Control and Optimization of Immune Responses Induced by Nucleic Acid Vaccines

Abstract

DNA vaccines have emerged as a promising platform for immunization due to their safety, scalability, and potential to induce both humoral and cellular immune responses. However, their efficacy in generating robust and long-lasting protective immunity has often fallen short of expectations. Various strategies, including viral and non-viral delivery methods, new adjuvants, and rational antigen design, are being explored to improve the immunogenicity of DNA vaccines. Despite all these efforts, to address the existing limitations and unlock the full potential of DNA vaccines as powerful tools in preventing infectious diseases and combating emerging pathogens, there is still a pressing need to develop efficient while safe approaches to boost the efficacy of DNA vaccines. In my thesis, I developed two methods to address this problem, with one of them being using sucrose-encapsulated lipid nanoparticles (LNPs) to interfere with the intracellular lysosomal degradation of DNA vaccines, and the other being using DNA cocktails composed of tunable amounts of vaccine DNA and cytokine DNA to controllably recruit and activate the antigen-presenting cells (APCs). Moreover, I also explored a previously undiscovered pathway by which antigens expressed at the vaccination site, such as skeletal muscle, are transported to immune cells residing in the draining lymph nodes. Together, my work demonstrated efficient methods to improve the efficacy of DNA vaccines while maintaining an excellent safety profile, and provided important clues of molecular mechanisms underlying antigen transport, which are critical in guiding the design of next-generation adjuvants for DNA vaccines targeting the antigen packaging and delivery.