Monday, August 11, 2014

Ebola- Experimental Therapeutics


Fig 1: Status of Ebola outbreak as on 6 Aug 2014.
    A lot of international focus is currently on "Ebola outbreak". The concern is genuine and it is absolutely right on the part of major health players to be concerned. As a matter of fact, there never has been such a large Ebola Outbreak. Read my previous post on Ebola outbreak here.

    As per the WHO estimates dated 6 August 2014, the cumulative number of cases in the four countries stands at 1 779, including 961 deaths. The details are published in WHO website (Link). I have prepared a graph (Fig 1) based on the data which summarises the situation.

      As I have mentioned earlier, there is no licensed vaccine or drug available against Ebola. This is where the question of basic research comes in. In a time when the only kind of research encouraged is the term "Translational", the lack of basic biology understanding of Ebola has put up a stagnation. My point is by doing basic science we would have been much more prepared to develop therapeutics. So is there no hope?

Fig 2: Ebola outbreak Timeline of important events.
       The passive immunisation approach has been dubbed by some as the secret serum and its use is currently debated. Use of passive protection is a old trick. It is known that, not all patients die of Ebola infection and the people who survive are immune from further infection, since they develop blocking antibodies. Serum from such patients can be administered to others and used as passive immunization. Currently a monoclonal antibody approach is seen as the most potential candidate. A a mixture of three monoclonal antibodies (called ZMapp) which had been previously shown to block infection of cells with Ebolaviruses, and prevent lethal infection of non-human primates when given within 24-48 hours after infection.

     ZMapp, is a mixture of three humanized monoclonal antibodies for immunological protection against Ebola. The mixture consists of humanised antibodies- c13C6, h-13F6, and c6D8. Original study was published in PNAS (2012) by Olinger etal. The trio mAb was called as the MB-003. This is produced in a tobacco plant Nicotiana benthamiana. The product now produced by Mapp Biopharmaceutical has not yet been clinically tested. At least a phase 1 is required to evaluate the potential outcomes of the drug. However, there is an ethical issue of with holding the potential drug during an outbreak when there is no other option. Considering that there is a urgent need many scientists have called for the drug to be released and it has been seen as an opportunity to test the drug.

       Vaccine development has been tried in EBOV infections. The Ebola glycoprotein has been loaded into a variety of carrier particles such as Attenuated Rabies virus, Adenovrius or Virus like particles have been studied. The best results are probably represented by a replication competent VSV (Vesicular stomatitis virus) carrying Ebola Glycoprotein. E coli expressing Ebola has been reported and may also be used as a immunogen. It is to be noted that these are experimental vaccines and none of them have been clinically tested. Hence the performance is not well known.

     Vaccines are more useful to control an outbreak and as a pre exposure prophylaxis. Drugs which can attack the virus directly may be of great field benefit. Experimental drug that has gained international focus is the TKM-Ebola and AVI-6002, BCX4430, Favipiravir etc. AVI 6002 or Sarepta’s drug (Combination of AVI-7357 and AVI-7539) is anti sense RNA PMO (phosphorodiamidate morpholino oligomers), that targets VP24. TKM Ebola or Tekmira's drug is a lipid nanoparticle with siRNA, currently under phase 1 trial. BCX4430, is a RNA-dependent RNA polymerase (RdRp) inhibitor. Favipiravir (Earlier known as T-705) is a viral RNA polymerase inhibitor, with broad spectrum activity.

   The sudden fear of Ebola outbreak and its spread has now created a global alert condition. Provided the fact that there is no well tested treatment option available, scientists are debating the deployment of experimental drugs and vaccines in an attempt to curb the expanding number of cases. A clear case of emergency.
Arie S (2014). Ebola: an opportunity for a clinical trial? BMJ (Clinical research ed.), 349 PMID: 25098954

Olinger etal (2012). Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques. PNAS, 109 (44), 18030-5 PMID:3071322

Geisbert TW, & Feldmann H (2011). Recombinant vesicular stomatitis virus-based vaccines against Ebola and Marburg virus infections. The Journal of infectious diseases, 204 Suppl 3 PMID: 21987744

Choi JH, & Croyle MA (2013). Emerging targets and novel approaches to Ebola virus prophylaxis and treatment. BioDrugs, 27 (6), 565-83 PMID: 23813435

Check Hayden, E. (2014). Ebola declared a public-health emergency. Nature . DOI: 10.1038/nature.2014.15689

Iversen PL, Warren TK, Wells JB, Garza NL, Mourich DV, Welch LS, Panchal RG, & Bavari S (2012). Discovery and early development of AVI-7537 and AVI-7288 for the treatment of Ebola virus and Marburg virus infections. Viruses, 4 (11), 2806-30 PMID: 23202506

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