Marburg Virus Disease Emergence: An Update

March 28, 2023

Marburg virus TEM image.
Negative stained transmission electron microscopic (TEM) image of Marburg virus virion.
Source: CDC PHIL 7219/ Fred A. Murphy

Fifty-six years following its discovery, Marburg virus (MARV)—a cousin to Ebolavirus in the Filoviridae family—remains a feared pathogen with high fatality and no licensed treatments or vaccines. Recent outbreaks of the disease have captured headlines and demonstrated that its geographic range is expanding.

Zoonotic Agents Enter the Human Population Through Spillover Events

Marburg virus, influenza A viruses, Ebola viruses, rabies virus, Zika virus, Nipah virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and many other pathogens are characterized as zoonotic agents that have emerged into our human world via an intricate and complex biological process known as spillover. Spillover of novel pathogens typically occurs through the intersection of the agent (e.g., viruses, bacteria, parasites) with livestock, vectors, wildlife or even the natural environment.

Almost any emergence and reemergence of zoonotic viruses is influenced by human encroachment on na├»ve animal habitats and modification (good or bad) to these areas because of climate change. Zoonotic pathogens occur, and sustain themselves, through enzootic cycles. Zoonotic disease emergence frequently arises as a consequence of direct or indirect transmission of a multi-host pathogen from an animal host to a human. Onward human-to-human transmission may or may not occur.

Unfortunately, the spillover event is almost always invisible and undetected in the index case, making it even more confusing—and sometimes dangerous—for public health. Detecting emerging pathogens relies on strong public health surveillance systems and astute clinicians. Without well-resourced public health and health care infrastructure, such as advanced molecular epidemiology techniques for wastewater and animal surveillance, emerging pathogens and strains or variants of known pathogens can go unnoticed for long periods, resulting in delays in targeted treatment, control and prevention measures.

Marburg Virus Disease Outbreaks Confirmed in 4 New Countries Over 2 Years—Will the Trend Continue?

A cluster of severe illnesses characterized by fever, weakness, vomiting and diarrhea in rural Equatorial Guinea beginning in January 2023, are linked to the country’s first known outbreak of Marburg virus disease (MVD). Twenty-seven of 29 individuals with probable or confirmed MVD have died, with dozens of contacts under monitoring as part of an ongoing international response effort. Tanzania reported its first known MVD outbreak on March 21, 2023, with 8 confirmed cases and 5 deaths. It appears that these 2 concurrent MVD outbreaks were sparked by separate spill-over events, though the source of both outbreaks remains unknown.

Outbreaks of MVD have most commonly been traced to cave-dwelling bat exposures in the neighboring East African countries of Uganda, Kenya and Democratic Republic of Congo (DRC). Exceptions include a single case cluster initiated in Zimbabwe and a large outbreak in Angola with undetermined exposure events.

The past 2 years have seen the emergence of human MVD infections in regions without previously recognized cases, including outbreaks in the West African countries of Guinea and Ghana, as well as an ongoing outbreak in the western Central African country of Equatorial Guinea. Why is the geographic range of MVD expanding, and will it continue to grow?

As is the case with other emerging zoonotic infectious diseases, the reasons for this shifting epidemiology may include factors related to pathogen evolution, the zoonotic reservoir and the human-animal interface, as well as improved surveillance, clinical recognition and diagnostic tools.

How are Humans Exposed to MARV, and is the Risk Increasing?

Human MARV infections can result from exposure to virus-laden bat excreta, as occurs with occupational or recreational entrance into mines or caves where bats are roosting. Infections are also caused by exposure to body fluids and tissues of infected persons or non-human primates, facilitated by close contact or laboratory handling. Zoonotic transmission risk appears to peak biannually, corresponding to reproductive cycles and increased infection rates in juvenile bats upon the loss of passively transferred maternal antibodies. MARV is shed in oral secretions, urine and fecal material of experimentally infected, juvenile bats and remains infectious on fruit contaminated by infected bats.

Virus persistence on fruit or other contaminated surfaces may be relevant to MVD outbreaks without a clear link to bat or cave exposure, characteristic of the west Central and West African outbreaks. Seroprevalence studies suggest that human exposures occur in countries without documented MVD cases, despite known MARV reservoirs in bats, highlighting the importance of improved surveillance and laboratory diagnostics in case recognition. The frequency of recognized outbreaks is likely to increase as these capabilities are strengthened in countries with known and predicted MVD risk.

MVD Geographic Risk Modelling Predicts the Recent Outbreaks—and Then Some

Egyptian fruit bats roosting upside down in a cave.
A colony of Egyptian fruit bats in a roost at Ha-Teomim cave in Israel.
Source: Wikipedia

Egyptian rousette bats (ERB, Rousettus aegyptiacus) maintain a natural reservoir of circulating MARV. Specimens collected from wild ERB demonstrate serological and virological evidence of MARV carriage in countries with documented MVD outbreaks (Uganda, Kenya, DRC), as well as countries spanning the ERB habitat range without recognized index cases (South Africa and Zambia in Southern Africa, Gabon in western Central Africa and Sierra Leone in West Africa). Accordingly, Guinea, Ghana, Equatorial Guinea and Tanzania (which shares border with Uganda, Kenya, DRC and Zambia) fall within the predicted range of MARV circulation maintained by ERB colonies. In contrast, natural MARV reservoirs have not yet been observed outside of Africa, despite ERB habitat extending into the Middle East, eastern Mediterranean and southern Asia regions.

MVD Outbreaks Represent Discrete Spillover Events from Established and Diverse Zoonotic MARV Reservoirs

Phylogenetic evidence suggests that the MARV ancestral strain originated in Uganda. MARV transmission between bat colonies, followed by localized strain evolution, has given rise to rich genomic diversity with >80 unique MARV genomes identified in wild bats. Two MARV lineages—commonly referred to as Marburg and Ravn—show 16% nucleotide variance, with further grouping of the Marburg lineage into 2 clades and 5 subclades with distinct geographies.

MARV genomes characterized during the recent West African outbreaks represent novel strains that cluster with strains found in ERB colonies in Sierra Leone, suggesting local spillover events from a regional reservoir that has likely been established and diversifying for several decades. These strains are closely related to the Angola MVD 2004-2005 outbreak strain, which caused the largest and most fatal recorded human outbreak and shows greater virulence in non-human primate studies, compared with other strains in the Marburg and Ravn lineages. The origin and phylogenetic analyses of the ongoing MVD outbreaks in Equatorial Guinea and Tanzania are not yet available.

Current Tools for MVD Detection, Management and Prevention

Routine clinical laboratory testing for patients suspected of MVD or other viral hemorrhagic fever infection is critical to support patient care, warranting careful risk assessment and planning by all health facilities. While no therapeutics or vaccines are currently licensed for MVD, this remains a global research and development priority with several candidates under investigation.

Diagnostic testing for MVD in the United States utilizes PCR-based detection of MARV RNA in blood. Current diagnostic PCR tests do not differentiate MARV lineages, and performance characteristics are not well defined across diverse and emerging strains.

Referral testing is available from the Viral Special Pathogens Branch at Centers for Disease Control and Prevention (CDC), public health laboratories participating in the Laboratory Response Network and clinical laboratories supporting Regional Special Pathogens Treatment Centers. The National Emerging Special Pathogens Training and Education Center (NETEC) maintains current guidance for safe specimen collection, packaging and shipment for MVD diagnostic testing.

Final Thoughts

MVD outbreaks historically have been infrequent since the virus was first detected in the late 1960’s. However, like other zoonotic microbes such as influenza A viruses, Ebola viruses, emerging coronaviruses (SARS-CoV, MERS-CoV and SARS-CoV-2), arboviruses, Nipah virus, Mpox virus and others, their recent frequency is rising and sounding more global public health alarms.

If the current SARS-CoV-2 pandemic and Mpox emergency have taught us nothing else, spotlighting this issue is imperative to be better prepared for future pandemics.

Interested in learning how the CDC's National Center for Emerging and Zoonotic Infectious Diseases (NCEZID) is responding to zoonotic threats?

Author: Jana Broadhurst, M.D., Ph.D., DTMH

Jana Broadhurst, M.D., Ph.D., DTMH
Jana Broadhurst, M.D., Ph.D., DTMH is an assistant professor in the Department of Pathology and Microbiology at the University of Nebraska Medical Center.

Author: Rodney Rohde, Ph.D., SM(ASCP), SVCM, MBCM, FACSc

Rodney Rohde, Ph.D., SM(ASCP), SVCM, MBCM, FACSc
Dr. Rodney Rohde is the Associate Director of the Translational Health Research Initiative at Texas State University.