Studentship projects 2019

 

Antigen design for a single-dose adenovirus-vectored rabies vaccine

Supervisor: Alexander (Sandy) Douglas

Rabies is a uniquely lethal viral infection, with nearly 100% mortality. Although a rabies vaccine has been available since the 19th century, around 60,000 people still die of the disease each year. Current vaccines are based on old technology, require multiple doses, and are too expensive for inclusion in routine childhood immunisation programmes.

A single dose of an adenovirus-vectored rabies vaccine is highly protective in animal models, and our group is therefore preparing for a clinical trial of such a vaccine: we aim to enable low-cost single-dose routine vaccination of children in rabies-endemic areas.

Our current vaccine candidate uses the wild-type rabies glycoprotein transgene(1). The protein is expressed in the recipients’ cells, leading to induction of virus neutralising antibody. This design is simple and effective, but we also know that it induces a large amount of non-neutralising antibody, suggesting that much of the expressed protein is conformationally inaccurate.

It is likely to be possible to improve the efficacy of the vaccine by optimising the transgene to favour the expression of correctly folded trimeric antigen. The project will explore a variety of approaches to achieve this. Successful constructs would be taken forward to produce new candidate vaccines.

The project will provide training in a range of molecular biology, cell-based and immunological techniques, within the environment of a translationally-focused group. It will last for four months (longer than the typical NDM internship, but with additional funding provided). The intention would be for the work to lead to publication. The ideal applicant would have an interest in a career in vaccine development, and possibly some experience of DNA cloning and mammalian cell culture.

1. Wang C, Dulal P, Zhou X, Xiang Z, Goharriz H, Banyard A, et al. A simian-adenovirus-vectored rabies vaccine suitable for thermostabilisation and clinical development for low-cost single-dose pre-exposure prophylaxis. PLOS Neglected Tropical Diseases. 2018;12(10):e0006870.

 

A vaccine for multiple sclerosis? Structure, function and immunology of Epstein Barr virus glycoproteins

Supervisor: Alexander (Sandy) Douglas

EBV causes >100,000 deaths due to cancer each year, and there is increasingly strong evidence it contributes to – or perhaps is even necessary for – the development of multiple sclerosis. We already have vaccines against another herpesvirus, VZV, and there are good grounds to believe that a vaccine against EBV is also possible.

The lab has a track record in the development of antibody-inducing vaccines against malaria and rabies, and in the study of related protein-protein and protein-antibody interactions. We are starting an exciting new project to design and test vaccines for EBV, and to perform collaborative structural studies.

The project will involve expression and purification from mammalian cells of a candidate vaccine antigen. It will provide training in a range of molecular biology, cell-based and immunological techniques, within the environment of a translationally-focused group. It will last for four months (longer than the typical NDM internship, but with additional funding provided). The intention would be for the work to lead to publication. The ideal applicant would have an interest in a career in vaccine development, and possibly some experience of DNA cloning and mammalian cell culture.

1. Cohen JI. Epstein-barr virus vaccines. Clin Transl Immunology. 2015;4(1):e32.

2. Douglas AD, Williams AR, Knuepfer E, Illingworth JJ, Furze JM, Crosnier C, et al. Neutralization of Plasmodium falciparum merozoites by antibodies against PfRH5. J Immunol. 2014;192(1):245-58.

3. Wright KE, Hjerrild KA, Bartlett J, Douglas AD, Jin J, Brown RE, et al. Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies. Nature. 2014;515(7527):427-30.

 

Bisulfite-free and base-resolution cell-free DNA epigenetic sequencing for cancer diagnostics

Supervisor: Chunxiao Song

5-Methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are the two major epigenetic modifications found in the mammalian genome and they played important roles in a broad range of biological processes from gene regulation to initiation and progression of many human diseases. Therefore, epigenetic modifications are valuable biomarkers for diagnostics. Circulating cell-free DNA (cfDNA) is the DNA found in our bloodstream, which provides a noninvasive window for disease diagnosis. Although there has been great interest in using cfDNA as liquid biopsies for cancer detection, it has been challenging to identify the tissue-of-origin of cfDNA and hence the location of the tumour. Detecting epigenetic information such as 5mC and 5hmC in cfDNA is attractive for early cancer detection because it is known to be tissue and cancer-specific. Despite both a strong need and a compelling hypothesis for using epigenetic information in cfDNA for noninvasive diagnostics, it is far less explored than genetic information because the current methods (bisulfite sequencing) for detecting DNA epigenetic modifications are not feasible for the low amounts of highly fragmented cfDNA.

We combine various chemical biology and genome technologies to develop novel tools in epigenetics. Recently we developed novel bisulfite-free and base-resolution sequencing technologies for DNA methylation and hydroxymethylation (bioRxiv doi: https://doi.org/10.1101/307538, Accepted in Nature Biotech). It could replace bisulfite sequencing as the new standard in DNA epigenetic analysis. We expect it to revolutionize DNA epigenetic analysis, and to have wide applications in academic research and clinical diagnostics, especially in sensitive low-input samples, such as circulating cell-free DNA and single-cell analysis. This project aims to apply this method to develop comprehensive, systematic, and unbiased sequencing of the circulating cell-free methylation and hydroxymethylation. It will be applied to cell-free DNA from various solid tumours, with a focus on extracting tissue and disease-specific information for early detection.

 

The Burden of Antimicrobial Resistance in Acinetobacter baumannii in Asia

Supervisors: Dr Catrin Moore and Prof Susanna Dunachie (Big Data Institute and the Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, U

Project duration: 8 weeks

Drug resistant infections are a major global health threat. Many estimates have been published recently, one study estimates that 700,000 people die of resistant infections every year, with low and middle income countries (LMICs) being disproportionally affected.

The Global Research on Antimicrobial Resistance (GRAM) study (previously GBD-AMR study) is a collaboration between the University of Oxford (Centre for Tropical Medicine and Global Health and the Big Data Institute) and the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, USA. The project aims to synthesize drug resistance data worldwide, create geospatial maps as far as possible with the available data, of the distribution of resistance of selected bug-drug combinations and lead the incorporation of the impact of AMR into the disease estimates of the Global Burden of Disease Study.

This summer internship will focus on drug-resistance in Acinetobacter baumannii infections, which are associated with high morbidity, mortality and costs in many countries. The infection rate is higher in high dependence wards and in countries such as Asia and other resource-limited settings where significantly higher rates of resistant infections with Acinetobacter baumannii have been reported compared to developed countries. Antimicrobial resistance of these infections poses a unique challenge. This project will focus on the burden of infections caused by these resistant Gram-negative bacteria. The candidate will perform a systematic review to examine the geospatial distribution of this resistant pathogens.

 

The role of HIF in proliferation and cancer: carotid body physiology/pathology as a paradigm for pseudohypoxic cancers

Supervisors: Dr Tammie Bishop and Professor Sir Peter J. Ratcliffe

Hypoxia is common to many cancers, as the oxygen needs of proliferating tumour cells cannot be met via delivery from local blood vessels. Tumour cells must adapt to this reduced oxygen environment in order to survive. This is in part achieved through hypoxia-induced stabilisation of hypoxia-inducible factor (HIF) - a master transcription factor that activates a massive transcriptional cascade affecting multiple cellular and systemic processes. Many of these processes aid tumour growth, for example metabolic changes including a switch to glycolytic metabolism to support anaerobic ATP production; angiogenesis to support tumour growth and, potentially, metastasis1. In addition, HIF may alter processes such as proliferation and apoptosis that are less obviously concerned with oxygen balance but which may impact tumour growth/survival.

Whilst it is well documented that activation of HIF target genes may facilitate tumour growth, it is less clear whether HIF can initiate cancer per se. The high incidence of genetic mutations in HIF pathway components in tumours provides some evidence for this. For example, von Hippel Lindau (VHL) - one of the major negative regulators of HIF - is a tumour suppressor and patients with germline mutations develop VHL syndrome, a familial cancer syndrome characterised by tumours in a restricted set of tissues: haemangioblastomas (spinal and cerebellar), retinal angioblastomas, renal clear cell carcinomas, phaechromocytomas and carotid paragangliomas. Given the role of VHL in both HIF regulation and as a tumour suppressor, this suggests that activation of HIF could drive tumourigenesis, at least in certain tissues.

Tumours of the adrenal medulla or carotid body, collectively termed phaeochromocytomas/ paragangliomas (PCC/PGL), not only have a high incidence of VHL mutations, but also have been shown to contain a number of gain of function mutations in HIF-2alpha (see recent review2). Further, the carotid body is unique in that hypoxaemia, low arterial oxygen as experienced at altitude or in patients with chronic obstructive pulmonary disease (COPD), induces marked proliferation and overgrowth of the carotid body. This is thought to mediate ventilatory acclimatisation, an increase in ventilation in response to chronic hypoxia that helps redress oxygen balance. In line with this enhanced proliferation, the incidence of carotid body tumours, or carotid body paragangliomas, is ~10x more common at altitude/in COPD. Taken together, this suggests that HIF is capable of initiating tumourigenesis in sympathoadrenal tissues of the carotid body and adrenal medulla, perhaps via stimulation of proliferation.

Using transgenic mouse models, we have demonstrated that HIF-2 is necessary for hypoxia induced carotid body proliferation and the associated ventilatory acclimatisation3. Further, we have shown that inactivation of the principle negative regulator of HIF: HIF prolyl hydroxylase enzyme 2 (PHD2) results in carotid body overgrowth with near 100% incidence of markedly enlarged, dysplastic carotid bodies with features characteristic of human PGL tumours and that this process is dependent on HIF-24,5.

The aim of this studentship would be to characterise the mechanisms by which aberrant HIF-2 activation leads to the development of these PGLs. In the first instance, we would seek to understand which cellular processes (metabolic, secretory or other) are dysregulated; for example through a transcriptomic study of early HIF-2 dependent gene expression changes and through analysis of cellular features including dense core vesicle secretion. We would test whether these HIF-2 effects extend to other tissues, in particular those that develop tumours in VHL disease. From a clinical perspective, we would test whether pharmacological modulation using recently described HIF-2 antagonists can moderate the development of PGL, as has been described in renal clear cell carcinoma6.  

We anticipate that these mice will form a paradigm not only for the study of PGL tumours but also for other ‘pseudohypoxic’ cancers – that is, cancers associated with genetic mutations affecting hypoxia signalling such as renal clear cell carcinoma associated with inherited or sporadic VHL mutations.

1. Bishop T, Ratcliffe PJ. Signaling hypoxia by hypoxia-inducible factor protein hydroxylases: a historical overview and future perspectives. Hypoxia (Auckl). 2014;2:197-213.

2. Toledo RA. New HIF2alpha inhibitors: potential implications as therapeutics for advanced pheochromocytomas and paragangliomas. Endocr Relat Cancer. 2017;24(9):C9-C19.

3. Hodson EJ, Nicholls LG, Turner PJ, et al. Regulation of ventilatory sensitivity and carotid body proliferation in hypoxia by the PHD2/HIF-2 pathway. J Physiol. 2016;594(5):1179-1195.

4. Fielding JW, Hodson EJ, Cheng X, et al. PHD2 inactivation in Type I cells drives HIF-2alpha-dependent multilineage hyperplasia and the formation of paraganglioma-like carotid bodies. J Physiol. 2018.

5. Bishop T, Talbot NP, Turner PJ, et al. Carotid body hyperplasia and enhanced ventilatory responses to hypoxia in mice with heterozygous deficiency of PHD2. J Physiol. 2013;591(14):3565-3577.

6. Chen W, Hill H, Christie A, et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature. 2016;539(7627):112-117.

 

Mapping travel patterns in relation to malaria risk with GPS trackers

Professor Richard J Maude (Epidemiology Dept, Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand)

Exposure to malaria infected mosquitoes in the Greater Mekong Subregion (GMS) occurs mostly away from the home in forests and forest fringes. Sites of malaria transmission are difficult to identify due to challenges in accurately mapping where people have visited during the time in which they became infected. Reasons for this include poor recall, lack of identifiable landmarks in rural areas and an inability to track movements using cellphone records due to lack of mobile phone towers in many remote and forested areas.

MORU is collecting GPS tracking data from people at high risk of malaria using tracker devices and cellphones. This is a near continuous data stream of a person’s location over time and can be used to map their movements over a period of weeks or months. By combining GPS tracks from multiple people over time together with forest and settlement maps, a detailed understanding of locations at high risk for malaria transmission can be gained. These locations can then be targeted for more intensive investigation and measures instigated to prevent transmission.

This project will analyse GPS tracking data from studies in the Greater Mekong Subregion to identify likely areas with high risk for malaria transmission.

Methods will include GIS and spatial analysis.


Potential for prophylaxis to prevent forest malaria in the Greater Mekong Subregion

Professor Richard J Maude (Epidemiology Dept, Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand)

Most malaria in the Greater Mekong Subregion (GMS) is transmitted in and around forests. However risk behaviours leading to infection have not been well characterized which makes it challenging to design appropriate interventions to prevent and treat infections. One proposed intervention that could reduce forest malaria is antimalarial prophylaxis for forest goers. Trials of this are planned in the near future however it is not clear in how it would be administered and monitored and by whom in different healthcare settings. The acceptability of prophylaxis as an intervention for populations in the GMS is also not known.

This project will design and conduct interviews among malaria control programme staff and healthcare workers in countries in the Greater Mekong Subregion to identify a mechanism for administering and monitoring antimalarial prophylaxis to forest goers. It may also be possible to conduct interviews amongst high risk forest goers to determine the acceptability of prophylaxis as an intervention.

The results will help National Malaria Control Programmes to decide how to roll out this intervention in their country.

Methods will include qualitative interviews and health systems research.


Retrospective analysis of a malaria outbreak in the Greater Mekong Subregion

Professor Richard J Maude (Epidemiology Dept, Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand)

There have also been a number of focal outbreaks of malaria in the Greater Mekong Subregion (GMS) in the past few years. In many cases the causes of these outbreaks were not well understood and responses suboptimal due to limitations in data and capacity for analysis. This limits countries’ ability to act efficiently to contain these outbreaks and to prevent future outbreaks and has the potential to threaten the achievement of planned elimination timelines.

This project will analyse retrospective surveillance data together with intervention data to describe a recent malaria outbreak in the GMS and investigate possible causes. Questions that the project will aim to address will include: what was the contribution of climate factors to this outbreak/epidemic? What was the contribution of changes in treatment/vector control measures to this outbreak/epidemic? What are the geographical and temporal extent of the epidemic? Which demographic and risk groups were affected? Where data are available what was the contribution of changes in population movement patterns and antimalarial resistance to this epidemic?

Methods will include statistical analysis, GIS and spatial analysis.

The results will help the National Malaria Control Programme understand which factors contributed to the outbreak should report as possible causes of the epidemic/outbreak and inform planning of interventions for future outbreaks.

Developing viral vectored vaccines for MAGE-expressing tumours

Supervisors: Professor Benoit Van Den Eynde and Dr Carol Leung

Cancer vaccines have the potential to induce anti-tumour specific immune responses to reject tumours. This project aims to produce and test new MAGE-targeting cancer vaccines optimized to induce strong cytotoxic T lymphocyte (CTL) responses. We are using an effective viral vector platform and different immunogen design to induce potent CTL responses against tumours. Different mouse tumour models are employed to assess the vaccine efficacy.
This study will create a next - generation cancer vaccine against MAGE - positive tumours, and lay a foundation for clinical testing in cancer patients.

The project involves techniques in molecular biology and immunology.

Novel cell cycle regulators in human cells

Supervisor: Professor Catherine Green

This project will assist in the characterisation of newly identified cell cycle regulated proteins in human cells. As a collaborative project with Prof. Ross Chapman’s group we are undertaking a systematic analysis of a set of cell cycle regulated proteins identified in a screen. The screen identified known proteins essential for DNA replication and mitosis along with a set of novel genes of unknown function. We therefore predict that these uncharacterised proteins are likely to have important functions during the cell cycle. This project will use molecular biology (cloning, regulated expression of recombinant proteins, CRISPR/Cas9 knockout), advanced microscopy, FACS, and biochemical methods to determine the function of these novel proteins and the consequences of their disruption or perturbation. These proteins will then be investigated as possible targets for preventing cell proliferation in cancer of other diseases.

Infectious disease dynamics, using mathematical modelling, pathogen genetics, and/or evolutionary approaches

Supervisor: Professor Christophe Fraser

This project is open to applicants from Africa only.

The development of vaccines against viruses responsible for emerging and outbreak diseases

Supervisor: Professor Teresa Lambe

Evaluation of immune responses induced by candidate malaria vaccines in clinical trials

Supervisor: Associate Professor Katie Ewer

Preference will be given to applicants from Africa for this project.

Mechanisms of immunity to HIV-1 or HIV-2 in people with long-standing infection

Supervisor: Professor Sarah Rowland-Jones

Applicants from Zimbabwe, Cameroon or Japan would be particularly welcome for this project.

Development of, or characterisation of immune responses to, candidate vaccines against the asexual blood-stage of Plasmodium falciparum or P. vivax

Supervisor: Professor Simon Draper

Investigating immune responses and protection induced by candidate malaria vaccines in pre-clinical models

Supervisor: Dr Alex Spencer

This project is open to applicants from Africa only.

Developing novel vaccine formulations for single-dose immunisation

Supervisor: Dr Anita Milicic

Background
Almost all current vaccines require administration in two or three doses and at specific time intervals to achieve full efficacy. Single dose immunisation is a long-standing concept that could significantly improve vaccination coverage globally. Attempts to develop a single dose vaccine have so far been unsuccessful with one of the key obstacles being the design of formulations capable of achieving pulsatile (time-determined) vaccine release in vivo, while preserving antigen stability and immunogenicity.

The overall aim of this project is to develop vaccine delivery formulations that would allow prime-boost vaccination to be combined into a single dose by encapsulating the booster vaccine into microcapsules and administering it together with the priming vaccine in soluble form. The timing and kinetics of the booster vaccine release will be determined by the chemical composition and method of preparation.

Project description
We are using different biocompatible and biodegradable polymers with a range of degradation profiles to produce particles with different kinetics (continuous/pulsatile) and time to antigen release.

In addition, through a collaboration with engineers from the Institute for Biomedical Engineering (IBME) at Oxford, a particular focus is placed on novel production techniques, including electrohydrodynamic atomisation (EHDA) and microfluidics, to develop highly homogeneous microcapsule preparations suitable for testing in vivo in mice.

The successful candidate will be trained in particle making techniques starting with double emulsion and, as appropriate, moving to more sophisticated methodologies such as microfluidics. Microcapsule chemical formulations will be selected and designed based on our current research, using BSA or BSA-FITC as a model antigen.

Microcapsule production will be followed by in vitro analysis of particle size, monodispersity, encapsulation efficiency and release kinetics under simulated “in vivo” conditions. If time allows, new formulations will be tested in vivo in mice for pharmacokinetics, safety and immunogenicity.

Eventually, successful formulations will be taken forward into mouse disease challenge models and compared with standard prime-boost regimens.

This project has emphasis on chemical composition and formulation and the ideal candidate will have background in chemistry, pharmacology or engineering.

 

Inhibiting Inflammation: Structural and Functional Characterisation of Pro-Inflammatory Protein-Protein Interactions

Supervisor: Associate Professor Wyatt Yue, SGC

Toll-Like Receptor 4 (TLR4) is a surveillance receptor traditionally responsible for initiating a protective immune response upon the detection of dangerous pathogenic molecules. However, recent evidence demonstrates that hyperactive TLR4 signalling, especially in response to a family of proteins known as “FRePs”, causes chronic inflammation and disease progression in rheumatoid arthritis, multiple sclerosis, fibrosis, cancer, and more. This mysterious receptor-ligand interaction could represent a novel target for anti-inflammatory drug discovery, although structural and functional data are sorely lacking.

Working within the Structural Genomics Consortium (SGC), the world’s leading open-source structural biology initiative, the student will apply biophysical and biochemical methods to characterize the TLR4:FReP protein-protein interaction. The project will involve the expression and purification of both FReP family members and TLR4:FReP protein complexes, followed by experiments including, but not limited to, x-ray crystallography and SPR. If time permits, structural and functional data will be leveraged to implement a biophysical screening assay necessary for fragment-based inhibitor discovery. We welcome students who are intrigued by protein structures, and have an interest in learning structural biology and/or drug discovery.

 

Investigating a protein folding machine involved in proteome regulation

Supervisor: Associate Professor Wyatt Yue, SGC

The process by which cells regulate protein folding, termed proteostasis, is an emerging field of therapeutic importance as the cause of many diseases can be traced back to aggregated or misfolded proteins. The eukaryotic chaperonin TRiC is a 16-subunit mega-complex comprising two rings of eight different subunits (CCT1-CCT8). Each subunit contains an apical domain that recognizes protein folding substrates, an equatorial domain for ATP binding and hydrolysis, and an intermediate linker that connects the two. The essentiality of TRiC in cell viability is reflected by its role in folding a diverse range of substrates including cytoskeletal proteins, and in suppressing aggregation of key neurodegenerative proteins e.g. huntingtin, and α-synuclein.

How does TRiC specifically recognizes the nascent polypeptide substrates for folding? What molecular mechanisms are involved in the folding process? Our lab at the SGC employs structural biology techniques to address these questions, by isolating the substrate-binding apical domains and co-crystallizing them with nascent folding substrates. The project would include expression, purification, and crystallization of the CCT subunit apical domains, as well as protein-peptide interaction studies using biophysical methods, leading to high resolution snapshots of an important protein folding event.

Organoids to model tumour development in the stomach

Supervisor: Dr Benjamin Schuster-Böckler

More than 15,000 patients in the UK are diagnosed with adenocarcinoma of the gastric or oesophageal epithelium each year, making these tumours the 5th most frequent type of cancer in the UK. With an average 5-year survival of less than 20%, the prognosis is very poor. At the same time, incidence of these cancer types is increasing the western world. This suggests that environmental factors have an influence in the development of the disease. On a genomic level, gastric cancers are characterised by a distinct pattern of somatic mutations, commonly referred to as Signature 17, whose primary feature are frequent TT to GT mutations. Our previous work has led us to hypothesize that oxidative stress due to bile reflux acts on stem-cells in gastric and oesophageal gland cells, leading to incorporation of the damaged nucleotide 8-oxo-G into nascent DNA during replication. In order to test this hypothesis, we are now growing organoids from gastric gland cells under different conditions. Comparative whole-genome sequencing of exposed and control cells will then reveal changes in the mutational landscape.

In this project, you will extract mutation information from the sequencing data from the first batch of organoids, and compare these data to known cancer mutations. This is a great opportunity to learn the fundamentals of genome bioinformatics, and at the same time be involved in a cutting-edge project that is addressing an important question in cancer biology. You should have at least basic computer skills, and some understanding of how DNA sequencing works. You will get training on how to run the necessary programs during the course of the internship.

Protein:protein interactions leading to transcriptional repression

Supervisor: Panagis Filippakopoulos

Protein:protein interactions leading to transcriptional repression
Transcriptional programs are often deregulated in disease, offering opportunities for therapeutic intervention. One of the most promising over recent years is through targeting epigenetic readers of the bromo and extra-terminal (BET) family. In this internship we seek to understand the contribution of the extra-terminal (ET) domain of BETs in the assembly of transcriptional complexes leading to repression of lineage-specific programmes using recombinant and cell biology techniques.

Lambert, J. P., Picaud, S., Fujisawa, T., et al Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains. Mol Cell (2019) 73, 621-638 e617

Fujisawa, T.&Filippakopoulos, P. Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat Rev Mol Cell Biol (2017) 18, 246-262

Assessment of pre-erythrocytic vaccines to prevent P. vivax malaria infection

Supervisors: Professor Arturo Reyes-Sandoval and Dr. Barbara Dema-Jiménez

Malaria is caused by four parasite species in humans: Plasmodium falciparum, P. vivax, P. ovale and P. malariae. Of these, P. vivax is the most widely distributed human malaria, representing the major cause of this disease outside Africa [1]. It is considered that P. vivax threatens nearly 40% of the human population [2] and current estimates indicate a burden of 132 and 391 million cases per year of malaria caused by P. vivax [3] with 2.6 billion persons at risk of infection, actually slightly greater than that of P. falciparum [2]. Despite the widespread distribution of Plasmodium vivax, most attention has focused on P. falciparum due to the severity of the disease and the number of deaths that this parasite causes. However, recent reports have shown a strong association between P. vivax infection, severe disease and death [4].

Our group has experience in vaccine development, using platforms such as Virus-like Particles and recombinant Virus vectored vaccines, which proved promising results for clinical trials. The proposed project will consist on participating in the assessment of novel P.vivax vaccines to demonstrate immunogenicity and protective efficacy in preclinical models. Approaches for such development will include:

1. Immunogenicity by using the flow cytometry, ELISA, and ELISPOT assays.
2. Determine whether the novel malaria vaccine can protect mice after an infection with transgenic P. berghei malaria parasites.

References:
1. Mendis, K., B.J. Sina, P. Marchesini, and R. Carter, The neglected burden of Plasmodium vivax malaria. Am J Trop Med Hyg, 2001. 64(1-2 Suppl): p. 97-106.
2. Price, R.N., E. Tjitra, C.A. Guerra, S. Yeung, N.J. White, and N.M. Anstey, Vivax malaria: neglected and not benign. Am J Trop Med Hyg, 2007. 77(6 Suppl): p. 79-87.
3. Hay, S.I., C.A. Guerra, A.J. Tatem, A.M. Noor, and R.W. Snow, The global distribution and population at risk of malaria: past, present, and future. Lancet Infect Dis, 2004. 4(6): p. 327-36.
4. Barcus, M.J., H. Basri, H. Picarima, C. Manyakori, Sekartuti, I. Elyazar, M.J. Bangs, J.D. Maguire, and J.K. Baird, Demographic risk factors for severe and fatal vivax and falciparum malaria among hospital admissions in northeastern Indonesian Papua. Am J Trop Med Hyg, 2007. 77(5): p. 984-91.

Immune Correlates in TB Vaccine Immunology

Supervisors: Professor Helen McShane, Dr Iman Satti and Dr Rachel Tanner

Tuberculosis (TB) remains a major global health problem, and has recently surpassed HIV as the biggest killer due to an infectious disease. In 2017 there were 10m new cases of TB and 1.4m deaths. Given the rise of drug-resistant and multi-drug resistant TB, an efficacious vaccine would be the most effective intervention strategy. The only currently available vaccine, BCG, has variable efficacy against pulmonary TB. Efficacy is high in the UK (~80%), but very poor in regions with the greatest burden of TB, such as sub-Saharan Africa. A more effective vaccine is desperately needed.

One of the major barriers to development of an effective new TB vaccine is the lack of a validated correlate of protection. This project will explore various immune parameters using samples from TB vaccine trials to identify those associated with improved protection from TB infection or disease. The student will use and become familiar with laboratory techniques which may include ELISA, ELISpot, flow cytometry and mycobacterial growth inhibition assays. The student will participate in departmental seminars, have access to field experts, and receive assistance from laboratory staff.