The Ebola Epidemic in West Africa Proceedings of a Workshop (2016) / Chapter Skim
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4 Current and Future Research Opportunities
4 Current and Future Research Opportunities
Pages 45-66
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Bats as Reservoir Hosts for Filoviruses Learning where Ebola and Marburg viruses reside in nature and how they are transmitted from these natural reservoirs to humans will lead to better understanding of how outbreaks start, Towner explained. A reservoir host species' natural history must support viral persistence at the population level, he observed, as evidenced by the following characteristics: consistent infection in host populations; maintenance of viral circulation through adequate viral loads and rates of viral shedding; and host populations that are, overall, clinically healthy.
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As the West African epidemic unfolded, researchers pursued an extensive ecological investigation of the index case, a 2-year-old boy reported to have
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You know, those viruses perpetuate in those species in the long term." The restricted cave biome in which Marburg virus was detected in bats helped narrow the search for its reservoir, Towner observed -- an advantage researchers seeking the Ebola virus reservoir do not have. That is especially unfortunate if -- as for Marburg virus -- the number of active Ebola virus infections in reservoir host populations is low, so hundreds of animals of a single species will need to be tested to find them.
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Comparing genetic differences between the West African isolates and the sequences of other Ebola viruses, and taking into account the rate by which the virus typically undergoes sequence change -- its substitution rate -- they were able to determine that the specific variant of Ebola-Zaire that sparked the West African epidemic had emerged within the past 10 years in Central Africa, he noted. Further, he said, "We were able to show that it was actually one individual introduction from the animal reservoir into the human population that then was sustained in the population by human-to-human contact afterward." Tracing Ebola in Sierra Leone Looking to the immediate past, the researchers identified three lineages (comprising 55 mutations)
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While lineage 2 died out in Sierra Leone, limited evidence suggests it could have reseeded Ebola in Liberia, he added. Evolution Without Change Overall, the researchers found that a higher rate of viral sequence substitution occurred during the West African Ebola outbreak than between previous outbreaks, according to Gire.
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DIAGNOSIS Many groups and agencies have worked to improve the laboratory diagnosis of Ebola in West Africa and other low-resource settings, noted Heinz Feldmann of the National Institute of Allergy and Infectious Diseases' Rocky Mountain Laboratories. He presented an overview of current diagnostic approaches, then used his recent experience in an Ebola treatment unit (ETU)
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These laboratories greatly increased capacity for both research and product development, and specifically have expedited work on vaccines and therapeutics, he said. NIAID personnel proficient in BSL-4 safety skills have not only conducted diagnostic work in West Africa but have also provided instruction to local health care workers, according to Kurilla.
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A mobile plastic BSL-3 laboratory under negative pressure was also available but was not used because sample loads did not reach critical levels, he said. The ELWA 3, an MSF Ebola management center, operated a laboratory during the West African epidemic, and employed quantitative reverse transcriptase polymerase chain reaction (qRT-PCR)
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CONTAINMENT CARE Health care workers responding to Ebola outbreaks have all too frequently become victims of the disease, and in disproportionate numbers to the general population. In West Africa, as of June 4, 2015, 869 health care workers had become infected over the course of the epidemic, and 507 had died (ECDC, 2015b)
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Evolution of Containment Care In a 2006 consensus article (Smith et al., 2006) , Ribner and colleagues defined a biocontainment patient care unit as a clinical facility designed specifically for the care of patients to prevent nosocomial transmission of highly hazardous and contagious diseases, and incorporating those engineering or safety measures that are often used in containment laboratories and have been tested over time in laboratories.
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What Next? The aforementioned advances in containment care have not prevented shocking numbers of health care workers from becoming infected with Ebola in West Africa, Kortepeter acknowledged.
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Vaccines Several promising Ebola vaccine candidates existed years prior to the West African epidemic, Geisbert noted. However, because of the limited market for such products and lack of financial incentives for their development, all had stalled in animal trials; moreover, he asserted, progress toward a human vaccine was slowed by the constraints of the FDA's Animal Rule.7 This legislation, FDA Animal Rule (CFR Title 21)
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Geisbert briefly characterized four "fast-tracked" Ebola vaccines known to have entered clinical trials at the time of the workshop. Two had already completed phase I safety trials in humans: ChAd3, a chimpanzee adenovirus vector bearing surface glycoprotein genes from two Ebola strains, developed by GlaxoSmithKline (GSK)
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The potency of the virus used to create the current group of Ebola vaccines has also been called into question. New data suggest that these Ebola-Zaire virus seed stocks represented a less-pathogenic genetic variant of the wild-type virus, Geisbert remarked (Kugelman et al., 2012; Volchkova et al., 2011)
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Ebola patients, many of whom received experimental or compassionate use drugs, fared well compared with their West African counterparts. "I don't think we can point to any one
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" Kurilla wondered -- and might all organisms have this capacity? More specifically, he continued, this discovery suggests a reason why past Ebola vaccine candidates have failed: perhaps the expression systems used to produce the vaccine antigens failed to fold the protein to a conformation that would generate an effective immune response.
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The immune response to this scenario is predictably complex, Saphire observed. "You can actually generate a lot of antibodies against those glycosylated regions and the upper glycan caps and the mucin-like domains," she said, but "once the virus is brought into the endosome, all of those antibody epitopes are stripped right off the virus along with the antibodies bound [to it]
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• Some protective antibodies nonetheless bind "decoy" sGP; could that actually confer some benefit to the host? • As Geisbert noted, the optimal antibody therapeutic would protect against all known Ebola and Marburg viruses.
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. At the time of the workshop, several antibodies in the VIC collection had yet to be tested in vivo, and the researchers planned to extend their studies to include antibodies isolated from survivors of the West African epidemic.
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, as described by Fukuda. At the time of the workshop, the international community had committed $5 billion to the response to the West African Ebola epidemic, Dzau reported.
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Convening a Global Conversation At the urging of World Bank president Jim Kim, Dzau agreed to guide the NAM to lead the development of a global health risk framework -- and to do it as the West African crisis was still being addressed, in order to take advantage of the "real-time learning" under way. At a December 2014 meeting at the NAM, chaired by the WHO Director-General Margaret Chan and including major stakeholders in the Ebola epidemic, sentiment was overwhelming to proceed as a group to create such a framework, Dzau recalled.
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. 11 The commission's report is titled The Neglected Dimension of Global Security: A Framework to Counter Infectious Disease Crises and can be accessed at https://nam.edu/initiatives/global-healthrisk-framework (accessed November 3, 2016)
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