A groundbreaking discovery from the University of Cincinnati suggests a future where fighting off viruses like the flu, COVID-19, or even new pandemics might no longer require an injection. Instead, it could be as simple as taking a pill. New research reveals how specially designed bacteria, swallowed like any other medication, can act as a delivery system for both antiviral treatments and vaccine components directly to your body’s defenses. This isn’t just about avoiding needles; it’s a significant leap toward a more accessible and convenient way to protect ourselves from a wide range of viral threats.
Unpacking the “Pill Power”
Central to this innovative work is a common, beneficial bacterium known as Escherichia coli Nissle 1917, or EcN. Many might recognize it as a probiotic. Dr. Nalinikanth Kotagiri and his team at UC’s James L. Winkle College of Pharmacy have cleverly transformed this harmless gut resident into a versatile microscopic factory. Their aim? To transport antiviral therapies and vaccine-like ingredients directly to the gut, a primary entry point for numerous viruses.
“Oral delivery lets us target the mucosal surfaces where pathogens first gain a foothold while avoiding needles and cold-chain logistics,” explains Dr. Kotagiri, an associate professor at UC. This is a critical advantage. Many traditional vaccines and antiviral medications face obstacles like the need for constant refrigeration during shipping and storage, plus the common aversion to injections. An oral solution bypasses these issues entirely, making distribution and administration far simpler, especially in remote areas or during widespread public health crises.
The team initially focused on the COVID-19 virus, SARS-CoV-2, to demonstrate their concept. What truly stands out about this platform is its adaptability. It’s designed to be a “plug-and-play” system. If scientists identify a new virus and develop specific “nanobodies” (tiny, potent antibodies) or “antigens” (pieces of a virus that can trigger an immune response) against it, these can be rapidly integrated into the EcN system. This capability offers the potential for swift development of new defenses against emerging threats like influenza or RSV.
How These Tiny Helpers Fight Viruses
The UC team’s strategy employs a dual approach, aiming for both immediate protection and long-term immunity.
For immediate protection, they engineered EcN to display special nanobodies on its surface. These nanobodies function like tiny hooks, ready to grab onto the virus’s “spike” protein—the part it uses to infect our cells. This creates immediate defense by blocking the virus from attaching to our cells, effectively neutralizing it. These nanobodies are particularly useful because they are smaller than typical antibodies, making them exceptionally stable and easy to produce in large quantities using bacterial systems. The researchers specifically used two powerful nanobodies, VHH72 and Ty1, known for their strong ability to bind to the SARS-CoV-2 spike protein.
Most engineered bacteria keep their therapeutic cargo inside, but the UC team wanted to expose these viral components to the immune system more directly. They achieved this by having the viral proteins displayed on the bacterial surface. Furthermore, they harnessed naturally occurring “outer membrane vesicles” (OMVs)—nano-sized bubbles that bacteria naturally release. These OMVs act as miniature delivery vehicles, carrying the nanobodies and viral components. Once released from the bacteria in the gut, these tiny bubbles can pass through the gut lining, enter the bloodstream, and deliver their contents to distant organs, including the lungs and even the brain, which are frequently targeted by viral infections. This is a significant finding, indicating that oral delivery could offer broad protection, not just in the gut.
For long-term immunity, the researchers engineered EcN to display the SARS-CoV-2 spike protein on its surface. This acts much like a traditional vaccine, prompting the body’s own immune system to produce antibodies and specialized immune cells that “remember” the virus, providing lasting protection. The combination of immediate neutralization from nanobodies and long-term immune memory from the spike protein display offers a comprehensive defense strategy.
The Research Journey: From Lab to Living Systems
The team’s research followed a thorough scientific process, beginning with laboratory experiments and progressing to animal models to test their hypotheses.
The process started with the precise engineering of E. coli Nissle 1917. Scientists created “synthetic modular vectors”—essentially genetic instructions—to tell the bacteria how to produce and display the SARS-CoV-2-specific nanobodies on their outer surface. They used different “anchor proteins” to ensure these nanobodies were securely attached and effectively presented. Tests confirmed that the nanobodies were indeed being produced and displayed as intended.
The next step was to verify that these surface-displayed nanobodies could perform their intended function: blocking the interaction between the SARS-CoV-2 spike protein and the human ACE2 receptor. The team demonstrated that the engineered EcN, with its surface-displayed nanobodies, significantly prevented this binding. This confirmed the immediate neutralizing capability of the engineered bacteria in a lab setting.
Moving beyond lab dishes, the researchers then tested their engineered EcN (specifically, EcN expressing the Ty1 nanobody) in mice. A small group of mice received EcN-Ty1 daily by mouth for four days. Analysis of blood samples from these mice confirmed the presence of Ty1 nanobodies in their bloodstream. This was a critical finding, demonstrating that the nanobodies, likely carried by those tiny OMVs, could indeed cross from the gut into the body’s general circulation. The study also showed that the nanobodies’ ability to inhibit the virus-receptor binding in the mice’s blood progressively increased with repeated doses, peaking after the third dose.
What makes this finding even more compelling is that researchers investigated whether these nanobodies could reach other vital organs. Analysis revealed the presence of nanobodies in the lungs and brains of mice treated with the engineered bacteria, but not in control mice. This strongly indicates that the OMVs serve as a viable transport system for delivering therapeutic agents to organs beyond the gut, suggesting widespread protection.
The study also looked at the “active immunity” aspect by engineering EcN to display the SARS-CoV-2 spike protein (EcN-Spike). Giving EcN-Spike to mice by mouth successfully triggered both systemic (body-wide) and mucosal (at entry points like the gut) immunity. This was evident from a notable increase in IgA levels in the blood and a greater presence of immune cells in the intestines of treated mice. In a comparison, the EcN-Spike platform was tested against a traditional mRNA vaccine. While the mRNA vaccine caused a strong overall antibody surge later on, EcN-Spike showed better performance in terms of early and lasting immune responses in the gut. This is particularly significant because mucosal immunity is crucial for preventing infections where they often begin. The sustained IgA levels observed with EcN-Spike suggest it could offer prolonged protection at these key entry points. Throughout the animal experiments, the mice did not show any noticeable negative effects, further supporting the safety of this approach.
What This Means for Your Health
This research presents a compelling vision for the future of viral prevention and treatment. The ability to deliver both immediate antiviral therapy and long-term vaccination through a single, orally administered bacterial system marks a significant leap forward. While the study focused on SARS-CoV-2, the adaptable nature of this platform means it could be quickly tailored to combat a wide range of existing and new viral threats. The implications are vast: easier access to treatments, especially in areas with limited resources, and a more convenient, needle-free experience for everyone. The next steps will involve rigorous human clinical trials to confirm the safety and effectiveness of this innovative delivery system. If successful, a simple pill could indeed become our first line of defense against the next viral challenge, changing the landscape of global health for the better.
Paper Summary
Methodology
This study engineered Escherichia coli Nissle 1917 (EcN), a probiotic, to deliver anti-spike nanobodies or SARS-CoV-2 spike protein. Researchers verified protein expression and function in the lab before testing in mice. Mice were orally administered the engineered bacteria, and the researchers monitored nanobody presence in blood and organs, and compared immune responses from the oral vaccine to an mRNA vaccine. Animal study groups typically consisted of 4 mice.
Results
The engineered EcN successfully displayed viral components, leading to effective virus neutralization in lab tests. In mice, nanobodies traveled from the gut to the bloodstream, lungs, and brain, demonstrating widespread delivery. The oral vaccine also triggered strong, lasting immune responses, particularly in the gut, and showed superior early mucosal immunity compared to an mRNA vaccine. No adverse effects were observed in the animal models.
Limitations
Key limitations include the absence of testing in a live SARS-CoV-2 infection model due to safety constraints. Further research is needed on long-term effects, optimal dosing, interactions with the gut microbiome, potential toxicity to the brain, and the precise transport mechanisms. Challenges such as degradation in the gastrointestinal tract and variable efficacy due to individual gut microbiota also require more investigation. Human clinical trials are necessary for full validation.
Funding and Disclosures
The research was supported by grants from the National Institutes of Health (NIH) and the Congressionally Directed Medical Research Programs (CDMRP), along with funding from the University of Cincinnati. Two authors have filed a patent application related to this work. All other authors declared no competing interests.
Publication Information
The paper, titled “Engineered bacteria as an orally administered anti-viral treatment and immunization system,” was authored by Nitin S. Kamble and colleagues. It was published online on May 8, 2025, in the journal Gut Microbes, Volume 17, Issue 1, and can be accessed via DOI: 10.1080/19490976.2025.2500056.