Towards a subunit vaccine from a Shigella flexneri ΔtolR mutant

Pastor, Yadira; Camacho, Ana I.; Zúñiga-Ripa, Amaia; Merchán, A; Rosas, Pablo; Irache, Juan M.; Gamazo, Carlos

doi:10.1016/j.vaccine.2018.10.066

Cited by 20 publications

(20 citation statements)

References 47 publications

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“…MNs were loaded with HT-∆tolR antigenic complex, an outer membrane vesicle-based vaccine obtained from heat-inactivated S. flexneri ∆tolR strain. The complex was previously characterized and demonstrated to be immunogenic and protective in a murine model of shigellosis [18]. To our knowledge, this is the first time that outer membrane vesicles have been administrated through dissolving MNs.…”

Section: Discussionmentioning

confidence: 85%

“…An antigenic complex based on outer membrane vesicles was obtained from the S. flexneri ∆tolR mutant strain, as previously described [18]. The parental strain S. flexneri 2a is a clinical isolate ("Clínica Universidad de Navarra", Spain).…”

Section: Outer Membrane Vesicle Obtentionmentioning

confidence: 99%

“…However, it was considered only as a basic proof of concept, since studies were not carried out to elucidate the mechanism involved.The aim of the present study was to design and develop a dissolving MN patch made of aqueous blends of w/w poly (methyl vinyl ether-co-maleic anhydride), commercialized as Gantrez AN ® (Gz), which is not cytotoxic and has been shown to posses immunoadjuvant properties [15,16] and evaluate its capacity for ID vaccination. For that purpose, and based on previous reports by our group [17,18], a subunit vaccine based on outer membrane vesicles from Shigella flexneri was introduced into dissolving MNs as an antigens model. The mechanical and dissolving properties of MNs, as well as their immunogenic and protective capacity in mice, were evaluated.…”

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confidence: 99%

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Dissolving Microneedles for Intradermal Vaccination against Shigellosis

et al. 2019

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Intradermal (ID) immunization is of increasing interest due to the easy accessibility and excellent immunogenic properties of the skin. Among ID immunization methods, dissolving microneedles (MNs) have appeared as an alternative to traditional hypodermic immunization, offering many advantages, such as being an easily administered method, with no need for health personnel, painless, and avoiding the use of needles and sharp wastage. In this study, an affordable and easy-to-produce MNs method was developed based on aqueous blends of 30% w/w poly (methyl vinyl ether-co-maleic anhydride). As an antigen model, a subunit vaccine candidate based on outer membrane vesicles from Shigella flexneri was used. Both unloaded and antigen-loaded MNs were synthetized and characterized. The MNs were successfully validated in an in vitro Parafilm M ® skin model and in a pig skin ex vivo model. Biodistribution studies were performed in BALB/c mice using 99m TcO 4 − radiolabeled samples. Results indicated that the vesicle vaccine was successfully released from the MNs and targeted gastrointestinal tract after 6 h post-administration. In vivo immunization and protection studies were performed in BALB/c mice. Mice were intradermally immunized through ear skin with one single dose of 200 µg antigenic complex, eliciting the production of specific systemic IgG and mucosal IgA. Moreover, MNs were able to protect mice from an experimental infection with 1×10 6 CFU/mouse of S. flexneri four weeks after immunization. This work demonstrates for the first time the potential of outer membrane vesicle-loaded dissolving MNs for ID vaccination against enteropathogens like Shigella.Vaccines 2019, 7, 159 2 of 15 (SALT), formed by a great network of immune cells, including Langerhans cells (LC), lymphocytes, and dendritic cells (DCs), which recognize the antigens and present them in the proximal lymph nodes [3]. Different ID vaccination methods have been used already, such as the Mantoux technique, microinjection systems, or jet injectors, used for smallpox, rabies, or Bacillus Calmette-Guérin (BCG) vaccines. However, they require the use of needles [4]. Microneedle patches (MNs) have appeared as a novel and attractive approach for ID immunization [5]. They are painless devices formed by arrays of micron-size projections that can pass through the stratum corneum and epidermis without reaching the nerves of the dermis layer [6]. Thus, they are a self-administered, minimally invasive method, well tolerated by human patients in proof of concept trials [7,8], that can directly target the skin immune cells [9].Several types of MNs have been developed for the delivery of antigens: solid, coated, hollow, and dissolving MNs [10]. Among them, and based on their self-disabling properties, dissolving MNs (MNs) have been selected for this work. These MNs are made of a soluble matrix, generally a biocompatible polymer or polysaccharide, which includes the antigenic complex. After the array insertion into the skin, the needle tips dissolve and the antigenic cargo i...

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Section: Discussionmentioning

confidence: 85%

Section: Outer Membrane Vesicle Obtentionmentioning

confidence: 99%

mentioning

confidence: 99%

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Dissolving Microneedles for Intradermal Vaccination against Shigellosis

et al. 2019

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“…Furthermore, E. coli mutants in genes encoding Tol-Pal components showed defective O-antigen polymerization ( Vinés et al, 2005 ), while Pseudomonas aeruginosa defective in a Tol-Pal component (TolA) showed membranes with high affinity for cationic compounds, including polymyxin B, due to changes in the LPS ( Rivera et al, 1988 ). Furthermore, the hypervesiculating Shigella flexneri Δ tolR produces OMVs with alterations in the LPS O-chain ( Pastor et al, 2018 ). Thus, we propose that OMVs from S. Typhi Δ tolR present a higher affinity for polymyxin B than the other OMVs tested due to changes in their membrane profile.…”

Section: Discussionmentioning

confidence: 99%

“One for All”: Functional Transfer of OMV-Mediated Polymyxin B Resistance From Salmonella enterica sv. Typhi ΔtolR and ΔdegS to Susceptible Bacteria

et al. 2021

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The appearance of multi-resistant strains has contributed to reintroducing polymyxin as the last-line therapy. Although polymyxin resistance is based on bacterial envelope changes, other resistance mechanisms are being reported. Outer membrane vesicles (OMVs) are nanosized proteoliposomes secreted from the outer membrane of Gram-negative bacteria. In some bacteria, OMVs have shown to provide resistance to diverse antimicrobial agents either by sequestering and/or expelling the harmful agent from the bacterial envelope. Nevertheless, the participation of OMVs in polymyxin resistance has not yet been explored in S. Typhi, and neither OMVs derived from hypervesiculating mutants. In this work, we explored whether OMVs produced by the hypervesiculating strains Salmonella Typhi ΔrfaE (LPS synthesis), ΔtolR (bacterial envelope) and ΔdegS (misfolded proteins and σE activation) exhibit protective properties against polymyxin B. We found that the OMVs extracted from S. Typhi ΔtolR and ΔdegS protect S. Typhi WT from polymyxin B in a concentration-depending manner. By contrast, the protective effect exerted by OMVs from S. Typhi WT and S. Typhi ΔrfaE is much lower. This effect is achieved by the sequestration of polymyxin B, as assessed by the more positive Zeta potential of OMVs with polymyxin B and the diminished antibiotic’s availability when coincubated with OMVs. We also found that S. Typhi ΔtolR exhibited an increased MIC of polymyxin B. Finally, we determined that S. Typhi ΔtolR and S. Typhi ΔdegS, at a lesser level, can functionally and transiently transfer the OMV-mediated polymyxin B resistance to susceptible bacteria in cocultures. This work shows that mutants in genes related to OMVs biogenesis can release vesicles with improved abilities to protect bacteria against membrane-active agents. Since mutations affecting OMV biogenesis can involve the bacterial envelope, mutants with increased resistance to membrane-acting agents that, in turn, produce protective OMVs with a high vesiculation rate (e.g., S. Typhi ΔtolR) can arise. Such mutants can functionally transfer the resistance to surrounding bacteria via OMVs, diminishing the effective concentration of the antimicrobial agent and potentially favoring the selection of spontaneous resistant strains in the environment. This phenomenon might be considered the source for the emergence of polymyxin resistance in an entire bacterial community.

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“…These vesicles can present multiple protective antigens and innate signaling molecules (such as Toll-Like Receptors ligands) to the immune system; thus, they are capable of stimulating different branches of the immune response and potentially possess an intrinsic self-adjuvanting activity. 160 OMVs have been used in vaccine development for the prevention of bacterial infections, such as those caused by Neisseria meningitidis ( N. meningitidis ) serogroup B 161 or Shigella flexneri, 162 and NTS-derived OMVs have recently been tested in animal models, yielding promising immunogenicity and protection data. 163 – 165 …”

Section: Ints Vaccine Developmentmentioning

confidence: 99%

Pathogenic signature of invasive non-typhoidal Salmonella in Africa: implications for vaccine development

Piccini

Montomoli

2020

Human Vaccines & Immunotherapeutics

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Invasive non-typhoidal Salmonella (iNTS) infections are a leading cause of bacteremia in Sub-Saharan Africa (sSA), thereby representing a major public health threat. Salmonella Typhimurium clade ST313 and Salmonella Enteriditis lineages associated with Western and Central/Eastern Africa are among the iNTS serovars which are of the greatest concern due to their case-fatality rate, especially in children and in the immunocompromised population. Identification of pathogen-associated features and host susceptibility factors that increase the risk for invasive non-typhoidal salmonellosis would be instrumental for the design of targeted prevention strategies, which are urgently needed given the increasing spread of multidrug-resistant iNTS in Africa. This review summarizes current knowledge of bacterial traits and host immune responses associated with iNTS infections in sSA, then discusses how this knowledge can guide vaccine development while providing a summary of vaccine candidates in preclinical and early clinical development.

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Towards a subunit vaccine from a Shigella flexneri ΔtolR mutant

Cited by 20 publications

References 47 publications

Dissolving Microneedles for Intradermal Vaccination against Shigellosis

Dissolving Microneedles for Intradermal Vaccination against Shigellosis

“One for All”: Functional Transfer of OMV-Mediated Polymyxin B Resistance From Salmonella enterica sv. Typhi ΔtolR and ΔdegS to Susceptible Bacteria

Pathogenic signature of invasive non-typhoidal Salmonella in Africa: implications for vaccine development

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