Abstract
With 2.5 billion people at risk, dengue is a major emerging disease threat and an escalating public health problem worldwide. Dengue virus causes disease ranging from a self-limiting febrile illness (dengue fever) to the potentially fatal dengue hemorrhagic fever/dengue shock syndrome. Severe dengue disease is associated with sub-protective levels of antibody, which exacerbate disease upon re-infection. A dengue vaccine should generate protective immunity without increasing severity of disease. To date, the determinants of vaccine-mediated protection against dengue remain unclear, and additional correlates of protection are urgently needed. Here, mice were immunized with viral replicon particles expressing the dengue envelope protein ectodomain to assess the relative contribution of humoral versus cellular immunity to protection. Vaccination with viral replicon particles provided robust protection against dengue challenge. Vaccine-induced humoral responses had the potential to either protect from or exacerbate dengue disease upon challenge, whereas cellular immune responses were beneficial. This study explores the immunological basis of protection induced by a dengue vaccine and suggests that a safe and efficient vaccine against dengue should trigger both arms of the immune system.
Highlights
The four serotypes of dengue virus (DENV1-4) are mosquitoborne and cause a spectrum of diseases ranging from a self-limiting flu-like illness to the potentially lethal dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) [1]
The disease caused by dengue virus ranges from mild to lethal
An efficient vaccine is urgently needed to slow down the progression of dengue disease, but little is known about the way the immune system protects the body against dengue reinfection
Summary
The four serotypes of dengue virus (DENV1-4) are mosquitoborne and cause a spectrum of diseases ranging from a self-limiting flu-like illness (dengue fever, DF) to the potentially lethal dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) [1]. The more severe disease resulting from DENV infection, DHF/ DSS, usually occurs in individuals who have pre-existing denguereactive antibodies (Abs), acquired either from a previous infection with a heterologous DENV serotype or by passive transfer from an immune mother in the case of infants [5] Based on these epidemiological observations, Halstead and colleagues hypothesized that sub-protective levels of DENV-specific Abs may amplify viral infection and exacerbate disease, a phenomenon termed antibody-dependent enhancement of infection (ADE) [6,7]. We and another group have recently confirmed this hypothesis by demonstrating in mice that a sub-protective amount of anti-DENV Abs can turn a mild illness into a lethal disease upon infection with DENV [8,9]
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