Unlocking Barriers to DNA Vaccine Immunogenicity: A Cross-Species Analysis of Cytosolic DNA Sensing in Skeletal Muscle Myocytes
Abstract
DNA coding for proteins that are normally produced by dangerous viruses and bacteria has been used as a "genetic vaccine" in numerous mouse models of human disease and a growing number of clinical trials in humans. Remarkable results in mouse models have suggested that these DNA vaccines have tremendous potential to prevent infections in humans. Unfortunately, despite repeatedly demonstrating that DNA vaccines are safe in humans, researchers have been incapable of matching the tremendous immune responses seen in mice. If this "loss in translation" could be surmounted, DNA vaccines would provide an efficient and flexible platform for vaccine development in numerous situations including rapid response to influenza pandemics, protection against emerging respiratory viral pathogens and hemorrhagic fever viruses, new bioterror threats, and of course devastating global threats such as HIV (human immunodeficiency virus). Mouse models do not always reflect reality in humans, particularly when it comes to the functioning of the immune system. All cells in our body contain receptors and sensors that recognize invading infectious organisms. Notably, a growing number of "foreign DNA" sensors have been discovered, and their role in defense against viruses and bacteria is only now being appreciated. Little is known about the differences in DNA sensors in mice versus humans. Indeed, the impact of these DNA sensors on our immune response to DNA vaccines is only now being discovered. Remarkably, nothing is known about how these DNA sensors work in muscle cells, the predominant cell that takes up the DNA at the site of immunization. We speculate that the DNA sensing machinery in muscle cells influences the strength of the immune response to DNA vaccines and that differences between mice and humans explain why DNA vaccines have not reached their potential in humans. Bringing cutting-edge technology to bear on human and mouse muscle cells, we hope to uncover the differences between species in the components of the DNA sensing machinery. Besides contributing to our fundamental knowledge on the DNA sensing machinery of the cell, we envision that this information will contribute to the development of more potent DNA vaccines that can be used safely and effectively to protect humans. Furthermore, we envision that novel insights stemming from our work will provide a springboard for our laboratory and others to develop highly potent or "immunogenic" DNA vaccines targeting HIV. Ultimately, we hope that our endeavor will provide a key to unlock DNA vaccine immunogenicity for humans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510505
Entities
People
- Gerasimos Zaharatos
Organizations
- Jewish General Hospital
- United States Army