Abstract
Dengue viruses (DENV) are the most important mosquito transmitted viral pathogens infecting humans. DENV infection produces a spectrum of disease, most commonly causing a self-limiting flu-like illness known as dengue fever; yet with increased frequency, manifesting as life-threatening dengue hemorrhagic fever (DHF). Waning cross-protective immunity from any of the four dengue serotypes may enhance subsequent infection with another heterologous serotype to increase the probability of DHF. Decades of effort to develop dengue vaccines are reaching the finishing line with multiple candidates in clinical trials. Nevertheless, concerns remain that imbalanced immunity, due to the prolonged prime-boost schedules currently used in clinical trials, could leave some vaccinees temporarily unprotected or with increased susceptibility to enhanced disease. Here we develop a DENV serotype 1 (DENV-1) DNA vaccine with the immunodominant cross-reactive B cell epitopes associated with immune enhancement removed. We compare wild-type (WT) with this cross-reactivity reduced (CRR) vaccine and demonstrate that both vaccines are equally protective against lethal homologous DENV-1 challenge. Under conditions mimicking natural exposure prior to acquiring protective immunity, WT vaccinated mice enhanced a normally sub-lethal heterologous DENV-2 infection resulting in DHF-like disease and 95% mortality in AG129 mice. However, CRR vaccinated mice exhibited redirected serotype-specific and protective immunity, and significantly reduced morbidity and mortality not differing from naїve mice. Thus, we demonstrate in an in vivo DENV disease model, that non-protective vaccine-induced immunity can prime vaccinees for enhanced DHF-like disease and that CRR DNA immunization significantly reduces this potential vaccine safety concern. The sculpting of immune memory by the modified vaccine and resulting redirection of humoral immunity provide insight into DENV vaccine-induced immune responses.
Highlights
Dengue viruses (DENV) are the most prevalent arthropod-borne viral pathogens infecting humans
VACCINE CONSTRUCTION Based upon previously published and unpublished results with DENV and other flaviviruses (Crill and Chang, 2004; SukupolviPetty et al, 2007; Gromowski et al, 2008; Crill et al, 2009; Hughes et al, 2012a), we introduced specific substitutions into crossreactive B cell epitopes of the envelope protein of a DENV serotype 1 (DENV-1) prM/E expression plasmid (Chang et al, 2003) to generate a DENV-1 DNA vaccine candidate with reduced ability to induce the crossreactive antibodies that can be associated with antibody-dependent enhancement (ADE)
The DENV-1 WT DNA vaccine utilized as the template for the cross-reactivity reduced (CRR) vaccine in this study was based upon previous studies with DENV-2 vaccines and contains a potent CD4+ epitope identified in West Nile virus (WNV) and demonstrated to increase the immunogenicity of DENV-2 DNA vaccines (Hughes et al, 2012b)
Summary
Dengue viruses (DENV) are the most prevalent arthropod-borne viral pathogens infecting humans. Dengue vaccine development faces both biological and immunological challenges These include the necessity for a multivalent vaccine inducing balanced immunity, the lack of an animal model for DENV disease, and concerns regarding vaccine-induced immunopathology (Murphy and Whitehead, 2011; Heinz and Stiasny, 2012). There are a number of risk factors associated with DHF such as virus and host genetics, the strongest risk factor for severe dengue pathology is secondary infection with a previously unencountered (heterologous) serotype (Murphy and Whitehead, 2011).
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