T cell immunity rather than antibody mediates cross-protection against Zika virus infection conferred by a live attenuated Japanese encephalitis SA14-14-2 vaccine

Abstract

Zika virus (ZIKV) and Japanese encephalitis virus (JEV) are closely related to mosquito-borne flaviviruses. Japanese encephalitis (JE) vaccine SA14-14-2 has been in the Chinese national Expanded Program on Immunization since 2007. The recent recognition of severe disease syndromes associated with ZIKV, and the identification of ZIKV from mosquitoes in China, prompts an urgent need to investigate the potential interaction between the two. In this study, we showed that SA14-14-2 is protective against ZIKV infection in mice. JE vaccine SA14-14-2 triggered both Th1 and Th2 cross-reactive immune responses to ZIKV; however, it was cellular immunity that predominantly mediated cross-protection against ZIKV infection. Passive transfer of immune sera did not result in significant cross-protection but did mediate antibody-dependent enhancement in vitro, though this did not have an adverse impact on survival. This study suggests that the SA14-14-2 vaccine can protect against ZIKV through a cross-reactive T cell response. This is vital information in terms of ZIKV prevention or precaution in those ZIKV-affected regions where JEV circulates or SA14-14-2 is in widespread use, and opens a promising avenue to develop a novel bivalent vaccine against both ZIKV and JEV. Key points • JEV SA14-14-2 vaccine conferred cross-protection against ZIKV challenge in mice. • T cell immunity rather than antibody mediated the cross-protection. • It provides important information in terms of ZIKV prevention or precaution.

Japanese Encephalitis Virus Vaccination Elicits Cross-Reactive HLA-Class I-Restricted CD8 T Cell Response Against Zika Virus Infection

“…It has been shown in Dengue virus infection, efficient CD8 T cells response is sufficient to inhibit ADE in infected mice. Our present study together with previous findings (18,24) all suggest that cross-reactive JEV-specific CD8 T cells are protective to ZIKV infection in wild-type mice that are not HLA-transgenic (18,19,25). Thus, JEV vaccine can be clinically used for the prevention of ZIKV infection and also is at low risk of ADE induction in immune-competent humans.…”

“…Previous studies by us and others have independent shown that antibodies against JEV are cross-reactive to ZIKV, but passive transfer of JEV antisera fails to protect ZIKV infection in Ifnar1 −/− mice (18,24). Thus, antibody response is unlikely to mediate the protection of JEV vaccine-immunized HLAtransgenic or non-transgenic Ifnar1 −/− mice from ZIKV infection.…”

“…Thus, antibody response is unlikely to mediate the protection of JEV vaccine-immunized HLA-transgenic or non-transgenic Ifnar1 –/– mice from ZIKV infection. Although JEV antibodies exhibit antibody-dependent enhancement (ADE) of infection in vitro , the ADE effect was not observed in JEV vaccine-immunized mice or JEV antisera transferred mice ( 18 , 24 ). It has been shown in Dengue virus infection, efficient CD8 T cells response is sufficient to inhibit ADE in infected mice.…”

The legacy of ZikaPLAN: a transnational research consortium addressing Zika

“…We found that T cell responses triggered by pre-existing dengue virus infection are protective against Zika virus infection [ 68 ]. In a mouse model, specific T cells to Japanese encephalitis virus, another flavivirus, could also protect against Zika [ 69 ].…”

Widespread interspecific phylogenetic tree incongruence between mosquito-borne and insect-specific flaviviruses at hotspots originally identified in Zika virus

“…2020 ). Importantly, it has recently been demonstrated that the T-cell response following immunization with a live-attenuated JEV vaccine, produced a cross-protection against ZIKV infection in humans ( Wang et al. 2020 ).…”