Taiwan, situated in East Asia with the Tropic of Cancer crossing the southern part of the island, detects only imported ZIKV cases without any local transmission, based on the nationwide surveillance system established by the Taiwan Centers for Disease Control and Prevention (Taiwan-CDC), even though periodic DENV epidemics in southern Taiwan have occurred since 1980. Meanwhile, the first JEV case was documented in Taiwan in 1931 and became endemic in the island, prompting the implementation of a national pediatric JEV immunization program in 1968. We hypothesize that the sequential exposure of JEV and DENV can induce broadly neutralizing antibody response against Zika virus, which prevents Zika virus infection.

First, we tested the neutralizing activity from the sera collected from 60 dengue fever patients and 80 healthy controls. We demonstrated that the percentage of individuals with high JEV and DENV titers and consequently high ZIKV titers was statistically higher than the proportion of individuals with only one immunity, suggesting that sequential exposures to JEV and DENV could potentially induce high and cross-neutralizing antibodies against ZIKV that have yet to be
encountered by the host.

Second, to confirm if such cross-neutralizing ZIKV antibodies persist, we successfully recalled one recovered donor (KH1891) from the same Taiwan cohort more than 18 months after the dengue infection. We utilized the peripheral blood mononuclear cells from donor KH1891 and successfully isolated 24 human monoclonal antibodies (hMAbs) recognizing various flaviviruses. Among them, two hMAbs displayed the broadest and most potent neutralization (FRμNT50) against DENV-1 to 4, JEV, and ZIKV. 

Third, the binding epitopes of hMAb K8b to DENV-2 virus-like particles were successfully resolved using cryoelectron Microscopy. The results indicate that  K8b-IgG1 may function not only as an interdomain antibody but also as an inter-dimer antibody.

The interdisciplinary research team led by Professor Day-Yu Chao from National Chung-Hsing University, Taiwan, provided the first epidemiological, immunological, and structural evidence that the low ZIKV incidence and ZIKV-associated microcephaly in Southeast Asia could be partly explained by the high endemicity of JEV and DENV in the region, which induced cross-neutralizing antibody responses against Zika virus. This study, consistent with the findings from the mice, expands our current understanding of Zika in the context of DENV and JEV cross-reactive immunity against three different serocomplexes after sequential exposure to different flaviviruses within a lifetime, which are established human pathogens with known active transmission in SEAsia.

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https://www.nature.com/articles/s42003-023-05661-w