Dylan DeCandia, PharmD Candidate 

Clostridium difficile (C. diff) infection (CDI) is a gram positive, anaerobic infection that plagues communities and health care settings. In the United States, C. diff infects 230,000 people annually and kills 12,000 people. 

Although CDI can be treated in 10 days with current regimens, it has a high recurrence rate, leading to increased health care costs and long hospital stays.

Recurrence occurs in 15%-30% of patients treated for the first time and 45%-65% of patients with recurrent CDI. With an increasing need to prevent CDI and recurrence, researchers are aiming to develop a vaccine.

 published a study describing the development of a novel, multi-epitope vaccine through immunoinformatics. “Multi-epitope” refers to the 5 cytotoxic T-cell lymphocyte epitopes, 5 helper T-cell lymphocyte epitopes, and 7 B-cell linear epitopes that make up the vaccine. Thus, this vaccine differs from other common vaccines.

Several companies have attempted to make a toxin-based C. diff vaccine, including CDIFFERENSE from Sanofi, and VLA84 from Valneva. Some vaccines were successful in clinical trials, but multiple programs were cancelled pursuant to worry about increasing the number of asymptomatic C. diff carries. Others, such as Sanofi’s CDIFFERENSE, were cancelled after discouraging trials.

Immunoinformatics allows researchers to develop vaccines without microbial culturing, thus saving time and money. The previous vaccines had issues targeting multiple mechanisms of a CDI, such as pathogenic adhesion, sporogenesis, and spore adhesion, all of which this vaccine can target. Other benefits include avoiding potential toxicity of inactivated or attenuated vaccines and alleles in the new vaccine that recognize and combine with epitopes to overcome allele difference in humans.

Researchers simulated tests to see how the vaccine might perform in clinical trials. They simulated the vaccine’s ability to induce IFN‐γ, IL-2, and IL-4. All 5 helper T-cell lymphocyte epitopes induced the production of IFN‐γ and IL-4, but only 3 of 5 epitopes induced IL-2.

IFN‐γ and IL-4 are responsible for activating immune cells, whereas IL-2 is responsible for TH2 differentiation and macrophage activation. With this information, researchers could predict the combination of epitopes that will help produce a stronger immune response in the body.

Researchers also preformed molecular docking simulations on the vaccine to understand its ability to bind to the B-cell receptor, MHC complex, and toll-like receptors. These simulations attempt to predict whether the vaccine can bind to the pathogen.

The vaccine-HLA-A*0201 (vaccine-MHC) complex stabilized in 10 ns, whereas the vaccine-TLR2 complex took more time to stabilize. Both complexes were flexibly bound.

Against the B-cell receptor, the vaccine was recognized and bound comfortably. All of these were promising results.

Although the vaccine is predicted to be stable, soluble, and thermostable, it has flaws. Even with an adjuvant, the immunogenicity was still very weak.

Researchers believe that adding another adjuvant may be necessary for the vaccine to succeed. Additionally, the study only performed simulations, so in theory the vaccine will perform, but 

Dylan DeCandia is a 2023 PharmD candidate at the University of Connecticut.

Tan C, Zhu F, Xiao Y, et al. Immunoinformatics Approach Toward the Introduction of a Novel Multi-Epitope Vaccine Against 

. Front Immunol. 2022;13:887061. doi: 10.3389/fimmu.2022.887061. PMID: 35720363; PMCID: PMC9204425.

Centers for Disease Control and Prevention. (2021, July 20). 

. Centers for Disease Control and Prevention. Accessed July 8, 2022. https://www.cdc.gov/cdiff/clinicians/faq.html

Sanofi ends development of clostridium difficile vaccine

. Sanofi. (n.d.). Accessed July 8, 2022. 

https://www.sanofi.com/en/media-room/press-releases/2017/2017-12-01-21-00-00-1216392

Song JH, Kim YS. Recurrent Clostridium Difficile Infection: Risk Factors, Treatment, and Prevention. Gut Liver 2019:13(1):16–24. doi: 10.5009/ gnl18071

CDC. About CDC’s Urgent Threats (2019). Accessed June 8, 2022. https://www.cdc.gov/ drugresistance/biggest-threats.html#cdiff.

Articles

Immunoinformatics allows researchers to develop vaccines without microbial culturing, thus saving time and money. 

Using Immunoinformatics to Create a Clostridium Difficile Vaccine

As medication experts, pharmacists provide information to patients regarding their prescriptions. Because pharmacists are easily accessible, patients frequently call and visit community pharmacies for guidance.

Without information about medications, patients may experience drug-related problems, which leads to high costs and even morbidity or mortality. A British study reported that 66% of patients who started new medications experienced drug-related problems within 10 days of initiation.

The National Centre for Development of Pharmacy Practice in Norway researched the effects of pharmacist intervention on drug-related problems. Patients who initiated new cardiovascular medications received counseling from pharmacists 1-2 and 3-5 weeks after filling the prescription.

Afterwards, patients completed a questionnaire about counseling satisfaction. Medisinstart, a standard pharmacy health care service in Norway, tracked pharmacist counseling and patient drug-related problems later to identify trends.

Pharmacist interventions provided advice that was patient-specific to identify and solve problems. Some patients had adverse effects (AEs), but not all of them received counseling regarding management.

Compared to patients who did not receive advice, those who received guidance during the first consultation were more likely to have their problems solved at consultation 2 (61.2% vs 42.6%). The researchers were interested in examining problems that persisted or developed after consultation 1 because they demonstrate that repeated consultation is necessary for optimal intervention.

Repeated consultation is also important for medications such as statins, which has symptoms that could develop months after consultation 2. If given the opportunity to counsel more, pharmacists could fix drug-related problems and medication adherence issues.

The study used 2 questionnaires: a beliefs about medicine questionnaire (BMQ) and a satisfaction survey. The BMQ was scored for patients’ belief in the necessity of the medication and their concerns for the medication.

Higher scores indicated a strong necessity or strong concern for a new medication. Patients with higher BMQ concern scores were associated with more drug-related problems and AEs.

Investigators believe these AEs were due to the nocebo effect (detrimental effects because of belief). These patients were more concerned at baseline and reported more AEs during consultations.

The satisfaction survey showed that female patients, older patients, those with longer first consultations, and those receiving their first consultation face-to-face were more likely to report higher satisfaction. Improved communication (longer consultation, face-to-face interaction) directly corresponded with improved satisfaction scores. Patient satisfaction is one way to measure quality of health care services.

The study enrolled 629 patients with 566-570 of the patients responding to the questionnaire. The study’s limitations were the lack of the control group and the non-validated questionnaire.

These limitations prevented researchers from concluding that a reduction in the need for information and a decrease in drug-related problems were directly related to intervention. The investigators demonstrated that there could be a relationship between intervention and a decrease in drug-related problems, however, additional randomized, controlled trials are necessary.

DylanDeCandia is a 2023 PharmD candidate at the University of Connecticut.

Bremer S, Henjum S, Sæther EM, Hovland R. Drug-related problems and satisfaction among patients receiving pharmacist-led consultations at the initiation of cardiovascular drugs. Res Social Adm Pharm. 2022 Jun 16:S1551-7411(22)00183-8. doi: 10.1016/j.sapharm.2022.06.005. Epub ahead of print. PMID: 35750567.

Barber N, Parsons J, Clifford S, Darracott R, Horne R. Patients’ problems with new medication for chronic conditions. Qual Saf Health Care. 2004;13:172–175.

Pharmacist interventions can provide patient-specific guidance to identify and solve problems with medication regimens to ensure optimal outcomes.