Linking Antigenic Diversity to Dengue Disease Risk

Abstract

Background & aims of study.

Antigenically variable pathogens continuously change in response to immune driven selection. Variation in epitopes caused by shifting protein structure results in poorly targeted or sub-neutralizing immunity typically associated with weakened protection, but in the case of dengue virus, sub-neutralizing antibody titers are linked to severe disease. The role of the antigenic relationship between the viruses inducing initial immune responses and viruses involved in subsequent exposures in determining dengue disease risk remains unknown. We aim to use long-term virus antigenic characterization data and hospital-based case surveillance data to infer the role of antigenic diversity in driving dengue disease risk.

Methods & results

We combined detailed genetic (N=2,587 viruses) and antigenic (N=348 viruses) characterization of dengue viruses from Bangkok Thailand over a 21-year period (1994-2014), with long-term serotype and age-specific case data from a large children’s hospital in the city (N=15,281 cases). We developed a mathematical framework that integrates over birth-cohorts lifetime exposures to the virus. We reconstructed the changing immune profile of the human population and find that the risk of severe dengue from a secondary infection depends on both the specific serotypes and the antigenic distance between viruses that are responsible for an individual’s primary and secondary infections, with risk maximized at intermediate antigenic distances.

Implications

Our findings challenge the prevailing paradigm that the introduction of a new serotype is responsible for shifts in disease risk in a population. Instead, our findings suggest a more nuanced picture where the specific impact of a new virus on patterns of disease will depend on both the characteristics of that virus and the characteristics of the population immunity derived from previous circulations of antigenically different viruses. These findings show that immunity from initial infections is critical to subsequent disease risk, consistent with immune imprinting, with implications for vaccine development and use.

Note: This conference abstract was presented at the 9th International Conference on Infectious Disease Dynamics organized by the journal Epidemics. This abstract has not been screened by SSRN for potential for public harm and should not be used to inform any clinical decision making. No competing interests or funding statements have been declared.