Development and characterization of Shigella multiepitope fusion antigen (MEFA) for a broadly protective subunit vaccine against shigellosis with extended utility against enterotoxigenic Escherichia coli.

Shigella spp. remain a notorious and dominant threat to public health, mainly affecting children and with increasing multidrug resistance. Vaccines represent a significant preventive measure against infectious diseases; however, no approved vaccines are currently available to protect against Shigella spp. A critical challenge in developing vaccines for Shigella lies in achieving cross-protection among the diverse subspecies of Shigella. A vaccine candidate, “Shigella MEFA” was designed by applying the epitope- and structure-based multiepitope-fusion-antigen vaccinology platform (MEFA), which incorporated the immune-dominant epitopes from the IpaD (invasion plasmid antigen D), IpaB (invasion plasmid antigen B), GuaB (IMP dehydrogenase), VirG (intracellular cell spreading protein) Stx1A (Shiga toxin 1 subunit A), Stx2A (Shiga toxin 2 subunit A) and StxB (Shiga toxin subunit B). Upon intramuscular administration, multivalent antibodies were induced and achieved broad neutralization of various Shigella serotypes invasion and cytotoxicity by Shiga toxin 1 and Shiga toxin 2d in vitro. Furthermore, Shigella MEFA administered via intranasal route conferred cross-protection against S. sonnei, S. flexneri 2a, 3a, 6 in the mouse pulmonary challenge model. Even though the vaccine has demonstrated significant protection, additional epitopes of IpaB and IpaD were characterized in pursuit of identifying more effective neutralizing epitopes to further maximize the Shigella MEFA 's protection. The IpaB epitopes 1 (LAKILASTELGDNTIQAA), 2 (HSTSNILIPELKAPKSL), and 4 (QARQQKNLEFSDKI), and the IpaD epitope 1 (SPGGNDGNSV), and IpaD epitope 5 (SPNNTNGSSTET) have shown the greatest potential for building the optimized Shigella MEFA, as the antibodies induced by these antigens exhibited the comparable effectiveness to those of recombinant IpaB and IpaD protein, respectively. More importantly, Shigella MEFA has demonstrated compatibility with the well-characterized MecVax vaccine against enterotoxigenic Escherichia coli (ETEC), which was referred to as ShecVax. Upon co-administration in mice, Shigella MEFA and MecVax synergistically induced robust antibody responses against both Shigella and ETEC antigens, with significant neutralization ability against bacterial adhesion, invasion, and enterotoxicity, in comparison to the effectiveness observed when each vaccine is delivered individually. Furthermore, the intranasal administration of ShecVax efficiently protected mice against lethal pulmonary challenges with S. sonnei and S. flexneri 2a. The ShecVax is potentially an attractive approach to combating both Shigella and ETEC, which are currently two major diarrheal pathogens.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

VMS - Pathobiology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2024

Author dc:creator

• Li, Siqi

Contributors dc:contributor

• Zhang, Weiping
• Gaskins, H. Rex
• Lau, Gee W.
• Witola, William Harold

• Shigella
• Mefa (multiepitope Fusion Antigen)
• Polyvalent Immunogen
• Multivalent Vaccine
• Invasion Plasmid Antigen B (ipab)
• Invasion Plasmid Antigen D (ipad)
• Epitope Mapping
• Enterotoxigenic Escherichia Coli (etec)

Statement dc:rights

• Copyright 2024 Siqi Li

Language dc:language

eng, en

Handle dc:identifier

https://hdl.handle.net/2142/124671

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/124671