COVID-19 has taken a front seat as it continues to spread across the developed world; however, in countries with fewer resources, SARS-CoV-2 is far from the only infectious disease to be concerned about. Diarrheal diseases, in particular, are prevalent in nations with poorer water and sanitation infrastructure. One of these diseases, shigellosis, is caused by the bacterial species Shigella, which, on its own, causes over 74,000 deaths a year. Over the years, the only treatment available for shigellosis has been antibiotics; however, the pool of effective antibiotics to treat Shigella is shrinking due to the rising prevalence of antibiotic resistance. As the treatment options narrow, scientists have shifted their priorities to developing tools for prevention.
Shigella has been notoriously difficult to develop a vaccine for due to its ability to evade the human immune system, and, as a group of species, it is incredibly diverse. Unlike diseases like COVID-19 where there is a single spike protein that can be used as a target, bacteria produce many different proteins that all work together to infect humans. Not only is there a diversity in proteins, but there are also 4 separate disease-causing species of Shigella, and within those 4 species, there are nearly 50 different subtypes that produce different variations of proteins, meaning immunity against one subtype still leaves a patient vulnerable to all the others.
Another part of the delay in vaccine development for shigellosis is that scientists lack the options for testing vaccines prior to testing in humans. These preclinical studies are essential to understanding if vaccines are safe and effective to be used on healthy humans. For other vaccines, preclinical studies are often done in animals to observe the immune response and safety. Shigella is not so simple. Getting the right animal species is a challenge for Shigella studies because the bacteria specifically infect human cells. Some of the more affordable animal models like rabbits and mice can be used to observe parts of Shigella’s disease process, but they cannot capture the whole thing. Scientists can use non-human primates like rhesus monkeys; however, monkeys are costly to keep, and it is difficult for other scientists to replicate findings without access to other monkeys. All of these hurdles slow the development for safe and effective vaccines for Shigella.
With all of this in mind, researchers at the University of Maryland and the University of Oxford set out to create a candidate for a Shigella vaccine. They chose to make a live attenuated vaccine. These kinds of vaccines are versions of the live bacteria that have been weakened in some way. In this case, Shigella was mutated in a way that made it unable to invade the cells in the intestine. A live attenuated vaccine for Shigella presents an advantage for developing immunity against the bacteria, because the weakened version of the bacteria still produces weakened versions of all the proteins the immune system would encounter in a real infection. This prepares the immune system on multiple fronts before encountering the real thing.
But then comes the testing portion. How would the researchers find an adequate system to test their vaccine? They found their answer in stem cells. Recent advances in stem cell technology have made it so researchers can cultivate things that resemble human tissue in petri dishes—scientists call them organoids. Stem cells have the unique property of being able to divide nearly endlessly, which makes them particularly useful for lab work where scientists need to repeat experiments over and over. Stem cells also have the property of being able to differentiate, or become other cell types. With special preparations, human stem cells can be differentiated into the cells you would find in the human intestine, which is incredibly useful for Shigella researchers.
Because these stem cell “mini-guts” are made from human cells, they much more closely resemble the human intestine than any rabbit, mouse, or monkey model could. The group at the University of Maryland has been utilizing this new mini-gut model to study how Shigella infects the human intestine. Now, they have begun to use this model to observe the safety of vaccines. They were able to demonstrate that the live attenuated vaccine strain of Shigella was not able to infect the human intestine, which is critical for the safety of the vaccine.
While this potential vaccine candidate is still in the early stages of development, the stem cell mini-gut model serves as an essential jump in our ability to assess the safety and efficacy of future potential Shigella vaccine candidates. As Shigella learns to evade treatment through antibiotic resistance, we continue to advance in our understanding of the human body and our ability to prevent illness.