The development of a mathematical modelling framework to translate TB vaccine responses between species and predict the most immunogenic dose in humans using animal data

Background: Preclinical animal experiments measuring vaccine immunogenicity and safety are essential, not only to establish if the vaccine should progress further, but to generate information on how the vaccine should be administered in humans. Animal models that represent human vaccine responses well are vital to translate information about vaccine dose to clinical phases. Vaccine dose is a key aspect in creating an effective vaccine. However, if the wrong dose is chosen, vaccine candidates may be mistakenly discarded and considerable resources wasted. Current methods of finding optimal vaccine dose are mostly empirically based, which may be leading to sub-optimal doses progressing into later clinical trials. A current example of this is in the tuberculosis (TB) vaccine developmental pipeline, where a series of adjuvanted subunit vaccines, the H-series, have progressed through to later stages of clinical development with a high dose that has been shown to less immunogenic than lower doses. In drug development, mathematical model-based methods are routinely used alongside empirical evaluations, to inform dose-finding. I hypothesised that vaccine development may benefit from the application of similar quantitative methods. As such, I launched the new field of vaccine immunostimulation/immunodynamic (IS/ID) mathematical modelling. My aims for this thesis were 1) to establish differences in Bacillus Calmette–Guérin (BCG) Interferon-Gamma (IFN-γ) response by human subpopulation, then develop a IS/ID model to represent these response dynamics and identify the most representative macaque subpopulation for human BCG responses. Aim 2) was to predict human H-series vaccine IFN-γ response using IS/ID model calibrated to mouse multi-dose IFN-γ data and allometric scaling. Methods: For aim 1, longitudinal data on IFN-γ emitting CD4+ T cells following vaccination BCG were available in humans and macaques. Human (sub)population covariates were: baseline BCG vaccination status, time since BCG vaccination, gender and monocyte/lymphocyte cell count ratio. The macaque (sub)population covariate was colony of origin. I developed a two-compartmental mathematical model describing the post-BCG IFN-γ immune response dynamics. The model was calibrated to the human and macaque data using 4 Nonlinear Mixed Effects Modelling (NLMEM) to establish if there were differences in IFN-γ dynamics for both species subpopulations. I then established which macaque subpopulation best described human data. For aim 2, longitudinal data on IFN-γ emitting CD4+ T cells following two vaccinations with five doses of novel TB vaccine H56+IC31 in mice were generated. I then assessed the shape of the dose response curve at early and late time points. I calibrated the T cell model to the mouse data and established the change in key model parameters across dose. Using the change in model parameters across dose found in the mice, I predicted the immune response dynamics in humans for different doses and which dose was most immunogenic. Results: In aim 1, I found that BCG status in humans (baseline BCG-naïve or baseline BCG-vaccinated) was associated with differences in the peak and end IFN-γ response after vaccination with BCG. When the mathematical model was calibrated to the BCG data for both macaques and humans, significant differences (p<0.05) in key model parameters were found after stratification by macaque colony and human baseline-BCG status. Indonesian cynomolgus macaques had the closest immune response dynamics to the baseline BCG-naïve humans. In aim 2, a peaked curve was the best description of the mouse H56+IC31 dose response curve for early and late time points. Calibrating a revaccination model to the data and mapping changes in the estimated mouse model parameters across dose group to the estimated human model parameters, I found at day 224 (a latest time point), the model-predicted median number of human IFN-γ secreting CD4+ T cells were the highest for the dose group in the range 1-10μg H56/H1+500 nmol IC31. This suggests a dose of 1-10μg may be the most immunogenic in humans. Discussion: Finding the most predictive animal model and optimal vaccine dose is essential for efficiently accelerating the development of new, effective, TB vaccines. I demonstrated that mathematical modelling was a useful tool to quantify BCG immune response dynamics in macaques and humans. I established which macaque subpopulation should be used to represent a human BCG (or potentially new TB vaccine) induced IFN-γ response in future clinical trials. Using IFN-γ as marker of vaccine immunogenicity, mathematical modelling predictions using preclinical data suggested that doses in current novel TB vaccines clinical 5 trials on healthy BCG-vaccinated participants should be between 1-10μg H56/H1+500 nmol IC31, a result which has been recently corroborated in an empirical H56+IC31 dose-ranging trial. This project has demonstrated the potential utility of mathematical modelling in vaccine development. I believe future work on IS/ID modelling should include data on more complex immune response networks and different animal and human subpopulations. This future work is entirely feasible and would establish IS/ID modelling as a legitimate tool to accelerate vaccine development

Diversity in place: narrations of diversity in an ethnically mixed, urban area

This paper explores the implications of representations of places as ‘diverse’, particularly for those who live in them. Arising from an interdisciplinary research project, the paper takes one neighbourhood in Manchester (Cheetham Hill) and explores some of the narratives about it produced by residents and those who have a ‘professional’ stake in the area. These are put in the context of public narratives of the area, as well as Census data. The paper examines how different types of data generate different stories and how different methodological approaches can produce varied understandings of place, which have implications for how a place comes to be known and for the potential impact on the distribution of resources. Cheetham Hill is known as ‘diverse’, or even ‘super-diverse’, but the paper examines how this label serves to obscure lived experience and inequalities and can reveal ambivalences over the ethnic difference and urban living

Patient and public involvement in primary care research - an example of ensuring its sustainability

Background The international literature on patient and public involvement (PPI) in research covers a wide range of issues, including active lay involvement throughout the research cycle; roles that patients/public can play; assessing impact of PPI and recommendations for good PPI practice. One area of investigation that is less developed is the sustainability and impact of PPI beyond involvement in time-limited research projects. Methods This paper focuses on the issues of sustainability, the importance of institutional leadership and the creation of a robust infrastructure in order to achieve long-term and wide-ranging PPI in research strategy and programmes. Results We use the case of a Primary Care Research Centre to provide a historical account of the evolution of PPI in the Centre and identified a number of key conceptual issues regarding infrastructure, resource allocation, working methods, roles and relationships. Conclusions The paper concludes about the more general applicability of the Centre’s model for the long-term sustainability of PPI in research

Facilitating personal development for public involvement in health-care education and research: a co-produced pilot study in one UK higher education institute

BACKGROUND: Public involvement in the education of students enrolled on higher education programmes has gained impetus. For students enrolled on professional health-care programmes and health-related modules in the UK, there is also a requirement by professional bodies to include "service user" involvement in preparation for entry to a professional health-care register and continuing professional development. Actively involving patients and members of the public in research is also a requirement by many research funders. In this article, the term Patient and Public Involvement (PPI) will be used throughout to include lay members, volunteers, user and carers. OBJECTIVES: A unique pilot study was introduced across a health faculty to integrate PPI in a deliberate way. It aimed to provide an educational, focused programme of events that was meaningful to develop and inform peoples' knowledge, skills and confidence for their involvement in the health faculty. DESIGN: PPI members volunteered to sit on a steering group to determine the educational journey; the outcomes of three focus groups with PPI members (N = 32) and academics informed the programme content which included a range of workshops covering the exploration of public roles and barriers to involvement, introduction to research and interviewing skills. RESULTS: The workshops were well attended, and outcomes indicated the importance of co-production when designing, delivering and evaluating programmes. DISCUSSION: Co-production underpinned this pilot study, resulting in a programme which was meaningfully received by public contributors. RECOMMENDATIONS: Co-production was seen as integral to this research to ensure that outcomes were indeed "fit for purpose"

Genetic Diversity of PCR-Positive, Culture-Negative and Culture-Positive Mycobacterium ulcerans Isolated from Buruli Ulcer Patients in Ghana.

Culture of Mycobacterium ulcerans from Buruli ulcer patients has very low sensitivity. Thus confirmation of M. ulcerans infection is primarily based on PCR directed against IS2404. In this study we compare the genotypes obtained by variable number of tandem repeat analysis of DNA from IS2404-PCR positive cultures with that obtained from IS2404 positive, culture-negative tissue. A significantly greater genetic heterogeneity was found among culture-negative samples compared with that found in cultured strains but a single genotype is over-represented in both sample sets. This study provides evidence that both the focal location of bacteria in a lesion as well as differences in the ability to culture a particular genotype may underlie the low sensitivity of culture. Though preliminary, data from this work also suggests that mycobacteria previously associated with fish disease (M. pseudoshottsii) may be pathogenic for humans

Sequential Effects in Judgements of Attractiveness: The Influences of Face Race and Sex

In perceptual decision-making, a person’s response on a given trial is influenced by their response on the immediately preceding trial. This sequential effect was initially demonstrated in psychophysical tasks, but has now been found in more complex, real-world judgements. The similarity of the current and previous stimuli determines the nature of the effect, with more similar items producing assimilation in judgements, while less similarity can cause a contrast effect. Previous research found assimilation in ratings of facial attractiveness, and here, we investigated whether this effect is influenced by the social categories of the faces presented. Over three experiments, participants rated the attractiveness of own- (White) and other-race (Chinese) faces of both sexes that appeared successively. Through blocking trials by race (Experiment 1), sex (Experiment 2), or both dimensions (Experiment 3), we could examine how sequential judgements were altered by the salience of different social categories in face sequences. For sequences that varied in sex alone, own-race faces showed significantly less opposite-sex assimilation (male and female faces perceived as dissimilar), while other-race faces showed equal assimilation for opposite- and same-sex sequences (male and female faces were not differentiated). For sequences that varied in race alone, categorisation by race resulted in no opposite-race assimilation for either sex of face (White and Chinese faces perceived as dissimilar). For sequences that varied in both race and sex, same-category assimilation was significantly greater than opposite-category. Our results suggest that the race of a face represents a superordinate category relative to sex. These findings demonstrate the importance of social categories when considering sequential judgements of faces, and also highlight a novel approach for investigating how multiple social dimensions interact during decision-making

The Role of Important Non-Parental Adults (VIPs) in the Lives of Older Adolescents: A Comparison of Three Ethnic Groups

Previous research has consistently documented the importance of VIPs (mentors or important non-parental adults) in the lives of adolescents. Little is known, however, about whether VIPs play the same important roles across ethnic groups and whether VIPs remain influential when adolescents are older and involved in romantic relationships. The present study compared VIPs of 355 Hispanic, Asian, and European American older adolescents (age range = 17–19 years; M = 18.7 years; 62% female). Results indicated that, despite ethnic differences in their social capital, VIPs’ psychological characteristics (e.g., warmth and acceptance, depressive symptoms, and problem behavior) were similar. VIPs were perceived to have more positive psychological profiles than parents and peers, and in some cases, romantic partners. Moreover, with a few exceptions, the associations between VIP characteristics and adolescent adjustment (e.g., self-esteem, depressive symptoms, and problem behavior) were largely similar across ethnic groups. Finally, VIPs made unique contributions to adolescents’ self-esteem and problem behaviors even after the effects of romantic partners were considered. Implications of the findings are discussed

A Self-Reference False Memory Effect in the DRM Paradigm: Evidence from Eastern and Western Samples

It is well established that processing information in relation to oneself (i.e., selfreferencing) leads to better memory for that information than processing that same information in relation to others (i.e., other-referencing). However, it is unknown whether self-referencing also leads to more false memories than other-referencing. In the current two experiments with European and East Asian samples, we presented participants the Deese-Roediger/McDermott (DRM) lists together with their own name or other people’s name (i.e., “Trump” in Experiment 1 and “Li Ming” in Experiment 2). We found consistent results across the two experiments; that is, in the self-reference condition, participants had higher true and false memory rates compared to those in the other-reference condition. Moreover, we found that selfreferencing did not exhibit superior mnemonic advantage in terms of net accuracy compared to other-referencing and neutral conditions. These findings are discussed in terms of theoretical frameworks such as spreading activation theories and the fuzzytrace theory. We propose that our results reflect the adaptive nature of memory in the sense that cognitive processes that increase mnemonic efficiency may also increase susceptibility to associative false memories

A randomised feasibility study to investigate the impact of education and the addition of prompts on the sedentary behaviour of office workers

Abstract Background Office workers have been identified as being at risk of accumulating high amounts of sedentary time in prolonged events during work hours, which has been associated with increased risk of a number of long-term health conditions. There is some evidence that providing advice to stand at regular intervals during the working day, and using computer-based prompts, can reduce sedentary behaviour in office workers. However, evidence of effectiveness, feasibility and acceptability for these types of intervention is currently limited. Methods A 2-arm, parallel group, cluster-randomised feasibility trial to assess the acceptability of prompts to break up sedentary behaviour was conducted with office workers in a commercial bank (n = 21). Participants were assigned to an education only group (EG) or prompt and education group (PG). Both groups received education on reducing and breaking up sitting at work, and the PG also received hourly prompts, delivered by Microsoft Outlook over 10 weeks, reminding them to stand. Objective measurements of sedentary behaviour were made using activPAL monitors worn at three time points: baseline, in the last 2 weeks of the intervention period and 12 weeks after the intervention. Focus groups were conducted to explore the acceptability of the intervention and the motivations and barriers to changing sedentary behaviour. Results Randomly generated, customised prompts, delivered by Microsoft Outlook, with messages about breaking up sitting, proved to be a feasible and acceptable way of delivering prompts to office workers. Participants in both groups reduced their sitting, but changes were not maintained at follow-up. The education session seemed to increase outcome expectations of the benefits of changing sedentary behaviour and promote self-regulation of behaviour in some participants. However, low self-efficacy and a desire to conform to cultural norms were barriers to changing behaviour. Conclusions Prompts delivered by Microsoft Outlook were a feasible, low-cost way of prompting office workers to break up their sedentary behaviour, although further research is needed to determine whether this has an additional impact on sedentary behaviour, to education alone. The role of cultural norms, and promoting self-efficacy, should be considered in the design of future interventions. Trial registration This study was registered retrospectively as a clinical trial on ClinicalTrials.gov (ID no. NCT02609282 ) on 23 March 2015

Enhanced climate instability in the North Atlantic and southern Europe during the Last Interglacial.

Considerable ambiguity remains over the extent and nature of millennial/centennial-scale climate instability during the Last Interglacial (LIG). Here we analyse marine and terrestrial proxies from a deep-sea sediment sequence on the Portuguese Margin and combine results with an intensively dated Italian speleothem record and climate-model experiments. The strongest expression of climate variability occurred during the transitions into and out of the LIG. Our records also document a series of multi-centennial intra-interglacial arid events in southern Europe, coherent with cold water-mass expansions in the North Atlantic. The spatial and temporal fingerprints of these changes indicate a reorganization of ocean surface circulation, consistent with low-intensity disruptions of the Atlantic meridional overturning circulation (AMOC). The amplitude of this LIG variability is greater than that observed in Holocene records. Episodic Greenland ice melt and runoff as a result of excess warmth may have contributed to AMOC weakening and increased climate instability throughout the LIG