Antibodies Produced in Response to a Live-Attenuated Dengue Vaccine Are Functional in Activating the Complement System.

BACKGROUND: Antibody-driven complement system (CS) activation has been associated with protection against symptomatic dengue virus (DENV) infection. Aggregation, opsonization, lysis, and phagocytosis are mechanisms triggered by antibody-antigen immunocomplexes following fixation of the component 1q (C1q) and activation of the classical pathway. As a result, DENV neutralization and clearance are facilitated, whereas antibody-dependent enhancement of infection is inhibited. We investigated the ability of antibodies produced in response to Takeda's dengue vaccine candidate, TAK-003, to fix C1q and activate CS. METHODS: Serum samples were collected from seronegative and seropositive participants in a phase 2 clinical trial (DEN-203), pre- and postvaccination. Samples were evaluated for the presence of complement-fixing antibodies (CFAs) against DENV using a Luminex multiplex-based immunoassay. RESULTS: TAK-003 elicited production of CFAs against all 4 DENV serotypes, which persisted for 1 year postvaccination, irrespective of baseline serostatus. CFA levels were correlated with neutralizing antibody titers and virus-binding total IgG and IgG1 concentrations. Furthermore, efficiency of CFA fixation was greater in samples with higher polyclonal IgG avidity. CONCLUSIONS: These results indicate that antibodies produced after TAK-003 vaccination are functional in both activating CS and neutralizing virus infection by all DENV serotypes, which may contribute to efficacy of TAK-003. CLINICAL TRIALS REGISTRATION: NCT01511250.

Development and Characterization of a Multiplex Assay to Quantify Complement-Fixing Antibodies against Dengue Virus.

Antibodies capable of activating the complement system (CS) when bound with antigen are referred to as "complement-fixing antibodies" and are involved in protection against Flaviviruses. A complement-fixing antibody test has been used in the past to measure the ability of dengue virus (DENV)-specific serum antibodies to activate the CS. As originally developed, the test is time-consuming, cumbersome, and has limited sensitivity for DENV diagnosis. Here, we developed and characterized a novel multiplex anti-DENV complement-fixing assay based on the Luminex platform to quantitate serum antibodies against all four serotypes (DENV1-4) that activate the CS based on their ability to fix the complement component 1q (C1q). The assay demonstrated good reproducibility and showed equivalent performance to a DENV microneutralization assay that has been used to determine DENV serostatus. In non-human primates, antibodies produced in response to primary DENV1-4 infection induced C1q fixation on homologous and heterologous serotypes. Inter-serotype cross-reactivity was associated with homology of the envelope protein. Interestingly, the antibodies produced following vaccination against Zika virus fixed C1q on DENV. The anti-DENV complement fixing antibody assay represents an alternative approach to determine the quality of functional antibodies produced following DENV natural infection or vaccination and a biomarker for dengue serostatus, while providing insights about immunological cross-reactivity among different Flaviviruses.

Interferon epsilon and preterm birth subtypes; a new piece of the type I interferon puzzle during pregnancy?

PROBLEM: Interferon epsilon (IFNε) is a unique type I IFN that is expressed in response to sex steroids. Studies suggest that type I IFNs regulate inflammation-induced preterm birth (PTB), but no study has examined the role of IFNε in human pregnancy. METHOD OF STUDY: We used stored vaginal swabs between 8 and 26 weeks of gestation from the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) biobank and measured IFNε by enzyme-linked immunosorbent assay (ELISA). A total of 29 women with spontaneous preterm births, 34 women with medically indicated preterm births, and 134 women with term births were included. Secondary outcomes included a preterm birth with chorioamnionitis and preeclampsia with a preterm birth. Logistic regression calculated odds ratios (OR) and 95% confidence intervals (CI) adjusting for maternal age, race, body mass index, prior pregnancy complications, lower genital tract infections, chronic health conditions, and gestational age at blood draw. RESULTS AND CONCLUSIONS: There was no significant association between IFNε and spontaneous preterm birth (ORadj 1.0, 0.8-1.3) or chorioamnionitis (ORadj 1.6, 0.7-3.5). A trend toward increased odds of medically indicated preterm birth (ORadj . 1.3, 1.0-1.8) was observed. This was likely due to elevated IFNε among women with preterm preeclampsia (ORadj . 2.0, 95% CI 1.3-3.2). While exploratory, our novel findings suggest that larger longitudinal studies of IFNε across human pregnancy may be warranted.