The Department of Paediatrics offers a variety of doctoral opportunities across its research themes. Take a look at the outlines of prospective DPhil projects - and please get in touch with the relevant supervisor to discuss the details.

Microbiology

Impact of immunisation on pharyngeal carriage of meningococcus and pneumococcus

Supervisor: Dr Matthew Snape

The project will evaluate the impact of immunisation with vaccines against pneumococcus and meningococcus on pharyngeal carriage of these organisms. These will be determined in two projects assessing:

-          pharyngeal carriage of pneumococci in > 2000 children in the Thames Valley, informing our understanding of ongoing vaccine serotype disease despite high uptake of pneumococcal conjugate vaccines

-          the impact of two licensed group B meningococcal vaccines on pharyngeal carriage of meningococcus in adolescents, as evaluated in a clinical trial enrolling 24 000 year 12 students

Both projects are funded and are being led by the Oxford Vaccine Group.

Contact details: Matthew Snape matthew.snape@paediatrics.ox.ac.uk

Applications by: 11th January 2019

Further information: The use of 13-valent pneumococcal vaccines has led to a dramatic reduction in vaccine serotype invasive pneumococcal disease in immunised cohorts, with some impact also observed in older age groups related to reduced carriage and transmission of these bacteria from pre-school aged children. Nevertheless, ongoing disease due to vaccine serotypes such as 19A is observed in the elderly, suggesting a reservoir of carriage in the community. A study evaluating pneumococcal carriage in 2400 children is underway, and comparisons of data generated by this new survey with historical data will inform optimisation of infant pneumococcal immunisation schedule.

Despite evidence of direct protection from the group B meningococcal vaccine introduced into the infant immunisation schedule in 2015, no herd immune effect has been observed from this program. Pharyngeal carriage of meningococcus is uncommon in infants, but is present in approximately 10% of adolescents, suggesting the potential to generate reduced circulation of group B meningococcus by immunising adolescents against this bacterium. However, the impact of the two licensed MenB vaccines on carriage of meningococcus is uncertain, hence the need for a community based clinical trial to evaluate whether an adolescent MenB immunisation campaign could achieve protection in the broader community against MenB disease.

 

Efficacy and correlates of protection with a new paratyphoid vaccine in a controlled human infection model

Supervisor: Professor Andrew Pollard

The project will examine the potential efficacy of a new paratyphoid vaccine using a controlled human infection model. Human volunteers will be vaccinated with a new paratyphoid vaccine and then challenged with wild-type Salmonella Paratyphi by mouth in a bicarbonate solution. The volunteers will be closely monitored for 2 weeks, and treated either on developing infection or at 2 weeks if no infection is detected. We will examine antibody and cellular responses to ascertain the immune mechanisms associated with protection. The study will involve state-of-the-art cellular and serological techniques to provide new insights into immunity against this neglected disease.

Contact details: Andrew Pollard andrew.pollard@paediatrics.ox.ac.uk  

Applications by: 11th January 2019

Further information: The Oxford Vaccine Group is an interdisciplinary research environment with expertise form vaccine design and development through translation in to human studies, through phase 1-IV clinical evaluation and human challenge studies, and vaccine evaluation in the laboratory using state pf the art technology. Work on enteric fever is a major focus of the group with the aim of improving health among some of the most vulnerable populations through vaccine prevention of typhoid and paratyphoid.

Jin, C., Gibani MM, Moore M, Juel HB, Jones E, Meiring J, Harris V, Gardner J, Nebykova A, Kerridge SA, Hill J, Thomaides-Brears H, Blohmke CJ, Yu LM, Angus B and A. J. Pollard (2017). "Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial." Lancet 2017 Dec 2;390(10111):2472-2480

 

Functional properties of typhoid antibodies in endemic and non-endemic populations

Supervisor(s): Professor Andrew Pollard and Dr Jennifer Hill

Project outline: Antibodies against the Vi capsular polysaccharide of Salmonella Typhi generated in response to vaccination are protective against infection. Early indications from a human challenge study suggest IgA and antibody-mediated neutrophil phagocytosis of bacteria in particular may be highly important in conferring protection. Using high throughput antibody functionality assays, profiles following typhoid vaccination both in endemic and non-endemic populations will be explored. The project will test whether environmental exposure to S. Typhi and repeated vaccination result in maturation of effector profiles, and identify potential population differences in vaccine response. These data will support assessment of the impact of vaccination programs globally as well as shedding light on factors involved in antibody effector profile maturation.

Contact details: Jennifer Hill jennifer.hill@paediatrics.ox.ac.uk

Applications by: 11th January 2019

Further information: The Oxford Vaccine Group (OVG) carries out research into novel vaccines to prevent infectious diseases. Uniquely OVG conducts human challenge studies for typhoid and paratyphoid in order to accelerate vaccine development and facilitate exploration of the immunology of infection. In addition the group is a member of consortia involved in overseas typhoid surveillance and vaccination trials; well positioned to explore findings from human challenge trials in (para)typhoid endemic populations and vice versa.

Jin, C., Gibani MM, Moore M, Juel HB, Jones E, Meiring J, Harris V, Gardner J, Nebykova A, Kerridge SA, Hill J, Thomaides-Brears H, Blohmke CJ, Yu LM, Angus B and A. J. Pollard (2017). "Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial." Lancet 2017 Dec 2;390(10111):2472-2480

 

 

Development of a novel vaccine to protect against plague: exploration of optimal viral vectored vaccines use in humans

Supervisor: Dr Christine Rollier  

Project outline: The Oxford Vaccine Group has created a novel vaccine to tackle plague epidemics, based on the use of an adenovirus vectored platform. The new vaccine will be entering phase I clinical trial in September 2019, to assess its safety and immunogenicity in healthy adults. We will test the hypothesis that a single dose is sufficient to induce functional immune responses in naives individuals, and characterise the innate immune signals associated with immunogenicity. In this project, we will also investigate new delivery modalities, including mucosal needle-free delivery platforms and judicious prime-boosting approaches that may be critical in extending the use of this vaccine platform in humans.

The project involves techniques in human immunology using a range of established and cutting edge technologies, combining ex vivo and in vitro experiments, and including fluorospot (B and T-cell responses), flow cytometry, neutralisation assays. The ultimate aim is to progress an innovative vaccine to prevent infections caused by Y. pestis (the plague) to the target populations.  

Contact details: Christine Rollier christine.rollier@paediatrics.ox.ac.uk 

Applications by: 11th January 2019

Further information: The focus of the group is the pre-clinical and early clinical development of new or improved vaccines against infectious diseases affecting vulnerable populations (children and developing countries), and if successful to progress these vaccines to clinical development (GMP production and clinical trials). We aim to understand the mechanisms supporting the induction of functional and protective antibody responses using different vaccine technologies against the bacterial diseases. 

Ewer KJ, Lambe T, Rollier CS, Spencer AJ, Hill AV, Dorrell L. Viral vectors as vaccine platforms: from immunogenicity to impact. Curr Opin Immunol. 2016 Aug;41:47-54. doi: 10.1016/j.coi.2016.05.014.

 

Immunopathogenesis of TB/HIV in Children

Supervisor: Dr. Rinn Song

Project outline: Compared to adults, young children are more likely to progress to active TB, including severe clinical manifestations. The immunologic mechanisms for this age-dependent susceptibility to TB are not yet fully understood. In addition to young age, HIV-infection is the other major predisposing factor associated with higher susceptibility to TB. Despite the substantial number of HIV-infected children globally, many of them living in TB-endemic areas, their immunopathophysiology is largely unexplored. In a comprehensive study in Kampala, we aim to delineate differences in innate and adaptive immunity in Ugandan children with TB and latent TB infection, stratified by their HIV status.

Contact details: Rinn Song rinn.song@paediatrics.ox.ac.uk

Applications by: 11th January 2019

 

DPhil opportunities in  the Holländer lab

Supervisor: Prof. Georg Holländer

Background information: T cells are essential for the generation and resolution of an adaptive immune response as they orchestrate an individual’s critical capacity to distinguish between benign self and harmful non-self antigens. Exclusively formed in the thymus, T cells rely during their development on the continuous physical and functional proximity to thymic epithelial cells (TEC), the major stromal component of the thymus. TEC instruct haematopoietic cells to adopt a T cell lineage fate, expand, mature and be selected according to their antigen-receptor specificity to become functionally competent T cells that can exit the thymus to the periphery. Maturing T cells gain the competence to remain tolerant (i.e. non-responsive) when exposed to and recognising an individual’s own antigens while the same cells - as a population - remain completely responsive to all other antigens. For this capacity to be correctly instructed, TEC express practically all of an individual’s protein-coding genes via a process designated promiscuous gene expression and thus present a comprehensive library of self-antigens to developing T cells. 

 

Project outlines: Given the central importance of TEC for thymus function, the laboratory of Developmental Immunology is focusing its research on the genetic programmes and the epigenetic mechanisms that control TEC differentiation, maintenance and function. Present projects open for DPhil projects focus on

  1. The structure and function of the TEC-autonomous master regulator FOXN1: This transcription factor belongs to a large family of forkhead molecules which are very well preserved across many vertebrate species. Mutations in FOXN1 in humans, mice and others are the genetic cause of a lack of normal TEC formation and a complete absence of T cells and thus an adaptive immune system that is operative. FOXN1 structure::function analyses are carried out following the identification of several patients with single heterozygous, compound heterozygous or homozygous mutations in the coding sequence of this transcription factor in patients diagnosed to lack a normal complement of functional T cells. To test specific FOXN1 mutations in vivo, mouse models have been created that allow a detailed analysis of the consequences of mutant FOXN1 for thymus development and function.
  2. The competence of TEC to express almost all of an individual’s protein-coding genes: This capacity unique to TEC is in part accomplished by the presence of the transcriptional facilitator AutoImmune REgulator, AIRE. AIRE-regulated gene transcription is marked by repressive chromatin modifications, including H3K27me3. Mice have been generated and will be analysed for their capacity of promiscuous gene expression as they have gain- or loss-of-function mutations affecting the placement of post-translational histone modifications.
  3. The role of the haploid loss of the Tbx1 and Crkl genes resulting in the 22q11 Deletion Syndrome (previously named DiGeorge Syndrome) characterised by a complex phenotype including the absence of regular TEC formation and function. A mouse model has been created that genetically mimics the the 22q11 Deletion Syndrome exclusiverly to TECs and thus allows a detailed molecular and cellular analysis of the cells’ bioloigy in the absence of TBX1and CRKL.

 

Contact details: Sabrina Harris sabrina.harris@paediatrics.ox.ac.uk

Applications by: 11th January 2019

 

Imaging pain in the developing human brain

 

Supervisor: Professor Rebeccah Slater and Dr Eugene Duff

Project outline: Little is known about how and when the human infant develops the ability to perceive and modulate pain. In adults, verbal report can quantify individual pain experience and assess analgesic efficacy, whereas in the infant, reliance on surrogate measures is necessary to infer pain perception. As cortical activation is a fundamental requirement for an experience to be interpreted as painful, inferences based on brain activity patterns may provide the most reliable surrogate measures. Building on recent advances in adult brain imaging, the aim of this project will be to adapt and advance these methods for use in the developing brain to create reliable and sensitive age dependent measures of infant pain. 

Contact details: Rebeccah Slater rebeccah.slater@paediatrics.ox.ac.uk

Applications by: 4th January 2019

Further information: The focus of the lab is to undertake a series of mechanistic studies in human infants to enhance understanding of the developing central nervous system (CNS), provide insights into how the environment shapes CNS function during early development, and improve understanding and treatment of infant pain.

 

 

The impact of apnoea on brain activity in preterm infants

 

Supervisor: Dr Caroline Hartley

Project outline: Apnoea - the cessation of breathing - is a common pathology associated with prematurity. These potentially life-threatening events can result in reduced cerebral oxygenation and frequent apnoeas have been associated with long-term effects including reduced childhood cognitive ability. Brain activity drives brain development during the critical preterm period but the immediate impact of apnoeas on brain activity is not well understood. The aim of this project will be to characterise the relationship between apnoeas and brain activity in preterm infants, and how this changes with development. EEG (electroencephalography) and physiology will be recorded simultaneously, and signal processing approaches will be used and developed to fully characterise this relationship. This research will enhance our understanding of apnoeas, and ultimately seeks to improve outcomes for prematurely-born children.

Contact details: caroline.hartley@paediatrics.ox.ac.uk

Applications by: 11th January 2019

Further information: The focus of the lab is to understand the impact of physiological instability on brain development in premature infants. 1 in every 10 babies are born prematurely; understanding and mitigating the long-term impact of premature birth is important to improve the lives of these children. We develop novel methodologies with the aim to provide a greater understanding of infant brain development and derive tools which can be translated to the clinical setting.

Intestinal inflammation and primary immunodeficiency

 

Supervisor: Professor Holm Uhlig

Project outline: Inflammatory bowel diseases (IBD) are a complex group of disorders with genetic predisposition. A minority of patients harbour extremely rare generic variants associated with Mendelian disorders. Maladaptation of the intestinal host microbial cross-talk towards intestinal bacteria can result in inflammatory bowel disease. Intestinal macrophages are key in this process since these cells phagocytose and remove translocating bacteria under homeostatic conditions without causing inflammation, whereas monocytes and monocyte derived macrophages can be major contributors of inflammatory cytokines if tolerance is broken. A genetically informed mechanistic concept of IBD suggests that immunosuppressive and anti-cytokine strategies should be combined with reinstalling of antimicrobial activity to induce and/or maintain remission. This project aims to characterise intestinal macrophage differentiation  and antimicrobial activity in patients with Mendelian forms if intestinal inflammation. A functional genomic approach characterising the functional effects of rare variants via technologies such as  single cell sequencing, proteomics and in vitro infection models will allow to understand key aspects of defective autophagy and resulting hyperinflammatory responses in those patients.

Contact details: Holm.Uhlig@ndm.ox.ac.uk

Applications by: 4th January 2019

Further information: The focus of the lab is to understand rare genetic defects that affect key mechanisms of the intestinal barrier function. We aim to understand patients that develop intestinal inflammation due to Mendelian disorders as proof of concept and understand how those mechanisms can direct novel diagnostics and treatments as well as inform on more common forms of intestinal inflammation (Uhlig & Powrie Annual Review Immunology 2018).