Communicable E55: Bonus episode – Bundibugyo ebolavirus outbreak 的完整文字稿

really being prepared for everything else, right? Everything outside it- Yeah ... alongside [00:06:00] it. Daniel: I think there's data, Angela, from, the large West Africa outbreak that had, around 30,000 cases, that there were probably more people who died of malaria during that outbreak than died of Ebola. Which isn't to, simplify and say, "Okay, Ebola's not important," but nevertheless, as Martin puts, the other things still go on, and addressing those in the context of these outbreaks is complex Angela: Yeah. So now to this topic indeed, first of all, listeners should be aware that Martin and other members of the Emerging Infection Subcommittee have created a lovely infographic just published in CMI Communications summarizing the clinical characteristics of this virus, as well as a companion summary article published in CMI. We'll leave links to both in the show notes, so everything we're gonna talk about now can be found in writing there. So Martin, can you start us off with a quick overview? How many species of Ebola are there in this genus of orthoebolavirus, and how many of them are known to cause human disease? Martin: In this genus, we put together six distinct [00:07:00] viruses, of which four, are of real, importance to us in terms of causing human disease. the foremost one is certainly Zaire ebolavirus, which has been named after the country, which is now the Democratic Republic of Congo. It emerged first in 1976, almost at the same time in Uganda then the second one which causes also quite a number of outbreaks over the years is Sudan Ebola virus. And the third one now is Bundibugyo virus, which occurs in the same area and which has caused to date three outbreaks, including the one in Quest. And then we do have three other viruses in this genus. One is Tai Forest. Tai Forest is area in the Ivory Coast. One human case is known, so far actually, but it's possible that there will be more in the future, but you can see it is [00:08:00] nothing as compared to the others. Then there is Bombali virus, a virus which has been isolated from fruit bats in Sierra Leone and adjacent areas, not known having caused human cases up to now. And then there is an out-of-area virus, the Reston virus, which has its home in the Philippines actually. It has never been causing really human diseases, but we do see sero-positives in those having had contacts with the zoonotic reservoir. But this is the Orthoebolavirus genus. We do have more filoviruses we do have Marburg which is very close to the Ebola viruses. And then we have even something very exotic, the Cuevavirus, which is a European filovirus found in bats which has never caused human diseases so far. Anne: Thank [00:09:00] you, Martin, , can you also tell us like where this Bundibugyo species was identified , Martin: So the first cases, Bundibugyo virus were recorded in 2007, so not long ago, in an area of, the Congo and it caused about 150 cases. The counts vary a bit with about 40 death, so a

death rate of about, 25%, and that was precisely in this area, of the Eastern Democratic Republic of Congo, the adjacent areas in Uganda where the epicenter of this current outbreak lies. And then there was a second recorded outbreak which occurred five years later, 2012, which was slightly smaller, about 57 cases, with mortality rate of about 50%. As compared to the two other viruses, [00:10:00] Bundibugyo hasn't caused that many outbreaks as we know from Zaire and then Sudan. Anne: What is the presumed animal reservoir? Martin: Amongst the two of us, Daniel is really the specialist on this because he was involved in hunting and identifying the reservoir. But all what we know, everything points into the direction that similarly to Marburg, for which it is confirmed that the African fruit bats are most likely the definitive hosts. the only problem here is that we haven't been able to prove that definitively, but there are no other very hot candidates, and until proven otherwise, our work hypothesis works very well, Daniel: Maybe just to add a word As Martin said, we have worked out, the collective we, of course, scientists, different people ha- have worked out over the years that, the Egyptian fruit bat, Rousettus aegyptiacus is the scientific name, is the reservoir for Marburg virus. And so that these days is quite clear, and the [00:11:00] disease ecology has been fairly well elaborated. That's not so for any species of Ebola. And so for all the Ebola viruses, the ones that Martin mentioned that, cause human disease, as well as the others, for the most part, we have never isolated a virus from a bat. We have a few bats in different areas of the world with some disease ecology studies and reservoir studies that have PCR positive and some serology, but we have never isolated the virus. And so that theory of bats,, being the reservoir comes really from extension that since this is a similar virus, in the overall family as Marburg, , that it would make sense. It should be mentioned also that, Ebola viruses can get into other primates , and other animals, and we have seen outbreaks that have started clearly when there's been exposure to, for example, non-human primates from hunting and different things. Those are clearly not the reservoirs because those animals fall sick with a disease similar to Ebola virus in humans, [00:12:00] and so they're certainly not maintaining it. But we have seen, for example, in Gabon years ago, a bunch of kids walking through a forest, found a dead chimp and decided that would be, the right thing for lunch you know, a logical thing in that area of the world. But, , then, they all fell sick with Ebola, and we were able to isolate Ebola virus from the humans and from , the remaining chimp meat. And so, that's a way that this virus can get introduced to human populations, but it's certainly not maintained in non-human primates or other mammals. Angela: I didn't know it wasn't so well worked out actually for Ebola virus this would be a good moment, I think, to just talk about the current epidemic, where we are with it, w-how it all started as far as we know. We know that the case count right now t-seems to be rising very quickly. What's actually happening here? What's going on? Daniel: Yeah. Very complex situation. May-maybe I'll start with saying that, in the last outbreak in this area of the world that, , happened a few years ago and recorded over three thousand cases, as Martin mentioned, it was second-biggest outbreak on record after the [00:13:00] large West Africa one. At the time I was working, leading UK outbreak team, and, , so spent a lot of time there, and also was the co-PI on a Ebola vaccine trial that we did. So extremely, extremely difficult area to work. I've often, , kind of facetiously said, like, if this was a movie script, and you said, "Okay, here's a movie script for something happening in the area," people would say, " that's too unrealistic. You need to change that," 'cause, , all sorts of things happen with insecurity vehicles being stolen and, the volcano blowing and a whole bunch of things. But, nevertheless, to break it down , a bit more seriously, you know, first of all, this is, an area of, eastern DRC that has been for a long time now in just a very fragile state and a very fragile and traumatized population with over 100 different, militia groups that circulate in the area, related mostly, of course, to the mineral, , resources that are there and controlling the economy and controlling really many things about life. you'll see in the news mostly about the M23 rebel group that took, control of [00:14:00] Goma maybe a year ago now. It's not the first time that a rebel group has taken control of Goma, the major city, to south o-of, the area in question for this outbreak. So first of all, you have this incredibly difficult situation where it's not safe necessarily, to circulate, but nevertheless, because of the instability, people are forced to circulate quite a bit. the bor-borders between Democratic Republic o- of Congo and Uganda and also neighboring, Rwanda and Burundi are, quite porous, honestly. And so it's easy to cross borders lots of reasons for people to do so for social and economic reasons. so it's just an extremely difficult area to operate in. And, We know how to, face Ebola outbreaks. , As Martin said, we've been doing it for fifty years. . But it requires the classic measures of implementing good case finding , and contact tracing and getting people into isolation and care, and that's not an easy thing to do in this setting with many of the logistical elements. And, as I say, contact tracing seems like a [00:15:00] fairly simple thing, right? To go around , and trace all the people who have been potentially exposed but it's a lot harder to do when there's a lot of people walking around with AK-47s Martin: Yeah, I mean, the 2018 outbreak Daniel just alluded to is very worthwhile visiting because it was remarkable

because in theory or even in practice, we had all the tools at hand to bring it under control. Remember the 2013 to 2016 outbreak in West Africa, as devastating as it was, was long enough to enable us to develop effective interventions, hm, not only in terms of treatment, but particularly in terms of vaccines. And everything was ready in 2018 to clamp down on this outbreak, which was for the same reasons as the ongoing outbreak, relatively late discovered, so it had already [00:16:00] reached an enormous dimension. But in theory, we had the intervention tools. The only problem there was because it was caused by Zaire ebolavirus, and all the interventions we do have are specifically targeting Zaire ebolavirus. Now, the additional tragedy here is that whilst it's precisely in the same area, which comes with all the challenges Daniel mentioned, we are also without working tools because for every single ebolavirus, we need specific tools, specific vaccines, specific monoclonal antibodies. So we are, in almost all aspects back to square one and we are late. The index case probably occurred end of April. 5th of May was the first signal reaching WHO. It took another week to recognize the dimension of what was already ongoing, and now by any standards we are late with very few tools in our hands. Anne: Yeah, [00:17:00] that's really interesting how you both talk about this outbreak. It's really a socioeconomic, maybe we , as researchers or clinicians don't really even imagine all the aspects you have to consider there. Daniel, in virological terms, how does this Bundibugyo differ from, , Zaire Ebola virus structurally, et cetera? Daniel: , On the technical side, , this virus is about 30% divergent from Zaire virus, in terms of its nucleotide sequence, which is around really , the borderline to classify it as a different species. And that's about all we can say really. One, One of the things that people should recognize is that, there's some anecdotal evidence, but in terms of if we look at all the pathogenic Ebola viruses, there's really nothing that we can identify very easily on scientific grounds in terms of, when a clinician sees a patient, there's nothing that, will allow that person to say, "Well, this is Zaire virus," or, "This is, Bundibugyo virus," or, "This is Marburg virus." And even worse than that, when I first got into this field [00:18:00] many years ago, I'd read the books that, talked about people with their eyeballs bleeding and their liver turning to mush , and naively thought like, ", why did it take so long to identify an outbreak?" But of course, that, that's not reality. In reality- people present, with fever and headache , in the early stages and something that's extremely difficult to identify, even if you're a great and experienced clinician, in order to say, , that this is a, an Ebola virus or a filovirus infection in its early phases rather than malaria or dengue or typhoid fever. So that early presentation for all the viruses, for Bundibugyo, for Marburg, for Zaire, there's nothing that really clinically identifies that. And it's same in terms of what we know in terms of, modes of transmission , and the other characteristics. So obviously there are some differences, on the nucleotide level, but on a practical level, we lump them into the same group in how we deal with them. Angela: Can I ask you there, Daniel? Overall, what percentage of people who present with an Ebola virus, species, included, [00:19:00] what percent of people actually have hemorrhagic disease, just so clinicians can be aware? Daniel: Yeah. So great question, a-a-and it's a minority of patients. In the early years of identifying these diseases, of course, which initially weren't identified through any laboratory, at least not real-time laboratory results. , It's only, I think maybe the Gulu outbreak in two thousand in Uganda was the first time we ever had, real-time laboratory results. And prior to that, it was all just clinical case definitions. And so you think, who are , the cases in that situation that are, , going to be noticed? And it's the most severe cases, right? And so you go back to nineteen seventy-six , early outbreaks, and it's the patient who presents with severe bleeding and, and severe disease that's gonna be noticed. And so consequently, with any, , outbreak-prone disease, , the case fatality rates will be very high early on because the sickest patients present. And then, what you'll notice is the kind of the most dramatic signs and symptoms. And so, hemorrhage was noted in many [00:20:00] patients very early. But as we get better over the years with case detection and diagnostics, then we start to recognize that somebody who just had fever and headache and, maybe some nausea and vomiting, but no bleeding, was also a case of Ebola because we have the lab, and we have greater awareness. So unfortunately, people do have hemorrhagic signs and symptoms often in filovirus disease. They occur late. But, usually people will have a few days of nonspecific, signs and symptoms of fever and headache, and then a few days of nausea and vomiting, which can be quite profuse, and really have very significant volume losses. And in the later stages, , bleeding and hemodynamic instability. But the, external bleeding, is seen in a minority of cases. Martin: Yeah, and if I may add, as Daniel said, it's a great mimicker and, virtually all serious infectious diseases begin in the same way, and also the non-serious ones. It's fever, not feeling well. Most of our knowledge naturally comes from the biggest outbreak, and if you revisit the [00:21:00] clinical signs and symptoms of the patients during the West African outbreak, there are a couple of things which strike. There were good reasons, as Daniel also mentioned, which were misleading in a way that the majority of patients presented with watery diarrhea as a lead symptom, leading to suggestions a cholera outbreak. Almost everybody, but by far

not everybody, had fever, so the first thought is always can that be, a micro-outbreak, a shift in epidemiology of malaria, which, as Daniel mentioned already, can amount to as many as 50% of cases even within a group of suspect Ebola patients. Very interesting, and this doesn't seem to be the case with Bundibugyo, but, , also something which is of big relevance and where I think we are not entirely honest in, discussing it, is that in Ebola in particular, not everybody has [00:22:00] fever throughout the course of the disease, and I'm not talking about patients who are afebrile after having received some painkillers also. It's only 85 to 90% of all Ebola patients which ever have fever, so you have at least 10% of people who are highly viremic who might, , infect others, which do not exhibit the most important clinical sign, which we even use as backbone of the preliminary case definition when we try to filter out patients from a community with cases. So it's , really complex and, , there are many good reasons why at the beginning of an outbreak, even, very experienced clinicians might err. Angela: This is opening up so many more questions. As we go along, as we get better with our diagnostics, , we understand that the clinical picture changes, right? As we are able to identify the disease,- Case severity lessens. Does that mean-- Do we know what seroprevalence [00:23:00] is for,, Bundibugyo? Even in the DRC right now - Let's start with Zaire ebolavirus, right? What is seroprevalence there? How much of it is actually going around asymptomatically? And if we know anything yet for Bundibugyo, , have there been any seroprevalence studies on that? Martin: Well, it's always the case that you have a large number of people who are exposed probably then to lower, copy numbers of the virus who develop seropositivity. So whilst death rates are pretty high amongst Ebola virus cases, the number of asymptomatic cases who never develop a disease is probably outnumbering those who fall ill and either succumb or recover by far. But it's very difficult to come up with these specific figures whilst an outbreak is going on because there we focused on identifying the true cases. Maybe one other important aspect when it [00:24:00] comes to the death rate, they are always reported like as for Zaire, we do believe that more people succumb to the infection slightly more than through Sudan virus. For Bundibugyo, we have seen in one outbreak mortality of about 30 and in one case of 50%. We always need to take these figures with a pinch of salt because at the beginning of an outbreak, For the reasons Daniel mentioned, the number of severe cases and those who succumb to the infection is usually always much higher than at the end, even if we do not have specific interventions. The reason here is simply that the level of general care like resuscitation with copious amounts of fluids, , treating malaria early, having antibiotics at hand to, treat bacterial complications they

make a difference. And the death rates are usually at the end of an outbreak far [00:25:00] lesser than in the beginning, and usually we arrive a mortality, between 40 and 50% for most of my stats Daniel: Yeah, if I could come in. , Couple different things. So I confess first of all with the idea of asymptomatic cases to being slightly skeptical. , Not skeptical that they exist completely, but I think we need to be aware of the context. First of all, many of the serologic assays are not standardized, and so there's some issues about, you might get different results from different laboratories, and then questions of cross-reaction with other things. But the other thing that we have to realize is that the stigma for these diseases is extremely,, high. And so if you go to an area where there's an outbreak, , we can all understand this, right? In our respective cities, if you, thought you were exposed to Ebola, and then you said, "Well, I'm gonna raise my hand and tell everybody I'm exposed and I'm sick and I may have Ebola," , what's coming that day is probably not gonna be very agreeable to you. The idea that, , a lot of people are gonna [00:26:00] descend upon you, say you need to be admitted to an isolation ward, scary things with lots of people, not with your family. then, even if you don't, end up having Ebola or even if you survive Ebola , and you're okay,, the stigma still can be very strong. And so lots of stories of, , people , who come out of Ebola wards and come home and see that, someone has taken all their bags and their belongings and put them outside of their house . And so, when we say someone was asymptomatic, you ask the question, "Okay, were they really forthcoming with their symptoms?" So that's one thing that we at least need to consider in that. The other thing to consider is that in filovirus disease, for the most part, viremia, corresponds very well to the severity of illness. And one of the perhaps more reassuring things is if you had a patient who was asymptomatic or had very mild disease, you might reasonably, postulate I think , with good evidence that that person had relatively low viremia, and since they were asymptomatic or mildly [00:27:00] symptomatic, they had no symptoms or they had just mild fever and headache, that's not a patient that's probably very infectious. And so, they don't have diarrhea, they don't have, vomiting, they don't have bleeding by definition. Consequently, they're not, spewing virus out into the environment. And so in terms of epidemiological and clinical grounds, perhaps missing that patient is not particularly important, right? But , that, remains to be seen, but I think it's something that can make people feel a little bit, , more comfortable dealing with this disease. Angela: It's not clinically important in that moment for that patient, for you or me treating that patient, let's say. But it may be quite important for that group of, , human beings around that patient, right? ... Is that

one of the reasons that, case numbers go down? Obviously, we come to the outbreak, we do our bit, is the circulation at low level of this virus in patients who are post-asymptomatic, is that one of the ways that, , the outbreak Deals with itself a little bit Daniel: I think you're, getting at our idea of herd immunity. But I don't think [00:28:00] so, honestly. I don't think we have that degree , of circulation really. , And depending upon what's- Because Angela: we're accidental hosts, I guess? Daniel: Yeah, c- , we're accidental hosts. There are studies that show lots of, quote, "asymptomatic transmission," and there are studies that show no asymptomatic transmission. So it just depends on what you want to believe there, I think. But I don't think we get to widespread enough circulation to have kind of a, herd immunity, , effect. I do think... Well, two things. We see as we get in the late stages of outbreaks, we've usually had time to get good, care in place and, some of the, NGOs, um, MSF and, ALIMA and a few others, and WHO involved as well, have, , developed good, care systems. And so that makes a difference as people get better. You can also look, for example, in the,, big West Africa outbreak, you had I think it was 27 patients that were, , infected and ultimately medevaced and then seen in Europe or either United States., And the case fatality rate, for them was, quite low. And whereas you looked at the case [00:29:00] fatality rate, people who had to be cared for in West Africa where, realistically of course the care was not at that same level, was significantly higher. That's not a controlled trial, it's observational, but nevertheless, we see that. The other thing that happens as our case finding and our awareness may get better in the late stages of outbreaks, we may have people who present who have milder symptoms, right? And so they may be aware of Ebola, and our case finding may be better, so the patient who has mild headache and fever and maybe a little bit of nausea and vomiting and - nothing more, presents, and we count that person as a case of Ebola, and, obviously would go into the equation as a non-fatal case and bring the case fatality , rate down. Over to you, Martin. Martin: Thank you, Daniel. No, I fully agree. There are two aspects which help bringing an outbreak under control, and the most important one is irrespective of whether we do have working, specific therapies, is the enhancement of the general level of care. Identifying and isolating those [00:30:00] individuals who are diseased and who do have the disease. Treating those who have been ill for alternative reasons. Improving the care of the individual to that end that everybody receives, the necessary fluids. They make all the difference. could also make a difference in a large outbreak, and it might have played a role even already in the West African outbreak the first generation of Zaire ebolavirus vaccines were brought to phase two and phase three trials,

and Angela, you also have been involved in those, so you know That can make a difference in the late stage of an outbreak. Here, in this case, we will be too late. But the establishment of dedicated treatment centers, the reestablishment of basic medical care, the tracing of those who might have been exposed or were exposed and who might develop the disease, that makes a difference in the end. Anne: , If we, look at any targeted [00:31:00] treatment that can be available, for example, the monoclonal antibodies, for, , the virus , against Bundibugyo, just at in vitro level, is there any evidence that we could use this clinically, Daniel? Daniel: A-as we've said, this is a different virus, and all the medical countermeasures, really, the diagnostics, the therapeutics, and the vaccines that have been developed over the years have really been oriented towards the orthobolavirus that's associated with the highest case fatality and is the most common, and that's Zaire virus. So un-unfortunately, Since this is only the third outbreak of Bundibugyo virus, there really hasn't been a lot of work oriented towards this. Most of the early, I wanna say early assessments because it's not data-driven really, but, nevertheless, the early assessments are not very promising that the tools that we have so far in terms of therapeutics or vaccines, or diagnostics, that we can just suppose that they would work. And WHO has had , a number of meetings recently of the R&D blueprint , and experts and recently published Some guidance [00:32:00] on what they thought the initial stages were. If you look at, the PALM trial that happened in North Kivu during the last big outbreak, there were a couple different treatments, , a cocktail of, monoclonal antibodies from Regeneron and another monoclonal antibody, that, had efficacy. One of those, monoclonal antibodies in the cocktail from Regeneron seems to have activity against, Bundibugyo virus. Another antiviral drug that's often used a lot, Remdesivir, may have, activity. And then, , another, monoclonal MBP134. Those are kind of the lead candidates. That's based on informed science, but it's not based on clinical trials. There's also, the oral form of Remdesivir that's of interest for post-exposure prophylaxis. And then if we turn to vaccines, , the major vaccine of course, has been the, RVSV, Zebov vaccine made by Merck. There's really not a lot of optimism that would , allow cross-protection, but there's interest in using the same platform of an RVSV Bundibugyo [00:33:00] virus, vaccine, and then a chimp adeno, virus that is developed by Oxford. All of those things will take time. If we look at the vaccines, for example, the estimates of producing these vaccines, depending upon which one. In Oxford, I think they say a few months, maybe two, three months, they could have some vaccine. Some people are skeptical about that. And then i- if you look at , the RVSV, it's really more in the six to nine months. But that's just to have a

product to put into clinical trial, right? That's not to have a product that you can say, "This works." Often in these settings, it is true that we ethically, , but logistically, , try to kill two birds with one stone. I guess we could say, of putting a product into a controlled trial, but that we have reasonable, plausible evidence that we think will also have a positive impact. And we saw that with ring vaccination with the previous vaccines. But I think the reality, especially with vaccines and therapeutics, is that we have to be realistic that we're not gonna have [00:34:00] those anytime soon, I Martin: I think, Daniel is absolutely right. What will make a difference here is to establish treatment and diagnostic and tracing capacity. There are a couple of developments, Daniel alluded to them. Yes, maybe there is an oral variant, , of, , remdesivir, which probably doesn't work very well if we give it to the diseased, but which might have a, , role, if we give it to contacts while in the incubation period. This is certainly one of those things which is going to be sorted out over the next couple of months. There is one monoclonal antibody cocktail which seems to be promising in early animal testing. One wonders sometimes why some of these developments haven't been moved to phase one studies, for which you don't need an outbreak. This can be done as it was done with the, , currently available vaccines during the outbreak, but outside of the outbreak settings. But in [00:35:00] general, the problem with all these things is, that what you need to move on is a outbreak which lasts very long. So this is in contradiction to what we are striving for. Of course, we want to bring these outbreaks under control as quickly as possible, but if not, that might open up chances for clinical trials. But you don't do clinical trials in a chaotic situation. You cannot... you need to establish the research infrastructure. You need to establish the level of care needed to accompany these clinical trials. So, you need more than just a big outbreak to move on. , even doing trials on antimalarials also in a well-established, research setting is and remains a major effort. Maybe one word to monoclonals, are a fantastic tool, but it will be very difficult, even if we manage to identify, a working molecules during [00:36:00] this outbreak. The production is extremely tedious. Costly, et cetera. So the key to outbreak of that sort is really in establishing the clinical care, facilities which help patients survive by simple means like providing antimalarials, and fluids Anne: I think about this a lot, like in between, outbreaks, we have all the data, we have all the knowledge , and then we are actually not, utilizing what we could, we could do the preparedness work way better, and of course, the thunders are there to perhaps pull some of this. , Do you think the focus should be really in trying to get this vaccine and, early prevention direct antiviral or is it diagnostics or epidemiology? Is it all together or, Daniel: that of course is the key question, right? Fi-first of all, let me back up a little bit and I guess my realistic answer, I don't wonder, , why some of these things haven't gone beyond the phase they're at. We have to recognize that, medical countermeasures for [00:37:00] this and everything else are largely produced from the private sector. And the private sector is not particularly interested in, products for diseases that are so rare , and the populations that commonly have those diseases are so poor. And , that's just a reality. I don't mean that as an accusation, but I think we just have to be realistic about that. And, even if we look at some of the tools that have been developed for Zaire virus, for example, the RVSE Zebov vaccine that has been successful. That vaccine existed and had very, promising data from non-human primates. And if you talk with some of the people who developed that vaccine, colleagues and friends of mine over the years, they were very frustrated because they said, "Well, we have this vaccine there's really good data in non-human primates, and we've taken as far as we can take it. And so now we need, usually, , a pharmaceutical company or other groups , to take this up and move it forward." And I find that no one is really interested in that until you get to a certain level of transmission. And [00:38:00] then I think a sort of a, , in addition to many other things, a moral imperative does finally take over and people say, "Okay, now this is really so bad that we need to come in and money is not the major thing." My point of all of that is not that we should say, " pharmaceutical companies are evil, bad people that we should blame for everything." I just think we need to be realistic about the systems we've created. And even if we say Okay. Now Bundibugyo has to be the focus, and people will focus on that. And they will. And because this is a high-profile disease and it's a dangerous disease, at least in the area, where it's spreading. I don't think it's a dangerous disease in terms causing, pandemics or widespread things in, , high-income countries. The good news is that despite all the challenges that Martin mentioned and that I mentioned earlier of doing clinical research in these settings, we have done it. The PALM trial was done in North Kivu. The rVSV ZEBOV trial was done in difficult settings in West Africa and then continued again [00:39:00] in North Kivu. And so I have confidence, actually... Well, I would have confidence that these things would move forward, that is impacted, again, by the cuts in global health funding, seeing people and institutions that were key to some of that work, National Institutes of Health in the United States, CDC,, not only from the US, but, others as well, that have gone through severe funding deficits, and some of those experts are not so readily available. , That's a problem. Nevertheless, we do know how to do this ,

in difficult settings, but it's just gonna be a good while before we would have a product to really put into place. And so I think we, as Martin said, we need to have parallel tracks where we're going ahead with, some of the research for the medical countermeasures. I,, skipped over diagnostics, but I want to come back to it because I think if we look at, medical countermeasures, where I would say is our number one focus, I think it does need to be in diagnostics, right? Very difficult to gain control if you don't have a way to readily, diagnose a case of Ebola, and we talked about how difficult it [00:40:00] is to diagnose on clinical grounds as well. All the diagnostics that we have have really been based on Zaire. The Democratic Republic of the Congo and , the Institut National de Recherche Biom�dicale, or INRB, in Kinshasa and Goma, has done a very good job over the years. They're very familiar with, Ebola, and they have set up, , in that area of the world diagnostics that are relatively available, and they're automated. The GeneXpert system that, does not require a lot of education as a laboratory, , a laboratorian, but they're all oriented towards, Zaire virus. What we're, , forced to do right now is , to rely on traditional PCR. And of course, traditional PCR, that does require, an educated laboratorian, right? That requires a lab and a lot of things, and to make sure, of course, you don't have contamination , and c-can safely be done. And this is difficult to do. Because this covers a relatively broad geographic area and because of the instability and the difficulty of sending samples, we can't rely on a [00:41:00] central laboratory approach. We can't think that, "Okay, everything will be sent to the main laboratory , in Bunia Goma." That would be difficult to do. And the delays, we would miss cycles of transmission. So I think , the one area if you said, "Okay, we have to prioritize," fortunately, it's not one thing or the other, right? The people who develop diagnostics are generally not the same people who develop vaccines or therapeutics. But, I think we start with getting the diagnostics in place and making sure we're confident of the diagnostics. And then operational things on the ground. And I've even, questioned whether we need to go back in the early stages of using, clinical case definitions , and also perhaps prior-prioritizing, with our contact tracing and not thinking, we need to get every contact every day, which generally, of course, we want to do. But when you have thousands of contacts across, a broad geographic area and having the people to do that, to have the awareness and the language skills, they need to be locals. And then just, think about they're spread over lots of areas. How many vehicles do you have? How many cell phones do you have? Are you gonna [00:42:00] find all those people? , Or do we only need to find the people who , had high risk exposures, right? That took care of somebody during the most infectious period of that illness when they had nausea, vomiting and bleeding and things like that. Very difficult to operationalize. , No doubt. And so I can understand that there's skepticism about that, but I'm just wondering how many choices we will have in these early stages. Anne: What about you, Martin? What do you think? Martin: I think Daniel is absolutely right in the end, looking back at the West African Ebola outbreak experience, we will make a difference up from the point where we'll be able to cover the outbreak area with a solid network of treatment centers. Usually, diagnostic facilities will be linked to them. Usually, that would be an RT-PCR set up in a sort of box laboratory. The biggest obstacle here is, I think, the instability of the region. We had seen from the last outbreak in two thousand eighteen that [00:43:00] very easily lives of healthcare workers can be jeopardized,, in such a situation. So that will make all the difference. With regard to diagnostics, I'm not that concerned. . I'm more concerned that is there, sufficient funding, is there sufficient, , political, , initiative, and is it safe to establish the treatment center and diagnostic centers needed rapidly to bring this outbreak, quickly under control? Angela: Once again, it's coming back to the environs of an outbreak. It's not the development of the diagnostic tools that can be done fairly rapidly, it's implementing them in what is essentially a war zone, right? This is a vast expanse of terrain that is under control of multiple military gangs, if I understand correctly. Martin: But it is not all, Bad news, it's not that the whole area where this outbreak is unfolding is a, crisis region. I [00:44:00] wouldn't say so for Uganda, and I would like to comment and, also mention the, obvious preparedness of, , recognizing and clamping down on such an outbreak, at least in part of the region Daniel: I agree completely with you, Gandi, but it's also true, th-this is not because there are not qualified scientists and public health workers in the Congo, right? , It's not an issue of competence. Um, Ian Herbay and has a lot of experience with this. There's many good scientists, good epidemiologists, but it's just a very difficult area to work for anybody, right? And so it's, a challenge regardless your experience of Ebola and the sciences, this is a challenging place to implement. Angela: So right now in this epidemic, , there are about 900 suspected cases, some 200 plus deaths. First of all, it's probably a stupid, idea. It's probably never wise to do this, but what do you think the numbers are gonna be? We're at 900 suspected right now. How out of control is this? What do you think the peak will be before it gets turned around? Daniel: Martin and I were talking about this a [00:45:00] little bit before we started. First of all, Angela, I would never be foolish enough to give you a number. Gotcha. , And, nice try, but no. , - first of all, as I think everybody

recognizes, even the numbers that we have, th-those numbers are never absolute, right? And so, what you are more interested in is , the shape of the curve. I think given the many challenges that we have, we will have, quite an increase in number of cases You can always, , get into , the questions about that. Is that because your surveillance gets better, right? And you're capturing more cases, , that's a good thing, and so how to interpret those numbers. But, , despite the skills and experience of many people from different organizations and from our Congolese colleagues,, I have to say that I'm relatively pessimistic that we're going to get rapid control of this particular outbreak. I think it's gonna be a little bit of A long haul and, , I won't supply numbers, but I'll supply evidence, if you will, that even if you go back , and look at the last outbreak in this area, which had a similar profile, similar area, not that much has changed, at least not too much changed for the better, and [00:46:00] for which we did have some medical countermeasures, that outbreak dragged on for a few years and was the second biggest in history. So, , based on that, I think we need to prepared for a longer haul Martin: Yeah, I fully agree. . On the other hand,, what we witness over the past couple of weeks is a massive reaction, and that's different from the 2018 outbreak., It appears to me that, by now, , everybody tries to live up to the challenge and to assist those formidable doctors, healthcare workers who are in the region, and to support them so that they can, really unfold their full potential and help us clamping down on that. But it's, , - impossible to come up with a well-informed, , prognosis, but I can say the reactions are massive now, and the interest is big, . Angela: Hmm. Daniel: I like your, I like your positive spin on that, Martin, so I didn't mean to be overly negative, and I hope you're right. But, we all recognize the challenges, yeah. . . Anne: So thanks both. Starting to wrap up here and thinking about, perhaps the [00:47:00] clinician, , in Geneva, where you are, Daniel, or in Amsterdam, where you are, Martin, who might have come across, , a patient who has contracted Ebola. What could be the first steps there, and , what are we really looking at? Martin: If I may start, being faced with suspect viral hemorrhagic fever patients is something which happens all the time. The real number of Viral hemorrhagic fever patients out of those who are suspects in the end is usually very small numbers of those few suspect cases which translate into real cases. We really can count them, , the fingers of our hand over the past couple of years. That notwithstanding means we need to be prepared and the first level of preparedness is, , knowing about those diseases, knowing about the possibility of these differential diagnosis in the returning febrile traveler or in the visitor from an endemic area. The problem here [00:48:00] is that, , there is no guarantee that, patients will turn up in those units where, , there is this level of knowledge. So , the, art of preparedness lies in the fact that you need to train a certain vigilance and capacity to recognize, potential cases, , outside those specialist centers. What strikes me sometimes as an oddity is as soon as there is an outbreak, there is a lot of media interest. And usually,, the questions hinge on one thing, which is are we all going to die from Ebola or Lassa or what it is? And I do believe we need a change of mindset here because the real risk onwards transmission, there's always a risk of the odd imported case, but, , the chance for onward transmission, if there is a certain level of recognition , is , really low. And I do believe what I be looking forward in the next outbreaks would be that, , the public interest focuses more on [00:49:00] what can we do and help and support those afflicted by the outbreak rather than reflectively thinking is there a threat for us and laying back, once, , the specialists and experts have said, "No, there is no real risk of, , this, disease spreading throughout, a non-endemic area." That would be my personal wish. But I do believe in general that we are fairly well prepared, , but you can never, , these things don't, , develop as in a textbook and as I said, it's very unlikely that a patient presents to a specialist unit. The patient will present somewhere in the countryside to a general practitioner who might not experience that many cases. Anne: Thanks. Yeah, and I agree with you, and , it's media is difficult, right? What kind of rings , in my ears is that 30-day incubation period, and how much should we track all these people that are traveling Daniel: First of all, let's be very clear based on the science, , we mentioned the media , and, this thing over the years has [00:50:00] taken, , on a life of its own in ter- the media and the popular concept, which is often not, very helpful , and not very protective, honestly, and just adds to the panic. So with this disease, , , it's very clear that you're only infectious, during your period of illness, right? So unlike COVID, for example, there's no asymptomatic transmission. there can sexual transmission, male to female sexual transmission from survivors, and that's because virus persistence , in the gonads. , But if we're looking at people with acute disease, it's really only during the period of illness, and it's really during the later periods of illness where, again, we talked about people are, have nausea, vomiting, diarrhea, bleeding, where they're shedding virus out into the environment. So this idea that, , what if, people from the Congo, came to the World Cup , in North America, the people who are walking around at a football game are not the people who are spreading Ebola virus, even if they were incubating Ebola virus. And so that's, , one thing that, we need to recognize and orient [00:51:00] our public health and our clinical measures

along those lines. I always say that there's good and there's bad news. We'll start with the bad news is that everyone, over the years would like to have something, a clinical indicator that anyone could say, , there's a, be a big E that flashes on someone's forehead when they have Ebola that's not the case. That's the bad news the good news is that there's lots of evidence that transmission of these viruses is prevented by the things that any clinician should be doing, and that is the standard precautions and contact precautions. When we've had , the occasional imported case, and sometimes cases that weren't recognized or suspected, we haven't had big outbreaks or ongoing transmission is because, of course, , we don't have too many hospitals in Geneva or Amsterdam or wherever , in the high-income countries where people say, "We don't have any gloves," or, "We don't have any clean needles," or, "We don't..." A lot of hospitals I've worked in don't have running water, right? And consequently, you can have situations where people are not cared for in the safest way. , And, if that's the situation in the hospital, you can imagine what the [00:52:00] situation is in the community. But that's not the life that we live , in high-income countries. And so do we need to be ready for the, , possibility of a case that comes from the affected area and could introduce, , a case of Ebola? That is possible, but we don't need to be paranoid about it. The average person , does not need to be worried about it. We're not gonna have a large outbreak in Geneva or Amsterdam. People say, "Well, now that there's an Ebola outbreak, what do I do to ensure my safety?" And I say, ", wear your seatbelt and get your flu shot." so I think that's not to ignore this. It's not to say that, , we don't need to have enhanced surveillance. , I'm not generally in, agreement in terms of quarantining people who are asymptomatic despite exposures. I think, we need to think about the mental health problems of that. That doesn't mean that there doesn't need to be surveillance of those people, right? , But, restrictive measures are not very good. And the other thing about those sorts of restrictive measures is that it's a disincentive to communicate, all right? So if you think, I'm gonna get stuck somewhere for 21 days," the longest [00:53:00] possible incubation period, then, you don't really have a big motivation to say, "Yeah, I might have been exposed." So I think we just need to be realistic. And then, - lastly, as I mentioned, we're somewhat the victim of this sort of scary disease that we, , have created. Not created in terms of the virus, but the whole sort of stigma about this and image about Ebola. often , this is presented, , I'll hear on the news often , " there's no transmission from a, an asymptomatic person, but out of an abundance of caution," the term that I've come to hate, , "An abundance of caution, we're going to, , keep them isolated for 21 days." And when I hear that

term, , what I know is coming something that is not evidence-based and not really based on science, and I don't really think helps people understand this. It just adds to the paranoia. I saw on the news last week there was a person who was exposed to Ebola in America and then who was flown to the Czech Republic and being admitted there to an isolation. In full isolation garb, all the people who were working with them, the person was asymptomatic, and so was not infectious at that time, [00:54:00] and, transferred in a full isolator. And I think it's just giving the wrong idea, and it's making much harder for us to, , approach this by being diverted to things that don't matter from the things that really do. Angela: . Fully agree. Martin, any last messages, , Martin: I couldn't agree more with what Daniel said. Maybe one technical detail you were alluding to extremely long incubation periods, and so usually, it's a maximum of 21 days, in most cases, 14 days where we have to worry about. The one exception is Andes hantavirus, where we learned that, up to eight weeks, the outbreak of last week, so to say,, where we learned that, there are unusually long incubation periods. But with all these so-called viral hemorrhagic fever, as we still misname them, it's,, 14 to days maximum. And to everything else, I think it was famous last words by Daniel, so I concur with what he said. Thank you very much. Daniel: My last points, , are, you know, despite all the focus [00:55:00] on international response, , and of course that is important, what really stops outbreaks is communities, right? It's communities that, come together , and we haven't historically done a great job of involving communities. We're getting better at it. These are communities in this area of the world that are traumatized from the situations they've lived in , and very, suspicious often. And, you can imagine, when you've lived with lots of different health problems and other problems your life, and then all of a sudden people come in and say, "Well, we're worried about this one problem now." , We're like, "Well, where were you, , when all these other things were happening?" And so, community response is ultimately, I think, what controls outbreaks, and so we need to work with communities and to make that happen. And then, I think everybody on this line would agree des-despite our concern,, of, okay, what does this mean for us in high-income countries, we'd like really the focus to be what does this mean for the people who are impacted in that area. And , I always , make the argument, , even if it's not the moral imperative that drives you, I think the strategic imperative is there as well. So, , if you [00:56:00] say, "Well, we don't want Ebola, to come, to Geneva or Amsterdam or wherever it may be," , the answer isn't to stand at your door in Geneva and look out for cases. The answer is to go where the fire, is burning and help put it out. Angela: That's beautiful. Yeah, can't, can't disagree with that, Daniel thank you guys so much. Anne: Yeah. Thank you, yeah. . We do need to go where the fire is., I want to thank our guests so much , Martin Krobisch in Amsterdam in the Netherlands, and Daniel Bausch in Geneva, Switzerland. And thank you for listening to Communicable, the CMI Comms podcast. This episode was hosted by Angela Hatner in Geneva, , and me, Anne-Grete M�rtson, in Leiden, the Netherlands. This one will be edited by Angela Hatner. Theme music was composed and conducted by Joseph McDade. You can subscribe to Communicable wherever you get your podcasts, or you can find it on ESCMID's website for the CMI Comms journal. Thanks for listening and helping CMI Comms and ESCMID move the conversation in ID and clinical microbiology further along. [00:57:00] Angela: You two have another 20 minutes. Do you have something at nine o'clock? Daniel: I'm open so I can talk about this forever actually, you know. It's dangerous 'cause I might go for another three hours, but yeah, go ahead. Angela: would love it. Would love it. I could sit here with you.