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While the pursuit of antivirals for Ebola virus is important and necessary, the gold standard for protection against any viral disease is vaccination. The quest for a vaccine against Ebola virus is an active area of investigation by many laboratories. Some of the ongoing approaches being employed to develop an effective vaccine for Ebola virus are highlighted below. 7.7.1 Replicons
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The use of viral replicons has been explored as a strategy for developing an Ebola virus vaccine. The ef cacy of replicon-based vaccines seems to be dependent on dosing, viral proteins utilized, and the animal choice of study. A replicon system based on the alphavirus Venezuelan equine encephalitis (VEE) virus is one of the best characterized. An important advantage of this replicon is that most animal populations have no preexisting immunity to VEE, and sequential immunization with the replicon does not induce VEE-speci c antibodies.126 In addition, VEE replicon particles (VRPs) have been shown to target expression of genes to the lymph nodes and to antigen-presenting dendritic cells, thereby inducing high levels of mucosal and cell-mediated immunity.127
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Most studies involving VRP vaccination have examined the ability of lovirus GP and/or NP to elicit protective immune responses. For example, a study by Hevey and colleagues demonstrated that a VRP expressing Marburg virus GP conveyed complete protection to cynomolgus monkeys infected with Marburg virus. Furthermore, enhanced levels of protection were observed when NP was also expressed.128 When a similar VRP-vaccination strategy was employed for Ebola virus, although VRPs expressing Ebola GP and/or NP were protective in rodents lethally challenged with Ebola virus,129 the vaccine was not protective in cynomolgus monkeys.18 This nding suggests that pathogenesis of Marburg and Ebola virus infection differs, perhaps with regard to infection course, tropism, and/or host responses. In a separate study, a bivalent VRP vaccine composed of the viral glycoproteins of both Lassa virus and Ebola virus proved to be protective in guinea pigs lethally challenged with Ebola virus. It should be noted that the vaccinated animals that did succumb to disease had no virus in their tissues upon post mortem analysis.130 Additional viral proteins, such as VP24, VP40, VP30, and VP35, have been explored as possible vaccine candidates. For example, VRPs expressing VP24 proved to be the best candidate to induce protection in BALB/c mice, with VP40 and VP30 yielding protection levels between 55% and 85% depending on dose numbers. In contrast, VP35 was the only protein offering protection in C57BL/6 mice.131 Recombinant vaccinia viruses expressing NP, VP35, VP40, or VP24 did not elicit protection in guinea pigs lethally challenged with Ebola virus.132,133 As the development of these types of vaccination strategies proceeds, it will be important to keep in mind that primate models remain essential for evaluation of these therapies for humans.
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DNA vaccines represent another approach to elicit protection against Ebola virus. Plasmids encoding either Ebola virus GP, or NP, were shown to be protective in lethally challenged mice and guinea pigs.134,135 Working to improve the ef cacy of current replicon-based vaccination strategies, two groups have combined DNA vaccination with replicon administration in a prime boost manner. Sullivan and colleagues were successful in protecting macaques from challenge by administering a GP-expressing plasmid rst, followed by a boost with a GP-expressing adenoviral vector. Indeed, high antibody titers and increased cytotoxic T-lymphocyte (CTL) responses were observed in fully protected animals.136 A safety study involving 27 volunteers is underway for an initial evaluation of DNA primer vaccines in human subjects.137 Most recently, it was determined that immunization of nonhuman primates with only the adenoviral component (ADV-GP or ADV-NP) of this prime boost strategy induced a more rapid antibody response in animals, albeit less immunologically potent. Nonetheless, animals were protected against lethal challenge with virus.138 The rapidity of this vaccination strategy makes it an attractive candidate for the containment of sudden outbreaks of Ebola virus.
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