Dengue and Zika are closely related viruses that threaten millions of people worldwide each year. As climate change expands the reach of the mosquitoes that carry these viruses, the development of effective vaccines is becoming increasingly urgent.
The close relationship between the two viruses might seem like an advantage for vaccine design. Vaccines work by teaching the immune system to produce neutralizing antibodies, molecules that recognize and bind to a virus and block it from infecting cells. In theory, antibodies that recognize features shared by closely related viruses could provide protection against several of them at once. But with Dengue and Zika, that similarity comes with a catch.
Dengue virus exists as four distinct serotypes and infection with one serotype doesn’t necessarily provide lasting protection against the others. Even more concerning, antibodies produced during one infection can sometimes recognize another serotype without effectively neutralizing it. Instead of blocking infection, these antibodies can actually help the virus enter cells and make a subsequent infection more severe. Add the closely related Zika virus to the mix, and the challenge becomes even greater. A successful vaccine must generate broadly neutralizing antibodies, capable of recognizing and blocking multiple related viruses without enhancing infection.
Fred Hutch researchers previously discovered one such antibody, F25.S02, isolated from a patient who had experienced multiple exposures to both Dengue and Zika. Understanding exactly how F25.S02 recognizes and blocks all four dengue serotypes as well as Zika could provide valuable clues to design an effective vaccine.
Researchers in the Vaccine and Infectious Disease Division at Fred Hutch have now uncovered the structural basis for F25.S02’s remarkable breadth. Led by Nicholas Hurlburt, a staff scientist in the Pancera Lab, the team visualized precisely how F25.S02 binds to viral proteins using cryogenic electron microscopy and X-ray crystallography, two techniques that allow scientists to reveal the structures of biological molecules and their interactions with atomic-level detail. By determining exactly how this antibody interacts with both viruses, researchers have uncovered clues that could help guide the design of next-generation vaccines.
“By observing the structure of the most broadly neutralizing antibody to all four [Dengue] serotypes and Zika, you can understand its mode of action at the molecular level” explained Hurlburt.
The structures revealed that F25.S02 targets a vulnerable seam between proteins found at the surface of the virus. Dengue and Zika viruses are coated in envelope proteins that help them enter human cells. These proteins must dramatically rearrange their structures to bring the viral and host cellular membranes together so they can fuse. This fusion step allows the virus to release its genetic material into the host cell. F25.S02 interferes with this process by binding precisely where two neighboring envelope proteins meet. By bridging this interface, the antibody acts like a molecular lock, holding the proteins together and preventing the rearrangement required for the virus to infect the cell. Importantly, the features recognized by F25.S02 are highly conserved, meaning they remain similar across all four dengue serotypes and Zika virus. While other parts of these viruses vary, this shared vulnerability gives F25.S02 a common target and helps explain its unusually broad protection.
For Hurlburt, identifying that weak spot raises the obvious next question: can we make a vaccine that elicits broadly neutralizing antibodies that target this interface? The structural maps determined in this study could provide a roadmap for doing just that. By revealing exactly which features F25.S02 recognizes and how they are arranged in three dimensions, the structures could guide researchers in designing vaccines that direct the immune system toward this shared viral vulnerability and teach it to produce protective broadly neutralizing antibodies.
The spotlighted research was supported by the J. B. Pendleton Charitable Trust, Fred Hutch Vaccine and Infectious Disease Division Initiative grant, the Fred Hutchinson Cancer Center Electron Microscopy Shared Resource, the Howard Hughes Medical Institute, and the National Institutes of Health.
Hurlburt NK, Lubow J, Goo L, and Pancera M. 2026. Structural basis for antibody cross-neutralization of Dengue and Zika viruses. Communications Biology. DOI: 10.1038/s42003-026-09805-6.
Science Spotlight writer Thamiya Vasanthakumar is a postdoctoral research fellow in the Campbell Lab at Fred Hutch. As a structural biologist, she uses cryogenic electron microscopy (cryoEM) to visualize the molecular structures of receptors found on the surface of immune cells.