Annotation of Potential Vaccine Targets and Design of a Multi-Epitope Subunit Vaccine against Yersinia pestis through Reverse Vaccinology and Validation through an Agent-Based Modeling Approach.

Azaz Ul Haq,Yasir Waheed,Nasib Zaman,N Nizam-Uddin,Syed Shujait Ali,Dong-Qing Wei,Qian Wang,Fariha Kanwal,Abbas Khan,Shamaila Irum,Jafar Khan,Muhammad Waseem,Zahid Hussain,Aqel Albutti,Sajjad Ahmad

doi:10.3390/vaccines9111327

Abstract

Yersinia pestis is responsible for plague and major pandemics in Asia and Europe. This bacterium has shown resistance to an array of drugs commonly used for the treatment of plague. Therefore, effective therapeutics measurements, such as designing a vaccine that can effectively and safely prevent Y. pestis infection, are of high interest. To fast-track vaccine development against Yersinia pestis, herein, proteome-wide vaccine target annotation was performed, and structural vaccinology-assisted epitopes were predicted. Among the total 3909 proteins, only 5 (rstB, YPO2385, hmuR, flaA1a, and psaB) were shortlisted as essential vaccine targets. These targets were then subjected to multi-epitope vaccine design using different linkers. EAAK, AAY, and GPGPG as linkers were used to link CTL, HTL, and B-cell epitopes, and an adjuvant (beta defensin) was also added at the N-terminal of the MEVC. Physiochemical characterization, such as determination of the instability index, theoretical pI, half-life, aliphatic index, stability profiling, antigenicity, allergenicity, and hydropathy of the ensemble, showed that the vaccine is highly stable, antigenic, and non-allergenic and produces multiple interactions with immune receptors upon docking. In addition, molecular dynamics simulation confirmed the stable binding and good dynamic properties of the vaccine–TLR complex. Furthermore, in silico and immune simulation of the developed MEVC for Y. pestis showed that the vaccine triggered strong immune response after several doses at different intervals. Neutralization of the antigen was observed at the third day of injection. Conclusively, the vaccine designed here for Y. pestis produces an immune response; however, further immunological testing is needed to unveil its real efficacy.

Highlights

Yersinia pestis is an etiologic agent of plague, which is infamous for three major pandemics killing millions of people [1]
The pathogen proteome comprises a total of 3909 proteins. These proteins were subsequently subjected to the designed vaccine framework to prioritize potential vaccine targets and design a vaccine ensemble
Y. pestis proteins that were homologous to the human proteome were discarded from the complete proteome; 1021 proteins were filtered as non-homologous

Summary

Introduction

Yersinia pestis is an etiologic agent of plague, which is infamous for three major pandemics killing millions of people [1]. The second pMT1 plasmid codes for F1 capsular protein and murine toxin Ymt, which are significant in plague infection transmission. The same study found that two Y. pestis strains, the fully virulent Kimberley and the pgm attenuated EV76 strain, are less capable of inducing macrophage apoptosis, impairing NF-B activation, and activating caspase pathways than the virulent Y. enterocolitica O:8 strain under varied infection circumstances. These limitations correlate with inefficient translocation of YopJ by Y. pestis, which leads to slow accumulation of the effector in the target cells. They found that Y. enterocolitica-derived YopP can provide effective apoptotic potential to Y. pestis, and they suggested that this can be attributed to the fact that Y. enterocolitica O:8

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