Natural infection with many viruses results in the production of antibodies which help clear the virus and protect us from subsequent reinfection. Eliciting such a 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 reasons for this are not entirely clear. This project proposes to compare neutralizing antibody responses in HIV-1 and HIV-2 infection and explore whether stronger responses are found in HIV-2 infected patients who do not progress to AIDS, when compared to HIV-2 progressors and HIV-1 patients.||Early studies also suggested that HIV-2 antibodies could render HIV-1 non-functional and although some previous studies claimed HIV-2 infected individuals may be protected against subsequent HIV-1 infection, the majority suggest no protection or even an increased risk of acquiring HIV-1 superinfection. We therefore propose to compare HIV-1 cross-neutralizing antibody responses and enhancing antibody responses in HIV-2 patients who go on to 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.

The worldwide AIDS pandemic is largely caused by one HIV strain called HIV-1, which after a variable length of time leads to AIDS and death in most infected people. There is a second HIV strain called HIV-2, which is mostly found in West Africa. This virus behaves quite differently from HIV-1: some HIV-2-infeceted people develop AIDS just as if they had HIV-1 but others, as many as 80%, have a normal lifespan and die of old age instead. We want to see if the immune response to the virus is different in these two groups of HIV-2-infected people, which may give useful clues about how to develop an HIV vaccine. We will be looking predominantly at cells in the blood called cytotoxic (or killer) lymphocytes because these cells have the ability to recognise and destroy HIV-infected cells.

Yellow fever is a viral infection which is transmitted from person to person by mosquitos. The virus is found in a total of 44 countries across sub-Saharan Africa and South America and most recent estimates suggest that it now causes more than one-million infections each year including 180 000 severe cases and 78 000 deaths in Africa alone. These infections continue to occur despite the availability of a safe and highly effective vaccine which confers lifelong protection against disease after only a single injection. In 2016, the worst epidemic (disease outbreak) of yellow fever in 30 years occurred in Central Africa. Cases due to international travel, also occurred in China sparking fears of uncontrolled disease spread in Asia. The epidemic occurred on the background of progressive increases in yellow fever disease over the past two decades and drove the publication of a new 'Global Strategy to Eliminate Yellow Fever Epidemics' by the World Health Organisation (WHO) in late 2016. This document highlighted the emerging global threat posed by the yellow fever and the major role played by shortages of the yellow fever vaccine in the current disease resurgence. Nearly half of the 34 countries which have introduced the vaccine into their routine immunization schedule for infants ran out of vaccine between 2013 and 2015 with many countries receiving only 50% of the number of doses of the vaccine they needed. These shortages got worse during the recent epidemic when, faced with the possibility of running out of vaccine completely, the WHO took the decision to recommend that 'fractional' doses of the vaccine should be used in the emergency vaccination campaigns being used to control the outbreak. In this way, one fifth (0.1mL) of the normal dose (0.5mL) is given to each person meaning that five times as many people can be vaccinated. There are no studies to see how good fractional doses of the yellow fever vaccine are in babies and children and no studies of have tested fractional doses of the vaccine in sub-Saharan Africa. This is why this study is important. The mains questions we want to ask in 9 to 12 month old Gambian infants are: 1. Does giving a fractional dose of a yellow fever vaccine to an infant given them as much protection from yellow fever infection as giving them a full dose of the vaccine? 2. Is there a difference in the amount of protection from yellow fever generated when a fractional dose is given subcutaneously (under the skin - the normal way yellow fever vaccines are given) or intradermally (into the skin) 3. Is there any difference in the safety of a fractional dose of the vaccine depending on whether it is given subcutaneously or intradermally? The results of the study will give the WHO expert committee on vaccination policy important information. It will help them to decide if fractional rather than full doses of the yellow fever vaccine can be recommended for future emergency vaccination campaigns including infants and children. It will also help them to decide if fractional rather than full doses can be given to infants as part of their routine scheduled vaccinations or in preventative campaigns. It is hoped that the results of the study will help to stop yellow fever epidemics across sub-Saharan Africa in the future.

MRC, Gambia unit is extending its research activities and impact in the region by developing research network with regional research institutions. MRC has enabled the support of these networks through external grant funding that primarily assist to empower these local institutions in building skills and capacity in order to embark on collaborative research and joint clinical trials. A consortium called WAPHIR (West Africa Platform for HIV Intervention Research -2010-2014) funded by GHRI/IDRC is created between MRC, the Laboratoire Bacteriologie-Virologie (LBV) of University Cheikh Anta Dio (UCAD) of Senegal and the Institute of Public Health Laboratory and Research/Bandim Health Project (INASA/BHP) of Guinea Bissau. It is embarking on Capacity strengthening through work packages that include a unified HIV cohort resource database network; clinical trial support and training; laboratory resource management and skill training; postgraduate training; network and communication training. Individual institutional cohort data resources from partners of the consortium are migrated into a centralised network server and training for the operation of the unified system was carried out, making a significant contribution towards the establishment of a regional HIV platform for supporting clinical trials and intervention research. Another network called WANETAM and WANETAM plus (West African Network for TB AIDS and Malaria 2009-2013) are funded By EDCTP and comprised of wider regional partnership (Burkina Faso, The Gambia, Ghana, Guinea Bissau, Mali, Nigeria, and Senegal). This network is building expertise in clinical trials for HIV, TB and Malaria. Research has started for HIV-2 pathogenesis in the network.

Mycobacterium africanum causes up to half of TB in West Africa. It is closely related to regular M. tuberculosis, but we have identified some important differences. One of these is that a new diagnostic test does not perform well in people infected with M. africanum. This test is based on the protein ESAT-6, which is also used in a new generation TB vaccine. Another difference is that HIV infected people are even more susceptible to infection with M. africanum than with M. tuberculosis. Thirdly, people who were exposed to M. africanum are less likely to develop TB than those exposed to M. tuberculosis.||We now propose to study the bacterial genes in more detail, in an attempt to pinpoint the causes for the differences. Ultimately we hope our findings on genetic differences may assist in optimization of diagnostic tests and perhaps with the design of new vaccine candidates.