For immunologist Jeff Nolz ’03, it was a case of right place, right time.
Nolz, an associate professor at Oregon Health and Science University in Portland, has been studying T cells since he began his doctoral studies in 2003 at the Mayo Clinic College of Medicine. He has been in the molecular microbiology and immunology department at OHSU since 2014 and leads his own research program.
“My lab’s major focus is on the mechanisms that regulate various aspects of cellular immunity. Cytotoxic or “killer” T cells and how those cells become activated following an infection or vaccination and what things regulate their longevity and their ability to protect against another infection,” said Nolz, a microbiology graduate.
That focus was interrupted when the COVID-19 pandemic struck the nation in early 2020.
“The day we were told we couldn’t come back to the lab was March 23, 2020,” Nolz said. “Everything was very chaotic here. We had to find ways to reduce the size of our mouse colonies and how to shut down ongoing research projects. I brainstormed for a week to see if there were things I could do to benefit any of the ongoing efforts to understand the immune response against SARS-Coronavirus-2, the virus responsible for COVID-19.”
His brainstorming led him to realize “very little is known about either the quality of the adaptive immune response or the viral antigen targets that will be necessary to prevent the spread of the infection.”
Lab work slowed during shutdown
Oregon Health and Science University employees participating in Coronavirus-related studies could file for an exception to the governor’s stay-at-home order. Nolz received one.
“For the first two months, I was by myself in the lab. After that, one research tech could join me. The part of this study that takes the most time is generating a viral vector that could be tested as a vaccine. That takes a lot of cloning and molecular biology work. After about a month, I was able to generate the virus we wanted and get it highly purified. At that point, I put it into the hands of my lab technician and together we initiated animal studies,” Nolz said.
“Testing on mice started in mid-May, and we were able to get results within two to three months thanks to the lab’s expertise in analyzing immune responses against viruses.
“What our findings argue for is that depending on the delivery system used for the vaccine, that can change both the magnitude of the immune response, as well as what part of a protein becomes the dominant antigen,” Nolz said. An antigen is a foreign substance that causes the body’s immune system to produce antibodies designed to neutralize and kill the body’s invaders.
The neutralizing antibodies and T cells produced as a result of the immunization platform created in Nolz’s lab “expanded like crazy” in mouse models, he said.
Barriers to making vaccine
Nolz’s research is considered basic science. His lab wasn’t competing in the race to create vaccines to be given throughout the world.
“One of the issues with doing actual COVID-19 infection studies, you have to have a biosafety level 3 facility, which we don’t have in close proximity to our campus. Also, a normal mouse doesn’t get infected with SARS-Coronavirus-2, so you need to use mice that have been genetically engineered to express the human version of the gene used by SARS-CoV-2 to invade cells. As you can imagine, there was very high demand for those animals!”
“We can take a human serum sample or a mouse serum sample, make serial dilutions of that serum and see if it neutralizes the virus, its rather simple and easy, but trying to see how well T-cell populations can protect against the virus in vivo, that’s where you need animal models,” Nolz explained.
The experimental vaccine his lab created is dubbed Vaccinia Virus-S. The S represents the spike protein from SARS-CoV-2. This viral vector model is identical to the smallpox vaccine and is one of the only completely live viruses that has been used clinically to prevent disease. The first vaccine ever created, the smallpox vaccine has not been changed and no longer is given in the United States.
“It is largely assumed the virus that causes smallpox no longer exists in the wild on the planet,” Nolz said.
Vaccine development behind the scenes
“Most childhood vaccines are killed viruses in some way, but two of the current COVID-19 vaccines use what is called mRNA-based protein expression to deliver the antigen to the immune system. This type of technology has been building within research labs and biotech companies for a while.
“People have been testing mRNA (messenger RNA) vaccines in animals for a long time against other pathogens. (Unlike childhood vaccines using weakened germs, messenger RNA vaccines teach cells to make a protein to trigger an immune response in our bodies.)
“When time came around that it was urgently needed, the field could rapidly move into that. One thing that allowed the scientific community to do this quickly and efficiently is that this was the third coronavirus outbreak that has happened since 2000.
“We’ve had SARS-Coronavirus-1, MERS and now SARS-2. We already had the genome sequences for the other coronaviruses. It didn’t take the scientific community much time at all to sequence this new one. As soon as they had the sequence, they were able to analyze it, then reverse engineer an mRNA-based nucleotide and then it all came down to manufacturing,” Nolz said.
Study’s takeway development
As far as Nolz’s future use of Vaccina Virus-S, “We can use this reagent to help understand the connection between helper T cells and antibody production using the spike protein as a model antigen in that system.
“With our studies and some other published findings, it seems that getting the protein expressed on the surface of the cell and not having it be secreted seemed to have this really dramatic effect on the amount of antibody we were able to generate. We may have a great experimental system for understanding what’s the best strategy to generate stronger antibody responses in people,” he said.
As a biomedical science researcher, he has learned “discovery typically isn’t a ‘Eureka’ moment. It isn’t something you magically see. It takes lot of work. What always gives me satisfaction is when we put together a package of data that closes a knowledge gap, moves the field forward or even changes a biological paradigm.
“Those are the things that get me most excited to get up every morning.”
That wasn’t what Nolz foresaw when he graduated from Ethan High School in 1998 and enrolled at State on academic and music scholarships.
“I was really interested in math and science, and thought I would go to medical school. By the third or fourth year of undergraduate education, I found myself going down the path toward research and science. I took an immunology class with Dr. Alan Young. It was his first year of teaching, and I immediately found the immune system truly fascinating. Immunology is so much more complicated than people think it is,” Nolz said.
Research in the Nolz Lab is supported by grants from the National Institute of Allergy and Infectious Diseases.
–Dave Graves
