Why won’t approved Ebola vaccines work for the current outbreak in DRC and Uganda?

On May 17, the World Health Organization (WHO) declared the Ebola outbreak in the Democratic Republic of the Congo (DRC) and Uganda a public health emergency of international concern. At the time of the announcement, the WHO reported nearly 250 suspected cases and 80 suspected deaths from the outbreak. The outbreak has grown since then, and the WHO also warns that the number of cases might be considerably larger than health agencies have reported so far.

The WHO has also stated that there are no approved vaccines or therapeutics that could be of use to help contain the current outbreak. Yet Ervebo, the Ebola vaccine manufactured by Merck & Co. was approved by the US Food and Drug Administration and European Medicines Agency in 2019 and was highly effective at protecting against the disease during the 2018 DRC outbreak (Lancet 2024, DOI: 10.1016/S1473-3099(24)00419-5). Johnson & Johnson also has an Ebola vaccine approved in Europe, and two monoclonal antibody (mAb) treatments are approved for global use as well. So why aren’t these vaccines and mAbs being used now?

In short, Ebola is a catchall name for the disease caused by four of the six species of Ebolavirus (also called Orthoebolavirus). The vaccines and mAbs were designed to be protective against Zaire Ebola virus, one of the most commonly circulating species, whereas the current outbreak is of the rarer Bundibugyo virus.

Ervebo is based on a harmless vesicular stomatitis virus that’s been modified to present the Zaire Ebola virus glycoprotein on its surface. This way, the body’s immune system can produce antigens against the glycoprotein and then is primed to fight off the real Zaire Ebola virus.

But Kristian Andersen, an immunologist at Scripps Research Institute in La Jolla, California, says that “if we’re looking at the 2014 variant of Ebola Zaire, which was that big epidemic in West Africa, versus Bundibugyo, they are about 35% different in the glycoprotein.”

And Krutika Kuppalli, a physician at the University of Texas Southwestern Medical Center who ran an Ebola clinic in Sierra Leone during the 2014–16 Ebola outbreak, tells C&EN via email that “the immune response generated by Zaire-based vaccines may not recognize it well enough to provide reliable protection.”

“The glycoprotein is the only viral protein on the virion surface and is essential for attachment and fusion, making it the central target for vaccines and many antibody therapies. Even relatively modest structural or sequence differences in this protein can affect whether antibodies bind and neutralize effectively,” Kuppalli says.

While the Zaire and Bundibugyo virus glycoproteins are quite different, there are still some regions of the protein that are very similar between the two viruses, including the stalk of the glycoprotein, Andersen says. That has some experts hopeful that Zaire Ebola virus vaccines and treatments might have some protective effect, but the data are slim.

Earlier this week, STAT reported that the WHO is considering the possibility of using Ervebo in the current outbreak based on a 2011 paper suggesting some protective effect against Bundibugyo virus in a very small sample of nonhuman primates (J. Infect. Dis., DOI: 10.1093/infdis/jir350). But Andersen isn’t optimistic that that’s the best way to control the outbreak.

“There’s going to be some T-cell responses that are probably able to cross react, because we do have some layers of conservation across the glycoprotein, but it’s minimal,” he says. “It’s worth doing a clinical study, but I think the idea that, like, ‘Oh, let’s just roll out Ervebo and then hope for the best’ is misguided.”

Andersen shares a similar sentiment for the mAbs on the market and those in development, saying it’s worth studying them in the context of the outbreak but not relying on them to help contain it. The company Mapp Biopharmaceutical does have a stockpile of experimental mAbs designed to target multiple species of Ebolavirus, Andersen claims; the drug just hasn’t gone beyond Phase 1 trials in humans yet.

Vaccines and mAbs are relatively new tools for tackling Ebola, and the global public health community has a history of containing outbreaks without them.

“In the absence of a vaccine, response depends on the fundamentals: rapid case identification, isolation, safe and dignified burials, contact tracing and monitoring, infection prevention and control, PPE [personal protective equipment] for healthcare workers, community engagement, cross-border surveillance, and high-quality supportive care,” Kuppalli says via email. “The lack of a vaccine makes speed, trust, and health-system support even more important.”