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.

In the 1980s it began to be possible to produce potentially unlimited quantities of human proteins by placing the gene defining them in a simple organism such as yeast. From this grew a new kind of medicine capable of treating conditions such as severe arthritis, haemophilia, growth deficiency, and some cancers that previously had no satisfactory treatments. As well as having great clinical value the resulting technology has become the basis of a new and fastest growing part of the pharmaceutical industry, described as biopharmaceuticals. Because the molecules involved are proteins, they are orders of magnitude larger and more complex than conventional drugs such as aspirin and their processing is much more demanding. They are also so complex that they cannot in general be characterised with precision except in relation to the methods by which they are made. That means the capacity to precisely define such processes is critical to clinical safety and commercial success. Full scale trials of the processes are so costly they can only be conducted once clinical promise is established but, given the number of factors governing processing of even first generation products, there have often been hold-ups so extensive as to delay availability to patients. UCL has pioneered micro scale methods that are sufficiently good at predicting efficient conditions for large scale performance that far fewer and better focussed large scale trials suffice. That resolves part of the problem but an even greater challenge is now emerging. The early biopharmaceuticals were in general the easiest ones to produce. The final scales were also relatively modest. Now, the next generation of biopharmaceuticals are more complex materials and with rising demand the scales are far larger so that processes push the boundaries of the possible. The combined complexity of the product and the process with so many variables to consider means that the managers need better systematic means of supporting their decisions. Already the cost of developing a single biopharmaceutical can exceed 0.7 billion and take 10 years. With more advanced biopharmaceuticals these figures tend to rise and yet the world's governments are facing a healthcare cost crisis with more older people. They therefore exert pressure on companies to reduce prices. Because the public wishes to have medicines that do not pose risks, regulations become ever more stringent so they are a major factor in defining the bioprocess. This also adds to the need for managers to have sector-specific decisional-support aids well grounded in the detailed engineering of the processes. Finally, it is now possible to apply molecular engineering to proteins and vaccines to enhance their therapeutic properties but this can also cause serious bioprocessing problems. The research vision developed with detailed input from UK industry experts will apply these methods as the foundation for another step change whereby much faster and lower cost information can be gathered and integrated with advanced decisional techniques to give managers a better foundation on which to base their policies. The academic team from leading UK universities provides the necessary continuum of skills needed to assess the ease of manufacture of novel drugs, the costs of processing and of delivery to patients. We will work with companies to test the outcomes to ensure they are well proven prior to use on new biopharmaceuticals. This will cut costs so that all the patients who might benefit can receive them and at the earliest possible date achieved within the severely restricted budgets now available to the NHS.

The broad theme of the research training addresses the most rapidly developing parts of the bio-centred pharmaceutical and healthcare biotech industry. It meets specific training needs defined by the industry-led bioProcessUK and the Association of British Pharmaceutical Industry. The Centre proposal aligns with the EPSRC Delivery Plan 2008/9 to 2010/11, which notes pharmaceuticals as one of the UK's most dynamic industries. The EPSRC Next-Generation Healthcare theme is to link appropriate engineering and physical science research to the work of healthcare partners for improved translation of research output into clinical products and services. We address this directly. The bio-centred pharmaceutical sector is composed of three parts which the Centre will address:- More selective small molecule drugs produced using biocatalysis integrated with chemistry;- Biopharmaceutical therapeutic proteins and vaccines;- Human cell-based therapies.In each case new bioprocessing challenges are now being posed by the use of extensive molecular engineering to enhance the clinical outcome and the training proposed addresses the new challenges. Though one of the UK's most research intensive industries, pharmaceuticals is under intense strain due to:- Increasing global competition from lower cost countries;- The greater difficulty of bringing through increasingly complex medicines, for many of which the process of production is more difficult; - Pressure by governments to reduce the price paid by easing entry of generic copies and reducing drug reimbursement levels. These developments demand constant innovation and the Industrial Doctorate Training Centre will address the intellectual development and rigorous training of those who will lead on bioprocessing aspects. The activity will be conducted alongside the EPSRC Innovative Manufacturing Research Centre for Bioprocessing which an international review concluded leads the world in its approach to an increasingly important area .

It is now widely accepted that up to ten years are needed to take a drug from discovery to availability for general healthcare treatment. This means that only a limited time is available where a company is able to recover its very high investment costs in making a drug available via exclusivity in the market and via patents. The next generation drugs will be even more complex and difficult to manufacture. If these are going to be available at affordable costs via commercially viable processes then the speed of drug development has to be increased while ensuring robustness and safety in manufacture. The research in this proposal addresses the challenging transition from bench to large scale where the considerable changes in the way materials are handled can severely affect the properties and ways of manufacture of the drug. The research will combine novel approaches to scale down with automated robotic methods to acquire data at a very early stage of new drug development. Such data will be relatable to production at scale, a major deliverable of this programme. Computer-based bioprocess modelling methods will bring together this data with process design methods to explore rapidly the best options for the manufacture of a new biopharmaceutical. By this means those involved in new drug development will, even at the early discovery stage, be able to define the scale up challenges. The relatively small amounts of precious discovery material needed for such studies means they must be of low cost and that automation of the studies means they will be applicable rapidly to a wide range of drug candidates. Hence even though a substantial number of these candidates may ultimately fail clinical trials it will still be feasible to explore process scale up challenges as safety and efficency studies are proceeding. For those drugs which prove to be effective healthcare treatments it will be possible then to go much faster to full scale operation and hence recoup the high investment costs.As society moves towards posing even greater demands for effective long-term healthcare, such as personalised medicines, these radical solutions are needed to make it possible to provide the new treatments which are going to be increasingly demanding to manufature.