Analysis BMJ Glob Health: first published as 10.1136/bmjgh-2018-001112 on 7 February 2019. Downloaded from Diagnostics for filovirus detection: impact of recent outbreaks on the diagnostic landscape Devy M Emperador,1 Laura T Mazzola,1 Betsy Wonderly Trainor,2 Arlene Chua,3 Cassandra Kelly-Cirino1 To cite: Emperador DM, ABSTRACT Summary box Mazzola LT, Wonderly Trainor B, Ebolaviruses and Marburg virus (MARV) both belong to et al. Diagnostics for filovirus the family Filoviridae and cause severe haemorrhagic ► Ebolaviruses and Marburg virus (MARV), both of the detection: impact of recent fever in humans. Due to high mortality rates and potential outbreaks on the diagnostic family Filoviridae, cause severe haemorrhagic fever for spread from rural to urban regions, they are listed landscape. BMJ Glob Health in humans and are considered high-priority patho- 2019;4:e001112. doi:10.1136/ on the WHO R&D blueprint of high-priority pathogens. gens by WHO; recent ebolavirus outbreaks in Western bmjgh-2018-001112 Recent ebolavirus outbreaks in Western and Central Africa and Central Africa have led to rapid development of a have highlighted the importance of diagnostic testing in number of diagnostic tests for ebolaviruses. epidemic preparedness for these pathogens and led to the Handling editor Dr Seye ► Despite these advancements, gaps in diagnostic Abimbola rapid development of a number of commercially available preparedness for ebolaviruses remain, including dif- benchtop and point-of-care nucleic acid amplification tests ficulties obtaining full regulatory approval for tests ► Additional material is as well as serological assays and rapid diagnostic tests. published online only. To view approved under emergency licenses, lack of incen- Despite these advancements, challenges still remain. While please visit the journal online tive to continue development after an outbreak is products approved under emergency use licenses during (http:// dx. doi. org/ 10. 1136/ over, poor specificity and sensitivity of some existing bmjgh- 2018- 001112). outbreak periods may continue to be used post-outbreak, tests, and a need for tests able to use different sam- a lack of clarity and incentive surrounding the regulatory ple types. approval pathway during non-outbreak periods has ► For MARV, availability of diagnostic tests is still lim- Received 14 August 2018 deterred many manufacturers from seeking full approvals. ited; target product profiles for ebolavirus diagnos- Revised 17 September 2018 Waning of funding and poor access to samples after the Accepted 22 September 2018 tics should be extended to include MARV and should 2014–2016 outbreak also contributed to cessation of consider persisting challenges to diagnostic pre- development once the outbreak was declared over. There paredness for ebolaviruses. is a need for tests with improved sensitivity and specificity, http://gh.bmj.com/ and assays that can use alternative sample types could reduce the need for invasive procedures and expensive equipment, making testing in field conditions more The virus family Filoviridae is divided into feasible. For MARV, availability of diagnostic tests is still three genera, Ebolavirus, Marburgvirus and limited, restricted to a single ELISA test and assay panels Cuevavirus. Within the ebolavirus genus are designed to differentiate between multiple pathogens. five species: Zaire ebolavirus (EBOV), Sudan It may be helpful to extend the target product profile for on September 28, 2021 by guest. Protected copyright. ebolavirus (SUDV), Bundibugyo ebolavirus, ebolavirus diagnostics to include MARV, as the viruses have many overlapping characteristics. Tai Forest ebolavirus (TAFV) and Reston ebolavirus. The marburgvirus genus consists of Marburg marburgvirus (MARV), including the MARV POPP, MARV Angola, MARV INTRODUCTION Durba, MARV Ozolin and MARV Musoke 2 3 © Author(s) (or their Ebolaviruses and Marburg virus (MARV) variants, and Ravn virus. employer(s)) 2019. Re-use belong to the viral family Filoviridae and can Since the first report in Sudan and Zaire permitted under CC BY. cause severe haemorrhagic fever in humans in 1976, ebolavirus disease (EVD) has caused Published by BMJ. and non-human primates. Filoviruses are more than 30 outbreaks in the subsequent 1FIND, Emerging Threats Programme, Geneva, filamentous, negative-sense RNA viruses, 40 years (figure 2). EVD is a lethal illness Switzerland with a genome that encodes seven structural with an average case fatality rate of 78%. 2FIND, Geneva, Switzerland proteins: nucleoprotein (NP), polymerase Marburg virus disease (MVD) was first iden- 3Médecins Sans Frontières cofactor (VP35), matrix protein (VP40), tified in 1967 during epidemics in Marburg (MSF), Geneva, Switzerland glycoprotein (GP), replication-transcription and Frankfurt in Germany and Belgrade in Correspondence to protein (VP30), minor matrix protein (VP24) the former Yugoslavia from the importation 4 Dr Cassandra Kelly-Cirino; and the non-structural protein RNA-de- of infected monkeys from Uganda. Similar cassandra. kelly@ finddx. org pendent RNA polymerase (L) (figure 1).1 to EVD, MVD has a very high case fatality Emperador DM, et al. BMJ Glob Health 2019;4:e001112. doi:10.1136/bmjgh-2018-001112 1 BMJ Global Health BMJ Glob Health: first published as 10.1136/bmjgh-2018-001112 on 7 February 2019. Downloaded from and 70% in Guinea, Liberia and Sierra Leone by 2016.5 The most recent outbreak is located in the Democratic Republic of Congo, with 137 total cases, 106 confirmed cases and 92 deaths (61 confirmed) reported as of 12 September 2018.6 The fruit bat is thought to be the native host for filo- viruses (although this has not been definitively demon- strated for ebolaviruses),7 with a large ecological reach ranging from West and Central Africa to Southeast Asia.8–13 Reports show a seasonality in filovirus transmis- sion to humans that may correspond with mating and birthing seasons of fruit bat species.14 15 Primates and other animals can also be infected and suffer disease, although their ability to serve as a reservoir for filoviruses is unknown.9 Filoviruses are primarily transmitted to humans Figure 1 Schematic illustration of filovirus particle and through close contact with blood, secretions, organs, or ebolavirus and MARV genomes. Reprinted from J Clin Virol, other bodily fluids of infected humans or animals.8 15–17 64, Rougeron V et al., Ebola and Marburg haemorrhagic They are commonly spread among family and friends of fever, 111–9. Copyright (2015), with permission from Elsevier. infected individuals, although nosocomial transmission, GP, glycoprotein; L, non-structural protein RNA-dependent 18 RNA polymerase; MARV, Marburg virus; NP, nucleoprotein, especially among healthcare workers, occurs. As seen in sGP, secreted glycoprotein; VP24, minor matrix protein; the 2014–2016 ebolavirus outbreak, an increase in popu- VP30, replication-transcription protein; VP35, polymerase lation size, the rise of urbanisation and the interconnect- cofactor; VP40, matrix protein. edness of travel can expand the spread of filovirus disease beyond endemic regions.19 Isolation of patients, proper use of personal protective equipment (PPE) and disinfec- rate, measuring just over 80% in some of the most recent tion procedures have been effective in reducing human- outbreaks. to-human transmission of EBOV and MARV.16 Sporadic outbreaks of EVD and MVD typically occur 4 The incubation period for EVD and MVD is between 2 and are limited to countries in sub-Saharan Africa. and 21 days, with an average of 3–10 days.8 Both ebolavi- However, in 2014, an outbreak of EBOV was detected ruses and MARV can be clinically detected in blood after in rural Guinea, near the border of Liberia and Sierra onset of fever, which accompanies the rise in circulating Leone, resulting in 28 616 total cases of EVD and 11 310 virus within the patient’s body and remains elevated in deaths in 10 countries, with a mortality rate between 30% individuals who progress to death, especially among http://gh.bmj.com/ those with EVD.20 Treatment options for EVD and MVD are limited and rely on supportive therapy.8 21 While there are no proven effective drug treatments for EVD or MVD, experimental therapies (ZMapp, brincidofovir, TKM-Ebola and favi- piravir) were used during the 2014–2016 ebolavirus on September 28, 2021 by guest. Protected copyright. outbreak to treat infected patients.21 22 A number of EVD pharmacotherapies and immunological-based agents have been or are currently undergoing accelerated human trials in EVD endemic countries, including favip- iravir and ZMapp; some may also be effective for MARV (although ZMapp is specific to ebolavirus).21–23 Two of the most promising EBOV vaccine candidates, rVSV-EBOV and ChAd3-EBO-Z, underwent phase II/III efficacy trials in Liberia, Sierra Leone and Guinea during the peak of the 2014–2016 epidemic, showing high effi- cacy and long-term antibody responses.24–26 Vaccines for MARV have not seen a similar accelerated development to EBOV, although animal and early clinical studies show Figure 2 Reported outbreaks or isolated cases of MARV potential for MARV vaccine immunogenicity and protec- and ebolaviruses. Reprinted from J Clin Virol, 64, Rougeron 2 27 28 V et al., Ebola and Marburg haemorrhagic fever, 111–9. tion. Copyright (2015), with permission from Elsevier. EBOV, Zaire Due to the sporadic nature of outbreaks, high mortality ebolavirus; MARV, Marburg virus; SUDV, Sudan ebolavirus; rates and potential spread from rural to urban regions, TAFV,