A probiotic yeast-based immunotherapy against Clostridioides difficile infection.

Area of Science:

• Microbiology
• Immunology
• Biotechnology

Background:

• Clostridioides difficile infection (CDI) is a significant public health threat, causing over 29,000 deaths annually in the US.
• Toxins A (TcdA) and B (TcdB) are key virulence factors in CDI, and their neutralization is a promising therapeutic strategy.
• Current antibody-based antitoxin therapies face limitations including high cost, narrow spectrum, and parenteral administration.

Purpose of the Study:

• To develop a novel, orally administered immunotherapy for CDI.
• To engineer a probiotic yeast to produce a broad-spectrum neutralizing antibody against TcdA and TcdB.
• To evaluate the efficacy of this engineered yeast in preclinical models of CDI.

Main Methods:

• Engineered the probiotic yeast *Saccharomyces boulardii* to constitutively secrete a tetra-specific antibody targeting TcdA and TcdB.
• Administered the engineered yeast orally in prophylactic and therapeutic mouse models of CDI.
• Assessed the antibody's neutralization potency and breadth against both toxins.
• Evaluated protection against primary and recurrent CDI in mouse models.

Main Results:

• The engineered yeast successfully secreted a tetra-specific antibody with potent and broad neutralization activity against TcdA and TcdB.
• Oral administration of the yeast demonstrated significant protection against both primary and recurrent CDI in mouse models.
• The yeast-based immunotherapy was effective in both prophylactic and therapeutic settings.
• The approach is compatible with concurrent antibiotic use.

Conclusions:

• Engineered probiotic yeast offers a novel, orally administered platform for CDI immunotherapy.
• This tetra-specific antibody-secreting yeast effectively neutralizes key CDI toxins and protects against disease.
• This approach presents a promising alternative to conventional antibody therapies, with potential for prophylaxis and treatment of CDI.