In-silico identification of the vaccine candidate epitopes against the Lassa virus hemorrhagic fever

Prabin Baral,Elumalai Pavadai,Prem P Chapagain,Bernard S Gerstman

doi:10.1038/s41598-020-63640-1

Prabin Baral, Elumalai Pavadai + Show 2 more

Open Access

https://doi.org/10.1038/s41598-020-63640-1

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Abstract

Lassa virus (LASV), a member of the Arenaviridae, is an ambisense RNA virus that causes severe hemorrhagic fever with a high fatality rate in humans in West and Central Africa. Currently, no FDA approved drugs or vaccines are available for the treatment of LASV fever. The LASV glycoprotein complex (GP) is a promising target for vaccine or drug development. It is situated on the virion envelope and plays key roles in LASV growth, cell tropism, host range, and pathogenicity. In an effort to discover new LASV vaccines, we employ several sequence-based computational prediction tools to identify LASV GP major histocompatibility complex (MHC) class I and II T-cell epitopes. In addition, many sequence- and structure-based computational prediction tools were used to identify LASV GP B-cell epitopes. The predicted T- and B-cell epitopes were further filtered based on the consensus approach that resulted in the identification of thirty new epitopes that have not been previously tested experimentally. Epitope-allele complexes were obtained for selected strongly binding alleles to the MHC-I T-cell epitopes using molecular docking and the complexes were relaxed with molecular dynamics simulations to investigate the interaction and dynamics of the epitope-allele complexes. These predictions provide guidance to the experimental investigations and validation of the epitopes with the potential for stimulating T-cell responses and B-cell antibodies against LASV and allow the design and development of LASV vaccines.

Highlights

Lassa virus (LASV), a member of the Arenaviridae[1], is an ambisense RNA virus that causes a severe hemorrhagic Lassa fever in humans
The multiple sequence alignment of the 84 LASV GP sequences resulted in the LASV GP Mouse/Sierra Leone/ Josiah/1976) [UniprotKB ID: P08669] as a highly conserved strain, and we selected this strain for the sequence-based major histocompatibility complex (MHC)-I and MHC-II T-cell epitope predictions and for both structure and sequence-based B-cell epitope predictions
The LASV GP spike has emerged as a promising selective target for the development of novel vaccines as it plays an essential role in the virus-host interaction

Summary

Introduction

Lassa virus (LASV), a member of the Arenaviridae[1], is an ambisense RNA virus that causes a severe hemorrhagic Lassa fever in humans. The crystal structure of the trimeric LASV GP in complex with the 37.7 H neutralizing antibody from a human survivor (PDB ID: 5VK2, Fig. 1) has been determined, thereby providing insight into the structural basis for antibody design. Analysis of the GP-37.7 H antibody complex shows that the antibody simultaneously binds to two GP monomers at the base of the GP trimer. The GP2 subunit is lightly shaded to differentiate from the GP1 subunit, and some of the antibody binding sites (Site A, Site B) are highlighted (figure generated from the crystal structure of the LASV GP in the Protein Data Bank[21], PDB ID: 5VK24). The antibody predominantly binds to GP2, GP1 is required to maintain the proper prefusion conformation of GP2 for antibody binding[4]

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