An unlicensed vaccine, made by Merck, which performed exceptionally well during the deadly West African Ebola outrbreak of 2015, is being trialled in the latest Democratic Republic of the Congo in the hope that the 'experimental' intervention might help curb the outbreak and offer some insights for the future.
Science Mag reports that the DRC has approved one vaccine trial, and a second study piggy backed on it to assess immune response to the vaccine, in the hope that the “experimental” intervention might help curb the outbreak and offer some insights for the future.
The unlicensed vaccine, made by Merck, performed exceptionally well in a large clinical trial held in Guinea during the 2015 outbreak, but it came as that epidemic already was winding down and had little impact on bringing it to an end. At last count in the DRC, 52 cases were confirmed, probable, or suspected; 22 deaths had been reported; and the outbreak had spread to three locations in Équateur province, including a city of 1.2m people on the heavily trafficked Congo River.
The report says the new trial will mirror the strategy used in Guinea and vaccinate “rings” of people around cases: contacts (there are more than 600 already), contacts of contacts, and front-line responders. The study will follow vaccinated people to see whether they develop disease and to monitor for adverse events to assess safety. For ethical reasons, there is no control group, however, so the study will yield limited data about efficacy.
“The vaccine is just one part of the big response,” explains Yap Boum, a microbiologist with Médecins Sans Frontières (MSF) who lives in Yaoundé and is helping the DRC’s Ministry of Public Health run the study. (Studies of other experimental treatments like monoclonal antibodies and drugs may take place, but none has yet been approved by the DRC government.)
The second study will try to extract more data from the vaccine trial. Since 2015, a group led by epidemiologist Anne Rimoin from the University of California Los Angeles, has been working with colleagues in the DRC on an Ebola study that has taken blood samples from more than 1,000 health care workers, as well as about 100 survivors and their contacts. Now, in collaboration with Boum and the vaccine team, the group is expanding that work to collect samples from the new volunteers who are participating in the vaccine trial. “Usually during outbreaks you’re scrambling to get these protocols in place and luckily we already have one that matches up quite nicely with the objective of the government and everyone who is wondering how well these vaccines might work,” Rimoin says.
The blood work could clarify whether people have pre-existing immunity to Ebola, in which case the vaccine would be boosting an existing response. Analyses of various immune responses triggered by the vaccine in people who do and don’t develop Ebola also could help clarify why the vaccine succeeds or fails.
To properly collect and store blood samples, the report says Rimoin’s team travels to remote areas of the DRC with freezers that go down to –80°C, which they power with their own generators and batteries. They also cart in thousands of test tubes, pipettes, and other equipment to create their field lab. “When we’re doing this work we spend a lot of time on logistics of how we keep samples cold,” Rimoin says.
Although the Guinea trial found that the vaccine offered an astonishing 100% protection in vaccinated clusters, it did not take blood from participants. Rimoin points out that the Guinea population differs both genetically and immunologically from that of the DRC. In particular, she notes, Ebola had never been seen in Guinea before that epidemic, whereas this is the ninth outbreak in the DRC. “It’s very important to get as much data as you can to understand how the vaccine works in different populations,” Rimoin says.
The report says some investigators who worked on the Guinea study question the practicality and value of taking blood samples in the DRC. “Blood draws would complicate significantly field operations in communities affected by the disease, where blood is not just a fluid but is charged with symbolism,” says Marie-Paule Kieny, who helped run the study when she worked for the World Health Organisation. She is now director of research at INSERM, the French biomedical research agency, in Paris. At the time of the Guinea study, communities reacted violently to some outreach workers, and there initially was much concern that many people would not even volunteer to participate in a vaccine study—but nearly 8000 people did.
Mark Feinberg, who heads the International AIDS Vaccine Initiative in New York City and who worked for Merck during the trial in Guinea, also questions the value of Rimoin’s study. Merck’s vaccine was tested in many other studies, and several of those did blood draws to help clarify the relationship between the vaccination and various immune responses. Merck says it plans to use data from some 18,000 vaccinated people in those trials to support its application for licensure next year. “I am not sure that having additional data on immune responses in the current outbreak in DRC would add significantly to this data package,” Feinberg says.
But, the report says, to Anthony Fauci, who heads the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, more data are always good. “It’s always better to have material that you can examine than to not have any material,” he says.
And Linda Venczel, an epidemiologist with international health non-profit PATH in Seattle, Washington, who works in the DRC agrees. The study is “fantastic,” she says, and Rimoin’s group has the trust of public health leaders in the country. “Their sero-surveys are very important,” Venczel says. “This is the kind of quantitative data that we need.”
The MSF and the WHO are testing the Ebola vaccine in collaboration with the DRC’s Ministry of Health. Dr Charlotte J Haug writes in the New England Journal of Medicine that they must act in a state of extreme uncertainty: the situation is evolving by the hour, information is hard to come by, and the ethical dilemmas and practical hurdles are abundant. And they are using slightly different approaches.
“There are all these practical things,” Rebecca Grais says, “and you have the collision of all these different worlds at the same time: the humanitarian world, the research world, the North–South, different populations and languages.”
Grais is the director of research at the MSF Epicentre in Paris, an organisation created in 1986 to provide epidemiologic expertise to support MSF operations.
Haug writes: “I am meeting with her on 17 May – 9 days after the WHO was notified of two laboratory-confirmed cases of Ebola virus disease in the Équateur province of the DRC. People run in and out of her office, exchanging information and getting ready to travel to the DRC as quickly as possible. They will be leaving in a couple of days to study the effects of the rVSVΔG-ZEBOV-GP Ebola vaccine (Merck) in real time during an outbreak.
“The vaccine’s safety and efficacy were very promising when it was studied in Guinea and Sierra Leone in 2015,1 but the research was conducted at the tail end of the epidemic, so it was not clear how much of the reduction in transmission could be attributed to the vaccine and how much simply to the waning of the epidemic. Further investigation is needed to determine how the vaccine will work as this outbreak unfolds in a different country and setting.
“As Grais thinks about her upcoming journey, an envelope full of cash lands on her desk: you can’t swipe your credit card in Bikoro, the epicentre of the outbreak, where there isn’t even running water. But although the travel will not be easy, in many ways the outbreak may offer the best scenario for learning more about the vaccine. The DRC has had – and has controlled – multiple Ebola outbreaks. The country has experienced public health teams and has had excellent collaborations with MSF and other international organizations for many years. The collaborators should be able to implement their plans, but some things are different this year that make doing so more challenging.
“Équateur is different from other parts of the DRC – 40% of its population is Twa, an African Pygmy group that lives interdependently with agricultural Bantu-speaking populations, providing them with game in exchange for farm products. The Twa population is already marginalised and vulnerable, and the research effort will face many issues related to language and culture, beginning with understanding and communicating perceptions of risk, vaccination, and treatment.
“Grais notes that in addition to the rural outbreaks, ‘the other thing that makes this different is that there have been cases in Mbandaka, the capital of the Équateur province, with a population of about a million and connections to Kinshasa (the capital of DRC). This changes the degree of difficulty.’
“Yet the ministry of health, MSF, and the Epicentre team started preparing for such an effort before the last DRC epidemic in the spring of 2017: they wrote protocols and submitted them to the national health authorities in DRC, worked closely and trained with the ministry of health, discussed and modified the plans to be sure the people involved on the ground understood and agreed to them. ‘The protocol isn’t the part that is complicated here,’ Grais says. ‘The hard part is how do you make a series of quick judgment calls on the spot, keeping in mind the fact that you are a visitor and you want this information to be shared. That is the part that is tough.’
“It is, of course, impossible to run a randomised, placebo-controlled trial now. So, MSF is running an open-label, single-group study to provide additional information on the vaccine’s safety and effectiveness. Everybody who consents to take part will be included, and participants will be followed for at least 42 days (twice what is often considered to be the maximum incubation period of Ebola virus disease), whether or not they choose to be vaccinated. The plan is to include 500 people in the trial and to start as soon as possible after the teams are on the ground in the DRC.
“Peter Salama, WHO deputy director-general for emergency preparedness and response, speaks with me from his office in Geneva on 19 May, a day after a WHO emergency committee decided that the DRC situation did not yet meet the criteria to be declared a Public Health Emergency of International Concern. ‘But it is close,’ Salama says, ‘and the group can reconvene on short notice.’
WHO teams will start using the Ebola vaccine in the DRC on 21 May, Salama tells me: the WHO Strategic Advisory Group of Experts (SAGE) on Immunisation recommended in April 2017 that ‘the rVSVΔG-ZEBOV-GP vaccine be promptly deployed under the Expanded Access framework, with informed consent and in compliance with Good Clinical Practice’ if an Ebola disease outbreak ‘occurred before the candidate vaccine is licensed.2
“Since the vaccine is not yet licensed, this is the only way to use it, according to Salama. One of the advantages is that liability is covered by the WHO. But the WHO approach differs in some details from the research approach MSF described to me 2 days earlier. Early or expanded access programmes (EAPs), also called compassionate use programmes, are in place to provide access to medicinal products that have not yet received regulatory approval.
“In a clinical trial setting, the primary intent is research, whereas in an EAP the intent is treatment. Such a programme is therefore usually managed differently from a clinical trial in terms of both documentation and approval processes. But both MSF and the WHO are eager to see research integrated into the operational responses, because, as Salama says, ‘otherwise we simply will never learn’ what the best approach is.
“Salama believes the greatest challenges and risks involved in deploying the new vaccine are related to communication and logistics. ‘The communication has to be handled very carefully, since we are bringing in vaccine, but it is only going to very specific people,’ he says. ‘It is extremely important to get that right.’
“And getting the logistics right is even harder. The Équateur province is in the middle of one of the densest forests on the planet, with no roads except some tracks that are passable only by motorcycle. It takes a huge logistical effort just to get people and equipment there, not to mention a vaccine that needs to be stored at −60 to −80°C.
“Close collaboration with the local government and mutual trust are other keys to success. Salama explains how essential it is that Oly Ilunga Kalenga, the DRC minister of health, is hands-on, engaged, effective, and very committed. ‘He was at the airport texting me at midnight 2 nights ago because he wanted to make sure he would personally go and receive the vaccine that we flew from Geneva to Kinshasa, to make sure it didn’t get stopped in customs clearance processes and could be taken straight to the cold chain,’ Salama says. ‘It is a very delicate vaccine, and he didn’t want anything to happen to it. He personally met the vaccine at the airport and cleared it through customs – at a very odd hour of the night. It is that level of commitment that it takes. And we don’t often see that type of commitment anywhere around the world.’
“Conducting research alongside response is completely different from the usual setup of a research institution, Grais points out near the end of our conversation. It’s not necessarily more complicated – you just need to know how to do it. ‘When people say it is really hard – just look at these roads! – I think: this is Congo,” she says. ‘This is only difficult if this is not what you do every day. Sometimes even in terms of making compromises, that’s often used as an excuse: Oh well, the conflict is difficult, so we didn’t do that. But I would make the counterargument, which is that you are dealing with the most vulnerable, so if anything, your degree of rigor must be very high.’”
The vaccination campaign is already under way in Mbandaka, a city on the Congo River where four Ebola cases have been confirmed. The Independent reports that about 100 health workers have been vaccinated there as frontline workers face high risk from the virus, which is spread via contact with bodily fluids of those infected, including the dead. The vaccination campaign will also begin in the rural areas of Bikoro and Iboko in the country’s northwest, Health Ministry spokesperson Jessica Ilunga said.
Of the 10 confirmed Ebola deaths, five have occurred in Bikoro, two in Iboko and three in the Wangata area of Mbandaka. In addition to the confirmed Ebola cases there are also 13 probable cases and six suspected ones, the health ministry said.
The report quotes the WHO emergencies chief as saying that the next few weeks are crucial in determining whether the outbreak can be brought under control. Complicating factors include the spread of Ebola to a major city, the fact that health workers have been infected and the existence of three or four “separate epicentres” that make finding and monitoring contacts of infected people more difficult.
The report says this is Congo’s ninth Ebola outbreak since 1976, when the haemorrhagic fever was first identified. The WHO is using a “ring vaccination” approach, targeting the contacts of people infected or suspected of infection and then the contacts of those people. More than 600 contacts have been identified.
The organisation is also accelerating efforts with nine neighbouring countries to try to prevent the Ebola outbreak from spreading there, saying the regional risk is high. It has warned against international travel and promoted trade restrictions.
The report says the difficulties in keeping track of contacts was highlighted by the fact that two Ebola patients were taken from a treatment centre in Mbandaka earlier this week with the help of their families, according MSF. One of the patients died at home, and his body was returned to the hospital, while the second came back to the facility the next day but later died.
The WHO assumes 100 to 300 cases of Ebola in the DRC between May and July, under a revised response plan to the outbreak that it published on Tuesday. Polity reports that an earlier version of the plan, based on information to 15 May, had assumed 80 to 100 cases. The WHO says the new figure is not a prediction but part of its modelling to plan and budget for a response.
Congo's Health Ministry said late on Monday there had been 54 cases of Ebola in the outbreak – 35 confirmed, 13 probable and six suspected – and 25 deaths. There have been no deaths or new confirmed cases in the past two days.
The WHO's plan for Congo assumes each rural Ebola case would have 10 potentially infected contacts and each urban case would have 30. As of 26 May, there were 906 contacts being followed, WHO spokesperson Tarik Jasarevic said.
The report says identifying contacts is crucial for stopping the spread of the disease. Health workers hope to vaccinate every contact to effectively ringfence each Ebola patient and prevent further spread.
The WHO estimates 1,000 people move each day through major points of entry connected to Bikoro health zone, the remote area of Equateur province where the outbreak was first declared. Around 50 per day go by boat from Bikoro to neighbouring Republic of Congo.
Since the plan was written, the disease has spread to the provincial capital Mbandaka, with an estimated population of 1.5m people, and WHO has more than doubled its response budget, to $56m from an initial $26m.
The report says the plan also sets out targets for the disease response, including that 100 percent of new cases should come from known contacts and none of the cases should be health care workers. Zero contacts should be lost, and all people who die from suspected or probable Ebola should be buried in a safe way, to prevent the infection spreading.
The case fatality ratio for all confirmed cases admitted into Ebola treatment centres should be less than 50%, it said.
The WHO says it is awaiting formal approval from the DRC to send in unlicenced Ebola medication to help rein in an outbreak of the deadly virus. A "major innovation in this outbreak is the potential for use of therapeutic regimens," Salama is quoted in a News24 report as saying. He said the agency and the DRC health ministry were considering allowing the use of five as-yet unlicenced drugs. They are known by their laboratory names of ZMapp, Remdesivir (GS-5734), REGN3470-3471-3479, Favipiravir and mAb 114.
Salama stressed that all of the drugs were as yet "unregistered." Because of this, they can only be used under the protocols used for research and clinical trials, which also requires ethical reviews and informed consent from each recipient, he said. "But the government is very keen to begin using this and we expect to formally get approval and start within the coming days," he said. The two first drugs on the list had already been tested in humans, while the remainder had been tested in animals, he said, adding that there was "some data on safety."
He suggested the current outbreak presented an occasion to test which of the drugs was most effective. This way, there will be "more information in the future outbreaks on which drugs could be most effective."
The report says Tuesday's announcement came after DRC health authorities last week launched a small, targeted campaign using an unlicenced Ebola vaccine in Mbandaka.
Vaccination has also begun in Bikoro and is expected to start this week in Iboko.
The campaign, using the rVSV-ZEBOV vaccine, aims to immunise health workers and anyone known to have been in contact with people infected with Ebola, as well as contacts of those contacts.
Salama said the campaign had so far "gone quite smoothly", with more than 400 people vaccinated to date, and hailed that no one to date had refused the vaccine. He said it was too early to "conclude that we have safeguarded the city of Mbandaka, but we can say that so far there has not been an explosive increase in cases, so that is a positive sign." "We have reason to be cautiously optimistic," he said.
Salama said large-scale clinical trials of the vaccine in Guinea had showed it offered protection against Ebola for more than a year, and that researchers "suspect it's going to be much longer than that." And he said tests were being done using another vaccine which was believed to offer protection for even longer.
The report says there are large logistical challenges with delivering the rVSV-ZEBOV vaccine, including the fact that it needs to be stored at -80 degrees Celsius (-112 degrees Fahrenheit). Only about 40 vaccinations per day are feasible, Jean-Clement Cabrol, MSF's emergency medical coordinator, said.Sciencemag report New England Journal of Medicine article The Independent report Polity report News24 report