The Ebola Vaccine That Sat on the Shelf for 15 Years: Why a Promising Bundibugyo Candidate Is Only Now Racing Toward Human Trials
核心洞察
A promising rVSV-based vaccine against the Bundibugyo strain of Ebola, developed by Thomas Geisbert in 2011, has never entered human trials due to lack of funding and commercial interest.
The current outbreak in the DRC and Uganda has infected hundreds and killed around 200 people, prompting WHO to identify Geisbert's candidate as the most promising option.
CEPI has offered up to $3.2 million to prepare and start testing manufacturing materials, with prior rVSV safety data potentially expediting regulatory approval pathways.
Fever, weight loss, rectal bleeding, and nosebleeds ravaged the crab-eating macaques in a high-containment laboratory off the Texas coast after they were infected with the Bundibugyo strain of Ebola. But the three monkeys that had received a newly developed vaccine showed no symptoms at all, while two-thirds of their unvaccinated companions died. It was 2011, and virologist Thomas Geisbert's work developing the vaccine was done. If it protected primates, it was highly likely to protect humans.
Yet with an outbreak now raging in the Democratic Republic of Congo and Uganda, Geisbert's promising vaccine hasn't been deployed at all—or even put through human trials—because there hasn't been the funding or interest. "We've got the rVSV Bundibugyo vaccine (搜索) sitting on the shelf," says Geisbert, an immunology professor at the University of Texas Medical Branch in Galveston.
Hundreds of people have been infected in the current outbreak in Central and East Africa, and around 200 have died. Public health officials have been scrambling to develop a vaccine, with the World Health Organization identifying Geisbert's as the most promising candidate.
A Vaccine Born of Biodefense, Not Outbreak Response
Geisbert's work began in the early 2000s as a defense project. In the wake of September 11 and concerns that terrorists might deploy Ebola and similar pathogens as biological weapons—something the Soviet Union had investigated during the Cold War—the US Army provided funding to develop a vaccine. His first major breakthrough came in 2003, when he found monkeys could be protected from Ebola with a single injection of the vaccine he had developed.
But when Geisbert first published his findings a few years later, he found little commercial interest. "There just wasn't a global market for an Ebola vaccine," he says. "It's not a moneymaker, nobody really wanted to pick it up."
That led Geisbert to investigate whether the vaccine could protect monkeys from different strains of the disease, which would make it cheaper and easier to develop and mass-produce. He tested a blend of vaccines against three of the four Ebola viruses known to harm humans with success, publishing the results in 2009.
Interest reached a critical mass during the 2013 to 2016 Ebola epidemic, when the Zaire strain infected 28,600 people and killed 11,300 in West Africa. That crisis prompted a race to develop a vaccine, resulting in Merck (搜索)'s Ervebo—developed in part thanks to Geisbert's work—which was deployed in a ring vaccination strategy. The vaccine's success earned Geisbert a spot among Time magazine's "Ebola fighters," named people of the year in 2014.
Why Bundibugyo Was Left Behind
Geisbert's initial studies omitted the Bundibugyo strain because it has lower fatality rates and had caused just three outbreaks, including a 2012 outbreak that killed 30 people over about three months in the DRC but was contained fairly quickly through contact tracing and isolation. "We thought that's probably the one that's least likely to pop up," Geisbert says. "We guessed wrong."
The existing Ervebo vaccine doesn't reliably prevent transmission of the Bundibugyo species. While Ebola viruses share a very similar core structure, about 35 percent of the glycoproteins on their surface differ between Zaire and Bundibugyo strains. In experiment results published in 2011, three-quarters of monkeys who received the Zaire-specific vaccine survived infection with Bundibugyo—but that level of protection isn't sufficient for outbreak response.
"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?" Geisbert 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."
The Race to Catch Up
With the present outbreak rivaling the 2013 to 2016 epidemic in scale and scope, efforts to play catch-up are going into high gear. Geisbert suspects WHO's experience with Ervebo is one reason they favor his vaccine candidate, which is essentially "Bundibugyo Ervebo." WHO also noted the success of a similar rVSV-based vaccine targeting the Sudan strain of Ebola in a ring vaccination trial in 2025.
The rVSV-based Bundibugyo candidate's suitability for ring vaccination was backed by a 2023 study showing most monkeys were protected from the virus even when vaccinated after exposure. While the researchers vaccinated the monkeys an unrealistically quick 20 minutes after exposure, the proof of concept sets it apart from candidates under development by Moderna and the University of Oxford.
"There hasn't really been much development since that 2023 study, because we weren't really expecting to see that strain and also because historically it's been associated with lower-rate mortality as well," said Courtney Woolsey, lead author on the paper and an assistant professor at the University of Texas Medical Branch. "Nobody really makes money off these vaccines, so there are funding barriers as well to advance these vaccines where people likely aren't going to make money."
The nonprofit Coalition for Epidemic Preparedness Innovations (搜索) (CEPI) has offered funding of up to $3.2 million to prepare and start testing the material needed to manufacture Geisbert's vaccine, which would be the first step toward human trials. The "extensive safety data and prior regulatory experience" from the rVSV-based vaccines used to combat the Zaire strain "could help expedite approval pathways if it is shown to be successful," said Rachael Bonawitz, filovirus disease programme lead at CEPI, adding that developers would also be able to build on existing manufacturing processes.
Competing Platforms and Timelines
CEPI has prioritized several vaccine candidates. Two are Ervebo-like prototypes aimed at recognizing Bundibugyo's specific glycoproteins, being developed by the International AIDS Vaccine Initiative and Public Health Vaccines. VSV-based vaccines are front-runners because the weakened virus replicates robustly in humans, generating a strong immune response from a single dose. The tradeoff is a higher risk of side effects like fever, achiness, and fatigue, and WHO experts suggest it would take seven to nine months for a Bundibugyo-modified version to be ready for human testing.
Another candidate, ChAdOx1, uses a modified chimpanzee adenovirus that cannot replicate, making it less likely to cause side effects—but early clinical trials showed subjects needed two doses for sufficient 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.
Moderna's mRNA candidate offers speed advantages—an mRNA vaccine can be designed and synthesized in days—but no mRNA Ebola vaccines have ever been trialed in humans, so there is less prior safety data. Distribution is also complicated by cold-temperature storage requirements. CEPI's first round of investments will likely total just under $62 million.
Uncertainty and the Path Forward
Even as Geisbert's vaccine shows promise, there is still a chance it won't work. Scientists have not been able to obtain a live Bundibugyo virus sample from the current outbreak for testing due to stretched resources in the DRC and the logistical and bureaucratic complexity of obtaining and transporting refrigerated blood to the US. While scientists believe the current strain is around 98-percent similar to the strain that caused previous outbreaks, that unknown 2 percent presents a risk.
"When you look at the sequences it's not different enough that I would predict that there would be a problem, but nothing's foolproof," Geisbert says.
The International AIDS Vaccine Initiative in New York will prepare the vaccine candidate for production. "Even if it's not used in this outbreak, hopefully there will be clinical material that can be used in humans available for the next outbreak," Geisbert says, "because it will probably pop up again."
"The baton has been handed off, and I just sit back and hope that it works, whether it's the vaccine, whether it's somebody else's vaccine," he adds.