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Role of NS1 antibodies in the pathogenesis of acute secondary dengue infection.

ABSTRACT: The role of NS1-specific antibodies in the pathogenesis of dengue virus infection is poorly understood. Here we investigate the immunoglobulin responses of patients with dengue fever (DF) and dengue hemorrhagic fever (DHF) to NS1. Antibody responses to recombinant-NS1 are assessed in serum samples throughout illness of patients with acute secondary DENV1 and DENV2 infection by ELISA. NS1 antibody titres are significantly higher in patients with DHF compared to those with DF for both serotypes, during the critical phase of illness. Furthermore, during both acute secondary DENV1 and DENV2 infection, the antibody repertoire of DF and DHF patients is directed towards distinct regions of the NS1 protein. In addition, healthy individuals, with past non-severe dengue infection have a similar antibody repertoire as those with mild acute infection (DF). Therefore, antibodies that target specific NS1 epitopes could predict disease severity and be of potential benefit in aiding vaccine and treatment design.

SUBMITTER: Jayathilaka D

PROVIDER: S-EPMC6286345 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Role of NS1 antibodies in the pathogenesis of acute secondary dengue infection.

Jayathilaka Deshni D Gomes Laksiri L Jeewandara Chandima C Jayarathna Geethal S Bandara GSB Herath Dhanushka D Perera Pathum Asela PA Fernando Samitha S Wijewickrama Ananda A Hardman Clare S CS Ogg Graham S GS Malavige Gathsaurie Neelika GN

Nature communications 20181207 1

The role of NS1-specific antibodies in the pathogenesis of dengue virus infection is poorly understood. Here we investigate the immunoglobulin responses of patients with dengue fever (DF) and dengue hemorrhagic fever (DHF) to NS1. Antibody responses to recombinant-NS1 are assessed in serum samples throughout illness of patients with acute secondary DENV1 and DENV2 infection by ELISA. NS1 antibody titres are significantly higher in patients with DHF compared to those with DF for both serotypes, d ...[more]

PMID: 30531923

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Project description:IntroductionRapid diagnostic tests (RDTs) were evaluated, in this paper, for their utility as a reliable test, using resource-constrained studies. In most studies, NS1 antigen and immunoglobulin M (IgM)-based immunochromatographic tests (ICTs) were considered for acute phase detection. We aimed to evaluate the diagnostic accuracy of NS1, IgM, and NS1/IgM-based ICTs to detect acute dengue virus (DENV) infection in dengue-endemic regions.MethodsStudies were electronically identified using the following databases: MEDLINE, Embase, Cochrane Library, Web of Science, and CINAHL Plus. Keywords including dengue, rapid diagnostic test, immunochromatography, sensitivity, specificity, and diagnosis were applied across databases. In total, 15 studies were included. Quality assessment of the included studies was performed using the QUADAS-2 tool. All statistical analyses were conducted using RevMan, MedCalc, and SPSS software.ResultsThe studies revealed a total of 4135 individuals, originating largely from the Americas and Asia. The prevalence of DENV cases was 53.8%. Pooled sensitivities vs. specificities for NS1 (only), IgM (only) and combined NS1/IgM were 70.97% vs. 94.73%, 40.32% vs. 93.01%, and 78.62% vs. 88.47%, respectively. Diagnostic odds ratio (DOR) of DENV for NS1 ICTs was 43.95 (95% CI: 36.61-52.78), for IgM only ICTs was 8.99 (95% CI: 7.25-11.16), and for NS1/IgM ICTs was 28.22 (95% CI: 24.18-32.95). ELISA ICTs yielded a DOR of 21.36, 95% CI: 17.08-26.741. RT-PCR had a DOR of 40.43, 95% CI: 23.3-71.2. Heterogeneity tests for subgroup analysis by ICT manufacturers for NS1 ICTs revealed an χ2 finding of 158.818 (df = 8), p < 0.001, whereas for IgM ICTs, the χ2 finding was 21.698 (df = 5), p < 0.001.ConclusionNS1-based ICTs had the highest diagnostic accuracy in acute phases of DENV infection. Certain factors influenced the pooled sensitivity, including ICT manufacturers, nature of the infection, reference method (RT-PCR), and serotypes. Prospective studies may examine the best strategy for incorporating ICTs for dengue diagnosis.

Project description:BackgroundDengue virus infection results in a broad spectrum of clinical outcomes, ranging from asymptomatic infection through to severe dengue. Although prior infection with another viral serotype, i.e. secondary dengue, is known to be an important factor influencing disease severity, current methods to determine primary versus secondary immune status during the acute illness do not consider the rapidly evolving immune response, and their accuracy has rarely been evaluated against an independent gold standard.MethodsTwo hundred and ninety-three confirmed dengue patients were classified as experiencing primary, secondary or indeterminate infections using plaque reduction neutralisation tests performed 6 months after resolution of the acute illness. We developed and validated regression models to differentiate primary from secondary dengue on multiple acute illness days, using Panbio Indirect IgG and in-house capture IgG and IgM ELISA measurements performed on over 1000 serial samples obtained during acute illness.ResultsCut-offs derived for the various parameters demonstrated progressive change (positively or negatively) by day of illness. Using these time varying cut-offs it was possible to determine whether an infection was primary or secondary on single specimens, with acceptable performance. The model using Panbio Indirect IgG responses and including an interaction with illness day showed the best performance throughout, although with some decline in performance later in infection. Models based on in-house capture IgG levels, and the IgM/IgG ratio, also performed well, though conversely performance improved later in infection.ConclusionsFor all assays, the best fitting models estimated a different cut-off value for different days of illness, confirming how rapidly the immune response changes during acute dengue. The optimal choice of assay will vary depending on circumstance. Although the Panbio Indirect IgG model performs best early on, the IgM/IgG capture ratio may be preferred later in the illness course.

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Role of NS1 antibodies in the pathogenesis of acute secondary dengue infection.

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Role of NS1 antibodies in the pathogenesis of acute secondary dengue infection.

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