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Largest outbreak in history and mutating rapidly

The Ebola virus epidemic is spreading rapidly in Africa but has not yet impacted the populations of other continents. The virus was first detected in humans during the 1970s when the spread of the disease to humans was from contact with wild animals particularly bats. However, during the following years the virus spread to human populations and current genetic evidence indicates that the virus is now mainly transmitted from humans to humans and that the virulent virus is mutating rapidly. A genetic analysis in its largest outbreak shows that Ebola virus disease is spreading through Guinea, Liberia, Sierra Leone, and Nigeria.  Sequencing has been done on 99 Ebola virus genomes from 78 patients in Sierra Leone [1]. There was rapid accumulation of interhost and intrahost genetic variation, allowing the characterization of viral transmission over the initial weeks of the epidemic.

Transmission pattern defined

This West African variant likely diverged from Middle African lineages about 2004, crossed from Guinea to Sierra Leone in May 2014, and has exhibited sustained human-to-human transmission subsequently, with no evidence of additional zoonotic sources. Since 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 best evidence is that the virus mutates extensively and spreads mainly now by human to human contact. In the absence of effective therapies the virus poses a global threat.

Potential therapies

Previously I described the  production of ZMapp monoclonal  antibody in tobacco plants and the early success in treating Ebola infection [2].  On 4-5 September, the World Health Organization (WHO), 150 Ebola scientists, industry executives, clinical-trials experts, ethicists and regulatory officials met at the WHO’s headquarters in Geneva, Switzerland, to identify and prioritize the most promising products for use in clinical trials. Four drugs and two vaccines lead among the candidates for treatment of Ebola victims. The ZMapp monoclonal antibody cocktail leads the list of drugs with evidence that monkeys are protected by treatment with the drug and seven humans  infected with the virus five of whom survived and two died. The drug is currently in phase one clinical trial with healthy volunteers [3].

Tekmira pharmaceuticals of Canada has undertaken clinical trials of a small RNA inhibitor (RNAi) which prevents replication of the Ebola virus [4]. US FDA (Food and Drug administration) expressed concern over a potential cytokine release induced by the drug. Flavipiravir a small molecule inhibitor the viral RNA polymerase  has been effective in treating mice infected by Ebola virus and has proceeded to phase 3 clinical trials with humans infected with influenza virus [5]. Another small molecule inhibitor of virus RNA polymerase, designated BCX4430, protects monkeys infected with Marburg virus, a filovirus related to Ebola [6].

The vaccine candidate NIAID/GSK from the US National Institute of Allergy and Infectious Diseases includes a chimpanzee adenovirus carrying segments of Ebola virus genetic material, and was found safe for humans in preclinical trials [7]. The vaccine VSV-EBOV produced by NewLink Genetics USA is Vesicular Stomatitis Virus-Based Ebola Vaccine containing segments of Ebola virus genetic material. It prevents lethal Ebola infection in non-human primates [8].

The conclusion of the two day meeting was to postpone decision on the use of vaccines, monoclonal antibodies, and small RNA until November 2014 [9]. The only therapies immediately approved were blood sera and whole blood transfusions from patients who survive Ebola infection.

Tobacco therapeutics

The antibodies are produced in a Australian strain of the tobacco plant (Nicotiana benthamiana) by Kentucky Bioprocessing in Owensboro, Kentucky, a 23-acre, contract R&D and protein production company that was acquired in January by Reynolds America, Inc, the parent company of R.J. Reynolds Tobacco. In 2007, Mapp engaged KBP to manufacture a post-exposure treatment for Ebola infection. A number of therapeutic monoclonal antibodies are being produced in the Kentucky plant. According to KPB the tobacco plants are produced in an open field then transferred to a greenhouse where the leaves of the tobacco plants are treated using magnifection, then harvested and processed under stringent conditions.  RJ Reynolds is the second largest producer of cigarettes in the United States and monoclonal antibodies have been developed successfully elsewhere to treat small cell lung cancer [10]. It is hoped that that the corporation will be able to participate in the treatment of lung cancer at modest cost to the patients.