Clostridium difficile infection (CDI) has emerged as a worldwide public health issue in the past quarter century and is now the most common healthcare-associated pathogen in the United States.1 The Centers for Disease Control and Prevention (CDC) estimates the annual incidence of CDIs in the United States to be nearly half a million cases with more than 29,000 deaths,2 resulting in $4.8 billion in excess healthcare costs annually.3
CDI is not only observed in hospitalized patients and patients with antibiotic exposure but also in populations previously thought to be at low risk, such as healthy young adults and children. Community-associated CDI has also emerged as an important cause of diarrheal illness.4,5 The spectrum of CDI ranges from asymptomatic carriage and mild diarrhea to life-threatening pseudomembranous colitis, toxic megacolon, and fulminant colitis potentially requiring urgent colectomy.4-6 Furthermore, long-term resolution of symptoms is difficult to achieve in a large percentage of patients with CDI; approximately 20% of patients with CDI experience recurrent infection after responding to initial therapy.2
Although the pathophysiology of CDI is complex and multifactorial, toxin B (TcdB), a cytotoxin, is now thought to be the primary mediator of symptomatic infection. Toxin A (TcdA) and binary toxin (in particular strains such as epidemic strain BI/NAP1/027) are also likely to do so, but the extent to which they contribute to disease is unclear.5 A mature and varied intestinal microbiome confers resistance to colonization by C difficile, protecting against CDI.6 Thus, exposure to C difficile spores alone is rarely sufficient to cause CDI, while perturbation of the microbiome following antibiotic exposure permits C difficile spores to colonize, germinate, and release toxins that induce CDI symptoms.
Antibodies to TcdA and TcdB mediate protection against primary CDI and recurrences. High serum antitoxin levels, especially immunoglobulin G (IgG) antitoxin A, are associated with asymptomatic colonization and protection against CDI recurrence.7 Bezlotoxumab, a monoclonal antibody against TcdB recently approved by the US Food and Drug Administration (FDA), reduces the rate of CDI recurrence in adults.8 However, the protective effect of this passive immunization strategy is short-lived.
Vaccines appear to be a promising intervention that provides long-term protection against CDI episodes, and several are in various stages of development.6 There are 3 candidate vaccines currently undergoing phase 2 and 3 clinical evaluation for CDI prevention.6 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.9 The high-dose adjuvanted vaccine, which is currently being evaluated in a phase 3 clinical trial, 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.10
Pfizer is currently evaluating a genetically modified and chemically treated recombinant full-length TcdA and TcdB vaccine in a phase 2 trial. In a phase 1 trial with 3 different dosages given as a 3-dose schedule in adults 50 to 85 years old, satisfactory immunogenicity and safety were demonstrated for both the aluminum hydroxide-adjuvanted and non-adjuvanted vaccine.11 Best responses were observed with the non-adjuvanted formulation, and there were no differences in responses in 50- to 64 year-old and 65- to 80 year-old subjects.
Valneva, an Austrian pharmaceutical company, is developing VLA84, a genetic fusion of the truncated cell-binding domains of TcdA and TcdB that is purported to be less complex to produce and purify compared with the toxoid vaccines. In a phase 1 trial, VLA84 was shown to be highly immunogenic in adults and the elderly without serious adverse effects.12 A phase 2 clinical trial has been completed, but data are not yet available.
All 3 of these parenteral candidate vaccines are moving forward in development and appear promising for the prevention of symptomatic CDI. An oral mucosal vaccine using a genetically engineered Bacillus subtilis vector is also in development.13 Because host immune response against non-toxin antigens may additionally protect against colonization and subsequent transmission, an alternative possibility of developing vaccines against surface proteins that prevent C difficile mucosal adherence and colonization is attractive. To this end, a number of surface-associated antigens including flagellar proteins, S-layer proteins, proteases, and complex polysaccharides have been studied in animal models as possible vaccine candidates.14
Larry K. Kociolek, MD, is the associate medical director of Infection Prevention and Control at The Ann & Robert H. Lurie Children’s Hospital of Chicago and assistant professor of Pediatrics at the Northwestern University Feinberg School of Medicine in Illinois.
Stanford T. Shulman, MD, is the medical director of Infection Prevention and Control at The Ann & Robert H. Lurie Children’s Hospital of Chicago and Virginia H. Rogers Professor of Pediatric Infectious Disease at the Northwestern University Feinberg School of Medicine in Illinois.
- Magill SS, Edwards JR, Bamberg W, et al; Emerging Infections Program Healthcare-Associated Infections and Antimicrobial Use Prevalence Survey Team. Multistate point-prevalence survey of health care-associated infections. N Engl J Med. 2014;370:1198-1208. doi:10.1056/NEJMoa1306801
- Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372:825-834. doi:10.1056/NEJMoa1408913
- Dubberke ER, Olsen MA. Burden of Clostridium difficile on the healthcare system. Clin Infect Dis. 2012;55 Suppl 2:S88-S92. doi:10.1093/cid/cis335
- Chitnis AS, Holzbauer SM, Belflower RM, et al. Epidemiology of community-associated Clostridium difficile infection, 2009 through 2011. JAMA Intern Med. 2013;173:1359-1367. doi:10.1001/jamainternmed.2013.7056
- Kelly CP, Lamont JT. Clostridium difficile–more difficult than ever. N Engl J Med. 2008;359:1932-1940. doi:10.1056/NEJMra0707500
- Kociolek LK, Gerding DN. Breakthroughs in the treatment and prevention of Clostridium difficile infections. Nat Rev Gastroenterol Hepatol. 2016;13:150-160. doi:10.1038/nrgastro.2015.220
- Kelly CP, Kyne L. The host immune response to Clostridium difficile. J Med Microbiol. 2011;60:1070-1079. doi:10.1099/jmm.0.030015-0
- Wilcox MH, Gerding DN, Poxton IR, et al; MODIFY I and MODIFY II Investigators. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376:305-317. doi:10.1056/NEJMoa1602615
- de Bruyn G, Saleh J, Workman D, et al; H-030-012 Clinical Investigator Study Team. Defining the optimal formulation and schedule of a candidate toxoid vaccine against Clostridium difficile infection: A randomized phase 2 clinical trial. Vaccine. 2016;34:2170-2178. doi:10.1016/j.vaccine.2016.03.028
- de Bruyn G, Glover R, Poling TL, et al. Three year follow up for safety and immunogenicity of a candidate Clostridium difficile toxoid vaccine. Presented at: IDWeek 2016. New Orleans, Louisiana; October 26-30, 2016. Poster 746.
- Sheldon E, Kitchin N, Peng Y, et al. 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. 2016;34:2082-2091. doi:10.1016/j.vaccine.2016.03.010
- Bezay N, Ayad A, Dubischar K, et al. Safety, immunogenicity and dose response of VLA84, a new vaccine candidate against Clostridium difficile, in healthy volunteers. Vaccine. 2016;34:2585-2592. doi:10.1016/j.vaccine.2016.03.098
- Permpoonpattana P, Hong HA, Phetcharaburanin J, et al. Immunization with Bacillus spores expressing toxin A peptide repeats protects against infection with Clostridium difficile strains producing toxins A and B. Infect Immun. 2011;79:2295-2302. doi:10.1128/IAI.00130-11
- Ghose C, Kelly CP. The prospect for vaccines to prevent Clostridium difficile infection. Infect Dis Clin North Am. 2015;29:145-162. doi:10.1016/j.idc.2014.11.013