You may not have heard of human metapneumovirus, or HMPV, but every year this virus sends millions of people to the hospital. In children under five, it causes an estimated 14 million serious lung infections annually worldwide. For the elderly and immunocompromised individuals, death rates can be as high as 43%. Yet, unlike its close relative RSV, HMPV has no approved vaccines or treatments. Researchers in the Boonyaratanakornkit Lab at Fred Hutch are on a mission to change that. Their exciting progress, led by researchers Evelyn Harris and Morgan McGovern, is detailed in a new study published in Nature Communications.
How do researchers go about tackling a respiratory virus? Vaccines and monoclonal antibodies are strategies used to prevent and treat virus-induced infections, respectively. Since HMPV is particularly worrisome for immunocompromised individuals and bone marrow transplant recipients, for whom vaccines are often less effective, the researchers chose to focus on identifying an antibody that could neutralize and stop HMPV in its tracks. Their goals were ambitious: they sought to identify an antibody that was potent, could neutralize all subtypes and multiple strains of HMPV, and one that the virus would be unlikely to develop resistance to.
“HMPV has two major surface proteins: the G glycoprotein mediates attachment, whereas the F fusion protein mediates viral entry. In contrast to F, the G protein is highly variable, and others had previously found that vaccination with G protein failed to induce robust neutralizing antibodies or protective immunity in animals. Therefore, we focused our attention on the F protein. The F protein transitions between a metastable prefusion (preF) conformation and a stable postfusion (postF) conformation. Since preF is the major conformation on infectious virions, antibodies to preF tend to be the most potent at neutralizing virus.” Dr. Boonyaratanakornkit explains in a commentary on the work published in Research Communities.
They took the recombinant F protein from one subtype of HMPV—stabilized in the preF conformation—and tagged it with a fluorescent protein. They then introduced immune cells from human blood and spleen tissue and isolated cells that bound the preF protein by sorting the cells labeled with a fluorescent tag. Next, they stimulated these B cells to produce antibodies and tested the ability of these antibodies to reduce virus propagation of a different subtype of HMPV in cell culture. This design helped them zero in on 6 antibodies with broad effectiveness across multiple virus variants. One candidate, antibody 4F11, stood out dramatically: it was roughly 45 times more potent than a comparison antibody the authors previously discovered to cross-neutralize HMPV and RSV.
To understand why 4F11 works so well, the Boonyaratanakornkit Lab teamed up with the Pancera Lab to use cryo-electron microscopy to map the binding of 4F11 to HMPV. They found that 4F11 latches onto a specific vulnerable site at the very tip of the prefusion F protein, likely preventing the shape-change that allows the virus to enter cells. Critically, this binding site is nearly identical across all four major subtypes of HMPV, which explains why 4F11 can neutralize all of them. The antibody's interaction with the virus is also structurally unusual compared to previously described HMPV antibodies. Most similar antibodies squeeze through gaps in a molecular "glycan shield" coating the virus surface, but 4F11 approaches from straight above and actually grips part of that shield.
One of the biggest concerns with any antiviral antibody is resistance: can the virus mutate to escape it? When the researchers forced HMPV to evolve under constant antibody pressure in the lab, only a single escape mutation emerged, and that mutation, which weakens 4F11 binding to HMPV, also significantly crippled the virus's ability to replicate. Importantly, when the researchers searched a global database of nearly 800 HMPV sequences from patients around the world, they found this mutation in zero circulating strains, suggesting it would be an unlikely path for the real-world virus to take.
Finally, the team tested 4F11 as a treatment in infected hamsters. Administered just 24 hours after infection, a single dose effectively suppressed viral replication in the lungs of most animals and reduced virus levels in the upper airways. Effectiveness was shown at doses lower than those used for currently clinically approved RSV antibodies. Together, these results make a compelling case for advancing 4F11 into clinical development.
Co-lead author Evelyn Harris reflects on her team’s findings: “This work identifies a highly potent, broadly neutralizing antibody against human metapneumovirus and defines a previously underappreciated site of vulnerability on the viral fusion protein. By showing strong antiviral activity and a low potential for resistance, our findings highlight a promising therapeutic candidate and provide new insight into how effective antiviral antibodies can target this virus. Moving forward, we aim to use these insights to guide the development of antibody therapies and vaccines that provide broader and more durable protection."
The spotlighted research was funded by the Vaccine and Infectious Disease Division Faculty Initiative, Evergreen Beyond Pilot Award from the Fred Hutchinson Cancer Center, a sponsored research agreement with IgM Biosciences, a New Investigator Award from the American Society for Transplantation and Cellular Therapy, the Amy Strelzer Manasevit Award from the National Marrow Donor Program, and the National Institutes of Health.
Harris ED*, McGovern M*, Pernikoff S, Ikeda R, Kipnis L, Hannon W, Sobolik EB, Gray M, Greninger AL, He S, Chin C, Fu T, Pancera M, Boonyaratanakornkit J. 2026. Development of a potent monoclonal antibody for treatment of human metapneumovirus infections. Nat Commun. https://doi.org/10.1038/s41467-026-69328-w
Science Spotlight writer Kelly Mitchell is a postdoctoral fellow in the Paddison Lab at Fred Hutch Cancer Center. She utilizes live cell reporters and CRISPR screening to study how glioblastoma cancer cells resist chemotherapy and radiation treatment. She obtained her PhD in cellular biology from Albert Einstein College of Medicine.
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