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    Effect of Two Unique Nanoparticle Formulations on the Efficacy of a Broadly Protective Vaccine Against Pseudomonas Aeruginosa

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    Author
    Howlader, Debaki R
    Das, Sayan
    Lu, Ti
    Hu, Gang
    Varisco, David J
    Dietz, Zackary K
    Walton, Sierra P
    Ratnakaram, Siva Sai Kumar
    Gardner, Francesca M
    Ernst, Robert K
    Picking, William D
    Picking, Wendy L
    Show allShow less

    Date
    2021-08-18
    Journal
    Frontiers in Pharmacology
    Publisher
    Frontiers Media S.A.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3389/fphar.2021.706157
    Abstract
    Pseudomonas aeruginosa is an opportunistic pathogen responsible for a wide range of infections in humans. In addition to its innate antibiotic resistance, P. aeruginosa is very effective in acquiring resistance resulting in the emergence of multi-drug resistance strains and a licensed vaccine is not yet available. We have previously demonstrated the protective efficacy of a novel antigen PaF (Pa Fusion), a fusion of the type III secretion system (T3SS) needle tip protein, PcrV, and the first of two translocator proteins, PopB. PaF was modified to provide a self-adjuvanting activity by fusing the A1 subunit of the heat-labile enterotoxin from Enterotoxigenic E. coli to its N-terminus to give L-PaF. In addition to providing protection against 04 and 06 serotypes of P. aeruginosa, L-PaF elicited opsonophagocytic killing and stimulated IL-17A secretion, which have been predicted to be required for a successful vaccine. While monomeric recombinant subunit vaccines can be protective in mice, this protection often does not transfer to humans where multimeric formulations perform better. Here, we use two unique formulations, an oil-in-water (o/w) emulsion and a chitosan particle, as well as the addition of a unique TLR4 agonist, BECC438 (a detoxified lipid A analogue designated Bacterial Enzymatic Combinatorial Chemistry 438), as an initial step in optimizing L-PaF for use in humans. The o/w emulsion together with BECC438 provided the best protective efficacy, which correlated with high levels of opsonophagocytic killing and IL-17A secretion, thereby reducing the lung burden among all the vaccinated groups tested.
    Rights/Terms
    Copyright © 2021 Howlader, Das, Lu, Hu, Varisco, Dietz, Walton, Ratnakaram, Gardner, Ernst, Picking and Picking.
    Keyword
    IL-17
    L-PaF
    T3SS vaccine
    nanoparticle vaccine
    opsonophagocytosis
    protein formulations
    pseudomonas
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/16593
    ae974a485f413a2113503eed53cd6c53
    10.3389/fphar.2021.706157
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