Ebola future or investigational therapies
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Serge Korjian M.D.; Ahmed Younes M.B.B.CH [2]
Overview
There are no current antiviral therapies or vaccines for Ebola. Promising results from pre-clinical studies on agents such as ZMapp, AV6001, and TKM-Ebola have led to the development of phase I trials to evaluate the safety of these agents for human use. In August 2014, all Ebola-targeting therapies were granted fast-track designation by the FDA given the expanding outbreak.
Investigational Therapies
Antivirals
- Favipiravir, approved in Japan for stockpiling against influenza pandemics, appears to be useful in a mouse model of Ebola.[1] On 4 October 2014, it was reported that a French nun who contracted Ebola while volunteering in Liberia was cured with Favipiravir treatment.[2]
- Brincidofovir is a broad-spectrum antiviral drug. Its maker has been granted FDA approval to proceed with a trial to test its safety and efficacy in Ebola patients.[3] It has been used to treat the first patient diagnosed with Ebola in the USA, after he had recently returned from Liberia.[4][5]
- Lamivudine, usually used to treat HIV / AIDS, was reported in September 2014 to have been used successfully to treat 13 out of 15 Ebola-infected patients by a doctor in Liberia, as part of a combination therapy also involving intravenous fluids and antibiotics to combat opportunistic bacterial infection of Ebola-compromised internal organs.[6] Western virologists have however expressed caution about the results, due to the small number of patients treated and confounding factors present. Researchers at the NIH stated that lamivudine had so far failed to demonstrate anti-Ebola activity in preliminary in vitro tests, but that they would continue to test it under different conditions and would progress it to trials if even slight evidence for efficacy is found.[7]
ZMapp
ZMapp is an experimental drug composed of 3 humanized monoclonal antibodies currently being investigated for the treatment of Ebola virus disease. The component monoclonal antibodies are recombinantly manufactured in a variety of tobacco (Nicotiana benthamiana). It has not yet been tested in humans for safety or effectiveness. Zmapp was studied in a preclinical study involving rhesus macaques exposed to the virus. The drug was successful in rescuing 100% (21/21) of the macaques when the treatment was initiated within 5 days of the Ebola exposure. High grade fever, and significant viremia was present in many animals before the intervention. Full recovery was also observed in animals with advanced disease with elevated liver enzymes, mucosal hemorrhages and generalized petechia. ZMapp was also found to be cross-reactive with the Guinean variant of Ebola. [8]
AVI-6002
AVI-6002 is an investigational drug consisting of positively charged phosphorodiamidate morpholino oligomers (PMOplus). AVI-6002 is a form of antisense therapy whereby a particular gene can be silenced by synthesizing a strand of nucleic acid (DNA, RNA or a chemical analogue) that will bind the messenger RNA (mRNA) produced by that gene. Pre-clinical studies demonstrated that AVI-6002 administered intravenously within 30-60 min of exposure to the virus protects approximately 60% of rhesus monkeys against the Zaire Ebola virus (ZEBOV).[9] A phase I trial that involved 30 healthy volunteers enrolled in six-dose escalation cohorts demonstrated good safety and tolerability of AVI-6002.[10]
TKM-Ebola
TKM-Ebola is an LNP-siRNA (lipid nanoparticle-small interfering RNA). Small interfering RNAs are a class of double-stranded RNA molecules that interfere with gene expression by causing breakdown of mRNA. TKM-Ebola is a combination of siRNAs targeting three of the seven proteins in Ebola virus: Zaire Ebola L polymerase, Zaire Ebola membrane-associated protein (VP24), and Zaire Ebola polymerase complex protein (VP35). A proof of concept study that included monkeys and macaques demonstrated approximately full protection from the virus when the drug was given 30 minutes post-exposure and repeat dosing was administered daily over the next 6 days.[11] In January 2014, a phase I clinical trial evaluating TKM-Ebola in healthy volunteers was announced. Although the study was initially put on hold due to significant flu-like symptoms, the FDA modified this to a partial clinical hold. This action enables the potential use of TKM-Ebola in individuals infected with Ebola virus.[12]
Prevention of Ebola virus diease
rVSV-ZEBOV vaccine
- rVSV-ZEBOV vaccine is a a recombinant, replication competent vesicular stomatitis virus-based candidate vaccine carrying the glycoproteins of Zaire Ebola virus.[13]
- In 2015, A trial conducted in Guinea involving 11,841 subjects demonstrated the efficacy of rVSV-ZEBOV in preventing Ebola virus induced hemorrhagic fever in the 1st and 2nd degree contacts of patients infected with Ebola virus.[14]
- The study utilized a“ring vaccination” design whereby each case contact (household contacts, workmates, visitors, etc) for 3 weeks prior to the onset of symptoms was followed and their network was mapped to form a "cluster". A total of 117 clusters were identified; each one consisted of approximately 80 individuals. Subjects (contacts of the infected individual) were randomized either to receive the vaccine immediately or 3 weeks after the start of the trial. The vaccine was given to those who are above 18 years of age.
- After 10 days, none of the participants in the vaccinated group developed hemorrhagic fever. At the same time, 23 cases of Ebola virus infection were confirmed in the delayed vaccine group (who had not yet been immunized).
- The vaccine is not fully approved yet, however, it can be available prior to approval during an outbreak through a “compassionate use" approval, meaning that it can be administered after signing an informed consent.
- In light of the recent outbreak in the Democratic Republic of Congo[15], high hopes are held upon the "compassionate use" of rVSV-ZEBOV to limit the impact of the outbreak.
Videos
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Other vaccines under experimentation
INO-4212
- Designed to provide both cell mediated and humoral immunity, using plasmids from different ebola strains (incluidng strains from 2014 outbreak).[16]
- Primary outcome measures are expected to be released by May 2018.[17]
References
- ↑ Oestereich L, Lüdtke A, Wurr S, Rieger T, Muñoz-Fontela C, Günther S (2014). "Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model". Antiviral Res. 105: 17–21. doi:10.1016/j.antiviral.2014.02.014. PMID 24583123.
- ↑ "French nurse cured of Ebola contracted in Liberia". MSN. Retrieved 7 October 2014.
- ↑ "Chimerix gets FDA approval to test drug for Ebola". Associated Press. 17 October 2014.
- ↑ "Chimerix Announces Emergency Investigational New Drug Applications for Brincidofovir Authorized by FDA for Patients With Ebola Virus Disease". Retrieved 7 October 2014.
- ↑ Perrone, Matthew (6 October 2014). "Experimental Drug Provided to Dallas Ebola Patient". ABC. AP. Retrieved 6 October 2014.
- ↑ "Doctor treats Ebola with HIV drug in Liberia -- seemingly successfully. Elizabeth Cohen, CNN news. 29 September 2014". CNN. 27 September 2014. Retrieved 7 October 2014.
- ↑ "A Liberian doctor is using HIV drugs to treat Ebola victims. The NIH is intrigued. Elahe Izadi, Washington Post. 2 October 2014". Washington Post. Retrieved 7 October 2014.
- ↑ Qiu X, Wong G, Audet J, Bello A, Fernando L, Alimonti JB; et al. (2014). "Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp". Nature. 514 (7520): 47–53. doi:10.1038/nature13777. PMID 25171469.
- ↑ Warren TK, Warfield KL, Wells J, Swenson DL, Donner KS, Van Tongeren SA; et al. (2010). "Advanced antisense therapies for postexposure protection against lethal filovirus infections". Nat Med. 16 (9): 991–4. doi:10.1038/nm.2202. PMID 20729866.
- ↑ Heald AE, Iversen PL, Saoud JB, Sazani P, Charleston JS, Axtelle T; et al. (2014). "Safety and Pharmacokinetic Profiles of Phosphorodiamidate Morpholino Oligomers with Activity against Ebola Virus and Marburg Virus: Results of Two Single Ascending Dose Studies". Antimicrob Agents Chemother. doi:10.1128/AAC.03442-14. PMID 25155593.
- ↑ Geisbert TW, Lee AC, Robbins M, Geisbert JB, Honko AN, Sood V; et al. (2010). "Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study". Lancet. 375 (9729): 1896–905. doi:10.1016/S0140-6736(10)60357-1. PMID 20511019.
- ↑ [| About Investigational TKM-Ebola Therapeutic. Tekmira Pharmaceuticals Corporation.]
- ↑ Henao-Restrepo AM, Camacho A, Longini IM, Watson CH, Edmunds WJ, Egger M, Carroll MW, Dean NE, Diatta I, Doumbia M, Draguez B, Duraffour S, Enwere G, Grais R, Gunther S, Gsell PS, Hossmann S, Watle SV, Kondé MK, Kéïta S, Kone S, Kuisma E, Levine MM, Mandal S, Mauget T, Norheim G, Riveros X, Soumah A, Trelle S, Vicari AS, Røttingen JA, Kieny MP (2017). "Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!)". Lancet. 389 (10068): 505–518. doi:10.1016/S0140-6736(16)32621-6. PMC 5364328. PMID 28017403.
- ↑ "WHO | Final trial results confirm Ebola vaccine provides high protection against disease".
- ↑ "Congo reports death in new Ebola virus "outbreak" - CBS News".
- ↑ "Open-Label Study of INO-4212 With or Without INO-9012, Administered IM or ID Followed by Electroporation in Healthy Volunteers - Tabular View - ClinicalTrials.gov".
- ↑ "Ebola Immunotherapy".