Understanding the mechanisms behind variable neutralisation of dengue viruses

Antibody response to the millions of dengue virus infections each year stimulates mixtures of antibodies, some consistently protective while others enhance disease at low levels. Neutralisation titres measure collective effects of these mixtures in stopping a specific virus from infecting cells. This neglects the stark antigenic difference in naturally circulating viruses and the evolving nature of antibodies over time. Previously, I identified viral substitutions linked to variations in neutralisation, whose effects varied even across closely related strains. This project will decipher mechanisms behind these inconsistencies. First, I will develop models to decompose effects of variations in exposed epitopes across viruses, targets of the polyclonal sera, and epitope-antibody interactions. Next, I will use computational models to identify parts of the molecular cascade that influences epitope surfacing frequency. Finally, I will develop a model to characterise how specificity of the sera evolve over time and evaluate how this affects neutralisation of circulating viruses. Understanding the constituents of neutralisation, especially against viruses circulating in nature, will enable development of more efficient and informative strategies to study this important immunological function at scale. The developed methodology can be applied to other immune measurements and pathogens to further our understanding of pathogen immunology.