In the era of bloodletting and leeches, the discovery of a smallpox vaccine by Edward Jenner in 1796 caused a major paradigm shift in the science of disease prevention. The revolutionary idea that a disease could be prevented by inoculating patients with an inactivated or weakened pathogen spread as rapidly as the infectious agents themselves. When the first vaccines for smallpox and rabies were developed, their mechanism of action was largely unknown and proteins would not be discovered for another 75 years! However, despite not knowing exactly how they worked, scientists continued to develop effective vaccines using methods similar to Jenner’s. The first vaccines were made from live, attenuated or killed, inactivated pathogens. Scientists realized that when a person was inoculated with a non-virulent form of a pathogen, they developed protection against the virulent form. Pathogens could be rendered non-virulent by exposure to heat or certain chemicals (i.e. formaldehyde). Sometimes instead of inactivating a pathogen, a similar strain was used that was non-pathogenic in humans (i.e. cowpox). In honor of football season, here is a football related analogy for how vaccines work. Say your immune system is like a football team that snuck into the other team’s locker room and stole their playbook. Your team, or your immune system, knows the opponent’s offensive plays and can therefore effectively plan a defensive strategy to prevent the other team from scoring, or in this case, causing illness. As scientists gained more understanding into how vaccines actually worked, it became clear that inoculation with one or more antigenic proteins from a pathogen, as opposed to the pathogen itself, could be sufficient to induce a protective immune response. This type of vaccine, one that consists of whole proteins, is called a subunit vaccine. (Proteins consist of subunits). As our knowledge base expanded, it was proven that an entire protein was not even necessary to induce a sufficient immune response. This observation led to the development of recombinant vaccines, such as the current Hepatitis B vaccine, that consist of only 8-12 amino acids. While effective at preventing disease, protein-based vaccines face several major challenges. These include high cost, lengthy production times, and cold storage requirements; the latter of which has been a major factor in limiting their distribution to parts of the world that need vaccines the most – poor countries with limited infrastructure. The use of attenuated vaccines has several other disadvantages. First, if the pathogen used in the vaccine is not completely inactivated, it can cause disease in the people it is trying to protect. This type of event occurred during the development of the first polio vaccine which led to the establishment of FDA Good Manufacturing Practice (GMP). Another disadvantage is that attenuated vaccines can cause disease in people with compromised immune systems, like individuals infected with HIV or undergoing chemotherapy because their immune systems are too weak to fight off even weakened pathogens. Because of these limitations, there is an urgent need for a new class of vaccines that can be produced quickly and cheaply and is stable at room temperature. A new type of vaccine called a “DNA Vaccine” has the potential to solve both of these challenges. Like many of its predecessors, DNA vaccines were discovered by chance. A group of American researchers observed the ability of mouse skeletal muscle to take up naked DNA and express the proteins encoded therein. Further experiments led to the injection of DNA encoding an influenza virus into the skeletal muscle of mice, resulting in the synthesis of the viral proteins triggering an immune response. When later exposed to the same influenza virus, the mice were protected against infection. The results were published in a 1993 issue of the journal Science, and marked the beginning of the era of DNA vaccines. DNA Vaccines consist of a circular piece of DNA called a plasmid that is produced via bacterial fermentation. Depending upon the required dosage, upwards of several million doses of DNA Vaccines can be produced in just a few months. Alternatively, protein-based vaccines are produced in chicken eggs or cell culture which takes much longer and poses significant risks for those with certain allergies or food intolerances. Another advantage is that DNA is more stable than protein and does not require cold storage. Several DNA vaccines for veterinary applications have already been approved and are in use today in dogs, horses and fish. For humans, several DNA Vaccines are currently undergoing clinical trials for diseases such as HIV, AIDS, HPV, cancer, Hepatitis C, malaria and many more.