Clostridium difficile causes over 500,000 cases of infections per year, with an estimated 15,000 deaths and a conservatively estimated economic cost at $1-3 billion in the US annually. Currently, standard treatment for C. difficile infection (CDI) is the administration of one of several antibiotics which include metronidazole, vancomycin or the newly developed fidaxomicin. While effective, these treatments have a disease recurrence rate of 15-35%, due to their disruptive impact on the gut microbiome. More effective strategies to treat primary and recurrent CDI are urgently needed. No vaccine is currently licensed against CDI. The objective of this project is to develop novel vaccines that target both C. difficile colonization/growth factors and C. difficile toxins. The symptoms of CDI are attributed to liberation of two C. difficile toxins, TcdA and TcdB. We recently constructed a recombinant fusion protein, mTcd138, which contains the immunodominant regions of TcdA and TcdB. Since spores are the major cause of disease transmission and recurrence, we propose to enhance our prototype vaccine by including additional virulence factor antigens to reduce or eliminate the excretion of spores. Decreasing spore excretion will reduce or eliminate the risk of disease recurrence and transmission.
In Aim 1 we will first construct fusion immunogens containing mTcd138 and major C. difficile colonization factors, and then determine the immunogenicity and protection against CDI and C. difficile spore colonization in mice immunized intramuscularly or sublingually with the fusion immunogens. Mucosal is often more effective against enteric pathogens such as C. difficile.
In Aim 2 we will develop a mucosal/oral vaccine by expressing the chosen vaccine candidate from Aim1 in the Bacillus subtilis mucosal delivery system.

Public Health Relevance

We propose to generate a class of a multivalent vaccine(s) targeting both C. difficile toxins and key C. difficile colonization/growth factors. We expect thes vaccines will not only prevent C. difficile infection, but will also arrest gut colonization, reducng the risk of recurrence and environmental dissemination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI113470-03
Application #
9052700
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Ranallo, Ryan
Project Start
2015-04-10
Project End
2017-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of South Florida
Department
Biochemistry
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
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