Researchers are developing new vaccine strategies for COVID-19, including an inhalable COVID-19 vaccine.
Their new project produced two vaccine strategies. Both are scalable and adaptable and can be transported and stored at room temperature.
One strategy uses modified bacteriophage particles that can be inhaled to deliver protection via the lungs to the immune system. The other delivers injectable adeno-associated virus-phage particles that directly encode protection against the virus in immune cells.
Both approaches triggered strong production of antibodies in rodents.
The study appears in the Proceedings of the National Academy of Sciences.
José Onuchic, a physicist at the Center for Theoretical Biological Physics (CTBP) at Rice University and a co-principal investigator on the project, and his team worked on the first strategy. CTBP scientists simulated several epitopes, the part of antigen molecules that bind to specific biological targets. These can be placed on the surface of bacteriophage (aka phage) particles, viruses that infect bacteria but are safe for humans and have been used to treat bacterial infections for nearly a century.
The phage particles are engineered with an epitope from the SARS-CoV-2 spike protein, along with a small ligand peptide that helps the phage cross from the lungs into the recipient’s bloodstream. Once there, they essentially teach the immune system to guard against COVID-19.
An advantage to a phage-enabled vaccine, Onuchic says, is that one spike protein can carry a multitude of epitopes, and they can be easily customized to protect against COVID-19 variants. “The protection derived from some of these epitopes may be destroyed in a variant, but the remaining ones will continue to offer protection,” he says.
The researchers’ initial task was to see which of a small set of epitopes displayed by SARS-CoV-2 would best serve the purpose.
“We wanted to find fragments that mimic the spike structure, so they can be used to teach the immune system to recognize the virus,” says coauthor Paul Whitford, a CTBP senior scientist and an associate professor of physics at Northeastern University.
“Our work demonstrated the epitopes that show the smallest deviation from the original structure when put onto the surface of the phage are the most efficient in terms of immune response,” Onuchic says. “This is because their structures are mostly conserved when they are taken out of the protein environment. It appears that not only sequence but also structural conservation is needed for success.
“This also gives us the possibility of designing new epitopes, and now we have a methodology to look for them computationally,” he says.
In this study, the researchers, including coauthors Esteban Dodero-Rojas, a Rice graduate student, and Vinicius Contessoto, a former postdoctoral researcher at Rice and currently a CTBP affiliate, analyzed five epitopes Rutgers University scientists suggested and found that one of them was best able to retain its structure when transferred to a phage.
In experiments with rodents, that one, which they called Epitope 4, delivered the best immune response by nearly a factor of 10 over the other candidates.
In the next step, the researchers will expand the search for more and better epitopes.
“We will try to computationally screen the entire surface of the spike protein to find new epitopes,” Onuchic says. “If you just do this by trial and error, by brute force, it’s going to be too expensive or too long a process. By computational screening, we can come up with a short list of new candidates.”
“This paper proves the concept that, as of the last five or six years, it has become easier and cheaper to test vaccine constructs on the computer prior to experiments,” Whitford adds. “Before, one could typically test just a handful of possibilities, but now we’re ramping up to simulate hundreds or thousands of candidates.”
A single vaccine that protects against multiple COVID-19 variants and can be transported without the “cold chain” required for current vaccines will be key to finally curtail the worldwide epidemic, says Renata Pasqualini, who co-led the study.
“The structure and strength of the local health care system is a key consideration,” says Pasqualini, a professor and founding chief of the cancer biology division in the radiation oncology department at Rutgers New Jersey Medical School. “As such the global COVID-19 pandemic has raised awareness of public health inequity and the need for a rapid and accessible immunization process. In this context, the favorable biological attributes of phage particles might represent a potentially practical yet affordable alternative.”
Onuchic says the study serves as a powerful example of how theory and experimentation should work together. “You’re going to see a lot of papers going forward that are not theoretical or experimental, but a synergistic combination of both,” he says.
“Ongoing and planned studies will hopefully confirm that our first prototype is indeed neutralizing and leads to an Investigational New Drug application to the FDA,” says co-lead author Wadih Arap, director of the Rutgers Cancer Institute of New Jersey at University Hospital Newark. “In the meantime, the platform technology reported in this work will serve to respond promptly to emerging more virulent variants.”
Additional coauthors are from the Rutgers Cancer Institute of New Jersey; PhageNova Bio; MBrace Therapeutics; the Rutgers New Jersey Medical School; and Harvard Medical School.
The Rutgers Cancer Institute of New Jersey, National Science Foundation, Department of Energy, National Institutes of Health, Northeastern University, a Gillson Longenbaugh Foundation grant, and the Welch Foundation supported the research.
Source: Rice University
