This thesis investigates the discovery, development, and application of small molecule immunomodulators for vaccines. Over the past 5 years, modifiers of the immune system were identified via high-throughput screening that can reduce negative inflammatory side effects, or reactogenicity, associated with vaccines. These identified compounds also increase the overall protection and durability of vaccines. The immunomodulators were discovered through a high-throughput discovery pipeline. A landscape of immunomodulators was identified that can alter transcription factors and cytokine secretion over 5 orders of magnitude. The initial primary screen was supplemented with a broader screen that leveraged iterative loops of machine learning and experiments to map a 100K+ compound library by only physically experimenting on 2% of the compounds. Lead compounds from the high throughput screen were tested in a tolerance application. Top candidates were identified that, when mixed with commercial vaccines, allowed for protection against 1000x the lethal dose of flu. The findings were consistent across subunit and live attenuated vaccines as well as in models of Typhoid, Hepatitis B, and COVID-19. Finally, these modulators were seen to reduce reactogenicity in mRNA-based vaccines. Long term, we plan on commercializing these compounds in our goal to make every vaccine better.