Researchers explore protein to ramp up COVID-19 antigens' impact
Thomas Petro, PhD
In the race to produce a COVID-19 vaccine, researchers are using a wide range of strategies, from first-of-their-kind mRNA approaches to tried-and-true inactivated vaccines to oral, nasal and probiotic-based formulations.
Dr. Petro on the research
"Besides being used for components of COVID-19 vaccines, it is important to determine what the proteins of SARS-CoV-2 are doing to the immune system in order to establish the infection. One of my roles is to evaluate the effect of two of the proteins of SARS-CoV-2, the M-protein and N-protein. In other coronavirus infections the M-protein dampens early Type I interferon responses, which are needed to fight the virus infection early on. We found that SARS CoV2 M-protein dampens this interferon pathway somewhat in a cell type called macrophages. But surprisingly we also found that these viral proteins greatly enhanced production of one of the inflammatory factors from the same cells. M-protein and/or N-protein of SARS-CoV-2 may be playing a role in the hyperinflammatory syndrome seen with COVID-19."
Thomas Petro, PhD, professor of microbiology and immunology in the department of oral biology at the UNMC College of Dentistry and a member of the Nebraska Center for Virology, is partnering with University of Nebraska-Lincoln virologist Asit Pattnaik, PhD, to eye yet another approach.
With support from the Office of Research and Economic Development's (ORED) COVID-19 Rapid Response Grant Program, Drs. Pattnaik and Petro are beginning to develop a vaccine framework that exploits the properties of a naturally-occurring nanoparticle in an effort to produce a stronger, longer-lasting immune response than other vaccine candidates. They also are taking a closer look at how SARS-CoV-2, the coronavirus that causes COVID-19, inhibits the immune system.
The team's vaccine work capitalizes on a protein called ferritin, which is produced by almost all living organisms. In humans, ferritin is the primary iron storage protein and guards against iron deficiency or surplus. It's shaped like a symmetrical hollow sphere, or nanocage, built of 24 protein subunits. This cage structure, which Dr. Pattnaik calls a "spherical football," makes ferritin unusually stable, allowing it to withstand variable temperatures and chemical environments.
To Drs. Pattnaik and Petro, ferritin's well-organized, durable structure of 24 building blocks represents an opportunity to significantly ramp up the number of vaccine antigens - the molecules that trigger an immune response - delivered to a recipient. Their strategy is to fuse antigen to ferritin so that when the protein cage self-assembles, each nanoparticle will boast 24 molecules of the antigen on its surface, which is more than is found in many of the vaccines in development.
They are targeting SARS-CoV-2's spike protein, known as the S protein, as the antigen. The S protein contains a region called the receptor-binding domain, which is key to the virus's ability to enter the host cells and replicate.
"We are providing 24 molecules of receptor-binding domain in a single particle," said Dr. Pattnaik, professor of veterinary medicine and biomedical sciences and a member of the Nebraska Center for Virology. "Such an approach will stimulate a more robust response than a single molecule would. And that's the goal -- to stimulate a better response."
They believe that enhanced response will result from the higher antigen-to-immune cell ratio. The immune system's antibody-producing B cells should trap the antigen-loaded nanoparticles, resulting in tighter and prolonged interactions that increase production and secretion of antibodies. The approach has been successful in producing strong antibody responses against viral pathogens such as influenza, HIV-1, Epstein-Barr virus and hepatitis C virus, among others.
A vaccine with stronger immunogenicity means people may need fewer doses. The current frontrunners would require at least two injections, spaced a month apart, to be effective. Dr. Pattnaik is hopeful that his approach would require fewer shots, which also means lower costs associated with supplies and administration.
The ORED grant is supporting Drs. Pattnaik and Petro as they try to clear the first major hurdle of their vaccine strategy -- determining whether ferritin, fused with SARS-CoV-2's S protein, triggers the strong production of neutralizing antibodies.
Said Dr. Pattnaik: "With this disease, we need experts from all different fields to put their efforts into developing effective therapeutics and vaccines."