CVR Clinical Research Fellowships
Applications for 2024/25 are now open, with a deadline of the 8th January 2024. Apply here
Training in Virus Research for Medical Graduates
The CVR’s MRC-funded Clinical Research Fellowships (CRFs) are an excellent opportunity for clinically qualified medical doctors to develop advanced training in a range of research methodologies relevant to modern biomedical research, and to consolidate their academic career prospects by undertaking a higher degree (normally a PhD).
The fellowships are intended for applicants with an interest in infectious diseases or clinical virology. In most cases applicants should be an internal medicine trainee (IMT), UK speciality trainee, or international equivalent level from any specialty. Applicants must be at pre-consultant level, GMC registered at the time of starting the post, and be able to gain out-of-programme (OOP) approval.
CVR Clinical Research Fellows are integrated into a wider cohort of postgraduate research students at the CVR. The training and support provided to these cohorts is described here.
Project Selection
A CRF is funded for three years. CRFs differ from the more usual CVR MRC PhD studentships in two ways. First, CRFs are funded for only three years; therefore, it is not possible to carry out rotations projects before starting your main thesis project. In order to complete a PhD project within a three-year timeframe and to allow a return to run-through training or timely applications for academic training posts, we strongly encourage applicants to consider potential project areas and to reach out to potential supervisors prior to interview. Secondly, CRFs usually start in August rather than October in order to fit in with clinical rotations. Despite the earlier start date, you are encouraged to take part in the ‘CVR Introduction to Virus Research’ course.
We encourage projects in all areas of CVR research (fundamental, translational, and clinical virology), from computational biology, to molecular biology, to epidemiology and beyond. Opportunities also exist for collaborative projects, including in tropical medicine and emerging diseases, with opportunities to spend time working with partner institutions overseas. Following interview, the successful applicant will be supported to finalise their choice of project before starting their fellowship.
An overview of the research groups in the CVR can be found in the booklet linked below, and examples of possible projects are given in the following section.
Introduction to Postgraduate Research at the CVR Booklet
Benefits
You will work in a world-leading virology research institution, alongside the UK’s largest grouping of virologists. Your training experience will centre on a 'hands on' research project in your chosen supervisor's laboratory, leading to the submission of a PhD thesis. This training will be supplemented with mentorship, career advice and the acquisition of transferable skills. Although research forms the major component of this post, clinical duties and teaching can be incorporated according to individual needs.
The salary for Clinical Research Fellows will be on the Clinical Academic pay scale, and the studentship includes all University fees as well as a generous allowance to cover consumables and travel (including international conference attendance).
Application Process
Timeline:
Shortlisted applicants will be invited to come to Glasgow to visit the CVR. Reasonable travel expenses will be reimbursed and accommodation made available as required.
Any questions about the programme or eligibility requirements should be directed to ruth.jarrett@glasgow.ac.uk
Examples of Projects for Clinical Research Fellows
Research at the CVR spans investigations from the molecular, structural and cellular levels through to the individual host and affected population, allowing the integration of molecular and structural virology, cell biology, pathogenesis, epidemiology and mathematical modelling into your PhD project.
Clinical PhD Fellows are strongly encouraged to think about projects in advance of interview and to make contact with potential supervisors.
Examples of possible projects include (but are by no means limited to) the following:
Dr Chris Illingworth is interested in better understanding and preventing nosocomial transmission of viral illness.
The SARS-CoV-2 pandemic highlighted the importance of nosocomial transmission as a key problem in hospitals, with a study at one hospital estimating that as many as 15% of cases in the hospital were caused by this route. Recent work in viral genomics in the Illingworth group has identified new methods in virus genomics as being of use for understanding outbreaks in retrospect, and tracking outbreaks as they occur in real time. We carried out a provisional analysis of the role of PPE in nosocomial transmission, studying the consequences of FFP3 mask usage in a hospital in Cambridge. Via collaboration we have also explored the experience by health care workers of receiving real-time genomic data in real time. Genomic datasets generated during the pandemic provide a rich resource for retrospective analysis.
The aim of this project will be to explore a broad range of approaches combining genomic and other data to better understand and prevent nosocomial transmission. Potential avenues of exploration within the project include i) The development and use of simple methods in bioinformatics to better understand evolutionary relationships between viral sequences collected during an outbreak; ii) The use of more advanced methods for network reconstruction to elucidate patterns of viral transmission; iii) The exploration of methods from computational fluid dynamics to understand the role of the hospital environment in promoting or preventing transmission events; iv) Approaches to optimising the communication of genomic data to healthcare workers.
This project will provide training and experience in viral genomics, in bioinformatics, and in the use of quantitative methods for studying data from clinical settings.
Dr Chris Boutell and Professor Alfredo Castello are working to define the host-cell immunological response and barriers to MPOX infection.
MPOX (formerly known as monkeypox) is a disease caused by the MPOX virus (MPXV), a zoonotic pathogen transmitted from rodents to humans. Since January 2022, the WHO has reported a significant global rise in MPOX, totalling 86,309 confirmed cases and 107 deaths from 110 Member States across six WHO regions (https://worldhealthorg.shinyapps.io/mpx_global/). A high proportion of these cases have been reported from previously non-endemic regions, including Europe and the Americas (Thornhill et la., NEJM, 2022; Lum et al., Nat Rev Immunol, 2022). While MPOX is typically self-resolving, MPXV infection of the young or immunocompromised can lead to severe disease and increased likelihood of fatality. Human-to-human transmission occurs through contact with infected skin lesions, bodily fluids, and large respiratory droplets. Although smallpox vaccination and antiviral therapy (tecovirimat) can reduce MPOX replication and transmission, these countermeasures are not widely available or accessible in most countries. Thus, there is concern that MPXV may establish an endemic foot hold around the globe leading to an increase in MPOX morbidity and mortality within vulnerable groups. This MRC-funded Clinical Fellow (CF) project will investigate the host-cell tropism and immunological barriers to MPXV infection employing a range of two- and three-dimensional tissue culture model systems. Utilising a combination of genomic (RNA-seq) and proteomic technologies, this project will investigate whether strain dependent MPXV adaptation influences the kinetics of MPXV replication, activation of innate immune pathways, and sensitivity to immune suppression by the interferon response. This project will actively collaborate with our internal and external MPOX consortium partners to rapidly disseminate its findings in response to an ongoing outbreak.
This project will provide extensive training in infectious disease research across multiple technological platforms and research disciplines. The CF will actively participate in an existing collaboration between the Boutell group (CVR), other UKRI MPXV consortium members, and members of the CVR from Tissues to Molecules; Host-Cell Response to Infection programme to rapidly disseminate its research findings. This project will enable access to specialist knowledge and equipment not commonly found within an individual host institution or laboratory, for example BCL3 containment facilities, high-resolution light microscopy imaging, and bioinformatic support/training (MRC-UoG CVR). Outputs from this project will aid in the identification and characterisation of immune barriers and antiviral compounds that may restrict the replication or future re-emergence of zoonotic pathogens.
Prof Emma Thomson focuses on the use of NGS and functional assays to identify and investigate viruses that present a risk to human health in the UK and Uganda
Project 1: The orthonairoviruses CCHFV, Dugbe virus and Nairobi Sheep Disease virus are common in Uganda and other surrounding countries. A novel virus in the same family called Macira virus has also been identified recently, from tick collections in Uganda, by the Thomson group. The aim of this project is to investigate the role of cross-specificity in serological responses to these viruses by carrying out neutralisation assays using a non-infectious VLP system. Further, we will carry out a survey of ticks in Uganda to identify these viruses and to identify factors that may affect their distribution across the country.
Project 2: The group have recently identified a virus called adeno-associated virus 2 (AAV2) in children with otherwise unexplained hepatitis. The aim of project 2 is to investigate the immune response to AAV2 in children affected by this condition using ELISpot, flow cytometry, peptide binding assays and mass spectrometry.
Dr Antonia Ho, Dr Ana da Silva Filipe and Dr Joseph Hughes are interested in using NGS to better understand viral causes of severe respiratory infections
Acute lower respiratory tract infection (LRTI) causes 2.4 million annual deaths worldwide. Despite the availability of state-of-the-art, multiplex molecular tests in resource-rich diagnostic laboratories, the causative organism of these infections is seldom identified due to the limitations in microbial tests. This lack of definitive diagnosis often results in the overuse of antibiotics with poor outcomes and contributes to growing antimicrobial resistance. More sensitive diagnostic methods and pathogen discovery approaches are needed to better characterise the aetiology of LRTIs and thereby effectively target future interventions.
Metagenomic sequencing is an untargeted approach to detect viruses, bacteria, fungi and eukaryotic parasites across a range of patient specimens, which can aid in the diagnosis of infectious diseases when more conventional assays fail. Untargeted high-throughput sequencing is particularly useful for the identification of viruses, as these lack an universal conserved region to enable targeted pan-viral amplification, unlike bacteria. This approach has therefore been valuable for the discovery of new viruses and the identification of divergent strains. Metagenomics-based pathogen detection is also powerful when diverse pathogens co-contribute to disease development, as it allows the identification of viral-viral or viral-bacterial co-infections. Furthermore, this approach can also provide single-nucleotide resolution of pathogen genomes enabling the identification of mutations associated with severe disease or drug-associated resistance mutations, e.g., oseltamivir in influenza. Thus, untargeted pathogen sequencing is a useful resource to guide “precision microbiology” strategies.
Two prospective adult cohorts with detailed clinical metadata have been sampled: 1) adults (aged >18 years) hospitalised with LRTI in Blantyre, Malawi (BASH-FLU study); 2) adults (aged >16 years) hospitalised with severe acute respiratory illness in Glasgow, Scotland (CHARISMA2 study). Despite extensive microbiological tests, no aetiological pathogens were identified in up to one third of patients. We plan to focus our investigation on these samples by performing untargeted sequencing on these respiratory samples. The aim of the project is to systematically identify and classify the respiratory viruses and microbiomes of these patients, which will aid aetiological characterisation of severe respiratory infections in Malawi and UK, compare the aetiologies from the two settings, and improve understanding of associations between viral infections and disease outcome.
We hypothesise that a proportion of LRTI with unknown aetiology may be due to: 1) respiratory viruses untargeted by the multiplex real-time polymerase chain reaction (RT-PCR); 2) genotypes or variant strains that are sufficiently diverged from the target RT-PCR to fail amplification or; 3) viruses of zoonotic origin.
This project will provide training and experience in clinical epidemiology, viral genomics and bioinformatics. Importantly, it will generate knowledge that can improve diagnosis and management of patients with LRTI.
Prof Pablo Murcia, Ross Langley and Rory Gunson and interested in why infants and young adults have more viral coinfections than older children and adults
Prof Pablo Murcia, in collaboration with Ross Langley (QEUH) and Rory Gunson (West of Scotland Specialist Virology Centre), is interested in why infants and young adults have more viral coinfections than older children and adults.
Background. Respiratory viral infections are responsible for major disease burden. Different viruses can cause respiratory infections, including influenza viruses (IAV), coronaviruses (CoVs), respiratory syncytial virus (RSV), human rhinovirus (HRV), human metapneumovirus (hMPV) and parainfluenza viruses (PiVs), to name but a few. We have shown that viral coinfections represent ~10% of viral respiratory infections and that most of them occur in children under five years of age.
The interferon (IFN)-mediated innate immune response is the first cellular response against viral infections, and we and others showed that this response plays a key role in viral interference within the respiratory trac. For example, HRV, IAV and RSV trigger an IFN response that blocks SARS-CoV-2 replication. In contrast, RSV replication is minimally affected by IAV. This suggests that IFN-mediated virus interactions are specific and depend on i) the host's ability to mount an innate immune response; ii) the breadth and potency of the innate immune response triggered by each virus; and iii) the susceptibility of a given virus to the IFN response triggered by other viruses.
It is unclear why viral coinfections are more common in young children than in other age groups, and why certain viruses are more common than others in coinfections. Possible explanations are that very young children (0-3 years old) mount weaker innate immune responses than older children, and that certain viruses modulate the innate immune response in a way that facilitates viral coinfections. This project aims to address those two knowledge gaps by comparting the response to RSV infection and RSV/HRV coinfection in patients of different age groups. To this end we will generate transcriptomes from nasopharyngeal swabs collected from patients of different ages with a positive qPCR diagnosis for RSV, HRV, as well as coinfected with both viruses.
Results from this work will provide important insights on the impact of age on the response to virus infection and coinfection. Characterising the host response to viruses in patients is critical to identify markers associated with susceptibility to viral infection and/or altered disease outcomes.
Prof. Brian Willett and Prof. Margaret Hosie are interested in the development & application of techniques for analysis of humoral immune responses to viruses
Prof. Brian Willett & Prof. Margaret Hosie, in collaboration with Dr. Louisa Pollock (Queen Elizabeth University Hospital, Glasgow) & Dr. Helen Parry (Institute of Immunology and Immunotherapy, University of Birmingham) are interested in the development and application of novel techniques for the analysis of humoral immune responses to viral pathogens
Public Health Scotland (PHS) conducts community acute respiratory infection (CARI) surveillance to monitor respiratory infection across the country, to understand the burden of disease within the community and to estimate its impact on well-being. Samples are collected from representative sentinel practices and are screened for respiratory pathogens, including influenza, adenovirus, human metapneumovirus, Mycoplasma pneumoniae, parainfluenza, respiratory syncytial virus, rhinovirus, seasonal coronaviruses and SARS-CoV-2. A complementary scheme monitors severe acute respiratory infection (SARI) in secondary care. Together, these surveillance schemes enable PHS to contribute data to both the Scottish Government to formulate and refine healthcare policy, and to UK and international bodies such as JCVI and WHO to inform strategies for vaccination against influenza. At present, there are few national programmes investigating either serological evidence of pathogen exposure, or levels of immunity to infection in the general population. Healthcare strategies are focussed on achieving the levels of vaccine coverage that are predicted to confer sufficient immunity in the community to reduce onward transmission and prevent disease. For example, vaccine responses to measles, mumps and rubella are seldom measured following administration of the MMR vaccine; health boards simply aim to meet targets for vaccine coverage (>95% MMR coverage will prevent the spread of a measles virus with an R0 = 18 in a community).
This project aims to generate data with which healthcare policy can be better informed. The project will develop high-throughput assay systems with which functional immune responses can be measured rapidly and reliably. For example, as an adjunct to monitoring the current contribution of seasonal coronaviruses to acute respiratory infections, the project could assess the current level of immunity to seasonal coronaviruses (NL63, 229E, HKU1 & OC43), and other viral infections in the general population, identifying the demographic factors that influence immunity. For measles, current vaccines (eg M-M-RVaxPro and Priorix) are based on the genotype A Edmonston strain of measles virus. Circulating genotypes such as B3, C2, D8 and H1 might not be neutralised as effectively by responses elicited by current vaccination regimes. Moreover, immunity levels may differ significantly between children, adults, immunosuppressed and elderly individuals. Simple modifications to the number of doses administered, and the timing of doses could boost immunity sufficiently to confer longer-lasting immunity against all circulating genotypes.
This project will provide an opportunity to develop novel techniques with which antiviral immune responses can be measured. These techniques will then be applied to the analyses of sera from representative patient cohorts to assess levels of immunity in the general population.