This PhD opportunity is being offered as part of the LSTM and Lancaster University Doctoral Training Partnership. Find out more about the studentships and how to apply.
| Abstract | Crimean–Congo haemorrhagic fever virus (CCHFV) is a WHO-listed priority pathogen with expanding geographic range, severe clinical outcomes, and no licensed vaccines or specific antivirals. Survival correlates with rapid, robust humoral immunity, yet the protective features of human antibodies, across isotypes, IgG subclasses, Fc-effector functions, and B-cell memory, remain poorly defined. This studentship will dissect the quality, function, and durability of antibody responses to CCHFV in human infection, generating actionable evidence for vaccine design, therapeutic monoclonals, and improved serological diagnostics. Working within Liverpool School of Tropical Medicine’s virology and immunology platforms and established international collaborations, the student will: (i) quantify IgM, IgA, and IgG1-4 responses against the most diagnostically and immunologically relevant antigens (nucleoprotein [NP], glycoproteins Gn/Gc, and the secreted glycoprotein GP38) using multiplex bead assays and orthogonal ELISAs; (ii) define Fc-mediated functions including antibody-dependent cellular cytotoxicity and phagocytosis (ADCC/ADCP), complement deposition, and TRIM21-dependent intracellular restriction, linking these to antigen specificity and IgG subclass distribution; (iii) profile antigen-specific memory B cells by high-parameter flow cytometry and single-cell sequencing to resolve frequency, phenotype, clonal architecture, and somatic hypermutation; and (iv) establish and validate a BSL-2 pseudovirus platform for CCHFV glycoproteins to measure neutralisation and enable Fc-effector readouts on infected target cells, complementing work with bio-banked clinical samples. The project leverages clinically characterised serum from acute cohorts, with further sera and PBMC collections from acute, convalescent, and long-term survivor cohorts available as the project progresses. Integrated statistical modelling will relate antibody quality (isotype/subclass composition, Fc-function potency), antigen targeting (NP vs Gn/Gc vs GP38), and memory B-cell features to clinical parameters (disease severity, time since infection, putative viral clade exposure). The central hypothesis is that protection in human CCHFV infection is determined less by neutralisation alone and more by the coordinated quality of the antibody response, particularly Fc-effector mechanisms and sustained B-cell memory, shaped by infection outcome. Training spans advanced serology, multiplex immunoassays, functional Fc assays, viral pseudotyping, high-dimensional cytometry, single-cell immunogenomics, and reproducible data science. Deliverables include: (1) a benchmarked atlas of human anti-CCHFV antibody and memory B-cell responses; (2) a validated CCHFV pseudovirus toolkit for the community; (3) antigen/isotype combinations that improve diagnostic performance; and (4) mechanistic correlates to guide vaccine antigen selection and therapeutic antibody engineering (e.g., subclass choice, Fc optimisation, GP38/NP inclusion). The work directly addresses global health needs by enabling rational countermeasure development for a high-consequence, emerging tick-borne virus, while providing the candidate with a uniquely translational skillset suited to academia, public health agencies, and biotech. |
| Where does this project lie in the translational pathway? | T1 - Basic Research |
| Methodological Aspects | This project applies a multidisciplinary methodological framework combining advanced serology, immunology, virology, and quantitative data analysis. Serological profiling. Multiplex bead-based assays (e.g., Luminex/Magpix) and optimised ELISAs will be used to quantify IgM, IgA, and IgG subclasses (1–4) against CCHFV nucleoprotein, glycoproteins (Gn/Gc), and GP38. These assays allow high-throughput, quantitative determination of antibody concentrations and binding breadth across large sample sets. An optimised ELISA will be developed to diagnose acute patients at the time of presentation by triaging different detection targets (IgM + antigen types). Fc effector function assays. Functional assays will measure antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement deposition, and TRIM21-mediated intracellular restriction. All assays will yield quantitative outputs (e.g., reporter gene activity, flow cytometry readouts, complement fixation indices) that can be standardised across cohorts and analysed in dose–response formats. Pseudovirus neutralisation platform. A vesicular stomatitis virus (VSV)-based pseudovirus bearing CCHFV glycoproteins will be engineered to provide a safe BSL-2 surrogate for neutralisation studies. This system generates reproducible, quantitative readouts (luciferase/GFP) of viral entry, enabling detailed neutralisation curve fitting, IC50/IC90 estimation, and cross-clade comparisons. B-cell profiling. Antigen-specific B cells will be identified with fluorescent probes, followed by single-cell sorting and sequencing. This generates quantitative data on repertoire diversity, clonal expansion, and somatic hypermutation, enabling statistical modelling of B-cell dynamics across time and severity strata. Quantitative analysis and modelling. Data will be analysed using mixed-effects longitudinal models, multivariate clustering, and machine learning approaches to identify immune correlates of protection. The student will be trained in reproducible computational workflows (e.g., R/Python, version-controlled pipelines). Together, this integrated methodological approach ensures rigorous quantification of antibody quality, function, and persistence, linking immune mechanisms to clinical outcome and providing translational benchmarks for vaccines and therapeutics. |
| Expected Outputs | The project is designed to deliver a coherent portfolio of publishable outputs and translational assets. We anticipate at least one to two first-author research papers from the student: a comprehensive analysis of antigen-specific isotypes/subclasses and Fc-effector functions in human CCHFV infection, and a correlates-of-immunity study linking these quantitative immune readouts to clinical phenotype and outcome. In parallel, we expect a methods/technical manuscript detailing the validated BSL-2 CCHFV pseudovirus platform (constructs, SOPs, assay performance) and, if supported by the data, a short report on improved diagnostic antigen/isotype combinations. Additional co-authorships are likely through collaborative B-cell repertoire analyses and cohort extensions with partner laboratories. Dissemination will include abstracts and oral/poster presentations at leading national and international meetings (e.g. BSI, Microbiology Society, ASTMH, ECCMID, Keystone), with targeted engagement at translational fora focused on vaccine and antibody development. To maximise community uptake, the student will release curated datasets (multiplex serology, Fc-assays, neutralisation, single-cell repertoires) with reproducible analysis code, alongside open SOPs and a distributable pseudovirus toolkit (e.g. plasmids via repositories where feasible). These resources will position LSTM as a reference site for CCHFV immunoprofiling and preclinical evaluation. The body of work will directly underpin future grant applications to MRC/UKRI, NIHR, Wellcome, CEPI and others, strengthening bids in vaccine immunology, therapeutic monoclonals and diagnostics. The student will emerge with a strong quantitative and translational skillset, evidenced by publications, software/SOP releases and invited talks. In terms of impact, the project will generate actionable correlates of protection to guide vaccine antigen selection and Fc-engineering, provide a safe and scalable neutralisation platform to triage candidate antibodies, and inform diagnostic design for improved case detection. Where appropriate, assay innovations or antibody-engineering insights will be assessed with LSTM’s technology transfer office for intellectual property protection and partnering with industry and public-health stakeholders. |
| Training Opportunities | The student will benefit from a rich training environment that spans laboratory science, quantitative analysis, and professional development. Within LSTM, they will be trained in advanced serological techniques (multiplex bead assays, ELISA optimisation), Fc-effector function assays (ADCC, ADCP, complement deposition, TRIM21-mediated restriction), and pseudovirus engineering and neutralisation platforms. They will also gain expertise in high-dimensional flow cytometry, antigen-specific B cell sorting, and single-cell sequencing, with subsequent bioinformatic analysis of repertoire data. Alongside wet-lab skills, the student will be supported to develop strong quantitative and computational competencies, including statistical modelling of longitudinal immune responses, multivariate clustering, and reproducible coding practices in R/Python. LSTM’s postgraduate training programmes will provide formal modules in statistics, bioinformatics, research integrity, and project management, supplemented by opportunities to attend external workshops on advanced data science and immunological techniques. The studentship will also offer professional development through presentation and writing skills workshops, support for abstract and manuscript preparation, and mentoring for grant applications. There will be opportunities to present at national and international conferences, building communication and networking skills. Through the anticipated SME diagnostic placement, the student will gain experience of translational workflows, regulatory considerations, and product development in an industry setting. Overall, the training programme is designed to produce a well-rounded researcher with deep technical expertise, strong quantitative skills, and experience working across academic, clinical, and industrial environments, which aligning closely with MRC’s priority to equip future leaders with interdisciplinary and translational research capacity. |
| Skills Required | We’re looking for a motivated trainee with a solid grounding in experimental biosciences and an aptitude for quantitative analysis. The student should hold (or be completing) a good honours degree or MSc in immunology, virology, molecular biology, biomedical sciences, or a closely related discipline, with some hands-on experience of core wet-lab methods (e.g., ELISA or comparable immunoassays, sterile cell culture, basic molecular cloning or protein/antigen handling). They should be comfortable analysing data in Excel/R/Python, interpreting dose–response/standard curves, and applying basic statistics. Because the project spans functional immunology and viral pseudotyping, prior exposure to any of the following would be advantageous: flow cytometry, primary or engineered cell lines, luciferase/GFP reporter assays, antibody characterisation (isotypes/subclasses), and/or Fc effector assays. Familiarity with BSL2 working practices and good laboratory record-keeping is essential. Beyond technical skills, we value curiosity, careful experimental design, and the ability to troubleshoot. The student should demonstrate good written and verbal communication (e.g., lab reports, a thesis, or a conference poster), strong organisational skills, and the ability to work both independently and as part of a multidisciplinary team that includes clinicians, data scientists, and industry partners. An interest in translational research, linking mechanistic findings to diagnostics, vaccines, or therapeutics, will be important for success in this programme. |
| Subject Areas | NTD |
| Key Publications associated with this project |
https://pubmed.ncbi.nlm.nih.gov/40791526/ |