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  • Review Article
  • Published:

Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms

Nature Reviews Immunology volume 11, pages 532–543 (2011)Cite this article

Subjects

Key Points

  • Dengue is an emerging infection of tropical and subtropical regions caused by a group of four serotypes of dengue virus that are transmitted to humans by Aedes spp. mosquitoes. Infection with one dengue virus serotype provides long-lasting protective immunity to that serotype, but only short-term immunity (lasting less than 6 months) to other serotypes. Sequential infection with different dengue virus serotypes is common in dengue-endemic countries.

  • A small percentage of individuals infected with dengue virus develop a plasma leakage syndrome that can be life-threatening. This syndrome, termed dengue haemorrhagic fever, is associated with high circulating levels of cytokines (a 'cytokine storm') and immune activation. Beyond the first year of life, dengue haemorrhagic fever is significantly more common during an individual's second dengue virus infection than during the primary infection.

  • Antibody responses to dengue virus are principally directed towards two glycoproteins on the surface of the virion envelope, the precursor membrane (pre-M) and envelope (E) proteins, and a secreted viral glycoprotein, non-structural protein 1 (NS1). Depending on the specific epitope targeted and the antibody avidity and concentration, dengue virus-specific antibodies can inhibit viral infection (neutralization) or enhance the uptake of virions into cells bearing immunoglobulin receptors (a process referred to as antibody-dependent enhancement of infection).

  • T cells recognize epitopes that are distributed across the dengue virus genome, and many CD4+ and CD8+ T cells recognize more than one dengue virus serotype. Variant epitope sequences between dengue virus serotypes induce an altered profile of cytokine production and target cell lysis (the altered peptide ligand effect).

  • During a second dengue virus infection, the presence of pre-existing memory B and T cells (which were induced by the prior infection) alters the kinetics and specificity of the immune response, and this is referred to as original antigenic sin.

  • Clinical studies have shown associations between specific immune responses and disease severity. However, no single measure has shown a high correlation with clinical outcome. Further studies are needed to establish reliable correlates of protective or pathological immune responses.

  • Dengue virus vaccines currently in development contain different components of the dengue virus genome. Immune responses to the different vaccines may not be equivalent; incorporation of immunological studies into clinical trials is desirable to establish the necessary knowledge base to guide vaccine development and introduction.

Abstract

Dengue is a mosquito-borne viral disease of expanding geographical range and incidence. The existence of four viral serotypes and the association of prior dengue virus infection with an increased risk for more severe disease have presented significant obstacles to vaccine development. An increased understanding of the adaptive immune response to natural dengue virus infection and candidate dengue vaccines has helped to define the specific antibody and T cell responses that are associated with either protective or pathological immunity during dengue infection. Further characterization of immunological correlates of disease outcome and the validation of these findings in vaccine trials will be invaluable for developing effective dengue vaccines.

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Figure 1: Antibody responses to dengue virus protein targets and antibody functions.
Figure 2: T cell responses to dengue virus protein targets and T cell effector functions.
Figure 3: The antigenic make-up of various dengue vaccine approaches in development.
Figure 4: A balance between favourable and unfavourable factors determines the clinical outcome of dengue virus infection.

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  1. Institute for Immunology and Informatics and Department of Cell and Molecular Biology, University of Rhode Island, Providence, 02903, Rhode Island, USA

    Alan L. Rothman

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Alan L. Rothman has received research funding from Sanofi Pasteur to perform immunology assays on blood samples from participants in clinical trials of dengue vaccines. Sanofi Pasteur are also collaborating with his laboratory on a research project funded by the US National Institutes of Health.

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Glossary

Furin

An endoprotease that is important for cleaving and activating precursor proteins, such as transforming growth factor-β and von Willebrand factor. Viruses, such as HIV, may exploit the activity of host cell furin to promote viral assembly.

Altered peptide ligands

(APLs). Peptide variants that are derived from the original antigenic peptide. They commonly have amino acid substitutions at residues that contact the T cell receptor (TCR). TCR engagement by APLs usually leads to partial or incomplete T cell activation. Antagonistic APLs can specifically antagonize and inhibit T cell activation induced by the wild-type antigenic peptide.

Anamnestic response

The enhanced immune response that occurs against an antigen as a result of previous host exposure to a related antigen.

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Rothman, A. Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms. Nat Rev Immunol 11, 532–543 (2011). https://doi.org/10.1038/nri3014

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