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  • Review Article
  • Published:

New insights into the immunopathology and control of dengue virus infection

Nature Reviews Immunology volume 15, pages 745–759 (2015)Cite this article

Subjects

Key Points

  • Dengue virus has four distinct serotypes, and infection with one serotype results in the development of homotypic immunity. Subsequent infection with a different serotype is associated with an increased risk of developing severe disease, leading to the suggestion that severe disease is triggered by immunopathology.

  • Both T cell- and B cell-mediated adaptive immune responses are thought to be involved in the immunopathology of severe dengue. Antibody-dependent enhancement and a skewed T cell response through original antigenic sin may have a role in disease pathogenesis in secondary infections.

  • There are several vaccine candidates in development; the most advanced in clinical trials is the Sanofi Pasteur vaccine CYD-TDV. A recent 3 year follow-up study demonstrated an overall vaccine efficacy of 65%, with lower efficacies and higher hospitalizations in children younger than 9 years old.

  • A large number of dengue virus-specific monoclonal antibodies have recently been described, and antibodies targeting envelope (E) protein domain III are among the most potently neutralizing but are often serotype-specific. Recently, however, a broadly neutralizing antibody directed against the E protein dimer epitope (EDE) has been discovered.

  • Antibodies directed against precursor membrane (prM) protein can facilitate Fc receptor-mediated uptake of immature viral particles, which, although non-infectious in the absence of antibody, can undergo prM cleavage following endocytosis in the host cell, rendering them infectious.

  • Future vaccines need to target potently neutralizing epitopes, such as those found on E protein domain III, or the quaternary epitopes, such as EDE, and minimize poorly neutralizing and potentially disease-enhancing prM or FLE antibodies.

Abstract

Dengue virus poses a major threat to global public health: two-thirds of the world's population is now at risk from infection by this mosquito-borne virus. Dengue virus causes a range of diseases with a small proportion of infected patients developing severe plasma leakage that leads to dengue shock syndrome, organ impairment and bleeding. Infection with one of the four viral serotypes results in the development of homotypic immunity to that serotype. However, subsequent infection with a different serotype is associated with an increased risk of developing severe disease, which has led to the suggestion that severe disease is triggered by immunopathology. This Review outlines recent advances in the understanding of immunopathology, vaccine development and human monoclonal antibodies produced against dengue virus.

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Figure 1: The life cycle of dengue virus.
Figure 2: Structure of the dengue viral particle.
Figure 3: Adaptive immune responses to dengue virus infection.
Figure 4: Dengue vaccines.
Figure 5: Quaternary epitopes.

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Acknowledgements

This work was supported by the Wellcome Trust, the National Institute for Health Research (NIHR) Biomedical Research Centre funding scheme, and the European Commission Seventh Framework Programme [FP7/2007-2013] for the DENFREE project under the grant agreement n°282 378. G.S. is a Wellcome Trust senior investigator.

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Authors and Affiliations

  1. Division of Immunology and Inflammation, Department of Medicine, Hammersmith campus, Imperial College London, London, W12 0NN, UK

    Gavin Screaton, Juthathip Mongkolsapaya, Sophie Yacoub & Catherine Roberts

  2. Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand

    Juthathip Mongkolsapaya

  3. Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam

    Sophie Yacoub

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Correspondence to Gavin Screaton.

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Glossary

Aedes mosquito vector

The genus of mosquito by which dengue virus is transmitted; the primary vector being Aedes aegypti followed by Aedes albopictus.

Cytokine storm

An excessive production of pro-inflammatory cytokines that occurs during acute dengue infection and that has been proposed to drive the vascular leak.

Tetramer staining

A technique used to track antigen-specific T cells by flow cytometry. Biotinylated monomeric MHC molecules are folded in vitro together with a specific peptide in the binding groove. These peptide–MHC complexes are tetramerized using a fluorescently labelled streptavidin molecule. The tetramers bind T cells that express T cell receptors specific for the cognate peptide–MHC complex.

Original antigenic sin

An immune response to serial exposure to two pathogens of similar yet distinct sequences. Upon a second infection, rather than making an entirely new immune response to antigens of the secondary infecting pathogen, cross-reactive and potentially suboptimal memory cells that were generated during the first infection are expanded. Original antigenic sin was first described for antibody responses but has also been demonstrated in T cell responses.

Antibody-dependent enhancement

Antibodies that may not be of sufficient avidity or concentration to neutralize a virus instead opsonize it and promote viral uptake into Fc receptor (FcR)-bearing cells, leading to enhanced viral replication.

Heterologous prime–boost strategies

Vaccination strategies in which different immunogens are given sequentially to boost and focus an immune response to a given antigen. This is achieved by utilizing a variety of platforms — viral, DNA or protein — with the same antigen being delivered sequentially.

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Screaton, G., Mongkolsapaya, J., Yacoub, S. et al. New insights into the immunopathology and control of dengue virus infection. Nat Rev Immunol 15, 745–759 (2015). https://doi.org/10.1038/nri3916

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