Abstract
Antibody-dependent enhancement (ADE) is a phenomenon that occurs when cross-reactive antibodies generated from a previous flaviviral infection increase the pathogenesis of a related virus. Zika virus (ZIKV) is the most recent flavivirus introduced to the Western Hemisphere and has become a significant public health threat due to the unanticipated impact on the developing fetus. West Nile virus (WNV) is the primary flavivirus that circulates in North America, and we and others have shown that antibodies against WNV are cross-reactive to ZIKV. Thus, there is concern that WNV immunity could increase the risk of severe ZIKV infection, particularly during pregnancy. In this study, we examined the extent to which WNV antibodies could impact ZIKV pathogenesis in a murine pregnancy model. To test this, we passively transferred WNV antibodies into pregnant Stat2-/- mice on E6.5 prior to infection with ZIKV. Evaluation of pregnant dams showed weight loss following ZIKV infection; however, no differences in maternal weights or viral loads in the maternal brain, spleen, or spinal cord were observed in the presence of WNV antibodies. Resorption rates, and other fetal parameters, including fetal and placental size, were similarly unaffected. Further, the presence of WNV antibodies did not significantly alter the viral load or the inflammatory response in the placenta or the fetus in response to ZIKV. Our data suggest that pre-existing WNV immunity may not significantly impact the pathogenesis of ZIKV infection during pregnancy. Our findings are promising for the safety of implementing WNV vaccines in the continental US.
Highlights
Antibody-dependent enhancement (ADE) is a phenomenon by which antibodies elicited from a previous infection facilitate viral entry into a susceptible cell through the engagement of Fc gamma receptors (FcɣRs) [1, 2]
In the absence of thorough prospective human studies on the influence of West Nile virus (WNV) immunity on Zika virus (ZIKV) infections, we hope that these data provide the first insights into the safety of introducing greater WNV immunity into ZIKV endemic regions and regions at risk of ZIKV expansion
Based on ADE observed between the dengue virus (DENV) serotypes, ~68% identity at the amino acid level for the E proteins appears to be sufficient for enhancement to be observed [49]
Summary
Antibody-dependent enhancement (ADE) is a phenomenon by which antibodies elicited from a previous infection facilitate viral entry into a susceptible cell through the engagement of Fc gamma receptors (FcɣRs) [1, 2]. The most established example of ADE in humans occurs between the four serotypes of dengue virus (DENV), a mosquito-transmitted flavivirus that is estimated to cause ~390 million infections annually around the globe [3, 4]. While high concentrations of cross-reactive antibodies may offer protection in the short term, these same antibodies can promote pathogenesis through ADE if secondary infection occurs during a time when the concentration of antibodies falls below the neutralization threshold [13, 14]. Observing ADE in human populations is difficult and requires prospective studies in flavivirus endemic areas [15]. In the case of dengue, while the phenomenon of severe secondary infections has been observed for decades, the correlation between antibody titers and severe disease was only directly demonstrated recently [16]. The data generated by such studies hold broad implications for the development of any flavivirus vaccine [17]
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