Antibiotics are widely prescribed for patients with lower respiratory tract infection (LRTI) yet only a minority have a pneumonia which responds to antibiotic treatment. Unwarranted prescribing of antibiotics is associated with several problems aside from the financial implications of unnecessary treatment: increased incidence of hospital-acquired infections, including MRSA and Clostridium difficile and the problem of antibiotic resistance. The aim of this study was to investigate the influence of the history and examination findings on antibiotic prescribing where LRTI is the principal diagnosis, and to explore the attitudes towards antibiotic prescribing through an understanding of the clinician and patient experience. A mixed methodology study of adult hospitalised patients was employed, with a case series for the quantitative arm and thematic analysis employed for the qualitative arm of the research. Data was collected from patients’ medical notes using a coding matrix developed as part of a pilot study. Doctors were invited to participate in interviews to discuss the reasons for prescribing antibiotics in respiratory tract infection and a group of patients were interviewed for their views on antibiotics. 153 participants were enrolled into the quantitative arm and a further 10 in the qualitative arm. The data indicate that the diagnosis of LRTI and prescription of antibiotics is made on the recorded presence of a very small number of symptoms and signs, with 91% having shortness of breath, 77% having purulent sputum and 75% having a respiratory rate >20/minute. The parameters used to determine a bacterial cause for disease are often non-specific and can lead to inappropriate antibiotic prescribing. Antibiotic use must be targeted to those in whom there is benefit. To enable clinicians to do this they require access to pathology and x ray and these must be supported by expert input. In addition, rapid, reliable diagnostic testing for bacterial infections can assist.

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Vaccine research and development is becoming increasingly important because of the potential to create a blockbuster drug, such as Prevnar. However, the development pipeline continues to be a limiting factor in commercialising a vaccine. In this thesis a micro-scale platform is created to mimic the key features of a unit operation so that it is possible to calculate the impact of a commercial manufacturing process using this scaled down platform. Two model vaccines were applied to the micro-scale platform, a new Meningitis serogroup B vaccine based on the outer membrane vesicle proteins of Neisseria lactamica and the licensed UK Anthrax vaccine. To create the platform, cultures of Neisseria lactamica in microwells have been combined with statistical techniques such as Design of Experiments to increase biomass production by four fold and antigen yields by 165%. Microwell experiments were coupled with SELDI-TOF mass spectroscopy to enable a detailed insight into the changing vaccine composition with culture conditions. Microwell results here were scaled up to 2, 8 and 50 litre fermentations using dimensionless analysis based on the oxygen mass transfer co-efficient, kLa. The effects of pilot scale downstream processing were investigated using ultra scale down tools and models. It was possible to characterise product losses and the robustness of the process stream by conducting shear experiments. Furthermore, final product filter sterilisation was investigated using a microwell platform coupled with statistical analysis, particle sizing and DLVO theory. Through these studies it was possible to minimise aggregation and increase antigen transmission through the membrane from 35% to 78%. The platform was applied to cultures of Bacillus anthracis Sterne 34F2, the Anthrax vaccine strain. Microwells were used to mimic Thompson bottle cultures and ascertain the main factors which effect B. anthracis growth and antigen production. The cell density dependent signalling mechanism, known as quorum sensing was found to control growth and antigen production in B. anthracis and that a protein below 5kDa may be involved in the quorum sensing mechanism along with the auto inducer molecule, AI-2. Finally, transfer of B. anthracis vaccine production from static culture to a homogenous stirrer tank culture environment was investigated using a miniature bioreactor. It found that transfer was possible and that doing so reduced the culture time from 28 hours to just 14 hours, increasing production of PA and LF vaccine antigens by 25% and 78% respectively. Aeration of the culture showed that biomass production could be improved upon, but it had a detrimental effect on antigen expression.

The ageing population is predicted to exceed two billion by 2050; maintaining good health in older age has, thus, become a major global health priority. Ageing involves physiological changes, impairment in digestive function and the increased need for the use of prescribed drugs which can lead to lower status of folate and the metabolically related B-vitamins (vitamins B I2, B6, riboflavin). Deficiencies in these vitamins are increasingly linked with a number of chronic diseases of ageing. In particular, dementia affects 46.8 million globally, figures that are expected to triple by 2050, generating substantial societal and economic impacts. One-carbon metabolism is proposed as a critical pathway associated with health throughout life, especially in ageing. However, studies considering the association of one-carbon metabolism tend to focus on folate and vitamin B 12, few have considered all the relevant B-vitamins which are interlinked within one-carbon metabolism. The overall aim of this thesis therefore, was to investigate the causes, consequences and public health implications of low B-vitamin status in ageing with a particular focus on cognitive health. Results arising from new analysis of the Trinity, Ulster and Department of Agriculture (TUDA) Ageing cohort study (n 5186) indicated that the use of proton pump inhibitors (PPI), widely taken by older people, is associated with significantly lower status of B12 as previously reported, but also with lower status of vitamin B6 and riboflavin, vitamins which have not previously been linked with PPI use. Likewise, metformin use was associated with a significant increase in the risk of vitamin B12 deficiency and more than doubled the risk of vitamin B6 deficiency, in older people with or at-risk of diabetes (HbAic<42mmol/mol). The thesis showed that older adults with or at-risk of diabetes were at a 25% higher risk of vitamin B6 deficiency, and a 67% increased risk of cognitive dysfunction, with some evidence that low status of vitamin B6 may be driving the cognitive dysfunction in these patients. In a follow up study of almost 600 participants, 5 years after the initial investigation (i.e. TUDA+5), low status of vitamin B6 (OR: 1.75, P 0.008) and riboflavin (OR 1.63, P 0.018) were found to be significant predictors of accelerated cognitive decline, as measured by RBANS. The totality of the evidence in this thesis supports the wider public health benefits of optimising B-vitamin status, through natural food sources, fortified foods and supplements, to alleviate B-vitamin depletion in those on long term prescribed drugs and as a means of maintaining cognitive health in ageing. In conclusion, results from this thesis suggest that updating food fortification policies worldwide to optimise all the relevant B-vitamins could offer a cost-effective strategy for maintaining better health in ageing and preventing adverse outcomes.

This project focuses on a vaccine candidate MSP 119 which is present in the asexual blood stages of the malaria parasite's lifecycle. Immunisation with MSP 119 has been shown previously to protect against growth of the blood stage parasite. Previous studies have shown there are three types of antibodies produced against Plasmodium falciparum MSP 119: inhibitory, blocking and neutral with only inhibitory antibodies giving protection. It is vital to identify the epitopes recognised by inhibitory antibodies to engineer an effective vaccine. The aim of this project is to map the antibody binding sites of Plasmodium yoelii (a rodent parasite) MSP119. Three protective Plasmodium yoelii MSP119 specific monoclonal antibodies that had been created previously were used. MSP119 variants containing amino acid changes in residues 12, 16, 17 and 28 were created and binding to the monoclonal antibodies was investigated using western blotting, ELISA and surface plasmon resonance analysis. This showed that all four residues were involved in antibody binding. A comparison of the residues found to be important for MSP119 antibody binding in Plasmodium yoelii and inhibitory antibody binding in Plasmodium falciparum show they lie within the same area. This suggests there are conserved areas for inhibitory antibody binding across the species implying a common mechanism of action. Immunisation studies with the MSP 119 variants have shown that changes to residue 28 abolish the protective immune response to challenge infection with Plasmodium yoelii YM seen with wildtype MSP 119. Structural NMR studies of wildtype and MSP119 variants have shown that residue 28 plays a vital structural role. The information presented in this project could be important in developing antigens for vaccination to specifically stimulate production of inhibitory antibodies. It could help direct research into understanding the mechanism of action of inhibitory antibodies and aid in the development of new therapeutic strategies targeting MSPI19.

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