۱٫ Introduction

۲٫ Materials and methods

۳٫ Results

۴٫ Discussion

Acknowledgements

References

Abstract

Dengue virus (DENV) and Zika virus (ZIKV) are antigenically related mosquito-transmitted viruses which represent a big public health problem. Although the antigenic cross-reactivity between two viruses were intensively investigated at the antibody and T cell levels, how DENV envelope protein domain III (EDIII)- elicited antibodies (Abs) impact the outcome of ZIKV infection is uncertain. Here, our results show that the sera isolated from DENV-EDIII-immunized wild-type mice recognized ZIKV-EDIII and cross-neutralized ZIKV in vitro. Passive transfer of DENV-EDIII-immune sera protected 1-day-old mice against lethal ZIKV challenge. Finally, maternally acquired anti-DENV-EDIII Abs significantly increased the survival of 1-day-old mice born to DENV-EDIII-immunized mothers post ZIKV challenge. These results reveal that DENV-EDIIIinduced Abs provide cross-protection against ZIKV and may not mediate the Ab-dependent enhancement of ZIKV infection at the concentration used here. The present study would contribute to the development and application of DENV-EDIII-based vaccines.

Introduction

Family flaviviridae, genus flavivirus has more than 100 members including Yellow fever virus (YFV), Dengue virus (DENV), Japanese encephalitis virus (JEV), Zika virus (ZIKV), etc. According to the nucleotide variation, DENV is divided into four serotypes (DENV1-4) which generally cause dengue fever and occasionally dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS)(Gintarong et al., 2018; Ko et al., 2018; Thomas et al., 2018). DHF and DSS usually occur in secondary heterotypic DENV infection and are supposed to be mediated by antibody (Ab)-dependent enhancement (ADE)(Dejnirattisai et al., 2010; Katzelnick et al., 2017). Currently, DENV spreads on a global scale and affects about 390 million people annually(Bhatt et al., 2013). Since the first isolation in Uganda in 1947, ZIKV did not attract attention until the circulation in Micronesia in 2007(Duffy et al., 2009; Posen et al., 2016) and big outbreaks in French Polynesia during 2013-2014 and South America during 2015-2016(Fauci and Morens, 2016; Musso et al., 2018). Like DENV, ZIKV infection usually gives rise to mild fever, rash but can cause the microcephaly of newborn when infecting pregnant women(Bautista, 2018; Hoen et al., 2018).

Tetravalent live attenuated DENV vaccine developed by Sanofi was licensed in 20 countries in Asia, Latin America, and Australia (Wilder-Smith et al., 2019). However, this vaccine is suggested to be applied only in people aged 9-45 years with DENV infection history and not to be used in individuals without DENV infection history because it may cause ADE of secondary heterologous DENV infection in vaccine-vaccinated population(Aguiar, 2018; Wilder-Smith et al., 2019). Therefore, it is urgent to develop a universal DENV vaccine which could be used in individuals without any limitation. The extracellular part of Flavivirus envelope (E) protein has three domains [I, II, and III (EDI, EDII, and EDII)] and EDIII is the major target for antiflavivirus Ab response(Rey, 2013). Many studies demonstrated that DENV-EDIII-induced Ab mediates the neutralization of or protection against homologous or heterologous DENV infection in vitro or in vivo(Poggianella et al., 2015; Ramasamy et al., 2018; Zaneti et al., 2019). Therefore, EDIII is becoming a promising vaccine candidate for DENV. Blast searching results show that DENV-EDIII shares high level of amino acid homology with ZIKV-EDIII. But, whether and how DENV-EDIII-induced Abs affect the outcome of ZIKV infection is uncertain