Abstract
Dental caries is one of the most common global chronic diseases affecting all ages of the population; thus a vaccine against caries is urgently needed. Our previous studies demonstrated that a fusion protein, KF-rPAc, in which rPAc of S. mutans is directly fused to the C-terminal of E. coli-derived flagellin (KF), could confer high prophylactic and therapeutic efficiency against caries. However, possible side effects, including the high antigenicity of flagellin and possible inflammatory injury induced by flagellin, may restrict its clinical usage. Here, we produced a second-generation flagellin-rPAc fusion protein, KFD2-rPAc, by replacing the main antigenicity region domains D2 and D3 of KF with rPAc. Compared with KF-rPAc, KFD2-rPAc has lower TLR5 agonist efficacy and induces fewer systemic inflammatory responses in mice. After intranasal immunization, KFD2-rPAc induces significantly lower flagellin-specific antibody responses but a comparable level of rPAc-specific antibody responses in mice. More importantly, in rat challenge models, KFD2-rPAc induces a robust rPAc-specific IgA response, and confers efficient prophylactic and therapeutic efficiency against caries as does KF-rPAc, while the flagellin-specific antibody responses are highly reduced. In conclusion, low side effects and high protective efficiency against caries makes the second-generation flagellin-rPAc fusion protein, KFD2-rPAc, a promising vaccine candidate against caries.
Highlights
Bacterial flagellin is one of a small number of protein pathogen-associated molecular patterns (PAMPs), which can be recognized by cell surface Toll-like receptor 5 (TLR5)[17] and the cytosolic NOD-like receptor protein 4 (NLRC4) inflammasome receptor NAIP5/NAIP618, 19
Mice splenocytes from C57BL/6 WT or Tlr5 knockout mice (TLR5 KO) mice were used as an in vitro model to test the TLR5 agonist efficacy of the recombinant proteins
We characterized the second-generation flagellin-rPAc fusion protein, a vaccine candidate designed to avoid an undesired flagellin-specific antibody response and inflammatory side effects while inducing efficacious antibodies against PAc and providing high protective efficacy against dental caries
Summary
Bacterial flagellin is one of a small number of protein pathogen-associated molecular patterns (PAMPs), which can be recognized by cell surface Toll-like receptor 5 (TLR5)[17] and the cytosolic NOD-like receptor protein 4 (NLRC4) inflammasome receptor NAIP5/NAIP618, 19. To offer efficient and safe protection, an effort must be made to reduce the inflammatory response but maintain the adjuvanticity induced by flagellin. In another aspect, the very potent immunogenicity of flagellin itself led to a concern that immunity to flagellin might affect the potency of this molecule and induce possible side effects when used as a mucosal adjuvant[29]. Based on the flexibility of flagellin, a second-generation flagellin-rPAc fusion protein, KFD2-rPAc, was constructed to reduce the antigenicity of the flagellin part and possible related side effects by replacing the main antigenicity region, the hyper-variable region of KF with rPAc. The resulting chimeric protein, KFD2-rPAc, was comparatively analyzed with KF-rPAc in respect to side effects and protective efficiency against caries
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