Ebola vaccines: One species down, three to go

Issue: April 2020

ByKati Shihadeh, PharmD, BCIDP

ByBriana Williams, PharmD

Ebola virus was first discovered in 1976 near the Ebola River in Zaire, Africa, an area now known as the Democratic Republic of the Congo (DRC). Two consecutive outbreaks of fatal hemorrhagic fever in two separate regions of Central Africa prompted the discovery of two genetically distinct viruses: Zaire ebolavirus and Sudan ebolavirus. Upon discovery, scientists concluded that the viruses, while similar, actually came from two separate sources and spread independently to people in each of the affected areas.

Epidemiologic data suggest that the virus has been around for much longer. It is postulated that the likely cause for the emergence of disease was growth in population, encroachment into forested areas and direct interaction with wildlife (such as consuming bushmeat). The African fruit bat is known to be involved in the spread of the virus and may be the reservoir host because they are able to effectively replicate the virus and survive infection, although this has yet to be confirmed.

Microbiology and transmission

The Ebolavirus is a member of the family Filoviridae in the order Mononegavirales. There are six known species within the genus Ebolavirus, but only four are known to infect humans: Zaire ebolavirus, Sudan ebolavirus, Taï Forest ebolavirus and Bundibugyo ebolavirus.

The virus is thought to be initially transmitted to humans from infected animals such as the African fruit bat and nonhuman primates. Once a human is infected with the virus, it is spread from human to human through blood or body fluids, including urine, saliva, sweat, feces, vomit, breast milk and semen.

Clinical presentation

The onset of disease after the incubation period is typically abrupt and can be categorized into four phases of disease. Phase 1 typically begins with influenza-like symptoms, also known as “dry symptoms,” which include fever, fatigue, headache, nausea and myalgias. Phase 2 is the acute phase, which lasts about 6 days and includes the “wet symptoms” of profuse diarrhea, vomiting and unexplained bleeding, which are the hallmark symptoms associated with the disease. Phase 3 is pseudoremission, in which the person starts feeling improvement in symptoms and, in some cases, people may completely recover and survive. Many people, however, progress to phase 4, in which the disease worsens, and other symptoms arise, including skin manifestations such as petechiae and purpura; respiratory symptoms such as cough, dyspnea and hiccups; and cardiovascular manifestations, including hypovolemic shock.

Treatment

There are currently no FDA-approved treatments for Ebola virus disease (EVD). The disease is managed symptomatically with electrolyte and fluid replacement, along with blood pressure and oxygen support. There are various monoclonal antibody medications currently being evaluated in clinical trials that have promising preliminary results for treatment of EVD.

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Prevention

In December 2019, the first FDA-approved vaccine for Zaire bolavirus was approved for adults aged 18 years or older, marketed under the trade name Ervebo (Merck). This is a live, recombinant, vesicular stomatitis vaccine expressing the glycoprotein of Zaire ebolavirus. It has not been demonstrated to protect against any other Ebolavirus species. It is administered as a one-time, 1 mL intramuscular injection.

Soon after the development of the vaccine, a phase 3 efficacy trial in Guinea was conducted that ultimately provided sufficient evidence for the vaccine to gain FDA approval. It was designed as a ring vaccination, cluster-randomized controlled study in which participants were identified based on their epidemiologically linked encounters to people infected with EVD. A list of all contacts and contacts of contacts of an index case were compiled and included individuals who lived in the same household, visited or were visited by the index case after the onset of symptoms, provided him or her with unprotected care, or prepared the body for the traditional funeral ceremony. Clusters were initially randomly assigned to immediate vaccination or vaccination delayed by 21 days. However, interim analysis showed 100% vaccine efficacy, and 4 months into the trial, the delayed vaccination arm was discontinued. All participants thereafter received the vaccine immediately if they met inclusion criteria.

Participants were initially included if they were a contact or contact of contacts of the index patient and were aged 18 years or older. After randomization was stopped, children aged 6 to 17 years were also included in the trial. Participants were excluded if they had a history of EVD (self-declared or laboratory confirmed), were pregnant or breastfeeding, received other experimental treatments within the past 28 days, experienced anaphylaxis to a vaccine or had a serious illness requiring hospital admission. The primary outcome was a laboratory-confirmed case of EVD with onset 10 or more days from randomization. The trial compared the incidence of EVD in vaccinated individuals in the immediate arm vs. individuals who were randomly assigned to the delayed arm.

The randomized portion of the trial included 2,119 individuals in the immediate vaccination arm and 2,041 individuals in the delayed vaccination arm. Ten or more days after randomization, there were no cases of EVD in the immediate vaccination arm compared with 16 cases in the delayed vaccination arm, for a vaccine efficacy of 100% (95% CI, 68.9%-100%). In the nonrandomized portion of the trial, 1,677 participants, including 194 children, were immediately vaccinated, and there were no cases of EVD 10 days or more after vaccination. In total, 5,837 participants received the vaccine and were followed for 84 days. Of them, 53.9% of participants reported at least one adverse event in the 14 days following the vaccination, which were mostly mild, consisting of headache, fatigue and muscle pain. Eighty serious adverse events were identified, with two events related to the vaccine: febrile reaction and anaphylaxis.

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Overall, the trial showed that the vaccine was 100% effective with a low risk for adverse events when it is administered immediately to people with recent contact to individuals infected with Zaire ebolavirus. The vaccine also was widely used during the most recent outbreak in the DRC, where it was shown to be more than 97% effective in a preliminary estimate published by WHO.

The durability of the vaccine and whether another dose is required sometime in the future to maintain immunity is currently unknown. In the United States, the CDC’s Advisory Committee on Immunization Practices voted unanimously in February to recommend that healthy adults at occupational risk for Ebola receive the vaccine.

Research

More research is needed to further characterize the safest and most effective use of Ervebo and determine if it can be safely used in special populations such as children and pregnant or breastfeeding women. Additionally, there are three other identified species of Ebolavirus known to infect humans that do not have an approved vaccine. The other species are known to carry a high mortality rate as well, but Zaire ebolavirus, which has caused the most damage recently, now has an effective vaccine.

References:
CDC. Ebola virus disease (EVD) information for clinicians in U.S. healthcare settings. https://www.cdc.gov/vhf/ebola/clinicians/evd/clinicians.html. Accessed January 26, 2020.
CDC. History of Ebola virus disease. https://www.cdc.gov/vhf/ebola/history/summaries.html. Accessed January 26, 2020.
CDC. Signs and symptoms. https://www.cdc.gov/vhf/ebola/symptoms/index.html. Accessed January 26, 2020.
CDC. Transmission. https://www.cdc.gov/vhf/ebola/transmission/index.html. Accessed January 26, 2020.
CDC. What is Ebola virus disease? https://www.cdc.gov/vhf/ebola/about.html. Accessed January 26, 2020.
FDA. First FDA-approved vaccine for the prevention of Ebola virus disease, marking a critical milestone in public health preparedness and response. https://www.fda.gov/news-events/press-announcements/first-fda-approved-vaccine-prevention-ebola-virus-disease-marking-critical-milestone-public-health.
Henao-Restrepo AM, et al. Lancet. 2017;10.1016/S0140-6736(16)32621-6.
Kaner J, Schaack S. Global Health. 2016;doi:10.1186/s12992-016-0194-4.
Sullivan N, et al. J Virol. 2003;doi:10.1128/jvi.77.18.9733-9737.2003.
Rewar S, Mirdha D. Ann Glob Health. 2014;doi:10.1016/j.aogh.2015.02.005.
WHO. Preliminary results on the efficacy of rVSV-ZEBOV-GP Ebola vaccine using the ring vaccination strategy in the control of an Ebola outbreak in the Democratic Republic of the Congo. https://www.who.int/csr/resources/publications/ebola/ebola-ring-vaccination-results-12-april-2019.pdf. Accessed March 31, 2020.

For more information:
Briana Williams, PharmD, is a PGY-1 pharmacy resident at Denver Health Medical Center.
Kati Shihadeh, PharmD, BCIDP, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. Shihadeh can be reached at katherine.shihadeh@dhha.org.

Disclosures: Shihadeh and Williams report no relevant financial disclosures.

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