 Hi, everyone, my name is Barbara. I'm a postdoc in Susie Downey's community group. I've been with Susie for more than six years now, seven. So basically, from the start of her lab here in Oxford, she moved back from Thailand in 2015. And after that, we set up her lab as a paper manager building for attitude research. So it's a pleasure to introduce you to all of our group members. Some of them are here today and have already worked for three of our equal students. So we recently hired a new postdoc, Marta, who's joined us from Ethiopia. Then Jenny is our project manager, Bianca, our research assistant. And then we have six great talents that equal students in the group who is probably going to submit his thesis on Friday this week. Ali has just started his fourth year. And Sandra and Isabelle just started their second year. And then Yanni and Sana were in the first year. And Sana just joined us this week. Actually, she hasn't even officially started now and yet she'll start on Monday. But it's using today as an opportunity to just get to know what everyone else is doing here. And Jake was visiting us for half a year from Thailand. Only he thinks it was working with one of our long standing collaborators there. Before I tell you a bit more about our research, I want to just give you a bit of the insight into what life in the lab looks like. And we had some nice lab photographs taken recently. And basically, we are dealing with human samples on a basis, which means isolating the immune cells from blood or patients, but also health volunteers and processing the blood to also extract serum and plasma for storage and for the downstream NSAIDs. And this just gives you a bit of a taste of how it looks like in the lab. And when we're not taking scientific challenges, we're usually probably shooting freezers and making sure that we have enough space to store all of these precious samples. So now I'm going to tell you a bit more about the research that we're doing. Really what we're doing, the core of what we're doing, revolves around people who are vulnerable to infections and more severe outcomes from infections. So we've turned these vaccines for the vulnerable because at the center of this are really people with chronic metabolic disease, since having type 2W, this obesity, but also the ageing population who have some sort of immune dysfunction that predisposes them then to get more likely to be infected with different pathogens more frequently. And then also they might have more severe outcomes from infection, or they might not react as efficiently to the vaccine as you would expect from a healthy patient. And around this, we're studying two different infectious diseases that were not transmitted. There was just a tropical neglect, neglect of tropical disease. And since it has been working on this for more than 10 years now. And on the other hand, we have COVID-19, which is of course, as you all know, very recent, but really important. But if you look at the, just silent steps, the funding for those two is actually not quite so badly managed, which is a neglected, neglected problem. Because it's not even on the WHO, this for neglecting the disease. But of course, COVID, as you would all imagine, attracts much more families. So it just highlights how tricky it can be to work with the neglect of tropical disease. But we're fortunate to have lots of support for these portraits. And I'm going to walk you through all of these in the next slide. So I'll start with melliodosis, because that's what we've been working on for a long time. Melliodosis is caused by the form negative insulin of the serum. Propagation is so much of the mullet. It's soil swelling. It's also to your wall pathogens. So it's considered a baroterrorist threat as well. It's an accident, humans are an accident, of course. So it enters the human body through cuts, cutaneous infection, or for inhalation or ingestion. Melliodosis is very prevalent in Southeast Asia and northern Australia, so basically the profits. And we can see a very high mortality rate and it's up to 40% in some regions of Thailand, not in Thailand. There's a very defined at risk population. So people who get the infection and are admitted to hospital but other have diabetes, reimbursed, alcohol abuse. They might be on steroids or they are very old. So diabetes, as I said, is a risk factor and there's a powerful increase for getting melliodosis if you have type 2 diabetes. And this is only three or four in the case of 2D. There is not enough data on how many cases of melliodosis we have worldwide because there is this pregnancy between labs picking up the bacterium and reporting of the cases. But it's predicted that there are around 89,000 deaths per year worldwide, which is more than 90. And interestingly, so what this graph here shows you is that the endemic region is really over that with the highest prevalence of diabetes worldwide. And especially if you look at this country, it's like lonely and this is of course really affected by this. And most importantly, there's no vaccine available. So basically this disease is free of antibiotics, but we don't have preventative measures yet. And this is something we would like to change. And given that more than 50% of people who are admitted to hospital with melliodosis have diabetes, the vaccine really has to be targeted at this population. Before we think about vaccine development, but also including treatments for the disease, we really need to understand more about the correlation protection in melliodosis. And so this is a summary slide of what our group has done over the past 10 years really. And obviously this is also supported by many other researchers who are studying melliodosis. And so what you can see is on the left side, we have immune cells or in-features that are increased in people who survive from the disease. And then on the right top, you see a few things that are increased in people who die. So what we see is that T cells on the left and interval gamma production by T cells, which is crucial to high infection, interest in infection like the one caused by buccal barriers to the ballet, they are increased in people who survive. And then in the immune cells are increased like in case of a chemical infection cells, which is critical to contain infection, as well as excavators in immune cells like the pre-exhaust and londocytes, which are important to present antigens to T cells and indicate those T cells to generate memory responses. And then antibodies are really important. ITG2 has been shown to be a higher survival. And of course antibody mediators, phagocytosis of bacteria and inhibition of bacterial growth in cells is increased in people who survive. And then in people who die, we can see that they have increased levels of certain cytokines about 15 and 18, which we would consider as pro-inflammatory cytokines, but then also our 10, which is very anti-inflammatory cytokines, dampens down immune responses, also high increase. And certain genetic traits like PHA types are also enriched in people who die. And we've also seen that in immune cells like neutrophils either are high or low levels are associated with that. Now this summary slide is really lovely slide that Pam has generated for his thesis and just highlights how important it is that you have a very well-regulated immune response in order to take infection and for the host to survive this. So what we want from an infection, from a, not from an infection, but what we want from the body when it fights infection is a very well-balanced sequence of events and well-timed sequence of events, basically inducing inflammation in the first place for cells to come into the site of infection then kill bacteria or viruses, it's a very general thing. So any pathogen basically, and then bringing more cells, different cells to exert their effective functions in order to reduce the pathogen burden. And then you want induction of resolutions. So you want this to stop and then you want healing to induce. So any tissue damage will then be healed. And what Pam has shown here in a blood transcriptomic signature, associated with mortality, is that you get this prolonged inflammation on the top here. So either all the things that are elevated, highly elevated in people who do not survive metatosis. So there's prolonged inflammation and then obviously lead eventually to organ take and death. But then on the other hand, I'll put the blue down here. You can see that there's also high levels of anti-inflammatory responses, basically acting against the inflammatory responses that are not able to retain pathogen burden. And so both of these are elevators in people who die. And then we actually, oh, sorry. And then this is eventually a phase to that. Something else we are really interested in as well is whether certain anti-diabetic drugs potentially are sort of favorable outcome in the doses. And so we've looked at metatomic treatment because this is a very widely used anti-diabetic drug. And within our cohorts that we have for acute metatosis really categorized people with diabetes into free drugs. Those who already have pre-existing diabetes at the time of enrollment. And those were then split up into people who were taking metatomic treatment or those who were not. And so on the, yes. So the left part here is the number of patients who are not a metatomic and have pre-existing diabetes. And in the brown, you see the people who survived and in the gray, who died. You can see 33% of the people that died. And then if we look at the metatomic work here, you can see only 9% died. And what's also interesting, you can see that much less people are actually on metatomic treatment in our cohorts here. And the ones with pre-existing, I would note pre-existing diabetes diagnosis were basically diagnosed at enrollment or at hospital admission. Also had a similar frequency of death compared to no metatomic work. So when we put this into a logistical rational and this is only taking into account the people who are already diagnosed with diabetes at enrollment. So pre-existing diabetes, sorry. And correct this for different compounding factors like age, history of regal impairment and blood glucose levels. Then you can see that there's a significant advantage of taking metatomic treatment. Metatomic treatment is associated with favorable outcome for many users. So significantly less likely to die. And interestingly, there seems to be a bit of an inference based on, say, so women seem to be here. There seems to be more of a lot of outcome in women than there is, but this might be a bit underpowered, but it wasn't an interesting observation. So now I would like to tell you a bit about what's first thing proud of a new disease vaccine, which is left by Susie here at Oxford. And we're really proud to do this. I think those, as I said, there's no vaccine in the way that one just needs to get started and we have to just pave the way for other groups as well to put more candidates in, more vaccine candidates in the plan to test them. So what we are doing here is this is in collaboration with colleagues in the University of Nevada, Reno, and they have developed a vaccine for many doses, which has shown really a great efficacy in treatment for house models, 100% effective. And basically they are using a conjugate vaccine, which is composed of two components of the bacteria. One is the CPS and Capsule polysaccharide, and one is HCP-1 protein, which is part of the type six secretion system, so that's a really light structure that the bacterium uses to enter cells and infect cells. And so what has been shown is that CPS really induces antibodies and HCP-1 protein induces T cells, a T cell memory. And that's really what we want. We want a combination of antibodies and T cells for our vaccine. So the phase one trial, and also to mention that the vaccine is currently in manufacture, so it will be available at the end of next year. So that means the phase one trial will start in 2023, and these are the three groups that we will look at. So the stage one is basically the dose escalation study, and we're looking at the individual components of the vaccine separately. So there will be 12 participants and then four each will receive different doses of the CPS components. And in the stage two, four of each participants in each group will receive different doses of the protein component, the HCP-1. And then in the third stage, the entire product, the entire vaccine will be given to 12 healthy individuals. And the next stage will be to give this to the CPS for the type two, that is to see how their response is those five points of the vaccine. And we'll have, this is just a timeline for the vaccine and, you know, pre-vaccinations and for all our time points and all the volunteers up to 12 months for the third dose. And this study will be written by Jenny Marta and Bramco. In addition to this, we are also collaborating with our colleagues at Morrow and up in North-East Highland, Ulaanbaataratani at the hospital, who will be running a study of attitudes to dose vaccination and clinical trials. So this is really important as a preparation for any clinical trial or phase two vaccine trials in the region where we want to test the vaccines in the endemic population. And the study will involve different groups of people that are participating of our host family doses patients. Here give us at risk, people at risk of a high probability of patient malexposure and key informants. And there will be a series of interviews and focus groups in order to better understand the burdens of familial doses, understand, increase the understanding of infection risk, improve the understanding of infection risk and figure out what the concerns about vaccines are as well as looking at views of people to participate in trials. Okay, so now I'm going to move to a different infectious disease, COVID-19, and for when you heard it about Pitch Consortium by Isabelle and Sandra this morning. So Pitch Consortium is really an extension of the large NPSI study which is looking at more than 40,000 health care workers and looking at antibody responses and within a few people. But Pitch is more targeted at cellular responses to the vaccine and to date it was more than 2,000 health care workers already. It is a national collaboration and a prospective constitution and all cohorts are recruited at five different sites. Oxford is one of them and then Liverpool, Sheffield, Robinham and Castle as well as contribution by UK which is saying. So the question that the Pitch Consortium wants to answer are the following. Does previous infection impact on response to vaccination? Does the new response differ between plies that they work in the law versus short dosing interval and this is over in that to inform national policy and basically led to the UK government implementing the law dosing interval for Pfizer. And then how long do the responses last and what happens if we encounter different variants of concern, especially Omicron and any future variants of concern. And so the figure that I'm showing here that's taken from the most recent work within the Pitch Consortium following, let me just do it in a link, following the vaccine responses, these are these anti-body responses of these health care worker boards and splitting these people out into naive and those higher immunity and when we say higher immunity we mean that they were either infected with something to prior to their first vaccine dose or anytime after the second dose. And you can appreciate probably based on your own experience that the main purpose for us going to train substantially over the years. So what we can see in black are the people who are naive and in green, red, people with hybrid immunity and there's definitely at the start of the first dose you can see that there is an advantage of having been exposed to SARS-CoV-2. So there's a high antibody response here and the T cells start higher up here but then people who have been previously naive to SARS-CoV-2 they catch up. And what is interesting to see with the antibodies they are very versus the T cells they always seem to follow a very oscillating pattern here. So they are high once you receive your vaccine and they were down again and then you're boosted up again and they picked it up and boosted even further. And this is less pronounced when you've had previous infection already. And for the T cells they basically do not decline or just marginally decline after the dose of vaccination or decline but then they are boosted a bit and just increase slightly and then there seems to be some sort of flexible effect as well. And for the variants of concern we've shown and others have shown that in response to Omicron our antibodies are less efficient in binding to the Omicron variant whereas T cells are less affected by Omicron so there's still recognition of the virus. We're also involved in the cytokine vibrance which is looking at the art of dedication of respect for vaccine breakthrough infection using the SIREN pitch consortia and soon as you use the CoV-i on this as well and this is basically using all vaccine breakthrough cases involved in SIREN and they will be invited to use an online questionnaire to find more about possible reasons why they are more prone to the kind of infection at all. And then there will be the success of these people who will do these studies in more detail and give them the knowledge of studies. And something that we're really excited about is a new study that we're starting this October. This is in collaboration with Professor Saint-Levan at Oprope and it is called Zika Variants. So it's looking at, it's basically a Southeast Asia initiative to comment SARS-CoV-2 variants. There are four sites in Southeast Asia, Indonesia, Singapore, Thailand, Vietnam and they'll work together with researchers in the UK like us and the USA. And the objective is to really enable locally led investigators, investigations into new variants into evaluating the impact on antibody and T-cell responses in Southeast Asian populations and of course cleaning the consequences of infection. And what this next slide you're touching nicely with is international home in collaboration because at the heart of our lab is really a lot of teaching and capacity development and we do regularly work together with all of our international collaborators to share protocols, to train people, people are coming to our lab obviously less so in the past few years, but this is just restarting now, but obviously remotely as well so we try to support them, especially labs who are not regularly running T-cell immunity in the lab so we're trying to help them set up the capacity to actually run some of the technology locally and this involves a lot of SP sharing, clinical training, but also help with data analysis and interpretation. And I've just put this lovely photo here which is Priyanka, the third from the left, our agent who went out to Vietnam in the summer for two weeks and very successfully trained staff who were there in how to run T-cell antibodies. And finally, just the last bit I would like to share with you something else we're interested in is in all of this we would like to understand more at a basic level what really makes these new cells of people who are more resistant to infection dysfunctional. So what we're looking at is basically this function of the cells metabolism. So we are trying to investigate whether cells from people with diabetes or who have been infected or who are old whether they are using different, sorry that's one, but their ability to generate energy is different and basically that has an impact on them actually. And we're using different methods to do this. I'm not going to tell you right now what they are exactly, but we've also established a small research facility to instruments that's accessible for researchers across the university but also international collaborations. And this is just looking at how cells produce energy. It's called a C-force instrument and it's very exciting. This is also Ali Chase and Ali's research interest. And we're also doing some single cell RNA-C currently which Ali is leading on to look at differences in people with diabetes and without diabetes and see whether we can piece out any of the insights there.