While Ebola virus disease in the U.S. is a rare occurrence, the FDA approval of Merck & Co. Inc.’s Ervebo, the agency’s first for preventing Ebola Zaire virus in people age 18 and older, will have a ripple effect across the world, especially Africa where its effects have been devastating for decades.
Stockpiling such a vaccine is crucial to world safety as Ebola has long been a potential bioterrorism threat, especially after 9/11. In the world of theoretical biological warfare, where the virus could be weaponized and disseminated by aerosol, Ebola virus is considered the most dangerous, with fatality rates estimated between 25% to 90%.
In 2017, the U.S. HHS’s Biomedical Advanced Research and Development Authority (BARDA) began its efforts to battle Ebola. To meet the U.S.’s biodefense goals this past August, BARDA provided $23 million to Merck to produce Ebola vaccine doses over the next year, bringing its total to $176 million to support its development.
In 2016, Gavi, the Vaccine Alliance, paid Merck $5 million to conduct Ebola vaccine research. Gavi is putting up $178 million by 2025 for stockpiling Ebola vaccines, for both response and prevention, around the world. Gavi-supported low- and middle-income countries will be able to access the stockpile at no charge and be supported for operational costs of vaccination campaigns. Wealthier countries may also access the cache, but they’ll do it on their own tab.
While Merck is in line to obtain conditional marketing authorization from the European Union for Ervebo following a positive recommendation for approval from the EMA's Committee for Human Medicinal Products at its October meeting, the FDA nodded to its partners, including the HHS and the World Health Organization, when announcing the approval.
According to the CDC, Ebola can be spread through direct contact (through broken skin or mucous membranes) with infected blood or body fluids or objects that have been contaminated with infected body fluids. Symptoms usually begin after an incubation ranging from two days to 21 days. During outbreaks, it can spread quickly through families and healthcare settings.
Plenty of others are working to stop Ebola. Aside from Merck’s Ervebo, there are seven other Zaire Ebola virus vaccines being developed.
Regeneron Pharmaceuticals Inc., of Tarrytown, N.Y., is in a phase III study of REGN-EB3 (atoltivimab + odesivimab + maftivimab), a viral structural protein inhibitor to treat Ebola virus infection. In August, the Palm trial of 681 patients during an ongoing outbreak in the Democratic Republic of the Congo showed the triple-antibody cocktail outperformed the Zmapp (Mapp Biopharmaceutical Inc., Defryus Inc.) control arm across multiple measures, including a primary endpoint of mortality at day 28 (33.5% vs. 51.3%, p=0.002) and a secondary endpoint of reduction in days until virus was undetectable in bloodstream.
Bavarian Nordic A/S, of Copenhagen, said Johnson & Johnson, of New Brunswick, N.J., is providing up to 200,000 regimens of its investigational Ebola vaccine to the Republic of Rwanda to support a new immunization program led by the Rwanda government. The vaccine regimen, which consists of the MVA-BN Filo vaccine from Bavarian Nordic and the Ad26.ZEBOV vaccine from J&J unit Janssen Pharmaceuticals, will help protect Rwandans from the current Ebola outbreak in the neighboring country, the Democratic Republic of Congo, the companies said. A marketing authorization application was submitted to the EMA in early November.
The FDA decision on Ervebo comes well before the March 14, 2020, PDUFA date. Merck expects to make doses of the live attenuated vaccine (rVSVΔG-ZEBOV-GP) available to patients in the third quarter of 2020. Ervebo was on the receiving end of a priority review and a tropical disease priority review voucher from the FDA, as well as being granted breakthrough therapy designation.
It’s been a long time since the virus was first identified, in 1976, to the first FDA-approved protective vaccine. Ervebo, which has been genetically engineered to contain a protein from the Zaire Ebola virus, is administered as a single-dose injection, and it has its limits. The duration of protection conferred is unknown, it doesn’t protect against other species of Ebola virus or Marburgvirus and its effectiveness when administered concurrently with antiviral medication, immune globulin and/or blood or plasma transfusions is not known.
Ervebo, a replication-competent recombinant vesicular stomatitis vector expressing Zaire Ebola virus glycoprotein, was initially engineered by the Public Health Agency of Canada’s National Microbiology Laboratory. The technology was then licensed by a subsidiary of Ames, Iowa-based Newlink Genetics Corp. In late 2014, at the peak of the 2013-16 epidemic in Guinea, Merck acquired the rights to develop the drug from Newlink in a $500 million deal.
A phase III field trial conducted during the epidemic, involving 5,837 individuals, appeared to provide 100% protection after a single shot. None of those who received the vaccine became infected, whereas 23 cases occurred in a control group who received the vaccine 21 days after randomization.
The Republic of Burundi is using the vaccine under a protocol allowing expanded access and compassionate use during Ebola outbreaks related to the Zaire strain. "No cases of Ebola have been reported in Burundi, but preparation remains crucial," the WHO said.