In silico design of Mycobacterium tuberculosis epitope ensemble vaccines.

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.

Designing Epitope Ensemble Vaccines against TB by Selection: Prioritizing Antigens using Predicted Immunogenicity.

Tuberculosis (TB) is a global health burden, and a major cause of mortality and morbidity in West Africa. Here, we select key conserved pathogen epitopes of proven immunogenicity to form a potential TB epitope ensemble vaccine. We compared two vaccine formulations: one comprising class I epitopes from the 13 most prevalent class I epitope-bearing antigens and class II epitopes deriving from the 20 most prevalent class II epitope-bearing antigens and another consisting of epitopes derived solely from 5 antigens identified as the most immunogenic by VaxiJen. In the prevalence analysis, 279 class I and 561 class II epitopes were collected and a subset selected using our published methodology, yielding 32 conserved epitopes. Combining 9 conserved epitopes gave a putative vaccine with predicted population coverage (PPC) over 95%. This consists of ISSGVFLLK, AVAGAAILV, WYYQSGLSI, YQSGLSIVM, MPVGGQSSF, QSSFYSDWY, WDINTPAFEWYYQSGLSIVM, DAPLITNPGGLLEQAVAVEE and NQAVTPAARALPLTSLTSAA. 5 immunogenic antigens VaxiJen-identified yielded 187 epitopes, which we again analyzed using published protocol. This identified 11 conserved epitopes. From this set the highest PPC value (<85%) was obtained by combining: GQQYQAMSAQAAAFH, DDIKATYDKGILTVSVAVSE and AVAGAAILV. We conclude that prioritizing epitope selection using predicted immunogenicity alone is likely to be unduly restrictive and is currently not an optimal or advisable strategy in the design of epitope ensemble vaccines.