 Thank you very much. Nice to be here, albeit joining remotely. So I'm going to talk about monkeypox, which is an envelope DNA virus part of the orthopox family. So in that same group as the extinct smallpox virus, but also cowpox virus. And it's quite a large DNA virus. It's unusual as all orthopox viruses in that replication takes place within the cytoplasm of cells. But that's probably all the virology that I'm going to mention other than the characteristic appearances that you see on electron microscopy shown on the top right there. It was actually first detected in captive monkeys that were being used for laboratory research imported from Africa. This was in Denmark in 1958. We believe rodents are the likely reservoir for antibiotic transmission in affected African countries. And there's actually quite a broad host range in terms of mammalian species that are susceptible in terms of rodents, not all rodents are susceptible to infection. So it's quite interesting in terms of identifying the reservoirs. So there is shown a rope squirrel and also a giant pouch Gambian rat. The first human case was reported in 1970 and a child in what was then Zaire now the Democratic Republic of the Congo. And since then cases and outbreaks have occurred both in countries in Central Africa and also in West Africa. So between 1970 and 2018 we've seen a steady increase in reported cases and outbreaks across African countries, as I said, Central and West Africa. And that really reflects the the rodent pools, if you like, in terms of why we're seeing increased and varying outbreaks in different countries in these regions. Nobody's quite sure, but probably something to do with the change in population immunity against all thepox viruses. Monkeypox in Africa. So there are two clades. We used to call clade one West African and thankfully we're moving away from geographical names. So we now call that clade one and then there's clade two, which. Sorry, they're the wrong way around clade two is West African clade one is Central African or Congo based and that's its old name clade one is more severe. There's some inherent changes in the virus genome that means it can evade host immunity. It causes more fatal cases and it appears to be more transmissible than animal experiments. In 2018 we started seeing increase in outbreaks in certain countries, particularly in West Africa, but also in the DRC as well and the Central African Republic. So why this reemergence. So people used to suffer from smallpox and then of course we eradicated smallpox in the 70s using a very successful global vaccination campaign. That immunity is not long lasting and clearly new people are being born who don't have any orthopox immunity. It's it's cross protective generally orthopox immunity. So as that wanes we've started to see zoonotic spillovers into susceptible populations. Other potential factors are really sort of one health factors that affect how we interact with the animal reservoirs so increasing deforestation potentially the effect of climate change affecting both human and animal behaviors. Hunting, seeking more sources of protein greater bush meat exposure as a result of that, particularly with with rodent meat. And also population movements as well so increased infrastructure and making it easy for people to infected people to travel over large distances spreading infection around. Of course we're also better at surveillance now. So that will factor in but there appears to be a genuine increase in these cases and outbreaks. So in the end zoonotic risk countries in Africa. The first thing to say is that the monkeypox names a bit of a misnomer. So yes, monkeys do get infected and there is some human interaction. So for example, one ethnic group that we work with in Central African Republic, the Acre tribe do you hunt monkeys and sometimes report that the monkeys that they they kill for food. Do you have lesions typical of monkey pox on their face for example. However rodents as I said the main reservoir and humans can be exposed either through contaminated environments through rodent excreta, but also direct contact with animals. So hunting them, butchering them, etc. And then we can see secondary transmission between humans once it's entered a human population. There was also a USA outbreak that was zoonotic in 2003. Thankfully, nobody died. They were all relatively mild cases, but this resulted resulted from the importation of Gambian pouch rats, which were then co housed in the same facility with prairie dogs and other type of rodent. The prairie dogs were being bred to be kept as pets. The transmission went from the pouch rats to the prairie dogs. And then it went into the people who handled those prairie dogs. And this was where we saw the phenomenon of worse disease more severe lesions more a greater number of lesions at the site of inoculation. So where people were bitten or scratched, often we saw more severe lesions, more numerous lesions. There was no conclusive evidence of any human to human transmission in that outbreak. And it was the first time that a type of smallpox vaccine one called drive acts have been used as part of outbreak control. So vaccinating exposed contacts in terms of human to human transmission. It's actually not that easy, which is unusual because we see a large amount of viral shedding. But clearly we don't understand all of the factors that lead to transmission between humans. And for example, in the in the current 2022 outbreaks, we've seen relatively little transmission to household contacts of cases, albeit that's based on the development of symptomatic disease. But all we know there may be some people getting asymptomatically infected in households. But we do know that if you have close contact with an infected human or their contaminated materials, then you can become infected and entry typically is through broken skin. You can also inhale the virus and it gets in through cells in the respiratory tract and also through contact with mucus membranes. In terms of the outbreaks in Africa, a person to person spreads been a lot of it is probably due to just limited surveillance to actually work out how much person to person spread is occurring. And again, we've got that factor of whether asymptomatic transmission is happening. So both from people asymptomatically infected but also symptomatic people transmitting and it not resulting in symptomatic infection in their infected contacts. There are certain items that we know can be heavily contaminated and are associated with human to human transmission. So particularly clothing or linen. So if you think about it, if you've got lots of skin lesions, you're rubbing against clothing, touting your bed sheet. That's a great way to scrub off skin. It happens naturally and that's those skin particles contain lots of virus, particularly those from skin lesions and the scabs that form at the end. Exposure to respiratory secretions. We're not sure how important this is. There's some animal data to show that it's definitely a route and it was certainly an accepted route of transmission with smallpox, but we need further research on that. It's also unknown whether infect people are infectious before the rash appears in the context of the 2022 outbreaks that have occurred. I think we're about to see some data from various groups suggesting that in the context of sexual transmission, that may be a possibility. And the viable virus will happily sit in detached scabs under the right environmental conditions for anything from weeks to months. In terms of classical monkeypox or Mpox, as we're now increasingly calling it, it's got an incubation period of up to 21 days, minimum five days. But typically in 2022 we've been seeing about seven days, seven to eight days, and it depends on the outbreak really and potentially also how people are getting infected. Typically, but not always it starts with a prodrome. So a flu like illness often with fever and then with onset of lymph adenopathy, which may be regional or diffuse. And then it's followed by a rash and lesions go through development stages. So starting with a small vesicle, then becoming more postular sometimes with umbilication. So that dots that you see in the middle and then they can become ulcerated sometimes. And some but not all lesions will eventually form a scab and then the scab will drop off and then that's when we call we say that the lesions resolved can be anything from a few lesions to a thousand. We're not sure why that's the case. It may be something to do with the virus clade that you're infected with something to do about the host who's been infected, the amount of inoculum people receive at the point of transmission. You get this classical centrifugal spread so it often starts on the face and the trunk and then the final parts of the body where the rash appears is the hands and the feet. In terms of differential diagnosis, there's lots of rash illnesses. Chicken pox is probably the one that is most frequently confused, particularly in West Africa. And indeed you can get both chicken pox and monkey pox at the same time. It's important to note that chicken pox isn't a pox virus infection. It's caused by varicella zoster virus. It does look quite different in terms of the lesion appearance, but sometimes the early vesicles that you see, which are quite transient in chicken pox can be mistaken. Other pox diseases, so whether they're orthopox diseases and we must always be on the lookout for deliberate release of small pox virus, but also naturally occurring ones can look similar. Malusky pox virus, so maluskum contangiosum, which is what you can see on that man's chest there. That can look quite similar and we've probably missed cases of orthopox previously thinking it was maluskum. The bottom left photo shows off, which is classically transmitted from sheep and you get it on fingers typically around lambing time. And the various other bacterial and viral infections that may be in the differential. So diagnostics just to say really it's molecular. People are working on rapid antigen tests, but at the moment PCR either for orthopox or monkey pox specific genes. Sometimes we have to exclude small pox virus, so the very older virus, and we may look in parallel for other parapox, malusky pox and also herpes viruses. It all depends on the contact, whether it's just an occasional case or whether we're doing mass throughput testing. We can detect the virus in other samples as well. So you're in blood, skin lesions, throat, but often we will just swap the skin lesions to get the diagnosis in the UK. There isn't any monkey pox specific serology. There is some vaccinia serology. It's not really used for acute diagnosis though. And it's it's classified as a group three organism by the ACDP group in the UK, which means we have to handle it in certain ways. The clinical course of classical monkey pox is normally mild and self limiting people recover in several weeks. Some people will be left with skin scarring, which can be disfiguring and stigmatizing reported complications from African outbreaks. So disfigurement through skin scarring and granulation tissue, secondary bacterial infections, particularly of the skin, but also chest infections sometimes leading to septicemia. The virus itself can cause a pneumonia. And if it gets into the eye, we can see quite nasty eye disease that can result in blindness. And occasionally it's a rare complication, but also encephalitis. Case fatality rates. So often we say West African. Sorry, that should be clay to disease is associated with a low mortality, typically 1% Central African can be up to 10% depending on the outbreak. In the USA outbreak in 2003, it was no fatalities that's changed in 2022. But in the UK we've still not had any monkey pox fatalities, which is good news. So coming on to the UK, we manage monkey pox or we did manage all monkey pox is a high consequence infectious disease prior to 2020, prior to May 2022. So it sits there with lots of these other rather exotic, sometimes fatal infections where we manage them in a specific way, often with high level PPE shown on the right. And they may be managed in specific centers. They may need experimental treatments. We often lack vaccines to prevent transmission, etc. In September 2018. So I was writing the monkey pox guidance for the country. So in my head, I had a rough idea of what monkey pox lesions looked like. And who tends to get monkey pox and then someone thrust this picture in front of me whilst I was on clinical duties. And they were being this person was being treated for assumed Staphylococcal infection but not improving. And then later that day we got some images showing that the rash was spreading and that's when the light bulb moment happened and that neural collection connection was made and I realized this could be monkey pox. And indeed it was it was actually the first case to be identified in Europe and I diligently documented every single lesion at presentation. So about 150 lesions at presentation. This led to awareness raising particularly through the media so we obtained new pictures and put those out and a completely unrelated second case was diagnosed in Blackpool after the Royal Free case. Which was complete coincidence, but we think was as a result of this raised awareness. Both of these cases were people who'd recently traveled to Nigeria. We then had a third case in 2018 which was one of the health care workers looking after the second case and this was before monkey pox had been considered. The patient was being treated for an assumed bacterial infection. High level PPE wasn't used and the health care worker changed the bedding and the the outbreak investigation suggested that it was changing the bedding that probably led to the virus being disrupted dislodged sort of creating a dust cloud. And that's how the health care worker became infected. Around this time we knew that Nigeria, NCDC had been putting out information so we knew that they were having an outbreak in 2017 but by 2018 it seemed to be becoming under control and things were dying down. They did have some fatal cases mostly in immune suppressed individuals. And their sequencing and epidemiological investigation suggested that there'd been multiple zoonotic introductions into the human population. So prior to 2022 in Africa there's some great research going on so Nigerian colleagues described their outbreaks and the reemergence of the disease there. Colleagues in the Democratic Republic of Congo have been dealing with monkey pox for decades and have done some great characterisation studies so describing the course of disease the manifestations of illness. And then there's been genomic work as well, such as this shown by Central African Republic scientists showing how their clade one virus relates to other viruses in other countries in Africa. I think it's safe to say that we don't know how much monkey pox is actually occurring in Africa and this is for multiple reasons and I think you heard in Anna's talk how there are competing health priorities and often limited resources in many African countries. So I think we've clearly got blind spots in surveillance and also in genetic surveillance. And indeed these journalists recently went to rural parts of Democratic Republic of Congo and identified outbreaks that weren't previously known including some fatal cases. So I think often the images that people have seen prior to 2022 are like these. So this is very much at the end of the spectrum and it's severe clade one disease. This isn't typical of all monkey pox. Most people with monkey pox will have much milder disease, but it's to remind us all that this can be a really horrible devastating illness that can result in fatality and can result in long term scarring and stigmatisation as well. Just going back to the UK now so we had a few more imported cases so another one in 2019 in 2020 we had a bit of a hiatus albeit with the 2019 case having a transient relapse of illness after having recovered. And then 2020 was quiet because of COVID, not much international travel. And then 2021 we had a traveller who unfortunately transmitted to his wife and child once he was back in the UK. So that was our first pediatric case. They all recovered, which was good. And we had seven total cases in total prior to May 2022 all clade 2A and we tried using some experimental treatments as well. We've written this up in Lancet infectious diseases and we did some nice longitudinal sampling using for clinical reasons but we've reported that in this paper showing how virus eventually disappears from the different compartments over time. There are also global collaborations going on before 2022 so lots of sequencing work between the states, the UK and Nigeria. We started a tech a very much extended access program so this antiviral in the Central African Republic, because it was too difficult to do an actual randomized trial there but we're collecting structured data around it. Also supporting a randomized controlled trial plan for tech a very much in the DRC being run by DRC colleagues along with colleagues from the states. And working with WHO orthodox secretary at developing monkeypox training tools and doing more sequencing in Nigeria. And then everything changed in May 2022 so at the beginning of May we had an isolated case recent travel to Nigeria very similar to what we've seen before. And then about a week later we then had a family cluster which was unusual because we think the father was the index case although he'd recovered by that point but no exposure risk was identified in this man. It did result in their young infant becoming very severely ill and requiring ICU admission, albeit with a concomitant adenovirus infection as well. Then it was really 16th of May that everything changed dramatically and that's when we saw four new confirmed cases with no travel history to link to sexual partners and they all identified as gay or bisexual or other men who have sex with men. And this is when we suspect a community transmission and we're very concerned that there could be a new outbreak that's about to occur in gay and bisexual men. So we raised alerts alerted the international community sexual health services where patients were likely to present and also adapted our case definitions as well. And this is the so-called clade to be monkeypox outbreak that's mostly affected, almost exclusively gay and bisexual and other men who have sex with men in 2022. Many countries outside Africa have seen large outbreaks with the United States having the biggest outbreak. And it was really raising the alert, the UK raising the alerts that allowed other countries to act quickly. So I think we, our public health agency should be quite proud of itself. It was a bold decision to make because of concerns about stigmatizing gay and bisexual men. This is 2022 cases. So we peaked in the summer and then everything came down. We've had about just under 4,000 total cases. The vast majority have been managed in the community and have been mild. As I said, gay and bisexual men have been mostly affected and if you dig into those data a bit more you'll see that often these are quite sexually active people who often will have multiple partners. Quite a high proportion living with HIV but not necessarily immunosuppressed, typically well controlled with their HIV and a high incidence of HIV pre-exposure prophylaxis use as well. And in May I went on the radio to speak about this on Radio 4 as someone who's seen monkeypox before and I kind of regret saying it's not dissimilar because I then didn't say but there are some different aspects. And it's really this anal genital and oropharyngeal disease sometimes localized to those areas, not necessarily across all the body that we were seeing. This has been very nicely described now in several papers. So describing community cases across the UK and Europe in the New England Journal, including images of rectal disease, genital disease, oropharyngeal disease. This is really important in terms of educating clinicians and also those at risk. And in terms of hospitalized cases, we're just writing this up now but you can see some quite gory pictures showing that we still do see severe disease. We had nearly 200 people hospitalized in England and Northern Ireland for medical purposes. Lots of severe pain requiring heavy analgesia, lots of secondary bacterial infections and antibiotic use. It's mainly genital and anal rectal complications that we saw, but also some severe oropharyngeal disease, eye disease and enkephalitis. More recently we've seen some pretty nasty persistent infection with severe disease in people with very low CD4 counts who thankfully are rare in the UK because we have such good HIV treatment. We're now in this slightly complicated situation where CLAID2B is managed as HCID, sorry, isn't managed as HCID, so the outbreak strain, whereas all the others are still supposed to be managed as HCID, that's currently under review, that policy. Where did we do well in the UK? So I think having that prior experience from 2018 to 2022 actually helped us, we had networks in place. We knew a bit about experimental treatments and there was a public health and clinical system that was working quite effectively. As I said that recognizing a new risk group who'd been affected very quickly, so hats off to UK HSA for that. And issuing advice without stigmatizing, so right from the early start working with patient advocacy groups and experts in sexual health in HIV infection and again by sexual groups as well. The case definitions were also adapted quickly. We shared information with WHO with many other countries, ECDC, NCDC. We had very good clinical networking and also we provided excellent care for inpatients and maintained our infection prevention and control measures, which is why thankfully we've not had any nosocomial transmission in the UK this year. We also used a third generation orthopox virus vaccine, so modified vaccinia and CARA for the highest risk and also healthcare workers. And we also initiated randomized control trials of studies and treatments. The obvious question is why is it come under control? Is it vaccine? The vaccination really ramped up after cases started to come down in the summer, so vaccine helps keep cases down, but I don't think it was the reason for the change. There's some evidence from questionnaire studies in the UK suggesting that the highest risk individuals were changing their behavior in response to the outbreak, effectively protecting themselves by reducing their number of sexual partners. And also we have some data from the UK shown in that graph at the bottom right, which suggested that we were seeing a decrease in Shigella and LGV infections as well around the same time which suggested a decrease. These are the in sexual activity that involves transmission through contact. These are also contact infections. I think areas where we can improve in the UK, so making vaccine more accessible, so not being so specific about qualifying for vaccine, just offering it to as many people as possible. Obviously that depends on whether it's available in large volumes. I think we should always aim to engage stakeholders, communities and advisors very early. We could have done it a bit earlier this time. Launching trials and studies more quickly. Unfortunately, for various reasons it looks like we've missed the boat slightly and we've got quite low recruitment numbers for the randomized control trials. And then not forgetting that, you know, we are in Ireland, but we're part of a global community, so it's self defeating if we don't also support other countries, particularly those in Africa with access to diagnostics, vaccines, treatments, surveillance, research, social science, reducing stigmatization, enabling access to all of these things. I would say all of this is obviously resource dependent and obviously the UK has got its own financial issues at the moment. Vaccinating during an outbreak is very challenging. We didn't have large stocks of vaccine in the UK. We had to get them quickly and then agree who should be vaccinated first. But I think we did a reasonable job. Some will say we should have done better. And then finally what's next. So I don't know. Possibly persistence and resurgence of this to be virus in game bisexual men in 2023. The problem if it has been brought under control by behavioral changes is whether those behavioral changes will persist. I don't think we should demand that they persist because this is people's lives and they want to live their normal sexual lives. Could we see this again but with a more severe virus such as clade one virus. I think we probably will see more recurring outbreaks in African countries and potentially intensification of those outbreaks. There may be changes in the virus as it passes through multiple populations. It's quite slowly evolving but the virus in 2022 has already got about 50 mutations different from the known nearest neighbor virus. And are there any other networking opportunities for this virus so it sees an opportunity if you like by getting into a sexual social network of gay and bisexual men and exploited that and spreads very easily by close contact. I think one thing I'm certain about is it's not just going to fade away. We've got lots of research going on at the Pandemic Science Institute looking at environmental sampling, effectiveness of tech of very much antivirals both in the UK and overseas. Ongoing sequencing work trying to provide those important develop and test those points of care diagnostics. Describing disease patterns because all of these outbreaks don't necessarily cause the same type of disease understanding why some people get more severe disease than others. And also assessing vaccine when it's used in real life outbreak settings. Global research, just to say that, you know, we really do need to focus our resources on where the greatest recurring burden occurs, I African countries. But equally all affected countries are deserving of research activities and their research questions will change. They're not all going to be the same. Endpoints will differ as well according to the country and also the affected population goes without saying that we must work with African colleagues to help them build and strengthen their research capabilities, particularly in lower income countries. And I think most importantly, we really need to understand better transmission. So both the overspills from zoonotic reservoirs, but also human to human in different settings and also how immunity from natural infection or vaccination protects people and how it wanes over time. So my final slide is to say this is not just one simple disease now. And equally it's not just another African disease that occurs in remote villages or a tropical disease, neither is it a disease of gay men. This is a disease that will spread by prolonged close contact. It's not a sexually transmitted infection as such, but sex includes close contact. So that's a great way to transmit as well. It's a global health problem and it affects specific populations in different ways. There are clear inequities that are affecting transmission spread the size of outbreaks and also health outcomes. If you look at some of the deaths in the United States, they're very disadvantaged people with poor access to HIV care. And as a result, they're getting severe infection. So it's not just about monkey pox. It's about the wider context. Don't believe anyone who says they know what's going to happen going forward. I don't think they can make predictions. We need to avoid saying it's mild in most some people will get severe disease and even mild disease in the community can be pretty miserable if you've got to isolate and suffer the pain of the lesions. The most effective response for a global health problem is going to be a global response. It's self defeating if we just deal with the problem in our own country because it will come back and we'll get more imported infections in the future. So if altruism alone isn't significant cause to help other countries, then protecting your own population by addressing this as a global health problem seems sensible. And whilst we can lament over, you know, perhaps neglect of this disease in Africa by the international community previously and also the challenges for people in those countries, their governments, their health bodies to deal with monkey pox in addition to all the other outbreaks and health problems that they see. I think the 2022 events now that it's global are an opportunity to correct and improve that situation through better access to research to sharing information and to improved equity for vaccines treatments and diagnostics. Thanks very much.