Molecular characterisation of Epstein-Barr virus in endemic Burkitt Lymphoma

Thesis

Epstein–Barr virus (EBV) is a near-universal human pathogen causally linked to multiple malignancies that arise in distinct geographic and clinical contexts. This disparity between widespread infection and restricted cancer incidence represents a central paradox in EBV biology. The current study explored this paradox by integrating comparative viral genomics, mutational signature analysis, tumour transcriptomics, and experimental immunology within a phenotype-aware analytical framework.

Whole-genome analysis, including newly generated data from East African isolates, reaffirmed substantial geographic structuring of EBV genomes, consistent with long-term host–virus coevolution. Comparative analyses identified elevated recombination signals in EBNA1 and LMP1 among Burkitt lymphoma (BL)– associated viruses relative to those from healthy carriers, nominating these loci as potential targets of disease-specific selective pressures. Mutational signature profiling revealed a BL-enriched single-base substitution pattern (SBS_EBV4) characterised by G-rich C>T, T>C, and T>G contexts, with weak similarity to known canonical COSMIC signatures. The biological interpretation remains open and could reflect a composite of host and viral mutational processes, potentially influenced by malaria-associated environmental pressures.

Transcriptomic profiling of BL tumours revealed heterogeneous viral gene expression, including the detection of both latent and lytic transcripts in a subset of cases. However, protein-level validation will be necessary to interpret these findings definitively. 

Guided by genomic and transcriptional insights, selected latent and lytic antigens were incorporated into Chimpanzee-derived Adenovirus Oxford-2 (ChAdOx2) and Modified Vaccinia Ankara (MVA) viral vectors for preclinical evaluation. Heterologous prime–boost immunisation elicited robust CD4⁺ and CD8⁺ T-cell responses, with multi-antigen constructs inducing broader and more polyfunctional responses than single-compartment formulations.

Collectively, this work provides not only a comprehensive description of the EBV genome in BL, but also insights into the interplay between EBV genome variation and immunogenicity. It reinforces geography-driven EBV diversity, identifies a candidate BL-enriched mutational signature, and highlights heterogeneous viral expression as a potential therapeutic vulnerability. These findings support the development of multi-antigen therapeutic vaccines targeting both latent and lytic compartments and provide a framework for rational intervention in EBVassociated malignancies.

Authors: Draguma, IL

• DOI: 10.5287/ora-zbgm4j4qq
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: t-cell immunity; mutational signatures; host-virus coevolution; Epstein-Barr virus (EBV); EBV-associated malignancies; Burkitt lymphoma; therapeutic vaccines; transcriptomics; viral genomics
• Subjects: Oncology; Vaccine Research; Genomics; Molecular virology; Immunology