Vaccines have benefited global health by controlling or eradicating multiple previously fatal diseases. While many early vaccines were efficacious, sophisticated new vaccines and immunotherapies need to address current challenges in the field, including diseases that avoid immune detection or lack strong molecular targets for the immune system. Overcoming these hurdles requires strategies to specifically control the magnitude and type of immune response generated. Biomaterials offer attractive features to achieve this goal, including protection of encapsulated signals, controlled release of cargos, and tunable features for cell targeting. Intriguingly, recent research reveals many common biomaterials activate the immune system, even without other signals. This intrinsic activation results, at least in part, from biomaterial physicochemical features that mimic pathogens and other foreign materials. Surprisingly, although degradable materials are being intensely studied as vaccines carriers, little research has investigated how the intrinsic immunogenicity of these materials changes as polymers degrade. The work in this dissertation reveals parameters impacting material intrinsic immunogenicity and exploits this new understanding to test the influence of biomaterial-based vaccines on the function of lymph nodes (LNs), key tissues that coordinate immunity. In the first aim, the immunostimulatory properties of a library of degradable polymers, poly(beta-amino esters) (PBAEs), were investigated in cell and animal models. PBAEs in soluble forms did not activate innate immune cells (e.g., dendritic cells, DCs). When PBAEs were formulated into particles to mimic a common vaccine strategy, DC activation increased in a molecular weight-specific manner. Using intra-lymph node (i.LN.) injection, a novel technique to control the dose, kinetics, and combination of signals in LNs, PBAE intrinsic immunogenicity was confirmed in mice. In the second aim, microparticles encapsulating immune signals were introduced into mice via i.LN. injection and immune responses were quantified in treated LNs, untreated LNs, and in blood. These results elucidated the interplay between local LN rearrangement and systemic antigen-specific responses which ultimately led to prolonged survival in cancer models. By understanding how the properties and administration of biomaterial-based vaccines impact immunity, this dissertation provides information that can help create new design rules for future vaccines that actively direct the immune system toward a desired response.