Induction of Neutralizing Antibodies against Four Serotypes of Dengue Viruses by MixBiEDIII, a Tetravalent Dengue Vaccine

Hui Zhao,Xi Zhou,Yong-Qiang Deng,Tao Jiang,Shun-Ya Zhu,Xi-Zhen Zhou,Xiao-Feng Li,Cheng-Feng Qin,Shui-Ping Chen,E-De Qin

doi:10.1371/journal.pone.0086573

Hui Zhao, Xi Zhou + Show 8 more

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https://doi.org/10.1371/journal.pone.0086573

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Abstract

The worldwide expansion of four serotypes of dengue virus (DENV) poses great risk to global public health. Several vaccine candidates are under development. However, none is yet available for humans. In the present study, a novel strategy to produce tetravalent DENV vaccine based on envelope protein domain III (EDIII) was proposed. Tandem EDIIIs of two serotypes (type 1–2 and type 3–4) of DENV connected by a Gly-Ser linker ((Gly4Ser)3) were expressed in E. coli, respectively. Then, the two bivalent recombinant EDIIIs were equally mixed to form the tetravalent vaccine candidate MixBiEDIII, and used to immunize BALB/c mice. The results showed that specific IgG and neutralizing antibodies against all four serotypes of DENV were successfully induced in the MixBiEDIII employing Freund adjuvant immunized mice. Furthermore, in the suckling mouse model, sera from mice immunized with MixBiEDIII provided significant protection against four serotypes of DENV challenge. Our data demonstrated that MixBiEDIII, as a novel form of subunit vaccine candidates, might have the potential to be further developed as a tetravalent dengue vaccine in the near future.

Highlights

Dengue fever (DF) and dengue hemorrhagic fever (DHF) are acute febrile diseases transmitted by mosquitoes, posing an increasing public health threat globally
Current vaccine candidates under development include live-attenuated, live-recombinant and inactivated viruses, as well as subunit vaccines based on recombinant proteins or naked DNA constructs, among which some vaccine candidates are progressing in clinical trials [3,4,5,6], but a licensed vaccine will not be available in a few years [7,8]
To produce the tandem bivalent recombinant dengue virus (DENV) envelope protein domain III (EDIII), the EDIIIs of two serotypes of DENV were sequentially connected by a (Gly4Ser)3 linker (Fig. 1)

Summary

Introduction

Dengue fever (DF) and dengue hemorrhagic fever (DHF) are acute febrile diseases transmitted by mosquitoes, posing an increasing public health threat globally. There is no effective dengue vaccine yet available for humans, efforts have been made for over 60 years. DENV contains four serotypes, and each of them can cause a wide spectrum of clinical manifestations, including mild DF, severe DHF and deadly dengue shock syndrome [9]. The pathogenesis of severe diseases remains poorly understood, and secondary infection with another DENV serotype is theoretically believed to increase the risk of severe diseases via the mechanism of antibody dependent enhancement (ADE) in Fcc receptor-bearing cells [10,11,12,13]. An ideal DENV vaccine should induce tetravalent, balanced, protective antibody response to the four serotypes while minimizing the risk of enhancement [14,15,16]

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Results

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