Tuberculosis is the leading cause of death worldwide from a single infectious agent, but vaccines developed to date have limited efficacy and pose safety concerns. Protein-based vaccines are a safe option but usually require powerful adjuvants. We present examples of fully synthetic, self-adjuvanted protein vaccine constructs. These vaccines comprise a low-dose immune-stimulating adjuvant, covalently fused to the ESAT6 protein from Mycobacterium tuberculosis, the causative agent of tuberculosis. When administered by inhalation, the vaccines generated powerful immune responses and significant protection from M. tuberculosis in the lungs of mice. The synthetic strategy we describe represents a method that could be used to rapidly generate vaccines for preclinical testing against many diseases, including novel pathogens such as SARS-CoV-2.