Filoviruses: Ebola and Marburg — Questions

• Marburg reservoir (confirmed): the Egyptian rousette bat, a cave- and mine-dwelling fruit bat from which the virus has been repeatedly isolated.
• Ebolavirus reservoir (unconfirmed): fruit bats are strongly suspected on antibody and genome-fragment evidence, but infectious virus has never been isolated from a wild bat.
• Endemism: Marburg spillover tracks the range of the Egyptian rousette and cave or mine exposure, while ebolavirus spillover occurs in the forest zones of central and West Africa.
• Non-human primates and forest antelope are amplifying spillover hosts for both, not reservoirs.

• Semen (male genital tract): persistence for up to around two years.
• The eye: persistence causing uveitis.
• The central nervous system: rarely, a late relapse as meningoencephalitis.

Implication: persistence allows late transmission, particularly sexual transmission from male survivors, which can reseed an outbreak after it appears controlled, so survivor follow-up and safe-sex advice are part of the outbreak response.

Tropism: filoviruses first infect monocytes, macrophages and dendritic cells, then spread to a broad range of tissues including endothelium, hepatocytes and the adrenal cortex.

Interferon inhibition: the VP35 protein masks viral RNA from the sensor RIG-I (retinoic acid inducible gene I) and blocks interferon induction; in the ebolaviruses VP24 additionally blocks interferon signalling through STAT1 (signal transducer and activator of transcription 1), while the marburgviruses use VP40 for the same effect. This lets the virus replicate to high titre before the immune response engages.

A complete answer covers the biphasic course and notes the clinical similarity of Ebola and Marburg disease.

Incubation. After an incubation of about 2 to 21 days, illness begins abruptly.

Dry phase. Fever, severe malaise, headache and myalgia, before the prominent fluid losses appear.

Wet phase. Profuse vomiting and watery diarrhoea within days, causing the fluid and electrolyte loss that drives shock; a maculopapular rash and conjunctival injection are common.

Haemorrhage and outcome. Frank bleeding occurs in a minority and is usually late. Marburg and Ebola disease are clinically very similar and cannot be reliably distinguished at the bedside, so laboratory testing is required.

A complete answer distinguishes supportive care, which is available, from specific countermeasures, which are not yet licensed.

Supportive care. The foundation of treatment is meticulous supportive care: aggressive fluid and electrolyte replacement, correction of coagulopathy, and organ support, which improves survival.

Specific therapeutics. There is no licensed antiviral or monoclonal antibody for Marburg virus, and the Zaire-specific Ebola antibodies do not apply. Candidate monoclonal antibodies and antivirals are investigational.

Vaccines. There is no licensed Marburg vaccine; candidate vaccines are in clinical trials. Prevention therefore rests on avoiding cave and mine exposure, infection control and outbreak response.

Filovirus can persist in immune-privileged sites such as the semen for up to around two years, allowing occasional sexual transmission that reseeds outbreaks.

The virus does not persist long term in the bloodstream, muscle, bile or sweat glands in this way.

Only for Marburg virus is the reservoir firmly established: the Egyptian rousette bat, from which the virus has been repeatedly isolated.

The ebolavirus reservoir is unconfirmed, since infectious virus has not been isolated from a wild bat, and filoviruses are not rodent- or tick-borne.

In the ebolaviruses, VP24 blocks interferon signalling through STAT1 (signal transducer and activator of transcription 1), while VP35 is the shared antagonist masking viral RNA from RIG-I (retinoic acid inducible gene I) and the marburgviruses use VP40 for the same effect.

VP24 is not the polymerase, matrix protein or nucleoprotein, and it does not edit the glycoprotein gene.

The licensed Ervebo vaccine protects against Zaire ebolavirus only.

Its glycoprotein is Zaire-specific, so cross-protection against the Sudan, Bundibugyo and Marburg viruses cannot be assumed.

The lymphopenia arises from bystander apoptosis of uninfected lymphocytes, since lymphocytes are not productively infected in filovirus disease.

It is not caused by direct lymphocyte infection, antibody lysis, marrow failure or splenic sequestration.

Ring vaccination targets the contacts of a case, and their contacts in turn, to build a protective ring around each case, which contains spread and works even with limited vaccine supply.

It is not mass national vaccination, health-worker-only vaccination, post-exposure-only use, or animal vaccination.

The main cause of shock and death is fluid and electrolyte loss from the profuse vomiting and diarrhoea of the wet phase, not exsanguination.

Frank haemorrhage is usually a late and minor feature, and the other mechanisms are not the primary cause.

The true intracellular receptor for filoviruses is Niemann-Pick C1 (NPC1), reached deep in the endosome after the glycoprotein is cleaved.

DC-SIGN is an attachment factor rather than the receptor, and angiotensin-converting enzyme 2, CD4 and sialic acid are receptors for other viruses.

Ervebo is a single-dose live recombinant vesicular stomatitis virus carrying the Zaire glycoprotein.

It is not an inactivated, subunit, DNA or mRNA vaccine.

Inmazeb and Ebanga, two antibody products against the Zaire glycoprotein, were shown effective in the PALM trial and are licensed for Zaire ebolavirus disease.

Ribavirin, favipiravir and oseltamivir have no established role, and ZMapp was superseded by the two licensed antibodies.

Reston ebolavirus infects pigs and macaques in Asia but has caused no human disease.

The Zaire, Sudan and Bundibugyo species cause large lethal outbreaks, and Taï Forest ebolavirus caused a single non-fatal human case.

The 2013 to 2016 West African epidemic of Zaire ebolavirus was by far the largest ever recorded, causing more than eleven thousand deaths across Guinea, Liberia and Sierra Leone.

The other outbreaks listed were far smaller.

• Marburg virus was recognised first, in 1967, when laboratory workers in Marburg and Belgrade were infected by imported African monkeys.
• The ebolaviruses were recognised in 1976, in simultaneous outbreaks of the Zaire and Sudan species in central Africa.
• Distribution: both are confined to sub-Saharan Africa; Marburg spillover clusters around cave and mine exposure, while the ebolaviruses occur across the forest zones of central and West Africa, the Zaire species causing the largest outbreaks.
• Marburg virus disease and Ebola disease are otherwise clinically very similar.

Definition: ring vaccination immunises the contacts of a confirmed case, and their contacts in turn, forming a protective ring around each case rather than vaccinating the whole population.

• It targets those at highest risk, the people most likely to have been exposed, concentrating protection where transmission occurs.
• It uses limited vaccine efficiently, achieving outbreak control without the supply needed for mass vaccination.

• Composition: a live recombinant vesicular stomatitis virus engineered to carry the Zaire ebolavirus glycoprotein, given as a single dose.
• Route: intramuscular injection.
• Cold chain: it requires ultra-cold storage, at around minus 60 to minus 80 degrees Celsius, which complicates field deployment.

• Healthcare workers: contact with a patient’s blood and body fluids without adequate infection control.
• Family carers and funeral attendees: contact with the body during care and traditional burial washing.
• Hunters and people handling wildlife: contact with infected bats, primates or forest antelope through the bushmeat trade.
• Sexual partners of survivors: exposure to virus persisting in semen after recovery.

Current WHO guidance recommends offering Ervebo to pregnant and breastfeeding women in areas with an active Ebola outbreak, with informed consent and after weighing the woman’s risk of exposure. This reverses the earlier practice of excluding them, which had been criticised for denying protection to a high-risk group.