This project aims to develop and validate better diagnostic tools for children with TB (Find and Treat), as well as looking at implementation of preventive therapy for those already infected but not yet ill, but who might progress to disease if not receiving the recommended intervention- (Screen and Prevent). Importance of TB in LMIC: Around 1 million children fall ill from TB each year and 140 000 die. Many countries struggle to deliver the age-stratified notifications for TB in children to the WHO, and there is reluctance to engage in diagnosing and treating TB in children in many settings, as staff feel ill equipped to confirm a "gold standard" diagnosis, based on microbiological evidence. This situation is pertinent in Africa and continues to lead to unnecessary morbidity and mortality and a reservoir of cases for the future. The roadmap for the elimination of TB sets priorities for achieving global TB control and within this effort, childhood TB has been identified as a neglected problem, but of great importance for overall TB control (WHO Global Plan for TB). This requires two interventions: 1. to appropriately diagnose the cases and place on treatment -find and treat- and 2. to prevent secondary cases in TB-exposed children, which can be done successfully by delivering preventive medication- screen and prevent. Why is it more difficult to diagnose TB in children? Due to the limited number of mycobacteria contained in their sputa, conventional microbiological diagnostics perform poorly in children. Unless more sensitive diagnostics for paucibacillary disease can be developed, it is unlikely that the current situation of two thirds of children receiving treatment for TB without a confirmed diagnosis will change. Host-derived biosignatures in blood or urine therefore hold promise for development into point-of care tests for childhood TB. What do we want to do? We have considerable experience in the management of childhood TB in both the UK and The Gambia, and this project aims to involve new partners in Africa to find and treat children with TB using existing and new diagnostics. We have already developed such new tests but they need to be further validate also in children who have HIV or malnutrition. We will therefor recruit a large prospective court of children likely o have TB to validate the new diagnostics. In addition, we want to work the National TB programs (NTP) in the partner countries to implement a preventive strategy, as supported by the WHO but not implemented on the ground. We want to understand the bottlenecks within the care path and train members of the NTP to recognise TB in children and take the necessary preventive steps to avoid secondary cases in families. Based on the UK model, we have already established a screen-and-prevent- program of contact screening for children exposed to TB in their households in The Gambia, which has the support of the NTP. Our find and treat and screen and prevent activities have increased the case notifications by 50% over the last 3 years. This approach now requires full integration into the NTP programs in other countries and systematic evaluation to determine its long term impact on national TB figures also in our partner countries. It could serve as an important model for the WHO strategy o improve prevention of TB worldwide but each country might have specific requirements and our project will deliver data from 4 different African settings to inform the recommendations. We expect that our work can improve TB control and that we can create a network of excellence with specialist knowledge for childhood TB in Africa, as we have already done in Europe.

The last decade has witnessed an important reduction of the mortality in children less than 5 years of age. Nevertheless, such reduction occurred mainly in children older than 1 month; no change was observed in newborns (between birth and one month of age). Mortality in this age group contributes half of all deaths occurring in children below 5 years of age. Sixteen out of the 20 countries with the highest neonatal mortality are in sub-Saharan Africa. In 1990, the United Nations established the Millennium Development Goals (MDG) aiming at improving by 2015 living conditions of the poorest populations. The MDG number 4 aims at reducing by two-thirds the under-five mortality, a result attainable only with a substantial reduction in neonatal deaths. Severe bacterial disease is among the leading causes of neonatal deaths. In Sub-Saharan Africa, different bacteria are responsible for these deaths during the first month of life. Severe neonatal disease follows bacterial infection. Individuals can be infected without developing disease (carriage stage) but infection is needed to subsequently develop disease. In Sub-Saharan Africa, bacterial carriage (i.e. in the birth canal and/or nasopharyngeal tract) is very common, with the consequence that the occurrence of bacterial disease is one of the highest in the world. Newborns can be infected during labour - when passing through the birth canal - and also during the first days/weeks of life, as a consequence of the close physical contact with the mother, if the latter carries bacteria in the nasopharyngeal tract. If the mother is an important source of bacterial infection to the newborn, treating mothers with a powerful antibiotic during labour should decrease bacterial carriage and therefore diminish the risk of bacterial transmission to the newborn during the first days/weeks of life, which should in turn result in the lower occurrence of severe bacterial disease and hence lower mortality. In the study proposed, we will determine whether a single antibiotic dose given to the mother during labour decreases the bacterial carriage of the newborn during the first month of life. We have selected an antibiotic (azithromycin) that in Sub-Saharan Africa has already shown both a strong impact on bacterial nasopharyngeal carriage and on all-cause mortality when administered to everybody in a community (mass drug administration). This specific antibiotic has several advantages for being deployable as a simple intervention in rural Africa, i.e. it requires a single oral administration, it has no special storage requirements and it has the potential to eliminate most of the bacteria commonly causing severe disease in newborn. A clinical trial will be conducted in a rural health facility in Western Gambia to evaluate the effect of treating mothers during labour on bacterial infection in the newborn during the first weeks of life. If an impact is shown, the next step would be to conduct a larger study aiming at establishing if the intervention, implemented at a lower level of care (as most African women deliver at home assisted by traditional birth assistants), decreases the occurrence of neonatal invasive bacterial disease.

This proposal addresses a critical career gap in MRC’s leadership and partnership strategy for global health research. The Programme aims to strengthen the pipeline of researchers from the West Africa region and the UK/EU with the potential to become leaders of global health research. It focuses on the critical career gap at the immediate/early postdoctoral level. Fellows appointed will enhance the excellence of The Gambia Unit and LSHTM research, leadership capacity in the region, MRC’s global health strategy and UK capacity for leadership and partnership in global health research. The fellowship targets recently-qualified doctoral graduates of outstanding ability, motivated to tackle important and challenging research questions by training and working in the West African region. The fellowship programme will enable these individuals to move towards research independence and eventual leadership by deploying the complementary research, training, mentoring and networking capabilities of MRC and LSHTM Working together, ensures that Fellows are appointed and managed to the highest standards, and that they have exceptional opportunities for research and training that is both excellent and relevant.

Natural infection with many viruses results in the production of antibodies which help clear the virus and protect us from subsequent reinfection. Eliciting such an antibody response is the basis of many effective vaccines, but unfortunately little is understood about protective antibody responses in HIV, which has hindered HIV vaccine design. Despite sharing many similarities with HIV-1, most patients with HIV-2 do not develop AIDS (although a minority do) and the reason for this is not entirely clear. This project proposes to compare antibody responses in HIV-1 and HIV-2 infected patients and explore whether stronger antibody responses are found in HIV-2 infected patients who do not progress to AIDS, when compared to those who do, and HIV-1 infected patients; at a stage where the immune system is relatively well preserved. Early studies also suggested that HIV-2 antibodies could render HIV-1 non-functional and we also propose to compare this ability in patients who are HIV-2 infected and go on acquire HIV-1 superinfection, with those who have remained HIV-2 mono-infected despite possible exposure to HIV-1. Such information could provide vital clues to how the HIV surface interacts with antibodies and the importance of eliciting an antibody response in future HIV vaccines.

Vaccines work by stimulating immune responses which fight against the vaccine disease if the person is exposed to it in the future. Despite years of successful vaccination campaigns there is still relatively little understanding of how vaccines work. Live vaccines (e.g. measles vaccine) consist of weakened live organisms, and killed vaccines consist of dead bits of organisms or toxins they produce. There is increasing evidence that the order in which live and killed vaccines are administered is important. Specifically, live vaccines provide beneficial effects other than protecting against the target pathogen, but killed vaccines cancel these beneficial effects sometimes leading to an increase in deaths. As our understanding of immunology advances it has become clear that the response to immune challenge, including vaccination, involves a complex network of responses. Until now our ability to investigate immune responses to vaccines in detail has been limited by the small volumes of blood that can be collected and the lack of suitable tests. This study proposes to use state of the art technology to look at the response of the whole human genome before and after giving vaccines to babies. We hope to identify easily measurable substances in the blood that can explain the non-specific effects of vaccines. We will then test these in big studies that are ongoing in Guinea-Bissau that are trying to understand the same things. Understanding interactions between commonly used vaccines will ultimately lead to recommendations regarding safer practices in the future, and provide vital information for the introduction of new vaccines.