Vaccines are one of the greatest public health tool and have saved more lives than any other medical intervention in human history. Yet, vaccine efficacy and safety can still be improved. Effective vaccination responses require sufficient activation of innate immunity, which, in turn, initiates adaptive immunity. Innate immune activation in current vaccines often requires adjuvants - helper molecules that generate a more robust response. Immunostimulatory adjuvants bind pattern recognition receptors (PRRs) on antigen presenting cells (APCs), eliciting cytokine and surface marker upregulation. While many novel adjuvants have been discovered, many of these agonists have never been implemented in approved vaccines. Adjuvants face the challenge of balancing adjuvanticity and reactogenicity. Excess reactogenicity can result in adverse events during clinical trials, causing vaccines to fail FDA safety standards. Current adjuvants amplify all downstream components roughly equally after ligand binding. A more potent agonist will improve the immune response, but at the cost of increased side effects and inflammation. We seek to solve this problem by using "immunomodulators" - molecules that selectively inhibit portions of the downstream signaling cascade. This gives a finer control of vaccine adjuvanticity and can potentially reduce reactogenicity while increasing vaccine efficacy. In Chapter 1, the components of the immune response are reviewed in the context of successful vaccination. In Chapter 2, a "first-generation" immunomodulator, honokiol, is applied to a CpG adjuvanted subunit vaccine against SARS-CoV-2. In Chapter 3, "second-generation" immunomodulators are identified through high-throughput screening of large libraries of commercially available, diverse small molecules. Data from various immunoassays was compiled to create a quantitative scoring system that highlighted top candidates to study in animal models. In Chapter 4, top candidates are combined with commercial vaccines. In influenza vaccines, immunomodulators increased vaccine efficacy, tolerability, and durability.