Researchers are developing an inhalable phage-based COVID-19 vaccine, which is scalable, adaptable, and can be transported and stored at room temperature. The project led by scientists at Rice University, Rutgers University, and Northeastern University, has produced two phage-based COVID-19 strategies.
The first strategy utilizes modified phage particles, known as phage particles, that are inhaled by patients. These phage particles deliver protection to the immune system of the patient through the lungs. The second strategy is in an injectable form that contains adeno-associated virus phage particles that directly encode protection in the immune cells, against the virus.
Both strategies triggered a strong antibody production in rodents.
Inhalable phage-based COVID-19 vaccine
The first strategy was worked on by 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. Several epitopes, the part of the antigen molecules that bind to specific biological targets, were simulated by the scientists. These epitopes can be placed on the surface of a bacteriophage particle.
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. They found that one was best able to retain its structure when transferred to a phage. In the experiments with rodents, that one epitope, which they called Epitope 4, delivered the best immune response by nearly a factor of 10 over the other candidates.
“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 the 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”.
Phage particles simulated at Rice were engineered at Rutgers, containing an epitope from SARS-CoV-2 spike protein together with a small ligand peptide, which assists the bacteriophage to cross from the lungs into the patient’s bloodstream. In the bloodstream, the phage particles teach the immune system to guard the system against COVID-19. “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.
The greatest advantage of a phage-base vaccine is that one spike protein can carry multiple epitopes, which can easily be customized to protect against COVID-19 variants, explains Onuchic. “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.
In the next step for this project, the researchers will be expanding the search for more and better epitopes.
Cost-efficiency in phage-based vaccines
Trial and error or a brute force approach have been proved to be both a time-consuming approach, as well as expensive. With computational screening, epitope candidates can be generated in a list much faster and cheaper. The study also proved that testing vaccine constructs on a computer prior to experiments, gives the researchers the ability to test many more possibilities in a faster and cheaper environment.
This study shows a powerful example of how theory and experimentation can work well together, says Onuchic. “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”.
The full study can be viewed in Proceedings of the National Academy of Sciences.