The fight against Ebola continues with news of a new outbreak in the Republic of Congo. That said, a discovery by scientists at the Albert Einstein College of Medicine offers reason to be optimistic: they have found the first human antibodies that can shut down all strains of ebolavirus.
The genus ebolavirus consists of five known strains: Ebola Zaire (which is also commonly referred to as Ebola virus), Sudan virus, Bundibugyo virus, Tai Forest virus and Reston virus. The first four are known to cause the Ebola virus disease (EVD, also known simply as Ebola) in humans, while the fifth has been known only to affect other primates so far.
From the moment the virus infects its victim, a deadly game of deception unfolds as it binds itself to the host cell's outer membrane (see illustration below). It is then transported into the cell in a membrane-bound bubble called an endosome, which eventually becomes a lysosome – a spherical membrane-enclosed structure that functions as the cell's digestive system.
Since the lysosome is located deep within the cell, the virus is able to evade the notice of the immune system and go about its business undetected. Eventually, the virus latches onto a protein receptor called NPC1 to infiltrate the host cell's cytoplasm (i.e. the fluid that fills a cell), where it can multiply and continue to infect the rest of the body's cells.
Previously, the only antibody that had been discovered came from a mouse. To find human antibodies that would be able to thwart the virus, the researchers surveyed 349 specimens that they got from the blood of a survivor of the 2013-16 Ebola epidemic and found two that fit the bill: ADI-15878 and ADI-15742, both of which were able to neutralize the five known ebolaviruses.
The two antibodies work by binding to the glycoproteins that protrude from the virus' surface before it has a chance to enter the lysosome. These proteins are essential for helping it escape from the lysosome and, with the antibodies bound to them, the virus is unable to do so and infiltrate the host cell's cytoplasm. This essentially stops it from replicating and neutralizes the infection.
According to study co-leader Kartik Chandran, a professor of microbiology and immunology, what makes this discovery so unexpected is that the antibodies come from an individual who has only been exposed to the virus once. Usually, it takes multiple exposures or a chronic exposure to a virus before such antibodies are produced, as in the case of patients infected with the dengue, influenza or HIV viruses.
"[By] knowing precisely where the antibodies attach to the glycoprotein molecules and when and how they act to neutralize ebolaviruses, we can begin to craft broadly effective immunotherapies," says John Dye, chief of viral immunology at the U.S. Army Medical Research Institute of Infectious Diseases, who was part of the study.
To observe their efficacy, the researchers tested the antibodies on human cells in a lab setting and found that they provided protection against several strains of ebolavirus. They also tested them on ferrets, wild mice and genetically modified mice and found that the antibodies were able to protect theses animals from the Bundibugyo virus, Zaire virus, and Sudan virus, respectively.
That said, it should be noted that there were instances in which the antibodies proved to be ineffective. One was when the ferrets were exposed to the Bundibugyo virus and treated with ADI-15742, which resulted in the virus developing a mutation that enabled it to escape the antibody's effects. In addition, the antibodies had no effect on the Lloviu and Marburg viruses, which are related to ebolavirus, in human cells.
Nevertheless, the researchers believe that with further studies, the antibodies could lead to the development of a therapy, in particular one that could confer protection against all known strains of the virus. At present, Ebola vaccines, such as rVSV-ZEBOV, target only one particular strain.
"Since it's impossible to predict which of these agents will cause the next epidemic, it would be ideal to develop a single therapy that could treat or prevent infection caused by any known ebolavirus," says study co-leader Zachary Bornholdt, director of antibody discovery at Mapp Biopharmaceutical.
In addition, since the antibodies can stay in the bloodstream for a long time, it could also be used in advance to dose those with a high chance of coming into contact with the.
"We'd like to synthesize vaccine immunogens [proteins that trigger antibody production] that can elicit the same types of broadly protective antibodies in people," says his fellow co-leader Kartik Chandran, a professor of microbiology and immunology at Albert Einstein College of Medicine.
The study was published in Cell.
Sources: Albert Einstein College of Medicine; National Institutes of Health
