 I'm really happy that this morning we can welcome for our keynote speaker, someone who really is exemplifying the solidarity that Jimmy has so rightly suggested we need. You mentioned that that's a medicine that's medicine to always work that well together, and we're now going to hear from a veterinarian who is working in a medical institution and developing vaccines which are appropriate for use across that divide in both livestock and humans. Professor George Warimwe is a veterinarian who is a PI at the Chemri Welcome Trust Unit here in Califi and is a assistant professor in the Center for Tropical Medicine and Global Health at the University of Oxford. He has just been awarded an incredible prize by the Royal Society, the Royal Society Africa Prize for his work on viral zoonoses and he's going to talk to us today about his experience as someone who crosses these boundaries and the development of a rift valley fever vaccine suitable for use in humans and livestock. So with that, I would like to pass across to Professor George Warimwe and we're really looking forward to hearing from you today. So thank you so much. Thank you Leigh Ann and I'd like to first start by thanking all the organizers for this fantastic conference. I mean, One Health has been on the fringes for a very long time, but it's now sort of center stage and this is our opportunity to really push this agenda that really makes sense in terms of disease control. So really like, you know, following Jimmy Smith's talk, I mean, that's going to be a tough act, but there are some things that he mentioned about siloed thinking and in all the sort of different facets that we deal with in health. And, you know, my view of One Health in this space of vaccinology is looking at developing vaccines for humans through the lens of animal health and vice versa. So if you're developing vaccines for veterinary use, looking at the impact of those vaccines and the development process from a human perspective. So I'm going to talk about the program that I've been working on for a while now. So this started sometime in 2012, which tells you about the sort of scale of time that you need to develop vaccines and also speaks to the sort of rapid development of COVID vaccines that we have seen, because that has been shrunk down to about a hundred days. So it's about developing a single vaccine for using humans and livestock against Rift Valley fever. This audience, I don't think I need to talk about, sorry, okay. I don't think I need to talk about the importance of animals to human health for this particular audience. In fact, this is a photo taken among a collection of lots of photos on the ill-reflected sites. So I would urge you all to look at that. It's got fantastic visual representations of the importance of animal health to humans. And I like this photo because it just demonstrates the pure joy that animals bring to humans, especially children. But of course, we also know about the economic importance. There's been lots of studies demonstrating the impact of animals to livelihoods, financial security. I always mentioned that I was only able to go to university because my grandparents who raised me own an animal and they sold that animal and that generated income, some funding for me to go to university. And I'm sure there are many others in the audience who have similar stories. One of the other things we share with livestock are infectious diseases. In fact, over 60% of infectious diseases in humans have involved an animal sort of transmission. And for the emerging infectious diseases that we're seeing now that are increasing in incidents, that percentage is much higher. So when you're thinking about controlling human disease, it just illustrates the point that you also have to think about animal health just because of that connection. So I'm going to talk about riff-valley fever, which is a virus that was identified in Kenya in the 1930s. It is an RNA virus in the family of any very day. There are no vaccines available for it or no specific therapeutics, which is why it has been prioritized by the African Union and the Wild Health Organization. So RVF has a complex transmission cycle by complexity, meaning that for me it involves quite a lot of mammalian species and lots of mosquito species. But the simplistic sort of explanation is that you have very heavy rainfall that causes floods, which increases the number of mosquitoes to transmit the virus. Sorry, not able to transmit the virus. This increase in mosquito numbers allows a mechanism for the virus to circulate in animals. Some of the mosquitoes are infected for life. The eggs, if they had had a blood meal that has infectious virus, the virus has gone through its progeny through the eggs. And so the virus transmits, I mean, the mosquitoes transmit the virus in animal species. Most commonly, sheep, goats, cattle and camels. And during these epidemics where you have very high levels of viremia, viral load circulating in these animals, the mosquitoes can then transmit the virus to humans or also to wildlife. Now the virus has been detected in wildlife by way of seroprevalent studies, but the impact of RVF in livestock is real not fully understood. But in domestic ruminants, like the ones I've mentioned, you get up to about that of animals. And of course, in young animals, the mortality is much higher. This is over 90%. And the classic sort of hallmark of disease is abortion storms. So nearly all animals in a farm that are pregnant would abort. In humans, the disease is described more like flu-like illness with very non-specific symptoms. But a proportion of these individuals develop severe disease with high case fatality rates. And there's been some sort of evidence, although anecdotal, suggesting that the case fatality has been, you know, recent epidemics in humans has been rather high. So ranging from about 30%, at least from the East African outbreaks. So where is RVF common? It's predominantly in Africa. And these maps, you know, are like you would have seen maps like these for all sorts of things. Basically, the darker it is, the more cases there are or have been reported. On the left, you've got humans. On the right, you have livestock. The most important thing here to note is that there is a lot more cases of RVF reported in livestock than in humans, which possibly just illustrates the poor sort of surveillance systems in humans in some of these settings. The other thing you will note is that Kenya and South Africa or East Africa and Southern Africa tend to be really severely affected by RVF outbreaks just based on the number over the previous years. So what can we do to control RVF? We have licensed inactivated and live vaccines for their use in livestock. These have some safety drawbacks and some need multiple doses to generate an effective immune response. You need high containment for their production because it's an actual sort of RVF virus that you're dealing with, whether you're activating it or modified in some way. And they're not diva compatible. So you cannot differentiate vaccinated animals from non-vaccinated animals because the antibody response to the whole virus is similar to that that's caused by natural infection. So there are no licensed vaccines for human use. And so the thrust of this program has really been about developing a vaccine for human use but also developing safer vaccines that can be used in livestock. This is a very old table from the 1930s. Just all I want to demonstrate here is that a humoral immune response. So an antibody response is sufficient for protection because of time I wouldn't really go into the table. But the point I want to sort of make is that if you pass that into animals again you can confer protection suggesting that antibodies are important. We also have from very many studies that have been done over the years demonstrating that neutralizing antibodies correlate to protection. And so if you're thinking about a target for a vaccine construct, you want to develop antibodies, develop a vaccine that can elicit neutralizing antibodies. And finally we know that if you recover from RVF infection then these neutralizing antibodies tend to be long-lived. And this is just a case demonstrating that an individual hard neutralizing antibody is up to 25 years later without exposure in the intervening period which is really remarkable. So we know what the target of these neutralizing antibodies are. It's the surface of the viral glycoprotein of the virus. Now these are viral glycoproteins known as GNNGC. The analogous sort of situation here is the spike protein for coronavirus. So it's like targeting the same sort of surface of the virus. It's an envelope RNA virus. So we set out to use the Chadox-1 platform because at that time the Chadox-1 vaccine platform which is basically just a vehicle to deliver the vaccine had been used in humans and had been shown to be safe in humans. This is very important as a sort of starting point for a human vaccine because you've already saved so much costs by having already a track record in the safety profile. I will talk about the costs of developing vaccines later. But the Chadox-1 platform was safe in humans previously when used for other vaccines and all we did basically is get the targets, the genes that encode the virus, RVF, GNNGC and inserted this into the Chadox-1 vector which when you vaccinate an individual gets into the cell, expresses the proteins and these RVF glycoproteins then stimulate an immune response and hopefully you've got a very high immune response to confer protection. So the methods of manufacture were already well established so it really was a matter of plug and play. So this image just illustrates the sort of pipeline for development is simplistic but it just illustrates the point. We've had the preclinical discovery period where we identified the RVF, I mean inserted the RVF-GNNGC into the Chadox-1 platform. The plan was to do preclinical studies in mice and then go on to livestock trials and human studies and hopefully if it all works well then you'd have a single vaccine for using multiple species. So the first really encouraging data we found was that if you immunize mice and expose them to RVF virus two months later you had 100% protection and you know this was very exciting whereas the group that were given a placebo did not you know are not protected and succumbed to infection. So the next sets of studies in livestock were studies that we did in very close partnership with Illry, with Vishnane and others and the idea here was to immunize animals and follow them up for a month for immune response to develop and then expose them to RVF virus. So this is a typical approach of evaluating vaccines. So the long and short of it was that a single immunization in all those species provided 100% protection so none of the animals that received Chadox-1 developed disease and in fact as illustrated on this plot with the blue representing Chadox-1 group and the black representing the licensed product and the gray representing placebo. All the Chadox-1 vaccinated animals mounted a neutralizing antibody response for the rift vaccine which is available in Kenya as a you know RVF vaccine. Two of the animals one in you know cattle and goats did not mount a neutralizing response and were not protected. Further supporting this idea that neutralizing antibodies are the main sort of thing you need to elicit to mount an immune response. So the publication is up there if anybody wants to to follow that. So the next step was to look at RVF in pregnancy again using a similar experimental design where you vaccinate for this we vaccinated early in gestation and challenged them later with the virulent virus and then monitoring the safety of the fetus and also our protection. So these studies were done in the Netherlands with Geron Kotakas and others and the top panels represent the results of the vaccine development in sheep and the bottom are the goats. So that both I mean in both species that the antibody response was really very high. It was within the range we observed in the Kenyan study artillery and the Chadox-1 vaccinated group in red here were protected against a viremia. So you see the viral load there it just means that the animals were protected against RVF infection. There was no illness in the pregnant animals and no sign of infection in the fetuses in sheep. In the goats again we had very high levels of protection although two of the 25 fetuses succumbed to infection suggesting that there might be differences in the either the mechanism of protection or other factor in goats in terms of the level of protection that you see following vaccination. But the primary aim of this experiment really was to demonstrate that the Chadox-1 vaccine was safe which is something that current you know most of the vaccines currently are unable to you know show you know that we really don't have any vaccines that can be used in pregnancy other than the inactivated vaccines that need multiple immunizations. So this was a really good point to sort of get that you know proceed from. Yeah so the next step was to look at the now that we've demonstrated the the safety of the product in in pregnant and non-pregnant animals and showed you know very high levels of protection. We the next step was to conduct a field trial looking at the whether the vaccine elicits a similar you know performs as well as the licensed product in a study that is powered to evaluate that at a sort of population level. So the previous studies were designed to look at efficacy you know for the first study and the second one was to look at safety in pregnancy whereas this is now looking at a field level and these are studies that we did in Capiti where we looked at 180 animals per species so this is with the as indicated there as a study protocol and this study was done to very high levels very high standard so to GCP and I believe it's probably the largest sort of GCP veterinary trial that's been done globally. I haven't had anybody object to that in the different places I've talked about this. So as I say the study is done in Kenya it's in healthy non-pregnant animals and the animals were followed up for a year and the endpoint of the trial the thing that we will use to say whether the vaccine performs as well as the licensed product is a neutralizing antibody titers. Now I don't have the results for this but analysis is underway but should be available sometime early next year but the whole point is that this data will be used to support the registration of the product for use in East Africa and other countries in Africa where there's very high sort of exposure to RVF so I'll switch gears a bit so now we're moving to humans so the veterinary development is of course very advanced and we are now you know at the point where we're thinking about registration but how about the human study so we've begun phase one study in humans in Oxford and this is the typical approach is to start with a low dose, go to a medium dose and a high dose for any of you who've been following you know the Oxford AstraZeneca COVID-19 vaccine development you would have seen some of this sort of experimental designs or trial designs very early on so this this sort of phase one study is is done in a small number of participants with the aim of just looking at the safety profile of the product and of course whether it also elicits an immune response the desired immune response so we already have for the platform in general so Chad Ox one in general we already have over safety database over a billion doses of course because of the Oxford AstraZeneca COVID vaccine but now we want to add data specific to the RVF vaccine and so far the vaccine is performing well both in terms of the safety and the immune response and again we expect this data to be ready you know for sort of dissemination sometime early next year so I've taken that fairly quickly just because of time but the summary of this work is that you know we've identified very high levels of protection in livestock now the vaccine is highly efficacious and safe in pregnant ruminants the safety and immunogenicity is expected to be as good as current licensed vaccine which is the sort of the Smith band vaccine supplied by Keve Vapi analysis is ongoing as is the analysis of the human phase one study that is going to be available as from next year so in terms of so for the veterinary development the veterinary use of the product that has a clear sort of pathway that we would follow for the as stipulated by the local regulators and you know NDA the veterinary medicines directorate and and so on and there is a actually a harmonized process for for doing this in eastern Africa but how about the the human landscape now one of the most difficult things to do as as you know the audience might appreciate is to predict when the next Rift Valley fever outbreak would be if you if if you are to predict that with very high sort of confidence you would be able to design a vaccine efficacy study so but in the absence of that it becomes really difficult to predict you know to design a vaccine efficacy study for you for RVF so an alternative approach would be to use correlates of protection as done for other vaccines so we know you know the threshold the antibody threshold you require to provide protection against rabies for instance and even yellow fever for instance another another route is to think about an animal rule which is something that's done by the FDA in the US but because this is a problem RVF is a problem that's predominantly restricted to Africa and the Arabian Peninsula I think we think that there is a need to engage the regulatory national regulatory authorities in the continent about the the best sort of strategy towards licensure of this vaccine whether it's a emergency use authorization as we have seen as we have seen for COVID-19 and then followed by sort of a phase three study where you're looking at efficacy evaluation if ever there was a massive sort of epidemic you also need to think about what vaccination regimen is going to be eventually used and so this relies on doing further studies phase two studies where you look at a single dose versus two doses and which of those performs well and think about the deployment and how would you deployment this vaccine would you deploy it in humans only or would you deploy it in humans and animals during an epidemic and you know this sort of thing calls for you know massive stakeholder engagement including the bodies listed there so very much a one health focused sort of strategy also not just the in the making of the vaccine and the planning of the experiment but also in the future work on the deployment of the product so I think we'll stop there um sorry yeah I'll stop there and just acknowledge that this is work that is involved very many partners and at the center of this has been the International Institute of Research Institute very close partners there as I mentioned earlier but also I can just or not I cannot overstate the importance of engagement with the regulatory and policies stakeholders including the national biosafety authority and the ministry of agriculture livestock and fisheries because this would not have been possible without their support and you know and guidance through the through the process at Ilri you know campus and Kapiti so I think I'll stop there and hand it over back to you Leanne or for any further questions thank you so much George for that great great talk and there's lots of questions in the chat but I'm going to just jump in with one that's maybe a little bit less technical we talked a bit at the beginning about the difficulty of breaking down silos so I'm going to ask you a personal question as a veterinarian now working at Chemri how have you felt how have you found that transition sort of moving from the veterinary field into sort of medical research how and have you got any suggestions for those of us here or online about talking across disciplines and making those forging those connections thank you yeah that's a good question I mean I think the first thing to say is I never left veterinary medicine my background is I'm a vet as you say it and I think the I have sort of enthused colleagues at Chemri and others you know that I collaborate with globally about the value of animal health not just from the perspective of you know at the public you know deployment because when you think of one health there's a there's a big sort of bias I think towards thinking of control programs like a you're deploying a control programs for brucellosis and you have to think about both but I think I've been using people to think about more even at the basic level that there are differences in animals and humans in terms of the immune sort of the way they mount an immune response the components of the immune response so you can understand pathogens and and how you know to how to control pathogens by looking at how the host parse you know house parasite or host virus interaction differs in the different species so it's been more about showing a different way of thinking about the particular problem that you know colleagues are working on and applying this sort of one health basically exploiting synergies in in sort of immunology in both humans and livestock it's not necessarily easy but to me it just makes sense yeah no that that's wonderful and very sort of reminiscent of that original one medicine concept and and also very great to hear that you never feel that you've left veterinary medicine I'm sorry if that was what came across I always have this myself where people said oh you're in research maybe you're not a vet anymore but we're still we're still veterinarians at heart um so I'm just going to pick up on a couple of questions that came in the chat so there was one question that suggested that given the the prolonged drought followed by very heavy rains that we've experienced in the country you know does this make you feel that an outbreak might be more likely and if so is there anything people should be considering to protect themselves or protect prepare yeah I mean I think that's again is a good question um there are others in the audience you know Bernadette and others who can make a really informed decision based on the sort of mathematical modeling and predictions I think I will I would emphasize more uh rather than moving rather than thinking about you know is there an outbreak that's going to happen because of these conditions I think I would emphasize being ready all the time which is something that Jimmy mentioned in in his sort of introduction introduction that we need to be ready we need to have surveillance systems that are ready to sort of go uh without necessarily um sort of having to wait for a set of circumstances to come to come into sort of existence so you can always if we have surveillance systems that are full you know that are not just focused on a particular disease not just focused on RVF then you will be able to respond quickly um regardless of whether there's a drought or whether there is not I think I would emphasize more on having um that of you know every day sort of readiness to address sort of outbreaks I don't know whether I'm making sense there rather than focusing more just on an RVF outbreak yeah absolutely I think that that's really clear that we really need to put um our efforts into preparedness and surveillance