Leah Katzelnick, PhD

GHES U.S. Fellow 2018-2019

FELLOWSHIP SITE: Centro Nacional de Diagnóstico y Referencia,
National Virology Laboratory, Managua, Nicaragua
U.S. INSTITUTION: University of california, berkeley

Project Title: Dynamics, determinants, and implications of anti-dengue virus antibody decay following primary and secondary dengue infection in the Pediatric Dengue Cohort Study in Managua, Nicaragua

Dengue viruses 1-4 (DENV1-4) are mosquito-borne flaviviruses that are a major cause of disease in Nicaragua and globally. Primary DENV infection generally induces long-lived, protective antibodies to the infecting virus and lower quality cross-reactive antibodies to other DENV viruses.  These cross-reactive antibodies initially seem to be protective against disease, but more than two years after primary DENV infection children are at elevated risk of severe dengue disease. It is hypothesized that this change in risk of severe dengue is due to the waning of cross-reactive antibodies below protective levels. At low levels, anti-DENV antibodies can induce 'antibody-dependent enhancement' by facilitating DENV infection of Fcγ receptor-bearing cells, resulting in increased viremia, immune activation, and severe dengue disease. In contrast, secondary DENV infection generally induces long-lived, mostly protective cross-reactive antibodies. A major question is: "how quickly do antibodies wane from protective to enhancing levels?" In a preliminary analysis of the Nicaraguan Pediatric Dengue Cohort Study (PDCS), we observed an antibody half-life of ~3 years, but surprisingly, subset analyses revealed that after primary DENV infection, antibody levels stabilized to a 'set point' within about half a year and were maintained at the set-point for many years, whereas after secondary DENV infection, antibody levels decayed for longer. This study will measure the dynamics and determinants of anti-DENV binding antibodies in the interval between DENV infections and explore the implications of these findings on paradigms of dengue disease risk. We will study healthy annual serum samples and acute- and convalescent-phase illness samples (n=59,096) from children in the PDCS (n=7669).  This project aims to: 1) estimate the dynamics of anti-DENV antibody decay following primary and secondary DENV infection, 2) identify determinants of antibody level and decay such as socio-economic status, environment, co-morbidities, and other individual-level effects, and 3) explore spatiotemporal factors that might explain why it take two years for individuals to become at risk for severe dengue disease. This study has potential implications for measuring vaccine efficacy in clinical trials and for building accurate models of DENV transmission.