2.3-Angstrom Map of Andes Virus Surface Protein Opens Path to Hantavirus Vaccines
Hantaviruses kill roughly 40 percent of the people they infect. No approved vaccines exist. No approved treatments exist. The pathogens circulate globally, spread from rodents to humans, and appear on the NIH list of viruses considered most dangerous for their potential to cause future pandemics. Betsy Arakawa's death from hantavirus infection in New Mexico in March of last year - she was the wife of actor Gene Hackman - brought them briefly into broad public awareness.
Against that backdrop, a team led by Jason McLellan at the University of Texas at Austin has produced what represents a significant advance in the structural biology of one hantavirus species. Their work, published in the journal Cell, maps the surface protein complex of the Andes virus at 2.3-angstrom resolution - fine enough to resolve details the size of a couple of atoms, and more than five times sharper than the previous best model of the same structure, which was resolved at 12 angstroms.
What a 2.3-angstrom resolution actually means
Structural biology is fundamentally about knowing the shape of molecules precisely enough to design something that fits them. An antibody therapeutic or vaccine-derived immune response needs to target the right region of a viral surface protein in the right conformation - ideally the pre-fusion state, before the virus has merged with a host cell and changed shape. At 12-angstrom resolution, the Gn-Gc tetramer - the mushroom-shaped protein complex on the Andes virus surface - was visible in outline, but key details were blurry enough to produce what McLellan's team describes as meaningful inaccuracies that the new work corrects.
At 2.3 angstroms, the picture becomes precise enough to show individual side chains on amino acids, the positions of water molecules, and the fine geometry of the binding surfaces that antibodies or antivirals would need to engage. "Now that we have a better blueprint of what the virus looks like, we can design effective vaccines and antibody therapies for hantaviruses," McLellan said.
The imaging innovation: sideways-only particles
Getting to 2.3 angstroms required a methodological twist. Conventional cryo-electron microscopy works by shining an electron beam through frozen samples and reconstructing three-dimensional structures from many two-dimensional images captured at different orientations. This works well for isolated proteins, where particles randomly orient in all directions.
The team produced virus-like particles - mimics of the Andes virus that carry the surface proteins but lack the genome that makes a real virus infectious. On these particles, the Gn-Gc tetramers stick out from the surface, and many point in different directions relative to the electron beam. The researchers made a deliberate choice: they identified and used only the shadow images from tetramers oriented sideways relative to the beam, discarding those pointing in other directions. This restriction allowed them to borrow reconstruction algorithms typically designed for individual isolated proteins, producing the 2.3-angstrom result. "People will start to apply this method to many other viruses," McLellan predicted.
From structure to vaccine candidate
Structural information is not an end in itself. The team used their high-resolution map to produce a vaccine candidate and tested it in mice. Animals that received the candidate produced neutralizing antibodies against the Andes virus - the kind of immune response that, in principle, would prevent infection. This is an early result in mice, not a clinical trial, and the path from mouse antibody data to a licensed human vaccine is long and uncertain.
The next technical target is stabilization. Surface proteins on viruses change shape when the virus fuses with a host cell, and vaccines are most effective when they target the pre-fusion conformation. The team plans to use AI tools to identify stabilizing mutations - small amino acid changes that lock the protein in its pre-fusion shape, preventing it from transitioning even when removed from the virus and injected as a vaccine antigen. This approach has been used successfully for several other respiratory viruses.
The work was funded through the NIH's ReVAMPP program, established after the agency identified hantaviruses as among the most dangerous unaddressed pathogen families. The program supports the Provident consortium, which is simultaneously developing structural and immunological tools against multiple high-concern viruses including Nipah and measles. Kartik Chandran of Albert Einstein College of Medicine served as co-senior author; collaborators at Texas A&M and UT Southwestern provided cryo-EM facilities, and HDT Bio in Seattle contributed to the research.