Using epitope predictions to evaluate efficacy and population coverage of the Mtb72f vaccine for tuberculosis

Abstract

Background: The Mtb72f subunit vaccine for tuberculosis, currently in clinical trials, is hoped to provide improved protection compared to the current BCG vaccine. It is not clear, however, whether Mtb72f would be equally protective in the different human populations suffering from a high burden of tuberculosis. Previous work by Hebert and colleagues demonstrated that the PPE18 protein of Mtb72f had significant variability in a sample of clinical M. tuberculosis isolates. However, whether this variation might impact the efficacy of Mtb72f in the context of the microbial and host immune system interactions remained to be determined. The present study assesses Mtb72f's predicted efficacy in people with different DRB1 genotypes to predict whether the vaccine will protect against diverse clinical strains of M. tuberculosis in a diverse host population.

Results: We evaluated the binding of epitopes in the vaccine to different alleles of the human DRB1 Class II MHC protein using freely available epitope prediction programs and compared protein sequences from clinical isolates to the sequences included in the Mtb72f vaccine. This analysis predicted that the Mtb72f vaccine would be less effective for several DRB1 genotypes, due either to limited vaccine epitope binding to the DRB1 proteins or to binding primarily by unconserved PPE18 epitopes. Furthermore, we found that these less-protective DRB1 alleles are found at a very high frequency in several populations with a high burden of tuberculosis.

Conclusion: Although the Mtb72f vaccine candidate has shown promise in animal and clinical trials thus far, it may not be optimally effective in some genotypic backgrounds. Due to variation in both M. tuberculosis protein sequences and epitope-binding capabilities of different HLA alleles, certain human populations with a high burden of tuberculosis may not be optimally protected by the Mtb72f vaccine. The efficacy of the Mtb72f vaccine should be further examined in these particular populations to determine whether additional protective measures might be necessary for these regions.

Figure 1

Boxplots of CD4+ T cell epitope nonamer cores (y-axis) in the Mtb72f vaccine predicted to bind to each of the twelve selected DRB1 alleles (x-axis) by the eight chosen epitope prediction programs. Epitopes found in the unmodified PepA protein but not in the vaccine have been excluded, as have epitopes found in the vaccine but not in the unmodified proteins. Boxes show the lower quartile, median, and upper quartile; whiskers show the minimum and maximum values excluding outliers (circles) and diamonds show the mean. The symbols next to the names of DRB1 alleles indicate the numbers of programs used to predict epitope binding to each allele: ! = 4, * = 5, # = 6, $ = 7, and + = 8. The highest outliers for alleles 0101, 0401, and 0701 on each chart are from MHCPred. a. Total vaccine epitope binding predictions. b. Vaccine epitope binding predictions for conserved epitopes only. Conserved epitopes are defined as epitope nonamer cores plus N- and C-terminal pentamer flanking sequences that are absent or mutated in no more than two of the variant strains sequenced. c. Epitopes in the vaccine but not in the native PPE18 or PepA proteins that are predicted to bind each DRB1 allele.