Targeting the C Diff Pathogen and Its Immune-Suppressing Toxins

In the next part of our conversation with Joseph Zackular, PhD the discussion centered on C difficile infections, the impact of antibiotics on the microbiome, and emerging approaches to treatment, including vaccines and monoclonal antibodies. One of the key takeaways is the potential of vaccination to prevent severe disease, even in recurrent infections, by overcoming the immune-suppressing effects of C difficile toxins.

As Zackular explains, antibiotics, which are the primary treatment for C difficile, also disrupt the very microbiome that normally protects against the pathogen. This creates a paradox where the treatment itself increases susceptibility to infection:

“When we think about recurrent and relapsing infections, that’s a big problem with C diff. The main risk factor for C diff is perturbation of your normal, healthy microbiome, which normally confers resistance to this pathogen. The main risk factor is antibiotics. So when you perturb this community, it becomes susceptible to C diff. But there’s this paradox where the way we treat C diff is antibiotics, which is the thing that makes you susceptible to C diff.” This paradox creates a cycle where patients suffering from recurrent C difficile infections are caught in a loop of antibiotic use, gut microbiome disruption, and persistent vulnerability to the infection.

The key to understanding why C difficile is so difficult to treat lies in the way the bacteria’s toxins interact with the immune system. When a person becomes infected, C difficile releases toxins that damage the gut lining, leading to the characteristic symptoms of the infection, diarrhea, fever, and abdominal pain. These toxins also have a more insidious effect: they suppress the body’s adaptive immune response, making it harder for the immune system to respond effectively.

“During natural infection with C difficile, the toxins actually stunt adaptive immune responses to themselves,” said Zackular. “The toxins don’t just go after the barrier itself but can translocate and impact immune cells that are critical for responding to the infection.”

This suppression of the immune system is one reason why C difficile infections tend to recur in certain patients. Their immune systems are effectively “hobbled” by the very toxins produced by the bacteria, preventing a full immune response. Zackular’s research has shown that a targeted vaccine could help reverse this immune suppression, potentially preventing recurrence.

“We were able to show that if you vaccinate after infection, you can overcome that stunting of the toxins on the immune system. This is important because people who suffer from recurrent infections aren’t getting help from their immune system. By vaccinating after the initial infection, we might be able to repair that stunted immune response and give the gut’s microbiome some help from the immune system.”

Historical vaccine attempts failed because they targeted only the toxins rather than the pathogen itself. mRNA vaccines offer a promising solution, addressing toxins and the pathogen while also providing flexibility to adapt to emerging strains.

“There have been several vaccines that showed early promise but ultimately failed in phase three clinical trials. These vaccines targeted the toxins C difficile produces two potent toxins that drive the disease. But just targeting the toxins and providing immunity to them might not be enough,” explained Zackular. “We found that focusing only on the toxins with protein-based vaccines didn’t provide the protection we had hoped.”

The emergence of mRNA vaccine technology, which has shown success in combating other infectious diseases like COVID-19, provides new hope for C difficile treatment. Unlike traditional protein-based vaccines, mRNA vaccines can be designed to target both the toxins and the pathogen itself. Additionally, mRNA platforms are highly adaptable, making them capable of addressing new and emerging strains of C difficile.

“The mRNA vaccine platform has real potential,” said Zackular. “We can target the toxins like previous vaccines did, but we can also make it multivalent and target other aspects of this complex system. This could help overcome some of the limitations of the initial vaccines.” This multivalent approach allows for broader protection and may offer a more effective way to address the complexities of C difficile infections.

While monoclonal antibodies are valuable tools, Zackular emphasized the need for a combined approach, one that includes both vaccines and antibody treatments to effectively combat the infection.

“An FDA-approved monoclonal antibody called bezlotoxumab from Merck can be given to patients and has shown to be relatively effective. We know there is promise here, but we still need to develop the right vaccine platform with high immunogenicity, like potent mRNA vaccines, to address the complexity of the infection and the emergence of new strains,” he noted.

The diversity of C difficile strains is an ongoing challenge. New strains are emerging, not only in healthcare settings but also in the community, further complicating treatment. Zackular believes that mRNA vaccines offer the flexibility needed to adapt to this evolving landscape.

“We’re starting to see all different types of strains of C difficile circulating across the globe, as well as the emergence of community-associated C difficile infections, which are driven by a variety of C difficile strains. The flexibility of mRNA vaccines gives us hope that we can adjust vaccines quickly for what we’re seeing in patients.” This adaptability could be important for staying ahead of new strains and ensuring that treatments remain effective over time.

Tune in for part 3 of our interview tomorrow on how hospital-acquired infections have decreased, community-acquired cases have risen, complicating targeting for prophylactic vaccination, and more.

Listen to part 1 of our interview here: mRNA Vaccine Shows Potential for C difficile Infections