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Published on: May 24, 2018
BECC-engineered live-attenuated Shigella vaccine candidates display reduced endotoxicity with robust immunogenicity
Matthew E Sherman1, Jane Michalski2, Sayan Das1
1University of Maryland-Baltimore, Department of Microbial Pathogenesis, Baltimore, MD 21201, USA.
Insights
Researchers engineered Shigella vaccines using bacterial enzymatic combinatorial chemistry (BECC). Modifying the lipopolysaccharide (LPS) reduced endotoxicity while maintaining immunogenicity, offering a promising path for safer Shigella vaccines.
Area of Science:
- Microbiology
- Immunology
- Vaccine Development
Background:
- Shigella spp. infections cause significant global disease, especially in children.
- Existing therapeutic options are limited by increasing antibiotic resistance.
- Current Shigella vaccine candidates have inflammatory lipid A structures, causing endotoxicity.
Purpose of the Study:
- To engineer live-attenuated Shigella vaccine strains with reduced endotoxicity.
- To assess the immunogenicity and safety of modified vaccine strains.
Main Methods:
- Bacterial enzymatic combinatorial chemistry (BECC) was used to modify lipid A structures.
- Lipid A dephosphorylation was compared to deacylation for reducing TLR4 signaling.
- Modified and unmodified Shigella strains were tested for immunogenicity and endotoxicity in mice.
Main Results:
- Dephosphorylation of lipid A significantly reduced LPS-induced TLR4 signaling in vitro.
- BECC-modified strains showed dampened endotoxic effects in vivo.
- Engineered vaccine strains retained invasion and immunogenicity without adverse effects.
Conclusions:
- Bacterial enzymatic combinatorial chemistry (BECC) is effective for engineering safer Shigella vaccines.
- Targeted lipid A modification, specifically dephosphorylation, reduces vaccine-associated endotoxicity.
- BECC-engineered live attenuated Shigella vaccines offer a promising approach for safe and effective disease prevention.
Abstract:
Shigella spp. infection contributes significantly to the global disease burden, primarily affecting young children in developing countries. Currently, there are no FDA-approved vaccines against Shigella, and the prevalence of antibiotic resistance is increasing, making therapeutic options limited. Live-attenuated vaccine strains WRSs2 (S. sonnei) and WRSf2G12 (S. flexneri 2a) are highly immunogenic, making them promising vaccine candidates, but possess an inflammatory lipid A structure on their lipopolysaccharide (LPS; also known as endotoxin). Here, we utilized bacterial enzymatic combinatorial chemistry (BECC) to ectopically express lipid A modifying enzymes in WRSs2 and WRSf2G12, as well as their respective wild-type strains, generating targeted lipid A modifications across the Shigella backgrounds. Dephosphorylation of lipid A, rather than deacylation, reduced LPS-induced TLR4 signaling in vitro and dampened endotoxic effects in vivo. These BECC-modified vaccine strains retained the phenotypic traits of their parental strains, such as invasion of epithelial cells and immunogenicity in mice without adverse endotoxicity. Overall, our observations suggest that BECC-engineered live attenuated vaccines are a promising approach to safe and effective Shigella vaccines.
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