Skip to 0 minutes and 13 secondsMARTIN HIBBERD: Ebola is a member of the Filoviridae family. So these viruses are relatively straightforward genetically. The variation within the genomes is relatively small, so I think a vaccine could be developed against these viruses. The difficulty is that at the moment there's no human vaccines against any of these Filoviridae. However, I think the prospects are good. So the first three vaccines that have gone to early clinical trials have involved using the surface glycoprotein as the target. So this is a specific component of the virus used in the viral entry process. So this is a standard vaccine approach.
Skip to 1 minute and 2 secondsPETER SMITH: There's a great attempt being made to speed the development of vaccines. There's really-- until a few months ago-- none of the potential Ebola vaccines has been put into people. Some have been shown quite promising results in monkeys, in non-human primates, but none of them had been put into people. Normally, that process of going from, as it were, animal trials to full-scale people trials would take many years. But given the state of this epidemic, the hope is to try and rush these vaccines through to trials where the effectiveness can actually be demonstrated by the middle of next year-- by the middle of 2015. So already there are two or three front running vaccines which are being tested.
Skip to 1 minute and 50 secondsTwo of those are already being put into so-called phase one safety trials in a small number of volunteers both in Europe, the US, and in Africa to test whether there are any adverse effects that are going to make those vaccines unusable. So far the early results have either been very promising, or they haven't shown any severe adverse effects.
Skip to 2 minutes and 13 secondsDR TRACY CHANTLER: So I'm taking part in a trial that is giving a candidate vaccine to humans for the first time. And, for me, the decision to take part initially was very easy, because I thought, well, this is something I can do. I can't go to West Africa, but I can support the development of a vaccine. But as I was going on in the trial for a while, I did start to worry a bit about the possibility of longer term effects. Actually, I was very well after I had the vaccine. I had very few side effects. But it is the first time it's being used in humans, and we're not sure about the longer term effects of that.
Skip to 3 minutes and 1 secondPETER SMITH: The next stage is the challenging stage, which is to go to trials in the Ebola affected areas and actually try and see if giving those vaccines prior to infection reduces the risk of an infection. Those trials are going to be challenging to conduct. And one of the things that isn't clear is whether it will be possible to use the classic way to evaluate vaccines that's been done in the past, which is essentially a placebo controlled trial, where some people are given the vaccine, some people are given either a placebo or, more usually, some other vaccine, which is beneficial to the individual but will have no effect on Ebola.
Skip to 3 minutes and 44 secondsAnd then those individuals are followed to see if there's any difference in the development of Ebola disease in the two groups. Whether that's going to be possible and acceptable in the present environment is unclear. So there are basically three different strategies that are being used to evaluate the vaccines. One approach that's being adopted in Liberia is to try and do a classic randomised controlled trial where some people receive another vaccine, some people receive an Ebola vaccine. And the development of Ebola disease will be studied in both of those groups. That may not work. So an alternative approach is being tried in Sierra Leone, where there's going to be a phased introduction of the vaccine to high-risk groups.
Skip to 4 minutes and 34 secondsSo, for example, people who are working in treatment centres who are going out into the community to trace cases, who are at relatively high-risk of being infected, then they will be vaccinated. But there are a number of these centres, so they will be vaccinated at different times. And so one can see whether those who are vaccinated first, as it were, have a lower risk of developing disease than those who are vaccinated later on. Again, whether that is going to be feasible remains to be seen.
Skip to 5 minutes and 4 secondsAnd then a third approach is probably going to be tried in Guinea, where there's going to be a strategy of so-called ring vaccination, where when a case is identified, an area around that case where there are likely contacts, or most of their contacts are likely to be, will be identified. And all of those individuals will be vaccinated, and they will be followed to see what the risk of Ebola virus disease is. And there will be other cases where there's not immediate vaccination of their contacts and people in the geographic area, but that will be delayed by a month or two. And then one can compare the risk of developing disease in the two groups.
Skip to 5 minutes and 40 secondsAgain, an approach that we don't know whether it's going to work. But the hope is that at least one or more of these approaches will be a successful way of evaluating whether or not the vaccines work. And once we've got that information, and if they do work, then by the end of 2015 it will be possible to roll out millions of doses of the vaccines.
Skip to 6 minutes and 4 secondsDR TRACY CHANTLER: When planning a vaccine trial, there are obviously several considerations. There's a whole technical aspect. But there's also the question of community, and how is this vaccine trial going to be accepted locally? How are you going to be working with a country? Where is it going to be situated? How is it going to fit in with routine health care services and support that? Now, in this instance, obviously there's a huge drive forward. It's got to be done quickly in order that a vaccine could possibly support the outbreak. So you have less time to build up trusting and relationships.
Skip to 6 minutes and 38 secondsAnd there's also less capacity at the moment in the country in terms of being able to find local investigators and working closely. So there's some key issues there about how do you, at the same time still, develop key relationships with both the local scientists, ministry of health officials, but also with community leaders. And this is going to be crucial in this instance, because although a vaccine's going to be a promise of hope, there's also a lot of fear in that area around vaccines and around participating in trials. What does a trial involve? Will I be given the vaccine? Won't I be given the vaccine? And the understanding of that.
Skip to 7 minutes and 17 secondsIn past work that I've been involved in in Kenya, when you interview participants who are on trial, sometimes, later on, they don't realise, again, that their child may not have received the vaccine. They may have been given a placebo. So that kind of understanding of the technical detail, even though you might have gone through it in the consent process, it doesn't necessarily stick. Or because these are new concepts, new ideas, there's also concerns about, well, what does it mean that I will be in one group or another group? And if I'm not in the group that gets the vaccine, will I receive it later? So questions around that.
Skip to 7 minutes and 55 secondsAnd some of the trial designs that are being thought about are, for example, that one village might receive a vaccine, and another doesn't. So what does that cause in terms of jealousy or wanting something that potentially could prevent me something that's really of huge value?
Skip to 8 minutes and 13 secondsPETER SMITH: Whether or not these vaccines work, or whether we're going to be able to evaluate that, is going to depend to some extent on just how effective they are. We know that in the animal studies that have been done, in certain circumstances the vaccines are 100% effective. We also know that in virtually any human vaccines, there are virtually none that are anywhere near that effective.
Skip to 8 minutes and 36 secondsAnd so if we're dealing with a vaccine which is much lower than that, say 50% effective, only prevents half of the cases, it's going to be much more difficult to evaluate it than if it is highly effective, because if it's highly effective, then no matter what sort of approach we use, it's probably going to be fairly clear that those who are vaccinated are at much lower risk than those who are not vaccinated.
Skip to 8 minutes and 59 secondsDR TRACY CHANTLER: The assessment of vaccines is really important. And it will offer, particularly, hope for the future-- future outbreaks-- but also, hopefully, for this outbreak too. But when we think about this, we do need to consider how the trials are fitting into the local health system. And this is particularly pertinent at the moment, because we know that both Liberia and Sierra Leone have very poor health systems. So I think there is a responsibility for us, as researchers, to think carefully about how the money and the resources that are supporting trials can provide long-term benefits. And this is going to be of importance for community members as well.
Skip to 9 minutes and 38 secondsHow can their health system be rebuilt, particularly given now that there's quite a lot of fear attached to some of the health care systems and the stigma? So how could possibly trials work with Ministry of Health and other people to build some of that up? And those are going to be big questions as the outbreak continues and as it comes to an end.
Trials of vaccines: from development to community
The normal process of vaccine development takes many years and involves several stages, starting from pre-clinical laboratory development and animal testing to clinical development. Due to the urgency of the Ebola outbreak, unprecedented efforts have been undertaken to develop a vaccine within months. This step considers the vaccine candidates and the issues in conducting vaccine trials. Since recording the video, exciting preliminary results have become available and are included below.
The processes for streamlining the development, testing and implementation of vaccines were agreed in October 2014.1 The first three vaccines to move to phase 1 human trials, in Europe the US and Africa were:
Chimpanzee adenovirus: This uses a chimpanzee adenovirus vector to carry an Ebola protein. The use of a booster with the Modified Vaccinia Ankara vaccine was being explored.2-3
Modified Vaccinia Ankara: This is based on the Modified Vaccinia Ankara virus which has been used to develop candidate vaccines for other diseases, including malaria and hepatitis C. This targets the same protein as the chimpanzee adenovirus vaccine.4
Vesicular stomatitis virus: This uses a live attenuated vesicular stomatitis virus, with one of its genes replaced by an Ebola virus gene.5
At least nine other vaccine candidates have undergone preclinical evaluation. These include oral, intranasal and injectable vaccines.
Expanding clinical testing
The stages of vaccine testing in humans are similar to those for new drugs described previously. Phase 1 is for safety and the ability to provoke an immune response. Phase 2 assesses the immune response in large numbers. Phase 3 tests the vaccine efficacy, or the ability of the vaccine to prevent the disease. Phase 4 tests effectiveness in practice. For Ebola these are being streamlined.6
In the video, Professor Peter Smith discusses the different trial designs being considered for phase 3 trials.
A classic randomised controlled trial, in which high risk or general population groups are randomised to receive either an Ebola candidate vaccine or a licensed vaccine against a different disease which is beneficial to the individual but will have no effect on Ebola. The incidence of Ebola is then compared between groups. This approach is planned for Liberia but there are questions about acceptability.
A step-wedge randomised trial was planned for health care workers in Sierra Leone. In this design the vaccine is introduced in a phased manner, and the order in which workers in different areas receive the vaccine is randomised. By the end of the study, all participants will have received the vaccine, but during implementation there will be vaccinated and unvaccinated groups who can be compared in an unbiased way.
A cluster randomised trial of “ring” vaccination was planned for the population in Guinea. Each cluster is made up of the people in a geographical area in a ring around an Ebola case. Clusters will be randomised to receive the vaccine either immediately or after a set time period. The incidence of Ebola in the different clusters will be compared.
As of August 2015 three different phaseII/III trials had started (see WHO website):
Randomised controlled trial in Liberia (PREVAIL) using the Chimpanzee adenovirus vaccine, ChAd3-ZEBOV, made by GSK and PHAC, and conducted by the US NIH and the MoH Liberia. Due to the lack of patients in Liberia the investigators hoped to extend it to Guinea.
Unblinded, individually randomized trial with phased introduction of the vaccine in front line workers in Sierra Leone of the vesicular stomatitis virus vaccine rVSV-ZEBOV, made by NewLink Genetics and Merck, conducted by the US CDC and MoH Sierra Leone
Ring vaccination trial “Ebola ca suffit” in Guinea, using rVSV-ZEBOV, conducted by WHO, MSF and MoH Guinea. In addition all front line workers are offered vaccination using rVSV-ZEBOV.
Preliminary results from the ring vaccination trial in Guinea published in the Lancet suggest the vaccine might be highly efficacious and safe. In the pre-specified interim analysis the primary endpoint was cases of Ebola arising at least 10 days after vaccination (to account for the incubation period of Ebola and the time taken to develop protective immunity after the vaccine). With this endpoint there were no cases in the immediate vaccine group and 16 in the control (deferred vaccine) group: vaccine efficacy 100%, 95% confidence interval 75%-100%. Ring vaccination is continuing (see WHO website) but without randomisation of clusters to delayed vaccine. So far the vaccine has only been given to adults: there are plans to extend this as further safety data become available. This trial is important not only because the vaccine appears to be protective, but also because it suggests that ring vaccination (as used in smallpox eradication) may be a suitable strategy for delivering it.
Practical considerations and acceptability
Vaccine developers have already increased their production in order to be able to conduct large scale trials,1 but there are many ethical and practical considerations that could affect these trials. These include who should be given the vaccine, and the need for the vaccines to be stored at -70°Celsius (-94° Fahrenheit) and associated cold chain challenges (i.e. maintaining proper vaccine temperatures during storage and handling to preserve potency). GAVI, the global vaccine alliance, has committed to purchasing millions of doses of any vaccine that is recommended for use by the WHO.7
It is essential to ensure that national stakeholders are involved in trial preparations and local communities are engaged in order to develop trust and allay fears. Given the conspiracy theories about the origins of Ebola, and general issues of distrust of vaccines (discussed in the next step), it is very important to ensure that people are able to discuss their concerns and ask questions.
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