The virus can be transmitted by exposure to one species offruit bats or it can be transmitted between people via body fluids through unprotected sex and broken skin. The disease can causehaemorrhage, fever, and other symptoms similar toEbola, which belongs to the same family of viruses. According to the WHO, there are no approved vaccines or antiviral treatment for Marburg, but early, professional treatment of symptoms such as dehydration considerably increases survival chances.[7]
Marburg virus was first described in 1967.[12] It was discovered that year during a set of outbreaks of Marburg virus disease in the German cities ofMarburg andFrankfurt and the Yugoslav capitalBelgrade. Laboratory workers were exposed to tissues of infectedgrivet monkeys (the African green monkey,Chlorocebus aethiops) at theBehringwerke [de], a major industrial plant in Marburg which was then part ofHoechst, and later part ofCSL Behring. During the outbreaks, thirty-one people became infected and seven of them died.[13]
The virus is one of two members of the speciesMarburgvirus, which is included in the genusMarburgvirus, familyFiloviridae, and orderMononegavirales. The name Marburgvirus is derived fromMarburg (the city inHesse, Germany, where the virus was first discovered) and thetaxonomic suffixvirus.[1]
Marburgvirus was first introduced under this name in 1967.[12] The virus name was changed to Lake Victoria marburgvirus in 2005, confusingly making the only difference in distinguishing between a Marburgvirus organism and its species as a whole italicization, as inLake Victoria marburgvirus.[14][15][16] Still, most scientific articles continued to use the name Marburgvirus. Consequently, in 2010, the name Marburgvirus was reinstated and the species name changed.[1]
Like allmononegaviruses, marburg virions contain non-infectious, linear nonsegmented, single-strandedRNAgenomes of negative polarity that possess inverse-complementary 3' and 5' termini, do not possess a5' cap, are notpolyadenylated, and are notcovalently linked to aprotein.[17] Marburgvirus genomes are approximately 19kbp long and contain sevengenes in the order3'-UTR-NP-VP35-VP40-GP-VP30-VP24-L-5'-UTR.[18]
Micrograph of the Marburg virusesColorized electron micrograph of a Marburg virus
Like allfiloviruses, marburgvirions are filamentous particles that may appear in the shape of a shepherd's crook or in the shape of a "U" or a "6", and they may be coiled, toroid, or branched.[18] Marburgvirions are generally 80 nm inwidth, but vary somewhat in length. In general, the median particle length of marburgviruses ranges from 795 to 828 nm (in contrast toebolavirions, whose median particle length was measured to be 974–1,086 nm), but particles as long as 14,000 nm have been detected in tissue culture.[19]
Marburgvirions consist of seven structural proteins. At the center is thehelicalribonucleocapsid, which consists of the genomic RNA wrapped around apolymer ofnucleoproteins (NP). Associated with the ribonucleoprotein is theRNA-dependent RNA polymerase (L) with the polymerase cofactor (VP35) and a transcription activator (VP30). The ribonucleoprotein is embedded in a matrix, formed by the major (VP40) and minor (VP24) matrix proteins. These particles are surrounded by alipid membrane derived from the host cell membrane. The membrane anchors a glycoprotein (GP1,2) that projects 7 to 10 nm spikes away from its surface. While nearly identical to ebolavirions in structure, marburgvirions areantigenically distinct.[20]
Niemann–Pick C1 (NPC1) cholesterol transporter protein appears to be essential for infection with bothEbola and Marburg virus. Two independent studies reported in the same issue ofNature showed thatEbola virus cell entry and replication requires NPC1.[21][22] When cells from patients lacking NPC1 were exposed to Ebola virus in the laboratory, the cells survived and appeared immune to thevirus, further indicating that Ebola relies on NPC1 to enter cells. This might imply that genetic mutations in the NPC1 gene in humans could make some people resistant to one of the deadliest known viruses affecting humans. The same studies described similar results with Marburg virus, showing that it also needs NPC1 to enter cells.[21][22] Furthermore, NPC1 was shown to be critical tofilovirus entry because it mediates infection by binding directly to theviral envelope glycoprotein[22] and that the second lysosomal domain of NPC1 mediates this binding.[23]
In one of the original studies, asmall molecule was shown to inhibit Ebola virus infection by preventing the virus glycoprotein from binding to NPC1.[22][24] In the other study, mice that were heterozygous for NPC1 were shown to be protected from lethal challenge with mouse-adapted Ebola virus.[21]
The Marburg viruslife cycle begins with virion attachment to specific cell-surfacereceptors, followed byfusion of the virion envelope with cellular membranes and the concomitant release of the virusnucleocapsid into thecytosol.[25]
Thevirus RdRp partially uncoats the nucleocapsid andtranscribes thegenes into positive-strandedmRNAs, which are thentranslated into structural and nonstructuralproteins. Marburgvirus L binds to a singlepromoter located at the 3' end of the genome. Transcription either terminates after a gene or continues to the next gene downstream. This means that genes close to the 3' end of the genome are transcribed in the greatest abundance, whereas those toward the 5' end are least likely to be transcribed. The gene order is therefore a simple but effective form of transcriptional regulation.[25]
The most abundant protein produced is thenucleoprotein, whoseconcentration in the cell determines when L switches from gene transcription to genome replication. Replication results in full-length, positive-stranded antigenomes that are in turn transcribed into negative-stranded virus progeny genome copies. Newly synthesized structural proteins and genomes self-assemble and accumulate near the inside of thecell membrane. Virionsbud off from the cell, gaining their envelopes from the cellular membrane they bud from. The mature progeny particles then infect other cells to repeat the cycle.[14]
In 2009, the successful isolation of infectious MARV was reported from caught healthyEgyptian fruit bats (Rousettus aegyptiacus).[26] This isolation, together with the isolation of infectiousRAVV,[26] strongly suggests thatOld World fruitbats are involved in the natural maintenance of marburgviruses. Further studies are necessary to establish whetherEgyptian rousettes are the actual hosts of MARV and RAVV or whether they get infected via contact with another animal and therefore serve only as intermediate hosts. In 2012 the first experimental infection study ofRousettus aegyptiacus with MARV provided further insight into the possible involvement of these bats in MARV ecology.[27]
Experimentally infected bats developed relatively low viremia lasting at least five days, but remained healthy and did not develop any notable gross pathology. The virus also replicated to high titers in major organs (liver and spleen), and organs that might possibly be involved in virus transmission (lung, intestine, reproductive organs, salivary gland, kidney, bladder, and mammary gland). The relatively long period of viremia noted in this experiment could possibly also facilitate mechanical transmission by blood sucking arthropods in addition to infection of susceptible vertebrate hosts by direct contact with infected blood.[27]
The viral strains fall into two clades: Ravn virus and Marburg virus.[28] The Marburg strains can be divided into two: A and B. The A strains were isolated fromUganda (five from 1967),Kenya (1980) andAngola (2004–2005) while the B strains were from theDemocratic Republic of the Congo epidemic (1999–2000) and a group of Ugandan isolates isolated in 2007–2009.[25]
The mean evolutionary rate of the whole genome was 3.3 × 10−4 substitutions/site/year (credibility interval 2.0–4.8). The Marburg strains had a mean root time of the most recent common ancestor of 177.9 years ago (95% highest posterior density 87–284) suggesting an origin in the mid 19th century. In contrast, the Ravn strains origin dated back to a mean 33.8 years ago (the early 1980s). The most probable location of the Marburg virus ancestor was Uganda whereas that of the RAVV ancestor was Kenya.[28]
MARV is one of two Marburg viruses that causesMarburg virus disease (MVD) in humans (in the literature also often referred to as Marburg hemorrhagic fever, MHF). The other one isRavn virus (RAVV). Both viruses fulfill the criteria for being a member of the speciesMarburg marburgvirus because theirgenomes diverge from the prototype Marburg marburgvirus or the Marburg virus variant Musoke (MARV/Mus) by <10% at thenucleotide level.[1]
Two different marburgviruses, MARV and Ravn virus (RAVV), cocirculated and caused disease. The number of cases and deaths due to MARV or RAVV infection have not been reported.[45][46][47]
The Guinean government detected the case from a sample of patients who died on August 2, 2021, in the southern prefecture of Gueckedou near the country's borders with Sierra Leone and Liberia.[61][62][63]
Four cases have been reported so far with preparations for a possible outbreak being made. On 17 July 2022, two cases were confirmed by Ghana,[64] with two more being subsequently confirmed on 27 July 2022.[65]
The Marburg virus is transmitted through the exchange of bodily fluids and through smear infection or contact infection. Virus particles remain infectious in clotted blood for a period of 4–5 days. In convalescent patients, the virus can remain in a pathogenic form in certain parts of the body, particularly in immunologically privileged sites such as the anterior chamber of the eye and in seminal fluid, where it can still be recovered several months after the acute infection has subsided. Survivors of Marburg virus infection should be advised and provided with condoms. As with many similar virusses, viral transmission can be reduced by taking suitableinfection prevention and control measures, such as effective identification, cleaning, case isolation, contact tracing and monitoring, using protective clothing, perform safe waste disposal and safe funeral practices for those killed by the disease.[78][79]
The first clinical study testing the efficacy of a Marburg virus vaccine was conducted in 2014. The study tested a DNA vaccine and concluded that individuals inoculated with the vaccine exhibited some level of antibodies. However, these vaccines were not expected to provide definitive immunity.[80] Several animal models have shown to be effective in the research of Marburg virus, such as hamsters, mice, and non-human primates (NHPs). Mice are useful in the initial phases of vaccine development as they are ample models for mammalian disease, but their immune systems are still different enough from humans to warrant trials with other mammals.[81] Of these models, the infection in macaques seems to be the most similar to the effects in humans.[82] A variety of other vaccines have been considered. Virus replicon particles (VRPs) were shown to be effective in guinea pigs, but lost efficacy once tested on NHPs. Additionally, an inactivated virus vaccine proved ineffective. DNA vaccines showed some efficacy in NHPs, but all inoculated individuals showed signs of infection.[83]
Because Marburg virus and Ebola virus belong to the same family, Filoviridae, some scientists have attempted to create a single-injection vaccine for both viruses. This would both make the vaccine more practical and lower the cost for developing countries.[84] Using a single-injection vaccine has shown to not cause any adverse reactogenicity, which the possible immune response to vaccination, in comparison to two separate vaccinations.[80]
There is a candidate vaccine against the Marburg virus calledrVSV-MARV. It wasdeveloped alongside vaccines for closely-related Ebolaviruses by the Canadian government in the early 2000s, twenty years before the outbreak. Production and testing of rVSV-MARV is blocked by legal monopolies held by theMerck Group. Merck acquired rights to all the closely related candidate vaccines in 2014, but declined to work on most of them, including the Marburg vaccine, for economic reasons. While Merck returned the rights to the abandoned vaccines to the Public Health Agency of Canada, the vital rVSV vaccine production techniques which Merck had gained (while bringing the closely relatedrVSV-ZEBOV vaccine into commercial use in 2019, withGAVI funding) remain Merck's, and cannot be used by anyone else wishing to develop a rVSV vaccine.[85][86][87][88]
As of June 23, 2022, researchers working with thePublic Health Agency of Canada conducted a study which showed promising results of a recombinant vesicular stomatitis virus (rVSV) vaccine in guinea pigs, entitled PHV01. According to the study, inoculation with the vaccine approximately one month prior to infection with the virus provided a high level of protection.[89]
Even though there is much experimental research on Marburg virus, there is still no prominent vaccine. Human vaccination trials are either ultimately unsuccessful or are missing data specifically regarding Marburg virus.[90] Due to the cost needed to handle Marburg virus at qualified facilities, the relatively few number of fatalities, and lack of commercial interest, the possibility of a vaccine has simply not come to fruition[91] (see alsoeconomics of vaccines).
As most performed research was highlyclassified, it remains unclear how successful the MARV program was. However, SovietdefectorKen Alibek claimed that a weapon filled with MARV was tested at theStepnogorsk Scientific Experimental and Production Base inStepnogorsk,Kazakh Soviet Socialist Republic (todayKazakhstan),[92] suggesting that the development of a MARV biological weapon had reached advanced stages. Independent confirmation for this claim is lacking. At least one laboratory accident with MARV, resulting in the death of Koltsovo researcher Nikolai Ustinov, occurred during the Cold War in the Soviet Union and was first described in detail by Alibek.[92]
^abcSiegert R, Shu HL, Slenczka W, Peters D, Müller G (December 1967). "[On the etiology of an unknown human infection originating from monkeys]".Deutsche Medizinische Wochenschrift.92 (51):2341–2343.doi:10.1055/s-0028-1106144.PMID4294540.S2CID116556454.
^abFeldmann H, Geisbert TW, Jahrling PB, Klenk H, Netesov SV, Peters CJ, et al. (2005). "Family Filoviridae". In Fauquet CM, Mayo MA, Maniloff J, Desselberger U, Ball LA (eds.).Virus Taxonomy—Eighth Report of the International Committee on Taxonomy of Viruses. San Diego, US: Elsevier/Academic Press. pp. 645–653.ISBN978-0-12-370200-5.
^Pringle CR (2005). "Order Mononegavirales". In Fauquet CM, Mayo MA, Maniloff J, Desselberger U, Ball LA (eds.).Virus Taxonomy—Eighth Report of the International Committee on Taxonomy of Viruses. San Diego, US: Elsevier/Academic Press. pp. 609–614.ISBN978-0-12-370200-5.
^Stille W, Böhle E, Helm E, van Rey W, Siede W (March 1968). "[On an infectious disease transmitted by Cercopithecus aethiops. ("Green monkey disease")]".Deutsche Medizinische Wochenschrift.93 (12):572–582.doi:10.1055/s-0028-1105099.PMID4966281.S2CID260058558.
^Bonin O (May 1969). "The Cercopithecus monkey disease in Marburg and Frankfurt (Main), 1967".Acta Zoologica et Pathologica Antverpiensia.48:319–331.PMID5005859.
^Jacob H, Solcher H (July 1968). "[An infectious disease transmitted by Cercopithecus aethiops ("marbury disease") with glial nodule encephalitis]".Acta Neuropathologica.11 (1):29–44.doi:10.1007/bf00692793.PMID5748997.S2CID12791113.
^Gear JH (March 1977). "Haemorrhagic fevers of Africa: an account of two recent outbreaks".Journal of the South African Veterinary Association.48 (1):5–8.PMID406394.
^Conrad JL, Isaacson M, Smith EB, Wulff H, Crees M, Geldenhuys P, Johnston J (November 1978). "Epidemiologic investigation of Marburg virus disease, Southern Africa, 1975".The American Journal of Tropical Medicine and Hygiene.27 (6):1210–1215.doi:10.4269/ajtmh.1978.27.1210.PMID569445.
^Nikiforov VV, Turovskiĭ I, Kalinin PP, Akinfeeva LA, Katkova LR, Barmin VS, et al. (1994). "[A case of a laboratory infection with Marburg fever]".Zhurnal Mikrobiologii, Epidemiologii I Immunobiologii (3):104–106.PMID7941853.
^Bertherat E, Talarmin A, Zeller H (1999). "[Democratic Republic of the Congo: between civil war and the Marburg virus. International Committee of Technical and Scientific Coordination of the Durba Epidemic]".Médecine Tropicale.59 (2):201–204.PMID10546197.
^Roddy P, Marchiol A, Jeffs B, Palma PP, Bernal O, de la Rosa O, Borchert M (February 2009). "Decreased peripheral health service utilisation during an outbreak of Marburg haemorrhagic fever, Uíge, Angola, 2005".Transactions of the Royal Society of Tropical Medicine and Hygiene.103 (2):200–202.doi:10.1016/j.trstmh.2008.09.001.hdl:10144/41786.PMID18838150.
^"MSF's response to CEPI's policy regarding equitable access".Médecins Sans Frontières Access Campaign. September 25, 2018.Archived from the original on March 21, 2021. RetrievedApril 10, 2020.In vaccine development, access to know how is important. Knowledge and expertise including but not limited to purification techniques, cell lines, materials, software codes and their transfer of this to alternative manufacturers in the event the awardee discontinues development of a promising vaccine is critically important. The recent example of Merck abandoning the development of rVSV vaccines for Marburg (rVSV-MARV) and for Sudan-Ebola (rVSV-SUDV) is a case in point. Merck continues to retain vital know-how on the rVSV platform as it developed the rVSV vaccine for Zaire-Ebola (rVSV-ZEBOV) with funding support from GAVI. While it has transferred the rights on these vaccines back to Public Health Agency of Canada, there is no mechanism to share know how on the rVSV platform with other vaccine developers who would like to also use rVSV as a vector against other pathogens.
^Dulin N, Spanier A, Merino K, Hutter JN, Waterman PE, Lee C, Hamer MJ (January 2021). "Systematic review of Marburg virus vaccine nonhuman primate studies and human clinical trials".Vaccine.39 (2):202–208.doi:10.1016/j.vaccine.2020.11.042.PMID33309082.S2CID229178658.
^US Animal and Plant Health Inspection Service (APHIS) and US Centers for Disease Control and Prevention (CDC)."National Select Agent Registry (NSAR)". Retrieved2011-10-16.
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