Advances in Designing and Developing Vaccines, Drugs, and Therapies to

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Abstract

Ebola virus (EBOV), a member of the family Filoviridae, is responsible for causing Ebola virus disease (EVD) (formerly named Ebola hemorrhagic fever). This is a severe, often fatal illness with mortality rates varying from 50 to 90% in humans. Although the virus and associated disease has been recognized since 1976, it was only when the recent outbreak of EBOV in 2014–2016 highlighted the danger and global impact of this virus, necessitating the need for coming up with the effective vaccines and drugs to counter its pandemic threat. Albeit no commercial vaccine is available so far against EBOV, a few vaccine candidates are under evaluation and clinical trials to assess their prophylactic efficacy. These include recombinant viral vector (recombinant vesicular stomatitis virus vector, chimpanzee adenovirus type 3-vector, and modified vaccinia Ankara virus), Ebola virus-like particles, virus-like replicon particles, DNA, and plant-based vaccines. Due to improvement in the field of genomics and proteomics, epitope-targeted vaccines have gained top priority. Correspondingly, several therapies have also been developed, including immunoglobulins against specific viral structures small cell-penetrating antibody fragments that target intracellular EBOV proteins. Small interfering RNAs and oligomer-mediated inhibition have also been verified for EVD treatment. Other treatment options include viral entry inhibitors, transfusion of convalescent blood/serum, neutralizing antibodies, and gene expression inhibitors. Repurposed drugs, which have proven safety profiles, can be adapted after high-throughput screening for efficacy and potency for EVD treatment. Herbal and other natural products are also being explored for EVD treatment. Further studies to better understand the pathogenesis and antigenic structures of the virus can help in developing an effective vaccine and identifying appropriate antiviral targets. This review presents the recent advances in designing and developing vaccines, drugs, and therapies to counter the EBOV threat.

Keywords: Ebola virus, Ebola virus disease, vaccines, prophylactics, drugs, therapeutics, treatment

Introduction

Ebola virus (EBOV; Zaire ebolavirus) is the causative agent of a severe hemorrhagic fever disease, Ebola virus disease (EVD; formerly called Ebola hemorrhagic fever). It was first recognized in 1976 in northern Democratic Republic of Congo, at that time Zaire (1–3). Since then, EVD is endemic in Africa. Fruit bats are the best-known reservoirs of EBOV (4). EVD is a well-established zoonotic disease; the initial cases of the EVD outbreaks occur after contact with reservoir or materials contaminated with the virus and followed by human-to-human transmission (5). EBOV is not only a serious public health issue but now also designated as category A pathogen and considered as a potential bioterrorism agent (6, 7). EBOV causes high mortality rates of up to 88% in the infected humans (8); therefore, it is classified as a risk group 4 agent and handled under biosafety level-4 containment. The risk of mortality is relatively greater in the elderly and/or patients with high viral load and poor immune response at the initial stage of the infection (9).

The EBOV belongs to the Filoviridae family and has a unique thin filamentous structure that is 80-nm wide and up to 14-µm long. Its envelope is decorated with spikes of trimeric glycoprotein (GP1,2) which are responsible for mediating viral entry into target cells (function of GP1) (10) and release of viral ribonucleoprotein from endosome to cytoplasm for replication (function of GP2) (11, 12). EBOV infects primarily humans, simians, and bats; but other species such as mice, shrew, and duikers may also contact infection (3, 13). Of the five identified EBOV species, four species, viz., EBOV, Sudan virus (SUDV; Sudan ebolavirus), Tai Forest virus (TAFV; Tai Forest ebolavirus, formerly Côte d’Ivoire ebolavirus), and Bundibugyo virus (BDBV; Bundibugyo ebolavirus), are known to infect humans and cause disease, whereas Reston virus (RESTV; Reston ebolavirus) is non-human primate (NHP) pathogen.

After an initial incubation period of 3–21 days, the disease progresses quickly to fever, intense fatigue, diarrhea, anorexia, abdominal pain, hiccups, myalgia, vomiting, confusion, and conjunctivitis (14) which may lead to the loss of vision (15). EBOV can spread from males to females through semen (16) and from mother to fetus and infant during gestation and lactation, respectively (17). Of the note, in an EBOV-infected patient, higher concentration of Ebola viral RNA in semen was noticed during the recovery period than the viral concentration in the blood during peak time of infection, suggesting male genital organ as virus predilection site for replication (18). Usually the human immune system mounts a response against infectious pathogens by sensing the pathogen-associated molecular patterns via a variety of pathogen-recognition receptors. Nevertheless, in the case of EBOV, innate immunity is impaired by the immunosuppressive viral proteins including VP35 and VP24, and lymphocytes are depleted as a result of apoptosis caused by inappropriate dendritic cell (DC)–T-cell interaction (7, 19). A thorough understanding on the pathogenesis of this deadly virus is essential because of its severe health impacts (20).

The increased incidences and fast spread of EBOV paving into a pandemic flight has compelled more focus of research to develop strategies and remedial measures for mitigating the impact and consequential severity of the viral infection. Even before delineating the less studied Ebola viral genome fully, researchers throughout the globe and health industry were pressured to focus on the development of effective and safe Ebola vaccines and therapeutics (21, 22). As of now, no licensed vaccines and direct-acting anti-EBOV agents are available to protect against the lethal viral infection or to treat the disease. To minimize the suffering, EBOV-infected patients are only provided with symptomatic treatment and supportive care. Because of its high pathogenicity and mortality rate, preventive measures, prophylactics, and therapeutics are essential, and researchers worldwide are working to develop effective vaccines, drug, and therapeutics, including passive immunization and antibody-based treatments for EVD (23–26). Prior to the 2014–2016 EBOV outbreak in West Africa, which has been the deadliest EBOV outbreak to date, convalescent blood products from survivors of EVD represented the only recommended treatment option for newly infected persons. Administration of monoclonal antibody (mAb) cocktails (ZMapp, ZMAb, and MB-003) as post-exposure prophylactics have been found to reverse the advanced EVD in NHPs and/or effectively prevented morbidity and mortality in NHPs (27–30).

There is the need for an effective vaccine against EBOV, especially in high-risk areas, to prevent infections in physicians, nurses, and other health-care workers who come into contact with diseased patients (31). Regular monitoring and surveillance of EBOV is essential to control this disease. In the EBOV outbreak, novel surveillance approaches include contact tracing with coordination at the national level and “lockdown” periods, during which household door-to-door reviews are conducted to limit the spread of the virus. Swift identification and confirmation of the Ebola cases and immediate follow-up of appropriate prevention and control measures, including safe burial of dead persons, are crucial practices to counter EBOV (32).

After the onset of EVD, treatment is required, whereas, when EBOV is circulating in population dense areas before infection, prophylactic measures like vaccination are necessary. One of the main challenges in containing EBOV is its presence in remote areas that lack technology and equipment to limit the virus spread. Because of its lethality, EBOV can only be handled in laboratories with biosecurity level-4 containment; thus, only few laboratories in the world can conduct EBOV research and testing of the counter measures against the authentic virus. Recent efforts by several organizations have focused on identifying effective therapies and developing appropriate vaccination strategies (33). Several drugs and vaccines have been developed against EBOV, and the production of low-cost drugs and vaccines against EBOV is essential for everyone, including those in the high-risk areas of the world, to be protected (26, 34). As of the acquisition of better knowledge against the pathogen due to improvement in the field of genomics and proteomics, there has been expansion in the field of vaccine synthesis where epitope-based vaccines are gaining top priority (35–37).

The present review aims to discuss advances in designing and development of EBOV vaccines, drugs, antibody-based treatments, and therapeutics, and their clinical efficacy in limiting EVD, thereby providing protection against the disease and alleviating high public health concerns associated with EBOV.

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Advances in Developing Vaccines Against EBOV

There is a clear need for an effective vaccine to prevent the rapid spread of EVD. An inactivated EBOV vaccine was first produced in 1980. This vaccine was tested for efficacy in guinea pigs (7). Since that time, several vaccines against EBOV have been developed, but no vaccine is licensed and available in the market (7). After the massive 2014–2016 outbreak of EBOV, several researchers have begun working to develop an effective vaccine (38). For an EBOV vaccine candidate, a long-lasting immune response is essential; as EBOV remains in the seminal fluid of EVD survivors as long as 401 days post-infection (39, 40). Keeping this window of virus persistence, a vaccine conferring immunity at least for 2 years is recommended by the Wellcome Trust-CIDRAP Ebola Vaccine Team B initiative (41). Vaccines like the chimpanzee adenovirus type 3 (ChAd3)-based non-replicating ChAd3-EBO vaccine, prime-boost recombinant adenovirus type 26 vector (Ad26.ZEBOV) followed by the modified vaccinia Ankara vector (MVA-BN-Filoa) vaccine, adenovirus 5-vectored EBOV vaccine, EBOV DNA vaccine, and recombinant vesicular stomatitis virus (rVSV) vector-based vaccine are undergoing clinical trials to evaluate their efficacy against EVD (38). The RNA-dependent RNA polymerase (L) epitope-based vaccine was designed using immunoinformatics. Various software have been used to analyze immunological parameters, and this epitope vaccine was found to be a good candidate for use against EVD (42). Two conserved peptides of EBOV, 79VPSATKRWGFRSGVPP94 from GP1 and 515LHYWTTQDEGAAIGLA530 from GP2, were identified as targets for the development of an epitope-based vaccine (43). Collection of the sequences of EBOV glycoproteins and examination for determining the proteins with greatest immunogenicity have been performed using in silico methods. The best corresponding B and T cell epitopes included peptide regions encompassing residues 186–220 and 154HKEGAFFLY162, respectively. Such predicted epitopes can confer the long-lasting immunity against EBOV with better ability of protection (36).

Ebola virus-GP fused with the Fc fragment of a human IgG1 subunit vaccine administrated with alum, QS-21, or polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose adjuvant induced strong humoral immunity in guinea pigs (44). Effectiveness of a ring vaccine using rVSVΔG/EBOVGP in cases of simulated EBOV disease was studied and even this approach can be employed during an outbreak situation (45). Notably, the neutralizing antibodies play a major role in conferring protection against EBOV infections. Thus, an EBOV vaccine capable of effectively inducing a long-lasting neutralizing antibody response is desirable for developing appropriate prevention strategies in combating the infection. In this line, the mucin-like domain of EBOV envelope glycoprotein GP1 has been identified to be critical in induction of protective humoral immune response (46, 47). Filorab 1 vaccine revealed desirable immunogenicity without the side effects. The main advantage of this vaccine is its higher immune response induction in chimpanzees (captive) when given orally and also with a single dose [instead of multiple doses as is required by virus-like particle (VLP) vaccine] (48). Modified mRNA-based vaccine constructs, formulated with lipid nanoparticles (LNPs) to facilitate delivery, are being tested against EBOV challenge in guinea pigs. These mRNAs induced robust immune responses and conferred up to 100% protection from the infection (49).

It is important to note that compilation of data in relation to immune responses (both induced by vaccines and natural infection) and the records of community members showing IgG seropositivity should be kept systematically. Assimilation of such information will help to handle next outbreaks with more rigidity, thereby helping to check EVD-associated disasters at an early stage (50). Vis-à-vis public health workers should also be vaccinated and mass vaccination programs should be undertaken through standardized and coordinated efforts (51).

The following section describes the various types of vaccines and vaccine platforms which are being explored for the development of a successful EBOV vaccine.

Inactivated Vaccines

Even though inactivated vaccines suffer with the problem of reversion to virulence due to inadequate viral inactivation, various strategies have been constantly explored in developing safe and potent non-replicating vaccine candidates for combating the EBOV infection (52). Both heat- and formalin-inactivated EBOV have been found protective against EBOV infection in a guinea pig model. Inclusion of inactivated vaccine with EBOV E-178 along with interferon (IFN) and immune plasma saved the life of a scientist working on EBOV (53). The protective efficacy of liposome-encapsulated irradiated EBOV, tested in a mouse model, was 100%. However, these viral particles failed to protect NHPs (54). This suggests that murine model is excellent for evaluating vaccine efficacy, but the level of protection might be different in different species and, hence, it is essential to test vaccines in NHPs before proceeding to clinical trials in humans. Heat-, formalin-, or gamma irradiation-killed EBOV vaccines have been found ineffective against EBOV disease; thus, the novel effective vaccine is essentially required (55).

DNA Vaccines

In DNA vaccines, plasmids are used to express immunogenic antigens. This is an attractive vaccine approach because of the ease of production and simplicity. In addition, DNA vaccine induces both humoral and cellular immune responses. A three-plasmid DNA vaccine comprising the transmembrane-deleted GP sequences from EBOV species Zaire and SUDV-Gulu as well as nucleoprotein (NP) sequence from EBOV was tested in healthy adults. The vaccine was well tolerated, and both CD4⁺ and CD8⁺ T cell responses were elicited (56). An EBOV GP DNA vaccine designed on a consensus alignment of GPs (from strains obtained during 1976–2014), delivered intramuscularly and then electroporated, elicited a strong T cell response, and protected 100% of experimental mice from lethal challenge with EBOV (57). The DNA from three strains of EBOV was used to prime human volunteers and boosted with attenuated adenovirus, which acted as delivery vehicle for EBOV DNA into antigen-presenting cells, induced significant humoral- and cell-mediated immune (CMI) responses (58). Intramuscular inoculation of the DNA vaccine through electroporation with DNA plasmid containing codon-optimized GP genes of EBOV elicited high levels of IgG and a strong CMI response (measured by IFN-γ ELISpot assay) in cynomolgus macaques (59).

Though the preliminary trials using DNA constructs have provided the acceptable safety profiles, the development of low immune titer for a shorter window necessitates repeated vaccinations to overcome this problem. Thus, the use of a potent vaccination regimen based on DNA vaccine platforms does not appear logical for a large population (60, 61).

Virus-Like Particles

Ebola VLPs (EBOV-VLPs or eVLPs) are generated from the expression of viral transmembrane glycoprotein (GP) and structural matrix protein (VP40) in mammalian cells, which undergo self-assembling and budding from host cells and display morphological similarity to infectious EBOV particles (47). Baculovirus-derived eVLPs comprising GP, VP40, and NP of EBOV have been found to induce human myeloid DC maturation, suggesting their immunogenicity. Baculovirus-generated VLPs were able to elicit similar levels of protection as 293T cell-derived VLPs and showed protection against virus challenge in a dose-dependent manner (62). Nano-VLPs, produced by sonication of VLPs and filtering to have a mean diameter of approximately 230 nm, increased their thermostability. Unlike native VLPs where GP protein is denatured in a solution by heating, the nano-VLP maintained the conformational integrity of the GP protein at temperature up to 70°C and could confer protection in a mouse model (63). VLP containing only VP40 was sufficient to protect mice from EBOV infection. VLP injection leads to an enhanced number of natural killer (NK) cells, which play a crucial role in innate immune protection against lethal EBOV. NK cell protection is dependent on perforin, but not recombinant viral vector vaccines on IFN-gamma secretion (64).

Ebola virus VP40 and GP have been demonstrated to interact with the host protein, BST2, and are associated with viral infections by trapping the newly assembled enveloped virions at the plasma membrane in the infected cells, ultimately induce NF-κB activity. The effects of EBOV GP1,2, VP40, and BST2 converge on an intracellular signaling pathway leads to neddylation, resulting in the additive response with respect to the induction of NF-κB activity. Exploring the dynamics of this interaction could provide targets for vaccine developments and therapies that can modulate the inflammatory response during EVD (65).

Quantitation of EBOV antigenic particles using proteomic assays like liquid chromatography high resolution mass spectrometry method can be employed for determining the batch quality of vaccine constructs as well as in optimizing the dosages by assessing the amount of GP1 needed to confer effective protection (47).

It is to be noted that though anti-EBOV antibody can mediate effective protection, VLP-vaccinated murine models were shown to survive the EBOV challenge in the absence of detectable serum anti-EBOV antibodies (66). It could also be revealed that adjuvant signaling may circumvent the necessity for B-cell immunity in conferring protection against EBOV. These studies can be valuable for the future characterization, development, and optimization of effective EBOV vaccine candidates (66).

Virus-Like Replicon Particles (VRPs)

The VRPs are the alternative to live-attenuated vaccines. The use of VRPs eliminates the risk of reversion to the original pathogenic form of live vaccine strains. To generate VRPs, generally filoviruses or alphaviruses are required. Here, while keeping the genes essential for replication, viral structural genes are deleted from full-length genomic cDNA clones. Viral structural genes are replaced with alternative gene(s) coding for an immunogen. Such replicons are able to replicate and transcribe upon transfection in competent cells. The resulting VRPs are able to infect cells only for one cycle. Because of the lack of structural genes, viral progeny are not formed. Viruses such as Venezuelan equine encephalitis virus (VEEV) can be used for production of EBOV antigen instead of structural proteins for the replicon vector. Thus, such vaccines are also quite safe (67). The gene inserted is typically GP, the main target of neutralizing antibodies. VRPs expressing EBOV VP24, VP30, VP35, and VP40 have been evaluated for their protective efficacy in a mouse model, but these were found not to be as protective as EBOV GP and NP antigens. VEEV replicons containing GPs from both EBOV and SUDV showed promising results in cynomolgus macaques after administration of a single dose. Here, two VRPs were constructed that contained the GP of EBOV or SUDV. The animals intramuscularly injected with both of the VRPs, survived viral challenge without exhibiting any clinical signs. The final results indicated that VRP-EBOV GP was able to confer cross-protection against SUDV, whereas VRP-SUDV GP was unable to provide complete protection against EBOV-Zaire challenge (68).

Recently, Ren et al. (69) constructed an alphavirus Semliki forest virus based recombinant replicon vector DREP for efficient and unchecked ex vivo co-expression of EBOV GP and VP40. Active immunization with recombinant DREP vectors possessing GP and VP40 induced cellular and humoral immune responses in murine model against EBOV antigens. This path breaking approach may provide key insights and strategies for designing further effective vaccines to contain EBOV permanently.

Reverse Genetics System for EBOV Vaccine

A full-length recombinant EBOV infectious clone was constructed using cDNA. By employing reverse genetics method, viable but replication incompetent virus lacking entire VP30 ORF was constructed. The resultant EbolaΔVP30 is biologically contained and replication deficient, until VP30 is provided extraneously. Virus replication in cell culture was allowed by growing the virus in Vero cell line that stably expresses VP30, designated VeroVP30 (70). The safety of EbolaΔVP30 has been evaluated in mice and guinea pig model and was able to protect from lethal infection (71). The EbolaΔVP30 virus inactivated by using hydrogen peroxide protected NHPs after a single immunization. To avoid any incidence of potential recombination events that might result in regaining the replicative efficiency, the vaccine candidate was inactivated by hydrogen peroxide, that creates nicks and breakages in single- or double-stranded DNA or RNA and the virus is completely inactivated while retaining antigenic determinants unaffected (72).

Recombinant Viral Vector Vaccines

Engineered viruses are gaining popularity because of their ability to efficiently induce CMI responses (a major part of adaptive immunity along with humoral response), as the antigen is expressed and processed in the cytoplasm. Replication-competent rVSV and chimpanzee adenovirus 3 (ChAd-3/cAd3) are the most efficient platforms for designing new vaccines (73). A recombinant vesiculovirus vector containing EBOV GP region (rVSVΔG/EBOVGP) was found to be highly effective after a single injection in NHPs (74, 75). The vaccine evaluated in pigs showed no disease development and no viral shedding. This indicated that the vaccine could be utilized for herd immunization and it also suggested the safety of the live-attenuated rVSVΔG/EBOVGP vaccine (76). Recently, this rVSVΔG/EBOVGP vaccine was evaluated in a randomized double blinded placebo phase III trial in 1,197 humans. There were no adverse effects or death following vaccination, supporting its use as a vaccine (77). The vaccine protected immunocompromised rhesus macaques that had a high number of CD4⁺ T cells (78). The rVSVΔG/EBOVGP vaccine was also studied for its efficacy as a therapy in rhesus monkeys after exposure to EBOV-Makona. This vaccine showed minimal prophylactic efficacy after exposure (79). Efficacy trials initiated to test the rVSV-vectored EBOV vaccine showed greater efficiency at the time of EVD outbreak, if deployed following the strategy of ring vaccination (80).

Another recombinant vaccine (VSV based), i.e., rVSV-Zaire EBOV has been shown to provide substantial protection. From 10th day of vaccination with this vaccine, no report of any disease was documented, which proved efficacy and effectiveness of rVSV-vectored vaccine in preventing EVD (81). It is interesting to note that seroconversion has been noticed in recipients of recombinant VSV-EBOV (rVSV-EBOV) vaccine by the end of fourth week (i.e., by 28 days) against the Kikwit strain glycoprotein (82). Another recombinant vaccine viz., rVSV-EBOV vaccine was tested as a candidate vaccine. This particular vaccine is under trial in human (phase II/III). It provides protection against only EBOV and is clinically efficient in the clinical set up of ring vaccination format (38, 83, 84). EBOV and SUDV glycoproteins have been assimilated into a cAdVax vector (adenovirus-based vaccine). In mice, this vaccine has provided full protection (85, 86). During recent outbreak in Democratic Republic of the Congo (DRC), rVSVΔG-EBOV-GP is being used for ring vaccination in the affected area. Though the vaccine is yet not approved and still under investigation.

In Russia, clinical trial of a vaccine, GamEvac-Combi, has been performed and has been approved to enter in phase III clinical trial (87). The vaccine GamEvac-Combi contained two heterologous expression systems. One is live-attenuated rVSV and the second is a recombinant replication-defective adenovirus type-5 (Ad5). Both the vectors are expressing the same glycoprotein. The rationale to use a combination of two vectors expressing glycoprotein of EBOV is that widely present preexisting immunity to Ad5 limits the use of Ad5 and also a negative correlation between EBOV glycoprotein-specific immune response and preexisting antibodies to Ad5 has been reported (88). Hence, prime immunization with VSV vectored vaccine and then boosting with AD5 vectored vaccine might contribute in compensating negative impacts of preexisting immune response to Ad5. This heterologous vaccine evoked glycoprotein-specific immune response in 100% volunteers on day 28th. Also, the vaccine is well tolerated and did not significantly altered the body physiological parameters and vital organs. In Liberia, Sierra Leone, and Guinea; the VSV and ChAd3 vectored vaccine are in focus (89).

Another study in mice models has reported that the adoption of a heterologous prime-boost vaccine strategy can result in a durable EBOV-neutralizing antibody response. The chimpanzee serotype 7 adenovirus vectors expressing EBOV GP (AdC7-GP) was used for priming and a truncated version of EBOV GP1 protein (GP1t) was used for boosting. Vaccination response studies showed that AdC7-GP prime/GP1t boost strategy was more potent in generating a sustained and strong immune response as compared to using an individual vaccine construct (90).

Replication-defective recombinant chimpanzee adenovirus type 3-vectored EBOV vaccine (cAd3-EBO) elicited both cell-mediated and humoral immunity in NHPs. A vaccine dose of 2 × 10¹¹ particle units was found sufficient to induce protective immunity in the NHPs and to eliminate the effect of prior immunity to cAd3 (91). Recombinant VSV vaccine expressing EBOV GP and A/Hanoi/30408/2005 H5N1 hemagglutinin (VSVΔG-HA-ZGP) protected mice against challenge with both viruses and also cross-protected against H5N1 viruses (92).

The utility of adenovirus-vectored EBOV vaccines is limited with preexisting anti-adenoviral antibodies, which significantly lower the GP-specific humoral and T cell responses (88). Six mutations in the genome of MVA virus restrict its host specificity and make it unable to replicate in mammalian cells. A randomized study of a multivalent MVA vaccine encoding GPs from EBOV, SUDV, Marburg virus (MARV), and TAFV NP (MVA-BN-Filo) conducted in 87 participants resulted in no fever. The quadrivalent vaccine formulation has demonstrated the boosting up of both cellular and humoral immune responses against EBOV to several folds (93). Twenty-eight days after immunization, GP-specific IgG was detected with EBOV-specific T cell responses (94). EBOV GP and TAFV NP expressed in an MVA platform assembles into VLPs. Heterologous NPs enhanced VLP formation and offered GP-specific IgG1/IgG2a ratios comparable to those of MVA-BN-Filo (95).

Recombinant cytomegalovirus expressing EBOV GP was found to evoke protective immunity in rhesus monkeys challenged with EBOV (79). Baculovirus-expressed EBOV-Makona strain GP administered with Matrix-M (saponin adjuvant) showed better immunogenicity. Administration of Matrix M-adjuvanted vaccine resulted in increased IgG production and CD4⁺ and CD8⁺ T cell production (96). A human parainfluenza virus type 3-vectored vaccine expressing the GP of EBOV (HPIV3/EboGP) was developed as an aerosolized vaccine, and studies in Rhesus macaques showed 100% protection against challenge with EBOV (97).

Adenovirus 26 vectored glycoprotein/MVA-BN vaccine has recently passed the phase I trial (94). In the European countries including United Kingdom and United States, for the purpose of clinical trial, administration of ChAd-3 vectored vaccine has been adopted. This vaccine expresses the EBOV GP and is available in monovalent and divalent forms (91, 98).

Ebola vaccine potency trials employing replication defective adenoviral vectors (rAd) encoding EBOV GP have come up with promising results in NHP models. Based on such studies, multiple mutant glycoproteins were developed (such as glycoprotein with deleted transmembrane domain) which offers reduced in vitro cytopathogenicity but possessed reduced vaccine-mediated protection. In contrast to this, a point mutated glycoprotein has been reported to offer minimal cytopathogenicity and appropriate immune protection even with a two logs lower vaccine dose (99).

Plant-Based Vaccines and Antibodies

Viral antigens, including GP, VP40, and NP, elicit protective immune responses. ZMapp, the cocktail of antibodies being used to treat EBOV, is a biopharmaceutical drug. To note, the component antibodies in ZMapp are manufactured in Nicotiana benthamiana using a rapid antibody manufacturing platform. Gene transfer is mediated by a viral vector, and the expression is transient. N. benthamiana-derived antibodies produced stronger antibody-dependent cellular cytotoxicity than the analogous anti-EBOV mAbs produced in a mammalian Chinese hamster kidney cell line (100). Phoolcharoen (101) expressed a GP1 chimera with the heavy chain of 6D8 mAb, forming an immune complex that was co-expressed with the light chain of the same mAb in leaves of tobacco plant. The ammonium sulfate-precipitated purified antibodies, along with poly(I:C) adjuvant, a synthetic analog of double-stranded RNA capable of interacting with toll-like receptor (TLR)-3, was found to elicit strong neutralizing anti-EBOV IgG. In addition, the immune complex along with poly(I:C) adjuvant was capable of stimulating a Th1/Th2 response. The experiment suggested the potential application of plant-produced Ebola immune complexes as vaccine candidates. EBOV VP40 was expressed in tobacco plants, and a mouse immunization study showed results that suggested this approach can be used to produce an EBOV vaccine (102).

The utility of plants as bioreactors for the bulk production of ZMapp could be considered to meet the required demand. The glycosylation pattern of mAbs may alter their efficiency and bioactivity, including their binding with the antigenic epitope. Several glycoforms of EBOV mAb13F6 have been prepared using a magnICON expression system. These glycoforms have human-like biantennary N-glycans with terminal N-acetylglucosamine, resulting in a structure similar to that of human mAbs. Hence, these are beneficial for humans (103).

Both RNA and DNA viruses have been modified to serve as plant-based vectors for the expression of heterologous proteins. Bean yellow dwarf virus, a single stranded-DNA virus, can replicate inside the nucleus of plant cells using their cellular machinery. A vector containing deletions in the coat-encoding genes and gene for the desired antigen may be inserted to form an expression cassette. The delivery of vectors to plants is Agrobacterium-mediated (23). mAbs against EBOV are produced by the process of agroinfiltration. In this context, it is noteworthy that lettuce acts as a very good host for the process of agroinfiltration. In lettuce cells, Agrobacterium tumefaciens has been used for delivering viral vectors (104). Neutralizing and protective mAb6D8 against EBOV has been expressed at a concentration of 0.5 mg/g of leaf mass. This quantity is similar to that generated in magnICON expression system (105). The plant-derived approach to vaccine development is attractive because of the large amount of transient proteins that can be expressed, with the potential for use during high demand for therapeutics and prophylactics (106). Advances in the field of vector expression like plant transient expression system and associated host cell engineering and manufacturing processes paved way for developing biopharmaceutical proteins and therapeutics in commercial basis. The great potentials of such novel approaches have been exploited for evolving therapeutics to counter emerging pandemics of EBOV and influenza that is evidenced from the production of experimental ZMapp antibodies (107).

An overview of various types of vaccines for countering EVD is presented in Table Table11 and depicted in Figure Figure11.

Table 1

Vaccines for treating Ebola virus disease.

S. No.	Type of vaccine platform	Vaccine	Adjuvant/mode of delivery	Model	Antigen	Inference	Reference
1	Inactivated vaccine	Rabies virus based on inactivated vaccine (FILORAB1)	Glucopyranosyl lipid A	Cyanomolgus and rhesus monkeys	GP	100% protection against lethal Ebola virus (EBOV) challenge, with no to mild clinical signs of disease	Johnson et al. (108)

		Virulent EBOV	Formalin inactivation/heat inactivation	Guinea pig	Complete virus as antigen	Reduction in mortality	Lupton et al. (53)

2	Attenuated vaccine	Live replication-competent EBOV and rabies virus-based bivalent vaccine	Direct inoculation of live-attenuated vaccine	Rhesus macaques	GP	100% protection from lethal challenge	Blaney et al. (109)

3	DNA vaccine	Multiagent filovirus DNA vaccine containing GP of Zaire, Sudan, and Marburg virus (MARV)	Electrical stimulation at an amplitude of 250 V/cm using TriGrid™ electroporation device	BALB/c mice	GP	100% protection from lethal challenge	Grant-Klein et al. (110)

					Mutant GP

		Synthetic polyvalent-filovirus DNA vaccine against Zaire, Sudan, and MARV	pVAX1 mammalian expression vectors, injected intradermally with 200 µg DNA	Guinea pigs	Codon-optimized GP	100% protection from lethal challenge	Shedlock et al. (111)

		DNA vaccine against EBOV	Intramuscular electroporation (IM-EP) 500 µg dose	Rhesus macaques	Codon-optimized GP	86% protection	Grant-Klein et al. (59)

		DNA encoding Zaire and Sudan glycoproteins	4 mg dose in 1 ml volume	Human healthy adults	Wild-type GP	Antibody response to the Ebola Zaire glycoprotein generated	Kibuuka et al. (60)

4	mRNA vaccine	mRNA molecule encapsulated in a lipid nanoparticle (LNP) formulation	0.2 mg/ml	Guinea pigs	A human Igκ signal peptide or the wild-type signal peptide sequence of GP attached to GP	Potency of mRNA vaccines is enhanced by LNP	Meyer et al. (49)

5	Ebola virus-like particles (VLPs)	pWRG7077 plasmid vectors encoding for Ebola VP40 and GP	10 µg of eVLPs	Balb/c mice	GP and matrix protein (VP40) in mammalian cells	Dose-dependent protection against lethal challenge	Warfield et al. (112)

		MARV GP and EBOV VP40 or vice-versa	Intramuscular vaccination with 100 µg of VLPs + 200 µl RIBI adjuvant	Strain 13 guinea pigs	GP and VP40	Homologous GP is essential and sufficient for protection against lethal challenge with homologous virus	Swenson et al. (113)

		pWRG7077 plasmid vectors encoding for GP, NP, and VP40	3 intramuscular injections of 250 µg of eVLPs + 0.5 ml of RIBI adjuvant	Cynomolgus macaques	GP, NP, and VP40	All animals were protected without showing signs of clinical illness	Warfield et al. (114)

		293T cells transfected with	VLP containing 10 µg GP	C57BL/6 mice	GP + VP40	VLP-mediated anti-EBOV immunity in B cell-deficient mice	Cooper et al. (66)

6	Vaccinia virus-based vaccine	Modified vaccinia virus Ankara-Bavarian Nordic^® (MVA-BN) co-expressing VP40 and glycoprotein (GP) of EBOV Mayinga and NP of Taï Forest virus	Intramuscular or intravenous application of 10⁸ TCID₅₀ of MVA-BN-EBOV-GP or MVA-BN-EBOV-VLP	CBA/J mice	GP + VP40	Production of non-infectious EBOV-VLPs	Schweneker et al. (95)

		Modified vaccinia Ankara (MVA)-based vaccine expressing the EBOV-Makona GP and VP40	1 × 10⁸ TCID₅₀	Rhesus macaques	GP + VP40	100% protection with single or prime/boost vaccination	Domi et al. (115)

7	Venezuelan equine encephalitis virus (VEEV)-based vaccine	VEEV-like replicon particles (VRP)	10⁷ IU VRP	Strain 2 or strain 13 guinea pigs	NP or GP	NP-VRP and GP-VRP immunized animals completely protected against lethal challenge	Pushko et al. (116)

		VRP expressing SUDV GP + EBOV GP	10¹⁰ focus-forming units	Cynomolgus macaques	GP (EBOV + SUDV)	100% protection against intramuscular challenge with either SUDV or EBOV	Herbert et al. (68)

8	Cytomegalovirus (CMV)-based vaccines	CD8⁺ T cell epitope from EBOV NP (VYQVNNLEEIC) cloned in mouse CMV vector	5 × 10⁵ plaque forming units	C57BL/6 mice	NP	High levels of long-lasting (>8 months) CD8⁺ T cells are produced	Tsuda et al. (117)

9	Kunjin virus-based vaccine	Kunjin virus VLPs expressing GP	5 × 10⁶ VLPs	Dunkin–Hartley guinea pigs	GP	More than 75% survival of animals post challenge	Reynard et al. (118)

10	Paramyxovirus-based vaccines	Human parainfluenza virus type 3 (HPIV3) clone containing GP	10⁷ plaque-forming units	Rhesus monkeys	GP	Double immunization protected animals	Bukreyev et al. (119)

		Newcastle disease virus clone containing GP	10⁷ plaque-forming units	Rhesus monkeys	GP	NDV/GP is highly attenuated for replication in the respiratory tract of immunized animals and developed GP-specific mucosal IgA antibodies	DiNapoli et al. (120)

11	Adenovirus-based vaccines	Adenovirus (rAd5) vaccine GP	2 × 10⁹ virus particle	Phase I human study	GP	Antigen specific humoral and cellular immune responses were generated	Ledgerwood et al. (121)

		Adenovirus (ChAd3) vaccine boosted with MVA	Priming dose 2.5 × 10¹⁰ PFU of ChAd3 and a boosting dose of 1.5 × 10⁸ PFU of MVA	Healthy adult volunteers	GP	Elicited B-cell and T-cell immune responses	Ledgerwood et al. (91)

		Chimpanzee serotype 7 adenovirus vaccine expressing GP (AdC7-GP)	Prime boosting with AdC7-GP (1 × 10¹⁰) and boosting with 20 mg Drosophila S2 cells expressed truncated GP	BALB/c mice	GP	Long-lasting high-titer neutralizing antibodies production in mice and efficiently prevented luciferase-containing reporter EBOV-like particle entry even at 18 weeks post-immunization	Chen et al. (90)

12	Vesicular stomatitis virus (VSV)-based vaccines	VSV GP replaced with EBOV GP	2 × 10⁷ PFU	Healthy adult volunteers	GP	Anti-Ebola immune responses were documented	Regules et al. (82)

		VSV GP replaced with EBOV GP	3 × 10⁵ PFU	Healthy adult volunteers	GP	Lowered antibody responses observed with vaccine associated side effects like vaccine-induced arthritis and dermatitis	Agnandji et al. (122)

13	Semliki forest virus based vaccines	From DNA-launched replicons (DREP)-eGFP vector, eGFP replaced with GP and NP to make DREP-GP and DREP-VP40 vectors, respectively	10 µg plasmid DNA	Balb/c mice	GP + VP40	EBOV filamentous VLPs were observed in the supernatant of cells resulting from co-expression of GP and VP40 and post immunization, specific humoral accompanied with a mixed Th1/Th2 cellular immune response was obtained	Ren et al. (69)

14	Liposome-encapsulated vaccine	Liposome-encapsulated irradiated EBOV-Zaire (6 × 10⁶ rads of γ-irradiation from a ⁶⁰Co source)	Intravenous inoculation of 1.0 ml dose containing 194 µg of irradiated EBOV Zaire + 100 µg of lipid A	BALB/c mice and Cynomolgus monkeys	All native EBOV antigens	All mice protected, however the immunization failed to protect Cynomolgus monkeys	Rao et al. (54)

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Introduction

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Advances in Developing Vaccines Against EBOV

The following section describes the various types of vaccines and vaccine platforms which are being explored for the development of a successful EBOV vaccine.

Inactivated Vaccines

DNA Vaccines

Virus-Like Particles

Virus-Like Replicon Particles (VRPs)

Reverse Genetics System for EBOV Vaccine

Recombinant Viral Vector Vaccines

Plant-Based Vaccines and Antibodies

An overview of various types of vaccines for countering EVD is presented in Table Table11 and depicted in Figure Figure11.

Table 1

Vaccines for treating Ebola virus disease.

S. No.	Type of vaccine platform	Vaccine	Adjuvant/mode of delivery	Model	Antigen	Inference	Reference
1	Inactivated vaccine	Rabies virus based on inactivated vaccine (FILORAB1)	Glucopyranosyl lipid A	Cyanomolgus and rhesus monkeys	GP	100% protection against lethal Ebola virus (EBOV) challenge, with no to mild clinical signs of disease	Johnson et al. (108)

		Virulent EBOV	Formalin inactivation/heat inactivation	Guinea pig	Complete virus as antigen	Reduction in mortality	Lupton et al. (53)

2	Attenuated vaccine	Live replication-competent EBOV and rabies virus-based bivalent vaccine	Direct inoculation of live-attenuated vaccine	Rhesus macaques	GP	100% protection from lethal challenge	Blaney et al. (109)

3	DNA vaccine	Multiagent filovirus DNA vaccine containing GP of Zaire, Sudan, and Marburg virus (MARV)	Electrical stimulation at an amplitude of 250 V/cm using TriGrid™ electroporation device	BALB/c mice	GP	100% protection from lethal challenge	Grant-Klein et al. (110)

					Mutant GP

		Synthetic polyvalent-filovirus DNA vaccine against Zaire, Sudan, and MARV	pVAX1 mammalian expression vectors, injected intradermally with 200 µg DNA	Guinea pigs	Codon-optimized GP	100% protection from lethal challenge	Shedlock et al. (111)

		DNA vaccine against EBOV	Intramuscular electroporation (IM-EP) 500 µg dose	Rhesus macaques	Codon-optimized GP	86% protection	Grant-Klein et al. (59)

		DNA encoding Zaire and Sudan glycoproteins	4 mg dose in 1 ml volume	Human healthy adults	Wild-type GP	Antibody response to the Ebola Zaire glycoprotein generated	Kibuuka et al. (60)

4	mRNA vaccine	mRNA molecule encapsulated in a lipid nanoparticle (LNP) formulation	0.2 mg/ml	Guinea pigs	A human Igκ signal peptide or the wild-type signal peptide sequence of GP attached to GP	Potency of mRNA vaccines is enhanced by LNP	Meyer et al. (49)

5	Ebola virus-like particles (VLPs)	pWRG7077 plasmid vectors encoding for Ebola VP40 and GP	10 µg of eVLPs	Balb/c mice	GP and matrix protein (VP40) in mammalian cells	Dose-dependent protection against lethal challenge	Warfield et al. (112)

		MARV GP and EBOV VP40 or vice-versa	Intramuscular vaccination with 100 µg of VLPs + 200 µl RIBI adjuvant	Strain 13 guinea pigs	GP and VP40	Homologous GP is essential and sufficient for protection against lethal challenge with homologous virus	Swenson et al. (113)

		pWRG7077 plasmid vectors encoding for GP, NP, and VP40	3 intramuscular injections of 250 µg of eVLPs + 0.5 ml of RIBI adjuvant	Cynomolgus macaques	GP, NP, and VP40	All animals were protected without showing signs of clinical illness	Warfield et al. (114)

		293T cells transfected with	VLP containing 10 µg GP	C57BL/6 mice	GP + VP40	VLP-mediated anti-EBOV immunity in B cell-deficient mice	Cooper et al. (66)

6	Vaccinia virus-based vaccine	Modified vaccinia virus Ankara-Bavarian Nordic^® (MVA-BN) co-expressing VP40 and glycoprotein (GP) of EBOV Mayinga and NP of Taï Forest virus	Intramuscular or intravenous application of 10⁸ TCID₅₀ of MVA-BN-EBOV-GP or MVA-BN-EBOV-VLP	CBA/J mice	GP + VP40	Production of non-infectious EBOV-VLPs	Schweneker et al. (95)

		Modified vaccinia Ankara (MVA)-based vaccine expressing the EBOV-Makona GP and VP40	1 × 10⁸ TCID₅₀	Rhesus macaques	GP + VP40	100% protection with single or prime/boost vaccination	Domi et al. (115)

7	Venezuelan equine encephalitis virus (VEEV)-based vaccine	VEEV-like replicon particles (VRP)	10⁷ IU VRP	Strain 2 or strain 13 guinea pigs	NP or GP	NP-VRP and GP-VRP immunized animals completely protected against lethal challenge	Pushko et al. (116)

		VRP expressing SUDV GP + EBOV GP	10¹⁰ focus-forming units	Cynomolgus macaques	GP (EBOV + SUDV)	100% protection against intramuscular challenge with either SUDV or EBOV	Herbert et al. (68)

8	Cytomegalovirus (CMV)-based vaccines	CD8⁺ T cell epitope from EBOV NP (VYQVNNLEEIC) cloned in mouse CMV vector	5 × 10⁵ plaque forming units	C57BL/6 mice	NP	High levels of long-lasting (>8 months) CD8⁺ T cells are produced	Tsuda et al. (117)

9	Kunjin virus-based vaccine	Kunjin virus VLPs expressing GP	5 × 10⁶ VLPs	Dunkin–Hartley guinea pigs	GP	More than 75% survival of animals post challenge	Reynard et al. (118)

10	Paramyxovirus-based vaccines	Human parainfluenza virus type 3 (HPIV3) clone containing GP	10⁷ plaque-forming units	Rhesus monkeys	GP	Double immunization protected animals	Bukreyev et al. (119)

		Newcastle disease virus clone containing GP	10⁷ plaque-forming units	Rhesus monkeys	GP	NDV/GP is highly attenuated for replication in the respiratory tract of immunized animals and developed GP-specific mucosal IgA antibodies	DiNapoli et al. (120)

11	Adenovirus-based vaccines	Adenovirus (rAd5) vaccine GP	2 × 10⁹ virus particle	Phase I human study	GP	Antigen specific humoral and cellular immune responses were generated	Ledgerwood et al. (121)

		Adenovirus (ChAd3) vaccine boosted with MVA	Priming dose 2.5 × 10¹⁰ PFU of ChAd3 and a boosting dose of 1.5 × 10⁸ PFU of MVA	Healthy adult volunteers	GP	Elicited B-cell and T-cell immune responses	Ledgerwood et al. (91)

		Chimpanzee serotype 7 adenovirus vaccine expressing GP (AdC7-GP)	Prime boosting with AdC7-GP (1 × 10¹⁰) and boosting with 20 mg Drosophila S2 cells expressed truncated GP	BALB/c mice	GP	Long-lasting high-titer neutralizing antibodies production in mice and efficiently prevented luciferase-containing reporter EBOV-like particle entry even at 18 weeks post-immunization	Chen et al. (90)

12	Vesicular stomatitis virus (VSV)-based vaccines	VSV GP replaced with EBOV GP	2 × 10⁷ PFU	Healthy adult volunteers	GP	Anti-Ebola immune responses were documented	Regules et al. (82)

		VSV GP replaced with EBOV GP	3 × 10⁵ PFU	Healthy adult volunteers	GP	Lowered antibody responses observed with vaccine associated side effects like vaccine-induced arthritis and dermatitis	Agnandji et al. (122)

13	Semliki forest virus based vaccines	From DNA-launched replicons (DREP)-eGFP vector, eGFP replaced with GP and NP to make DREP-GP and DREP-VP40 vectors, respectively	10 µg plasmid DNA	Balb/c mice	GP + VP40	EBOV filamentous VLPs were observed in the supernatant of cells resulting from co-expression of GP and VP40 and post immunization, specific humoral accompanied with a mixed Th1/Th2 cellular immune response was obtained	Ren et al. (69)

14	Liposome-encapsulated vaccine	Liposome-encapsulated irradiated EBOV-Zaire (6 × 10⁶ rads of γ-irradiation from a ⁶⁰Co source)	Intravenous inoculation of 1.0 ml dose containing 194 µg of irradiated EBOV Zaire + 100 µg of lipid A	BALB/c mice and Cynomolgus monkeys	All native EBOV antigens	All mice protected, however the immunization failed to protect Cynomolgus monkeys	Rao et al. (54)

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Figure 2

Different therapeutic agents and drugs available for the treatment of Ebola virus disease (EVD). Some agents block the viral entry, some block the RNA polymerase, while some inhibit gene expression. Neutralizing antibodies and mAbs have shown the potential to effectively inhibit Ebola virus (EBOV).

Of the note, a luciferase reporter system (EBOV-like particle/EBOVLP) has been developed. It helps in evaluating the in vivo anti-EBOV agents, viz., vaccines and drugs without the necessity of biosafety level-4 facilities. The system appears suitable in studying the process of viral entry also (259). The molecular tweezer CLR01 has been recently reported to inhibit EBOV and Zika virus infection. CLR01 interacts with the lipids in the viral envelop but not with the cellular membrane, thereby it is having very less effect on viability of cells (270). This small molecule has earlier been shown to possess antiviral activity against HIV-1 and herpes viruses. Such broad-spectrum antiviral agents need to be further explored to develop an effective drug against EBOV.

Currently, priority is being given toward investigating various proteins in the host system and viral targets (druggable) (271). Further research works need to be strengthened to identify potent viral or host targets that can be exploited to treat EVD or inhibit EBOV. With advances in bioinformatics tools, it is now possible to identify the active sites of the viral targets which can be utilized as a critical step toward designing and discovering anti-EBOV drugs (272). The involvement of computational tools has widened our approach toward designing drugs (target based) widely. Computational approaches can also countervail the endemic burdens in development of drugs traditionally (271, 273). Large libraries can now be effectively screened, ultimately stimulating research activities toward identifying potent anti-EBOV drugs. Therapeutic applications of cytokines, recombinant proteins, RNAi technology/RNA interference, TLRs, avian egg yolk antibodies, plant-based pharmaceuticals, nanomedicines, immunomodulatory agents, probiotics, herbs/plant extracts, and others may be explored appropriately to combat EBOV, as these have been found promising against other viral pathogens (2, 249, 274–282).

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Conclusion and Future Perspectives

The 2014 EBOV outbreak has been marked as the most widespread lethal viral hemorrhagic attack and prompted a hasty leap in the researches for developing effective vaccines and therapies to counter it. In the case of Ebola, deviations in the touchstone drug/vaccine research approaches may be permitted by authorities to an appropriate extent, considering the devastating and alarming pandemic threat from the disease. In recent years, several therapies have emerged to tackle lethal EBOV infections. A plant-derived formulation of humanized mAbs: “ZMapp” has been used to treat some patients. However, the shortage of ZMapp supply warrants the evaluation and development of new mAbs. Various drugs have been repurposed to treat potentially lethal disease like EVD. There is a long list of repurposed compounds that have been evaluated as inhibitors of EBOV, including microtubule inhibitors, estrogen receptor and reuptake modulators, kinase inhibitors, histamine antagonists, and ion channel blockers. In-depth studies are still required to understand the pathogenesis and the role of different EBOV peptides, proteins, and antigens and host–virus interactions in EVD. There is also a need to develop economic and effective antivirals and vaccines against EBOV having approach/utility to any part of the world including resource poor countries.

Although the development of vaccines against EBOV began in 1980, there is still no effective vaccine available to prevent this deadly disease. Hence, the hunt for an effective vaccine is still on. Ebola VLPs play an imperative role in high-throughput screening of anti-EBOV compounds. Because five EBOV species have been reported, a polyvalent vaccine having immunogenic determinants such as GP from each of species would provide broader immunity; indeed, in nonhuman primate experimental studies with a DNA vaccine, this is commonly true. The best first-generation vaccine candidates for EBOV are rVSV and ChAd3, as reflected by their application in providing long duration protection during sporadic outbreaks. Various combinations of antigens from different species of EBOV may be explored to achieve higher protective immune response. The rVSV-based vaccine is being used in Democratic Republic of the Congo. Due to absence of preexisting immunity to VSV, it eliminates several drawbacks and safety concerns associated Ad5-based vaccine. Also, it has show long-term protection in several NHP models, it is an ideal vaccine platform to be used at time of outbreak. Together, the GamEvac-Combi vaccine also seems to be equally promising as it generated immune response in 100% volunteers.

In addition, mAbs with broad cross-reactivity that will neutralize all five species of EBOV are required to be developed and evaluated for prophylactic and therapeutic uses. Furthermore, effective antibodies may be engineered for homogeneity with human antibodies. Many nucleic acid-based modalities like siRNA, miRNA, and PMOs have been tested against EBOV and found functional. In the era of genomics, a computational approach may also be employed to screen large numbers of inhibitory molecules to safeguard human health. Available treatments within the disaster settings; mostly combination of appropriate supportive care and boosting of patient’s immune responses, need to be optimized to ensure minimum research/medical ethics being followed in such settings.

There is always scope for future investigations on the basis of clinical studies that are designed well and statistically supported. Maximum use of supportive therapy (MUST) should be introduced for studying the effects of new therapeutics. The side effects of newer drugs can also be revealed very efficiently by MUST and for this more resources are needed for the Ebola clinics. Though several drugs have been evaluated and vaccines are in development; however, more research is required to develop potent therapeutic and prophylactic agents against EBOV. Apart from these advances, adaptation of appropriate preventive measures and strict biosecurity principles are essential to stop the EBOV outbreaks, limit the spread of virus, and address its public health significance.

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Author Contributions

All the authors substantially contributed to the conception, design, analysis and interpretation of data, checking and approving final version of the manuscript, and agreed to be accountable for its contents. KD, RK, AM, and KK initiated this review compilation. SC, SL, and RK updated various sections. RKS, YM, DK, and MR reviewed virology and biotechnology aspects. RKS, SM, RS, and WC reviewed recent vaccines and therapies. RK designed tables. KK designed the figures. WC, AM, and KD overviewed and edited final.

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Conflict of Interest Statement

All authors declare that there exist no commercial or financial relationships that could in any way lead to a potential conflict of interest.

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Acknowledgments

All the authors acknowledge and thank their respective Institutes and Universities.

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Footnotes

Funding. This compilation is a review article written, analyzed and designed by its authors, and required no substantial funding to be stated.

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Advances in Designing and Developing Vaccines, Drugs, and Therapies to Counter Ebola Virus

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