Designing and testing broadly-protective filoviral vaccines optimized for cytotoxic T-lymphocyte epitope coverage.
We report the rational design and in vivo testing of mosaic proteins for a polyvalent pan-filoviral vaccine using a computational strategy designed for the Human Immunodeficiency Virus type 1 (HIV-1) but also appropriate for Hepatitis C virus (HCV) and potentially other diverse viruses. Mosaics are sets of artificial recombinant proteins that are based on natural proteins. The recombinants are computationally selected using a genetic algorithm to optimize the coverage of potential cytotoxic T lymphocyte (CTL) epitopes. Because evolutionary history differs markedly between HIV-1 and filoviruses, we devised an adapted computational technique that is effective for sparsely sampled taxa; our first significant result is that the mosaic technique is effective in creating high-quality mosaic filovirus proteins. The resulting coverage of potential epitopes across filovirus species is superior to coverage by any natural variants, including current vaccine strains with demonstrated cross-reactivity. The mosaic cocktails are also robust: mosaics substantially outperformed natural strains when computationally tested against poorly sampled species and more variable genes. Furthermore, in a computational comparison of cross-reactive potential a design constructed prior to the Bundibugyo outbreak performed nearly as well against all species as an updated design that included Bundibugyo. These points suggest that the mosaic designs would be more resilient than natural-variant vaccines against future Ebola outbreaks dominated by novel viral variants. We demonstrate in vivo immunogenicity and protection against a heterologous challenge in a mouse model. This design work delineates the likely requirements and limitations on broadly-protective filoviral CTL vaccines.
Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. paulf@lanl.gov
Paul W
PW
Fenimore
Majidat A
MA
Muhammad
William M
WM
Fischer
Brian T
BT
Foley
Russell R
RR
Bakken
James R
JR
Thurmond
Karina
K
Yusim
Hyejin
H
Yoon
Michael
M
Parker
Mary Kate
MK
Hart
John M
JM
Dye
Bette
B
Korber
Carla
C
Kuiken
D016915:AIDS Vaccines / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D019295:Computational Biology / Q000379:methods; D003429:Cross Reactions / Q000276:immunology; D015195:Drug Design; D046129:Ebola Vaccines / Q000008:administration & dosage / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D016563:Filoviridae / Q000276:immunology* / Q000378:metabolism; D018702:Filoviridae Infections / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D016174:Hepacivirus / Q000276:immunology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014761:Viral Hepatitis Vaccines / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*
D016915:AIDS Vaccines; D000914:Antibodies, Viral; D046129:Ebola Vaccines; D018984:Epitopes, T-Lymphocyte; D014761:Viral Hepatitis Vaccines; D014764:Viral Proteins; D014765:Viral Vaccines