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.
Highlights
Pseudomonas aeruginosa (Pa) is an important opportunistic human pathogen responsible for severe infections in patients with burns, severe wounds, pneumonia, and critically ill patients who require intubation or catheterization (Grimwood et al, 2015; Anantharajah et al, 2016)
The zeta potential of ME mixed with L-PaF had a slight positive value as compared to the negative values of ME or L-PaF alone, which suggests that their association significantly alters the resulting particle’s surface features (Table 1)
We have previously demonstrated that L-PaF is protective against multiple Pa serotypes (Das et al, 2020), so here we focused on showing that the protective efficacy of L-PaF could be improved by formulating it into a nanoparticle containing the TLR4 agonist BECC438
Summary
Pseudomonas aeruginosa (Pa) is an important opportunistic human pathogen responsible for severe infections in patients with burns, severe wounds, pneumonia, and critically ill patients who require intubation (ventilator-associated pneumonia) or catheterization (urinary tract infections) (Grimwood et al, 2015; Anantharajah et al, 2016). Multidrug-resistant (MDR) Pa was classified as a serious threat in the CDC Antibiotic Resistance Threats report 2019. In 2017, there were ∼32,600 cases of MDR Pa infection in hospitalized patients causing an estimated 2,700 deaths and costing $757 million in health care costs in the United States (CDC, 2019). A 2016 report describes Pa as the most common Gram-negative infection amongst troops with combat-related injuries in Afghanistan with 10% being MDR (Merakou et al, 2018). Despite the ability to cause disease in humans who have been injured or hospitalized, aging represents the biggest risk factor for acquiring acute lethal Pa infection (Merakou et al, 2018)
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