From the start of the global monkeypox outbreak, researchers have hoped that people could only spread the virus once they developed symptoms.
But a study from Britain's Health Security Agency published Wednesday in The BMJ suggests that pre-symptomatic transmission is possible, and may even be relatively common — a finding that could make it difficult to eliminate new cases entirely or prevent future outbreaks.
The study examined more than 2,700 people with monkeypox in the U.K. from May 6 to Aug. 1. The researchers were able to link 13 of those cases to the people they infected. Ten pairs showed evidence of pre-symptomatic transmission, meaning the first patient spread the virus to the second before the first felt sick or had developed lesions.
Using models, researchers estimated that 53% of monkeypox infections could spread pre-symptomatically. The virus could be transmitted up to four days before symptoms start, the researchers found.
In addition to painful lesions, monkeypox symptoms can include fever, chills, swollen lymph nodes, headaches, muscle aches, back pain and fatigue.
The study is the first to demonstrate that poxviruses, which include both monkeypox and smallpox, can spread in this manner. Past research suggested that asymptomatic and pre-symptomatic transmission of monkeypox was possible, but only symptomatic transmission had been documented.
“There is still more work needed to understand pre-symptomatic and asymptomatic infections and what that might mean for future policies and management of the monkeypox outbreak,” Dr. Nachi Arunachalam, the monkeypox incident director at the Health Security Agency, said in a statement.
Dr. Esther Freeman, the director of global health dermatology at Massachusetts General Hospital and Harvard Medical School, said 53% might be the upper limit of pre-symptomatic transmission. Monkeypox lesions aren't always easy to detect, so some people may mistakenly report that they’re symptom-free, she wrote in an editorial published Wednesday alongside the study. The lesions start out as bumps that can look similar to ingrown hairs, then turn into fluid-filled blisters that can resemble chickenpox, syphilis or herpes.
"We are seeing a substantial portion of our patients that have less than five lesions. I think it is possible to miss it," Freeman said.
Nevertheless, the U.K. study "raises the chance that there may be more pre-symptomatic transmission going on than we realized," she said.
The findings also suggest that some cases won't be prevented by only isolating people who develop symptoms. Freeman said the data supports expanding vaccine eligibility in the U.S., assuming that more doses become available and high-risk groups in other countries are able to get vaccinated, too.
“The fact that there can be pre-symptomatic transmission makes our likelihood of being able to completely eliminate this virus harder,” Freeman said.
But the current outbreak appears to be winding down. Average daily cases in the U.S. have fallen 93% since their peak on Aug. 7. The U.S. recorded 30 daily cases, on average, on Oct. 26. Cases have also declined since July in the U.K. and European Union.
Several mysteries still remain
Monkeypox hasn't behaved in predictable ways over the last several months. The virus is primarily spreading through close contact during sexual activity, with the majority of cases occurring among men who have sex with men. During past outbreaks, people were exposed through contact with infected wildlife, the exchange of respiratory droplets in household or health care settings, or contact with contaminated items like clothing or bedding.
Since the start of the current outbreak in May, many studies have detected the virus in semen, and New York state recently designated monkeypox as a sexually transmitted infection to expand access to testing, treatment and vaccination.
“There’s been a lot of conversation about the potential for truly sexual transmission versus what we call transmission during sex," said Dr. Wafaa El-Sadr, a professor of epidemiology and medicine at Columbia University. "Until we have definitive proof, we still would always tell people to assume that sexual transmission can occur."
Scientists also have more to learn about how often people develop symptoms in the first place. In October, researchers in France detected 11 asymptomatic cases of monkeypox, as well as two people who tested positive before their symptoms started. In total, those patients represented around 6% of monkeypox cases in the study. A month earlier, researchers in Belgium identified three asymptomatic cases among four people who tested positive for monkeypox.
"It's quite feasible that, even though the individual may not already have symptoms of those lesions, they may have been shedding the virus without even knowing it," El-Sadr said.
For the monkeypox vaccine to be effective, it must be administered before symptoms develop, ideally within four days of exposure to the virus. The U.S. is currently offering vaccines to men who have sex with men, transgender people and nonbinary people with multiple sex partners or recently diagnosed sexually transmitted diseases, as well as people who have had sex at bathhouses, sex clubs or sex parties. The U.K. has similar criteria for vaccination, but it is also vaccinating health care workers who are caring for monkeypox patients.
El-Sadr said the U.S. vaccination strategy could be sufficient to end the country's outbreak, though others have said eliminating the virus entirely is unlikely.
With this new observation about pre-symptomatic spread, Freeman said, it may be impossible to reach a point of zero cases.