Mpox is a viral disease caused by the monkeypox virus, an orthopoxvirus related to smallpox. Although mpox has circulated for decades in parts of Central and West Africa, the virus spread globally in 2022 through interconnected sexual networks, causing nearly 100,000 cases across more than 117 countries. In the United States, cases surged before declining sharply later that year. Yet unlike many outbreaks that either grow exponentially or disappear entirely, mpox has persisted at low levels ever since.
A new study from the Bedford Lab in the Vaccine and Infectious Disease Division, published in Nature Communications, investigated why mpox continues to circulate in Los Angeles County years after the initial outbreak subsided. By combining viral genome sequencing with epidemiological microsimulation modeling — a computational approach that simulates disease spread across individuals in a population — the researchers found that ongoing transmission is sustained by repeated viral introductions into Los Angeles rather than a single persistent chain of local spread.
“We found that mpox cases in Los Angeles County are made up of a fluctuating stream of viral introductions coming into the county,” explained study lead Dr. Miguel Paredes. “Instead of having just continued and persistent local transmission, it seems like the many introductions of the virus into LA create multiple small clusters of infections, which start to overlap on one another, creating the illusion that the virus is persisting at a constant rate.”
The researchers compare this to behavior of some fires. “I like to think of it like a fire that is maintained by constant small sparks that get replaced before the old one dies out, rather than one big fire that never extinguishes,” explained Paredes.
To untangle the dynamics behind these low-level but persistent infections, the team paired two complementary computational approaches. First, they used phylodynamics, a method that reconstructs viral transmission history using viral genome sequences. They analyzed nearly 500 mpox genomes collected in Los Angeles County alongside more than 7,000 sequences from around the world to track how viruses moved into and out of the region over time.
These analyses revealed distinct seasonal waves of viral introductions into Los Angeles, particularly during the spring and early fall. Most introductions sparked little onward transmission, but some seeded larger clusters that persisted for weeks or months before dying out.
The team then integrated these genomic findings into a microsimulation model of mpox transmission among men who have sex with men (MSM) in Los Angeles County. Previous versions of the model predicted that mpox transmission should have largely disappeared by early 2023. But when the researchers incorporated repeated viral introductions into the simulations, the model closely matched the persistent low-level transmission observed in real-world surveillance data.
The simulations also suggested that sexual behaviors, which changed substantially during the height of the 2022 outbreak, largely returned to baseline by 2023 and 2024.
“The 2022 epidemic was controlled by a combination of MSM decreasing their sexual activity and vaccine- and infection-induced immunity,” said Dr. Miguel Paredes. “Given the return of baseline sexual behavior, how do we keep mpox cases low and prevent it from increasing again?”
Notably, the researchers found that local transmission alone likely remained below the threshold needed to sustain a major outbreak. Instead, repeated introductions from outside Los Angeles continually replenished the virus in the community.
The study also highlights how combining genomics with epidemiological modeling can help guide public health interventions. The researchers used computer modeling to test how different intervention strategies might affect mpox spread and found that targeted public health efforts timed to periods with the highest rates of viral introductions — such as vaccination campaigns or behavioral messaging in the spring and early fall — could substantially reduce case numbers.
“Our microsimulation model showed how targeting the months where the introductions are the highest could be an effective way to keep the local number of mpox cases at bay,” said Paredes. “To control mpox you need to intervene frequently, rather than just a single one-off intervention.”
The findings also raise new questions about what drives these waves of viral introductions and why some transmission clusters grow larger than others. The researchers suspect that travel patterns, Pride events, and students returning to campuses may contribute to seasonal increases in introductions, but more detailed studies will be needed to understand the underlying drivers.
“We’d love to be able to work with local health departments to investigate, at an individual level where we can combine patient data with viral genomic information, why some infection clusters are larger and more long-lasting than others,” said Paredes. “Are the individuals in the larger clusters more likely to be younger or unvaccinated or partially vaccinated? So many questions to explore.”
Beyond mpox, the study demonstrates how integrating viral genomics with mechanistic modeling can provide a framework for studying infectious disease transmission in real time.
“I think our results act almost as a template for how to conduct detailed epidemiology analysis of infectious diseases which allows us to tailor our interventions to the local population rather than rely on a one-size-fits-all playbook,” Paredes added.
As mpox continues to circulate globally, the researchers hope their combined genomics and modeling framework can help public health officials respond more proactively to future outbreaks. Rather than treating transmission as a single, continuous epidemic, the study highlights how repeated introductions, changing behavior, and local network dynamics can together sustain persistent disease spread — and how understanding those patterns may help stop the next spark before it spreads.
The spotlighted research was funded by the ARCS Foundation, the Howard Hughes Medical Institute, the National Institutes of Health, the UC Noyce Initiative, the National Science Foundation and the Centers for Disease Control.
Paredes MI, Liang C, Suen S, Holloway IW, Garrigues JM, Green NM, Bedford T, Müller NF, Osmundson J. 2026. Viral introductions and return to baseline sexual behaviors maintain low-level mpox incidence in Los Angeles. Nature Communications. DOI: 10.1038/s41467-026-71993-w.
Science Spotlight writer Jenny Waters is a postdoctoral research fellow in the Hsieh lab at Fred Hutch. She studies how mRNA translation coordinates bladder cancer transformation and metastasis by post-transcriptionally regulating expression of oncogenic proteins. Outside of the lab, Jenny enjoys spending time with her dogs, convincing her husband to join her on trail runs, and pretending every steep hill is just a "gentle incline."