In ANCA-associated vasculitis (AAV), the body's own white blood cells attack blood vessels. The kidneys are most commonly involved in AAV, frequently leading to kidney failure and dialysis. Amongst people that require dialysis, 2-3 out of 10 do not survive, and 4 out of 10 do not recover kidney function. Importantly, infection and heart disease are leading causes of death. Without treatment AAV is life-threatening; treatment involves powerful immunosuppression. Whilst prognosis has significantly improved, there remains significant risk of damage from the disease and its treatment, especially during the first 12 months. Cytomegalovirus (CMV) is a common virus, present in over half the population. After initial infection, the virus remains in the body for life and undergoes periods of reactivation. In a healthy person, the immune system keeps the virus under control. Recent research within my supervisors' group, showed that asymptomatic CMV reactivation occurs in roughly 1 in 4 people with stable AAV and leads to expansions of harmful immune cells able to damage blood vessels. We know that CMV reactivation and expansion of these harmful cells are associated with reduced kidney function and increased risk of infection and heart disease. What we do not yet know is how often asymptomatic CMV reactivation occurs in patients with newly diagnosed or recently relapsed AAV. We anticipate that CMV will reactivate much more frequently during the first 12 months following diagnosis or relapse (the acute phase), due to the medication needed to suppress the immune system and inflammation from the vasculitis, and that this will be linked with worse outcomes. We also do not yet know how CMV reactivation may amplify the damage that vasculitis can do to the kidney. Our preliminary work suggests that CMV reactivation increases the proportion of a specific inflammatory group of white blood cells called monocytes (CCR2 expressing monocytes) in AAV. Our preliminary findings suggest that in these patients, the more CCR2 expressing monocytes in the blood, the worse the kidney function. There is also an increasing amount of evidence now that blocking CCR2 monocytes in mice reduces kidney damage across a wide variety of kidney conditions. This suggests that this monocyte-induced kidney damage pathway is not just limited to patients with vasculitis. The main aims of this study are to measure the frequency of CMV reactivation during the first 12 months and determine whether this is linked to increased disease activity, ongoing dialysis requirement and increased damage from AAV. We will then explore whether CMV reactivation causes an increase in CCR2 expressing monocytes, and whether these monocytes cause persistent kidney damage in AAV. We will aim to recruit all patients with newly diagnosed or recently relapsed AAV. Patients will be followed up with 10 study visits over 12 months. At each visit, participants will be required to give blood and urine samples to determine if CMV has reactivated and measure other inflammatory chemicals and proteins. Participants will also be asked to fill in a questionnaire on their health and quality of life. A kidney biopsy is performed routinely to confirm a diagnosis of AAV. We will use some of this kidney tissue to identify the number of monocytes in the tissue and assess if this is related to the kidney damage we see on the biopsy. If our current proposed study confirms that CMV reactivation is common during acute AAV and is linked with significant complications, this may lead to future research of suppression of CMV in a trial, aiming to improve outcomes for people with AAV. This research will also improve our understanding of the importance of CMV in driving kidney damage which may be relevant to other kidney conditions.

The WHO has recently announced its commitment to end cervical cancer as a public health problem globally. Cervical cancer is the commonest cancer among women aged between 15 and 44 years in East Africa and is the leading cause of cancer-related mortality. It is caused by infection with human papillomavirus (HPV), a sexually transmitted virus. Infection with HPV can also cause other diseases such as genital warts, which affect both men and women. In high income countries, cervical cancer is prevented by vaccinating girls against HPV infection before they start having sex and screening sexually active women for HPV infection and/or cervical abnormalities. However, in many countries in Africa and other parts of the world, many women still die of the disease because screening programmes are absent or limited, and vaccination is only just starting to be rolled out. In Tanzania, which has one of the highest rates of cervical cancer in the world, HPV vaccines were introduced to 14-year-old girls in 2018. Evidence suggests that setting up and sustaining an HPV vaccination programme for young girls requires considerable investment in human and financial resources. These new programmes are finding it challenging to deliver the vaccines to most girls who should be receiving them. This will make it difficult to eliminate cervical cancer as HPV will still be able to spread in young people. Scientists therefore need to explore novel ways to deliver the vaccine to prevent infection to those who are not vaccinated. If enough people receive the HPV vaccine, then their unvaccinated sexual partners can also be protected. This has been shown in countries like Australia and Scotland, where vaccination of girls resulted in a decline in rates of HPV-related diseases in boys as well as girls. Given the challenges in getting enough girls vaccinated in many countries, one approach to controlling cervical cancer by preventing infection in unvaccinated girls is to offer the vaccine to their potential male sexual partners (known as gender-neutral vaccination). We propose to conduct a trial to test this strategy in Tanzania. We will see if we can reduce the amount of HPV infection present in communities by vaccinating of boys alongside vaccination of girls. We will do this using a single dose of HPV vaccine in boys, which may be sufficiently protective to prevent infection in boys and also prevent spread of HPV to unvaccinated girls. We will conduct a study called a cluster-randomised trial among communities in Tanzania (where each community is a cluster). In 2020, we will start by doing a baseline survey in 26 communities to determine how many boys and girls aged 16-22 years have HPV infection. We will then randomly select 13 communities where boys aged 14-18 years will be given HPV vaccine alongside the routine female HPV vaccination that is being given by the Tanzanian government. Three years after offering boys the vaccination, we will go back into the communities and do another survey to determine how many boys and girls aged 16-22 years-old have HPV infection. We will then be able to show whether the proportion of people infected with HPV differs between the communities that did and did not have male vaccination. At the same time, we will also be able to measure the impact of the girls-only vaccination on HPV infection by comparing the proportion of 16-22-year-old girls infected with HPV in the female-only vaccination communities at baseline and 3 years later. In our study, we will also follow up 200 vaccinated boys in order to check their immune responses to the vaccine, and we will do interviews in the communities to explore people's views about offering boys vaccination. We will also look at the cost of adding in vaccination of boys to the programme. This work will be extremely important in informing future HPV vaccination strategies and will be the first randomised trial of gender-neutral vaccination in Africa.

Analysis of molecular and cellular events is crucial in modern life sciences research, for a better understanding of (i) fundamental biological processes, (ii) the changes that characterise associated disease states, and (iii) the development of therapeutics. This research proposal brings together seven research areas, spanning the regulation of the immune and nervous systems, haemopoiesis, tissue development and regeneration and cell metabolism that share a common theme of wanting to utilise sensitive, quantitative and high throughput state-of-the-art instrumentation to analyse a range of cellular mechanisms. This instrument is the Mesoscale Discovery (MSD) SECTOR Imager (SI) 6000 which offers a sensitive, adaptable platform with which to measure several analytes in cell or cell-derived samples. The technology relies on the use of chemically tagged antibodies that recognize the analytes of choice. When bound to their target, the Abs emit light upon electrochemical stimulation which is measured and quantified. The main features provided by the instrument are: - the ability to accurately quantify activation of specific signals; - it facilitates detection of multiple signals simultaneously. - in situations where cell samples may be limiting, information on several different signalling molecules can be generated simultaneously. - the system allows for more rapid analysis, - provides platform for developing our own custom made assays for future applications.

Lumpy skin disease virus (LSDV) is the causative agent of lumpy skin disease (LSD), an endemic disease of cattle in Africa and the Middle East where it produces significant economic loss and acts as a barrier to trade. Since 2012 LSDV has spread into Turkey, Europe, the Caucasus and Russia . The epidemic has resulted in the slaughter of thousands of cattle, mass vaccination campaigns, animal movement restrictions and export bans. One of the key knowledge gaps hampering control efforts is an understanding of how LSD is transmitted from animal to animal and herd to herd. LSD expert panels and numerous LSD-themed workshops in recent years have all identified research into vector-borne transmission of LSD as a high priority. This will be addressed in this research project. The project hypothesis is: Viable LSDV persists in insect vectors at suitable sites and for sufficient time to allow onward transmission to cattle hundreds of kilometres distant. This proposed work involves two objectives running in parallel over 18 months. Objective 1 To identify the most likely vector group responsible for transmission of LSDV. This objective will undertake experimental transmission of LSDV from infected cattle by potential insect vectors in the high containment facilities at The Pirbright Institute. These studies will use contemporary virus detection techniques to distinguish between mechanical and biological transmission, and estimate the risk of different insect vectors that are present in Europe. The vector potential of four insect species, Stomoxysis calcitrans (stable flies), Culicoides nubeculosus midge, and Aedes aegypti and Culex quinquefasciatus mosquitoes, will be investigated. The four species were each selected on the basis of their distribution in affected and / or threatened areas, evidence from the literature of their experimental or epidemiological link to LSDV transmission, and because they represent different feeding mechanisms (solenophagous vs telmophagous). Objective 2 To assess the risk posed by LSDV and the potential impact of different control measures. This objective will integrate the experimental results into models of LSDV and, hence, explore the risk of disease and impact of different control measures. Overall the project will provide scientific evidence on vector-borne transmission of LSDV to enable effective and proportional LSD control programmes to be designed and the current Eurasian LSD epidemic to be contained. The project utilises the unique and world-class expertise at Pirbright in lumpy skin disease research, multi-scale modelling of viral diseases of livestock, the biology of blood-feeding insects, in vivo transmission studies of viruses between natural ruminant hosts and vectors, and cutting-edge bioimaging of arthropods to study vector-borne transmission of LSDV. The project is sponsored by an industrial partner MSD Animal Health, producer of the widely used Lumpyvax vaccine against LSD. MSD Animal Health are partnering Pirbright in this project to enable LSD vaccination campaigns to be augmented with scientifically rational control programmes aimed at reducing vector-borne transmission of LSDV. This approach is in accordance with Merck Animal Health's philosophy that their responsibilities extend beyond their primary business goals. By supporting this research project they aim to add value to efforts to control and eradicate LSD and thereby provide benefit to the environment and wider society as a whole. The project is also supported by DEFRA, the UK government department responsible for protecting the UK from exotic diseases such as lumpy skin disease (LSD). This support emphasises the impact this research will have on reducing the risk of LSD incursion into the UK, and facilitating its rapid eradication if it does occur.

Some radioactive molecules emit gamma radiation that can be detected outside the body and so when injected into humans and animals, in safe low levels, can be used to generate images, using sophisticated scanners, of the brain for biomedical research and clinical diagnosis. However, the molecules have to be designed to target the sites of the brain to be investigated, which is done by attaching a biological compound to the radioactive molecule to create products called radiopharmaceuticals. Due to the severe lack of scientists in the UK who have the specialised skills to design and prepare these radiopharmaceuticals we plan to recruit and train a scientist to join our multidisplicinary team. To achieve this we have created a bespoke training programme which will involve learning from researchers in academia and industry, who are either developing and/or using this imaging technology. As part of this training the scientist will help design new radiopharmaceuticals that would then be used in our on-going research programmes to understand the biological mechanisms of some major diseases and disorders of the brain, and thereby identify some possible treatments. For this specific programme we would be undertaking research projects on traumatic brain injury, depression, schizophrenia, obsessive compulsive disorder and drug addiction.