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Conservation of M72/AS01E vaccine epitopes in 31,428 Mycobacterium tuberculosis isolates

K Dewaele(1) B C de Jong(1) O Tzfadia(1)

1:Institute of Tropical Medicine Antwerp

M72/AS01E is a protein subunit vaccine consisting of two Mycobacterium tuberculosis (Mtb) proteins, PPE18 and pepA. It is unclear how well M72’s epitopes are conserved among clinical strains, which might affect the vaccine’s efficacy. Existing studies have used small and/or phylogenetically monotonous datasets. We quantified non-synonymous SNPs (nSNPs) in PPE18 and pepA genes of 31,428 public domain Mtb strains, representative of the near-complete phylogenetic diversity of global clinical strains. We geographically resolved conservation data by Mtb complex lineage and correlated with predicted M72 epitope regions for that geographic region, using high-resolution typing of strains and worldwide MHC-II allele distribution data. All nSNPs at a frequency of more than 0.1% were situated in the PPE18 portion of M72. M72 regions most consistently predicted to be epitopes were mostly situated in the N-terminal portion of pepA. Defining an M72 residue as non-conserved if it is changed in 1% of strains, we found that M72 epitopes were generally well-conserved, with epitope non-conservation rates reaching at most 9% in Southeast Asia and 10% in Australia. MHC-II alleles DRB*11:01 and DRB*13:01 expressed the least number of M72 epitopes. Lineages, and 2.2.1 stood out as having the highest number of nSNPs in epitope regions. We present the most comprehensive epitope conservation study of M72 to date, demonstrating limited loss of M72 epitopes due to non-conservation of epitopes among clinical strains. The ongoing phase 3 trial can test whether these findings predict vaccine failure.

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