Safe and potent adjuvants are highly demanded to aid in development of new and improved vaccines. Due to the slow progress in developing novel chemical adjuvants, we took a different approach to develop physical radiofrequency adjuvant (RFA) to boost vaccination. RFA emits alternating electromagnetic fields in the skin surface and induce tissue stress to alert innate immune systems to enhance intradermal vaccine-induced immune responses. Significant progress was made in evaluation of its safety and potency to boost intradermal influenza vaccination with several major findings: 1) RFA shows similar potency to AddaVax adjuvant in potentiation of influenza vaccine-induced humoral immune responses; 2) RFA has potent dose-sparing effects and can aid nanograms of influenza vaccine to induce protective immunity; 3) RFA enables the induction of cross-protective immunity; 4) RFA induces transient low-level local inflammation and minimally changes local tissue proteome, in sharp contrast to traditional chemical adjuvants; 5) HSP70 and MyD88 play crucial roles in RFA effects. Currently, we try to understand how HSP70 and MyD88 contribute to the potent and low-inflammatory RFA effects and evaluate the potential of RFA for human use. The ultimate goal of this project is to develop a highly potent RFA to safely boost intradermal vaccination without inducing significant local or systemic adverse reactions.