Why existing vaccines won’t help this Ebola outbreak
As scientists race to develop a new Ebola vaccine to combat the Bundibugyo species, a few leading candidates have emerged.
The first Ebola vaccine wasn’t developed because of an outbreak.
“The former Soviet Union was looking to weaponize those viruses,” says virologist Thomas Geisbert. In the 1990s, Geisbert and his then-colleagues at the U.S. Army Medical Research Institute of Infectious Diseases were tasked with finding a way to thwart the Soviets.
A pivotal discovery came when one of his collaborators, a Canadian virologist named Heinz Feldmann, was playing around with ways to study the outer coatings of threadlike Ebola viruses. He had tweaked a weakened version of vesicular stomatitis virus, or VSV, which causes mouth and hoof blisters in livestock, to display part of Ebola's outer coat instead of its own. He then tested what that coating did to mice injected with the hybrid virus.
As an experiment aimed at proving the coating’s deadliness, it was a failure: None of the mice got sick. Feldmann’s discovery that those mice later stayed healthy when exposed to regular Ebola viruses proved a spectacular breakthrough on the path toward an Ebola vaccine. When Geisbert—now a virologist at the University of Texas Medical Branch in Galveston—and a multinational team of scientists were able to replicate those findings in monkeys a few years later, they were “bouncing off the walls.”
That science laid the groundwork for the Ebola vaccine developed in response to the 2014 West African outbreak of the Zaire species of the virus, which killed more than 11,000 people over roughly two years. It has helped curb transmission in multiple outbreaks since.
Now as the Democratic Republic of the Congo confronts a catastrophic wave of infections due to a far more rare species of Ebola, the world is turning to the same science—and the same strategy—that failed to prevent this.
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However, there’s one major problem: The original VSV-based Ervebo vaccine created to combat Zaire virus doesn’t reliably prevent transmission of the Bundibugyo species of virus. Neither does a less commonly used alternative vaccine.
In response, officials have scrambled to fast-track new vaccine prototypes for development. But will they be able to stop this outbreak before it devastates the DRC even further?
Why doesn’t the existing vaccine work for Bundibugyo?
Vaccines work by safely introducing the immune system to part of a germ so it recognizes and fights that germ, if and when it invades. In the case of Ebola viruses, the most obvious part to use for that training is its outer coat of glycoproteins.
If Ebola viruses were Christmas trees, glycoproteins would be their ornaments, says Erica Ollman Saphire, an immunologist and CEO of the La Jolla Institute for Immunology.
Those ornaments are easily visible both to the immune system and to researchers who want to study them. That makes them prime targets for making vaccines quickly, as scientists had to do when producing Ervebo within the pressure-cooker timeline of the West African epidemic.
However, they vary considerably between different species of Ebola virus. Zaire is the most common Ebola virus while Bundibugyo is the most rare: Although they share a very similar core structure, about 35 percent of the glycoproteins they wear on their surface are different. If a Zaire tree were covered with red balls, says Saphire, about a third of the ornaments on a Bundibugyo tree would instead be silver stars.
Ervebo probably would provide some protection from Bundibugyo virus, but not enough to rationalize deploying it in the DRC to beat back the current outbreak, says Geisbert. In experiment results published in 2011, three-quarters of monkeys who received the Zaire-specific vaccine survived infection with Bundibugyo.
That might sound good, says Geisbert, but in an outbreak setting where distrust in health authorities has already proved so lethal, it’s not good enough.
“If you vaccinate a bunch of people, and then half of them start dying because you don't get good enough cross protection, are you getting a lot of backlash against vaccines in general?” he says. “It's just an awful decision to have to make.”
The WHO has called the evidence on Ervebo’s cross-protection for other Ebola virus species “limited and inconclusive.”
Vaccine candidates are racing to fill the gap
The Coalition for Epidemic Preparedness Innovations (CEPI)—a multinational nonprofit organization that finances vaccine development for emerging infectious diseases—has so far prioritized several vaccine candidates for development.
Two are Ervebo-like prototypes aimed at recognizing Bundibugyo’s specific blend of glycoproteins, a platform that showed experimental potential years ago: In 2013, an early version of the vaccine protected 100 percent of monkeys infected with Bundibugyo. However, because most Ebola outbreaks didn’t involve this species, the vaccine didn’t get the investment needed to become licensed. That’s an outcome CEPI aims to remedy with its latest investment.
The International AIDS Vaccine Initiative and Public Health Vaccines are developing the vaccines which, like Ervebo, also rely on the vesicular stomatitis virus. The World Health Organization (WHO) called this technology the most promising of the candidates.
VSV-based vaccines are front-runners because the weakened version of the virus used to produce them is so good at replicating itself inside humans—including the small chunk of whatever germ it’s been hybridized with—without causing harm. As a result, a single dose typically leads to a strong immune response.
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The tradeoff is that the strong protection comes with a higher risk of side effects like fever, achiness, and fatigue, and in theory would carry more risks for pregnant and immunocompromised people. Additionally, growing live virus takes time and specialized manufacturing capacity; WHO experts suggested it would take seven to nine months for a version modified for Bundibugyo to be ready for testing in humans.
Another candidate, called ChAdOx1, operates using a similar concept: A virus shows the immune system part of a pathogen to generate a protective response. However, it uses an adenovirus that causes colds in chimpanzees—and is also harmless to humans—that University of Oxford scientists modified to keep it from replicating.
That makes it less likely to cause side effects, but in early clinical trials, subjects needed two doses to get a strong enough immune response. AstraZeneca produced its COVID-19 vaccine using this platform in partnership with Oxford and the Serum Institute of India, which would also manufacture this candidate. It could take two to three months to become available for human trials.
There’s also a vaccine candidate based on Moderna’s mRNA science, which was also used to produce the company’s COVID-19 vaccines. This vaccine employs tiny fat bubbles to deliver genetic instructions to cells on how to produce a small part of the Bundibugyo virus. The immune system generates a protective response, and the mRNA degrades quickly without causing lasting changes to cells’ genetic codes.
Speed is this candidate’s advantage: You can design and synthesize an mRNA vaccine in days. However, the product is harder to distribute globally because it needs to be kept at colder temperatures than other vaccines. Plus, no mRNA Ebola vaccines have ever been trialed in humans, so there’s less prior safety data. That means it couldbe months before a version is available for testing.
In its announcement, CEPI said it had put out a call for proposals from other vaccine developers and anticipated adding more candidates to its portfolio. In total, this first round of investments will likely total just south of $62 million.
The holy grail of Ebola vaccines
If the VSV-based candidate shows the immune system a panoply of shiny red and silver ornaments, you might think of ChAdOx1 as presenting a somewhat duller display, and the mRNA candidate as providing a manual for making your own gleaming decorations. Each has different strengths and weakness.
Importantly, none of them accomplish what experts hope a hypothetical holy grail of Ebola immunizations would: protect recipients from all species of Ebola, and perhaps even related Marburg viruses. That would require scientists to go beyond identifying the right proverbial bauble, says Saphire.
“What the immune system should be looking at is the tiny, dull little hook” that attaches each ornament to the tree—in other words, a shared component that’s less noticeable, but more likely to elicit an immune response protective against all Ebola species.
Finding a shared component takes a lot of time, which makes it easier to do between outbreaks rather than in the midst of one. In February, before the current outbreak began, CEPI had announced a five-year strategy aimed at enabling that work. “If this Bundibugyo outbreak had happened in five or 10 years,” scientists would be starting much closer to the finish line on a vaccine, says Richard Hachette, CEPI’s CEO.
Saphire says her heart breaks to see so much money in “another whack-a-mole game” of attempting to prevent an outbreak that is already underway.
“In between outbreaks,” she says, “the whole field is starving for investment to do the research to make something even better available."
