Use of tiny particles of genetic material to interfere in the replication process of the lethal Zaire Ebola virus (ZEBOV) has protected monkeys exposed to the virus from death from haemorrhagic fever. This proof-of-concept study shows that such protection should also be possible in humans, and further studies in monkeys to analyse dosing and toxicology will be required before the treatment is licensed for human use. While a number of previous studies have shown complete protection of monkeys against ZEBOV using vaccines given before exposure to the virus, this new study is the first to show the complete protection of monkeys when a treatment is given after exposure to the deadly ZEBOV. The findings are reported in an Article in this week's Lancet, written by Professor Thomas W Geisbert, National Emerging Infectious Diseases Laboratories Institute, Boston University School of Medicine, Boston, USA, and colleagues1.
The research centres on agents called small interfering RNAs (siRNAs), which target a protein (the L protein) in the Ebola virus essential for replication. The researchers used a very new technique of delivering the siRNAs in stable nucleic acid-lipid particles. Previous research showed that these siRNAs completely protected guineapigs when administered shortly after a lethal dose of ZEBOV was administered. A high proportion of the animals (whether guinea pig or monkey) would normally be expected to die from haemorrhagic fever after being infected, and others would exhibit symptoms. While rodent studies are useful for screening prospective countermeasures* they are frequently not useful for prediction of efficacy in the more stringent non-human primate models. The authors therefore assessed the efficacy of siRNAs in monkeys that had been administered a lethal dose of ZEBOV expected to cause haemorrhagic fever.
A group of three macaques was given anti-ZEBOV siRNAs intravenously, after 30 min, and on days 1, 3, and 5 after infection with ZEBOV. A second group of four macaques was given the treatment after 30 min, and on days 1, 2, 3, 4, 5, and 6 after infection with ZEBOV. Two of the three animals given four postexposure treatments of the pooled anti-ZEBOV siRNAs were protected from lethal ZEBOV infection and survived; whereas all four macaques given seven postexposure treatments were protected. The treatment regimen in the second study was well tolerated with minor changes in liver enzymes that might have been related to viral infection.
The authors say: "The development of treatments for EBOV-induced haemorrhagic fever has been slow and no previous candidate treatment has shown complete protection against ZEBOV haemorrhagic fever in non-human primates."
They conclude: "Here, we show a substantial progress in the treatment of ZEBOV infections in non-human primates compared with previously described postexposure methods that afforded only partial protection of non-human primates against ZEBOV. To progress to license, studies will be done in guinea-pig and non-human primate models of ZEBOV infection in accordance with the US Food and Drug Administration's guidelines for the assessment of treatments for Centers for Disease Control and Prevention category A threats. Additionally, studies will need to be done to obtain data about pharmacology, dosing, and toxicology in uninfected non-human primates."
Professor Geisbert adds: "We are excited to publish the first demonstration of complete postexposure protection against a lethal human infectious disease in non-human primates using siRNAs. We believe this work justifies the immediate development of this treatment as an agent to treat EBOV-infected patients either in outbreaks or accidental laboratory exposures."
In an accompanying Comment, Dr Heinz Feldmann, Rocky Mountain Laboratories, Hamilton, MT, USA; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA; and Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada, says: "The specialty of haemorrhagic viruses is in desperate need of approved countermeasures against Ebola-virus infections. To wait for the next incident to happen in a high-containment laboratory before any progress takes place seems intolerable. We also urgently need to improve outbreak support and go beyond transmission control, and actually provide specific care for affected individuals, which should be an ethical obligation for all of us. This provision can only happen in a timely fashion if existing experimental approaches, such as the siRNA strategy presented by Geisbert and colleagues today, are investigated in clinical trials and are given at least approval as investigational new drugs that are ready to use in emergencies. Funding is needed, and could come from government and non-governmental agencies and industry."
Professor Thomas W Geisbert, National Emerging Infectious Diseases Laboratories Institute, Boston University School of Medicine, Boston, USA. T) +1 325-518-0040 E) email@example.com
Dr Heinz Feldmann, Rocky Mountain Laboratories, Hamilton, MT , USA; and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA; and Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada. Please contact Ken Pekoc. T) +1 406-375-9690 E) firstname.lastname@example.org
For full Article and Comment, see: http://press.thelancet.com/ebola.pdf
*Note to editors: If a particular vaccine or drug cannot protect a rodent then it will probably not protect a nonhuman primate. However, protection of rodents using a particular vaccine or drug does not guarantee protection of non-human primates using the same drug or vaccine - and in many cases vaccines or drugs that protect rodents are not able to protect non-human primates
**This quote is direct from Professor Geisbert and cannot be found in the text of the Article.
1The study was carried out in collaboration with the US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA, and Tekmira Pharmaceuticals, Burnaby, BC, Canada.