RESEARCHTable 3. Mutation analysis of candidate therapeutic drug and diagnostic binding sites for EBOV*Referenceposition TypeReferencebase Called base EBOV-WA, % EBOV-LIB, % Codon Feature name850 SNP A G 100 100 G:GGA @ 127 G:GGg NP852 SNP A G 100 100 K:AAA @ 128 R:AgA NP895 SNP A G 100 100 T:ACA @ 142 T:ACg NP907 SNP T C 1 0 N:AAT @ 146 N:AAc NP919 SNP T C 100 100 F:TTT @ 150 F:TTc NP1288 SNP A T 1 0 V:GTA @ 273 V:GTt NP1495 SNP A G 100 100 Q:CAA @ 342 Q:CAg NP1498 SNP C T 1 4 L:CTC @ 343 L:CTt NP1507 SNP T A 100 100 A:GCT @ 346 A:GCa NP1552 SNP C T 100 100 R:CGC @ 361 R:CGt NP1862 SNP A G 100 100 S:AGC @ 465 G:gGC NP6359 SNP T C 100 100 N:AAT @ 107 N:AAc GP6909 SNP T A 1 0 W:TGG @ 291 R:aGG GP7730 SNP G A 100 100 E:GAG @ 564 E:GAa GP7775 SNP A G 100 100 L:CTA @ 579 L:CTg GP7778 SNP C A 100 100 R:CGC @ 580 R:CGa GP10252 SNP A T 1 410253 SNP A G 1 012694 SNP T A 100 100 I:ATT @ 371 I:ATa L12886 SNP A C 2 0 L:CTA @ 435 L:CTc L12952 SNP A G 100 100 L:CTA @ 457 L:CTg L13267 SNP C T 100 100 T:ACC @ 562 T:ACt L13607 SNP G A 1 4 V:GTC @ 676 I:aTC L13624 SNP T G 1 0 N:AAT @ 681 K:AAg L13630 SNP A G 100 100 P:CCA @ 683 P:CCg L*EBOV, Ebola virus; GP; glycoprotein, ; L, RNA-dependent RNA polymerase; LIB, Liberia; NP; nucleoprotein; SNP, single-nucleotide polymorphism; WA,Western Africa.EBOV lineages within Liberia appear to be geographicallywidespread within the sampled regions.Previous analysis of EBOV/Mak genomes from SierraLeone and Guinea suggests that the evolutionary rate withinthe current EVD outbreak might be higher than the ratebetween outbreaks (12). After incorporation of sequencesfrom Liberia, which were collected later in the outbreak,our estimates of substitution rate fell between the previousestimates for EBOV/Mak only and for all EBOV (12,38).As more sequence data become available, it will be interestingto see whether a significant change in the evolutionaryrate can be detected within the current EVD outbreak.Our ability to quantify international EBOV exchangeis limited because few isolates from other countries wereavailable during the sampled timeframe. However, sharedancestry between isolates from Mali and 3 isolates fromLiberia suggests at least 1 transmission event across nationalborders (3). All EVD cases in Mali have been attributedto movement of infected persons into Mali fromGuinea (39). With the current dataset, it is impossible tosay whether the shared Liberia/Mali lineage originated inLiberia and was then transported to Mali through Guineaor whether the lineage emerged in Guinea and later movedindependently to Liberia and Mali. Active EBOV outbreakswere occurring in both Liberia and Guinea duringthe period estimated for the emergence of this shared lineage(July–September 2014).The genomic changes observed for EBOV/Mak duringits circulation in Liberia append 5 additional mutationsto the list of changes that might affect the bindingof the 13C6 mAb, a component of ZMapp. All ofthese changes, however, were present at relatively lowfrequency (1 change per therapeuticdrug type. We observed no significant changes(i.e., likely to affect efficacy) in the binding sites for the2 diagnostic assays known to be used in Liberia. Overall,no dramatic changes were observed in the samplesevaluated; the risk assessment for the impact of genomicdrift during the outbreak should remain low. As previouslystated (6), our analysis is not without caveats. Ourcurrent analysis covers only the late period of the outbreakin Liberia; no analysis has yet been published withdata for similar time points from Guinea or Sierra Leone.In addition, to complete our assessment of the evolutionof EBOV in Liberia, an earlier period of time from theintroduction of the virus in March 2014 to early September2014 needs to be investigated.Our findings offer a concise evaluation of the potentialimpact of the evolution of EBOV/Mak based on genomereconstruction of 25 isolates from Liberia obtained duringSeptember 2014–February 2015. This work would nothave been possible without the establishment of a genomicsurveillance capability in Liberia, which emphasizes the1140 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 21, No. 7, July 2015
Monitoring Ebola Virus Makona EvolutionFigure 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 ofa therapeutic drug or diagnostic assay that have not yet been tested (highlighted in yellow/orange) (20–24,27,30,31). Changespreviously described are highlighted in yellow; changes that appeared during circulation in Liberia are highlighted in orange. Thereference nucleotide positions reported here are in relation to EBOV/Kik-9510621 (GenBank accession no. AY354458), which is oneof the primary isolates used as reference for developing these therapeutic drugs and diagnostic assays. A summary of the changesto the probes is available in online Technical Appendix 1 Table (http://wwwnc.cdc.gov/EID/article/21/7/15-0522-Techapp1.<strong>pdf</strong>). PMO,phosphorodiaminate morpholino oligomer; mAB, monoclonal antibody; siRNA, small interfering RNA; Ref pos, reference positive;VP, viral protein.need for global sequencing capabilities to be part of thefirst response during future virus outbreaks.AcknowledgmentsWe thank Matthew A. Voorhees, Brian J. Kearney, Gary W.Carter, Jason Kindrachuk, Anthony R. Jones, Alex Hail, AlissaL. Byrne, Melissa A. Dugan, Mark M. Bailey, Krisztina Janosko,Joanna Fishback, Joshua Johnson, Richard Bennett, SusanaPadilla, Michelle A. Jefferson, Jonathan Marchand, and MichaelR. Holbrook for providing the infrastructure, isolation of viralgenomic material, and Ebola diagnostic screening on which thisstudy is built. We thank Aaron T. Momolu, Josiah S. George,Charlesetta Kanneh, Vera Yatta Walker, and Augustine Fallahfor their help, support, and enthusiasm. We thank Neal Woollen,Dave Norwood, and Peter Jahrling for their full support on thisendeavor. We also thank Deborah R. Malac for her support ofthe USAMRIID and NIH/IRF Ebola Response Team; TabithaAustill for arranging the shipment of equipment and suppliesto LIBR; and Sean Lovett and Brad Pfeffer for the expediteddeposition of sequence data in public repositories. We also thankLaura Bollinger for providing technical writing services.This work was supported by Defense Threat Reduction Agency,the Global Biosurveillance Technology Initiative, the USAgency for International Development, and Illumina.J.H.K. performed this work as an employee of Tunnell GovernmentServices, Inc., a subcontractor to Battelle MemorialInstitute under its prime contract with the National Instituteof Allergy and Infectious Diseases, under contract no. HH-SN272200700016I.Dr. Kugelman is a biodefense research scientist, computationalbiologist, and head of Bioinformatics at the Center for GenomeSciences at USAMRIID. His research interests include the genomicstudy of filovirus and orthopoxvirus infections.Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 21, No. 7, July 2015 1141
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BOOKS AND MEDIAin the port cities o
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