Preventable and treatable diseases cause a huge amount of illness and a huge number of deaths in Africa. Infectious diseases, like malaria, are some of the biggest killers. Not only do these diseases cause major health problems for those infected, they are also a major financial burden to individuals and communities, and they hinder economic and societal development for whole countries. The poorest and most marginalized communities are usually the worst affected, and so these diseases exacerbate inequalities associated with geography, gender and ethnicity. Current strategies to tackle infectious diseases in the poorest settings rely on rudimentary approaches to diagnosis and treatment, such as reliance on a few clinical features (like fever, difficulty breathing or pallor) and very few simple tests to decide the treatment someone should receive. This approach is necessary because there are rarely diagnostic laboratories nearby to provide comprehensive testing, and even if there are, their services are often too expensive. Unfortunately, the simple methods of diagnosis often result in incorrect diagnosis, and provide little data from which to learn how to improve. A wrong diagnosis can mean the wrong treatment is given, resulting in prolonged illness or death, whilst at the same time encouraging overuse of some treatments like antibiotics or anti-malaria drugs, which can drive resistance to these drugs. A revolutionary solution to this problem is to develop a new generation of digital diagnostic tests which can be used at the point-of-care in even the hardest-to-reach communities. These diagnostic tests are not only more accurate and faster than current alternatives but potentially cost saving. Digital diagnostics have the potential to transform the situation by linking the precision typical of an advanced laboratory with the portability, connectivity, analysis and support that can be provided through a modern smart phone. This means tests can be administered anywhere and anytime by a wide range of healthcare workers with minimal training. For example, a drop of blood collected from the tip of the finger of child by a health worker in their community, could be applied to a tiny microchip powered by a mobile phone battery, and within 15-20 minutes a result could be available to make a diagnosis. The results are transmitted from the microchip to a smartphone via Bluetooth so no internet connection is required. If "Malaria" is detected, the device can notify the healthcare worker of the type of malaria and the correct treatment. The smartphone could also send the result and location data via the mobile network to a remote computer system, which could determine whether there is an unusually high level of malaria in that area and, if so, notify the national Malaria control program that extra resources are required to tackle an outbreak before it gets worse. Thus the child benefits from the right treatment, the community benefits from the intervention, and the health authorities benefit from being able to allocate the resources available to where they are most needed or will work best. The real-time data also allows international organizations to make more effective policies to tackle malaria and allocate funding. In our proposal we are developing a network of scientists with diverse skills and expertise, joining them together with commercial companies that manufacture diagnostics, and organizations who work directly in African countries putting new disease control tools and strategies into practice. This network will plan how best to develop new digital diagnostic devices to tackle health problems in Africa. The network will test its strategies by specifically planning the development of a new digital diagnostic test device for malaria and drawing out a roadmap to its implementation.

Rotavirus infection causes severe diarrhoea and is responsible for about 130,000 child deaths every year in low-income countries in Africa and Asia. Two vaccines have recently been introduced worldwide and have started to reduce the burden of rotavirus disease. Unfortunately, these orally administered vaccines are less effective in the low-income countries where they are needed compared with high-income countries. This means rotavirus remains the main cause of hospitalisation for diarrhoea even after their introduction. To tackle this challenge, we need a next-generation of rotavirus vaccines that overcome the barrier to effective oral vaccines in low-income countries. These vaccines are in the development pipeline. However, their assessment in clinical trials is challenging because comparison with placebo is no longer considered ethical and immune correlates of protection (CoP) that could be used as alternative trial endpoints have not been identified. Controlled human infection studies, where participants are deliberately exposed to wild-type or attenuated infections, are increasingly playing a role in the clinical development of new vaccines and global recommendations concerning their use. We propose to use a licensed live-attenuated oral rotavirus vaccine (Rotarix) as a controlled human infection challenge in infants in Zambia to investigate a novel injectable rotavirus vaccine used alone or in combination with oral vaccination. This is an exciting opportunity to see whether this injectable VP8 subunit vaccine can overcome the barrier to oral immunisation and whether its effectiveness is improved through combined use with oral vaccine. Use of a live-attenuated vaccine as a challenge agent has many advantages compared with wild-type infection, including its established safety profile, highly regulated (GMP) manufacture and its suitability for use in children. The relevance of this infection model (rather than clinical disease) is supported by recent findings showing acquired immunity to rotavirus acts primarily by preventing infection rather than reducing the risk of disease following infection and will be further validated by comparison with results from an ongoing phase 3 clinical trial of the efficacy of this vaccine. This human infection model will also allow us to investigate the development of intestinal (mucosal) immunity following oral and parenteral immunisation and to efficiently explore potential immune correlates of protection (CoP) against infection that can be measured in blood or saliva samples taken from infants after vaccination. These will be based on recent advances in our understanding of rotavirus immunology and focus on systemic and mucosal antibodies targeting different rotavirus antigens. If we find that combined use of an oral and injectable vaccine is more effective than current schedules, this will support further studies and programmatic evaluation that could ultimately lead to a greater impact of vaccination in Africa and Asia on rotavirus disease and mortality. At the end of this project, we will also have improved our understanding of vaccine-induced rotavirus immunity and established a live-attenuated rotavirus infection model in African infants that can be used to assess new rotavirus vaccines under development.