New data from human studies provide further support for the idea that Merck’s Ebola virus vaccine Elvevo, which was licensed to target the Zaire strain of Ebola, may also provide some protection against another species currently circulating in a rapidly expanding outbreak in the Democratic Republic of the Congo.
The new paper, published online in the New England Journal of Medicine on Wednesday after being posted online ahead of peer review, is one of a growing number of studies pointing to the possibility that a vaccine could be used to target the Bundibugyo strain of the Ebola virus.
These studies have spurred increasing calls to study the use of Erbebo in endemic areas of the DRC, but the World Health Organization has so far expressed lukewarm support for the idea. WHO’s vaccination drive has prioritized testing Bundibugyo-specific vaccines, but it will still be several months before these vaccines are ready for clinical trials in endemic areas.
The WHO said in an email Wednesday that its vaccine expert committee, the Expert Strategic Advisory Group on Immunization, will consider the idea further at its next meeting in early October.
“I think we have reached the point where this issue should no longer be debated, but should be tested in carefully designed prospective clinical studies,” Edouard Rohm, lead author of the new study and a professor at the University of Bordeaux in France, told STAT in an email. “Preparedness is not just about developing the next generation of vaccines, it’s also about rapidly learning whether the tools we already have can save lives.”
Apparently such research is underway. Bloomberg reported earlier this week that the Africa Centers for Disease Control and Prevention is planning a trial to test a two-dose vaccine regimen on health care workers. Médecins Sans Frontières (MSF) is running the trial in partnership with the Africa CDC. At the time of publication, the Africa CDC had not responded to STAT’s questions about the proposed study.
More than 1,000 people die in Ebola outbreak in Congo
The study appears to mimic a study conducted in primates more than a decade ago, which showed that a small number of animals exposed to a potentially lethal dose of the Bundibugyo virus had increased survival after being vaccinated with a vaccine targeting the Ebola virus in Zaire and Sudanese species. IAVI, the nongovernmental organization developing Sudan’s experimental vaccine that uses the same vaccine platform as Merck’s Elvebo, has doses of that vaccine and is in talks with the Africa CDC about making some available for research.
IAVI said in an email: “We intend to supply doses of the investigational Sudanese virus vaccine, subject to coordination between our clinical partners and the relevant authorities in the Democratic Republic of the Congo, and approval of the clinical trial protocol.”
The international stockpile of vaccines, managed by the United Nations Children’s Fund (UNICEF), WHO and other partners, includes 500,000 doses of Elvevo. Merck said in an email that it shares WHO’s concerns that evidence supporting potential cross-protection against the Bundibugyo virus is “very limited” and that the stockpile can only be released at the request of UNICEF.
As of Monday, the number of confirmed cases in the outbreak in northeastern Democratic Republic of Congo had reached nearly 2,500, of which nearly 1,000 had died. These numbers make this outbreak the third largest on record and the fastest-growing infectious disease to date.
WHO Director-General Tedros Adhanom Ghebreyesus told STAT in an interview last month that efforts to control the outbreak were severely hampered by political instability and violence in the region, large numbers of displaced people, and distrust of outsiders’ intentions to help contain the outbreak.
There is currently no licensed Bundibugyo vaccine available, but a number of NGOs developing vaccines specifically for this type of virus are rushing to produce trial doses in endemic areas or conduct preliminary safety and dosing trials, or phase 1 trials. However, the start of these field trials is likely still several months away.
The WHO said Elvebo could be studied under strict clinical protocols, but raised concerns that the cross-protection seen in laboratory studies of blood samples may not translate into meaningful benefit to people. The report suggested that the use of the vaccine could create a “false sense of security in affected communities and response personnel” who may not take necessary precautions to avoid contracting Ebola, potentially undermining efforts to control this outbreak and undermining confidence in Ebola vaccines against future outbreaks if vaccinated people later become infected.
In the weeks since the outbreak was declared underway, multiple research groups have been studying blood samples taken from people who have been given Elvevo for years, looking for evidence of whether Elvevo produces antibodies that may protect against the Bundibugyo virus. Although the results are not completely consistent, they tend to suggest that the vaccine causes the production of what appear to be cross-protective antibodies in some people, but the researchers cautioned that the only way to determine whether those antibodies are truly protective is to test the vaccine in humans.
Isaac Bogach, author of a modeling study that looked at the question of whether Elvevo could help contain the outbreak, said the only way to answer that question was to conduct a clinical trial.
“It is very encouraging that clinical trials for the new Bundibugyo virus vaccine are currently underway,” he said, referring to the phase 1 clinical trials being conducted in the UK for the Bundibugyo vaccine produced by the Oxford Vaccine Group at the University of Oxford. This study to test safety and determine the most effective and acceptable dosage is needed before the vaccine can be tested in the field in large-scale efficacy trials.
“At the same time, increasing evidence from animal studies and human immune response data suggests that existing and licensed Ebola vaccines may provide some degree of cross-protection. Trials evaluating the efficacy of vaccines against Bundibugyo virus should also proceed in parallel, especially given their ready availability,” said Bogach, an infectious disease expert at the University of Toronto.
A commentary published in the journal The Lancet on Monday also promoted Elvevo’s clinical trials, pointing to some suggestive data from the region. This new Ebola outbreak is occurring in the region that experienced the second-largest Zaire Ebola virus outbreak on record from 2018 to 2020. During that period, more than 300,000 people in the region were vaccinated with Elvevo.
The comment authors noted that as of June 24, of the 1,000 confirmed cases with known vaccination status, only nine had received Ervevo during the initial outbreak. All nine survived. Of the 242 deaths for which vaccination status was known at the time of writing, none died.
The commentary also cited unpublished data on a cluster of eight infected health care workers who developed very high-risk infections. They operated on a pregnant woman who was later found to be infected with Ebola. Three had previously been vaccinated. they survived. Five health care workers who had not been vaccinated died.
The authors suggested that Elbebo may be effective even if its protection against Bundibugyo is lower than against Zaire Ebola virus (which is expected). They pointed to the fact that modern malaria vaccines do not provide complete protection, but their effectiveness has proven to be substantial when used in combination with other preventive measures due to the high burden this disease poses to affected countries.
“If the observed signals of (mutual) protection prove to be genuine, the decisions made during this outbreak may be remembered not only for the evidence they generated, but also for the lives they saved,” said the authors, who include Jean-Jacques Muyembe Tamhum, a prominent Ebola expert in the Democratic Republic of the Congo.
Questions remain about El Bevo’s impact on the spread of infection. One unpublished study (posted online as a preprint) looked at serial blood samples taken over five years from about 1,100 people who had been vaccinated during past outbreaks. There was a large difference in the proportion of people who appeared to have developed antibodies against the Bundibugyo virus in the two regions of the country, with the proportion being higher in areas near the areas where the infection is currently raging.
And a modeling study conducted by Bogach and his colleagues suggested that ring vaccination (vaccinating people who have been in contact with a known infected person and the contacts of those contacts), a common approach when using Ebola vaccines, may not be as useful in this outbreak. This is because many infected cases become apparent only after death, making contact tracing extremely difficult. The WHO recently announced that two-thirds of the deaths confirmed in this outbreak were among people who did not seek treatment and were only tested post-mortem.
The Bogach paper warned that “low confirmations or delays in contact tracing could make biologically active vaccines appear ineffective at the population level.”
Paradoxically, if case detection and contact tracing improve, these measures themselves could have a major impact on containment efforts, and the contribution of vaccines (even if used in a ring vaccination strategy) could potentially be modest, the authors write. According to their model, a larger impact could be seen in that setting if a region-wide vaccination approach was used.
