Abstract
Clostridium difficile causes nearly 500,000 infections and nearly 30,000 deaths each year in the U.S., which is estimated to cost $4.8 billion. C. difficile infection (CDI) arises from bacteria colonizing the large intestine and releasing two toxins, toxin A (TcdA) and toxin B (TcdB). Generating humoral immunity against C. difficile’s toxins provides protection against primary infection and recurrence. Thus, a vaccine may offer the best opportunity for sustained, long-term protection. We developed a novel single-cycle adenovirus (SC-Ad) vaccine against C. difficile expressing the receptor-binding domains from TcdA and TcdB. The single immunization of mice generated sustained toxin-binding antibody responses and protected them from lethal toxin challenge for up to 38 weeks. Immunized Syrian hamsters produced significant toxin-neutralizing antibodies that increased over 36 weeks. Single intramuscular immunization provided complete protection against lethal BI/NAP1/027 spore challenge 45 weeks later. These data suggest that this replicating vaccine may prove useful against CDI in humans.
Highlights
Clostridium difficle is an anaerobic, Gram-positive, spore-forming bacterium that has emerged as a significant enteric pathogen.Each year in the United States, C. difficile is estimated to cause 500,000 infections and results in Vaccines 2020, 8, 470; doi:10.3390/vaccines8030470 www.mdpi.com/journal/vaccinesVaccines 2020, 8, 470 about 29,000 deaths [3]
A codon-optimized cDNA encoding a novel fusion of the receptor binding domains (RBDs) of C. difficile toxins A and B was synthesized by Genscript (Piscataway, NJ)
Groups of male and female outbred CD-1 mice were immunized via i.m. injection a single time with phosphate-buffered saline (PBS), 1010 virus particles of SC-Ad6-TcdA/B, or a negative control vector SC-Ad6-PEB1 that expresses a mismatched protein from another bacterium, Campylobacter jejuni (n = 10 per group)
Summary
Clostridium difficle (recently renamed Clostridioides difficile [1]) is an anaerobic, Gram-positive, spore-forming bacterium that has emerged as a significant enteric pathogen (reviewed in [2]).Each year in the United States, C. difficile is estimated to cause 500,000 infections and results in Vaccines 2020, 8, 470; doi:10.3390/vaccines8030470 www.mdpi.com/journal/vaccinesVaccines 2020, 8, 470 about 29,000 deaths [3]. C. difficile infection (CDI) occurs most after antibiotic therapy. CDI can cause symptoms ranging from frequent watery diarrhea to bowel perforation and death [5]. C. difficile vaccines generally target the pathogenic, secreted toxins, toxin A (TcdA) and/or toxin B (TcdB), which are expressed by most clinical isolates [7]. In a hamster model, targeting both toxins with antibodies reduces CDI incidence more than targeting either toxin alone [8,9,10]. Protection against CDI in humans and in hamsters correlates with antibody responses to TcdA and TcdB [8,11]. This suggests that targeting both virulence factors in a vaccine would be the optimal strategy
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