Age in dengue antibody response and risk after primary natural infection

PROJECT SUMMARY/ABSTRACT Dengue is the most prevalent vector-borne virus plaguing our world. In 2010, there were an estimated 390 million infections worldwide, 25% of which were symptomatic. The pathogenesis of dengue is complex because of the existence of four serotypes. Infection with one serotype protects the individual against future infections of the same serotype, but subsequent infection with a different serotype increases the risk of symptomatic disease, which includes potentially life-threatening dengue hemorrhagic fever and dengue shock syndrome. In endemic countries, children are most at risk of infection and disease. An immunizing vaccine is crucial for population protection but large trials of live-attenuated vaccine in children show that younger age is associated with future infection and severe disease independent of other variables. Vaccination is a correlate to natural infection, where in previously unexposed individuals, antibodies that cross-react to many serotypes protect against multiple dengue serotypes but are short-lived. Long-lasting protection most likely comes from a small fraction of durable antibodies that are specific to one dengue serotype. What determines the production of these type-specific antibodies and the viral epitopes that they target is not well understood. Immunologic studies incorporating longitudinal observational data are needed to understand protective antibody responses after primary natural dengue infection in children. This study will address relationships between age, antibody quality, and dengue infection or disease. The proposed research will utilize previously collected data and sera from an ongoing longitudinal observational study, the Pediatric Dengue Cohort Study in Managua, Nicaragua. Using state-of-the-art recombinant viral techniques and epidemiologic methods in this one-of-a-kind dataset, the proposal aims to 1) compare how epitopes targeted by antibodies vary in younger and older children with known dengue serotype 2 infection and 2) assess the risk of dengue reinfection in younger and older children with prior natural dengue infection. The results will establish the variation in antibody specificity and avidity in younger and older children and inform future policy decisions regarding vaccination against dengue virus in this population and possibly other Latin American countries. Through the completion of these research aims the trainee will gain a unique set of skills in advanced epidemiologic methods, virology, and immunology research, including analysis and interpretation of complex immunologic and longitudinal data. Expert mentors in virology, immunology, and epidemiology will support the trainee's successful completion of the proposed research, associated training plan, and MD/PhD degree at the University of North Carolina at Chapel Hill. This F30 fellowship will critically aid the applicant's development as a future interdisciplinary physician-scientist practicing at the intersection of virology, immunology, and infectious disease epidemiology.