Pseudomonas aeruginosa PAO1 outer membrane vesicles-diphtheria toxoid conjugate as a vaccine candidate in a murine burn model

Abstract

Pseudomonas aeruginosa is an opportunistic pathogen considered a common cause of nosocomial infection with high morbidity and mortality in burn patients. Immunoprophylaxis techniques may lower the mortality rate of patients with burn wounds infected by P. aeruginosa; consequently, this may be an efficient strategy to manage infections caused by this bacterium. Several pathogenic Gram-negative bacteria like P. aeruginosa release outer membrane vesicles (OMVs), and structurally OMV consists of several antigenic components capable of generating a wide range of immune responses. Here, we evaluated the immunogenicity and efficacy of P. aeruginosa PA-OMVs (PA-OMVs) conjugated with the diphtheria toxoid (DT) formulated with alum adjuvant (PA-OMVs-DT + adj) in a mice model of burn wound infection. ELISA results showed that in the group of mice immunized with PA-OMVs-DT + adj conjugated, there was a significant increase in specific antibodies titer compared to non-conjugated PA-OMVs or control groups. In addition, the vaccination of mice with PA-OMVs-DT + adj conjugated generated greater protective effectiveness, as seen by lower bacterial loads, and eightfold decreased inflammatory cell infiltration with less tissue damage in the mice burn model compared to the control group. The opsonophagocytic killing results confirmed that humoral immune response might be critical for PA-OMVs mediated protection. These findings suggest that PA-OMV-DT conjugated might be used as a new vaccine against P. aeruginosa in burn wound infection.

Enterococcal Membrane Vesicles as Vaccine Candidates

“…One OMV-based vaccine, 4cMenB protective against Neiserria meningitidis [15], has been in use for several years. (O)MVs of other bacteria have been investigated for their potential as vaccines against infection, such as against Bordetella pertussis [30], Vibrio cholerae [31], Escherichia coli [32], Haemophilus parasuis [33], Pseudomonas aeruginosa [34], Acinetobacter baumannii [35], Salmonella [36], S. pneumoniae [37], S. aureus [38], and others [29]. This is the first study to show the potential of enterococcal MVs as vaccine candidates in the fight against VRE.…”

Recent advances in therapeutic targets identification and development of treatment strategies towards Pseudomonas aeruginosa infections

“…In addition, this treatment induced cGAS-STING pathway triggering (innate immune response), modulation of Toll-like receptors, apoptosis, pyroptosis, CD8 + T-cell proliferation, Th1 and Th2 cytokine responses, and reduced levels of inflammatory factors (IL-6, TNF-α and IL-8) in DC [ 129 ]. Another report confirmed that vaccination of mice with P. aeruginosa’s outer membrane vesicles (PA-OMVs) conjugated with the diphtheria toxoid (DT) formulated with alum adjuvant, namely PA-OMVs-DT + adj conjugated, resulted in a lower bacterial load, drastic decrease of inflammatory cell infiltration with less tissue damage and conferred an efficient protection against P. aeruginosa in the mice burn model [ 130 ]. Of notes, OMVs are particularly attractive as a vaccine platform due to their non-replicating nature, ability to accumulate in lymph nodes, their natural and innate composition of pathogen-associated molecular patterns, and ability to be produced in large quantities by bacterial fermentation [ 131 , 132 ].…”

Extracellular Vesicles of Pseudomonas: Friends and Foes

“…Studies with EVs from Pseudomonas show that LPS and proteins from EVs are recognized and can induce a strong immune response. Banadkoki and colleagues recently found that OMVs from P. aeruginosa conjugated with diphtheria toxoid, formulated with alum adjuvant, generated effective protection when used as a vaccine in a mice burn model for Pseudomonas infection [ 80 ]. Similarly, Zhang and colleagues showed that immunization with EVs from Pseudomonas, formulated with aluminum phosphate adjuvant, protected mice challenged with P. aeruginosa in a model of acute lung infection, reducing cytokine secretion, bacterial colonization, and tissue damage [ 81 ].…”

“…However, there is no vaccine licensed for commercial use and there are currently no ongoing clinical trials [ 83 ]. In this context, formulations containing EVs seem promising for finally generating a clinically approved vaccine for this pathogen [ 80 ].…”