Exclusive: Vaccine Trial Against Sudan Ebolavirus – With No Recent Infections in Uganda, What’s Plan B? Analysis 23/12/2022 • Elaine Ruth Fletcher Share this:Click to share on Twitter (Opens in new window)Click to share on LinkedIn (Opens in new window)Click to share on Facebook (Opens in new window)Click to print (Opens in new window) The first vaccine candidates against the Sudan Ebola virus arrive in Kampala, Uganda. What to do now? The World Health Organization (WHO) isn’t talking about it publicly, but behind the scenes WHO is planning a meeting for 12 January to evaluate next steps, Health Policy Watch has learned, as the absence of new cases in the Uganda outbreak makes it impossible to begin a clinical trial based on a ring vaccination of recent Ebolavirus contacts. WHO’s plans to launch a clinical trial with Uganda to test three new vaccine candidates designed to combat the Sudan strain of the deadly Ebolavirus. That could come to an end, however, if the current outbreak that has claimed 55 lives since it began is declared over by 11 January, after the elapse of 42 days without new cases. ”There have been no new Ebola cases in Uganda for three weeks. The countdown to the end of the Ebola outbreak in Uganda has begun,” said WHO Director General Dr Tedros Adhanom Ghebreyesus at a press conference on Wednesday, 21 December. “If no new cases are detected, the outbreak will be declared over on the 11th of January.” Already, more than 21 days has now elapsed since any contacts of existing Ebola cases were traced and identified, according to the latest Situation Report, published Monday (December 19) by the Government of Uganda and WHO’s African Regional Office. Contacts identified within 21 days of their exposure to Ebola comprise the test group that was supposed to receive doses of the experimental Sudan Ebolavirus vaccines, as part of the “ring vaccination” approach of the clinical trial planned jointly by WHO and the Ugandan Health Ministry. Original clinical plan to test three vaccines is increasingly unworkable In the original WHO protocol, three Ebola vaccine candidates were to be tried. That plan looks increasingly unworkable. Until late last week, WHO, which led the design of the trial, was still saying that the clinical trial would go ahead, as planned, based on a protocol that would randomize contacts of Ebola cases into two groups for each of the three vaccines to be tested – a test group that would receive the vaccine within 21 days of exposure and a “control” arm of contacts who would also receive the vaccine but only after 21 days of their exposure. “The trial will start by including the contacts of the recently confirmed cases of Ebola (those with date of onset less than 21 days),” a WHO spokesperson told Health Policy Watch on Friday 16 December. “For more details refer to the protocol that is already online.” Follow-up emails requesting more elaboration received no response. However, insofar as “no active contacts are currently under follow-up,” according to the Uganda/WHO AFRO Situation report published on Monday, it is impossible to start a trial right now along the lines of the WHO and Uganda-approved Tokomeza Ebola ring trial protocol, a number of expert observers, as well as one of the three vaccine developers, confirmed in recent interviews. And if only sporadic new cases were to re-appear, testing three vaccines by immunizing recent contacts of Ebola cases along the ring model proposed for the trial would be unlikely to yield statistically relevant results, according to several clinical trial experts close to WHO. The experts agreed to be interviewed by Health Policy Watch only on condition of anonymity. All three vaccines now in place, but no one to receive the doses Swati Gupti, IAVI “The good news is it does definitely look like the outbreak is subsiding,” said Swati Gupta, head of emerging infectious disease and scientific strategy at IAVI, in an IAVI Report, 14 December. IAVI is the non-profit institute overseeing development of one Ebola vaccine candidate for the Sudan strain of the virus, and the candidate also deemed by an independent WHO advisory team to be the most promising. “By definition, if you are doing a ring vaccination trial, where the rings are formed by vaccinating contacts of cases; if there are no new cases, you’re not going to be able to use that particular design,” Gupta told Health Policy Watch in an interview on Friday. That, despite the fact that 2,160 doses of IAVI’s vaccine candidate arrived in Uganda on 17 December, following the arrival of a batch of 1,200 Sabin vaccine candidates on 8 December. On 15 December, meanwhile, 40,000 doses of the Oxford vaccine candidate, manufactured in record time by the Serum Institute of India, also arrived in Uganda. WHO, when asked repeatedly by Health Policy Watch for clarifications of a possible way forward on testing the three vaccine candidates against a virus that has a 40% fatality rate, declined to comment further, saying it would be “speculation.” Behind the scenes, however, WHO appears to be preparing for a re-evaluation. It is planning a 12 January meeting with vaccine experts and developers to discuss a way forward, Health Policy Watch has learned. Not coincidentally, that meeting is planned for the day after the 42-day waiting period is over to determine if the current outbreak is declared over or not. Although that meeting hasn’t yet been publicly announced, it appears to reflect a dawning realization that a new approach will likely be needed in either scenario. Key strategic decisions to be made Conversations with vaccine experts inside and outside of WHO, as well as with two of the three manufacturers of the current vaccine candidates, underline that a new strategy will very likely be needed in order to advance potential vaccines candidates in scenarios where new cases are sporadic or nil. Health workers at Uganda’s Madudu Health Center assemble in meeting with a visiting UNICEF director during the recent outbreak. That would involve critical choices about how many vaccines can realistically be tested – as well as whether animal models should be used to prove efficacy to speed regulatory approval of the vaccine candidates. “What is needed is a plan A and a plan B,” said one such expert and WHO insider, speaking on condition of anonymity to Health Policy Watch. “Historically the number of cases of the Sudan Ebolavirus has been very limited. We don’t know what the trajectory of this is, whether this is a small outbreak that will lead to only sporadic cases in the future, or if it is the beginning of something new. But work being done now is absolutely paramount. The current trial protocol calls for testing all three vaccine candidates. These include two adenovirus vaccines, developed by the Sabin Vaccine Institute and Oxford University respectively, and IAVI’s VSV-vactored candidate. The IAVI vaccine is based on the vaccine developed by Public Health Canada and Merck & Co. against the Zaire Ebolavirus strain, successfully tested and deployed during the 2014-2015 West Africa Ebola outbreak, and, following regulatory approval, in the Democratic Republic of Congo’s 2018-2020 outbreak. An independent advisory committee has already advised WHO that in the event that testing all three vaccines simultaneously isn’t feasible, the IAVI vaccine should be prioritized, since it is based on an adapted version of an already proven vaccine. Narrowing candidates down to one vaccine? Contact tracers and village health teams tackling Sudan ebolavirus at its height in October – their efforts proved effective in bringing the outbreak under control. Even in the unfortunate scenario where new cases of Sudan Ebolavirus occur, WHO and its Ugandan counterparts need to carefully weigh the feasibility of clinically testing all three vaccines against an alternative testing strategy that would test just one vaccine candidate, experts told Health Policy Watch. The WHO-approved trial protocol that was to be deployed in Uganda, dubbed the Solidarity/Tokomeza Ebola trial, was designed on the basis of the vaccine clinical trial staged during the 2014-2016 West African outbreak. That trial successfully tested a first-ever vaccine against the Zaire Ebolavirus strain. In that Ebola outbreak, the largest in recorded history, up to 30,000 people were infected and more than 11,000 died before it came to an end. But even in that much larger outbreak, just one Ebolavirus vaccine candidate, Merck’s, was initially tested on its own in a trial staged in Guinea. The trial involved more than 7,600 contacts of Ebola patients, randomized to receive the vaccine immediately or after 21 days. A second candidate, Johnson & Johnson’s two-dose regimen of Ad26.ZEBOV and MVA-BN-Filo, was later tested as a prophylactic, and finally approved for use by the European Medicines Agency only in July 2020. In the case of the Sudan strain, however, outbreaks historically have been smaller and more sporadic than those involving the Zaire Ebolavirus strain that has repeatedly afflicted West and Central Africa over the past decade. And no one inside or outside of WHO is hoping for more Ebola cases simply to test vaccines. But in a context, where the likelihood is that future outbreaks may be small and more scattered, the ambitious aim of conducting trials on the efficacy of three vaccines simultaneously may no longer be fit for purpose. “It’s natural that in October, when cases were increasing and you didn’t know what the epidemic curve was going to look like, that the WHO would want to review all three candidates, especially given they didn’t know when they would receive doses from all three developers,” Gupta, of IAVI, said about the original approach. “But as cases start to substantially decrease… you may not have the power to show the efficacy of all three vaccines.” Preference for trialing the IAVI vaccine Nurse administers the Merck-developed ebolavirus vaccine during a 2018 outbreak of the Zaire strain in DRC; IAVI’s Sudan ebolavirus vaccine is an adaptation. The summary recommendations of an independent Ebola vaccine prioritization working group say just as much in their 16 November report. The working group further recommended that in the event the number of cases are too few for a trial of all three vaccine candidates, then the candidate produced by IAVI should be preferred. That vaccine candidate is based on the approved one-shot Merck VSV-vectored vaccine against the Zaire strain, with the genetic insert of Sudan-strain Ebola as an antigen. “This was ranked highest on the basis of the proven safety and efficacy of the rVSV ZEBOV GP (ERVEBO™) vaccine with the Zaire strain developed by Merck, and for which IAVI now held the licensure rights for the technology,” the advisory group stated in its 16 November recommendations. “There is extensive experience with use of rVSV ZEBOV GP in the field with approaching 400,000 doses given as part of outbreak control measures and experience with compassionate use in over one thousand pregnant women.” Shifting to animal models for regulatory approval? Should future cases be nil or very sporadic, WHO and its Uganda partners may also need to pivot to animal trial models of efficacy. This, in fact, is already a strategy being considered by at least one vaccine developer, IAVI. Such a model was used by Bavarian Nordic to gain US Food and Drug Administration approval of its MVA-BN® vaccine in 2018 against smallpox, which was then available for a rollout this year on a compassionate use basis in response to the global outbreak of monkeypox, which WHO now recommends calling mpox. The FDA’s animal efficacy rule is designed for just such situations, allowing initial regulatory approval of a vaccine for rare but deadly diseases based on animal model studies that replicate human disease, combined with evidence of safety and a strong immune response from clinical trials in healthy volunteers. “One would have to decide if it would be possible to test the vaccines clinically, or go for plan B, and accept the animal rule, whereby the vaccine is approved on the basis of experimental work, with non-human primates along with very robust safety and immunogenicity trials,” said a clinical trial expert with knowledge of the trial who spoke with Health Policy Watch. “So this might have to be the direction here too,” the expert added. “A strategic decision would have to be made. This means having a discussion about the strategy, having a conversation with the regulators, having a plan A and a plan B, and defining a breaking point where you move to plan B.” Added another expert: “it would make a lot of sense to use the impetus of this outbreak, and the momentum that has been built, to do safety and immunogenicity trials, and then work in parallel on designing different Phase 3 trial [human] types that could be suitable for different types of outbreaks that might come in the future – trials of different intensity and so on, so that everything is ready to start the Phase 3 trials when the next outbreak comes.” Steering strategic changes at WHO, the big battleship WHO Headquarters, Geneva. Nimble change is not an easy feat in a global organization with over 100 offices and +8,000 employees. Steering big, strategic shifts in direction, however, is not always an easy task within WHO, which tends to move like a massive battleship: steady and sturdy, but with difficulties in making a rapid change of course. Internally, decision making may be further complicated by the fact that Ebola vaccine R&D is currently housed within WHO’s Emergencies team rather than in a research-focused team or department such as the Chief Scientists’ Office, insiders told Health Policy Watch. During the 2014-2016 West African outbreak, Dr Marie Paul Kieny, then Assistant Director General for Health Systems and Innovation, personally coordinated WHO’s R&D efforts at testing the first Ebolavirus vaccine (rVSV‐ZEBOV), developed by Merck & Co., which led to US FDA approval. But Kieny has since left WHO to become director of research at the French National Institute of Health and Medical Research Inserm, as well as chair of the board of Geneva’s Drugs For Neglected Diseases initiative (DNDi). WHO’s lines of authority have meanwhile shifted considerably, with Executive Director Mike Ryan, a well-respected authority on crisis response, now put in charge of the current vaccine R&D plan. But Ryan, observers note, is not a research expert. “Mike Ryan brings a lot of positive competencies,” one WHO insider said. “I like him. He’s got huge strengths. But this is not one of them.” Added another WHO observer, “It’s ridiculous to expect them [Emergencies] to have that expertise. I mean, would I go to an ophthalmologist if I have appendicitis? No, of course not.” While some WHO departments house R&D talent, others do not, the researcher noted, saying that a cross-disciplinary approach to managing such research should perhaps be better organized within the agency. Recognition of the need to pivot? At the same time, the planned 12 January meeting signals that WHO has begun thinking about a new way forward even if it is not saying so publicly just yet. “I don’t think anything will be decided, but it’s more about having a meeting of the minds and figuring out what are the options now?” said one stakeholder. “Putting together a strategy for developing a vaccine in the midst of an outbreak is not an easy thing. As soon as you are able to gain momentum on plan A, the outbreak has shifted and you realize you now need plan B. Outbreaks require constantly adjusting your plans based on where we are in the epidemic curve. It requires having all hands on deck. “So it will also be important for all parties involved to agree on an appropriate partnership model moving forward. This includes WHO, CEPI, vaccine developers and others. It’s important for all parties involved to have a seat at the table to brainstorm how to move forward in the future for Ebola Sudan vaccine evaluation.” Vaccine developers moving ahead Meanwhile, IAVI as well as Sabin Vaccine Institute say that they are already laying plans for a plan B, if need be, to generate safety and immunogenicity data. (Oxford could not be reached in time for this story’s publication.) “Yes, Sabin is currently planning for Phase 2 clinical trials for both our Ebola Sudan and Marburg vaccine candidates. We’ll be happy to share updates on that as details become clearer in the New Year,” Rajee Suri, vice president of communications at the Washington, DC-based Sabin Vaccine Institute, told Health Policy Watch. And in the case of IAVI, Gupta says that the organization is contemplating different strategies for licensure of its vaccine candidate, including the pathway of FDA’s “animal rule” that would allow for proof of efficacy to be based on trials in non-human primates. “We’ve been thinking about this development program for a while,” said Gupta, noting that IAVI last year received funding from the US Biomedical Advanced Research and Develompent Authority (BARDA) to advance its vaccine candidate. “Even if the ring vaccination trial cannot be conducted as currently designed, we’ll keep moving forward as quickly as we can,” she said. “We are planning a Phase 1 trial in the US to look at the safety and immunogenicity of the vaccine. And we’re targeting to start in the early part of next year. We are also thinking about safety and immunogenicity studies in Uganda, outside of the ring trial structure,” said Gupta. “So even if the ring trial is not able to go forward as designed, we will continue with the plan that we developed with BARDA, which does include a number of animal studies and clinical trials.” Gupta added that IAVI is very familiar with doing clinical trials in Africa. “We have clinical research center partners that we work with in Uganda, with established relationships,” she said. “So we have been talking to those people as well.” Can Chief Scientist’s office chart a new direction? Sir Jeremy Farrar, is leaving his post as Wellcome director to become WHO’s Chief Scientist in early 2023. Observers are hopeful that WHO’s incoming Chief Scientist Jeremy Farrar, who has significant research standing and experience, could help steer a new direction in handling thorny questions regarding both the Sudan Ebolavirus vaccine research and similar R&D challenges that are likely to keep emerging in outbreaks. “We’re very excited that Farrar is going to be at WHO, we have lots of trust in Jeremy,” one stakeholder told Health Policy Watch. Farrar will assume the post in the second quarter of 2023, taking over from Soumya Swaminathan, WHO announced last week. But along with R&D leadership around the big picture strategies, research “worker bees” also are desperately needed, one senior WHO scientist pointed out. Within WHO, pockets of R&D competencies do exist. But they are scattered across different departments – which typically remain siloed and focused on their own research themes – with little cross collaboration in times of need. Stockpiling drugs in the field that are ready for deployment Microscopic image of an ebolavirus – one of a number of deadly filoviruses that cause severe hemorraghic fever. Regardless of what direction is taken on a Sudan Ebolavirus vaccine trial or organizationally within WHO to manage such R&D collaborations, there is one aspect of the current experience from which WHO and other global health agencies have already drawn lessons. That is the need to produce and stockpile drug candidates for neglected but deadly diseases in advance to enable more rapid deployment in moments of need. Gavi’s CEO Seth Berkley has, for instance, talked about the creation of a stockpile of experimental vaccines that could be housed in ultra-cold freezers around Africa so that they could be mustered almost immediately in an emergency. As the experience in Uganda demonstrates, even if the first vaccine candidates arrived in Kampala in a record 79 days after the Ebola outbreak was first declared on 20 September, that is still not fast enough. “We should definitely be getting the drugs to the field and developing various clinical trial protocols for various scenarios ready meanwhile, while testing for immunogenicity … so everything is ready to go,” said one WHO clinical trial expert. Gupta said everyone agrees on the need to have stockpiles of vaccines available and ready to go for all of these different emerging infectious diseases in case of an outbreak. “When there is no outbreak, we need to ensure that we have adequate funding and resources are allocated so that people can produce the stockpiles, and then have a discussion about where you’re going to keep them, and how you would utilize them if there was a need,” she said. “So we 100% support generating stockpiles and being prepared in advance.” And while there is no well-defined mechanism for stockpiling vaccine candidates, as such, a stockpile for approved vaccines for the Zaire ebolavirus strain does exist. Now, though, the recent outbreak in Uganda has triggered a discussion about the need to extend such a mechanism to vaccine candidates, and particularly for deadly filoviruses like Ebola, as well as Marburg disease, which cause severe and potentially deadly hemorrhagic fever. “A number of organizations are involved in these conversations, such as CEPI, GAVI, UNICEF, and the developers,” Gupta said. “We are trying to determine the most efficient path to getting stockpiles on the African continent.” Paul Adepoju in Nigeria contributed reporting to this story. Image Credits: Photo by Diana Polekhina on Unsplash, WHO , UNICEF, WHO, MSF/Louise Annaud, AdobeStock, Wikimedia Commons, Megha Kaveri/Health Policy Watch , Brittanica © jaddingt/Shutterstock.com. 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