Abstract
Dengue virus (DENV) infection is a major emerging disease widely distributed throughout the tropical and subtropical regions of the world affecting several millions of people. Despite constants efforts, no specific treatment or effective vaccine is yet available. Here we show a novel design of a DNA immunisation strategy that resulted in the induction of strong antibody responses with high neutralisation titres in mice against all four viral serotypes. The immunogenic molecule is an engineered version of the domain III (DIII) of the virus E protein fused to the dimerising CH3 domain of the IgG immunoglobulin H chain. The DIII sequences were also codon-optimised for expression in mammalian cells. While DIII alone is very poorly secreted, the codon-optimised fusion protein is rightly expressed, folded and secreted at high levels, thus inducing strong antibody responses. Mice were immunised using gene-gun technology, an efficient way of intradermal delivery of the plasmid DNA, and the vaccine was able to induce neutralising titres against all serotypes. Additionally, all sera showed reactivity to a recombinant DIII version and the recombinant E protein produced and secreted from mammalian cells in a mono-biotinylated form when tested in a conformational ELISA. Sera were also highly reactive to infective viral particles in a virus-capture ELISA and specific for each serotype as revealed by the low cross-reactive and cross-neutralising activities. The serotype specific sera did not induce antibody dependent enhancement of infection (ADE) in non-homologous virus serotypes. A tetravalent immunisation protocol in mice showed induction of neutralising antibodies against all four dengue serotypes as well.
Highlights
Dengue disease is a mosquito-borne viral infection caused by Dengue virus (DENV), one of the most important human pathogens worldwide
dengue virus (DENV) infection produces a systemic disease with a broad symptomatic spectrum ranging from mild febrile illness
We show here a strategy of immunisation, tested in mice, that elicits a strong immune response against the four different DENV serotypes
Summary
Dengue is a mosquito-borne viral infection caused by dengue virus (DENV), one of the most important human pathogens worldwide [1]. In ADE, recognition of viral particles by cross-reacting, but weakly or non-neutralising antibodies, leads to an increased Fc receptor-mediated uptake of immature or incompletely neutralised viruses by monocytes, macrophages, and dendritic cells, which represent the primary targets of dengue virus infections in humans, resulting in increased infectivity and deterioration of the patient’s clinical condition [11]. This is critical in dengue vaccine development, since an immunogen that does not elicit fully neutralising antibodies to all four serotypes may contribute to disease, rather than prevent infection [12]. Given the lack of efficient treatment against the infection and the risk to human health, in particular (but ) in developing countries, research to develop an efficient vaccine has become an increasing but yet unsuccessful task
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