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

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;