HIV-1/AIDS vaccines must address the extreme diversity of HIV-1. We have designed new polyvalent vaccine antigens comprised of sets of 'mosaic' proteins, assembled from fragments of natural sequences via a computational optimization method. Mosaic proteins resemble natural proteins, and a mosaic set maximizes the coverage of potential T-cell epitopes (peptides of nine amino acids) for a viral population. We found that coverage of viral diversity using mosaics was greatly increased compared to coverage by natural-sequence vaccine candidates, for both variable and conserved proteins; for conserved HIV-1 proteins, global coverage may be feasible. For example, four mosaic proteins perfectly matched 74% of 9-amino-acid potential epitopes in global Gag sequences; 87% of potential epitopes matched at least 8 of 9 positions. In contrast, a single natural Gag protein covered only 37% (9 of 9) and 67% (8 of 9). Mosaics provide diversity coverage comparable to that afforded by thousands of separate peptides, but, because the fragments of natural proteins are compressed into a small number of native-like proteins, they are tractable for vaccines.
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The authors thank J.H. Fischer for helpful comments on the manuscript. This work was funded through an internal directed-research grant for vaccine design at Los Alamos National Laboratory (to W.F., S.P., T.B., J.T., B.T.K., K.Y., R.F. and B.H.H.), a US National Institutes of Health (NIH) HIVRAD grant (P01 consortium (to B.H., B.H.H. and N.L.).
A patent application has been made, covering the methods and materials presented in this paper.
Full overall coverage of vaccine candidates: coverage of nine-mers in B-clade, C-clade, and M-group sequences using different input data sets for mosaic optimization, allowing different numbers of antigens, and comparing to different candidate vaccines. (PDF 2773 kb)
The distribution of nine-mers by frequency of occurrence in natural, consensus, and mosaic sequences. (PDF 546 kb)
HLA binding potential of vaccine candidates. (PDF 736 kb)
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Fischer, W., Perkins, S., Theiler, J. et al. Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants. Nat Med 13, 100–106 (2007). https://doi.org/10.1038/nm1461
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