Reconstruction of antibody dynamics and infection histories to evaluate dengue risk

Abstract

As with many pathogens, most dengue infections are subclinical and therefore unobserved1. Coupled with limited understanding of the dynamical behavior of potential serological markers of infection, this observational problem has wide-ranging implications, including hampering our understanding of individual- and population-level correlates of infection and disease risk and how they change over time, assay interpretation and cohort design. We develop a framework that simultaneously characterizes antibody dynamics and identifies subclinical infections via Bayesian augmentation from detailed cohort data (3,451 individuals with blood draws every 91 days, 143,548 hemagglutination inhibition assay titer measurements)2,3. We identify 1,149 infections (95% CI: 1,135–1,163) that were not detected by active surveillance and estimate that 65% of infections are subclinical. Post infection, individuals develop a stable setpoint antibody load after 1y that places them within or outside a risk window. Individuals with pre-existing titers of ≤1:40 develop hemorrhagic fever 7.4 (95% CI: 2.5–8.2) times as often as naïve individuals compared to 0.0 times for individuals with titers >1:40 (95% CI: 0.0–1.3). PRNT titers ≤1:100 were similarly associated with severe disease. Across the population, variability in the force of infection results in large-scale temporal changes in infection and disease risk that correlate poorly with age.

A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates

“…Vaccines for ZIKV are under development, but the path to approval may be exceedingly difficult because of antibody cross-reactivity with other flaviviruses and the possibility of disease enhancement (Bardina et al, 2017; George et al, 2017; Halstead, 2018; Harrison, 2016; Heinz and Stiasny, 2017; Katzelnick et al, 2017; Salje et al, 2018; Stettler et al, 2016). Passive administration of monoclonal antibodies represents an alternative approach to vaccines because human monoclonal antibodies can effectively neutralize the virus in vitro and protect against ZIKV infection in mice (Fernandez et al, 2017; Robbiani et al, 2017; Sapparapu et al, 2016; Stettler et al, 2016; Swanstrom et al, 2016; Yu et al, 2017).…”

Functional characterization and lineage analysis of broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

“…In vitro, antibodies can mediate ADE of infection in cells expressing Fc gamma receptor (FcγR) at sub-neutralizing concentrations (Pierson et al, 2007). Recent studies in humans have also demonstrated that the risk of severe dengue disease following secondary infection is greatest within a range of intermediate titers of pre-existing DENV-specific antibodies, while higher titers are protective against symptomatic infection (Katzelnick et al, 2017;Salje et al, 2018). Thus, eliciting potently neutralizing antibodies is desirable to limit the concentration range within which ADE can occur.…”

“…Approximately 20% of DENV-infected individuals develop a mild febrile illness, of which 5% to 20% progress to potentially fatal severe disease, characterized by bleeding, plasma leakage, shock, and organ failure (Guzman & Harris, 2015;Khursheed et al, 2013;Thein, Leo, Lee, Sun, & Lye, 2011). Epidemiological studies have shown that pre-existing antibodies from a primary DENV infection are a risk factor for severe disease following subsequent infection with a heterologous DENV serotype (Katzelnick et al, 2017;Salje et al, 2018;Sangkawibha et al, 1984). This is partly attributed to the prevalence of cross-reactive antibodies from the initial infection that can bind, but not neutralize the secondary heterologous virus.…”

“…Instead, these nonneutralizing antibodies have the potential to facilitate viral uptake into Fc gamma receptorexpressing target cells in a process known as antibody-dependent enhancement (ADE) (Guzman & Harris, 2015;Halstead, 2014). Recent studies of clinical cohorts demonstrated that the risk of severe disease following secondary infection is greatest when pre-existing titers of cross-reactive antibodies fall within a narrow, intermediate range (Katzelnick et al, 2017;Salje et al, 2018). To limit the potential for ADE, an effective vaccine must therefore elicit durable and potent neutralizing antibodies of high titer against DENV1-4 simultaneously.…”

Dengue antigenic relationships predict evolutionary dynamics

“…Subsequent heterotypic secondary infection induces broad cross-protection, and symptomatic tertiary and quaternary cases are rare (Gibbons et al, 2007;Olkowski et al, 2013). However, a small subset of secondary infections are enhanced by non-neutralizing, cross-reactive antibodies, resulting in severe disease via antibody dependent enhancement (ADE) (Halstead, 1979;Katzelnick et al, 2017;Salje et al, 2018;Sangkawibha et al, 1984). Approximately 1-3% of cases progress to severe dengue hemorrhagic fever, causing ∼9,000 deaths each year (Bhatt et al, 2013;Stanaway et al, 2016) and relative risk of severe dengue from secondary heterotypic infection relative to primary infection is estimated to be ∼24 (Mizumoto et al, 2014).…”