Shigella flexneri Vaccines

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Shigella flexneri

Shigella flexneri belongs to the genus Shigella and is a Gram-negative bacterium which could cause diarrhea in humans. S. flexneri has a virulence plasmid that encodes T3SS (type-3 secretion system), IcsA and ipa proteins (invasion plasmid antigen proteins). When infecting cells, S. flexneri first injects ipa proteins into the cytoplasm through T3SS, and the membrane ruffling formed by ipa proteins on the host cell membrane further forms a membrane pocket and captures and absorbs the bacteria into the host cell. After the bacteria enter the cell, the actin is used as a driving force for bacteria to move from one cell to another through the paracytophagy mechanism. The large plasmid of S. flexneri encodes the OspI protein, which is secreted by T3SS and inhibits the host's inflammatory response at the initial stage of infection. OspI indirectly affects the activation of TRAF6 (TNF-α-receptor-associated factor 6) through its glutamine deamidase activity and interferes with inflammatory responses.

Host Immune Response to Shigella flexneri

The inflammatory response produced by shigellosis can last for at least one month in gut, accompanied by the upregulation of a variety of cytokines including TNF-α, TNF-β, IL-1, IL-4, IL-6, IL-8, IL-10, TGF-β, and IFN-γ. Infiltrating monocytes and settled macrophages are unable to kill S. flexneri in these endocytic phagosomes, which in turn leads to apoptosis in these cells themselves. Apoptotic macrophages can release IL-18 targeting T lymphocytes and NK cells, induce the production of IFN-γ by these cells, and promote the clearance of bacteria and the inhibition of bacterial replication. Epithelial cells infected by Shigella activate NF-κB by LPS-dependent mechanism, and induce infected cells to produce and secrete IL-8. IL-8 is a strong chemoattractant of PMN cells, and subsequent migration of PMN cells is the most important result of the innate immune response. The phagocytic vacuoles of PMN cells are able to kill Shigella in their phagosomes. In addition, studies have shown that neutrophil elastase can rapidly degrade bacterial virulence proteins after Shigella infects it. Moreover, glycoproteins and lactoferrin in the breast milk and mucosal secretions as well as in phagocytic cells of the host can also disrupt the invasion of Hela cells by S. flexneri.

The humoral immune response is the primary protection mechanism for the host against S. flexneri. Serotype-specific LPS may be the main target of the body's immune response. The humoral immunity of the host against S. flexneri includes systemic and mucosal. In the human body infected with S. flexneri, the presence of IgA, especially the anti-LPS IgA, is detected, so it is speculated that it may be the main force for body to stop the re-infection of bacteria. After inputting serotype-specific sIgA hybridoma cells to mice, the mice were able to resist the intranasal challenge of a lethal dose of S. flexneri. In addition, anti-LPS IgG and IgM also showed protection against Shigella in mouse experiments. After immunization, IgA-deficient mice were able to fully survive the Shigella challenge. Moreover, mice lacking T lymphocytes were able to resist the challenge of Shigella after immunization, suggesting the role of the predominating anti-LPS IgM antibodies.

Development of the Shigella flexneri Vaccines

Shigella vaccines are mostly designed based on their O polysaccharides. There are two main strategies for the development of the S. flexneri vaccine, one is live attenuated vaccines, and the other is inactivated vaccines including subunit vaccines and whole cell vaccines. As early as the 1960s, scientists had attenuated Shigella by the way of serially passages. SmD is a streptomycin-dependent Shigella strain that loses mucosal invasiveness and shows good tolerance in field assays and has serotype-specific protection. T32 is an attenuated live strain of S. flexneri 2a, which also showed tolerance and protection in field trials in China and Romania. The results also showed that the vaccine candidate can protect animals against infections of S. flexneri 1b, S Sonnei, and S. boydii 1-6. However, such vaccines require repeated vaccination and regular boosters, in addition to the possibility of back mutations. The development of recombinant DNA technology has brought new strategies for the development of live attenuated vaccines. EcSf2a-1 is a hybrid strain prepared by inserting the invasive plasmid of S. flexneri 5, the gene expressing S. flexneri 2a and the group-specific O antigen into E. coli. EcSf2a-1 has certain immunogenicity and protection, but it also causes several adverse reactions. The vaccine candidate SC602 prepared after deletion of the icsA and aerobactin coding systems in S. flexneri 2a was safe and effective in clinical trials and could provide protection. WRSf2G11, WRSf2G12, and WRSf2G15 vaccine candidate for S. flexneri 2a were prepared by deleting the gene involved in bacterial virulence and knocking out the set locus encoding ShET1 and they are undergoing preclinical evaluation at present. The S. flexneri 2a vaccine candidate CVD1208 containing the guaAB, sen and set mutations also has good tolerance and immunogenicity.

Despite some attempts to inactivate whole-cell vaccines, none of these vaccines provide protection. O-specific polysaccharides that do not cause adverse reactions are often used as targets for vaccines, but children and infants have limited immune responses to sugars, so the focus of such vaccines is to improve their immunogenicity. Vaccines prepared by covalently binding serotype-specific polysaccharides to carrier proteins have demonstrated safety and minor systemic adverse reactions and local adverse reactions in infants, children, and adults, and are highly immunogenic. The currently popular S. flexneri vaccine method uses a synthetic oligosaccharide and a lipopolysaccharide O antigen in combination with a carrier protein. The S. flexneri 2a vaccine prepared by this method is capable of eliciting effective protection in mice. The subunit vaccine prepared by the hydrophobic binding of S. flexneri 2a and S. sonnei lipopolysaccharide to protease and meningococcal outer membrane protein can significantly improve the immunogenicity of the LPS-based vaccine. Purified subunit vaccines containing Shigella ribosomes and O-PS also showed safety, immunogenicity and protection in a mouse model. IpaD-, IpaB-based T3SS-targeted multivalent vaccines have also been shown to be immunogenic and protective in combination with adjuvants. The outer membrane vesicles released from Shigella are also able to induce an immune response and protect the mice from bacterial challenge after being encapsulated into the nanoparticles.

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