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Update to Chapter 234: Ebolavirus and Marburgvirus

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There have been efforts to create a vaccine against Ebola virus ever since it was identified as a devastating cause of viral hemorrhagic fever in 1976. Although numerous outbreaks occurred and ~1600 people died between 1976 and 2014, the more recent 2014 outbreak of Ebola—which claimed ~11,000 lives in Africa and triggered fear of the disease throughout the world—provided the political, economic, and scientific landscape necessary to finalize development and human testing of an Ebola vaccine.

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Henao-Restrepo and colleagues (2016), working in Guinea, tested the efficacy of a recombinant, replication-competent, vesicular stomatitis virus–based vaccine that expresses a surface glycoprotein of Zaire Ebola virus (rVSV-ZEBOV). Given that this trial took place at the tail end of the outbreak when the incidence of disease was low and decreasing, the authors used a novel trial design based on identifying clusters (or rings) of at-risk individuals in order to generate robust data. After an index case was identified, the authors enumerated contacts (e.g., household members, unprotected caregivers) and contacts of contacts (e.g., neighbors of the index case, household members of high-risk contacts) to define a cluster of at-risk individuals. At the start of the trial, clusters were randomized (1:1) to immediate or delayed (21 days later) vaccination with a single IM dose of rVSV-ZEBOV. The primary endpoint was a laboratory-confirmed case of Ebola with onset ≥10 days after randomization; this delay of at least 10 days was chosen to account for the incubation period of disease, the delay between onset of symptoms and laboratory confirmation, and the lag period between vaccination and vaccine-induced immunity. In all, 51 clusters (2119 patients) were randomized to immediate vaccination, while 47 clusters (2041 patients) received delayed vaccination. There were no cases of Ebola virus disease in the immediate-vaccination clusters, whereas there were 16 cases (7 affected clusters) in the delayed-vaccination clusters [vaccine efficacy, 100%; 95% confidence interval (CI), 68.9–100; p = .0045].

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On the basis of an interim analysis, the data and safety monitoring board recommended that randomization be discontinued. An additional 19 nonrandomized clusters (1677 patients, including 194 children age 6–17 years) were immediately vaccinated with rVSV-ZEBOV; none of these patients developed Ebola virus disease. Data from all 117 randomized and nonrandomized clusters showed that rVSV-ZEBOV was 100% efficacious (95% CI, 79.3–100; p = .0033) in preventing disease ≥10 days after vaccination.

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Of patients receiving the vaccine, 54% reported at least one adverse event, of which 87.5% were mild, 11% moderate, and 1.2% severe; half of the severe events were the development of Ebola virus disease within 10 days of randomization. Headache, fatigue, and muscle pain were the most commonly reported adverse events.

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Perspective: This study provides convincing evidence that rVSV-ZEBOV is effective in humans against the 2014 outbreak strain of Ebola virus. More broadly, this vaccine provides a general scaffold that can likely be modified (e.g., by alteration of the surface glycoprotein) as needed during future outbreaks of Ebola virus infection, which will almost certainly occur. Furthermore, the novel study design using a ring vaccination approach may be useful in the evaluation of vaccines for other emerging and/or re-emerging infectious diseases. Although this vaccine was ultimately effective and may have contributed to the end of the outbreak in Guinea, it should be noted that this vaccine had been proved to be efficacious in multiple animal models, including nonhuman primates (Jones et al, 2005), a decade earlier. It could be argued that the 2014 outbreak might have been averted earlier had these findings been pursued sooner. It is to be hoped that the death of thousands of people in the first year of this outbreak will serve as a wake-up call to governments, funding agencies, and pharmaceutical companies regarding the critical need to continue the basic and translational science necessary to protect the world's population from these “infections of mass destruction.”

References +
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Henao-Restrepo  AM  et al.: Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: Final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!). Lancet, 2016
[PubMed: 28017403]
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Jones  SM  et al.: Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses. Nat Med 11:786, 2005
[PubMed: 15937495]