Title: Preventing Invasive Salmonella Disease in Africa
Funder: Department of Health and Social Care

Abstract: I am a clinician-scientist who has worked for 21 years in Malawi towards vaccine-prevention of invasive disease caused by 2 distinct groups of Salmonellae: Typhoid fever (caused by Salmonella Typhi), causing >3M cases and 33,000 deaths annually in sub-Saharan Africa. Typhoid predominantly affects healthy school-aged children (5-18y). I am leading the first typhoid conjugate vaccine (TCV) trial in Africa, of >28,000 children. Invasive non-typhoidal Salmonella disease, also called 'iNTS disease' (caused by Salmonella Typhimurium and Salmonella Enteritidis), which causes 3.4M cases of serious illness and over 680,000 deaths annually. Two thirds of these occur in sub-Saharan Africa. iNTS disease predominantly affects very young children (Over the next 5 years, I will make translational advances in typhoid and iNTS disease, in 3 workstreams: Workstream 1: Epidemiology: I will lead research to understand the burden and distribution of typhoid and iNTS disease, and their transmission in urban and rural populations and communities. We will achieve this by census and geospatial mapping of urban and rural areas, including sanitation and water supplies, level of poverty and schools. We will then conduct enhanced passive disease incidence surveillance for disease by blood culture and community serosurvey. We will follow-up cases, to understand typhoid and iNTS transmission in the household and broader community using Susceptible-Infected-Recovered (SIR) and geospatial models. The same platforms will be used to measure vaccine impact. Workstream 2: Host: I will lead studies on the immune responses to Salmonella infection, in order to optimise vaccines or other preventive strategies. We will study the interactions of cells, antibodies and complement to understand susceptibility and to optimise vaccine strategy. We will study the gut mucosal cellular response to understand gut colonisation, persistence and invasion, and the way in which gut exposure primes a protective systemic immune response. And we will study the gut microbiota, to describe how it influences and modulates invasion, persistence, immunity and transmission of Salmonella. Workstream 3: Vaccine: In the next 5 years we will measure TCV immunogenicity in healthy and HIV-exposed children. We will conduct cost-of-illness and cost effectiveness analyses. We will measure the impact of the vaccine in lives saved, cases of typhoid prevented, and prevention of antibiotic resistance. We will, at the same time, accelerate emerging iNTS disease vaccines into early clinical trials among very young children, using our experience, expertise and tools from typhoid vaccination.To support these workstreams, I will conduct 3 cross-cutting activities: Discussing and explaining Salmonella science and research to engage the communities with whom we work. We will also engage nationally through newspapers, radio and television Engaging, supporting and advocating with the Malawi government and other stakeholders and agencies, using our research findings, to accelerate the introduction of vaccines Training the next generation of doctors and scientists to be the researchers of the future

Lay abstract: I am a doctor-scientist who has worked for 21 years in Malawi on understanding and preventing 2 serious blood-stream infection diseases, both caused by bacteria called Salmonella: Typhoid fever (caused by Salmonella Typhi), which causes over 3 million cases of serious illness and over 33,000 deaths each year in sub-Saharan Africa. Typhoid predominantly affects healthy school-aged children (5-18y). It can be prevented by a new vaccine, for which I am leading a clinical trial in Malawi Invasive non-typhoidal Salmonella disease, also called 'iNTS disease' (caused by Salmonella Typhimurium and Salmonella Enteritidis), which causes 3.4M cases of serious illness and over 680,000 deaths annually. Two thirds of these occur in sub-Saharan Africa. iNTS disease predominantly affects very young children (Over the next 5 years, I will make advances in the vaccine prevention of both of these diseases, by research in 3 workstreams: Workstream 1: Epidemiology: In this workstream, I will lead research to understand how much typhoid and iNTS disease are happening, and how they are transmitted in urban and rural populations and communities - we will achieve this with censuses and mapping people in their communities using geospatial technology, including their ages, gender, sanitation and water supplies, level of poverty and schools. We will then track cases of Salmonella, by offering blood tests at their local health centre whenever people have a fever, and with blood antibody tests in the community. We will follow cases up in their homes and families, to understand how Salmonella is transmitted between people and animals, in the household and in the broader community. This will help us prevent Salmonella by vaccination, better treatment, and improved sanitation measures. Workstream 2: Host: We will study how people's bodies make protective immune responses to Salmonella infection, in order to design better vaccines or other preventive strategies. We will study blood to understand how cells, antibodies and complement interact to protect the body, and how to design vaccines. Salmonella is acquired thought the gut and spread by contact with faeces, so we will study how Salmonella lives and persists in the gut and how it invades across the gut, to help us prevent Salmonella invading, persisting and being transmitted in the faeces. And we will study the gut's natural microbiota bacteria, to understand how they influence invasion, persistence, and transmission of Salmonella Workstream 3: Vaccines: I am already leading the first clinical trial of the new typhoid vaccine in Africa. In the next 5 years we will measure how well it works in healthy children and in children whose mothers had HIV. We will find out how much money it will save Malawi to introduce the vaccine nationally. We will measure the impact of the vaccine in lives saved, cases of typhoid prevented, and prevention of antibiotic resistance. We will, at the same time, accelerate the new developing iNTS disease vaccines into early clinical trials among the very young children who need them, using our experience, expertise and tools from typhoid vaccination.To support these workstreams, I will conduct 3 cross-cutting activites: Discussing and explaining Salmonella science and research among the communities we work with. We will also engage nationally though media, using newspapers, radio and television Engaging, supporting and advocating with the Malawi government and other stakeholders and agencies, using our research findings, to accelerate the introduction of vaccines Training the next generation of doctors and scientists to be the researchers of the future

Research activity codes: 3.4 VACCINES
Health categories: INFECTION