Abstract
Botulinum neurotoxin (BoNT), produced by Clostridium botulinum, is generally known to be the most poisonous of all biological toxins. In this study, we evaluate the protection conferred by intratracheal (i.t.) inoculation immunization with recombinant Hc subunit (AHc) vaccines against aerosolized BoNT/A intoxication. Three AHc vaccine formulations, i.e., conventional liquid, dry powder produced by spray freeze drying, and AHc dry powder reconstituted in water are prepared, and mice are immunized via i.t. inoculation or subcutaneous (s.c.) injection. Compared with s.c.-AHc-immunized mice, i.t.-AHc-immunized mice exhibit a slightly stronger protection against a challenge with 30,000× LD50 aerosolized BoNT/A. Of note, only i.t.-AHc induces a significantly higher level of toxin-neutralizing mucosal secretory IgA (SIgA) production in the bronchoalveolar lavage of mice. In conclusion, our study demonstrates that the immune protection conferred by the three formulations of AHc is comparable, while i.t. immunization of AHc is superior to s.c. immunization against aerosolized BoNT/A intoxication.
Highlights
Botulinum neurotoxin (BoNT), which is secreted by Clostridium botulinum, is the most poisonous substance known in nature[1]
Using a mouse model of delivery through intratracheal (i.t.) inoculation[29,31], we found that i.t. immunization of AHc vaccines in three different formulations could induce protection against 30,000× LD50 of BoNT/A aerosol challenge in BALB/c mice, which is associated with the production of BoNT/Aneutralizing AHc-specific secretory IgA (SIgA)
LD50 of BoNT/A that was preincubated with bronchoalveolar lavage (BAL) from CpG-immunized mice (Fig. 5a–f) and PBS-immunized mice died within 1 day. These results indicate that both AHc-specific IgG and SIgA in the BAL could neutralize the toxicity of BoNT/A, while AHc-specific SIgA alone might contribute to the enhanced neutralizing activity
Summary
Botulinum neurotoxin (BoNT), which is secreted by Clostridium botulinum, is the most poisonous substance known in nature[1]. It is classified into eight serotypes (A–H)[2,3], with sequence differences of 37.2–69.6% at the amino acid level[4]. BoNT exerts its pathological effects by inhibition of acetylcholine release through binding to peripheral cholinergic nerve endings, leading to flaccid paralysis and death[5,7,8,9,10]. BoNT can be disseminated by food, water, or air, and enter the body through mucosal surfaces. It is most likely to be disseminated by bioterrorists through air. It can lead to neuronal tissue damage, so it requires extraordinary biosafety precautions[9,11]
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