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The Use of Reverse Vaccinology in the Design and Construction of Nano-glycoconjugate Vaccines against Burkholderia pseudomallei.

ABSTRACT: Burkholderia pseudomallei (Bpm) is a Gram negative, facultative intracellular pathogen that causes the disease melioidosis in humans and other mammals. Respiratory infection with B. pseudomallei leads to a fulminant and often fatal disease. It has previously been shown that glycoconjugate vaccines can provide significant protection against lethal challenge; however, the limited number of known Burkholderia antigens has slowed progress towards vaccine development. The objective of this study was to identify novel antigens and evaluate their protective capacity when incorporated into a nano-glycoconjugate vaccine platform. First, an in silico approach to identify antigens with strong predicted immunogenicity was developed. Protein candidates were screened and ranked according to predicted subcellular localization, transmembrane domains, adhesive properties and ability to interact with Major Histocompatibility Complex (MHC) I and II. From these in silico predictions, we identified seven "high priority" proteins that demonstrated seroreactivity with anti-Bpm murine sera and convalescent human melioidosis sera, providing validation of our methods. Two novel proteins, together with Hcp1, were linked to lipopolysaccharide (LPS) and incorporated onto the surface of a gold nanoparticle (AuNP). Animals receiving AuNP-glycoconjugate vaccines generated high protein- and polysaccharide-specific antibody titers. Importantly, immunized animals receiving the AuNP-FlgL-LPS alone or as a combo demonstrated up to 100% survival and reduced lung colonization following lethal challenge with Bpm. Together, this study provides a rational approach to vaccine design that can be adapted for other complex pathogens, and provides rationale for further pre-clinical testing of AuNP-glycoconjugate in animal models of infection.

SUBMITTER: Muruato LA

PROVIDER: S-EPMC5674190 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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Use of Reverse Vaccinology in the Design and Construction of Nanoglycoconjugate Vaccines against Burkholderia pseudomallei.

Muruato Laura A LA Tapia Daniel D Hatcher Christopher L CL Kalita Mridul M Brett Paul J PJ Gregory Anthony E AE Samuel James E JE Titball Richard W RW Torres Alfredo G AG

Clinical and vaccine immunology : CVI 20171106 11

Burkholderia pseudomallei is a Gram-negative, facultative intracellular pathogen that causes the disease melioidosis in humans and other mammals. Respiratory infection with B. pseudomallei leads to a fulminant and often fatal disease. It has previously been shown that glycoconjugate vaccines can provide significant protection against lethal challenge; however, the limited number of known Burkholderia antigens has slowed progress toward vaccine development. The objective of t ...[more]

PMID: 28903988

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Project description:Burkholderia cepacia is a Gram-negative nosocomial pathogen and is considered as a troublesome bacterium due to its resistance to many common antibiotics. There is no licensed vaccine available to prevent the pathogen infections, thus making the condition more alarming and warrant the search for novel therapeutic and prophylactic approaches. In order to identify protective antigens from pathogen proteome, substantial efforts are put forth to prioritized potential vaccine targets and antigens that can be easily evaluated experimentally. In this vaccine design investigation, it was found that B. cepacia completely sequenced proteomes available in NCBI genome database has a total of 28,966 core proteins. Out of total, 25,282 proteins were found redundant while 3,684 were non-redundant. Subcellular localization revealed that 18 proteins were extracellular, 31 were part of the outer membrane, 75 proteins were localized in the periplasm, and 23 were virulent proteins. Five proteins namely flagellar hook protein (FlgE), fimbria biogenesis outer membrane usher protein, Type IV pilus secretin (PilQ), cytochrome c4, flagellar hook basal body complex protein (FliE) were tested for positive for antigenic, non-toxic, and soluble epitopes during predication of B-cell derived T-cell epitopes. A vaccine peptide of 14 epitopes (joined together via GPGPG linkers) and cholera toxin B subunit (CTBS) adjuvant (joined to epitopes peptide via EAAAK linker) was constructed. Binding interaction of the modeled vaccine with MHC-I, MHC-II, and Toll-like receptor 4 (TLR-4) immune receptors was studied using molecular docking studies and further analyzed in molecular dynamics simulations that affirms strong intermolecular binding and stable dynamics. The maximum root mean square deviation (RMSD) score of complexes in the simulation time touches to 2 Å. Additionally, complexes binding free energies were determined that concluded robust interaction energies dominated by van der Waals. The total energy of each complex is < -190 kcal/mol. In summary, the designed vaccine showed promising protective immunity against B. cepacia and needs to be examined in experiments.

Dataset Information

The Use of Reverse Vaccinology in the Design and Construction of Nano-glycoconjugate Vaccines against Burkholderia pseudomallei.

Publications

Use of Reverse Vaccinology in the Design and Construction of Nanoglycoconjugate Vaccines against Burkholderia pseudomallei.

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