Evaluating the Safety of West Nile Virus Immunity During Congenital Zika Virus Infection in Mice

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.

Low Immune Cross-Reactivity between West Nile Virus and a Zika Virus Vaccine Based on Modified Vaccinia Virus Ankara

“…For example, the possibility of both ADE or cross-protection in vitro between ZIKV and WNV has been documented [ 19 , 21 ]. In the case of in vivo experiments in the mice model, ZIKV infection exacerbation by pre-existing WNV immunity was proposed [ 20 ], although recent reports do not further support this possibility in pregnant mice [ 22 ]. Even more, we have previously documented that cross-protection against subsequent WNV challenge by previous ZIKV infection can occur [ 8 ].…”

“…By now, the flavivirus West Nile virus (WNV) is the main medically relevant mosquito-borne viral threat in European and Eastern Mediterranean countries, being responsible for recurrent outbreaks of febrile illness and meningoencephalitis [ 16 , 17 ]. Interestingly, a diverse degree of cross-reactivity between ZIKV and WNV has been reported, going from a lack of cross-reactive immunity to ADE of infection, or even to heterologous cross-protection [ 8 , 14 , 18 , 19 , 20 , 21 , 22 ]. Therefore, ZIKV vaccine candidates that could be used to combat hypothetical future ZIKV outbreaks should consider the potential cross-reactions between WNV and ZIKV.…”

The increasing complexity of arbovirus serology: An in-depth systematic review on cross-reactivity

“…This possibly might be explained by the DENV antibody levels and length of the time interval between the sequential heterologous infections being crucial in determining whether it will lead to protection or enhancement of ZIKV infection [ 63 ]. Although ADE and the risk of developing severe disease has been demonstrated for ZIKV and DENV, it remains to be determined whether this also plays a role for other arboviruses [ 64 ].…”