Bovine antibodies targeting primary and recurrent Clostridium difficile disease are a potent antibiotic alternative

Abstract

The increased incidence of antibiotic resistant ‘superbugs’ has amplified the use of broad spectrum antibiotics worldwide. An unintended consequence of antimicrobial treatment is disruption of the gastrointestinal microbiota, resulting in susceptibility to opportunistic pathogens, such as Clostridium difficile. Paradoxically, treatment of C. difficile infections (CDI) also involves antibiotic use, leaving patients susceptible to re-infection. This serious health threat has led to an urgent call for the development of new therapeutics to reduce or replace the use of antibiotics to treat bacterial infections. To address this need, we have developed colostrum-derived antibodies for the prevention and treatment of CDI. Pregnant cows were immunised to generate hyperimmune bovine colostrum (HBC) containing antibodies that target essential C. difficile virulence components, specifically, spores, vegetative cells and toxin B (TcdB). Mouse infection and relapse models were used to compare the capacity of HBC to prevent or treat primary CDI as well as prevent recurrence. Administration of TcdB-specific colostrum alone, or in combination with spore or vegetative cell-targeted colostrum, prevents and treats C. difficile disease in mice and reduces disease recurrence by 67%. C. difficile-specific colostrum should be re-considered as an immunotherapeutic for the prevention or treatment of primary or recurrent CDI.

Hyperimmune bovine colostrum reduces gastrointestinal carriage of uropathogenic Escherichia coli

“…The repeated vaccination of separate cows with a single antigen should yield highly targeted HBC that can be combined to produce a final product with a high concentration of antibodies targeting multiple antigens. 22 The identification of these antigens may be facilitated by mechanistic studies of the protective effect of UPEC-HBC, as these were not performed in the work presented. The final product should also confer protection against various UPEC strain types, including emerging multidrug resistant UPEC lineages such as ST131 and ST1193, 10,23 as well as strains of various O-antigen and H-antigen subtypes, which might also contribute to cross-reactivity with other gram-negative pathogens, as discussed previously for Travelan.…”

“…A pregnant Holstein dairy cow was vaccinated with 1 × 10 9 E. coli EC958 cells, as described previously. 22 Vaccine was prepared by emulsifying 1 ml of fixed E. coli EC958 cells with 1 ml of Montanide ISA206VG adjuvant (Tall Bennett).…”

Status of vaccine research and development for Clostridium difficile

“…An alternative approach is the use of orally delivered colostrum-derived antibodies, which are generated by immunisation of pregnant cows with spores, vegetative cells and TcdB purified from C. difficile [89]. In preclinical evaluation of mouse infection and relapse models, administration of these antibodies prevented 80% of primary CDI and reduced disease recurrence by 67%.…”

Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections

“…Repeated immunization of a pregnant cow with recombinant mutants of toxin A and B produced hyperimmune bovine colostrum (HBC) that was able to reduce the disease severity of CDI in piglets . Similarly, HBC was shown to prevent, treat, and reduce recurrence of CDI in mouse models . A phase II/III clinical trial (NCT00747071) to test the efficacy and safety of colostrum‐derived antibodies for the prevention of CDI was withdrawn.…”

“…117 Similarly, HBC was shown to prevent, treat, and reduce recurrence of CDI in mouse models. 118 A phase II/III clinical trial (NCT00747071) to test the efficacy and safety of colostrum-derived antibodies for the prevention of CDI was withdrawn. Further clinical trials are needed to assess the ability of colostrum-derived antibodies to prevent, treat, and reduce recurrence of CDI.…”