In the past decade several candidate malaria vaccines have undergone clinical trials in artificial challenge studies and studies of natural infection under field conditions. GlaxoSmithKline’s RTS,S vaccine against Plasmodium falciparum infection has taken the lead, with Phase III trials in African children demonstrating 55.8% (97.5% CI, 51.3% - 59.8%) efficacy against clinical malaria and 34.8% (95% CI, 16.2% – 49.2%) efficacy against severe malaria. Mathematical models can contribute to multiple stages of malaria vaccine development, from measuring efficacy in clinical trials, understanding the relationship between naturally acquired and vaccine-induced immunity, identifying correlates of protection, and predicting the likely impact of vaccination programs in the field. When measuring vaccine efficacy in field trials under natural exposure to malaria, there are many factors which can bias estimates of efficacy. We demonstrate how heterogeneity in exposure can cause efficacy to be underestimated and heterogeneity in vaccine response can cause efficacy to be overestimated. Most infection-blocking vaccines rely on boosting some element of the pre-erythrocytic immune response, however the relationship between the naturally acquired pre-erythrocytic responses and protection from infection remains poorly understood. By analysing studies from a systematic of the published literature, I demonstrate that although many studies report a statistically significant relationship between cellular pre-erythrocytic immune responses and protection from infection, many studies do not have sufficient statistical power to evaluate the effects of the pre-erythrocytic immune response. Mathematical models are developed for investigating the relationship between pre-erythrocytic antibodies and protection from infection, and fitted to data from a longitudinal study of malaria infection in Kenyan adults. The relationship between antibodies to the antigens circumsporozoite protein (CSP) and thrombospondin-related adhesion protein (TRAP) and protection from infection is characterised using dose-response curves. Using data from an artificial challenge trial of the RTS,S malaria vaccine, I demonstrate that vaccine-induced protection from infection depends on both anti-CSP antibodies and CSP-specific T cells. I estimate that RTS,S causes a 97.7% (95% CI, 96.3% – 98/7%) reduction in the number of parasites entering the blood from the liver. The immune effector mechanisms determining the duration of vaccine-induced protection from infection are likely to be similar to those involved in naturally acquired immunity. Models of antibody kinetics were fitted to data from longitudinal studies of the antibody response to P. falciparum infection in Ghanaian and Gambian children, and the parameters determining the duration of antibody response are estimated. Upon licensure, a successful malaria vaccine is likely to be administered to young African children. A model of malaria transmission, extensively fitted to clinical data, is used to investigate the impact of vaccination in different transmission settings; the interaction between vaccines and other interventions such as insecticide treated nets; and the interaction between vaccination and naturally acquired immunity. Finally, the potential cost-effectiveness of vaccination is explored.

Malaria and lymphatic filariasis (LF) cause the largest public health burden of all vector-borne diseases worldwide. Some 350-500 million clinical episodes and 1 million deaths each year are caused by malaria, of which approximately 60% and 80% respectively occur in Africa. More than 50 million people are also thought to be infected with lymphatic filariasis in 39 endemic countries in sub-Saharan Africa, with approximately 14.6 million individuals living in these endemic countries estimated to suffer from the two major filarial debilitating conditions, lymphodema or hydrocele. These two infections are co-endemic in large parts of Africa and are transmitted by the same vector, namely the Anopheles mosquito. The overall aim of the PhD was to develop a framework which could be used to evaluate the economic costs and benefits of different control strategies for reducing or eliminating the transmission of LF and malaria in Africa and, in particular, considering whether integrated control could offer a more effective approach for disease control. This problem was split into three key areas: 1) Mapping the geographic distribution of malaria and LF infection in Africa and identifying areas where the infections are co-endemic. Initially a maximum entropy modelling approach was used to identify areas at risk of LF based on environmental factors and population density. Then, a Bayesian spatial modelling approach was used to map the prevalence of malaria and LF in Africa, to estimate the number of people infected, and to identify areas of co-endemicity. 2) Developing a combined malaria-LF transmission model for humans and mosquitoes. This involved integrating a LF transmission model into a malaria transmission model. Interactions between the infections were captured using the model, specifically the increase in vector mortality as a result of LF larvae infection, and alterations in the host immune response as a result of co-infection. The model was used to investigate how the presence of one infection affected the prevalence of the other. 3) Finally, performing an economic evaluation of the economic costs and benefits of different control strategies, focusing on the potential for an integrated control approach. The economic benefits of the two primary control approaches (long lasting insecticidal nets for malaria and mass drug administration for LF) were modelled for a range of different scenarios using the co-infection model. The benefit of a control strategy was defined as the financial cost of the resulting reduction in treatment costs and work days lost due to infection and disease. The cost-benefit analysis was used to identify the optimal control strategy for different infection prevalence scenarios and the results were combined with the maps created in 1) to produce maps showing the optimal control strategy for different regions of Africa.

Methicillin-resistant Staphylococcus aureus (MRSA) is a global public health problem and is a major cause of morbidity and mortality worldwide, imposing serious economic costs on patients and hospitals. Prior to the mid-1990s, MRSA was largely a healthcare-associated pathogen, causing infection predominantly in people with frequent or recent contact with healthcare facilities (HA-MRSA). Since then, community-associated MRSA (CA-MRSA), which often causes infection among healthy children and young adults with no exposure to the healthcare setting, has become increasingly prevalent. Worryingly, there is evidence that CA-MRSA is penetrating the healthcare MRSA reservoir, and even replacing traditional HA-MRSA strains. This highlights the need to keep abreast of the changing epidemiology of MRSA in order to implement effective infection control strategies. To investigate the composition of the healthcare MRSA reservoir and ascertain the extent to which CAMRSA has penetrated this reservoir, a countywide, population-based cohort study of MRSA in hospital inpatients and nursing home residents was conducted in Orange County (OC), California, covering a total of 46 facilities. CA-MRSA was found to be fully mixed with HA-MRSA in the hospital setting. The predominant CA-MRSA clone in the US, USA300, was the most commonly isolated MRSA clone in OC hospitals. In OC nursing homes, HA-MRSA (specifically a variant of USA100 that is also very common in OC hospitals but has not been reported elsewhere) predominates, but USA300 made up just over a quarter of the isolates and was the second most frequently isolated clone. Both OC hospitals and nursing homes were dominated by the same three strains: USA300, USA100 and a variant of USA100. Not only are community-based infection control strategies needed to stem the influx of community associated strains, in particular USA300, into the hospital setting, but also strategies tailored to the complex problem of MRSA transmission and infection in nursing homes, to minimise the impact of the unique nursing home MRSA reservoir on overall regional MRSA burden. A key component of effective infection control strategies is prompt isolation of MRSA carriers, facilitated by rapid diagnostics. PCR-based methods of MRSA detection offer a much faster alternative to traditional culture techniques, but are expensive and often complex to operate. A novel nucleic acid amplification technique developed by my industrial sponsor, TwistDx Ltd, called recombinase polymerase amplification (RPA), has been incorporated into a probe based detection system called TwistAmp MRSA, and offers a simple and cheap alternative to current commercial PCR-based assays, amplifying MRSA to detectable levels within 20 minutes. I tested the assay with diverse collections of MRSA and discovered that 4% of isolates from a UK MRSA collection could not be detected by the assay. I subsequently developed RPA primers for their detection. Nonetheless, TwistAmp MRSA was able to detect most MRSA strains, and was comparable to current commercial assays in this respect. Despite a very high analytical sensitivity of approximately 20 CFU/swab, the clinical sensitivity of TwistAmp MRSA was lower than expected with respect to the current market leader, Xpert MRSA. I investigated lysis and filtration methods to improve the assay's clinical sensitivity, but found that such methods did not currently warrant inclusion in the TwistAmp MRSA protocol. While TwistAmp MRSA performance is in line with current assays, and is a faster, cheaper and simpler assay, a problem faced by all molecular methods of MRSA detection is the constant emergence of undetectable MRSA strains, necessitating continual assay evaluation and improvement where possible.

Body fluids such as blood are amongst the most important biological evidence recovered from crime scenes. Identification of the donor can be achieved through STR profiling; however, extracting additional information regarding the tissue type or the donor’s physical appearance such as age could prove very useful in police investigations. Firstly, the performance of existing tissue-specific mRNA-based systems was assessed via collaborative exercises. All proposed methods have shown to be highly sensitive; however, issues regarding markers’ specificity, especially for the vaginal detection, were observed. Analysing complex casework samples revealed the need for interpretation guidelines and the use of a scoring system when implementing mRNA profiling in casework. It was understood that developing DNA-based testing would overcome the limitations of existing methods so the main aim of this study was to evaluate the applicability of DNA methylation profiling in forensics. Using three approaches various tissue-specific differentially methylated CpG sites in 18 different loci were evaluated by analysing various forensically relevant body fluids and tissues. As a result, a set of suitable blood- and semen-specific markers were validated using aged and mock casework samples; however, the identification of other tissues like saliva, vaginal fluid and menstrual blood seemed to be challenging. Regarding age prediction, a set of age-associated CpG sites were selected from genome-wide DNA methylation studies and the correlation of their blood methylation levels with age was assessed on two sequencing platforms. Using a subset of 16 CpG sites and taking advantage of artificial neural networks’ capabilities, age could be accurately predicted in 1,156 blood samples (mean error of 4.1 years). The applicability of the proposed prediction model was also tested by means of next generation sequencing. Although further research is required prior to implementing these results in casework, it can be concluded that epigenetics could shed light on the proposed forensic applications.

The treatment and recovery of forensic psychiatric inpatients can take many months and often years, within which time health issues such as obesity and diabetes can develop. Encouraging beneficial health behaviours with this client group is notoriously difficult for a variety of reasons and anti-psychotic medication paradoxically often serves to exacerbate physical health concerns. There is a dearth of research concerning effective interventions for improved physical health for this client group, perhaps because security and staffing issues present significant challenges to conducting research in this environment. This exploratory piece of action research employed multi-staged Motivational Interviewing (MI) sessions in nine case studies, the aim of which was to explore the utility of the approach in increasing physical activity (PA) with forensic psychiatric inpatients. Changes in PA and intrinsic motivation were assessed over three months and clients were surveyed on their views of the approach. A question exists over the propriety of client-centred care in a setting that is often necessarily restrictive and controlled. Challenges to a broader implementation of MI for health promotion amongst the multi-disciplinary care team (MDT) are considered, and were explored through the use of a staff survey. Outcomes for the research suggest that MI is a useful and valued approach to facilitating changes in physical activity levels with forensic psychiatric clients. There may be others from this environment for whom the approach is inappropriate, and there is a need for further research with clients whose health concerns are significant but who do not readily present for activity sessions. Outcomes from this research further suggest some of the MDT may be philosophically aligned with some aspects of the client-centred ethos of MI, yet still maintain a belief in the propriety of directive and authoritarian methods for promoting health. This may present a challenge to the training of MI if a broader implementation of MI for physical health issues is considered, and limited survey data may not have revealed the full extent of this challenge.

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