By Kara Leasure Shanley

Shot at a Cure

Bryce Chackerian Custom-Builds Vaccines, One Particle at a Time

The image on the screen looks like a bumpy soccer ball, studded with red, green and blue patches (and some random yellow points)

But this odd ball has nothing to do with sports. Rather, it represents a bold new way to build something you probably received from your doctor years ago: a vaccine.

Under a microscope, this bumpy sphere multiplies into many identical ones in a grayscale image. "It's just the shell of the virus," explains Bryce Chackerian, PhD.

For decades, these shells - known as virus-like particles or VLPs - have been giving him an advantage against his opponents on their own turf.

Chackerian, a professor and vice chair of the Department of Molecular Genetics & Microbiology, grew up in the Bay Area, where his father worked as a chemist for NASA. Though he says science was not discussed often in their home, Chackerian went to the University of California, Berkeley, during the molecular biology revolution in the 1980s.

There, he studied bacterial genetics, and eventually went on to receive a doctorate in microbiology at the University of Washington while studying human immunodeficiency virus (HIV) with Julie Overbaugh, PhD. "It was in that lab that I got interested in looking at basically host-pathogen interactions," Chackerian says.

Normally, the immune system watches for foreign invaders, including viruses. "Viruses are unique sorts of structures," says Chackerian. "They're very different from things you have in your body." It's because of their unique geometry that your immune system can recognize and fight against the virus.

Some viruses and pathogens have found ways to hide their alien qualities, using a "shield" of sugars that enable them to avoid detection or evolve before being recognized. "These are all things that have what's called antigenic variation, so the proteins are constantly changing to evade immune responses," Chackerian says.

So, how do you beat a virus that has already outmaneuvered your immune system? Simply put, you mimic it.

Chackerian first learned this working with John Schiller, PhD, one of the researchers whose work led to the human papillomavirus (HPV) vaccine, at the National Cancer Institute. "It was an exciting time in the lab because they had developed this virus-like particle technology," Chackerian recalls.

Schiller's team found that a surplus of viral proteins could spontaneously weave themselves into a particle that looks like a virus, but lacks the infectious parts. When Chackerian started in Schiller's lab, they had started using these particles to create vaccines, including one for HPV. "Because it looks like the virus," Chackerian explains, "if you use it as an immunogen, it elicits antibody responses that can protect you from infection by the virus."

This was only the beginning of what this technology could be used for.

Wondering whether these particles could be used in vaccines for other conditions, Chackerian started adding things to the VLPs that would normally not prompt an immune response. These included pieces of our own proteins - like CCR-5, the receptor involved in HIV infection, or TNF-a, a protein involved in arthritis and psoriasis - that are often treated with pharmaceutically produced antibodies.

"Basically, it works," states Chackerian. "We take a little piece of TNF-a or CCR5, array it on the surface of the VLP and then use those VLPs as an immunogen. You can get really, really strong responses against self-antigens."

By saturating the VLPs with these self-antigens, Chackerian sees stronger antibody production by the immune system that lasts longer than other therapies. This opens the door for more effective vaccines against diseases that no one would consider as preventable.

"One of the reasons why we thought a vaccine might be a good idea is that monoclonal antibodies, in particular, are really expensive and vaccines are generally cheap," Chackerian says. A 2018 study published in the American Journal of Managed Care reported that the average annual cost of monoclonal antibody treatments for diseases like cancer or cardiovascular conditions was about $100,000.

"This might be a way of providing an alternative to monoclonal antibody-based therapies," he says.

In 2004, Chackerian found other researchers with whom to develop this versatile technology after he took a faculty position at UNM. He quickly found a partner in David Peabody, PhD, who shared an interest in this work and had been studying bacteriophages - viruses that target bacteria - for decades.

Chackerian explains that Peabody's phages were not only able to organize into VLPs, but that these particles were easier to produce and attach short antigen pieces onto. He says that this collaboration has been essential to where their work is today.

"It's been great - we basically run a joint lab," explains Chackerian. "It's always good to have people to throw ideas off of."

His collaborative mindset has extended to several other laboratories in other departments on campus. "It's been a really nice thing about working at UNM - to set up those collaborations was easy," he says.

They also collaborate with universities across the country, studying vaccines for malaria, chlamydia, and Zika, as well as high cholesterol and cancer.

The work by Chackerian and Peabody has produced multiple patents, as well as a new approach to the use of VLPs: discovery of immune targets using a library of potential targets.

"The idea behind this other system is that it basically eliminates that whole (trial and error) process," he explains. "We can create these random libraries and then see which sticks the best to whatever we want to target."

Their target-driven VLP platform became the basis for a new biotechnology company called Agilvax, which Chackerian and Peabody helped found and for which they serve as advisory board members. The company is currently using the platform to develop a breast cancer vaccine.

In spite of his multi-faceted career, Chackerian believes that his legacy also resides in the next generation of researchers. He passes on the knowledge and passion that he learned from his mentors to his own students and technicians.

"I've been really lucky that I've had so many great people working in the lab," he says, adding that watching them move on to their own careers has been just as rewarding as his own.

Chackerian's present goal is to get a vaccine to clinical trials, though he knows it will be challenging. "We have vaccines against most of the things where it's easy to make a vaccine for," he explains, "so, what's left are the hard things."

This doesn't seem to bother him though - instead, it drives his desire to learn as much as possible from the experts he collaborates with in order to use his VLPs for better treatments.

"I like being in academics," he says. "I like being the R&D person - well, more the R person and not the D person - that's the stuff that I like doing."

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