# Bacterial Flagellar Filament: A Supramolecular Multifunctional Nanostructure
## 6 Filament-Host Interaction
### Flagellin in Vaccines  
Due to their ability to modulate innate immunity, flagellins are increasingly considered as a potential adjuvant in vaccines [207; 219; 220; 221; 222]. Several vaccines using flagellin as adjuvant are in preclinical trials, including vaccines against influenza, malaria, AIDS, tetanus and leptospirosis. In these formulations, either an antigen can be fused to flagellin (on its termini or instead of its D3 domain) or the two can be co-administered [207]. The booster effect of flagellins relies on its ability to stimulate TLR5, promoting Th1 and Th2 responses and production of IgM, IgG1, and IgG2c [223; 224; 225]. Potential obstacles for usingflagellin as an adjuvant come from its immunogenicity, and flagellin-specific antibodies could neutralize its adjuvant effects. This could be overcome by removing the variable region. It was shown that _Salmonella_ FliC in which D3 and parts of D2 were deleted (\(\Delta\)174-400) has significantly lower antigenicity while still being able to activate TLR5 [226]. Apart from monomeric flagellin, the entire flagellum could also be used to generate immunity. In the case of _P. aeruginosa_, antibodies against the whole flagella were more effective in preventing infection in mice [227].  
Until now, only flagellin-based influenza vaccines, composed of recombinant fusion proteins, have advanced to phase III clinical trials, but none of the flagellin-adjuvant vaccines has yet received FDA approval for clinical use. Despite potent adjuvant effects induced at low doses of flagellin prior to induction of maximal innate immunity, four of these flagellin-based influenza vaccines (VAX125, VAX102, VAX128, VAX2012Q) induced systemic adverse reactions in clinical studies [228]. Considering these difficulties, [PERSON] et al. recently reported a promising approach to improving both immunogenicity and safety of flagellin-based vaccines [229]. They designed a construct inserting the full-length flagellin FliB from _S. typhimurium_ into hepatitis B core protein (HBc) for a high-density display of flagellin onto the surface of virus-like particles (VLPs). Using this strategy they demonstrated that flagellin on the VLP surface significantly reduced its ability to activate TLR5 or induce systemic IL-6 release compared to flagellin alone, which may be due to the D0/D1 domains of flagellin being embedded in the interior of VLPs [229]. The use of active immunomododulation through TLR5 could trigger the release of interferon and inflammatory cytokines, which may aid in minimizing viral replication and serve as a new therapeutic strategy for vaccine or adjuvant development to fight against SARS-CoV-2, as was recently proposed by [PERSON] et al. [230]. More research is needed to understand how TLR5 could act as a modulator of the immune system in order to induce virus-related specific antibodies and to control the infection. Moreover, formulating engineered flagellins with reduced immunogenicity and targeting specific tissues, cells, or signaling pathways will be the next step of innovation in immunologic adjuvants.