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Observation

Evaluation of the Potential Impact of Ebola Virus Genomic Drift on the Efficacy of Sequence-Based Candidate Therapeutics

Jeffrey R. Kugelman, Mariano Sanchez-Lockhart, Kristian G. Andersen, Stephen Gire, Daniel J. Park, Rachel Sealfon, Aaron E. Lin, Shirlee Wohl, Pardis C. Sabeti, Jens H. Kuhn, Gustavo F. Palacios
Jack R. Bennink, Editor
Jeffrey R. Kugelman
aCenter for Genome Sciences Division of the United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, USA
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  • ORCID record for Jeffrey R. Kugelman
Mariano Sanchez-Lockhart
aCenter for Genome Sciences Division of the United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, USA
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Kristian G. Andersen
bCenter for Systems Biology, Harvard University, Cambridge, Massachusetts, USA
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Stephen Gire
bCenter for Systems Biology, Harvard University, Cambridge, Massachusetts, USA
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Daniel J. Park
bCenter for Systems Biology, Harvard University, Cambridge, Massachusetts, USA
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Rachel Sealfon
cComputer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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Aaron E. Lin
bCenter for Systems Biology, Harvard University, Cambridge, Massachusetts, USA
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Shirlee Wohl
bCenter for Systems Biology, Harvard University, Cambridge, Massachusetts, USA
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Pardis C. Sabeti
bCenter for Systems Biology, Harvard University, Cambridge, Massachusetts, USA
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Jens H. Kuhn
dIntegrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA
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  • ORCID record for Jens H. Kuhn
Gustavo F. Palacios
aCenter for Genome Sciences Division of the United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, USA
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Jack R. Bennink
National Institute of Allergy and Infectious Diseases
Roles: Editor
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DOI: 10.1128/mBio.02227-14
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  • FIG 1 
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    FIG 1 

    Mutation analysis of candidate therapeutic binding sites. An SNP table is combined with a heat map based on three categories: (i) mutation shown to be tolerated by the therapeutic (10), (ii) mutations that are within the binding region of the therapeutic but have not been tested (8–12, 15, 18, 19), and (iii) tolerated diversity between development strains. %EBOV-WA, percentage of genomes containing a change in the West African (WA) sequences of 2014 from EBOV/Kik-9510621.

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    FIG 2 

    EBOV therapeutic map. Each of the therapeutics was mapped onto the genome of EBOV/Kik-9510621 according to published binding information. Blue arrows represent the nine open reading frames conserved among all Ebola viruses. A graphic representation of the SNPs is above the genomic position scale. Red vertical bars denote nonsynonymous mutations, blue vertical bars represent synonymous mutations, and green vertical bars represent noncoding mutations.

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  • TABLE 1 

    Summary of binding and postexposure efficacy data available for EBOV therapeuticsa

    Candidate therapeutic componentTreatment modalityTherapeutic(s)Nucleotide position based on GenBank/RefSeq entrybAmino acid residues of target proteinTarget geneTreatment time p.i.Treatment success (% survival range)Reference(s)
    EK-1-modsiRNATekmira17,396–17,418NAL30 min to 6 days66.7–100c8
    VP24-1160-modsiRNATekmira11,043–11,065NAVP2430 min to 6 days66.7–100c8
    VP35-855-modsiRNATekmira3884–3906NAVP3530 min to 6 days66.7–100c8
    1H3 MabPassive immunizationZMAB6039–65081–157GP3–9 days50–100d10, 18
    2G4 MabPassive immunizationZMAPP, ZMAB7540–8039501–676GP3–9 days50–100d,e10, 12, 18
    4G7 MabPassive immunizationZMAPP, ZMAB7414–7542459–501GP3–9 days, 5 days50–100d,e10, 12, 18
    13C6 MabPassive immunizationMB-003, ZMAPP6039–75421–501GPf1–2 days, 5 days66.7–100e11, 12, 18, 19
    6D8 MabPassive immunizationMB-0037204–7254389–405GP1–2 days66.711, 19
    13F6 MabPassive immunizationMB-0037240–7290401–417GP1–2 days66.711, 19
    AVI-7537PMOAVI-600210,331–10,349NAVP2430–60 min609, 15
    AVI-7539PMOAVI-60023133–3152NAVP3530–60 min609, 15
    • ↵a MAb, monoclonal antibody; NA, not applicable; p.i., postinoculation; PMO, phosphorodiamidate morpholino oligomers; siRNA, small interfering RNA. Recognition sequences for PMO and siRNA are listed in the supplemental methods.

    • ↵b siRNA positions include both sense and antisense oligonucleotide positions. Mutations specific to each are designated in Fig. 1.

    • ↵c Survival range is dependent on dosing.

    • ↵d Survival range is dependent on addition of Ad-IFN (interferon co-treatment) to treatment 1 day p.i.

    • ↵e Survival range is dependent on formulation.

    • ↵f Cross-reacts with TAFV (Tai Forest virus) and SUDV (Sudan virus) GP.

Supplemental Material

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  • Text S1 

    Supplemental materials and methods. Download Text S1, DOCX file, 0.01 MB.

    Copyright © 2015 Kugelman, et al.

    This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

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    Supplementary Data

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    • Text s1, DOCX - Text s1, DOCX
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Evaluation of the Potential Impact of Ebola Virus Genomic Drift on the Efficacy of Sequence-Based Candidate Therapeutics
Jeffrey R. Kugelman, Mariano Sanchez-Lockhart, Kristian G. Andersen, Stephen Gire, Daniel J. Park, Rachel Sealfon, Aaron E. Lin, Shirlee Wohl, Pardis C. Sabeti, Jens H. Kuhn, Gustavo F. Palacios
mBio Jan 2015, 6 (1) e02227-14; DOI: 10.1128/mBio.02227-14

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Evaluation of the Potential Impact of Ebola Virus Genomic Drift on the Efficacy of Sequence-Based Candidate Therapeutics
Jeffrey R. Kugelman, Mariano Sanchez-Lockhart, Kristian G. Andersen, Stephen Gire, Daniel J. Park, Rachel Sealfon, Aaron E. Lin, Shirlee Wohl, Pardis C. Sabeti, Jens H. Kuhn, Gustavo F. Palacios
mBio Jan 2015, 6 (1) e02227-14; DOI: 10.1128/mBio.02227-14
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