Research Article: Role of Humoral versus Cellular Responses Induced by a Protective Dengue Vaccine Candidate

Date Published: October 31, 2013

Publisher: Public Library of Science

Author(s): Raphaël M. Zellweger, Robyn Miller, William E. Eddy, Laura J. White, Robert E. Johnston, Sujan Shresta, Ron A. M. Fouchier.

http://doi.org/10.1371/journal.ppat.1003723

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.

Partial Text

The four serotypes of dengue virus (DENV1-4) are mosquito-borne 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]. DENV is endemic in more than 100 countries [2] and 2.5 billion people worldwide are at risk of infection, mostly in tropical and subtropical regions [3]. It is estimated that 390 million cases of DENV infection occur annually, of which 96 million are apparent, 500,000 are severe and 20,000 are fatal [4].

In this study, alphavirus VRP expressing the DENV2-E protein ectodomain (DENV2 E85-VRP) were used to immunize mice prior to challenge with DENV in order to assess the relative contribution of humoral and cellular immunity in a protective vaccine-induced immune response to DENV. A better understanding of the determinants of protection after dengue vaccination is urgently needed [14], especially after the recent report of the first phase IIb clinical trial of a tetravalent live-attenuated dengue-vaccine candidate [12]. For reasons that remain unclear, the phase IIb trial showed only limited efficacy of the vaccine despite induction of a balanced Ab response against all four serotypes. Our study begins to address this lack of knowledge by assessing the relative role of the humoral and cellular arms of a protective vaccine-induced immune response.

 

Source:

http://doi.org/10.1371/journal.ppat.1003723

 

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