Understanding the clinical course of Ebola virus infection

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The pursuit for finding a way to prevent and treat the Ebola virus infection is in full swing. The dreadful Ebola virus is the reason of the mortality of more than 10,000 people in three West African nations (Guinea, Liberia and Sierra Leone) (Martínez-Romero & García-Sastre, 2015). The recent Ebola virus outbreak in West African countries is unheard-of, (since its first occurrence in 1976), causing large number of cases and mortalities than all the earlier reported cases in combined. During the Ebola outbreak in Sierra Leone, the examination of patient outcomes confirmed 74% fatality rate (Schieffelin et al., 2014). This epidemic situation is however, revolving in and around the West African population, but the Ebola virus infection can also be a risk to healthy populations in different parts of the world, by inadvertent introduction of the diseased individuals from the endemic regions in the non infected population. The complete meta-analysis of the data provided by the WHO on the past 20 Ebola virus outbreaks including the recent one, showed an approximate case-fatality rate of 65.4% (Lefebvre et al., 2014). Although, the numbers of disease cases are going down in Guinea, Liberia and Sierra Leone, still new cases are emerging every day in the West Africa and rest of the world, thus we can assume that the goal of complete eradication of Ebola virus infection is yet to be achieved.

It is of crucial importance to know the specific molecular properties of Ebola virus pathogenesis, so that these aspects of viral pathogenesis can be used to develop effective drug therapy, against Ebola virus. The treatment of Ebola disease before 2014 largely included supportive care with antipyretics and rehydration therapy (Dixon & Schafer, 2014). The Ebola virus belongs to the Filoviridae family and is further categorized on the basis of their difference in the number, sequence and location of overlapping gene and their virulence, into 5 different species: the Bundibugyo, Reston agents, Sudan, Taï Forest, and Zaire (Baize, 2015; Sanchez et al., 2007). Ebola virus is a single stranded RNA based, non segmented virus which has been linked with frequent occurrences of serious hemorrhagic fever with high mortality rates (Feldmann & Geisbert, 2011). The entrance of the Ebola virus into the host cells is believed to be facilitated by the spikes of the glycoprotein envelope (Hunt et al., 2012). Mostly, the mucosal route, skin injuries and direct parental transmission are the main pathways of Ebola virus infection in human beings (Hofmann-Winkler Hofmann-Winkler et al., 2012) as confirmed from the biopsy reports of the skin samples and bodily fluids (Goeijenbier et al., 2014; Mahanty & Bray, 2004). Investigations of animal subjects and patients have shown that the widespread infection and replication of Ebola virus in the infected cells takes place very efficiently and it reflects its ability to neutralize the decisive innate immune responses by the interferon molecules (Wong et al., 2014).

A large number of organ system and physiological functions such as pulmonary, gastrointestinal, hepatic, genitourinary tract, endocrine, immunity responses and central nervous system, are directly affected by the Ebola virus infection due to its extensive propagation and these abnormalities are directly observed in patients (Bah et al., 2015; Connor et al., 2015; Davis et al., 1997;Dixon & Schafer, 2014; Jahrling et al., 1996; Kang & McGavern, 2010; Leroy et al., 2001; Martines et al., 2015; McElroy et al., 2014; Paessler & Walker, 2013; Schieffelin et al., 2014; Tandon & Acharya, 1987; West et al., 2014). Patients suffering from Ebola virus display a wide range of clinical manifestations like headache, high fever, malaise, nausea, fatigue, vomiting, diarrhoea, bleeding, hypotension etc. (Baize et al., 2014; West et al., 2014). Additionally, the chief ailments due to Ebola virus infection are associated with gastrointestinal abnormalities, like diarrhoea, vomiting, electrolytic imbalances etc. Significant loss of gastrointestinal fluids may cause hypovolemic shock and organ failure, which can be avoided by careful patient monitoring so as to avoid renal failure and cardiovascular collapse. However, patients may also show signs of sepsis or may require mechanical ventilation to reduce the risk of respiratory failure (Kreuels et al., 2014).

Vaccines and other management strategies for Ebola virus infection

Currently, there are no vaccines licensed for use in human beings against Ebola virus infection. Clinical studies of several potential candidate vaccines are at its maximal pace and it is expected that by the advent of 2016, an effective and safe vaccination will be developed. Till now, about 15 vaccines are being developed and two of which (VSB-EBOV and ChAd3-ZEBOV) are being subjected to clinical testing. VSV-EBOV (Vesicular Stomatitis Virus-Ebola Virus vaccine) is an investigational preparation, a replication-fit recombinant vaccine, developed by the Merck and New Link Genetics, USA in association with the Public Health group, Canada. The vesicular stomatitis virus has been genetically manipulated to display Ebola like features, so the immune system gets activated against Ebola virus (Andrea et al., 2011).

The other vaccine, ChAd3-ZEBOV or the cAd3-EBO Z, is a trial jab for two Ebola strains (Ebola and Sudan virus), generated by National Institute of Allergy and Infectious Disease and Glaxo Smith Kline. In this, the adenovirus type 3 (ChAd3) derived from chimpanzee, are genetically modified engineered to show properties of Ebola virus to stimulate the immunity against Ebola virus. As of now, clinical trials of both these vaccines are ongoing. The results of Phase I studies of these two vaccines were available in January and both showed positive results of being safe and well tolerated in humans. Although, some mild to moderate side effects like fever, arthritis, pain etc. were exhibited by VSV-EBOV (Martínez-Romero & García-Sastre, 2015). Presently, Phase II/III of clinical trials are in progress in Guinea and Sierra Leone for VSV-EBOV and the data from these two studies will be assessed by the Data Safety Monitoring Board which will determine whether the vaccine is effective or not.

Additionally, Johnson & Johnson has also developed a two dose vaccination strategy, which involved two different vaccines (Ad26-EBOV and MVA-EBOV). The phase I of this combination is complete and results of succeeding phases is awaited.

Many other organizations are also working to develop an effective and safe vaccine candidate against Ebola virus like the unconventional vesicular stomatitis virus candidate by Profectus Biosciences, an oral adenovirus proposal by Vaxart, a DNA based approach by Inovia, another recombinant protein candidate by Protein Sciences, and a modified rabies vaccine by Jefferson University. A novel vaccine candidate has just completed its initial human testing in China. Another US based biotech company, Novavax, has also developed a vaccine against Ebola based on Guinea 2014 strain of Ebola virus and the Phase I of the trial has been completed in Australia. Health Ministry, Russia is also working to develop an influenza recombinant vaccine for Ebola virus, and the Phase I trial has been started in the mid 2015.

Pharmaceutical companies are also devoted to boost their production capacity in case if the vaccine shows the desired safety and efficacy to fulfil the demand of finished product.

There are other medicines that were considered for treatment against Ebola virus infection. These potential candidates have been tested by the Science and Technical Advisory Committee on Emergency Ebola Interventions of the WHO. Some of them are either currently being tested in Ebola endemic settings or have already been employed in treating Ebola infection.

Among the various treatments for Ebola virus infection, the leading candidates for human trials include are: convalescent plasma, which is being isolated from an Ebola patients, as it possess the antibodies against Ebola virus; favipiravir, which is an antiviral compound presently licensed for influenza; the experimental drug brincidofovir, which was originally made against infections from cytomegalovirus and adenovirus. It has demonstrated to halt the reproduction of Ebola virus replication in-vitro and; the ZMapp, which is a mixture of three different monoclonal antibodies which specifically targets the glycoprotein envelope of the Ebola virus; some of them have shown promising results in animal models while other are being tried to some Ebola patients on a considerate basis. Some of the therapeutic options and their description in treatment of Ebola infection are given in the table.

Drug	Phase	Company	Details
TKM­100802 (siRNA)	II	Tekmira, Canada	It involves a small sequence of RNA that breaks RNA of Ebola virus in cells thus preventing its replication. Successful in treating monkeys. Although, the clinical trial was stopped as the trial end points were met.
MIL­77	I	MabWorks, China	A concoction of three monoclonal antibodies (same as in Zmapp). Equally effective in monkeys like Zmapp. Clinical trials is about to begin in China.
BCX­4430	I	Biocryst, USA	Broad spectrum nucleoside analogue. Ongoing Phase I safety trial. Trial will continue only after satisfactory data from Phase I studies
Interferons	II		Used for treatment of multiple sclerosis and Hepatitis-B, -C. Clinical trials were started in Guinea, but there is chance of exacerbation of symptom. Therefore, the patient’s recruitment on the basis of recent symptom onset.
Amiodarone	Observational		For treatment of cardiac dysrhythmia. It was found to reduce case mortality ratio in Sierra Leone. Although, this drug is no longer used.
Atorvostatin + Irbesartan +/­ Clomiphene			Used to treat hypercholesterolemia, hypertension, and infertility, respectively. In fact, used in Sierra Leone, but, official confirmation of their use and the clinical data was never available.
FX06			Peptide for use in treating vascular leakage. Empathetically given to only two patients. No conclusions.
Zmab			Investigational monoclonal antibody with no arrangements for large scale production. Administered to some patients as other drugs were not available, on a considerate basis.
Amodiaquine			Antimalarial drug when given to all the patients, the case fatality ratio were reduced. The cause is still unknown.

Conclusion

The recent Ebola virus outbreak in West Africa was a devastating emergency which led to the deaths of a large number people. Organizations at both national and global level have learnt a lesson in controlling this disease from turning into an epidemic, that they need a multidirectional policy that involves better disease surveillance, its fast and easy diagnosis, and availability of safe and effective therapeutic options. It was realized that the health care providers working in the infected area must be well equipped with effective diagnostic and therapeutic tools so win this battle.

A number of therapeutic agents are now under evaluation on both pre-clinical and clinical levels in hopes to acquire a potential cure for Ebola. It is expected that an efficient and safe therapy will materialize from the screening of a vast group of agents undergoing trials against Ebola virus infection. They may be agents like favipiravir, brincidofovir, BCX­-4430, TKM-­100802 etc. or the convalescent whole blood or plasma therapy and specific monoclonal antibodies. The entire international social order, under the guidance of the WHO and other organization of public/private partnership, is directed to find a potent cure for Ebola so that any future outbreak can be contained efficiently.

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