Are Ebola Mutations Making It More Deadly?

Genetic changes keep health officials on high alert

Ebola is a virus that causes fever, internal and external bleeding, and organ failure. Around 50% of those infected will die, often within days or weeks of the first appearance of symptoms. Perhaps the scariest thing about Ebola is that it is so easily spread through bodily fluids (including saliva, mucus, vomit, feces, sweat, tears, breast milk, urine, and semen) and contact with items recently contaminated with bodily fluids.

In recent years, there have been suggestions that the Ebola virus is rapidly mutating and may be increasing in virulence (ability to cause harm). Just how serious are these concerns?

Female laboratory worker using microscope
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History of Ebola

The first known outbreak of Ebola occurred in Sudan in June 1976, although the virus was not officially identified until August of that year, when it had spread to neighboring Zaire (now known as the Democratic Republic of Congo). By that time, over 500 people had died, with a mortality rate exceeding 85%.

The largest Ebola outbreak, affecting parts of West Africa, claimed over 11,000 lives and only officially ended in March 2016 after more than three years of aggressive disease control measures.

Since then, there have been three other outbreaks: one in the Democratic Republic of Congo (DRC) in 2017, a second in the Équateur province of the DRC in 2018, and a third in the Kivu province of the DRC starting in 2018.

By 2019, the Kivu outbreak had officially become the second-largest outbreak in history, with reports suggesting that the disease was more difficult to contain due, in part, to mutations that increase the virus's ability to infect human cells.

Some health officials warn that this may be a sign that Ebola is becoming more virulent and will eventually breach containment in West Africa. Although there is some historical and epidemiological evidence to support these claims, there remains considerable debate as to whether these mutations actually make the virus more infectious.

How Mutations Occur

As a rule of nature, all viruses mutate—from adenoviruses that cause the common cold right up to severe viruses like Ebola. They do so because the process of replication is prone to errors. With every replication cycle, millions of flawed viruses are churned out, most of which are harmless and unable to survive.

In virology, a mutation is simply the alteration in the genetic coding of a virus from that of the natural, predominant type (called the "wild type"). Mutations don't inherently mean that a virus is "getting worse" or that there is any chance that the "new" virus will suddenly predominate.

With Ebola, the very fact that it made the leap from infecting animals to humans indicates that it underwent mutations in order to survive in human hosts.

Evidence strongly suggests that fruit bats are the species from which the Ebola virus was transmitted to humans.

Once the leap was made, further evolutions were needed to create the virus that we have today. Today, human infection with Ebola virus occurs through contact with wild animals (hunting, butchering, and preparing meat from infected animals) and through human-to-human contact.

Genetics of Ebola

Ebola is an RNA virus like HIV and hepatitis C. Unlike a DNA virus, which infiltrates a cell and highjacks its genetic machinery, an RNA virus must undergo conversion to DNA before it can override a cell's genetic coding.

Because of these additional steps (and the rapid pace of replication), RNA viruses are more vulnerable to coding errors. While the majority of these mutations are non-viable, some can persist and even thrive. Over time, the mutations that are the most hearty can predominate. It is a natural process of evolution.

For its part, Ebola doesn’t have a lot of genetic information. It is a single-stranded virus that is about 19,000 nucleotides long. (That isn't a lot, considering that a single human chromosome contains around 250 million pairs.)

Despite its massive impact, Ebola has only seven structural proteins, each of which plays a role in how the disease is transmitted, replicates, and causes disease.

Once inside the human body, Ebola can replicate quickly, creating millions of viruses per millimeter of blood within a span of days or weeks. With such rapid turnover, there is a lot of room for coding errors.

These errors can potentially alter the genotype (genetic makeup) and phenotype (physical structure) of the predominant virus. If a change allows the virus to bind to and infiltrate a cell more efficiently, it can theoretically increase the infectivity (ability to spread), pathogenicity (ability to cause disease), and virulence (disease severity) of the virus.

Evidence is inconclusive as to whether this is already occurring.

Current Evidence and Debate

Unlike other communicable diseases, in which the spread of an organism increases in tandem with the rise of drug resistance, there is currently no evidence showing that Ebola mutates in response to the treatments available.

In 2020, the U.S. Food and Drug Administration approved two medications for treating Ebola virus disease: Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn) and Ebanga (Ansuvimab-zykl). As of May 2022, no resistance to Inmazeb has been seen. As of June 2021, no trials have been done to look at resistance to Ebanga.

Other treatments are primarily supportive, involving intravenous (IV) blood transfusions, oral and IV hydration, and pain control. Although there are several experimental treatments that may help improve outcomes, none are able to control or neutralize the virus.

As such, any mutation of the Ebola virus occurs as part of natural selection (the process by which organisms better adapted to an environment are able to survive and produce offspring).

As benign as the process may seem, many experts are concerned that the natural evolution of Ebola—as it is passed from one person to the next and, as such, through different unique environments—will increase the "fitness" of the virus and make it all the more difficult to control and treat.

Experts in support of the theory point to the earlier outbreaks in which the spread of disease was controlled faster than it is today. For example, the 1976 outbreak in Zaire was contained in just two weeks. By contrast, the 2018 outbreak in Kivu was declared a global health emergency in July 2019, with experts suggesting that it could take up to three years to control.

On the surface, numbers like these seem to suggest the infectivity of Ebola has increased. Recently identified mutations in the Ebola virus (EBOV)-Makona genome (the causative strain in West Africa) seem to further support the hypothesis.

A study published in the May 2018 issue of Cell Reports has since challenged those ideas and demonstrated that not all mutations, even major ones, are inherently worrisome.

Research Findings

According to research conducted by the National Institute of Allergy and Infectious Diseases (NIAID), the genetic changes seen in EBOV-Makona were, in fact, similar to those occurring in certain virulent strains of HIV. However, unlike those involved with HIV, the mutations did not translate to a worsening of the disease.

In fact, when the altered Ebola strain was tested on mice, the progression of the disease was actually slower. In macaque monkeys, the strain exhibited reduced pathogenicity and had no effect on viral shedding (the release of virus into body fluids that increases the risk of transmission).

In their conclusions, the researchers suggested that other factors could account for the difficulties in disease control, including the immune status of vulnerable populations, poor healthcare systems, and increased travel and mobility.

The NIAID findings supported earlier research from Mali in which identified mutations of Ebola did not appear to increase the fitness of the virus or make it more transmissible.

Surveillance and Prevention

The current body of evidence should not suggest that ongoing mutations of the Ebola virus are without concern. As mutation builds upon mutation, new viral lineages can be created, some of which may weaken the virus (and effectively end the lineage) and others of which may strengthen the virus (and promote the lineage).

These concerns were highlighted in a 2016 study in Cell in which a split in a lineage of the Ebola virus was identified in 2014 at the height of the DRC crisis. According to researchers from the University of Massachusetts, this "new" lineage was better able to bind to host cells than the ancestral lineage.

While this change did not inherently increase the infectivity of the virus (mainly because binding is only part of the infection process), additional mutations could ostensibly build upon this effect and increase the overall pathogenicity of the virus.

Clearly, there is no way to predict if or when this might occur. Ongoing surveillance is the only viable means to detect mutations early and improve the chance of controlling their transmission.

Simply put, by reducing the number of people exposed to Ebola (through increased vaccination efforts and improved disease control measures), there is less opportunity for mutation. Currently, there is only one Ebola vaccine (Ervebo) approved in the U.S. Until a cure can be found, this may be the single best way to help prevent a global epidemic.

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By Megan Coffee, MD
Megan Coffee, MD, PhD, is a clinician specializing in infectious disease research and an attending clinical assistant professor of medicine.