The pill-based vaccine prevents urinary tract i | Tech Reddy

DURHAM, NC — Duke University biomedical engineers have developed a pill-based vaccine against urinary tract infections (UTIs) that dissolves quickly when placed under the tongue. The new treatment may offer an easy and practical alternative to the high-dose, oral antibiotics that are the current standard of care for UTIs.

The findings appeared online in the journal Nov. 23 Science Advances.

Urinary tract infections occur when bacteria infect the urethra, bladder, urethra, or kidneys. More than half of all women experience UTIs, and they pose a significant risk to patients requiring catheters. While UTIs often cause pain and discomfort, if the infection reaches the kidneys, organ damage and even sepsis can occur.

These infections can be treated with oral antibiotics, but some patients face recurrent UTIs that require prolonged, repeated, and sometimes expensive antibiotic use. Long-term use of antibiotics can have a negative effect on the patient’s microbiome, as antibiotics kill off beneficial bacteria and allow the proliferation of antibiotic-resistant bacteria. Today, many strains of bacteria that cause UTIs have become resistant to several antibiotics commonly used to treat these infections.

To solve this problem, a team of collaborators including Joel Collier, Theodore Kenny, professor of biomedical engineering at Duke, and Sean Kelly, who completed the work as a PhD student in Collier’s lab, developed a vaccine that can be absorbed under the tongue. and activates primary immune cells to specifically attack UTI-causing bacteria.

“Previous literature has shown that drugs absorbed through the sublingual mucosa trigger an immune response, particularly in similar mucosal tissues throughout the body,” said Kelly, now a postdoctoral fellow at Johns Hopkins University. “This was important because one of the challenges in developing a vaccine for UTI is that you have to induce an immune response in both the blood and the genitourinary tract, and intramuscular injections often don’t produce strong responses in those mucosal areas.”

“Furthermore, there are many obstacles to the easy delivery of the vaccine. Often requires refrigeration, trained personnel to administer shots, and supplies such as needles, Kelly said. “But the tablet delivery method offers a solution to many of these problems. It can be stored at room temperature without any problems. The patient takes it out of the package, places it under their tongue, and the hope is that it will be gone within seconds and the patient can go about their day.

The mucous layer under the tongue is difficult to penetrate because mucus is designed to prevent large molecules, viruses, and other materials from entering the body. But Collier’s lab specializes in developing biomaterials that self-assemble into useful structures, such as nanoparticles, nanofibers and gels, tailored to activate key cells of the immune system. The team discovered that these structures can add mucus-resistant modifications that allow them to easily pass through the mucosa.

After finalizing the sugars and other structural components needed for a fast-dissolving, vaccine-delivery pill, the team began researching how to specifically target UTI-causing bacteria.

“Sean identified certain proteins that appear frequently in a type of bacteria called uropathogenic E. coli, which causes most UTIs,” Collier said. “This gave us a precise target for the immune cells to attack.”

The team woven E. coli proteins into mucus-permeable nanofibers. Once this structure is absorbed, the added bacterial proteins activate immune cells, giving them specific instructions to kill bacteria in the blood and urinary tract.

“The efficacy of the vaccine delivered via tablet is comparable to antibiotics, and we found that the antibody responses elicited from the nanofibrous materials can be very durable for the lifetime of the mouse, so we hope the protection against UTIs will be the same in the long term,” Collier said. “Sean and the team also performed microbiome analyses, and they found that the gut microbiome of the mouse models was significantly less disrupted than antibiotics.”

The team will continue to refine the model as Collier and his collaborators wonder if the vaccine could be used to reduce or prevent UTI recurrence. They also plan to study additional disease models where a sublingual vaccine delivery mechanism would be particularly useful. Many of these diseases, including gonorrhea and chlamydia, also involve the genitourinary tract and face problems of antibiotic resistance.

Although the team is excited about the long-term UTI protection results, they are optimistic about the new possibilities with sublingual vaccine tablets.

“Especially in the wake of COVID, it’s becoming increasingly clear that vaccines will become more and more a part of our lives, so we need affordable vaccines that can be easily replicated,” Collier said.

“Current vaccines depend on continuous refrigeration, requiring significant infrastructure that is not available in large parts of the world. Tablet technology can be delivered in a much fairer way because it avoids dependence on refrigeration,” said Collier. “If we’re successful, anyone can get the vaccine, whether they’re close to a large hospital system or not. We are far from this reality, but we continue to work in this direction.

This work was supported by Duke University and the National Institutes of Health NIBIB 5R01EB009701)(NIAID 1R01AI167300), the National Science Foundation Graduate Research Fellowship Program (DGE-1644868) (NIH T32GM008555), and the North Carolina Biotechnology Center (NIH-7102).

Competing Financial Interests: JHC and SHK are investors in the following patent applications related to this work filed by Duke University: US Pat. 63/358,373, filed Jul. 5, 2022; US patent pending no. 17/764,406, filed Mar. 28, 2022; and US patent pending no. 16/632,226, filed Jan. 17, 2020. The authors declare no other competing interests.

CITATION: “A Sublingual Nanofiber Vaccine for the Prevention of Urinary Tract Infections,” Sean Kelly, Nicole Votau, Benjamin Cossette, Yaoying Wu, Shamita Shetty, Lucas Shores, Luqman Issa, Joel Collier. Science Advances, November 23, 2022. DOI: 10.1038/s41591-021-01339-0