Monkeypox outbreak questions intensify as cases soar

The sudden appearance of monkeypox in 13 countries on four continents has jolted the public health community into action. A much milder cousin of smallpox that sporadically causes small outbreaks in Africa, monkeypox is thought to spread slowly and is unlikely to be a pandemic in the making. But scientists worry about the spread among men who have sex with men (MSM), who make up a disproportionate number of the cases so far. The outbreak is a strange and unsettling return to the spotlight for poxviruses, a largely forgotten threat since the World Health Organization (WHO) declared smallpox eradicated in 1980.

The current outbreak surfaced on 7 May in the United Kingdom, which so far has confirmed 20 cases. In the past 3 days, more than 100 suspected cases were reported in Spain, Portugal, the United States, Canada, Sweden, Italy, Belgium, France, Germany, the Netherlands, Australia, and Israel. David Heymann, an epidemiologist at the London School of Hygiene & Tropical Medicine who helped eradicate smallpox and first worked on a large monkeypox outbreak in Africa 25 years ago, expects “many more cases” to come to light in the days and weeks ahead.

Monkeypox virus typically spreads by close contact and respiratory droplets, but sexual transmission appears to be contributing to this outbreak. “This is not typical at all,” says epidemiologist Rosamund Lewis, WHO’s lead for poxvirus diseases. “We should definitely be concerned about this new situation, which has literally just come about in the last 5 days.” WHO’s Strategic and Technical Advisory Group on Infectious Hazards with Pandemic and Epidemic Potential, which Heymann heads, met today to develop recommendations covering everything from the need for more aggressive surveillance to the use of monkeypox vaccines.

“Monkeypox” is a misnomer; the virus was discovered in 1958 in a colony of research monkeys, but its natural hosts are most likely rodents and other small mammals. The virus first surfaced in humans in 1970 in what is now the Democratic Republic of the Congo, causing fever, headaches, and lymph node swelling followed by an eruption of pus-filled blisters resembling smallpox lesions. Outbreaks occur occasionally in sub-Saharan Africa after someone comes in contact with an infected wild animal, and infected travelers sometimes carry the disease to other countries. In 2003, the United States had 47 cases that were linked to pet prairie dogs infected by other species imported from Ghana.

Most people recover within a few weeks. The Congo Basin strain kills up to 10% of those infected, but the recent outbreak appears to only involve the West African strain, which in past outbreaks had a fatality rate of about 1%.

Outbreaks “generally fizzle out on their own,” Lewis notes, because many infected people never infect anyone else. This outbreak, however, “is on such a broad geographic area that overall this number of suspected cases seems to be surprisingly high.”

Although “really rare and unusual,” the outbreak is not likely to become a major threat outside the MSM community, says Agam Rao, a scientist in the poxvirus and rabies branch of the Centers for Disease Control and Prevention (CDC), which confirmed the first U.S. case. “It’s a small subset of the population, and we don’t expect it to be taking off the way COVID-19, for example, took off,” Rao says.

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Scabs cover the skin lesions developed by a child and an adult who contracted monkeypox in the United States in 2003.CDC/Getty Images

Multiple introductions? 

The first reported case in the current outbreak is a traveler who on 4 May returned to the United Kingdom from Nigeria, a monkeypox hot spot. Clinicians confirmed the patient had monkeypox 3 days later. But that person had no connection to any of the other cases detected to date, according to the UK Health Security Agency, suggesting there may have been multiple introductions from Africa.

Yesterday, a team led by João Paulo Gomes at Portugal’s National Institute of Health posted the first full genome of the virus, which most closely resembles viruses that travelers exported from Nigeria in 2018 and 2019 to Singapore, Israel, and the United States. The Portuguese researchers sequenced the virus from a sample collected on 4 May, which means the infected person likely had no connection to the index patient in the United Kingdom. At the time, Portuguese doctors had no idea what caused their patient’s lesions, Gomes says, and they didn’t test the sample until they learned of the unusual clusters of cases in the United Kingdom. “No one could imagine a case of monkeypox,” he says.

Indeed, monkeypox is so rare that few doctors have ever seen a case. Its lesions resemble those seen with other diseases such as chickenpox and syphilis, and most doctors would not think to test for it. In addition to time-consuming tests that require sequencing the large virus—about 20 times larger than HIV—labs can also use the polymerase chain reaction assay, which can probe samples for tiny bits of monkeypox viral DNA and then amplify it to detectable levels.

Sexual transmission of monkeypox has never been proved, although Nigerian researchers in a 2017 report suspected it might have occurred, because several patients had genital ulcers. Fernando Simón, who directs the Spanish Ministry of Health’s coordination center for health alerts and emergencies, says all seven of the confirmed cases reported on 19 May in Spain were MSM or transgender people who had attended sex parties. (Spain today reported an additional 23 suspected cases.)

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“Most of the cases have lesions exclusively perigenital, perianal, and around the mouth,” Simón says. There is no evidence that semen can transmit the virus. “So far, the most acceptable hypothesis is that it is transmitted after the contact with lesions.” But he stresses that transmission could have occurred by contact that did not involve sex.

None of the patients in Spain so far became severely ill or remain hospitalized. Two have HIV infections that are well controlled with medication. MSM and transgender communities have a high prevalence of HIV, but there’s no evidence that compromised immune systems have played any role in this outbreak. Health officials in many affected countries have, for privacy reasons, offered few details about the infected people. (Simón notes that small groups on social media have used the occasion to make offensive remarks about gay, bisexual, and transgender people. “It’s a pity, but these groups exist,” he says.)

It’s possible that monkeypox began to spread in MSM well before May, Heymann says, but wasn’t detected. Transmission may have been at a very low level during COVID-19 lockdowns, he speculates, “and then all of a sudden, things opened up and people begin living their lives again.”

Filling a niche

Monkeypox’s cousin, smallpox, was a major scourge for centuries that killed up to 30% of those infected. A massive global campaign in the 1960s and ’70s brought transmission to a halt; today, the virus is the only human pathogen to have been eradicated, although samples still exist at laboratories in Russia and the United States. As cases plummeted in the early ’70s, countries began to stop using the smallpox vaccine because its risks outweighed potential benefits. The vaccine contained a labmade virus called vaccinia that replicates inside the recipient and sometimes caused severe side effects, killing one in 1 million vaccinated people. WHO’s vaccination campaign ended in 1977, the last year a natural case of smallpox occurred.

Smallpox infections and the smallpox vaccine both protect against monkeypox, so an increasing number of people have become vulnerable to monkeypox over the past 50 years. Some researchers have worried that monkeypox might evolve to fill the “ecological niche” left behind by smallpox. Indeed, reported cases have steadily increased in Africa over the years—and the new outbreak is the first one to take place on several continents simultaneously.

Two vaccines that protect against smallpox and monkeypox are available in Europe and North America. One, manufactured by Emergent BioSolutions, is similar to the vaccine used during the eradication campaign and can still cause severe disease and even death in people who have compromised immune systems. The other, from Bavarian Nordic, uses a nonreplicating form of vaccinia, specifically designed to cause fewer side effects. It is the only vaccine explicitly approved for monkeypox.

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Vaccines in short supply

Earlier this month, the United Kingdom started to offer vaccines to health care workers who had been in contact with monkeypox patients. Spain has yet to do so, says Simón, who notes that the country’s infectious disease clinicians have the personal protective equipment and experience to protect themselves. Massachusetts General Hospital, which is caring for the only confirmed case in the United States, also has not offered staff a vaccine. They, too, take appropriate precautions, says Paul Biddinger, who heads the hospital’s center for disaster medicine. But even though the United States has approved vaccines, clinicians cannot prescribe them: They only exist in a national stockpile that CDC controls. For now, it deems health care workers at the hospital in an “intermediate” risk category that doesn’t warrant vaccination.

The vaccines, which prevent disease even if used up to 4 days after a person is exposed to the virus, could also be used to protect contacts of suspected or confirmed monkeypox cases. So far, no countries have announced plans to do so. Both vaccines are in short supply and typically only available through national stockpiles.

In a bizarre coincidence, Bavarian Nordic held a meeting with Heymann and nine other public health leaders from around the world this week, planned 6 months ago, to discuss the need for more countries to stockpile its vaccine, given the increase in monkeypox cases over the past few years. “We were really thinking that experts in this field and authorities need to start to reflect on it,” says Bernard Hoet, the company’s vice president of medical strategy. “A company like ours cannot stockpile for all the countries forever. Today we have some doses available and we are going to distribute them, but how do you want us to decide if they go here or there?”

Drugs also exist to treat severe cases of monkeypox. One, tecovirimat, in 2018 became the first drug approved by the U.S. Food and Drug Administration (FDA) to treat smallpox after it proved safe in human trials and effective in animals given closely related viruses. Based on similar data, FDA approved a second drug for smallpox, brincidofovir, last year.

Although drugs and vaccines offer hope for limiting the severity and scope of this outbreak, a WHO statement issued on 18 May cautions that “these countermeasures are not yet widely available.” And alarm bells will likely ring louder and louder if cases continue to mount and the virus surfaces in ever more countries.

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