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

DOI: 10.1128/mBio.02227-14

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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.

TABLE 1

Summary of binding and postexposure efficacy data available for EBOV therapeutics^{^a}

Candidate therapeutic component	Treatment modality	Therapeutic(s)	Nucleotide position based on GenBank/RefSeq entry^{^b}	Amino acid residues of target protein	Target gene	Treatment time p.i.	Treatment success (% survival range)	Reference(s)
EK-1-mod	siRNA	Tekmira	17,396–17,418	NA	L	30 min to 6 days	66.7–100^{^c}	8
VP24-1160-mod	siRNA	Tekmira	11,043–11,065	NA	VP24	30 min to 6 days	66.7–100^{^c}	8
VP35-855-mod	siRNA	Tekmira	3884–3906	NA	VP35	30 min to 6 days	66.7–100^{^c}	8
1H3 Mab	Passive immunization	ZMAB	6039–6508	1–157	GP	3–9 days	50–100^{^d}	10, 18
2G4 Mab	Passive immunization	ZMAPP, ZMAB	7540–8039	501–676	GP	3–9 days	50–100^{^d}^,^{^e}	10, 12, 18
4G7 Mab	Passive immunization	ZMAPP, ZMAB	7414–7542	459–501	GP	3–9 days, 5 days	50–100^{^d}^,^{^e}	10, 12, 18
13C6 Mab	Passive immunization	MB-003, ZMAPP	6039–7542	1–501	GP^{^f}	1–2 days, 5 days	66.7–100^{^e}	11, 12, 18, 19
6D8 Mab	Passive immunization	MB-003	7204–7254	389–405	GP	1–2 days	66.7	11, 19
13F6 Mab	Passive immunization	MB-003	7240–7290	401–417	GP	1–2 days	66.7	11, 19
AVI-7537	PMO	AVI-6002	10,331–10,349	NA	VP24	30–60 min	60	9, 15
AVI-7539	PMO	AVI-6002	3133–3152	NA	VP35	30–60 min	60	9, 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.

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Copyright © 2015 Kugelman, et al.
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