Abstract
Enterotoxin-based adjuvants including cholera toxin and heat-labile toxin (LT) are powerful manipulators of mucosal immunity; however, past clinical trials identified unacceptable neurological toxicity when LT or mutant AB5 adjuvant proteins were added to intranasal vaccines. Here, we examined the isolated enzymatic A1 domain of LT (LTA1) for intranasal safety and efficacy in combination with influenza (flu) vaccination. LTA1-treated mice exhibited no neurotoxicity, as measured by olfactory system testing and H&E staining of nasal tissue in contrast with cholera toxin. In vaccination studies, intranasal LTA1 enhanced immune responses to inactivated virus antigen and subsequent protection against H1N1 flu challenge in mice (8-week or 24-months). In addition, lung H1N1 viral titers post-challenge correlated to serum antibody responses; however, enhanced protection was also observed in μMT mice lacking B-cells while activation and recruitment of CD4 T-cells into the lung was apparent. Thus, we report that LTA1 protein is a novel, safe and effective enterotoxin adjuvant that improves protection of an intranasal flu vaccination by a mechanism that does not appear to require B-cells.
Highlights
Vaccination is the most cost-effective method to prevent infectious diseases, yet 2.5 million deaths occur from vaccine-preventable illnesses annually[1]
We determined that 5–10 μg of cholera toxin (CT) IN was optimal for detection of olfactory system decline 24 h later
Since B-cells were not required for LTA1 mediated protection from flu challenge, we evaluated changes to other immune cell populations in the lungs of μMT or WT mice 6 days after H1N1-challenge who had been immunized prime/boost with either FZ or FZ + LTA1
Summary
Vaccination is the most cost-effective method to prevent infectious diseases, yet 2.5 million deaths occur from vaccine-preventable illnesses annually[1]. Intranasal (IN) vaccination is an attractive delivery route due to the ease of administration (including possibility of self-administration), lack of injection-related infections, low antigen doses, and induction of robust systemic and mucosal immunity[8,9,10] Adjuvants, such as aluminum salts, are useful additives to promote immunity to injected antigens. We recently began investigating the A-subunit and the A1 domain of LT (LTA1) for use as adjuvants Both LTA1 and A-subunit proteins have ADP-ribosyltransferase activity, but, unlike LT, no GM1 binding by ELISA or gastrointestinal toxicity by patent mouse assay[24]. While anti-A antibodies can neutralize LT toxicity, LTA1 is not a good antigen (in comparison with LTA and LT) and does not induce robust autoantibodies[25] These studies highlighted two properties that make LTA1 unique among LT- and CT-derived adjuvants: low antigenicity and lack of a B-subunit or ganglioside binding. We expanded upon these early studies and tested the hypothesis that LTA1 is a safe, effective adjuvant for IN vaccination to enhance protection from disease using a flu model
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
