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Rescue and Characterization of Recombinant Virus from a New World Zika Virus Infectious Clone
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Immunological and transcriptomic profile of chimeric live-attenuated Zika vaccine linked to protection in non-human

Ji Ma1, Bert Malengier-Devlies2,3, Babs E Verstrepen4,5

  • 1KU Leuven Department of Microbiology, Immunology & Transplantation, Rega Institute, Division of Virology, Antiviral Drug & Vaccine Research, Laboratory of Molecular Vaccinology & Vaccine Discovery (MVVD), Leuven, Belgium.

Nature Communications
|December 13, 2025
PubMed

Zika virus (ZIKV) is typically mild in humans but can cause severe congenital defects when contracted during pregnancy. Chimeric live-attenuated vaccine candidate YF-ZIK previously showed protective efficacy against lethal infection and developmental abnormalities in mice after a single dose. Here we demonstrate that YF-ZIK is safe, induces antiviral immunity, and protects rhesus macaques against high-dose experimental challenge. A single subcutaneous dose elicits neutralizing antibodies within 7-14 days, boosted by a second dose at 4 weeks. Passive serum transfer protects AG129 mice, supporting antibodies as a correlate of protection. YF-ZIK triggers balanced Th1/Th2 responses and a transcriptional profile resembling the licensed YF17D vaccine, involving multiple pathways favoring polyvalent immunity. Upon challenge, vaccinated macaques show no detectable viral RNA nor seroconversion to anti-ZIKV NS1 antibodies, suggesting sterilizing immunity. Systems analysis identifies TNFRSF17 as predictor of antibody responses to YF-ZIK, and GNAS and CD207 (Langerin) as potentially linked to clinical outcomes. The favorable preclinical safety, immunogenicity, and efficacy of YF-ZIK justify its future evaluation in humans.

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