Highly homogenous tri-acylated S-LPS acts as a novel clinically applicable vaccine against Shigella flexneri 2a infection
| Autor: | Vyacheslav L. L'vov, Marina Eduardovna Golovina, Anna Aleksandrovna Markina, Vladimir A. Ledov, Alexander L. Kovalchuk, Yuriy A. Knirel, Petr G. Aparin |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Lipopolysaccharides
Shigellosis Lipopolysaccharide Acylation Guinea Pigs 030231 tropical medicine medicine.disease_cause Article Shigella flexneri Microbiology Lipid A 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system Bacterial Proteins Shigella Vaccines Antigen Immunity Cell Line Tumor medicine Animals Humans Shigella 030212 general & internal medicine Dysentery Bacillary General Veterinary General Immunology and Microbiology biology business.industry Public Health Environmental and Occupational Health O Antigens U937 Cells medicine.disease biology.organism_classification Antibodies Bacterial Infectious Diseases chemistry Molecular Medicine lipids (amino acids peptides and proteins) business |
| Zdroj: | Vaccine. 37:1062-1072 |
| ISSN: | 0264-410X |
| DOI: | 10.1016/j.vaccine.2018.12.067 |
| Popis: | Shigellosis, a major cause of diarrhea worldwide, exhibits high morbidity and mortality in children. Specificity of Shigella immunity is determined by the structure of the main protective O-antigen polysaccharide component incorporated into the lipopolysaccharide (LPS) molecule. Endotoxicity, however, precludes LPS clinical use. Thus, there is still no vaccine against the most prevalent shigellosis species (serotype S. flexneri 2a), despite ongoing efforts focused on inducing serotype-specific immunity. As LPS is highly heterogenous, we hypothesized that more homogenous pools of LPS might be less toxic. We developed a method to generate a homogenous S. flexneri 2a LPS subfraction, Ac3-S-LPS, containing long chain O-specific polysaccharide (S-LPS) and mainly tri-acylated lipid A, with no penta- and hexa-acylated, and rare tetra-acylated lipid A. Ac3-S-LPS had dramatically reduced pyrogenicity and protected guinea pigs from shigellosis. In volunteers, 50 µg of injected Ac3-S-LPS vaccine was safe, with low pyrogenicity, no severe and few minor adverse events, and did not induce pro-inflammatory cytokines. In spite of the profound lipid A modification, the vaccine induced a prevalence of IgG and IgA antibodies. Thus, we have developed the first safe immunogenic LPS-based vaccine candidate for human administration. Homogenous underacetylated LPSs may also be useful for treating other LPS-driven human diseases. Clinical trial registry: http://grls.rosminzdrav.ru/ |
| Databáze: | OpenAIRE |
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