12. Vaccine candidates undergoing trials

Vaccines are one of the most effective means of managing viral infections especially for recurrent infections. This suggests that a vaccine for Ebola virus fever will be important for the management of the disease. Till date despite the several recurrent outbreaks of Ebola haemorrhagic fever, no licensed vaccine is available. However, several clinical trials are ongoing in Europe, United States, and West Africa, with preliminary findings on efficacy, and safety becoming available. These vaccine candidates are categorized as replication incompetent or non-replicative and replication competent vaccines [79]. Some of these vaccine candidates are summarized below.

#### 12.1. Recombinant adenovirus based vaccines

Adenoviruses are generally non-enveloped, double-stranded DNA viruses isolated from mammalian species. Following the deletion of the E1 region in their genome which renders the virus non-replicative, this property makes them suitable as recombinant vectors [80, 81]. Several Ebola vaccines that have been developed make use of a variety of recombinant Adenovirus serotypes which includes the human serotypes such as Ad26 and Ad35 and the chimpanzee Adenovirus serotypes; Ad3, Ad7 and Ad62 [82]. Recombinant Adenovirus 5 (rAd5) was the first recombinant Ebola vaccine to show protection to Non-human primates against the EBOV virus but required a period of over 6 months to attain complete immunization [83]. A double-blinded, placebo-controlled phase I clinical trial in 2010 showed rAd5 vaccine encoding the envelope GP from EBOV and SEBOV 1976 strain to be safe and immunogenic [84]. Following the 2014 West Africa outbreak, another phase 1 clinical trial was conducted with another rAd5 vaccine which encoded the envelope GP of EBOV 2014 strain. The findings showed that the vaccine was immunogenic and safe at high dose of immunization [85]. Studies with other recombinant adenovirus vaccines such as rAd26 and rAd35 have them to be immunogenic by stimulating T-cell responses of CD4+ and CD8+ as well as increase cytokine (TNF/IFN-γ) secretion. Recently, rAd26 vaccine expressing the full-length GP of EBOV is currently undergoing phase III trials [86].

ChAd3-EBOV defined as chimpanzee adenovirus serotype 3 encoding the monovalent Zaire strain of Ebola virus glycoprotein is a genetically modified non-replicative vaccine candidate produced by GlaxoSmithKline in collaboration with the National Institutes of Health, USA. In 2014, five phase 1 trials of ChAd3 conducted in Europe, North America, and Africa confirmed the vaccine to be immunogenic and safe [87]. As a result, Phase II and III trials were initiated in Sierra Leone, Liberia, and Guinea in 2015 [88, 89].

#### 12.2. Recombinant Vesicular Stomatitis Virus

from the infection [74]. Though this experimental drug was helpful during the outbreak, its therapeutic efficacy remained inconclusive since no randomized controlled clinical trial had

Another hopeful candidate drug that act by preventing viral replication is favipiravir (T-705), a pyrazinecarboxamide derivative which has shown to be effective against EBOV in in vitro and in vivo studies [76]. Also, a promising experimental drug for Ebola virus infection is BCX4430. This drug possesses antiviral activity for marburg, yellow and Ebola fever and it is also being tested for its ability to inhibit target enzymes in Ebola virus. BCX4430 has been shown to be effective in infected animals if the treatment was administered within 48 h after the infection [77]. Other therapeutic candidate drugs include RNA polymerase inhibitors as well as small interfering RNA nano particles that act as protein synthesis inhibitors. Studies in Ebola infected guinea pigs and non-human primate models showed small interfering RNAs agents

One of the major challenges for the availability of treatment against Ebola virus disease is the inconsistency and sporadic nature of the virus which has limited clinical trials in humans. In as much as several drug candidates have emerged and have been effective in pre-clinical studies, without clinical trials in humans, there is no guarantee that these experimental drugs can effectively treat infected patients. It is relevant for such trials to be conducted even though it remains difficult as the disease usually emerges periodically as outbreaks. Even though these challenges are limiting, efforts in identifying other potential drugs targets should be encouraged with emphasis on the key viral surface proteins as well as nucleoproteins involved in

Vaccines are one of the most effective means of managing viral infections especially for recurrent infections. This suggests that a vaccine for Ebola virus fever will be important for the management of the disease. Till date despite the several recurrent outbreaks of Ebola haemorrhagic fever, no licensed vaccine is available. However, several clinical trials are ongoing in Europe, United States, and West Africa, with preliminary findings on efficacy, and safety becoming available. These vaccine candidates are categorized as replication incompetent or non-replicative and replication competent vaccines [79]. Some of these vaccine candidates are

Adenoviruses are generally non-enveloped, double-stranded DNA viruses isolated from mammalian species. Following the deletion of the E1 region in their genome which renders the virus non-replicative, this property makes them suitable as recombinant vectors [80, 81]. Several Ebola vaccines that have been developed make use of a variety of recombinant Adenovirus serotypes which includes the human serotypes such as Ad26 and Ad35 and the

and gene-silencing drugs to protect against Ebola infections [78].

been conducted as of 2014 [74, 75].

140 Current Topics in Tropical Emerging Diseases and Travel Medicine

viral replication and pathogenesis.

summarized below.

12. Vaccine candidates undergoing trials

12.1. Recombinant adenovirus based vaccines

A recombinant Vesicular Stomatitis Virus (rVSV) was the first replicating Ebola virus vaccine developed in 2005. This vaccine was shown to provide 100% protection in non-human primates eliciting both humoral and cellular immune responses against lethal EBOV challenged animals [90]. Since then, eight human phase I trials of rVSV-EBOV vaccine has been conducted across Europe, North America and Africa. A phase III trial involving 7651 individuals to evaluate the efficacy of rVSV-ZEBOV showed a 100% vaccine efficacy after 6 days of vaccination [91]. These findings have shown that rVSV confers protection against Ebola between 6 and 21 days after vaccination [92].

Other potential vaccine candidates [35] which have initiated phase I clinical trials in 2015 include; EBOV GP Vaccine which is a recombinant nanoparticle vaccine using adjuvant Matrix-M. It is the first Ebola vaccine candidate based on the 2014 Guinea Ebola strain genetic sequence. DNA-EBOV is a multiagent filovirus DNA vaccine delivered into the body through intramuscular electroporation. Recombinant rabies EBOV is a chemically killed inactivated rabies virus virions containing EBOV glycoprotein.

Other forms of vaccine candidates include virus-like particle vaccines (VLPs). VLPs are produced by expressing certain viral proteins that mimics the conformation of natural Ebola virus in cells without any viral genetic material. EBOV VLPs have been produced by simultaneously expressing NP, GP, and VP40 proteins of EBOV in 293T cells. These particles when administered three times to NHPs in combination with Ribi adjuvant protected against EBOV [93, 94].

Following the recent Ebola outbreak in DRC, an experimental Ebola vaccine (rVSV-ZEBOV) developed by Merck, a German pharmaceutical company which is not yet licensed but was effective during the catastrophic Ebola epidemic of 2014 has been approved by WHO for vaccination. According to Peter Salama, WHO's deputy director-general for emergency, preparedness and response, 8000 individuals are expected to be vaccinated, thus, about 8000 dose are required with 4000 doses already deployed to DRC [95].

[3] Centers for Disease Control and Prevention. Ebola Virus Disease Information for Clinicians in U.S. Healthcare Settings. CDC USA Website. Available from: http://www.cdc.gov/ vhf/ebola/hcp/clinician-information-us-healthcaresettings.html#investigational-vaccines.

Ebola Virus Disease: Progress So Far in the Management of the Disease

http://dx.doi.org/10.5772/intechopen.79053

143

[4] World Health Organization. Ebola haemorrhagic fever in Sudan, 1976. Bulletin of the

[5] Baron RC, McCormick JB, Zubeir OA. Ebola virus disease in southern Sudan: Hospital dissemination and intrafamilial spread. Bulletin of the World Health Organization. 1983;

[6] Georges AJ, Leroy EM, Renaut AA, Benissan CT, Nabias RJ, Ngoc MT. Ebola haemorrhagic fever outbreaks in Gabon, 1994–1997: Epidemiologic and health control issues. The Journal

[7] Khan AS, Tshioko FK, Heymann DL, Le Guenno B, Nabeth P, Kerstiens B. The reemergence of Ebola hemorrhagic fever, Democratic Republic of the Congo, 1995. Commission de Lutte contre les Epid\_emies \_a Kikwit. The Journal of Infectious Diseases. 1999;179(1):S76-S86

[9] Pourrut X, Kumulungui B, Wittmann T, Moussavou G, D\_elicat A, Yaba P. Thenatural

[10] Towner JS, Sealy TK, Khristova ML, Albarino CG, Conlan S, Reeder SA. Newly discovered Ebola virus associated with hemorrhagic fever outbreak in Uganda. PLoS Pathogens.

[11] Albarino CG, Shoemaker T, Khristova ML, Wamala JF, Muyembe JJ, Balinandi S. Genomic analysis of filoviruses associated with four viral hemorrhagic fever outbreaks in Uganda

[12] Maganga GD, Kapetshi J, Berthet N, Ilunga BK, FK MD, Kingebeni PM. Ebola virus disease in the Democratic Republic of Congo. The New England Journal of Medicine.

[13] Centers for Disease Control and Prevention. Ebola Outbreak in West Africa Outbreak Distribution Map, CDC USA Website. 2014. Available from: http://www.cdc.gov/vhf/ ebola/outbreaks/2014-west-africa/distribution-map.html [Accessed: March 20, 2018]

[14] Chih-Peng T, Yu-Jiun C. Overview of Ebola virus disease in 2014. Journal of the Chinese

[15] Jahrling PB, Geisbert TW, Dalgard DW, Johnson ED, Ksiazek TG, Hall WC. Preliminary report: Isolation of Ebola virus from monkeys imported to USA. Lancet. 1990;335:502-505

[16] Feldmann H, Klenk HD. Filovirus. Medical Microbiology. 4th ed. Galveston (TX): Univer-

sity of Texas Medical Branch at Galveston; 1996. Chapter 72

and the Democratic Republic of the Congo in 2012. Virology. 2013;442:97-100

[8] Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2012;377:849-862

history of Ebola virus in Africa. Microbes and Infection. 2005;7:1005-1014

html#investigational-vaccines [Accessed: March 25, 2018]

World Health Organization. 1978;56:247-270

of Infectious Diseases. 1999;179(1):S65-S75

61:997-1003

2008;4:e1000212

2014;371:2083-2091

Medical Association. 2015;78:51-55
