As a college student in Brazil, Paulo Verardi, associate professor in the Department of Pathobiology and Veterinary Science, participated in a polio vaccination campaign, which sparked his interest in virology. He says, “I was going into the field and vaccinating children. I witnessed how vaccines provide such a great benefit to so many people.”
With an undergraduate degree in biological sciences and a PhD in comparative pathology, Verardi began working on vaccine development as part of his postdoctoral work at the University of California, Davis. When he joined the College in 2008, he continued with his research in the development of safer vaccines as a member of the Center of Excellence for Vaccine Research (CEVR).
Verardi develops vaccines for both animal and human diseases. He says, “The connection between animals and humans is an important one. We do not live in an isolated world. More than 60 percent of human diseases originate from animals, including the Ebola virus.”
“Whenever there is an outbreak, more attention is placed on the infectious disease field,” Verardi states. “But vaccine advancement requires years of research and clinical trials.”
“My primary focus is the development of safer, but effective, live viral vectors for vaccines and cancer therapies that incorporate built-in SMART molecular safety mechanisms,” he says. “The most effective viral vaccines tend to be live replicating viruses,” Verardi points out. These live replicating viruses are the vectors, or carriers, of the antigens that elicit the protective immune responses on the recipients of the vaccine.
SMART stands for Safety Mechanism Assisted by the Repressor of Tetracycline. Tetracycline is a common antibiotic that is used in developing these vaccines. Its role is to either repress or induce gene expression and viral replication.
After a vaccine is administered, the viral replication process begins, stimulating the immune system to produce responses such as antibodies against the antigens expressed by the virus. In most cases, vaccines are safe and highly effective. But some individuals are susceptible to side effects.
Smallpox is considered to be eradicated, but there is still a need for a safe vaccine should there ever be a re-emergence and for the routine vaccination of military personnel serving abroad. While the standard smallpox vaccine is quite effective, it can cause severe reactions in some, and over the past few decades, the population has acquired a higher risk of adverse reactions to the current vaccine.
Researchers are typically prohibited from working with the actual smallpox virus, so to develop a safer smallpox vaccine, Verardi works with vaccinia virus (VACV), the current smallpox vaccine. While viruses are not usually affected by antibiotics, he has developed VAVC as a viral vector whose replication is either induced or repressed in the presence of antibiotics.
For instance, when the vaccine is developed to make the viral vector susceptible to an antibiotic, should a person develop side effects, tetracyclines could be administered, which would effectively stop viral replication and wipe out the virus.
The opposite would apply if the vaccine were made antibiotic inducible. The vaccine virus would then only replicate if the person were first given antibiotics. Withdrawal of the antibiotic would stop any viral replication. This type of vaccine would be used when small, targeted groups of individuals needed inoculation, as in the case of military personnel.
SMART vaccines are safer for those administering the vaccine treatment to humans or animals. In addition, in situations where contact with a person recently vaccinated might expose others to the virus, the exposed individuals could be treated with antibiotics to prevent them from becoming infected.
Verardi is also using SMART techniques to develop safer immunotherapies with fewer complications for patients. Verardi points out that VACV works well for gene therapy applications: it is easy to work with in a laboratory setting, it is also thermally stable and elicits strong immune responses. Immunotherapies include therapeutic vectors that stimulate immune responses to cancers, and oncolytic treatment, where a genetically modified virus is used to destroy cancer cells.
Verardi’s SMART vaccine development has been funded by NIH, US Department of Defense and the UConn Research Foundation.
In a new project funded by USDA, Verardi is researching a single-vector vaccine to protect cattle against four bovine respiratory diseases, including parainfluenza-3 virus, bovine respiratory syncytial virus, bovine herpesvirus 1 and bovine viral diarrhea virus.
The application of one inoculation to treat multiple cattle diseases would be safer and cost effective for farmers and producers. Should initial research prove successful, the project will be expanded to include animal trials of this 4-in-1 vaccine.
“These animal studies give us insight into human diseases as well,” Verardi says. “That is why we learn and collaborate with other researchers. Everything is interrelated. We even share immune components with Drosophila, the common fruit fly.”