A fusion-loop-engineered vaccine against the Zika virus (ZIKV) has shown promise in a nonhuman primate model. The research was reported in Cell Reports Medicine on October 7.

This type of vaccine modifies a region of the viral envelope protein known as the fusion loop to stimulate protective antibodies while reducing the risk of antibody-dependent enhancement (ADE), in which antibodies can worsen infection rather than prevent it. ADE is a major concern in flavivirus vaccine development. These findings lay an important foundation for the further clinical evaluation of Zika virus vaccines.

The study was led by Prof. DAI Lianpan and Prof. George F. Gao from the Institute of Microbiology of the Chinese Academy of Sciences (CAS) and Dr. LU Shuaiyao from the Institute of Medical Biology of the Chinese Academy of Medical Sciences.

ZIKV is a mosquito-borne pathogen that can cause neonatal microcephaly. Currently, there are no licensed vaccines available, and prior ZIKV immunity may increase the risk of ADE, which can exacerbate dengue virus (DENV) infection—representing a major hurdle for vaccine development.

Previously, the research team designed the fusion-loop-engineered immunogen MutB, which achieved maternal–fetal protection while abolishing ADE in murine models. However, given the substantial differences between the murine and human immune systems, it was unclear whether fusion-loop-engineered vaccines could elicit the desired immune response in humans.

To investigate the immune response elicited by the vaccine, the researchers analyzed vaccine-induced B cells and found that more than 97% were ZIKV-specific. These cells were dominated by a convergent population using a germline ortholog of human IGHV5-10-1, a gene preferentially recruited during natural ZIKV infection in humans.

Antibodies derived from this population are highly potent and, mechanistically, achieve multistage viral entry blockade. Cryo-electron microscopy analysis revealed 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.

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 Programs), the Strategic Priority Research Program of CAS, and others.

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