Fusion-loop-engineered Zika mRNA vaccine elicits convergent B cell immunodominance to uncouple protection from ADE in macaques
14 affiliations
- 1Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- 2University of Chinese Academy of Sciences, Beijing 100049, China
- 3College of Animal Sciences and Veterinary Medicine, Guangxi University, Nanning, Guangxi 530004, China
- 4Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China
- 5Sino-Danish College, Chinese Academy of Sciences, Beijing 100010, China
- 6National Institute of Biological Sciences (NIBS), Beijing 102206, China
- 7Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
- 8State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430061, China
- 9Shanghai Juntuo Biomedical Technology Co Ltd., Shanghai 201210, China
- 10Department of Microbiology, Nanjing Medical University, Nanjing 211166, China
- 11Institute of Pediatrics, Shenzhen Children’s Hospital, Shenzhen 518038, China
- 12College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China
- 13National Institute of Biological Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- 14Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China
Abstract
Antibody-dependent enhancement (ADE) remains a major hurdle for flavivirus vaccine development. Engineering the fusion loop (FL) represents a promising solution, yet validations restricted to murine models limit human translatability due to profound species divergence. Here, we provide a primate-level demonstration that FL-engineered Zika virus (ZIKV)-M/E mRNA vaccination protects against ZIKV challenge with negligible dengue virus (DENV) ADE. 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 the epitope residues D67-M68-A69, whereas a homologous DENV N67-linked glycan imposes steric shielding to preclude cross-reactivity. Our findings demonstrate that FL engineering uncouples protective immunity from ADE for safer human flavivirus vaccines.
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BibTeX
@article{yang2026fusionloopengineered,
title = {{Fusion-loop-engineered Zika mRNA vaccine elicits convergent B cell immunodominance to uncouple protection from ADE in macaques}},
author = {Chenxi Yang and Shuxin Guo and Yaming Lu and Minrun Duan and Hao Yang and Weishen He and Yujie Cheng and Fujian Wan and Yuxuan Han and Shengfeng Wan and Huifang Ma and Junbin Wang and Cong Tang and Jun Wen and Kun Xu and Sheng Liu and Bo Shu and Shuijun Zhang and Niu Huang and Shuaiyao Lu and George F. Gao and Lianpan Dai},
journal = {Cell Reports Medicine},
year = {2026},
month = oct,
doi = {10.1016/j.xcrm.2026.103091},
url = {https://doi.org/10.1016/j.xcrm.2026.103091},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Fusion-loop-engineered Zika mRNA vaccine elicits convergent B cell immunodominance to uncouple protection from ADE in macaques
AU - Chenxi Yang
AU - Shuxin Guo
AU - Yaming Lu
AU - Minrun Duan
AU - Hao Yang
AU - Weishen He
AU - Yujie Cheng
AU - Fujian Wan
AU - Yuxuan Han
AU - Shengfeng Wan
AU - Huifang Ma
AU - Junbin Wang
AU - Cong Tang
AU - Jun Wen
AU - Kun Xu
AU - Sheng Liu
AU - Bo Shu
AU - Shuijun Zhang
AU - Niu Huang
AU - Shuaiyao Lu
AU - George F. Gao
AU - Lianpan Dai
PY - 2026
DA - 2026/10/07
JO - Cell Reports Medicine
DO - 10.1016/j.xcrm.2026.103091
UR - https://doi.org/10.1016/j.xcrm.2026.103091
AB - Antibody-dependent enhancement (ADE) remains a major hurdle for flavivirus vaccine development. Engineering the fusion loop (FL) represents a promising solution, yet validations restricted to murine models limit human translatability due to profound species divergence. Here, we provide a primate-level demonstration that FL-engineered Zika virus (ZIKV)-M/E mRNA vaccination protects against ZIKV challenge with negligible dengue virus (DENV) ADE. 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 the epitope residues D67-M68-A69, whereas a homologous DENV N67-linked glycan imposes steric shielding to preclude cross-reactivity. Our findings demonstrate that FL engineering uncouples protective immunity from ADE for safer human flavivirus vaccines.
SN - 2666-3791
ER -