A Vaccine for Clostridium difficile: Current Progress
JUN 10, 2018 | CONTAGION® EDITORIAL STAFF
Xingmin Sun, PhD, assistant professor, Molecular Medicine, University of South Florida, shares current progress on developing a vaccine for Clostridium difficileinfection.
Interview transcript (slightly modified for readability)
The major virulent factors [for Clostridium difficile (C difficile)] are the 2 large toxins (TcdA & TcdB), therefore, those are the major targets for our vaccine. We generated a chimeric fusion protein, "designated mTcd138 containing the glucosyltransferase and cysteine proteinase domains of TcdB and the receptor binding domain (RBD) of TcdA," according to the study abstract. To ensure that [the fusion protein] was toxic, "2 point mutations were introduced in the glucosyltransferase domain of TcdB, which essentially eliminates mTcd138 toxicity."
In terms of the immunization route, we are collaborating with different groups to create a different platform for mucosal immunization [in the future]; a nanoparticle, where we encapsulate the fusion protein for oral immunization. This is because the protein can be degraded in the stomach when you give immunizations through oral routes.
The second approach we are using is a live vector, the live (good) bacterium. If the pathogens do not produce toxins, they are not pathogenic, and they will not cause symptoms. They can be considered commensal bacteria. We are using this nonpathogenic strain to carry the chimeric fusion protein.
With this immunization, we hope that it can protect not only our body against the toxins, but we also hope that the nonpathogenic strain can compete with the pathogenic strains [for space, resources, etc.] in the colon. [Our hope is that] the vaccine would not only target the toxins, but also reduce transmission [of C difficile].
We used 2 animal models [to test the vaccine,] a mouse model of C difficile infection and a hamster model of C difficile infection. We evaluated this vaccine candidate in both animal models.
In the mouse model, we found that vaccination of the mice with the immunogens, including the protein immunogen and the live vector immunogen, provided full protection against infection with hypervirulent epidemic strains of C difficile.
We monitored several aspects of the infection: the major symptoms and weight loss. We also monitored mortality. In terms of the mortality rate, diarrhea, and weight change, we found 100% protection. After immunization, none of the mice had symptoms of inflammation, all animals survived, and none experienced weight loss.
For vaccine development, we need to have a minimum of 2 animal models. Hamsters are very sensitive to the toxins produced in C difficile infection. Only 100 of the spores can kill the hamster. This is why the hamster model is a very good model to evaluate the vaccine strains.
In the hamster model, the vaccine candidates also provided significant protection.
The next steps in terms of vaccine development are that we are going to further develop the vaccine candidate to enhance the immunogenicity of the vaccines. We are including the colonization factors in the fusion protein. We are also including Salmonella typhimurium flagellin (sFliC) in the fusion protein because sFliC is a known potent adjuvant which can enhance the immunogenicity [of the vaccine] significantly. We have already generated this new generation of fusion proteins and so we are going to further evaluate them in animal models and we are also going to incorporate them into the nonpathogenic strains as live vaccines. [According to the study abstract, "To generate a vaccine candidate targeting both toxins and C difficile colonization/growth, the team further fused mTcd138 with the RBD of TcdB and sFliC, resulting in Tcd169Fl."]
[Editor’s note: The team is currently working on developing a plan to submit this research for a clinical trial to test the vaccine in humans.]
In terms of the target population [in humans,] we need to think about the disease [and those at greatest risk.] The elderly population—those greater than 65 years of age—they are more susceptible to infection for many reasons, such as a compromised immune system, and may have some conditions being treated by antibiotic treatment, leading to a disruption of the intestinal microflora. The current standard treatment for the C difficile infection is still antibiotics and so while the antibiotics are still effective, [the vaccine] can eliminate the disease symptoms.
Furthermore, the C difficile infection may be recurrent because the antibiotics will further disrupt the microflora. (This is why the recurrence rate is very high.) And so, the target population is those individuals who are at an advanced age, and those individuals who have already developed 1 episode of C difficile infection. Once they have the first infection, if they receive the immunization in time, they will be protected from a second, or multiple episodes of infection.
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