Cell reports. MedicineOct 7, 2026

Zika mRNA vaccine with fusion-loop changes triggers focused B cell response that separates protection from antibody-related enhancement in macaques

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 8, 2026

Abstract

FL-engineered Zika virus (ZIKV)-M/E mRNA vaccination protects against ZIKV challenge with negligible dengue virus (DENV) antibody-dependent enhancement.

The vaccine induces B cells that are over 97% specific to ZIKV.
A convergent population of B cells uses a germline version of human IGHV5-10-1, similar to those seen in natural ZIKV infections.
Antibodies from this B cell population are highly potent and block multiple stages of viral entry.
Cryo-electron microscopy shows that these antibodies target a specific vulnerable area on the ZIKV.
ZIKV specificity is determined by specific epitope residues, while a related DENV glycan prevents cross-reactivity.

Simplified

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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Zika mRNA vaccine with fusion-loop changes triggers focused B cell response that separates protection from antibody-related enhancement in macaques

Abstract

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