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Mapping Global Prevalence of Acinetobacter baumannii and Recent Vaccine Development to Tackle It.

ABSTRACT: Acinetobacter baumannii is a leading cause of nosocomial infections that severely threaten public health. The formidable adaptability and resistance of this opportunistic pathogen have hampered the development of antimicrobial therapies which consequently leads to very limited treatment options. We mapped the global prevalence of multidrug-resistant A. baumannii and showed that carbapenem-resistant A. baumannii is widespread throughout Asia and the Americas. Moreover, when antimicrobial resistance rates of Acinetobacter spp. exceed a threshold level, the proportion of A. baumannii isolates from clinical samples surges. Therefore, vaccines represent a realistic alternative strategy to tackle this pathogen. Research into anti-A. baumannii vaccines have enhanced in the past decade and multiple antigens have been investigated preclinically with varying results. This review summarises the current knowledge of virulence factors relating to A. baumannii-host interactions and its implication in vaccine design, with a view to understanding the current state of A. baumannii vaccine development and the direction of future efforts.

SUBMITTER: Ma C

PROVIDER: S-EPMC8226933 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Mapping Global Prevalence of Acinetobacter baumannii and Recent Vaccine Development to Tackle It.

Ma Chaoying C McClean Siobhán S

Vaccines 20210601 6

Acinetobacter baumannii is a leading cause of nosocomial infections that severely threaten public health. The formidable adaptability and resistance of this opportunistic pathogen have hampered the development of antimicrobial therapies which consequently leads to very limited treatment options. We mapped the global prevalence of multidrug-resistant A. baumannii and showed that carbapenem-resistant A. baumannii is widespread throughout Asia and the Americas. Moreover, when a ...[more]

PMID: 34205838

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Project description:BackgroundThe World Health Organization has categorized Acinetobacter baumannii (A. baumannii) as a critical priority pathogen due to its high antibiotic resistance. This resistance complicates treatment and underscores the urgent need for new antibiotics and strategies. This study developed a multi-epitope vaccine (MEV) to address this significant public health threat.MethodsThis study employed a computational approach to design MEV targeting A. baumannii strain VB7036. Surface-exposed proteins were identified using PSORTb and TMHMM, followed by antigenicity and allergenicity predictions using VaxiJen and AlgPred. Linear B-cell epitopes and MHC-II binding sites were predicted using BepiPred and TepiTool, while physicochemical properties were analyzed with ExPASy ProtParam and Protein-Sol. The MEV construct was validated through molecular docking with TLR2 and TLR4 using HDOCK, revealing strong binding interactions. Molecular dynamic simulations confirmed the stability of the vaccine-receptor complexes, while PCA analysis indicated minimal conformational transitions. Immune simulations were conducted using C-ImmSim online software.ResultsThis study identified eight OMPs from A. baumannii strain VB7036 as potential immunogenic targets. MEV was designed using five critical B-cell epitopes from four proteins based on their antigenicity, non-allergenicity, and physicochemical properties. This MEV demonstrated strong binding to TLR2 and TLR4, indicating effective immune activation. Molecular dynamics simulations confirmed the structural stability of the MEV-TLR complexes. In silico immune simulations revealed that the MEV induced robust humoral and cell-mediated immune responses, including increased antibody production, T-cell activation, and cytokine release, suggesting the MEV's potential as an effective vaccine candidate for A. baumannii.ConclusionThis study developed an optimized MEV and identified novel drug targets against A. baumannii, providing broad protection against multidrug-resistant A. baumannii strains. MEV demonstrated significant potential due to its favorable physicochemical properties, as confirmed by molecular docking and dynamic simulations. However, more in vitro and in vivo studies are required to verify the drug's effectiveness.

Project description:To give an update on the molecular epidemiology and global distribution of carbapenemase encoding genes, we subjected 313 carbapenem-resistant Acinetobacter baumannii isolated from 114 study centers in 47 countries in five world regions, Africa, Asia, Europe, Latin America, and North America, to whole genome sequencing. Numbers of isolates investigated were proportional to the population size of the contributing countries. Molecular epidemiology was investigated using seven-loci and core genome multilocus sequence typing, whole-genome single nucleotide polymorphism phylogenies, and the intrinsic blaOXA-51-like variant. Carbapenemase encoding genes were identified by multiplex PCR and ResFinder. Among the total of 313 isolates, 289 (92.3%) were assigned to A. baumannii international clones (IC) IC1-IC8. IC2 predominated with 196 isolates (62.6%) and was spread worldwide, followed by IC5 with 44 isolates (14.1%) mainly confined to Latin America. Six isolates (1.9%) originating from Belgium, Egypt, Italy, and Pakistan represent the novel IC9. Acquired OXA-type carbapenemase genes were found in 300 (96%) isolates with blaOXA-23-like and blaOXA-40-like predominating, which constitutes a significant increase compared to our findings from 2010. Metallo-beta-lactamases were rare with seven isolates (2.2%). The distribution of ICs and carbapenemase determinants can vary widely among different geographical regions. IMPORTANCE Carbapenem-resistant Acinetobacter baumannii are of increasing public health importance, as they are resistant to last-line antibiotics. International clones with well-characterized resistance genes dominate globally; however, locally, other lineages with different properties may be of importance to consider. This study investigated isolates from a broad geographic origin from 114 hospitals in 47 countries and from five world regions ensuring the greatest possible diversity in an organism known for its propensity for clonal epidemic spread and reflecting the current global epidemiology of carbapenem-resistant A. baumannii. In Latin America, a lineage different from other geographic regions circulates, with a different resistance gene profile. This knowledge is important to adjust local infection prevention measures. In a global world with migration and increasing use of antimicrobials, multidrug-resistant bacteria will continue to adapt and challenge our healthcare systems worldwide.

Project description:Developing adjuvant vaccines to combat rising multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) infections is a promising and cost-effective approach. The aim of this analysis was to construct a pDNA-CPG C274-adjuvant nano-vaccine and investigate its immunogenicity and protection in BALB/c mice. The CPG ODN C274 adjuvant was chemically synthesized and cloned into pcDNA3.1( +), and the cloning was verified using PCR and BamHI/EcoRV restriction enzyme digestion. Then, utilizing a complex coacervation approach, pDNA-CPG C274 was encapsulated by chitosan (CS) nanoparticles (NPs). TEM and DLS are used to explore the properties of the pDNA/CSNP complex. TLR-9 pathway activation was investigated in human HEK-293 and RAW 264.7 mouse cells. The vaccine's immunogenicity and immune-protective effectiveness were investigated in BALB/c mice. The pDNA-CPG C274/CSNPs were small (mean size 79.21 ± 0.23 nm), positively charged (+ 38.87 mV), and appeared to be spherical. A continuous slow release pattern was achieved. TLR-9 activation was greatest in the mouse model with CpG ODN (C274) at concentrations of 5 and 10 μg/ml with 56% and 55%, respectively (**P < 0.01). However, in HEK-293 human cells, by increasing the concentration of CpG ODN (C274) from 1 to 50 μg/ml, the activation rate of TLR-9 also increased, so that the highest activation rate (81%) was obtained at the concentration of 50 μg/ml (***P < 0.001). pDNA-CPG C274/CSNPs immunized BALB/c mice produced increased amounts of total-IgG, as well as IFN-γ and IL-1B in serum samples, compared to non-encapsulated pDNA-CPG C274. Furthermore, liver and lung injuries, as well as bacterial loads in the liver, lung, and blood, were reduced, and BALB/c mice immunized with pDNA-CPG C274/CSNPs showed potent protection (50-75%) against acute fatal Intraperitoneal A. baumannii challenge. pDNA-CPG C274/CSNPs evoked total-IgG antibodies, Th1 cellular immunity, and the TLR-9 pathway, as well as protection against an acute fatal A. baumannii challenge. Our findings suggest that this nano-vaccine is a promising approach for avoiding A. baumannii infection when used as a powerful adjuvant.

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Mapping Global Prevalence of Acinetobacter baumannii and Recent Vaccine Development to Tackle It.

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Mapping Global Prevalence of <i>Acinetobacter baumannii</i> and Recent Vaccine Development to Tackle It.

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