In silico design of Mycobacterium tuberculosis epitope ensemble vaccines

Abstract

Effective control of Mycobacterium tuberculosis is a global necessity. In 2015, tuberculosis (TB) caused more deaths than HIV. Considering the increasing prevalence of multi-drug resistant forms of M. tuberculosis, the need for effective TB vaccines becomes imperative. Currently, the only licensed TB vaccine is Bacillus Calmette-Guérin (BCG). Yet, BCG has many drawbacks limiting its efficacy and applicability. We applied advanced computational procedures to derive a universal TB vaccine and one targeting East Africa. Our approach selects an optimal set of highly conserved, experimentally validated epitopes, with high projected population coverage (PPC). Through rigorous data analysis, five different potential vaccine combinations were selected each with PPC above 80% for East Africa and above 90% for the World. Two potential vaccines only contained CD8+ epitopes, while the others included both CD4+ and CD8+ epitopes. Our prime vaccine candidate was a putative seven-epitope ensemble comprising: SRGWSLIKSVRLGNA, KPRIITLTMNPALDI, AAHKGLMNIALAISA, FPAGGSTGSL, MLLAVTVSL, QSSFYSDW and KMRCGAPRY, with a 97.4% global PPC and a 92.7% East African PPC.

West Nile Virus Vaccine Design by T Cell Epitope Selection: In Silico Analysis of Conservation, Functional Cross-Reactivity with the Human Genome, and Population Coverage

“…Epitopes in adoptive immunotherapies may exhibit undesired side effects [23], such as CR when foreign peptide sequences resemble those of self-peptides sufficiently to initiate an unwanted autoimmune response. Addition of computational CR prediction to our design-by-selection protocol is a key advance over previous work [14][15][16][17][18][19][20] and should accelerate the early selection of safe vaccines. When using iCrossR [23], none of the epitopes were identified to elicit responses cross-reactive with human tissues.…”

“…The lack of extant WNV vaccines prompts us to evaluate potential epitope ensemble vaccines as an alternative, exploiting our evolving approach to vaccine design. We have exemplified this by identifying putative vaccines against hepatitis C [14], influenza [15], malaria [16], Epstein-Barr virus [17], TB [18,19], and dengue [20]. By focusing on highly conserved immunogenic epitopes with a broad population coverage, we identified optimal selections of prevalidated epitopes of proven immunogenicity.…”

Immunogenicity and Vaccine Potential of InsB, an ESAT-6-Like Antigen Identified in the Highly Virulent Mycobacterium tuberculosis Beijing K Strain

“…The identification of Mtb antigens eliciting antigen-specific IFN-γ–producing CD4 + T cell responses during Mtb infection has been approached through a variety of methods, including comparative proteomics using biochemical fractionation of the Mtb-secreted antigen pool, comparative transcriptomic analysis, and in silico epitope analysis (Shah et al, 2018). The identification of ESAT-6/Rv3875 (Sorensen et al, 1995) and Mtb10.4/Rv0288 (Skjot et al, 2000) via comparative proteomic analysis in a culture filtrate from Mtb is a successful example.…”

In Silico Strategies in Tuberculosis Drug Discovery

“…In silico methods have already been applied to tuberculosis studies in several different ways and combinations depending on the goal of the study implemented, such as for drug discovery [179,281], understanding protein structure and function [282,283], and others [284]. One example showing the integration of computational methods is a study implemented by Li et al involving 3D-QSAR, binding pocket prediction, docking, and MD simulation studies for FtsZ, which is a validated Mtb target and plays a significant role in cell division [285].…”