Development of an FhbB based chimeric vaccinogen that elicits antibodies that block Factor H binding and cleavage by the periopathogen Treponema denticola

• Published in: Molecular oral microbiology Vol. 36; no. 1; pp. 50 - 57
• Main Authors: O'Bier, Nathaniel S., Patel, Dhara T., Oliver, Lee D., Miller, Daniel P., Marconi, Richard T.
• Format: Journal Article
• Language: English
• Published: Denmark Wiley Subscription Services, Inc 01.02.2021
• Subjects: Anaerobic microorganisms; Antibodies; Antigens; Antisera; Bacterial Proteins - genetics; Bactericidal activity; Cell surface; chimeric immunogen; Cleavage; Complement component C3b; Complement factor H; Complement Factor H - genetics; dentilisin; Dentistry; Depletion; Etiology; Factor H; FhbB; Gum disease; Immunogenicity; Methane; Microorganisms; Monoclonal antibodies; Peptide Hydrolases; Periodontal disease; Periodontal diseases; Protease; Protein B; Proteinase; Proteins; Proteolysis; Replenishment; Spirochetes; Treponema; Treponema denticola; Vaccines; Treponema denticola; Factor H; FhbB; dentilisin; periodontal disease; chimeric immunogen
• ISSN: 2041-1006; 2041-1014
• DOI: 10.1111/omi.12325

Treponema denticola is a proteolytic anaerobic spirochete and key contributor to periodontal disease of microbial etiology. As periodontal disease develops and progresses, T. denticola thrives in the hostile environment of the subgingival crevice by exploiting the negative regulatory activity of the complement protein, factor H (FH). FH bound to the cell surface receptor, FhbB (FH binding protein B), is competent to serve as a cofactor for the Factor I mediated‐cleavage of the opsonin C3b. However, bound FH is ultimately cleaved by the T. denticola protease, dentilisin. As the T. denticola population expands, the rate of FH cleavage may exceed its rate of replenishment leading to local FH depletion and immune dysregulation culminating in tissue and ligament destruction and tooth loss. The goal of this study was to develop a T. denticola FhbB based‐vaccine antigen that can block FH binding and cleavage and kill cells via antibody‐mediated bactericidal activity. Tetra (FhbB‐ch4) and pentavalent fhbB (FhbB‐ch5) chimerics were engineered to have attenuated FH binding ability. The chimerics were immunogenic and elicited high‐titer bactericidal and agglutinating antibody. Anti‐Fhb‐ch4 antisera blocked FH binding and cleavage by the T. denticola protease, dentilisin, in a dose dependent manner. Precedent for the use of FH binding proteins comes from the successful development of two FDA approved vaccines for type B Neiserria meningitidis. This study is the first to extend this approach to the development of a preventive or therapeutic vaccine (or monoclonal Ab) for periodontal disease. Treponema denticola is a proteolytic, anaerobic, oral spirochete. The characteristic spiral ultrastructure of this keystone periodontal disease pathogen is shown above. The image was captured using dark‐field microscopy (oil immersion) at a total magnification of 1000 x.