Engineering Live Vaccines for Improved Immune Response

Bacterial proteins frequently outsmart the immune system, making fighting off the bacteria that cause illnesses like staph infections more challenging.

Aditya Kunjapur, a Biomolecular Engineer, and associates have now developed a method for producing bacteria that assemble and incorporate a crucial amino acid into their proteins, increasing their “visibility” to the immune system.

Kunjapur is the recipient of the 2024 BioInnovation Institute & Science Prize for Innovation in recognition of efforts to improve the foundation for potential bacterial vaccines in the future. The award aims to recognize and honor scientists who conduct research at the nexus of entrepreneurship and the life sciences.

Dr. Kunjapur’s outstanding research demonstrates the potential to engineer live bacterial cells to produce and incorporate nitrated amino acids into antigenic proteins, thus shining a spotlight on these proteins for the human immune system. This work provides a platform for antigen engineering that is adaptable, specific, and amenable to safety controls.”

Michael Funk, Senior Editor, Science

In his award-winning essay published on April 5^th, 2024, in Science, Kunjapur, an Assistant Professor of Chemical and Biomolecular Engineering at the University of Delaware, asserts that “our primary hypothesis is that engineering cells to access a broader chemical repertoire of building blocks can improve live bacterial vaccine efficacy.”

One of the components that attracted Kunjapur’s attention was derived from earlier studies that altered a bacterial protein using para-nitro-L-phenylalanine (nitro-Phe), an unusual amino acid. These nitrated proteins caused mice to produce antibodies continuously, indicating that the bacterial protein was now easier for the immune system to recognize or access due to the changed amino acid.

E. coli bacterial cells have been genetically modified by Kunjapur and associates to produce their own nitro-Phe and incorporate it into target proteins. The researchers speculate that these modified proteins may one day serve as the foundation for a live bacterial vaccine.

In principle, the nitro-Phe modified protein produced by the engineered bacteria within a patient would lead to a targeted, sustained, and protective immune response towards bacterial pathogens that contain the wildtype form of the protein.”

Aditya Kunjapur, Biomolecular Engineer and Assistant Professor, Department of Chemical and Biomolecular Engineering, University of Delaware

As a proof-of-concept, Kunjapur’s research team employed E. coli; however, Kunjapur stated that the strategy could also be applied to other bacteria, such as those that might be more adept at targeting specific pathogens or even tumor tissue.

Kunjapur added, “We could also continue to use E. coli as a platform vector that makes recombinant proteins that belong to other bacteria. So you can pick your chassis or your protein delivery vehicle, but the proteins you choose to nitrate should determine what immune cells respond to. While we have a platform technology with several promising directions, one attractive indication would be a vaccine for staph infections.”

The necessity for a staph vaccine was underscored during meetings organized by Kunjapur's postdoctoral researcher Neil Butler, who engaged with individuals from pharmaceutical firms, clinical trial operators, and hospital personnel as part of his involvement in the U.S. National Science Foundation Innovation Corps program.

Vaccines against bacterial infections would probably reduce the need for antibiotics, which might stop the emergence of antibiotic resistance in certain important medications. According to Kunjapur, the global market for bacterial vaccines is projected to reach $39.6 billion by 2030.

Securing funding for intellectual property filings proved challenging during the pandemic years, prompting Kunjapur to utilize his personal funds for his Patent Cooperation Treaty patent application.

Kunjapur said, “At the time I had cautious optimism in investing in new potential vaccine modalities during the height of a pandemic, but a lot of it was also a bet on the people behind the idea and our collaborators.”

Together with Butler, Kunjapur co-founded Nitro Biosciences, Inc. to further the nitro-Phe technology. Kunjapur claimed that launching the business has forced him to consider more carefully who will use the technology and what kinds of standards and data they will require to ensure its proper use.

Kunjapur said, “It’s a shame that a lot of academic work has the potential to make a difference in people’s lives, but academics aren’t ordinarily incentivized or trained to think about what the customer needs, who the customer is, and how do you advance the technology to the stage where it could be in the clinic.”

Along with these environmental bioengineering projects, Kunjapur and the students at the University of Delaware are working on containment strategies, “to prevent a genetically modified organism like bacteria from surviving where and when it shouldn’t.”

This year’s finalists have conducted some truly exceptional research and the standard of all entries was extremely high. Their work combines cutting edge science with entrepreneurial spirit, aligning with BII’s goals of improving human and planetary health.”

Jens Nielsen, Chief Executive Officer, BioInnovation Institute