Zika virus (ZIKV) is a mosquito-borne pathogen that can cause neonatal microcephaly. There are currently no licensed vaccines available, and prior ZIKV-immune increases the risk of antibody-dependent enhancement (ADE) that can exacerbate dengue virus infection, a major hurdle for vaccine development. The research team previously designed the fusion-loop-engineered immunogen MutB, which achieved maternal-fetal protection while abolishing ADE in murine models. Given the substantial differences between murine and human immune systems, it remained uncertain whether fusion-loop-engineered vaccines could recapitulate the desired immune response in humans.

On October 7, 2026, a team led by Prof. DAI Lianpan and Prof. George F. Gao from the Institute of Microbiology, Chinese Academy of Sciences, in collaboration with Dr. LU Shuaiyao from the Institute of Medical Biology, Chinese Academy of Medical Sciences, reported the first validation of a fusion-loop-engineered Zika vaccine for protection and ADE risk abrogation in a non-human primate model. The study was published online in Cell Reports Medicine and featured as the cover article of the October issue, providing an important foundation for further clinical evaluation of the vaccine.

The vaccine-induced B cells are overwhelmingly ZIKV-specific (>97%), dominated by a convergent population using a germline ortholog of human IGHV5-10-1, a gene preferentially recruited during natural human ZIKV infection. Antibodies derived from this population are highly potent, and mechanistically, achieve multi-stage viral entry blockade. Cryo-electron microscopy analysis reveals that these antibodies target a distinct, vulnerable hotspot on ZIKV. Notably, ZIKV specificity is dictated by epitope residues D67-M68-A69, whereas a homologous DENV N67-linked glycan imposes steric shielding to preclude cross-reactivity. These findings demonstrate that fusion-loop-engineering uncouples protective immunity from ADE for safer human flavivirus vaccines.

This work was supported by the National Science and Technology Major Project for Emerging and Major Infectious Diseases, the National Natural Science Foundation of China (Major Program), the Strategic Priority Research Program of the Chinese Academy of Sciences and others.

Figure: The fusion-loop-engineered Zika vaccine achieves protection in macaques and abolishes ADE risk. (Image by Prof. DAI Lianpan’s group)

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