Human trials of the Ebola vaccine have been temporarily shut down due to adverse side effects. What will it take to get it up and running again?
With Ebola still tearing through West Africa, surely the last thing anyone wants to hear about it are setbacks in the search for a vaccine. Unfortunately, in the face of nearly 7,000 dead and over 18,000 confirmed cases, the Merck-NewLink stage 1 Ebola vaccine trial has hit a snag.
On December 11th, representatives from the University Hospitals of Geneva, where the trial is behind held, issued a press release stating that four of the 59 participants had reported joint pain in the hands and feet, an unexpected adverse event necessitating a pause in the injection schedule. They added that the shutdown was temporary and they plan to resume the trial in January. The report also states that the onset of joint pain is a very common side effect after “infection or vaccination,” but given the stoppage in the study timeline, it appears researchers are scrambling to figure out what exactly is happening. After all, unlike the other vaccines currently in the pipeline, this one is alive and replication-competent. It’s important we know what the vaccine is doing once unleashed within the body. From the report:
“The onset of joint pain after infection or vaccination is very common. This happens, for instance, in one out of five vaccinations against rubella. This is a well-documented phenomenon which does not worry specialists. However, it deserves to be carefully studied in order to update the information which is provided to the volunteers. The temporary interruption of a clinical trial is a standard precautionary measure in such cases.”
But experts aren’t so quick to brush this off as business-as-usual, like Dr. Matthias Schnell, the researcher behind the Ebola-rabies combination vaccine at the Jefferson Vaccine Center in Philadelphia. “It’s definitely something they didn't expect. If it would be that common, then it would have been disclosed to the vaccines, right?” Schnell says. “So they didn't expect it, and if you don't expect something then you probably have no explanation, and if you don't have no explanation you'd better figure out what's going on. That's all.”
And while anyone who’s suffered seasonal body aches has felt the inflammatory pain the small signaling molecules of the immune system can bring, the inflammation reported by study participants is delayed-onset and away from the injection site. “[The injection is] not in the joint, you know? You get vaccinated in the arm, you shouldn't have inflammation in the joint. That's a little bit too much inflammation,” cautions Schnell.
Anything serious enough to cause a shutdown is implicitly cause for concern, but the answer as to why this is happening isn’t clear. Schnell rattled off a list of possible things to explore, such as whether the pain is temporary or permanent, where the virus might be replicating inside the body, and any potential mechanisms to understanding the cause of the inflammation.
But that’s not to say that this sort of complication is completely out of the ordinary for a new vaccine. “I just think that it's really difficult without knowing facts,” says Dr. Thomas Geisbert of the University of Texas, an Ebola vaccine researcher who has worked with most of the vaccines coming to market, in some capacity, over the years. He repeats the mantra of “hard to know” throughout his interview, slowing his enunciation of the word “facts” to draw out the word into a two second warning. “I think it's good that it doesn't look like there was any serious adverse event, I mean, nobody was hospitalized.”
“There [are] all kinds of side effects associated with vaccines. A lot times they're local, at the site of the immunization, where it was given. Common things would be like fever, nausea, you know,” Geisbert says, adding that it’s hard to quantify intangible symptoms of illness like aches and pains. “How do you define that? And so I think it's really difficult without knowing the facts.”
Geisbert was also quick to mention how the methodology of the study could be affecting the current results.
“I think the other thing to keep in mind here is…that these clinical trials are done blinded,” meaning that there are some people will get the vaccine and others will not, but those who receive the placebo are under the impression they are receiving the experimental substance. “I've seen nothing out there in the media or anywhere else…that indicates they've decoded [the results] yet,” Geisbert says, referring to going through the data and determining if any of the participants with joint pain were in the control group. “If even one of those four people is somebody that didn't actually get the vaccine, the results are meaningless.”
He continues, “You're talking about a population of people in a small geographic area. There could be some other kind of you know flu or infection of some kind going around that caused that that had nothing to do with the vaccine. That's why you have a control, placebo group.”
Anytime a virus grows in the body, like the VSV virus carrying the benign Ebola surface protein, the immune system has more time to see it, learn to recognize it, and ultimately learn to generate a good immune response to the pathogen. “At the same time, when you have a virus that grows, there's a better chance that you're going to have an adverse event,” says Dr. Geisbert. “So there's a trade-off. You could have a great, perfectly safe vaccine but it doesn't work. So it's trying to find some balance.”
However, just because a vaccine is replication-defective does not mean that you won't have an adverse event. Though the replication-competent VSV-based vaccine trial is having difficulty, the other leading Ebola vaccine candidate is not exactly soaring through testing without conflict. Unlike the VSV version, which uses a livestock virus capable of replication to deliver Ebola-fighting instructions to the body, GlaxoSmithKline is working on a replication-deficient vaccine based on a pathogen that causes chimpanzees to get the sniffles, a type of adenovirus.
“I think 80 percent of the people [in the trial] had some kind of a mild, adverse event at the high dose. And that was kind of surprising,” notes Geisbert. “All of these Ebola vaccines use the same antigen, or immunogen. They all use the surface glycoprotein, they all express it; it could be that there's something with the Ebola glycoprotein that may cause a small number of people to have some kind of a reaction, irrespective of which delivery vehicle you use. We don't know that.”
But there’s another side to the GSK vaccine that is perhaps even less palatable: open sores. The only way this adenovirus-based vaccine provided immunity was to booster it with another vaccine two months later, one based on a poxvirus. And, much like the smallpox inoculations of yore, these anti-Ebola jabs pummel the skin with a bifurcated needle and can leave a nasty sore.
“I'm not saying it's that particular vaccine, it’s just that class of vaccine,” Geisbert says. “It's a poxvirus. There's something with poxvirus vaccine vectors that when you put an Ebola glycoprotein in, and because it administers [by that bifurcated needle in the skin]…there's a very bad side effect that we've seen in non-human primates. Whether that translates to humans, I don't know.”
Geisbert says that in his experience with the GSK vaccine booster, “probably 20 percent of the non-human primates get really, really bad, local reactions.” Swelling, pus, the whole shebang; an angry reaction that lasted weeks. But again, ever the scientist, he’s quick to note that just because it works that way in monkeys, doesn’t mean that will necessary translate to those hairless primates.
So how concerned should people be about the fate of the VSV vaccine? It’s all about figuring out what is going on, and where the acceptable level of risk lies. “Any time you put a foreign substance into anybody you have the potential for an adverse event,” Geisbert reminds. “There's a certain percentage of the population that I don’t care what you give them, you could probably make them drink too much Coca-Cola and they'd, you know, get really sick.” Which is exactly why we do clinical trials. “It's what's an acceptable level. Because I guarantee you, if you do a study with enough people, you're going to find somebody who is going to react badly to whatever it is,” he says.
So which one would Geisbert take, if it came down to it? “I tell you, because I know a lot about Ebola vaccines, I'd never take [the GSK vaccine]. Not with the VSV. I'd take my chances with some joint pain.”
And Geisbert would know. As the first researcher to start working with VSV as an Ebola vaccine vector, he’s familiar with the options. “It’s the best vaccine virus I've ever seen for the kind of viruses we work with. I don't know why it’s so good,” he muses, rattling off a list of potential theories. “I really wish I had the answer to the question, quite honestly. I don't know. I don't know why.”