The disease formerly known as monkeypox, which spread around the world in an unprecedented outbreak in 2022, was circulating in humans for more than five years before the explosion of cases triggered a global public health emergency, researchers say. The discovery of longstanding, hidden transmission between humans has led to calls for improved global surveillance of the MPXV virus to eliminate the disease, renamed mpox last year, from humans and prevent it from re-emerging. “Any new or nascent outbreak may have potential to go global,” said Dr Áine O’Toole, an evolutionary biologist at the University of Edinburgh, who studied the virus’s evolution. “We need to focus on detecting outbreaks even when case numbers are low, and find a way of stamping it out before it establishes in the human population.” Mpox was first discovered in the 1950s when outbreaks of the disease struck monkeys held in laboratories for research. The first human case was recorded in 1970 in the Democratic Republic of the Congo (DRC). Sporadic cases over the next 50 years were largely in the DRC and Nigeria. Before 2020, most human mpox infections were blamed on contact with rodents that can carry the virus in countries where the disease is endemic. On the rare occasions that people passed the infection on, those affected were typically family members living under the same roof. The global mpox outbreak was different, however. Writing in the journal Science, O’Toole and her colleagues describe how viruses collected from patients in 2022 carried far more mutations than expected. The mpox virus is expected to pick up one mutation every three years, but compared with virus collected in Nigeria in 2018, mpox from patients in 2022 had a whopping 42 mutations. A closer look revealed that the majority of mutations were caused by skirmishes with the human immune system, in particular an antiviral enzyme called apobec3. The finding means that the human immune system is driving the evolution of the virus, marking the switch to its sustained spread in humans. Based on the rate of mutations, the scientists estimate that mpox has been circulating in humans since at least 2016. The global mpox outbreak was driven by a lineage called B.1, and cases have been in decline following public health advice and vaccination programs largely aimed at men who have sex with men, who accounted for the vast majority of cases. But the researchers point out that countries such as the UK, the US, Portugal, India and Thailand, continue to report other lineages of the virus, almost all of which trace back to Nigeria, suggesting that the human epidemic that sparked the 2022 outbreak continues “unabated”. Dr Emma Hodcroft, principal investigator at the Swiss Tropical and Public Health Institute in Switzerland, who was not involved in the study, said circulation of the virus in humans long before 2022 likely set the stage for the virus to be able cause a global outbreak. “Knowing [that the virus] has been, and still is, circulating in a sustained fashion in humans changes how we should approach prevention and eradication strategies, and serves as a reminder that undetected changes in viral behaviour can lead to later changes in virulence or transmissibility that pose a larger threat,” Hodrcroft told the Guardian. “To truly keep these viruses on the radar globally, we need to keep demanding more equitable training, funding and equipment distribution.”