Evaluating potential associations between prior maternal yellow fever vaccination and protection against infant adverse outcomes following Zika virus antenatal exposure

During the Zika virus (ZIKV) epidemic in Brazil, regional disparities in yellow fever (YF) vaccination coverage and microcephaly incidence led to the hypothesis that maternal YF vaccination could protect against ZIKV infection and microcephaly. This case-cohort study was conducted in Campo Grande, Brazil, from 2018 to 2022 and included children with confirmed in utero ZIKV exposure (2015-2018) and a matched control group, totaling 129 mother-child dyads. Maternal blood samples were collected to assess ZIKV exposure and neutralizing YF vaccine-induced antibody (NAb) titers. Associations between YF NAb titer, congenital anomalies, and infant neurodevelopmental delay were evaluated. Mean YF NAb titers differed between ZIKV-exposed and unexposed mothers (P = .011) and between mothers of children with and without microcephaly (P = .037). Congenital anomalies were associated with lower YF NAb titers (P < .001), prenatal ZIKV exposure (P = .001), and lower family income (P < .001). Neurodevelopmental delay was associated with prenatal ZIKV exposure [adjusted odds ratio (aOR): 4.35, 95% confidence interval (CI): 1.65-13.03], prenatal care with at least six visits (aOR: 0.22, CI: 0.06-0.78), and adequate or large for gestational age birth weight (aOR: 0.09, CI: 0.01-0.44). Differences in maternal YF NAb titers by ZIKV exposure and microcephaly suggest a potential protective effect of YF vaccination against ZIKV acquisition and/or development of microcephaly, which should be investigated. Developmental delay, although not associated with maternal YF immunity, was associated with antenatal ZIKV exposure, less prenatal care visits, and being small for gestational age.