunity. My work focuses on improving the innate immune system through two ways: the design of novel conjugates targeting multiple innate immune receptors and the design of novel biomaterials to control innate immune memory or trained immunity. Vaccines use adjuvants to improve the immune response towards the antigen of interest. Adjuvants targeting multiple innate immune receptors produce distinct responses capable of modulating downstream adaptive immunity. However, there is a gap in mechanistic understanding of multi- TLR agonists, limiting their use as adjuvants. In chapter 2, I will discuss the mechanism of action of novel covalently linked TLR agonist dimers. Similarly, antigen-adjuvant conjugates offer promising ways to ensure co-delivery and effective innate immune cell activation leading to better downstream adaptive immune responses. In chapter 3, I describe the design of a novel antigen-adjuvant conjugate with improved CD8+ T-cell responses in mice. An alternate method of targeting innate immunity to improve overall disease resistance involves inducing non-specific memory referred to as trained immunity. Existing training methods do not offer temporal control, potentially leading to uncontrolled inflammation in certain populations. In chapter 4, I discuss the design and application of a novel biomaterial for the temporal control of trained immunity using a sustained release mechanism. Finally, in chapter 5, I discuss our recent findings on the impact of trained immunity in improving antigen-specific antibody responses. Taken together, these chapters demonstrate two new avenues that make trained immunity an exciting tool for developing novel prophylactics for overall disease resistance and improved responses to vaccinations.