There are five known species (or strains) of the deadly Ebola virus. Dr. Jonathan Lai, associate professor of biochemistry at Einstein, recently developed new antibodies that could one day be used as a therapy for the Sudan ebolavirus strain.
The Doctor’s Tablet recently sat down with Dr. Lai to discuss his latest study; his ongoing work to develop “broadly neutralizing antibodies” that could target more than one strain of Ebola and other filoviruses; and the current race to find a cure for Ebola.
Before we get to the questions, some additional background:
Much is known about the Zaire strain of Ebola, now known as Ebola virus. The Zaire strain is responsible for the current outbreak in West Africa that has infected over 3,000 people in four countries, killing more than 1,500. Less is known about the Sudan strain. Prior to the current crisis, the Sudan strain had been responsible for one of the worst outbreaks (over 400 cases, 224 deaths) in 2000. Whereas there are experimental antibody therapies for the Zaire strain—such as ZMapp, which was given under limited circumstances in the current crisis—there is nothing yet available for Sudan ebolavirus.
Tell us about your research to develop a treatment for Ebola.
Though there are five different strains of Ebola, we have been focusing mostly on Sudan ebolavirus. We believe that this strain is of concern because outbreaks of it are occurring more frequently, and it has been responsible for large outbreaks in the past.
The current crisis in West Africa is due to the Zaire strain, which was first discovered in 1976 in the country that used to be Zaire and is now the Democratic Republic of Congo (DRC). It has the highest human-case fatality rate, with the Sudan strain in second place. In contrast to the Zaire strain, there are few antibodies and few treatments for Sudan ebolavirus. We think this gap needs to be filled, because it is unpredictable which of the strains will cause future outbreaks.
In our most recent paper, published in ACS Chemical Biology, we worked to develop a new antibody against Sudan ebolavirus. One antibody that’s been shown to be potent against the strain is a mouse antibody called 16F6, which was identified by my collaborator, Dr. John Dye, at the United States Army Medical Research Institute of Infectious Diseases. But mouse antibodies are not always effective therapies, because the human immune system may mount a response that neutralizes the “foreign” mouse antibodies and stops them from working. We engineered a human antibody by replacing the mouse parts of 16F6 with human parts using a method called “synthetic antibody engineering.” Our new antibody was protective in mice, which is a good first step toward developing a therapy. There is still a long way to go before it could be considered for use in humans.
We are also working to develop antibody therapies that are effective against more than one strain of Ebola simultaneously. We think it would be helpful if a treatment were available that is effective against all strains of the virus (or at least the most pathogenic ones) so it didn’t matter which strain was causing the outbreak.
What research challenges do you currently face?
One challenge moving forward will be figuring out how to scale our antibody production to test in larger animals. Also, most of what has been shown to work so far, at least for the Zaire strain, are cocktails of antibodies such as ZMapp. At this point, we don’t know if a single monoclonal antibody is good enough to do the job. Based on the data, it is hard to see a reason why a monoclonal antibody therapy wouldn’t work, but we just don’t know.
What types of treatments hold the most promise for Ebola?
There are currently two promising vaccines and two treatments that immediately come to mind.
One vaccine is VSV-EBOV, which is a vesicular stomatitis virus–based vaccine being produced in Canada, now being sent to Africa. There is also an adenovirus vector vaccine that is being developed by the National Institutes of Health. Both vaccines contain parts of the Ebola virus that have been placed into a different virus that’s not lethal to humans, as a way to induce protective immunity against Ebola.
In terms of therapeutics, the most advanced therapies are ZMapp, which is a cocktail of monoclonal antibodies provided to the American aid workers and a select group of others, and TKM-Ebola, which is an RNAi therapy.
Both therapies work to try to control the spread of the virus in the body, but the mechanism of how they stop that spread differs. The RNAi therapy tries to control the replication of the virus, while the antibodies try to prevent the virus from infecting cells in the first place.
How difficult is it to develop a therapy that could be effective against multiple strains of the virus?
Although the strains are all part of the same family, they are quite different from one another. So far, all the antibodies that have been discovered are strain specific; when there is an outbreak, the survivors produce antibodies that are specific to the strain causing the outbreak, so it hasn’t been clear how we would engineer something that would cross strains. I think we have a good approach to explore this, but it will take time.
Consider viruses such as HIV and influenza, for which broadly specific antibodies have been found. That just hasn’t happened for Ebola.
We are not sure why—is it because the strains are too far apart, or is it a reflection of how sporadic and deadly Ebola is?
Ebola pops up and causes an outbreak with a high fatality rate, and then goes away once it has been contained. Contrast this with HIV, which leads to chronic infections that people must constantly fight off, or with influenza, to which one might argue the population as a whole is chronically exposed. Each year we get a new flu vaccine or a new strain of flu, so people build up immunity. Those populations that have been chronically infected or exposed are good “sources” for trying to find broadly neutralizing antibodies, and this has been done for HIV and influenza.
Ebola works quite differently. It is rapidly fatal—the Zaire strain kills more than 50 percent, and in some cases as many as 90 percent, of the people infected, and then goes away. Therefore, people are not chronically infected nor are populations-at-large chronically exposed to Ebola as they are with other viruses, which is perhaps why it has been difficult to identify an antibody that works against multiple strains.