Safety and immunogenicity of an intranasal Shigella flexneri 2a Invaplex 50 vaccine

Riddle, Mark S.; Kaminski, Robert W.; Williams, Carlos; Porter, Chad K.; Baqar, Shahida; Kordis, Alexis A.; Gilliland, Theron; Lapa, Joyce A.; Coughlin, Melissa; Soltis, Chris; Jones, Erica; Saunders, Jackie; Keiser, Paul B.; Ranallo, Ryan T.; Gormley, Robert; Michael, Nelson; Turbyfill, K. Ross; Tribble, David R.; Oaks, Edwin V.

doi:10.1016/j.vaccine.2011.07.033

Cited by 75 publications

(43 citation statements)

References 33 publications

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“…Two chromatographic fractions, designated Invaplex 24 and 50, were immunogenic and protective against homologous virulent strains in mice and guinea pigs (34). The S. flexneri 2a Invaplex 50 vaccine was safe and immunogenic when administered intranasally to human volunteers in phase 1 clinical studies (43,48). However, this vaccine failed to protect subjects from a subsequent oral challenge with virulent S. flexneri 2a 2457TC.…”

Section: Discussionmentioning

confidence: 99%

Broadly Protective Shigella Vaccine Based on Type III Secretion Apparatus Proteins

et al. 2012

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Shigella spp. are food-and waterborne pathogens that cause severe diarrheal and dysenteric disease associated with high morbidity and mortality. Individuals most often affected are children under 5 years of age in the developing world. The existence of multiple Shigella serotypes and the heterogenic distribution of pathogenic strains, as well as emerging antibiotic resistance, require the development of a broadly protective vaccine. All Shigella spp. utilize a type III secretion system (TTSS) to initiate infection. The type III secretion apparatus (TTSA) is the molecular needle and syringe that form the energized conduit between the bacterial cytoplasm and the host cell to transport effector proteins that manipulate cellular processes to benefit the pathogen. IpaB and IpaD form a tip complex atop the TTSA needle and are required for pathogenesis. Because they are common to all virulent Shigella spp., they are ideal candidate antigens for a subunit-based, broad-spectrum vaccine. We examined the immunogenicity and protective efficacy of IpaB and IpaD, alone or combined, coadministered with a double mutant heat-labile toxin (dmLT) from Escherichia coli, used as a mucosal adjuvant, in a mouse model of intranasal immunization and pulmonary challenge. Robust systemic and mucosal antibody-and T cell-mediated immunities were induced against both proteins, particularly IpaB. Mice immunized in the presence of dmLT with IpaB alone or IpaB combined with IpaD were fully protected against lethal pulmonary infection with Shigella flexneri and Shigella sonnei. We provide the first demonstration that the Shigella TTSAs IpaB and IpaD are promising antigens for the development of a cross-protective Shigella vaccine.

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Section: Discussionmentioning

confidence: 99%

Broadly Protective Shigella Vaccine Based on Type III Secretion Apparatus Proteins

et al. 2012

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“…No approved vaccine is presently available to prevent shigellosis. Research efforts to develop prophylactic measures have produced a number of promising vaccine candidates, including whole-cell inactivated organisms [5], live attenuated Shigella strains [6–8], O-specific polysaccharide-protein conjugate vaccines [9;10] and subcellular complexes containing invasion plasmid antigens (Ipas) and LPS [11;12]. These vaccines have been evaluated in human clinical trials with various degrees of success [Reviewed in [13–15]].…”

Section: 0 Introductionmentioning

confidence: 99%

Evaluation of immunogenicity and protective efficacy of orally delivered Shigella type III secretion system proteins IpaB and IpaD

Heine¹,

Diaz-McNair²,

Martinez-Becerra³

et al. 2013

Vaccine

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Shigella spp. are food- and water-borne pathogens that cause shigellosis, a severe diarrheal and dysenteric disease that is associated with a high morbidity and mortality in resource-poor countries. No licensed vaccine is available to prevent shigellosis. We have recently demonstrated that Shigella invasion plasmid antigens (Ipas), IpaB and IpaD, which are components of the bacterial type III secretion system (TTSS), can prevent infection in a mouse model of intranasal immunization and lethal pulmonary challenge. Because they are conserved across Shigella spp. and highly immunogenic, these proteins are excellent candidates for a cross-protective vaccine. Ideally, such a vaccine could be administered to humans orally to induce mucosal and systemic immunity. In this study, we investigated the immunogenicity and protective efficacy of Shigella IpaB and IpaD administered orally with a double mutant of the Escherichia coli heat labile toxin (dmLT) as a mucosal adjuvant. We characterized the immune responses induced by oral vs. intranasal immunization and the protective efficacy using a mouse pulmonary infection model. Serum IgG and fecal IgA against IpaB were induced after oral immunization. These responses, however, were lower than those obtained after intranasal immunization despite a 100-fold dosage increase. The level of protection induced by oral immunization with IpaB and IpaD was 40%, while intranasal immunization resulted in 90% protective efficacy. IpaB- and IpaD-specific IgA antibody-secreting cells in the lungs and spleen and T-cell-derived IL-2, IL-5, IL-17 and IL-10 were associated with protection. These results demonstrate the immunogenicity of orally administered IpaB and IpaD and support further studies in humans.

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“…Several groups have explored different approaches in the search of a Shigella vaccine. These include live attenuated strains of Shigella (16), LPS-protein conjugates (17), mixtures of subunit components (18), and recombinant proteins (19). Our hypothesis is that a vaccine comprised of highly conserved protein antigens would provide broad, serotype-independent protection, thus bypassing the need to consider multiple serotypes as are needed for vaccines that target LPS or O antigen.…”

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confidence: 99%

Characterization of a Novel Fusion Protein from IpaB and IpaD of Shigella spp. and Its Potential as a Pan-Shigella Vaccine

et al. 2013

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Shigellosis is an important disease in the developing world, where about 90 million people become infected with Shigella spp. each year. We previously demonstrated that the type three secretion apparatus (T3SA) proteins IpaB and IpaD are protective antigens in the mouse lethal pulmonary model. In order to simplify vaccine formulation and process development, we have evaluated a vaccine design that incorporates both of these previously tested Shigella antigens into a single polypeptide chain. To determine if this fusion protein (DB fusion) retains the antigenic and protective capacities of IpaB and IpaD, we immunized mice with the DB fusion and compared the immune response to that elicited by the IpaB/IpaD combination vaccine. Purification of the DB fusion required coexpression with IpgC, the IpaB chaperone, and after purification it maintained the highly ␣-helical characteristics of IpaB and IpaD. The DB fusion also induced comparable immune responses and retained the ability to protect mice against Shigella flexneri and S. sonnei in the lethal pulmonary challenge. It also offered limited protection against S. dysenteriae challenge. Our results show the feasibility of generating a protective Shigella vaccine comprised of the DB fusion.

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Safety and immunogenicity of an intranasal Shigella flexneri 2a Invaplex 50 vaccine

Cited by 75 publications

References 33 publications

Broadly Protective Shigella Vaccine Based on Type III Secretion Apparatus Proteins

Broadly Protective Shigella Vaccine Based on Type III Secretion Apparatus Proteins

Evaluation of immunogenicity and protective efficacy of orally delivered Shigella type III secretion system proteins IpaB and IpaD

Characterization of a Novel Fusion Protein from IpaB and IpaD of Shigella spp. and Its Potential as a Pan-Shigella Vaccine

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