As a proof of principle, scientists showed that encapsulating whole-cell vaccines using metal-organic frameworks can induce long-term and durable immune responses and significantly improve survival in infected mice.
As their name suggests, urinary tract infections occur when bacteria infiltrate the urinary tract. This type of infection can involve the bladder, urethra, or kidneys. According to the American Urological Association, an estimated 150 million cases of urinary tract infections are reported annually worldwide. While untreated infections could lead to serious consequences and even become fatal, they are also highly treatable with the use of antibiotics. Unfortunately, the rapid emergence of antibiotic-resistant bacteria has endangered the efficacy of antibiotics, making previously treatable infections difficult to cure.
“Every subsequent infection becomes more difficult to treat. Even if you clear the bacteria from the bladder, populations persist elsewhere and usually become resistant to the antibiotic used. When patients accumulate antibiotic resistances, they’re eventually going to run out of options,” said Dr. Nicole De Nisco, assistant professor of biological sciences at the University of Texas at Dallas.
As part of an effort to fight the growing threat of antibiotic resistance, researchers at the University of Texas at Dallas have developed a whole-cell vaccine for urinary tract infections. In their study, Dr. Nicole De Nisco, Dr. Jeremiah Gassensmith, and colleagues demonstrated how metal-organic frameworks could be used to encapsulate and inactivate whole bacterial cells to create a “depot” that allows vaccines to be durable and long-lasting.
“Vaccination as a therapeutic route for recurrent [urinary tract infections] is being explored because antibiotics aren’t working anymore,” Dr. De Nisco said. “Patients are losing their bladders to save their lives because the bacteria cannot be killed by antibiotics or because of an extreme allergy to antibiotics, which is more common in the older population than people may realise.”
Developing vaccines against pathogenic bacteria is an inherently complicated and laborious process because bacteria, being significantly larger and more complex than viruses, have numerous biological components that can be used to create antigens. To eliminate the problem of selecting antigens, the team used the entire bacterial cell to develop their vaccine instead of mere pieces of a bacterium. However, whole-cell vaccines have limitations of their own.
“Vaccines using whole-cell dead bacteria haven’t succeeded because the cells typically don’t last long enough in the body to produce long-term, durable immune responses,” Gassensmith said. “That’s the reason for our [metal-organic framework] antigen depot: It allows an intact, dead pathogen to exist in tissue longer, as if it were an infection, in order to trigger a full-scale immune system response.”
The metal-organic framework designed by Gassensmith’s team encapsulates and immobilises an individual bacterium cell in a crystalline polymeric matrix. The matrix not only kills the bacterium but also preserves and stabilises the dead cell against high temperature, moisture, and organic solvents. To determine the efficacy of their new vaccine approach, the researchers biomimetically mineralised the E. coli strain CFT073 within a metal-organic framework. Currently, there are no vaccines against any pathogenic strain of E. coli even though uropathogenic E. coli causes approximately 80 per cent of all community-acquired urinary tract infections.
By creating a “depot” with the metal-organic framework, they were able to encapsulate the bacteria within 30 minutes in water and at ambient temperatures. When the formulation was tested on mice, the researchers discovered that using metal-organic frameworks significantly increased antibody production and substantially improved survival rates compared to standard whole-cell vaccine preparation methods.
“When we challenged these mice with a lethal injection of bacteria, after they were vaccinated, almost all of our animals survived, which is a much better performance than with traditional vaccine approaches,” Gassensmith said. “This result was repeated multiple times, and we’re quite impressed with how reliable it is.”
Although the technique has not been tested in humans, De Nisco believes that it has the potential to save millions. Besides recurrent urinary tract infections or urosepsis, the team is also optimistic that the antigen depot method could be broadly applied to other bacterial infections such as endocarditis and tuberculosis.
“We’re working on translating this approach to [tuberculosis], which is a very different organism, but like uropathogenic E. coli, when it enters the tissue, it stays, and it recurs,” Gassensmith said. “It requires a new way of thinking about how vaccines should work.
“Vaccine technology is about two centuries old, and it has evolved amazingly little. We hope our platform can open up using existing, well-studied pathogens to create more directed and engineered immune responses.” [APBN]
Source: Luzuriaga et al. (2021). Metal–Organic Framework Encapsulated Whole-Cell Vaccines Enhance Humoral Immunity against Bacterial Infection. ACS Nano, 15(11), 17426–17438.