New Flagellin-based Vaccine May Put the Bubonic Plague to Rest

Rarely does one scientist have the opportunity to witness the complete lifecycle of a therapeutic innovation, from concept to consumable product. Steve Mizel, PhD, is on the cusp of experiencing just this.

Mizel, a Professor of Microbiology and Immunology at Wake Forest School of Medicine, has created a biodefense vaccine against bubonic plague that has just completed its Phase 1 clinical trial. The story of this vaccine is over 30 years in the making.

Steve Mizel earned his PhD in pharmacology from Stanford University School of Medicine in 1973. Early in his career he was urged by a colleague to switch to a budding field in immunology focused on how immune cells communicate. Researchers had already discovered what appeared to be hundreds of proteins that served as the communication language of the immune system. Mizel’s background in pharmacology, biochemistry and cell biology gave him a fresh and unique perspective on the field and made him part of a revolution in immunology.

Creating a New Nomenclature

While attending an international immunology conference in Ermatingen, Switzerland in 1979, Mizel and a small group of peers forever changed the field of immune cell communication. Following the day’s presentations, the scientists met in a local pub and openly discussed what was being discovered in their individual labs, major findings that were too early in their development to be presented at the conference. The group of eight young scientists soon realized that the amount of chemical signals in the immune system vocabulary was much smaller than was thought. Most of the hundreds of proposed signals were actually the property of just two proteins.

Before the conference ended they agreed on the nomenclature interleukin 1 and 2 for these proteins, sparking a revolution in modern immunological research and the therapy of a broad range of human diseases.

Finding New Territory in Vaccine Research

This event initiated a 25-year commitment to the study of interleukins, with which Mizel established his academic reputation. One hypothesis, however, changed the trajectory of his career. After attending a seminar on how certain types of bacteria enter macrophages (an immune cell type at the front lines of our defense) and produce inflammation, Mizel hypothesized that bacteria entering the macrophage induced the production of interleukins and thus drove inflammation. Researchers had already discovered that the macrophage serves as a reservoir for HIV in infected individuals. Mizel posed the question: might internalized bacteria spur on the HIV virus inside macrophages?

In the lab, Mizel confirmed that bacteria induced macrophages to produce high levels of the virus. One of his graduate students further discovered the bacteria were releasing a protein, flagellin, which was potent as an activator of macrophages.

Uncovering flagellin, the major building block of the whip-like structure that bacteria use to propel themselves through their environment, led to a series of other discoveries, such as the extreme potency of the protein as an activator of not only macrophages, but also dendritic cells—a cell type that is critical for mounting the most protective forms of immunity.  Best of all, flagellin appeared to produce its effects with little or no damage to test animals.

Mizel moved from the study of signaling, the “great swamp,” as he calls it, into the world of vaccines. He raised the possibility that flagellin might make vaccines more effective by turning on dendritic cells and thus enhancing their ability to direct the expansion of T cells and B cells, the lymphocytes that are responsible for our ultimate protection against invading microbes.  Such enhancers are termed adjuvants and Mizel believed he had one of the best in hand.

A Shift in Thinking

Vaccine and adjuvant research meant expansive thinking, including a shift in perspective from the bench to bedside, which required substantial funding. The timing was right; it was the early 2000s, just after the anthrax attacks on news media and U.S. Senator offices. Bioterrorism was becoming a concern in Washington. Mizel observed this interest; he gathered his team to develop a NIH grant proposal that would move their findings into active vaccine research to investigate whether a flagellin-based vaccine could protect against Yersinia pestis (the bubonic plague), a new threat in the war on global terrorism.

Mizel’s group was awarded a $9.2 million grant from NIH and he and his team moved forward with their studies. When mice are exposed to pestis drops in the nose, the mice will die within a few days. However, mice that received the Mizel vaccine not only survived, but did not become sick. NIH quickly provided Mizel with more funds to begin studies in nonhuman primates. The results were the same.

Mizel then worked to find the most effective way to construct the vaccine.  Although his early work used flagellin mixed with proteins from pestis, he found that the vaccine would be even more potent if flagellin was physically connected to the pestis proteins.

Becoming a Drug Developer

With these kinds of results, Mizel found himself at the proverbial fork in the road. He had to decide if he would continue in traditional basic research or jump into the world of translational science and make a vaccine for human use. He chose the latter, even though, he reflected, “My education and research experience of over 40 years did not prepare me for this experience.”

He was quickly immersed in the complexity of the FDA’s Investigational New Drug process, including navigating various standards and benchmarks, garnering a partnership with a facility approved for human vaccine production and completing each time-intensive step.

Every piece was lengthy, laborious and expensive – often requiring multiple revisions or extensive lab work. “If I were asked, was it worth it, I would respond absolutely,” Mizel says. “If I were asked, would you do it again, I would respond absolutely not.” At the time, there was no drug discovery engine in place at Wake Forest. Today, Mizel notes, “with Wake Forest Innovations, we have the matrix we need to accelerate the commercialization of faculty discoveries.”

Once the final results of the Phase 1 clinical trial have been tabulated and reviewed, it is likely that the plague vaccine will advance to a Phase 2 clinical trial, a tremendous indicator of the vaccine’s potential to protect the American people should there be a need.

In addition to the anticipated success as a vaccination against bacteria like Yersinia pestis, Mizel’s continued research of his flagellin-based vaccines revealed its potential against not only dangerous microbes, but also cancer cells and other non-infectious diseases. Mizel’s work with flagellin is a model for the potential academic research possesses to impact the marketplace and provide real-world solutions.

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