In this chapter:
Clostridioides difficile (formerly Clostridium difficile) infection (CDI) is a major cause of antibiotic-associated diarrhoea and colitis and the most common pathogen in healthcare-associated infections. The spectrum of CDI ranges from asymptomatic carriage and mild diarrhoea to life-threatening pseudomembranous colitis, toxic megacolon, and fulminant colitis. Long-term resolution of symptoms is difficult to achieve in a large percentage of patients with CDI, where approximately 20% of patients with CDI experience recurrent infections after responding to initial therapy. The infection is associated with antibiotic use in healthcare settings, but has increasingly occurred in the community since the emergence of hypervirulent strains since the early 2000’s.
Antibodies to TcdA and TcdB confer protection against primary CDI and recurrences. Bezlotoxumab is a monoclonal antibody against TcdB recently approved by the US FDA, which reduces the rate of CDI recurrence in adults.
Currently no vaccine is registered. There are 3 candidate vaccines undergoing phase 2 and 3 clinical evaluation for CDI prevention.
- The Sanofi Pasteur toxoid vaccine uses formalin-inactivated full-length TcdA and TcdB administered by intramuscular injection at days 0, 7 and 30. In phase 2 trials, the vaccine was safely administered to adults older than 50, and seroconversion to TcdA and TcdB was 97% and 92% respectively. The high-dose adjuvanted vaccine has demonstrated elevated circulating titers for up to 3 years after the last dose of the primary series given at 0, 7, and 30 days.
The Phase 3 programme known as Cdiffense was discontinued by Sanofi Pasteur in December 2017. The multicentre, observer-blind, randomised, controlled trial was conducted at 326 hospitals, clinics, and clinical research centres in 27 countries in the USA, Canada, Latin America, Europe, and the Asia-Pacific region. It evaluated single injections of high-dose plus adjuvant vaccine, in about 16,500 adult volunteers at least 50 years old, who are at risk of CDI. Secondary endpoints include the number of PCR-confirmed primary CDI cases after two and three injections, maximum number of loose stools per day, CDI episode/illness duration, immunogenicity and injection site and systemic reactions. Prior Phase 2 trials demonstrated high rates of seroconversion (over 90%), but did not translate into protection against the disease during the Phase 3 trial. In adults at risk for C. difficile infection, the bivalent C. difficile toxoid vaccine did not prevent C. difficile infection. Since the vaccine candidate met the criteria for futility, the study was terminated and clinical development of this vaccine candidate was stopped.
- The vaccine being developed by Pfizer targets toxins A and B of C. difficile. Clostridium difficile Vaccine Efficacy Trial (CLOVER), a phase 3 clinical efficacy and safety study was started in early 2017 in over 20 countries globally. Completion is expected at the end of 2020. Subjects enrolled were 50 years of age and older who are at higher risk for CDI, consisting of about 16,000 participants.
The phase 2 trial which studied the safety, tolerability, and immunogenicity in 855 older US adults of the bivalent C. difficile vaccine was conducted from July 2015 through March 2017, in 15 US centres. It was shown that the C. difficile vaccine was safe, well tolerated, and immunogenic in healthy adults aged 65-85 years. These results support continued vaccine development. However, having similar toxoid-based mechanism of action to Sanofi’s vaccine, it raises doubt whether the seroconversion observed in Phase II trials can translate into clinical efficacy. Pfizer plans to investigate rates of both primary and recurrent infections.
- Valneva has developed toxins A and B into a single recombinant subunit protein or a fusion protein, containing the toxin A and B receptor binding domains. Valneva successfully completed Phase 2 development of its vaccine candidate VLA84.
The Phase 2 trial was a randomized, placebo-controlled, observer-blind multi-center trial with 500 subjects, designed to further study and confirm the candidate vaccine’s safety, immunogenicity and proposed doses of immunisations in two different age groups (50 to 64 years of age and 65 years of age and older). Final Phase 2 results of this vaccine candidate confirm positive initial Phase 2 data that were released at the end of 2015. VLA84 was immunogenic at all doses and formulations tested, in that Immunoglobulin G (IgG) and functional (neutralising) antibody responses were observed. The study met its primary endpoint in terms of identifying the dose/formulation with the highest seroconversion rate against both toxins A and B and confirmed the favourable safety profile observed in Phase 1. VLA84 is currently Phase 3-ready.
Table 20.2 difficile vaccines in clinical development
Kociolek LK, Gerding DN. Breakthroughs in the treatment and prevention of Clostridium difficile infections. Nat Rev Gastroenterol Hepatol. 2016; 13:150-160.
Further research is needed on C. difficile vaccine efficacy. Vaccine candidates targeting toxins A and B might prevent clinical illness but may not alter gastrointestinal tract colonisation. Prevention of C. difficile colonisation has generated interest in targeting non-toxin surface protein antigens. Other areas include the cross-reactivity of antibodies to antigens among different C. difficile strains, the need for adjuvants and the specific types of adjuvants, the optimal age for immunisation, demonstration of immune response in high-risk elderly individuals, and the duration of protection in humans.
B.zay, N., Ayad, A., Dubischar, K., Firbas, C., Hochreiter, R., Kiermayr, S., Kiss, I., Pinl, F., Jilma, B., & Westritschnig, K. (2016). Safety, immunogenicity and dose response of VLA84, a new vaccine candidate against Clostridium difficile, in healthy volunteers. Vaccine, 34(23), 2585– 2592. https://doi.org/10.1016/j.vaccine.2016.03.098
- de Bruyn, G., Gordon, D. L., Steiner, T., Tambyah, P., Cosgrove, C., Martens, M., Bassily, E., Chan, E.S., Patel, D., Chen, J., Torre-Cisneros, J., Francesconi, C.F., .. Gurunathan, S. (2020). Safety, immunogenicity, and efficacy of a clostridioides difficile toxoid vaccine candidate: A phase 3 multicentre, observer-blind, randomised, controlled trial. The Lancet Infectious Diseases, doi:10.1016/S1473-3099(20)30331-5
- de Bruyn, G., Saleh, J., Workman, D., Pollak, R., Elinoff, V., Fraser, N. J., Lefebvre, G., Martens, M., Mills, R. E., Nathan, R., Trevino, M., van Cleeff, M., Foglia, G., Ozol-Godfrey, A., Patel, D. M., Pietrobon, P. J., Gesser, R., & H-030-012 Clinical Investigator Study Team (2016). Defining the optimal formulation and schedule of a candidate toxoid vaccine against Clostridium difficile infection: A randomized Phase 2 clinical trial. Vaccine, 34(19), 2170–2178. https://doi. org/10.1016/j.vaccine.2016.03.028
- Ghose, C., & Kelly, C. P. (2015). The prospect for vaccines to prevent Clostridium difficile infection. Infectious disease clinics of North America, 29(1), 145–162. https://doi.org/10.1016/j. idc.2014.11.013
- Henderson, M., Bragg, A., Fahim, G., Shah, M., & Hermes-DeSantis, E. R. (2017). A Review of the Safety and Efficacy of Vaccines as Prophylaxis for Clostridium difficile Infections. Vaccines, 5(3), 25. https://doi.org/10.3390/vaccines5030025
- Kitchin, N., Remich, S. A., Peterson, J., Peng, Y., Gruber, W. C., Jansen, K. U., Pride, M. W., Anderson, A. S., Knirsch, C., & Webber, C. (2020). A Phase 2 Study Evaluating the Safety, Tolerability, and Immunogenicity of Two 3-Dose Regimens of a Clostridium difficile Vaccine in Healthy US Adults Aged 65 to 85 Years. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 70(1), 1–10. https://doi.org/10.1093/cid/ciz153
- Kociolek, L. K., & Gerding, D. N. (2016). Breakthroughs in the treatment and prevention of Clostridium difficile infection. Nature reviews. Gastroenterology & hepatology, 13(3), 150–160. https://doi.org/10.1038/nrgastro.2015.220
- Sheldon, E., Kitchin, N., Peng, Y., Eiden, J., Gruber, W., Johnson, E., Jansen, K. U., Pride, M. W., & Pedneault, L. (2016). A phase 1, placebo-controlled, randomized study of the safety, tolerability, and immunogenicity of a Clostridium difficile vaccine administered with or without aluminum hydroxide in healthy adults. Vaccine, 34(18), 2082–2091. https://doi. org/10.1016/j.vaccine.2016.03.010
- Wilcox, M. H., Gerding, D. N., Poxton, I. R., Kelly, C., Nathan, R., Birch, T., Cornely, O. A., Rahav, G., Bouza, E., Lee, C., Jenkin, G., Jensen, W., Kim, Y. S., Yoshida, J., Gabryelski, L., Pedley, A., Eves, K., Tipping, R., Guris, D., Kartsonis, N., … MODIFY I and MODIFY II Investigators (2017). Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. The New