Merck vaccine heads Ebola countermeasures

Swift intervention by local and international health authorities, combined with the rollout of mobile diagnostic labs and an effective vaccine, appear, so far, to have contained the current Ebola virus outbreak in the Democratic Republic of the Congo (DRC), which began in April. A ring vaccination campaign, focused on front-line healthcare workers, as well as infected patients' primary and secondary contacts, seems to have played a decisive role in limiting the spread of the virus. However, just one super-spreading event—traditional burial customs proved to be tragically potent at propagating infection during the calamitous 2013–2016 outbreak in West Africa—could alter the current cautiously optimistic outlook. Should the present outbreak escalate, the DRC and its international allies will also have recourse to five investigational drugs (Table 1), which, if necessary, will be administered under a compassionate-use protocol.

Table 1 Selected Ebola countermeasures in development

“It's a far better set of options than was available in the 2013–2016 outbreak,” says Larry Zeitlin, president of Mapp Biopharmaceutical (MappBio), producer of ZMapp, an antibody cocktail directed against Ebola virus glycoprotein (GP). “I think there was a lot of desperation in that outbreak, and people just wanted to do something. This time we have more data, and there are validated options that can be used.” The live attenuated vaccine developed by Merck and Newlink is the only Western-developed Ebola vaccine that has completed a phase 3 trial and is being administered under an expanded access clinical protocol sponsored by the Geneva-based World Health Organization (WHO). (Although vaccines have gained approval in China and Russia, neither is being deployed in the DRC.)

The first Ebola virus epidemic left a legacy of countermeasures, which were readily deployed during the recent outbreak. Credit: Cultura RM/Alamy Stock Photo

Merck's vaccine appears to act fast. Investigators on the Ebola Ça Suffit ('Ebola, that's enough') study in Guinea and Sierra Leone reported 100% efficacy after a single shot of the recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV), which was administered to 5,837 individuals as part of a ring vaccination campaign. No cases of infection (with an onset of ten days or more after vaccination) occurred among those who received the vaccine immediately after randomization, whereas 23 such cases occurred among a control group who received the vaccine 21 days after randomization (The Lancet, 389, 505–518, 2017).

“I'm not a biostatistician, but the data in that paper look incredibly strong, no matter how you look at it,” says Tom Geisbert, professor in the department of microbiology and immunology at The University of Texas Medical Branch. Geisbert has long experience of working with anti-Ebola agents in biocontainment safety level 4 (BSL-4) facilities. “The VSV [vector] outperforms everything else consistently, probably because it's replication competent,” he says. The vaccine's immunization schedule—a single shot—is an attribute that is particularly useful during an acute outbreak. Its rapid induction of protective immunity is probably due to an activation of the innate immune system, although the vaccine's duration is not yet fully known. “You may need a prime and boost for long-term immunity,” Geisbert says.

The vaccine was developed at Canada's National Microbiology Laboratory, in Winnipeg, Manitoba, and licensed to Newlink Genetics, which entered a development deal with Merck, in late 2014. The supplies that are being shipped to DRC come from a 300,000-dose stockpile, created through an advance purchase agreement Merck entered in 2016 with Gavi, the Vaccine Alliance, of Geneva, a multilateral international organization that promotes vaccine distribution in low-income countries. “We've been maintaining that stockpile. We continue to replenish that stockpile as appropriate,” says Beth-Ann Coller, executive director, vaccines clinical research, at Merck Research Laboratories. The company produces the material at a clinical-trial-scale production facility in West Point, Pennsylvania. A commercial-scale facility in Burgwedel, Germany, is still undergoing validation, which has delayed a regulatory filing for the vaccine. “We've had a few challenges there,” Coller says. “They're vanilla [ordinary] facility issues that just have to be addressed.”

On the therapeutics front, MappBio's ZMapp is ahead. “If you look at the preclinical work in non-human primate models, ZMapp is head and shoulders above the other treatments,” Geisbert says. The cocktail's three antibodies bind different epitopes on Ebola GP, which in its native state exists as a trimer and which mediates cell attachment and infection. The cocktail has been tested in several non-human primate models and in different BSL-4 facilities—and is the only drug with clinical efficacy data. A phase 2 study conducted during the West African outbreak demonstrated that the drug was protective—8 deaths among 36 patients who took the cocktail plus standard-of-care treatment, compared with 13 deaths among 35 patients on standard-of-care treatment only (N. Engl. J. Med. 375, 1448–1456, 2016). But as the epidemic began to abate, the trial did not reach its target enrolment of 100 patients, and the outcome was not statistically significant. Moreover, the study authors noted that the antibody cocktail may have been administered too late to benefit those patients who died—seven of them received just one of three planned doses, and the eighth received two doses. “There was 100% survival in low-risk patients,” says Zeitlin.

Even if ZMapp is administered in a timely fashion, its three-dose schedule is not optimal. MappBio's current production process, in tobacco plant leaves, is also an issue. “The problem we ran into is nobody has yet taken a drug to licensure using the tobacco production system,” Zeitlin says. For that reason, the company is moving to a conventional Chinese hamster ovary expression system. It aims to gain approval, under the US Food and Drug Administration's animal rule (for products that cannot be generally tested in humans), by 2022. In the meantime, MappBio is working on next-generation successors with more convenient dose schedules, a goal shared by the wider community of Ebola drug developers, as repeat dosing places a strain on limited healthcare resources. Remdesivir (GS-5734), a small-molecule antiviral drug, which Gilead Sciences is developing, requires daily intravenous infusion over 12 days, for example.

The first in a new wave of single-dose drugs could be Regeneron Pharmaceuticals' triple antibody cocktail REGN-EB3. “We are efficacious with a single dose,” says Leah Lipsich, vice president of strategic program direction at Regeneron. It was initially designed as a three-shot product, but non-human primate experiments demonstrated a protective effect after two doses. The company then found that a higher front-end dose provided similar protection, even in symptomatic animals (J. Infect. Dis. 10.1093/infdis/jiy285, 2018). The Vaccine Research Center at the National Institute of Allergy and Infectious Diseases and partners are working on another single-shot therapy. Mab114, a single-antibody drug, was identified by screening the memory B-cell repertoire of an Ebola virus infection survivor from a 1995 outbreak in the DRC. It protected macaque monkeys when given five days after an Ebola challenge (Science 351, 1339–1342, 2016). Mab114 is currently low on the WHO priority list, however, due to the paucity of clinical data. So, too, is favipiravir, developed by Fujifilm-owned Toyama Chemical. Its efficacy is uncertain, and the appropriate dose has not yet been established, according to the WHO's own assessment

Of course, with an agent such as Ebola, human clinical trials can only evaluate a drug's safety, tolerability and pharmacokinetic profile. To assess efficacy, drug developers must conduct non-human primate challenge studies and this requires access to BSL-4 facilities, which are limited in number. It's a major bottleneck for drug developers. “Data is very hard to come by because it's very hard to do these studies,” says Christos Kyratsous, senior director for infectious diseases and viral vector technologies at Regeneron. “Everybody is competing for the same space.”

The lack of commercial viability for anti-Ebola agents is another major drag on development. Some of the programs that started to scale up just as the first major crisis started to abate had built enough momentum to continue into the present time, but others have fallen by the wayside. Arbutus Biopharma, of Vancouver, British Columbia, shelved a promising lipid-nanoparticle-formulated short interfering RNA drug TKM-130803. Novavax parked an adjuvanted lipid-nanoparticle-based recombinant vaccine based on Ebola GP trimers, despite what Gregory Glenn, its president of R&D, describes as promising data and a clear path to licensure. “There is no market,” he says. “Kudos to Merck for being able to carry on with development, when there's very little opportunity there.” Last September, the US Biomedical Advanced Research and Development Authority (BARDA) earmarked four programs for development funding and stockpile purchases: vaccine programs from Johnson & Johnson and Merck, which received $44.7 million and $39.2 million, respectively, and MappBio's ZMapp and Regeneron's REGN-EB3 programs, which received $45.9 million and $40.4 million, respectively. Without a similar guarantee, Novavax was unable to move forward.

It's still an open question whether the resources that have been brought to bear on the present outbreak have been enough. The West African outbreak, which led to 28,616 cases and 11,310 deaths, was unprecedented in its scale and duration. Each of the eight Ebola outbreaks the DRC experienced between 1976 and 2017 involved fewer than 400 cases (some far fewer than that) and resolved within six months. These smaller outbreaks may offer a better benchmark against which to gauge the effectiveness of the Merck vaccine in limiting the current outbreak. The hope is that the health authorities' capabilities—and those of others tackling future outbreaks—will be strengthened by the addition of effective vaccines and drugs, but the management of the response will always remain critical. “If you look at the response now compared with 2014, it's just night and day,” says Richard Hatchett, the former deputy director and chief medical officer at BARDA, who is now the CEO of the London-based Coalition for Epidemic Preparedness Innovations, a multilateral body that has raised $620 million of its $1 billion target to accelerate the development of vaccines against emerging pathogens. The current response may offer a blueprint for future outbreaks. “This will be seen as a pivotal moment.”