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Impact of the TLR4 agonist BECC438 on a novel vaccine formulation against Shigella spp.
Shigellosis (bacillary dysentery) is a severe gastrointestinal infection with a global incidence of 90 million cases annually. Despite the severity of this disease, there is currently no licensed vaccine against shigellosis. Shigella’s primary virulence factor is its type III secretion system (T3SS)...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10512073/ https://www.ncbi.nlm.nih.gov/pubmed/37744341 http://dx.doi.org/10.3389/fimmu.2023.1194912 |
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author | Lu, Ti Das, Sayan Howlader, Debaki R. Jain, Akshay Hu, Gang Dietz, Zackary K. Zheng, Qi Ratnakaram, Siva Sai Kumar Whittier, Sean K. Varisco, David J. Ernst, Robert K. Picking, William D. Picking, Wendy L. |
author_facet | Lu, Ti Das, Sayan Howlader, Debaki R. Jain, Akshay Hu, Gang Dietz, Zackary K. Zheng, Qi Ratnakaram, Siva Sai Kumar Whittier, Sean K. Varisco, David J. Ernst, Robert K. Picking, William D. Picking, Wendy L. |
author_sort | Lu, Ti |
collection | PubMed |
description | Shigellosis (bacillary dysentery) is a severe gastrointestinal infection with a global incidence of 90 million cases annually. Despite the severity of this disease, there is currently no licensed vaccine against shigellosis. Shigella’s primary virulence factor is its type III secretion system (T3SS), which is a specialized nanomachine used to manipulate host cells. A fusion of T3SS injectisome needle tip protein IpaD and translocator protein IpaB, termed DBF, when admixed with the mucosal adjuvant double-mutant labile toxin (dmLT) from enterotoxigenic E. coli was protective using a murine pulmonary model. To facilitate the production of this platform, a recombinant protein that consisted of LTA-1, the active moiety of dmLT, and DBF were genetically fused, resulting in L-DBF, which showed improved protection against Shigella challenge. To extrapolate this protection from mice to humans, we modified the formulation to provide for a multivalent presentation with the addition of an adjuvant approved for use in human vaccines. Here, we show that L-DBF formulated (admix) with a newly developed TLR4 agonist called BECC438 (a detoxified lipid A analog identified as Bacterial Enzymatic Combinatorial Chemistry candidate #438), formulated as an oil-in-water emulsion, has a very high protective efficacy at low antigen doses against lethal Shigella challenge in our mouse model. Optimal protection was observed when this formulation was introduced at a mucosal site (intranasally). When the formulation was then evaluated for the immune response it elicits, protection appeared to correlate with high IFN-γ and IL-17 secretion from mucosal site lymphocytes. |
format | Online Article Text |
id | pubmed-10512073 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-105120732023-09-22 Impact of the TLR4 agonist BECC438 on a novel vaccine formulation against Shigella spp. Lu, Ti Das, Sayan Howlader, Debaki R. Jain, Akshay Hu, Gang Dietz, Zackary K. Zheng, Qi Ratnakaram, Siva Sai Kumar Whittier, Sean K. Varisco, David J. Ernst, Robert K. Picking, William D. Picking, Wendy L. Front Immunol Immunology Shigellosis (bacillary dysentery) is a severe gastrointestinal infection with a global incidence of 90 million cases annually. Despite the severity of this disease, there is currently no licensed vaccine against shigellosis. Shigella’s primary virulence factor is its type III secretion system (T3SS), which is a specialized nanomachine used to manipulate host cells. A fusion of T3SS injectisome needle tip protein IpaD and translocator protein IpaB, termed DBF, when admixed with the mucosal adjuvant double-mutant labile toxin (dmLT) from enterotoxigenic E. coli was protective using a murine pulmonary model. To facilitate the production of this platform, a recombinant protein that consisted of LTA-1, the active moiety of dmLT, and DBF were genetically fused, resulting in L-DBF, which showed improved protection against Shigella challenge. To extrapolate this protection from mice to humans, we modified the formulation to provide for a multivalent presentation with the addition of an adjuvant approved for use in human vaccines. Here, we show that L-DBF formulated (admix) with a newly developed TLR4 agonist called BECC438 (a detoxified lipid A analog identified as Bacterial Enzymatic Combinatorial Chemistry candidate #438), formulated as an oil-in-water emulsion, has a very high protective efficacy at low antigen doses against lethal Shigella challenge in our mouse model. Optimal protection was observed when this formulation was introduced at a mucosal site (intranasally). When the formulation was then evaluated for the immune response it elicits, protection appeared to correlate with high IFN-γ and IL-17 secretion from mucosal site lymphocytes. Frontiers Media S.A. 2023-09-06 /pmc/articles/PMC10512073/ /pubmed/37744341 http://dx.doi.org/10.3389/fimmu.2023.1194912 Text en Copyright © 2023 Lu, Das, Howlader, Jain, Hu, Dietz, Zheng, Ratnakaram, Whittier, Varisco, Ernst, Picking and Picking https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Lu, Ti Das, Sayan Howlader, Debaki R. Jain, Akshay Hu, Gang Dietz, Zackary K. Zheng, Qi Ratnakaram, Siva Sai Kumar Whittier, Sean K. Varisco, David J. Ernst, Robert K. Picking, William D. Picking, Wendy L. Impact of the TLR4 agonist BECC438 on a novel vaccine formulation against Shigella spp. |
title | Impact of the TLR4 agonist BECC438 on a novel vaccine formulation against Shigella spp. |
title_full | Impact of the TLR4 agonist BECC438 on a novel vaccine formulation against Shigella spp. |
title_fullStr | Impact of the TLR4 agonist BECC438 on a novel vaccine formulation against Shigella spp. |
title_full_unstemmed | Impact of the TLR4 agonist BECC438 on a novel vaccine formulation against Shigella spp. |
title_short | Impact of the TLR4 agonist BECC438 on a novel vaccine formulation against Shigella spp. |
title_sort | impact of the tlr4 agonist becc438 on a novel vaccine formulation against shigella spp. |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10512073/ https://www.ncbi.nlm.nih.gov/pubmed/37744341 http://dx.doi.org/10.3389/fimmu.2023.1194912 |
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