A randomized, placebo-controlled phase I study assessing the safety and immunogenicity of a<i>Pseudomonas aeruginosa</i>hybrid outer membrane protein OprF/I vaccine (IC43) in healthy volunteers

Westritschnig, Kerstin; Hochreiter, Romana; Wallner, Gerhard; Firbas, Christa; Schwameis, Michael; Jilma, Bernd

doi:10.4161/hv.26565

Cited by 72 publications

(60 citation statements)

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“…The outer membrane proteins OprF and OprI are abundant outer membrane porins present on the surface of bacteria and are implicated in OMV formation (30). Due to their immunogenicity and key bacterial functions, OprF and OprI are vaccine candidates against P. aeruginosa-initiated infections (32,33). Current vaccine efforts that utilize recombinant protein composed of OprF and OprI epitopes show that the recombinant vaccine is immunogenic and well tolerated in humans (32).…”

Section: Figmentioning

confidence: 99%

Distinct Susceptibilities of Corneal Pseudomonas aeruginosa Clinical Isolates to Neutrophil Extracellular Trap-Mediated Immunity

et al. 2014

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Ocular bacterial keratitis, often associated with Pseudomonas aeruginosa bacterial infection, commonly occurs in contact lens wearers and may lead to vision impairment. In this study, we analyzed the contribution of neutrophil extracellular traps (NETs) to the mediation of protection during ocular keratitis. Both invasive and cytotoxic P. aeruginosa clinical isolates induced NET release by neutrophils. NETs carried the characteristic histone proteins, elastase, lysozyme, myeloperoxidase, and metabolic enzymes. While the invasive P. aeruginosa strains PAO1 (serogroup O5) and 6294 (serogroup O6) were trapped by NETs, the cytotoxic P. aeruginosa strains 6077, 6206 (serogroup O11), and PA14 (serogroup 010) were less sensitive to NET capture. The mechanism of escape by the cytotoxic strains from adhesion to NETs involved the shedding of outer membrane vesicles (OMVs) that outcompeted the cytotoxic P. aeruginosa strains for NET binding. When ocular infection was caused by an invasive strain in vivo, NETs were released at the ocular surface to capture bacteria, limiting their spread. Treatment with MNase I had a dose-dependent effect, with low doses of MNase speeding up bacterial clearance and high doses of MNase having toxic consequences. Cumulatively, our data suggest that NET-mediated immunity is a two-step process. Initially, pathogens attach to NET fragments; subsequently, upon nuclease activity, active serine proteases, which proteolytically degrade NET-associated proteins and promote DNase activity, are released. Therefore, a balance between NET production and NET degradation is needed to achieve maximal NET immunity. Infections caused by Pseudomonas aeruginosa are frequently associated with bacterial ocular keratitis, a condition that carries the risk of vision impairment and occurs in contact lens wearers or after ocular trauma. The majority of bacterial clinical isolates derived from corneal ulcers arising during keratitis can be divided into two functionally distinct groups: invasive and cytotoxic isolates. These two groups have distinct phenotypes; the cytotoxic strains cause rapid cell lysis, whereas the invasive strains replicate in the target cells (1, 2). These differences translate into various severities of disease; in mouse keratitis studies where infection is induced by cytotoxic strains, disease pathology is worse than that caused by invasive strains (3). Consistent with these findings, patients infected with cytotoxic strains have experienced more severe pathology and, consequently, suffered from greater visual impairment after recovery from infection (4). The immune response to both invasive and cytotoxic strains is dominated by dense neutrophil infiltrates, yet the infiltration pattern and responses of polymorphonuclear neutrophils (PMNs) differ depending on the type of strain. Due to the recently described ability of neutrophils to release DNA in the form of neutrophil extracellular traps (NETs) (5) and the presence of extracellular DNA during cytotoxic infections, we questioned whether the cyt...

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Section: Figmentioning

confidence: 99%

Distinct Susceptibilities of Corneal Pseudomonas aeruginosa Clinical Isolates to Neutrophil Extracellular Trap-Mediated Immunity

et al. 2014

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“…Entre las secuencias encontradas por nuestro estudio, cabe resaltar la proteína GroEL que ha sido reportada en pacientes con infecciones pulmonares crónicas causadas por P. aeruginosa y que provoca una fuerte respuesta de anticuerpos (31) .…”

Section: Discussionunclassified

Caracterización molecular de bacterias patógenas de las vías respiratorias de pacientes peruanos con fibrosis quística

Aquino

Gonzáles

Samaniego³

et al. 2017

Rev Peru Med Exp Salud Publica

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“…Although several PA vaccines have been trialed including those using OprF, OprI, and flagellin (10)(11)(12)(13)(14)(15)(16)(20)(21)(22)(23)(24)(25), studies such as this one raise an additional possibility of exploiting the potency and flexibility of incorporating a large number of stimulatory T-and B-cell epitopes into epitope string vaccines. In other contexts, such as Plasmodium falciparum vaccination, these can be successfully administered in a "prime-boost" regime through incorporation into an adenoviral vector followed by DNA boost (62).…”

Section: Original Article Discussionmentioning

confidence: 99%

“…Various PA antigens have been considered in mouse, rat, and nonhuman primate, as well as trials in human CF or non-CF vaccinees (10)(11)(12)(13)(14)(15)(16). In a phase III vaccine trial of patients with noncolonized CF, a flagellin vaccine roughly halved the number of PA infections in the recipient cohort (10).…”

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confidence: 99%

Chronic Infection by Mucoid Pseudomonas aeruginosa Associated with Dysregulation in T-Cell Immunity to Outer Membrane Porin F

Quigley

Reynolds

Goudet

et al. 2015

Am J Respir Crit Care Med

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Rationale: Pseudomonas aeruginosa (PA) is an environmental pathogen that commonly infects individuals with cystic fibrosis (CF) and non-CF bronchiectasis, impacting morbidity and mortality. To understand the pathobiology of interactions between the bacterium and host adaptive immunity and to inform rational vaccine design, it is important to understand the adaptive immune correlates of disease.Objectives: To characterize T-cell immunity to the PA antigen outer membrane porin F (OprF) by analyzing immunodominant epitopes in relation to infection status.Methods: Patients with non-CF bronchiectasis were stratified by frequency of PA isolation. T-cell IFN-g immunity to OprF and its immunodominant epitopes was characterized. Patterns of human leukocyte antigen (HLA) restriction of immunodominant epitopes were defined using HLA class II transgenic mice. Immunity was characterized with respect to cytokine and chemokine secretion, antibody response, and T-cell activation transcripts. Measurements and Main Results:Patients were stratified according to whether PA was never, sometimes (,50%), or frequently (>50%) isolated from sputum. Patients with frequent PA sputumpositive isolates were more likely to be infected by mucoid PA, and they showed a narrow T-cell epitope response and a relative reduction in Th1 polarizing transcription factors but enhanced immunity with respect to antibody production, innate cytokines, and chemokines. Conclusions:We have defined the immunodominant, HLArestricted T-cell epitopes of OprF. Our observation that chronic infection is associated with a response of narrowed specificity, despite strong innate and antibody immunity, may help to explain susceptibility in these individuals and pave the way for better vaccine design to achieve protective immunity.

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A randomized, placebo-controlled phase I study assessing the safety and immunogenicity of aPseudomonas aeruginosahybrid outer membrane protein OprF/I vaccine (IC43) in healthy volunteers

Cited by 72 publications

References 28 publications

Distinct Susceptibilities of Corneal Pseudomonas aeruginosa Clinical Isolates to Neutrophil Extracellular Trap-Mediated Immunity

Distinct Susceptibilities of Corneal Pseudomonas aeruginosa Clinical Isolates to Neutrophil Extracellular Trap-Mediated Immunity

Caracterización molecular de bacterias patógenas de las vías respiratorias de pacientes peruanos con fibrosis quística

Chronic Infection by Mucoid Pseudomonas aeruginosa Associated with Dysregulation in T-Cell Immunity to Outer Membrane Porin F

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