Feldmann H, Sprecher A, and Geisbert TW. N Engl J Med. 2020;382:1832–1842
Ebola virus (EBOV) was the best-known and most extensively studied member of the Filoviridae family (Mononegavirales order), long before the 2013–2016 West African epidemic. Today, EBOV refers to the specific member virus of the type species Zaire ebolavirus in the genus ebolavirus. Current concepts on virology, epidemiology, disease, pathogenesis, diagnosis, treatment and prevention are included in this review.
The history of filoviruses largely involves human outbreaks. Marburg virus (MARV) was the first filovirus to be discovered in 1967. EBOV and Sudan virus (SUDV) were codiscovered in 1976 in the Democratic Republic of Congo (DRC) and South Sudan, respectively. Subsequently, 2 additional ebolaviruses were found to be pathogenic in humans: Tai Forest virus (TAFV) in Cote d’Ivoire in 1994 and Bundibugyo virus (BDBV) in Uganda in 2007. Reston virus (RESTV) imported into the United States from the Philippines in 1989–1990, has long been the exception, since it appears to infect humans only subclinically.
More recently, genomes of new filoviruses were detected in bat and fish species. Lloviu virus (LLOV) genus cuevavirus was sequenced from bats (Miniopterus schreibersii) in Spain and Hungary. Mengla virus (MLAV) sequences were found in Chinese rousettus species representing the newly proposed genus, dianlovirus. Bombali virus (BOMV) sequences were discovered in bats from Sierra Leone, Guinea and Kenya: the virus is considered to be a new ebolavirus species. Finally, fish-derived filoviruses constitute members of 2 new genera, striavirus and thamnovirus. Since no isolates are available, the unknown zoonotic and pathogenic potential of these new filoviruses is a public health concern.
Epizootic and endemic viruses circulate in animals and humans, respectively, but this has not been convincingly shown for any filovirus. The frequent reemergence of EBOV in the DRC and Gabon around 2000 and that of MARV in Uganda a decade later supports the hypothesis that these filoviruses are regionally epizootic. The discovery of EBOV persistence in humans may indicate a potential to circulate temporarily in persons. Currently, however, neither EBOV nor other filoviruses can be considered to be endemic anywhere; if they were, continuing human-to-human transmission could result.
The clinical disease is no longer referred to as Ebola or Marburg hemorrhagic fever but rather as Ebola or Marburg virus disease (EVD or MVD), which better reflects the variable symptoms and downplays bleeding as a clinical hallmark. Initially, infection is manifested as a nonspecific febrile illness characterized by malaise, fatigue and myalgia. A few days later, gastrointestinal manifestations develop in many patients, with anorexia, nausea, vomiting and diarrhea. Fluid losses can be substantial. Other common signs and symptoms include dysphagia, headache, conjunctival injection, abdominal pain, arthralgia and a maculopapular rash. Bleeding manifestations occur in less than half of affected patients.
During the 2013–2016 EBOV epidemic, musculoskeletal pain, headache, encephalitis and ocular problems were noted in survivors and were referred to collectively as the “post-Ebola syndrome.” Historically, filoviruses have been detected in multiple body fluids, including breast milk and semen, in survivors of infection. The persistence in semen, with the potential for sexual transmission more than 500 days after disease onset, is a serious concern. However, transmission this long after disease onset is very rare, with undetermined effects.
In the recent Ebola outbreak in the DRC, 4 investigational drugs, the monoclonal-antibody cocktails ZMapp (Mapp Biopharmaceutical, San Diego, CA) and REGN-EB3 (Regeneron Pharmaceuticals, Eastview, NY), a single monoclonal antibody (MAb114, Ridgeback Biotherapeutics, Miami, FL) and remdesivir (Gilead Sciences, Foster City, CA), a small-molecule antiviral drug, have been given to hundreds of patients under the Monitored Emergency Use of Unregistered and Investigational Interventions (MEURI) framework and in a randomized, clinical trial. The interim results of the Pamoja Tulinde Maisha (PALM) trial suggested significantly improved survival for patients receiving MAb114 or REGN-EB3, compared with those receiving remdesivir or ZMapp. Patients receiving care and treatment earlier in the course of illness fared better than those who entered Ebola treatment units later, and those in whom EVD developed despite previous vaccination for EBOV had much better outcomes than patients who had not been vaccinated.
Comment: Vaccine development started in the 1970s with inactivated viral preparations and was followed in the 1980s and 1990s by subunit and DNA vaccine approaches. One of the approaches is a single-shot, live-attenuated, vectored vaccine based on a recombinant vesicular stomatitis virus expressing the Zaire ebolavirus glycoprotein (rVSV-ZEBOV-GP) (ERVEBO, Merck, Kenilworth, NJ), which was successfully tested for efficacy in a randomized trial in Guinea during the West African epidemic. The vaccine, which was approved by the European Medicines Agency and the U.S. Food and Drug Administration, has been widely administered in the DRC EBOV outbreak, with promising preliminary results.
Advances in the development of other vaccines, such as the chimpanzee adenovirus 3 vaccine (ChAd3-EBO-Z, GlaxoSmithKline, Brentford, London) and the heterologous prime-boost regimen containing the Janssen AdVac for priming followed by Bavarian Nordic modified vaccinia Ankara (MVA-BN) technologies for boosting (Johnson & Johnson, New Brunswick, NJ) are closing the gap between investigational and clinical use.
