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PostPosted: Thu Mar 26, 2015 2:39 pm 
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Science paper describes stable evolution of Ebola in Mali.

http://www.sciencemag.org/content/early ... a5646.full

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PostPosted: Thu Mar 26, 2015 2:41 pm 
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Science DOI: 10.1126/science.aaa5646
REPORT
Mutation rate and genotype variation of Ebola virus from Mali case sequences
T. Hoenen1,*, D. Safronetz1,*, A. Groseth1,*, K. R. Wollenberg2,*, O. A. Koita3, B. Diarra3, I. S. Fall4, F. C. Haidara5, F. Diallo5, M. Sanogo3, Y. S. Sarro3, A. Kone3, A. C. G. Togo3, A. Traore5, M. Kodio5, A. Dosseh6, K. Rosenke1, E. de Wit1, F. Feldmann7, H. Ebihara1, V. J. Munster1, K. C. Zoon8, H. Feldmann1,†,‡, S. Sow5,†,‡
- Author Affiliations

1Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Hamilton, MT 59840, USA.
2Bioinformatics and Computational Biosciences Branch, NIAID, NIH, Bethesda, MD 20892, USA.
3Center of Research and Training for HIV and Tuberculosis, University of Science, Technique and Technologies of Bamako, Mali.
4World Health Organization Office, Bamako, Mali.
5Centre des Operations d’Urgence, Centre pour le Développement des Vaccins (CVD-Mali), Centre National d’Appui à la lutte contre la Maladie, Ministère de la Sante et de l’Hygiène Publique, Bamako, Mali.
6World Health Organization Inter-Country Support Team, Ouagadougou, Burkina Faso.
7Rocky Mountain Veterinary Branch, Division of Intramural Research, NIAID, NIH, Hamilton, MT 59840, USA.
8Office of the Scientific Director, NIAID, NIH, Bethesda, MD 20895, USA.
↵‡Corresponding author. E-mail: feldmannh@niaid.nih.gov (H.F.); ssow@medicine.umaryland.edu (S.S.)
↵* These authors contributed equally to this work.

↵† These authors contributed equally to this work.

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PostPosted: Thu Mar 26, 2015 2:45 pm 
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The occurrence of Ebola virus (EBOV) in West Africa during 2013–2015 is unprecedented. Early reports suggested that in this outbreak EBOV is mutating twice as fast as previously observed, which indicates the potential for changes in transmissibility and virulence and could render current molecular diagnostics and countermeasures ineffective. We have determined additional full-length sequences from two clusters of imported EBOV infections into Mali, and we show that the nucleotide substitution rate (9.6 × 10–4 substitutions per site per year) is consistent with rates observed in Central African outbreaks. In addition, overall variation among all genotypes observed remains low. Thus, our data indicate that EBOV is not undergoing rapid evolution in humans during the current outbreak. This finding has important implications for outbreak response and public health decisions and should alleviate several previously raised concerns.

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PostPosted: Thu Mar 26, 2015 2:48 pm 
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In December 2013, an outbreak of Ebola virus (EBOV) started in Guinea with a single index case, resulting in widespread human-to-human transmission in this country, as well as in neighboring regions of Sierra Leone and Liberia. Despite being by far the largest and longest lasting outbreak, there has been limited information regarding the evolution of EBOV. To date, the only sequences published have been from virus isolates derived from three patient samples in Guinea from March 2014 (1) and from a cluster of sequences derived from samples from Sierra Leone from June 2014 (2). However, no new information has been available during the intervening 6 months of large-scale virus circulation, and thus these virus sequences may no longer adequately inform us about the nature of currently circulating strains. This is of particular importance because diagnostics are based predominantly on reverse transcription polymerase chain reaction (3) and are thus sequence-dependent, as are some of the therapeutic options currently being considered for deployment (i.e., small interfering RNA–based treatments, such as TKM-Ebola). Further, mutations in the glycoprotein (GP) could affect the efficacy of vaccines or antibody treatments (e.g., ZMapp). Analyses based on the limited available sequence information have also been used to suggest that EBOV is mutating more rapidly during this outbreak than during previous outbreaks (2), potentially as a result of sustained and large-scale human-to-human transmission, which has, in turn, raised concerns about increased virulence or transmissibility (4).

Although the outbreak has been mostly limited to Guinea, Sierra Leone, and Liberia until now, there have been imported cases in Nigeria, Senegal, Spain, and the United States, without substantial subsequent spread of the virus. Recently, two independent introductions of EBOV into Mali also occurred: The first introduction in October 2014, from Kissidougou, Guinea, resulted in a single fatal case with no further transmission; the second introduction in November 2014, from Kouremale-Guinee, Guinea, resulted in six primary transmissions (five fatal, one nonfatal) and a single secondary transmission (nonfatal). We obtained patient samples from both introductions and determined the full-length sequences of the corresponding EBOV genomes [see (5) for materials and methods]. Surprisingly, the virus from the first introduction (hereafter referred to as “Mali-DPR1,” sampled 23 October 2014) showed only nine nucleotide differences from the most closely related virus (Makona-EM106, accession number KM233036), which was sampled in Sierra Leone almost 6 months earlier (2 June 2014). Additionally, Mali-DPR1 showed only 15 nucleotide differences to the most distantly related EBOV from the West African outbreak (Gueckedou-C05, accession number KJ660348.2) (fig. S1). In terms of amino acids, only one change had been acquired in comparison to the Makona-EM106 virus [g16514a:S>N (6) at position 1645 in the polymerase (L) gene] (fig. S1). The viruses isolated from the second introduction into Mali (hereafter referred to as “Mali-DPR2, -3, and -4,” sampled 12 to 21 November) were closely related to Mali-DPR1, although they remained clearly distinct from that sequence, with seven to nine nucleotide differences. However, in terms of amino acid sequence, only a single change (t15560c:F>Sat position 1327 in the L gene) was observed in Mali-DPR4, and no amino acid changes were observed in Mali-DPR2 and -3.

Phylogenetic analysis (5) of all published sequences showed that the West African sequences group into several well-supported clades that are consistently identified using Bayesian analysis (Fig. 1), as well as maximum-likelihood and neighbor-joining analyses (fig. S2), producing trees with comparable internal structure. The Malian sequences all form a discrete and well-supported branch derived from the second cluster of Sierra Leone sequences, despite being derived from two independent introduction events originating ~400 km from each other. This result is surprising, given the genetic diversity that had been shown to exist among viruses within the outbreak region during the sampling in Sierra Leone. Although we cannot completely exclude serendipitous introduction of two such closely related isolates, the strong support for coalescence of the Mali viruses to a common ancestor suggests that this genotype may be highly prevalent in this region at present and may thus represent a reasonable proxy for testing the efficacy of diagnostic, therapeutic, and vaccination approaches.

Fig. 1
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Fig. 1 Phylogenetic relationship among viruses from the ongoing outbreak.
A Bayesian tree of all currently published sequences from the ongoing outbreak is shown. Branch colors indicate posterior probability, with terminal branches shown in black. The x axis indicates time in years before acquisition of the last sample (21 November 2014). Although clade structure in the analysis is ambivalent for some of the Sierra Leone viruses, there is strong support for the placement of the Malian viruses as a distinct lineage originating from the main group of Sierra Leone sequences and distinct from both the Guinean viruses, as well as another well-supported clade of Sierra Leone viruses.

Based on these additional data, we recalculated the nucleotide substitution rate for the West African outbreak [see (5) for a full list of virus genomes]. By including the newly determined sequences from Mali, we obtained a mean substitution rate of 9.6 × 10–4 substitutions per site per year (Fig. 2). This matches previously reported nucleotide substitution rates of 6.2 × 10–4 to 9.5 × 10–4 for other EBOV sample sets (7–9) but differs from the substitution rate of ~1.9 × 10–3 that had been reported for this outbreak (2). Further analysis of this expanded data set also generated a comparable value (6.9 × 10–4 substitutions per site per year) when analysis parameters previously used to obtain these higher estimates (2) were employed. Surprisingly, reanalysis of the previously available data set from Gire et al. (2) using the model developed for this study also produced a similar value (8.2 × 10–4 substitutions per site per year). These findings appear to suggest that the strict clock used in the current analysis may be more suitable and robust for this data set and that the expanded time frame over which samples in our data sets were obtained adds additional robustness to the analysis.

Fig. 2
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Fig. 2 Nucleotide substitution rate in the current outbreak.
The probability distribution of substitution rates in the current EBOV outbreak in West Africa based on all currently published sequences from this outbreak, including those from Mali, is shown as a gray shaded area. Previously reported substitution rates for EBOVs from four different publications (2, 7–9) are indicated by dotted lines (further qualifying information is provided in brackets if several rates were reported in those publications).

Detailed analysis of the individual mutations observed among all currently known genotypes showed that the majority of mutations were synonymous or occurred in noncoding regions [particularly at the virion protein 30 (VP30)/VP24 gene border, which contains a long intergenic region] (fig. S3). Although up to four nonsynonymous nucleotide changes from the consensus sequence were observed for early sequences (i.e., those from March 2014), almost no nonsynonymous changes were observed in later sequences. Most nucleotide changes occurred only sporadically in a single genotype; however, a few changes were observed in several genotypes and might represent changes that remained conserved in later viruses. Early changes included two nonsynonymous changes, one each in the nucleoprotein (t800c:C>R) and GP (t6283c:V>A); three synonymous changes, one in VP30 (c8928a:P>P) and two in L (a15963g:K>K, c17142t:F>F); and one change in the VP24 noncoding region (g10219a). Later changes conserved among the Malian sequences were one nonsynonymous change in L (g16514a:S>N); four synonymous changes in GP (a6056c:I>I), VP30 (c8928a:P>P), and L (c14253t:G>G, a15963g:K>K); and an additional change in the VP24 noncoding region (c10315t). However, none of these nonsynonymous changes coincide with known functional domains or motifs within the affected proteins, and overall the genotypes observed have remained stable since June 2014, which is consistent with reports from earlier outbreaks of both EBOV and Marburg virus (10, 11).

In the past, EBOVs have been reported to undergo only limited genetic changes during outbreaks (10, 11), a phenomenon that also seems to be true in the current outbreak, despite prolonged human-to-human transmission. Thus, the potential for acquisition of virulence or increased transmissibility of EBOVs is constrained. Although the size and nature of the mutational targets associated with the acquisition of virulence clearly vary between viruses, and there are cases in which just a few mutations can substantially affect virus properties, there are also many limitations. These include the need for multiple mutations in some cases, as for mammalian transmission of H5N1 influenza (12), and these mutations may need to occur simultaneously or in a defined order (13). Studies aimed at identifying the virulence factors of EBOVs already indicate that virulence is a complex, multifactorial trait for these viruses, although further studies are required to better define these factors (14, 15). Furthermore, epidemiological and case management data do not support increased virulence in humans during the current outbreak (16). Thus, whereas from a public health perspective the current EBOV outbreak in West Africa continues to be an extremely pressing emergency, it is doubtful that either virulence or transmissibility has increased in the circulating EBOV strains. We have also shown that, despite the extensive and prolonged human-to-human transmission in this outbreak, the virus is not mutating at a rate beyond what is expected. Moreover, although it is certainly possible for different virus lineages to exhibit different evolutionary rates, those predicted using samples from various Ebola outbreaks have remained consistent. Similarly, on the basis of our data, it is unlikely that the types of genetic changes observed thus far would impair diagnostic measures or affect the efficacy of vaccines or potential virus-specific treatments. Nevertheless, monitoring of the situation remains paramount to ensure that this continues to be the case as this outbreak progresses and if further outbreaks arise.

Supplementary Materials

www.sciencemag.org/cgi/content/full/science.aaa5646/DC1
Materials and Methods
Figs. S1 to S3
References (17–23)
Received for publication 24 December 2014.
Accepted for publication 23 February 2015.

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PostPosted: Thu Mar 26, 2015 2:50 pm 
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References and Notes

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↵ A. Grolla, S. Jones, G. Kobinger, A. Sprecher, G. Girard, M. Yao, C. Roth, H. Artsob, H. Feldmann, J. E. Strong, Flexibility of mobile laboratory unit in support of patient management during the 2007 Ebola-Zaire outbreak in the Democratic Republic of Congo. Zoonoses Public Health 59 (suppl. 2), 151–157 (2012). CrossRefMedlineWeb of ScienceGoogle Scholar
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↵Materials and methods are available as supplementary materials on Science Online.
↵Single-letter abbreviations for the amino acid residues are as follows: A, Ala; C, Cys; D, Asp; E, Glu; F, Phe; G, Gly; H, His; I, Ile; K, Lys; L, Leu; M, Met; N, Asn; P, Pro; Q, Gln; R, Arg; S, Ser; T, Thr; V, Val; W, Trp; and Y, Tyr.
↵ R. Biek, P. D. Walsh, E. M. Leroy, L. A. Real, Recent common ancestry of Ebola Zaire virus found in a bat reservoir. PLOS Pathog. 2, e90 (2006). CrossRefMedlineGoogle Scholar
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↵ P. D. Walsh, R. Biek, L. A. Real, Wave-like spread of Ebola Zaire. PLOS Biol. 3, e371 (2005). CrossRefMedlineGoogle Scholar
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↵ J. S. Towner, M. L. Khristova, T. K. Sealy, M. J. Vincent, B. R. Erickson, D. A. Bawiec, A. L. Hartman, J. A. Comer, S. R. Zaki, U. Ströher, F. Gomes da Silva, F. del Castillo, P. E. Rollin, T. G. Ksiazek, S. T. Nichol, Marburgvirus genomics and association with a large hemorrhagic fever outbreak in Angola. J. Virol. 80, 6497–6516 (2006). Abstract/FREE Full Text
↵ S. Herfst, E. J. Schrauwen, M. Linster, S. Chutinimitkul, E. de Wit, V. J. Munster, E. M. Sorrell, T. M. Bestebroer, D. F. Burke, D. J. Smith, G. F. Rimmelzwaan, A. D. Osterhaus, R. A. Fouchier, Airborne transmission of influenza A/H5N1 virus between ferrets. Science 336, 1534–1541 (2012). Abstract/FREE Full Text
↵ K. A. Tsetsarkin, R. Chen, G. Leal, N. Forrester, S. Higgs, J. Huang, S. C. Weaver, Chikungunya virus emergence is constrained in Asia by lineage-specific adaptive landscapes. Proc. Natl. Acad. Sci. U.S.A. 108, 7872–7877 (2011). Abstract/FREE Full Text
↵ A. Groseth, A. Marzi, T. Hoenen, A. Herwig, D. Gardner, S. Becker, H. Ebihara, H. Feldmann, The Ebola virus glycoprotein contributes to but is not sufficient for virulence in vivo. PLOS Pathog. 8, e1002847 (2012). CrossRefMedlineGoogle Scholar
↵ A. Groseth, H. Feldmann, S. Theriault, G. Mehmetoglu, R. Flick, RNA polymerase I-driven minigenome system for Ebola viruses. J. Virol. 79, 4425–4433 (2005). Abstract/FREE Full Text
↵ WHO Ebola Response Team, Ebola virus disease in West Africa—The first 9 months of the epidemic and forward projections. N. Engl. J. Med. 371, 1481–1495 (2014). CrossRefMedline
↵ T. Hoenen, A. Groseth, F. Feldmann, A. Marzi, H. Ebihara, G. Kobinger, S. Günther, H. Feldmann, Complete genome sequences of three ebola virus isolates from the 2014 outbreak in west Africa. Genome Announcements 2, e01331-14 (2014). Abstract/FREE Full Text
K. Katoh, K. Kuma, H. Toh, T. Miyata, MAFFT version 5: Improvement in accuracy of multiple sequence alignment. Nucleic Acids Res. 33, 511–518 (2005). Abstract/FREE Full Text
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F. Ronquist, M. Teslenko, P. van der Mark, D. L. Ayres, A. Darling, S. Höhna, B. Larget, L. Liu, M. A. Suchard, J. P. Huelsenbeck, MrBayes 3.2: Efficient Bayesian phylogenetic inference and model choice across a large model space. Syst. Biol. 61, 539–542 (2012). Abstract/FREE Full Text
K. Tamura, D. Peterson, N. Peterson, G. Stecher, M. Nei, S. Kumar, MEGA5: Molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol. Biol. Evol. 28, 2731–2739 (2011). Abstract/FREE Full Text
D. J. Zwickl, “Genetic algorithm approaches for the phylogenetic analysis of large biological sequence datasets under the maximum likelihood criterion,” thesis, The University of Texas at Austin (2006).
↵ F. Tajima, M. Nei, Estimation of evolutionary distance between nucleotide sequences. Mol. Biol. Evol. 1, 269–285 (1984). Abstract
Acknowledgments: We thank S. Nichol and U. Ströher (U.S. Centers for Disease Control and Prevention); T. Schwan, R. Sakai, M. Niang, and M. Pineda (NIH, NIAID); and S. Diop, S. Tounkara, and F. Daou (Centre de Recherche et de Formation sur le VIH/TB SEREFO) for helpful discussion and help with logistics and sample preparation. We also thank the Research Technology Branch at the Rocky Mountain Laboratories, particularly S. Kramer, K. Barbian, and S. Porcella, for sequencing services. This study made use of the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD (http://biowulf.nih.gov), and the Office of Cyber Infrastructure and Computational Biology High-Performance Computing cluster at the NIAID, Bethesda, MD. This work was supported in part by the Intramural Research Program of the NIH, NIAID. The full-length sequences of the Malian EBOVs were deposited at GenBank under the accession numbers KP260799.1, KP260800.1, KP260801.1, and KP260802.1 (Ebola virus/H.sapiens-wt/MLI/2014/Makona-Mali-DPR1 to 4). There are no conflicts of interest, material transfer agreements, patents, or patent applications that apply to reagents, methods, or data in the paper for any of the authors.

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PostPosted: Thu Mar 26, 2015 2:53 pm 
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Ebola Virus in Latest Outbreak Does Not Show Unusual Mutations, Study Finds
By PAM BELLUCKMARCH 26, 2015
Image

Health workers in Sierra Leone cautioned a woman suspected of having Ebola in February to stay put until workers in protective equipment could come to her. Credit Bryan Denton for The New York Times

Fears that the current Ebola epidemic, the deadliest in history, was caused by a more lethal, fast-moving or easily transmissible virus than in previous outbreaks appear to be unfounded, according to a new study.

The study, a genetic analysis published in the journal Science on Thursday, is based on data that indicates that the virus has mutated over time in a way that is similar to that of previous, smaller outbreaks.

Researchers say studies of more cases and more recent ones are still needed to confirm these findings. But the new analysis offers encouraging evidence that tests used to diagnose Ebola patients, and vaccines and drugs being developed to prevent and treat the disease, can continue to be based on the typical mutation rate. It also means worries about doomsday scenarios, like the virus’ becoming transmissible by air, seem unlikely, experts say.

“It hasn’t become increasingly lethal or increasingly virulent,” said David Safronetz, an author of the study and a staff scientist for the Laboratory of Virology at the National Institute of Allergy and Infectious Diseases. “The virus — it’s doing what it’s always done.”

Image

Ebola virus isolated in November 2014 from patient blood samples obtained in Mali. Credit NIAID
Essentially, the study indicates, while this outbreak has infected 24,000 people and killed about 10,000, its scale has to do with where the epidemic erupted — at the intersection of three vulnerable countries — rather than with any unusual characteristics of the virus itself.

The scientists evaluated change in the virus over time by comparing genetic sequencing data from a small number of cases in Mali in October and November with data from patients infected in Guinea in March 2014 and Sierra Leone in June.

They found that the number of mutations was about the same as in viruses in previous outbreaks, suggesting that the virus was not mutating faster. And they reported that the genetic changes they identified were not significant enough to make the virus more transmissible or deadlier.

“It doesn’t suggest that the virus is getting any worse,” said Dr. Thomas Ksiazek, an Ebola expert at the University of Texas Medical Branch at Galveston, who was not involved in the study.

That supports the use and development of virus-specific lab tests and drugs calibrated according to the mutation rate seen in previous outbreaks.

“You would not predict from what they’ve published that we’re going to have trouble with the diagnostics and vaccines and therapeutics” being developed, said Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, which partly financed the research.

The cases analyzed in the study involved people who became infected in Guinea and traveled to Mali: a 2-year-old girl taken to Mali by relatives in October and an imam who went to Mali in November and whose illness spread to six other people before it was contained. Dr. Heinz Feldmann, chief of the institute’s Laboratory of Virology and an author of the study, said the team obtained complete genomes from the blood samples of the 2-year-old and three patients in the November cluster.

Data from the March and June blood samples came from two previous studies by other researchers. One of those, using the June samples, reported a mutation rate “roughly twice as high within the 2014 outbreak as between outbreaks,” and said that “because many of the mutations alter protein sequences and other biologically meaningful targets, they should be monitored for impact on diagnostics, vaccines and therapies critical to outbreak response.”

The authors of that study did not raise alarms about a fast-changing virus, but Dr. Fauci said some misinterpreted it to suggest that there might be problems with lab tests or drugs in development. The Mali study’s results allay those fears, he said.

The study of June samples was larger, with 99 genomes from 78 patients. But since those patients became ill earlier in the outbreak, the later Mali cases make it possible to document change over time.

“We go five months longer into the outbreak and we do not find that this virus has a higher evolution rate,” Dr. Feldmann said. His team used a different algorithm than the June team, and Dr. Feldmann said that when they applied their algorithm to the June samples, the resulting mutation rate was similar to previous outbreaks.

Pardis Sabeti, a Harvard geneticist and an author of the study on the June samples, said the new study was “consistent” with her team’s analysis, which she said found a similar number of mutations. She added: “There is no way to tell if the particular mutations change the biology of the virus without experimental studies. We shouldn’t be alarmist and we shouldn’t be complacent.”

Dr. Feldmann said the next step was to analyze a batch of samples from Liberia from August to the present. The studies to date, including his team’s, “are snapshots,” he said. “The analysis will get much better if we can look at the entire outbreak.”

http://www.nytimes.com/2015/03/27/healt ... times&_r=0

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PostPosted: Thu Mar 26, 2015 2:55 pm 
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NIH study finds no evidence of accelerated Ebola virus evolution in West Africa

The Ebola virus circulating in humans in West Africa is undergoing relatively few mutations, none of which suggest that it is becoming more severe or transmissible, according to a National Institutes of Health study in Science. The study compares virus sequencing data from samples taken from patients in Guinea (March 2014), Sierra Leone (June 2014) and Mali (November 2014).

Ebola virus, isolated in November 2014 from patient blood samples obtained in Mali. The virus was isolated on Vero cells in a BSL-4 suite at Rocky Mountain Laboratories.
“The Ebola virus in the ongoing West African outbreak appears to be stable—that is, it does not appear to be mutating more rapidly than viruses in previous Ebola outbreaks, and that is reassuring,” said Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. “We look forward to additional information to validate this finding, because understanding and tracking Ebola virus evolution are critical to ensuring that our scientific and public health response keeps pace.”

Obtaining virus samples for analysis was challenging for researchers during the outbreak. The NIAID study published today relies on data from the Guinea and Sierra Leone cases as well as samples from two case clusters in Mali obtained from the International Center for Excellence in Research (ICER) located in Bamako. NIAID and the Malian government have been partners in the ICER since 2002. The Mali case clusters originated from people who became infected in Guinea and traveled to Mali, where they were diagnosed.

Today’s study, from NIAID’s Rocky Mountain Laboratories, finds that there appear to be no genetic changes that would increase the virulence or change the transmissibility of the circulating Ebola virus, and that despite extensive human-to-human transmission during the outbreak, the virus is not mutating at a rate beyond what is expected. Further, they say, based on their data it is unlikely that the types of genetic changes thus far observed would impair diagnostic measures, or affect the efficacy of candidate vaccines or potential virus-specific treatments.

As of March 11, the World Health Organization listed more than 24,000 confirmed, suspected or probable cases of Ebola virus disease in West Africa, with about 10,000 deaths.

NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available at http://www.niaid.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Reference

T Hoenen, et al. Mutation rate and genotype variation of Ebola virus from Mali case sequences. Science DOI: 10.1126/science.aaa5646 (2015).

http://www.nih.gov/news/health/mar2015/niaid-26.htm

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