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Monitoring of Ebola Virus Makona Evolution through Establishment of Advanced Genomic Capability in Liberia.

Kugelman JR, Wiley MR, Mate S, Ladner JT, Beitzel B, Fakoli L, Taweh F, Prieto K, Diclaro JW, Minogue T, Schoepp RJ, Schaecher KE, Pettitt J, Bateman S, Fair J, Kuhn JH, Hensley L, Park DJ, Sabeti PC, Sanchez-Lockhart M, Bolay FK, Palacios G, US Army Medical Research Institute of Infectious DiseasesNational Institutes of HealthIntegrated Research Facility–Frederick Ebola Response Team 2014–20 - Emerging Infect. Dis. (2015)

Bottom Line: Twenty-five EBOV genomes were sequenced at the Liberian Institute for Biomedical Research, which provided an in-depth view of EBOV diversity in Liberia during September 2014-February 2015.The pace of change is generally consistent with previous estimates of mutation rate.We observed 23 nonsynonymous mutations and 1 nonsense mutation.

View Article: PubMed Central - PubMed

ABSTRACT
To support Liberia's response to the ongoing Ebola virus (EBOV) disease epidemic in Western Africa, we established in-country advanced genomic capabilities to monitor EBOV evolution. Twenty-five EBOV genomes were sequenced at the Liberian Institute for Biomedical Research, which provided an in-depth view of EBOV diversity in Liberia during September 2014-February 2015. These sequences were consistent with a single virus introduction to Liberia; however, shared ancestry with isolates from Mali indicated at least 1 additional instance of movement into or out of Liberia. The pace of change is generally consistent with previous estimates of mutation rate. We observed 23 nonsynonymous mutations and 1 nonsense mutation. Six of these changes are within known binding sites for sequence-based EBOV medical countermeasures; however, the diagnostic and therapeutic impact of EBOV evolution within Liberia appears to be low.

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Mutation analysis of candidate therapeutic drug and diagnostic binding sites used in outbreak of Ebola virus (EBOV) disease, Western Africa. A single-nucleotide polymorphism (SNP) table is combined with a heat map based on 2 categories: 1) mutations tolerated by the therapeutic drug or diagnostic target (highlighted in green); 2) mutations within the binding region of a therapeutic drug or diagnostic assay that have not yet been tested (highlighted in yellow/orange) (20–24,27,30,31). Changes previously described are highlighted in yellow; changes that appeared during circulation in Liberia are highlighted in orange. The reference nucleotide positions reported here are in relation to EBOV/Kik-9510621 (GenBank accession no. AY354458), which is one of the primary isolates used as reference for developing these therapeutic drugs and diagnostic assays. A summary of the changes to the probes is available in Technical Appendix 1 Table. PMO, phosphorodiaminate morpholino oligomer, mAB, monoclonal antibody; siRNA, small interfering RNA; Ref pos, reference positive; VP, viral protein.
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Figure 2: Mutation analysis of candidate therapeutic drug and diagnostic binding sites used in outbreak of Ebola virus (EBOV) disease, Western Africa. A single-nucleotide polymorphism (SNP) table is combined with a heat map based on 2 categories: 1) mutations tolerated by the therapeutic drug or diagnostic target (highlighted in green); 2) mutations within the binding region of a therapeutic drug or diagnostic assay that have not yet been tested (highlighted in yellow/orange) (20–24,27,30,31). Changes previously described are highlighted in yellow; changes that appeared during circulation in Liberia are highlighted in orange. The reference nucleotide positions reported here are in relation to EBOV/Kik-9510621 (GenBank accession no. AY354458), which is one of the primary isolates used as reference for developing these therapeutic drugs and diagnostic assays. A summary of the changes to the probes is available in Technical Appendix 1 Table. PMO, phosphorodiaminate morpholino oligomer, mAB, monoclonal antibody; siRNA, small interfering RNA; Ref pos, reference positive; VP, viral protein.

Mentions: Since the Western Africa outbreak began, at least 33 viral mutations have occurred that could affect countermeasures. We previously reported 27 of these mutations (6). Twenty-six (79%) mutations induced nonsynonymous changes to epitopes recognized by mAbs included in passive immunotherapy cocktails. Another 5 (15%) were located in published binding regions of siRNA-based therapeutic drugs. Tekmira has adjusted its siRNAs to account for 4 of these 5 changes since its initial publication (29; E.P. Thi et al., unpub. data). The final 2 mutations were located in the published binding region of primers or probes for quantitative PCR diagnostic tests that have been used during outbreak control activities in Liberia: 1 change each in the binding sites of the Kulesh-TM assay and the Kulesh-MGB assay (9). Nevertheless, reassessment of the assays at USAMRIID has suggested that the changes will be tolerated without loss in sensitivity (data not shown). Changes in all EBOV/Mak sequences are considered “interoutbreak” (n = 23); changes observed only in some sequences from Western Africa are considered “intraoutbreak” sites (n = 10, EBOV-WA <100%). We also examined the binding sites of an additional 18 publicly available EBOV quantitative PCRs, which might (or might not) also be used in Western Africa (Technical Appendix 1Figure 2, Technical Appendix 1 Table). We observed 25 changes, of which 6 were reported previously (12). Each SNP has the potential to affect the efficacy of available therapeutic drugs (original and updated versions) or diagnostic assays (Table 3; Figure 2; Technical Appendix 1Figure 2, Technical Appendix 1 Table; nucleotide positions are reported relative to EBOV/Kik-9510621, for consistency [6]).


Monitoring of Ebola Virus Makona Evolution through Establishment of Advanced Genomic Capability in Liberia.

Kugelman JR, Wiley MR, Mate S, Ladner JT, Beitzel B, Fakoli L, Taweh F, Prieto K, Diclaro JW, Minogue T, Schoepp RJ, Schaecher KE, Pettitt J, Bateman S, Fair J, Kuhn JH, Hensley L, Park DJ, Sabeti PC, Sanchez-Lockhart M, Bolay FK, Palacios G, US Army Medical Research Institute of Infectious DiseasesNational Institutes of HealthIntegrated Research Facility–Frederick Ebola Response Team 2014–20 - Emerging Infect. Dis. (2015)

Mutation analysis of candidate therapeutic drug and diagnostic binding sites used in outbreak of Ebola virus (EBOV) disease, Western Africa. A single-nucleotide polymorphism (SNP) table is combined with a heat map based on 2 categories: 1) mutations tolerated by the therapeutic drug or diagnostic target (highlighted in green); 2) mutations within the binding region of a therapeutic drug or diagnostic assay that have not yet been tested (highlighted in yellow/orange) (20–24,27,30,31). Changes previously described are highlighted in yellow; changes that appeared during circulation in Liberia are highlighted in orange. The reference nucleotide positions reported here are in relation to EBOV/Kik-9510621 (GenBank accession no. AY354458), which is one of the primary isolates used as reference for developing these therapeutic drugs and diagnostic assays. A summary of the changes to the probes is available in Technical Appendix 1 Table. PMO, phosphorodiaminate morpholino oligomer, mAB, monoclonal antibody; siRNA, small interfering RNA; Ref pos, reference positive; VP, viral protein.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4816332&req=5

Figure 2: Mutation analysis of candidate therapeutic drug and diagnostic binding sites used in outbreak of Ebola virus (EBOV) disease, Western Africa. A single-nucleotide polymorphism (SNP) table is combined with a heat map based on 2 categories: 1) mutations tolerated by the therapeutic drug or diagnostic target (highlighted in green); 2) mutations within the binding region of a therapeutic drug or diagnostic assay that have not yet been tested (highlighted in yellow/orange) (20–24,27,30,31). Changes previously described are highlighted in yellow; changes that appeared during circulation in Liberia are highlighted in orange. The reference nucleotide positions reported here are in relation to EBOV/Kik-9510621 (GenBank accession no. AY354458), which is one of the primary isolates used as reference for developing these therapeutic drugs and diagnostic assays. A summary of the changes to the probes is available in Technical Appendix 1 Table. PMO, phosphorodiaminate morpholino oligomer, mAB, monoclonal antibody; siRNA, small interfering RNA; Ref pos, reference positive; VP, viral protein.
Mentions: Since the Western Africa outbreak began, at least 33 viral mutations have occurred that could affect countermeasures. We previously reported 27 of these mutations (6). Twenty-six (79%) mutations induced nonsynonymous changes to epitopes recognized by mAbs included in passive immunotherapy cocktails. Another 5 (15%) were located in published binding regions of siRNA-based therapeutic drugs. Tekmira has adjusted its siRNAs to account for 4 of these 5 changes since its initial publication (29; E.P. Thi et al., unpub. data). The final 2 mutations were located in the published binding region of primers or probes for quantitative PCR diagnostic tests that have been used during outbreak control activities in Liberia: 1 change each in the binding sites of the Kulesh-TM assay and the Kulesh-MGB assay (9). Nevertheless, reassessment of the assays at USAMRIID has suggested that the changes will be tolerated without loss in sensitivity (data not shown). Changes in all EBOV/Mak sequences are considered “interoutbreak” (n = 23); changes observed only in some sequences from Western Africa are considered “intraoutbreak” sites (n = 10, EBOV-WA <100%). We also examined the binding sites of an additional 18 publicly available EBOV quantitative PCRs, which might (or might not) also be used in Western Africa (Technical Appendix 1Figure 2, Technical Appendix 1 Table). We observed 25 changes, of which 6 were reported previously (12). Each SNP has the potential to affect the efficacy of available therapeutic drugs (original and updated versions) or diagnostic assays (Table 3; Figure 2; Technical Appendix 1Figure 2, Technical Appendix 1 Table; nucleotide positions are reported relative to EBOV/Kik-9510621, for consistency [6]).

Bottom Line: Twenty-five EBOV genomes were sequenced at the Liberian Institute for Biomedical Research, which provided an in-depth view of EBOV diversity in Liberia during September 2014-February 2015.The pace of change is generally consistent with previous estimates of mutation rate.We observed 23 nonsynonymous mutations and 1 nonsense mutation.

View Article: PubMed Central - PubMed

ABSTRACT
To support Liberia's response to the ongoing Ebola virus (EBOV) disease epidemic in Western Africa, we established in-country advanced genomic capabilities to monitor EBOV evolution. Twenty-five EBOV genomes were sequenced at the Liberian Institute for Biomedical Research, which provided an in-depth view of EBOV diversity in Liberia during September 2014-February 2015. These sequences were consistent with a single virus introduction to Liberia; however, shared ancestry with isolates from Mali indicated at least 1 additional instance of movement into or out of Liberia. The pace of change is generally consistent with previous estimates of mutation rate. We observed 23 nonsynonymous mutations and 1 nonsense mutation. Six of these changes are within known binding sites for sequence-based EBOV medical countermeasures; however, the diagnostic and therapeutic impact of EBOV evolution within Liberia appears to be low.

Show MeSH
Related in: MedlinePlus