The Therapeutic Developments And Epidemiology Of Ebola

Introduction

The Ebola Virus Disease (EDV) solicited global attention in 2014. Ebola virus is an enveloped virus with a cylindrical shape that contains a nucleocapsid with negative-sense RNA2. Belonging to the Filoviridae family, it is responsible for causing severe, and often fatal hemorrhagic fever in those infected. In 2014, World Health Organization (WHO) declared EDV to be epidemic to regions of West Africa3. While there are no current antiviral therapeutics against the virus, scientists are screening certain molecules for effective antiviral properties which could set clinical trials in motion. The GS-5734 is a monophosphate nucleoside molecule that has been identified as a potential antiviral candidate against Ebola virus6. Furthermore, experiments in nonhuman primates – rhesus monkeys – present GS-5734 as a potential substance serving as post-exposure treatment for the disease.

Ebola as a Global Health Concern

Ebola left a total death toll of 11,325 individuals during the 2014-2016 epidemic. Fortunately, organizations such as the Center for Disease Control (CDC) and the WHO provided response efforts in the likes of, the outbreak was able to be contained3. However, in August of 2018, Ebola resurfaced again with an outbreak in the Democratic Republic of Congo (DRC) and made more than 2200 victims so far. A new vaccine Ervebo has recently been approved as a vaccine against Ebola and a second vaccine developed by Johnson & Johnson is scheduled to be injected to infected DRC residents.

Epidemiology of Ebolavirus

In nature, the virus resides in fruit bats but can be acquired by primates which can, in turn, transmit the infection to humans. While contact with infected bodily fluids is the main mode of transmission, contaminated surfaces such as bedding can also transmit the virus8. Ebola has an incubation period of 2-21 days and exhibits flu-like symptoms, which may be followed by diarrhea, vomiting, impaired organ function, and hemorrhagic bleeding.

Current methods of diagnosis include real-time PCR (RT-PCR), Nucleic acid test (NAT) and antigen detection. Electron microscopy can also be used, and blood is usually collected as the testing sample. Treatment for Ebola include rehydration to improve symptoms but there are no currently approved therapeutic treatment for the disease Vaccines such as rVSV-ZEBOV and Ervebo are available and greatly reduced the spread of the virus5. Primary methods of control consist of reducing the risks of animal-to-human and human-to-human transmission and improving outbreak containment measures.

Therapeutic Developments

When it comes to designing therapeutics, monoclonal antibodies, interfering RNAs and small nucleosides have been investigated in clinical trials to determine if they could be anti-Ebola agents. A 2017 study by Siegel et al. screened several RNA viruses from various families for certain candidate drugs such as Favipiravir, Sofosbuvir, and Galidesivir. They found that a certain molecule, GS-5734, had a much lower half-maximal effective concentration (EC50) in macrophages than the other chemicals tested. Hence, GS-5734 was selected for further development.

Remdesivir (GS-5734) Nucleoside Prodrug

GS-5734, also known as Remdesivir is a monophosphate of an adenosine nucleoside that is used as a prodrug – it is inactive but can be biologically metabolized into a drug. It was developed by Gilead Sciences as a drug against Ebola, and Marburg viruses and has shown to be effective against other viruses as well1. When GS-5734 is present in the body, it enables the cell to bypass initial rate-limiting phosphorylation reactions and optimizes the formation of active triphosphates molecules. The nucleoside triphosphate produced (NTP) acts as an alternative substrate and has shown to interfere with the action of viral RNA polymerases.

Various cell-based assays were carried out in order to access the antiviral properties of GS-5734. For instance, a viral antigen reduction assay was conducted with a fluorescence immuno-staining method to measure the EC50 of the cells. Cell viability assays shed more light on how the drug was toxic the cells, generating CC50 values for the candidate drugs.

GS-5734 was recently introduced in clinical trials with rhesus monkeys. The prodrug was administered intravenously once a day at a concentration of 10 mg kg-1 for 12 days in nonhuman primates. The study found that the prodrug effectively suppressed viral replication and protected the animals from lethal consequences while maintaining high NTP levels in their mononuclear cells. This post-exposure treatment is also being tested against other RNA viruses such as coronaviruses and arenaviruses in the hopes that it is suitable for large-scale manufacturing and further drug safety and pharmacokinetic studies.

Conclusion

The Ebola Virus Disease has had bad repercussions on populations across the world and collective control methods and vaccination have helped contain the virus. Moreover, candidate drugs are being screened for their efficiency against the virus, such as GS-5734. The nucleoside prodrug has shown promising results in effectively inhibiting viral replication in nonhuman clinical trials. Further studies are on-going to further assess whether GS-5734 could be a successful antiviral treatment option for EVD.