10 key questions about monkeypox the world needs to answer

Just over three months ago, public health authorities in the U.K., Europe, and the U.S. began to sound the alarm on the arrival of monkeypox. Since then, this long-neglected tropical disease — which until this year was mostly limited to periodic spillovers in the areas of Western and Central Africa where the virus is endemic — has gone global. As of Aug. 26, 100 countries had reported nearly 47,000 cases, according to the World Health Organization.

The explosive epidemic has caught governments off-guard and sent scientists scrambling to better understand the orthopoxvirus causing it.

Unlike with SARS-CoV-2, they’re not starting from scratch. Monkeypox is not a new virus. It was first discovered in research monkeys at a lab in Denmark in 1958, and identified as a human pathogen in 1970. But with little attention from the international community, monkeypox research received scant funding over the ensuing decades, leaving many key questions about the virus unanswered. The current outbreak, which is unique both in the speed of spread and the ways in which people are becoming infected, has also prompted new ones.

STAT examined some of the most pressing of these questions, many of which won’t be resolved without more time and data. Others may remain mysteries. But at least in some cases, emerging evidence is beginning to provide clues to what the eventual answers may be — clues that are likely to shape how public health agencies and health care systems respond to the current outbreak, and where it goes from here.

Where does the damn thing come from?

One thing we know: Monkeys aren’t the original source of the monkeypox virus. What is the actual reservoir host? That is an important but unanswered question.

A reservoir is a species that can carry a pathogen without being sickened by it. Bats, for instance, are thought to be reservoirs for all sorts of nasty viruses — Marburg virus, its cousins, the various species of Ebola, and untold numbers of coronaviruses, among others. These viruses can be deadly if they manage to make their way from bats to other species, including our own. But there’s no evidence they harm bats in any way.

As we’ve mentioned already, monkeypox got its name because monkeys were the first species seen to be infected with this poxvirus. But it was noticed because the virus made the monkeys ill, meaning they weren’t the reservoir.

Many species of animals can contract monkeypox. Hedgehogs, shrews, squirrels, anteaters, prairie dogs — all these can contract the virus, and, under certain circumstances, transmit it to people.

But all the identified rodents and other small mammals are victims of the virus, not the reservoir, Jean-Jacques Muyembe, the legendary microbiologist who runs the National Institute of Biological Research in the Democratic Republic of the Congo, cautioned during a recent panel discussion hosted by the Harvard Global Health Institute.

The search for the source continues. That fact underscores an important truth about monkeypox. Even if this multi-national outbreak is stopped, monkeypox will remain a threat.

(A quick P.S.: The rapid geographic spread of monkeypox has sparked fears that the virus will get seeded into susceptible species in parts of the world where it hasn’t traditionally been found, enlarging the area in which it is endemic.

The Centers for Disease Control and Prevention and other health authorities have warned people who contract monkeypox to refrain from contact with any pets they might have, for that very reason. And a recently published letter in The Lancet revealed the wisdom of that advice. A dog owned by two gay men in Paris appears to have contracted monkeypox from them.)

Why are lesions localized in some people who contract monkeypox, and disseminated in others?

Some people who contract monkeypox develop lesions over a variety of body parts — the torso, the face, the soles of feet, the palms of hands, and especially in this outbreak, which is occurring mostly in gay and bisexual men who have sex with men, in the anogenital area.

Some of the men infected in this outbreak have had their lesions situated almost exclusively on their penises or in or around their anuses.

Some, perplexingly, have had only a few lesions. Some diagnosed cases have had a single lesion.

Why this puzzling range of manifestations of lesions? This is something science doesn’t currently have an answer for, said Anne Rimoin, a monkeypox expert at the University of California, Los Angeles. “It could be the dose,” she said, referring to the amount of virus a person is exposed to when contracting monkeypox. In other words, it may be a matter of whether exposure was the result of fleeting contact with lesions or a more protracted event. Other factors may include the route of exposure — skin-to-skin or inhaled droplets, for instance. The immune status of the person being infected could also influence this outcome. “But it’s probably a combination of these elements,” Rimoin said.

What role are asymptomatic individuals playing in transmission?

Monkeypox prefers to replicate in the skin and mucous membranes. That’s why scientists tend to find the highest concentrations of virus in the lesions of infected individuals. It’s also why it would be surprising if people without such lesions were spreading monkeypox to others.

But several small studies have begun to raise concerns about that possibility.

During a retrospective screening of anorectal swabs collected from more than 200 asymptomatic men at a sexual health clinic in Paris, French researchers found virus on 13 samples. One of the men later developed an anal rash and the other experienced sore throat and fever. None of the others ever reported symptoms. A similar study, not yet peer-reviewed, from researchers in Belgium found three positive samples out of 224 asymptomatic individuals.

But it’s still not clear whether people without symptoms can pass monkeypox on to others. If they can, then post-exposure ring vaccination strategies might not be sufficient to contain further spread of the virus. (Ring vaccination involves immunizing individuals who have been exposed to monkeypox through close contact with an infected person. The idea is to catch people early enough that their immune systems can nip a potential infection in the bud before they become contagious.)

Getting a better grip on the extent of asymptomatic spread will require much more testing, including at-home, self-administered tests, said Celine Gounder, an infectious disease epidemiologist and editor-at-large for public health at Kaiser Health News.

“We need to start getting tests in people’s hands and making it possible for somebody to swab themselves,” Gounder said. “That would really help us get more data on this question.”

Can monkeypox, like Ebola, pose a post-infection risk of transmission?

Monkeypox is a poxvirus, as its name implies. Ebola is a filovirus. These are different beasts.

And yet a quirk of Ebola viruses — and their close cousin, Marburg virus — is casting a shadow over the current monkeypox outbreak.

Filoviruses can squirrel themselves away in parts of the body where immune system weaponry cannot reach them. These are known as “privileged sites” — the eyeball, synovial fluid (the fluid in joints), spinal fluid, and most importantly for this discussion, the testicles.

From the very earliest days of recorded outbreaks of filoviruses, there was a suspicion that survivors could harbor viruses and pass them to others, primarily through sex. Later, it became clear that viral persistence, as it is called, is a feature of these infections. A portion of people who survive filovirus infections will suffer a relapse later; a Scottish nurse infected when she worked on the West African Ebola outbreak in 2014 had two subsequent resurgences of illness. In other cases, male survivors have infected sex partners months, even years after recovering.

It is not known if monkeypox virus can similarly lodge in testicles and pose a post-infection transmission risk. But the fact that scientists are discovering monkeypox viral DNA in semen, and in one case even managing to grow live virus from semen, is raising the question.

It is thought that monkeypox is a one-and-done infection, that people who survive — as most people do — have life-long immunity. They cannot be reinfected and pose no transmission risk after they recover. But that calculus changes if survivors have monkeypox virus hiding in their testicles or other parts of their bodies.

Because of the unanswered questions, the Health Security Agency in the United Kingdom is recommending men who have had monkeypox wear condoms during sex for at least 12 weeks after recovering. The CDC says wearing condoms is advisable, but at present there is little data on which to make such a recommendation.

Do people who have recovered from monkeypox pose a near-term or longer-term transmission risk? It’s an important question that needs to be answered. With such a large pool of monkeypox survivors to study, this outbreak should provide opportunities to do so.

How well does the vaccine work at reducing symptoms and preventing infections?

Both the CDC and the WHO estimate that the available smallpox vaccines are about 85% effective against monkeypox. But experts caution that the highly cited figure should not be taken at face value, particularly in the context of the current outbreak.

The figure dates back to an observational study involving 245 people infected with monkeypox in Zaire (now the Democratic Republic of the Congo) between 1981 and 1986, and more than 2,000 of their contacts. Individuals who had a visible scar from a jab with the first-generation smallpox vaccine were about seven times less likely to contract monkeypox after exposure to an infected person than those who were unvaccinated.

Another study, also conducted in Zaire in the 1980s by the same WHO monkeypox surveillance team, took a closer look at how the vaccine impacted the severity of symptoms. Among 282 patients — the vast majority of them children under the age of 15 — unvaccinated individuals were twice as likely to have large numbers of lesions crop up, and three times as likely to have multiple lesions in the genital area.

Without a smallpox shot, monkeypox patients sometimes suffered gruesome outcomes, including complications that could turn deadly. The researchers reported that one out of 10 unvaccinated monkeypox patients died, with even higher fatality rates among the youngest children. One 5-year-old boy endured more than 4,500 lesions before succumbing to blood poisoning caused by a secondary bacterial infection. In contrast, none of the vaccinated patients died.

The historic smallpox vaccines administered in these studies are no longer in production. But newer ones, like MVA-BN, a third-generation smallpox vaccine manufactured by Bavarian Nordic, are expected to have similar efficacy against monkeypox, based on studies in people that showed comparable antibody responses. However, they haven’t been directly tested against the disease in clinical trials.

MVA-BN, known in the U.S. as Jynneos, is currently the only vaccine in this country licensed by the Food and Drug Administration to prevent monkeypox infection. Its initial approval for smallpox was based on favorable data from nearly two dozen clinical trials with more than 7,500 participants. But when the agency later approved the vaccine for monkeypox, its decision was based on data from animal experiments, including non-human primate studies. Eighty to 100% of the monkeys who got the jab later survived a lethal dose of the virus, compared to zero to 40% of the placebo group.

“I’m not aware of any good data on vaccine protection,” said Rimoin. Surveillance studies conducted by her group in the 2000s found hints that first-generation shots had been effective; 30 years after mass smallpox vaccination campaigns ceased in central Africa, incidence of monkeypox cases there increased 20-fold.

But she doubts that such data can be extrapolated to the current outbreak — which is primarily spreading through sexual contact. Mucosal surfaces are easier for the virus to infect, and the prolonged contact that happens during sex is likely exposing people to much larger doses of the virus than the groups of people who were studied in western and central Africa in previous decades.

“This is the crux of the problem,” said Rimoin. “I think that we are expecting more from these vaccines than they were designed for. This kind of intense, often repeat, mucosal exposures are very different from animal exposure, household, fomite, or respiratory droplet transmission.”

These perhaps outdated estimates of vaccine effectiveness are based on studies of pre-exposure vaccination. There’s even less data supporting the ring vaccination strategy being deployed by countries including the U.S., the U.K., and Canada. That strategy hinges on having rigorous contact tracing and a long incubation period in which to operate. And while the approach has proven very effective at curbing smallpox it’s not obvious yet that it will work as well for monkeypox.

So far, there’s been just a single observational study looking at the question directly. In a paper released (but not yet peer-reviewed) earlier this month, researchers in France reported that among 276 high-risk contacts who were vaccinated post-exposure, 12 of them later contracted the disease. However it’s hard to say whether these were true breakthrough infections because most of them received their shots more than a week after the exposure, outside the recommended four-day window.

“It’s possible they developed the disease because they were vaccinated a bit too late,” said Michaël Thy, a tropical infectious disease doctor at Paris Cité University who led the study. But he noted that none of the 12 who experienced symptoms required hospitalization, indicating that post-exposure vaccination may reduce the severity of infection, if not infection itself.

The study was small, and all the participants received a single dose of Jynneos so there’s no way to say whether the vaccine cut the risk of infection. The only way to do that is a randomized controlled trial — with some people getting the real deal and some people receiving a placebo shot.

Rimoin is among the researchers racing to set up such a study. If the funding comes through, her group hopes to quickly roll out trial sites in Los Angeles and the Democratic Republic of the Congo.

Until there’s more data, the most important thing that patients should know is that the vaccine, even two doses, does not provide 100% protection, said Thy. “It’s an important part of a combined strategy for lowering the risk of infection, but it’s not the only thing people should be doing.”

Will the virus continue to primarily infect men who have sex with men?

In the U.S. and Europe, monkeypox has so far primarily affected men who have sex with men. But historically, outbreaks that begin in one community do not stay there.

HIV famously spread far beyond gay and bisexual men in the ’80s, fueled in part by officials who ignored early warnings that there was no such thing as a gay disease. In the 2000s, an outbreak of drug-resistant bacteria was first spotted in gay men but ultimately spread to athletes and took its greatest toll on people in prison.

For now, monkeypox’s next move remains unclear. Much of the news is positive: The virus appears to be more difficult to transmit through casual contact than initially feared, narrowing its potential paths. Cases have also been declining in New York, San Francisco, and much of Europe, as more vaccines become available and people minimize their risk of exposure through sex.

“There are some encouraging trends,” said Chris Beyrer, an epidemiologist and incoming director of the Duke Global Health Institute. “If we can contain this epidemic of this outbreak in men who have sex with men, that is our best shot.”

And yet the news is not good everywhere. The monkeypox response has so far been marked by inequities. In North Carolina, 72% of people diagnosed with monkeypox are Black, according to data released earlier this month, but only 24% of vaccines have gone to Black residents — a glaring example of a racial disparity seen in much of the country.

The longer these disparities go unaddressed, the more likely the virus is to stick around and spread broadly, including into prisons and other overcrowded settings, or to even become endemic among animals in North America.

“We have this window of opportunity right now. We have encouraging data that vaccination and behavior change in combination are getting control of the outbreak in New York City,” said Beyrer. “ I wish the rest of the country looked like New York right now.”

When people with monkeypox die, what do they die from?

One thing that is becoming clear in this multi-country outbreak is that the monkeypox case fatality rate is not as high as was previously estimated, at least for clade II viruses (the former West African clade) and when infections are primarily in adults. Figures ranging from 1% to 3% have historically been cited. But out of the nearly 47,000 cases that have been detected so far this year, there have been roughly 15 deaths reported.

Some of the questions we’re exploring here aren’t currently answerable. For this one, there are data — though not enough. In the endemic countries, where most of the monkeypox deaths have occurred, there haven’t always been detailed records of the causes of death. But if you dig into the scientific literature, there are some clues.

In 1987, researchers from the WHO’s long-defunct smallpox eradication unit and the Democratic Republic of the Congo’s monkeypox surveillance team published a major piece of work that charted the disease course of 282 people who contracted the virus between 1980 and 1985. (We referred to this study in the section above on vaccine efficacy.) In the paper, they compared severity of symptoms and outcomes of patients who had previously been vaccinated against smallpox — a vaccine against a related virus that should offer some cross-protection against monkeypox — and those who had not.

There were no deaths among the monkeypox patients who had a smallpox vaccination scar. But among the 250 who did not, there were 27 fatal cases. All the deaths occurred in children under the age of 8, and the case fatality rate was more than twice as high among those 4 years of age and younger than among kids 5 to 9.

Nineteen of the children who died developed bronchopneumonia and pulmonary distress. One developed septicemia, an infection on the blood stream. One developed encephalitis — inflammation of the brain.

A paper on Nigeria’s 2017-2018 monkeypox, published in the journal The Lancet Infectious Diseases in 2019, reported that among 122 cases there, seven had been fatal. Four of those were people who were living with HIV but in whom the disease was untreated at the time of their monkeypox infection. They died rapidly, the authors reported, though they noted a precise cause of death was not available in these cases.

Two other deaths were attributed to secondary bacterial infections of monkeypox lesions, with apparent sepsis — a dangerous condition where the body’s attempt to curb an infection backfires and leads to organ damage. The seventh death was in a one-month-old infant.

A systematic review published in February in PLOS Neglected Tropical Diseases — presciently titled “The changing epidemiology of human monkeypox — A potential threat?” — noted that from the 1970s through the 1990s, 100% of recorded fatal monkeypox cases were in children younger than age 10. But in the first two decades of this century, pediatric deaths declined to 37.5% of monkeypox cases.

And in this outbreak? What have the fatal cases died from?

At least a couple of those patients were younger men — one 31, one 44 — who were not immunocompromised and had no underlying chronic diseases. These occurred in Spain. The men both developed encephalitis.

Some of the deaths have occurred in immunocompromised people. On Tuesday, Texas reported a fatal case in a person who was “severely immunocompromised.” Late last month Brazil recorded a death in a man who had lymphoma; Mexico recently registered a death in a man who was living with HIV. He died from septic shock and pneumonia; his death has not yet been recognized as a monkeypox-related death by the WHO. The autopsy of an Italian tourist who died recently in Cuba reportedly revealed he had sepsis linked to pneumonia and organ damage. A death in Ecuador was attributed to an unspecified pre-existing disease.

For most of the monkeypox deaths that have occurred this year, however, there isn’t a precise cause of death that has made its way into the public domain. In at least some of those cases, scientific papers are probably already in the works. So we’ll need to bide our time to get more answers.

Does having been vaccinated against smallpox decades ago protect against monkeypox today?

The age distribution of cases shows there are far fewer infections among people 60 and older — in other words, people who would have been vaccinated against smallpox when they were kids. But is that the effect of protection from previous vaccination or lower rates of exposure in older men? Or both?

It’s not 100% clear. But it is possible it has more to do with risk of exposure than residual protection from a jab given decades earlier.

The median age of cases in the global outbreak is 36. Men aged 18 to 44 make up 78% of all cases, according to WHO data. They would be too young to have been vaccinated against smallpox when they were children.

It’s apparent from some of the studies we cite in this article (see the references to the study of 282 monkeypox cases in Zaire) that even back in the 1980s, people who had been relatively recently vaccinated against smallpox could contract monkeypox. But they had a milder course of illness when they did.

A study conducted in the United States after an extraordinary monkeypox outbreak in 2003 sheds a little light here. In that event, the first recorded monkeypox outbreak outside of Africa, three of the 47 people who contracted the virus were completely asymptomatic. They had been vaccinated against smallpox when they were young — 13, 29, and 48 years earlier. Five other people previously vaccinated against smallpox developed monkeypox disease in that outbreak, but they had, in the main, fewer lesions than unvaccinated people.

How long does protection from prior smallpox vaccination last? Researchers have estimated that protection against severe disease erodes after about 32 years and protection against fatal disease lasts nearly 52 years. But those estimates are based 1) on protection against smallpox (monkeypox protection from smallpox vaccine starts out already reduced) and 2) calculated using data from a 1903 smallpox outbreak in Australia.

Has the virus changed in any consequential way — or will it?

When scientists started sequencing the viruses behind this outbreak, what was notable was just how many mutations the pathogen had picked up in a few years — and what clues those mutations contained. There was a concern early on that changes to the virus’s genome had made it more transmissible, explaining the unprecedented global spread of the virus. In actuality, though, the research has indicated that the mutations were evidence of a years-long fight with human immune systems, not signs of a fundamental change in the virus. Those genetic scars left over from past battles with immune systems also provided a roadmap for scientists, who used them to estimate that this line of viruses has been spreading among people since perhaps 2016.

Still, scientists are trying to determine if any of the mutations have given the virus some sort of advantage over other forms of the virus, even if at this point there are no obvious signs they did. But one thing they do know is that, as the virus spreads more, it has ever more chances to keep evolving and to perhaps pick up mutations that could make it even more of a threat.

What happens if individual communities contain their outbreaks?

There was a bit of good news last week: The WHO reported that cases globally had declined 21% from a week prior, largely due to a drop in newly confirmed cases from Europe. Even domestically, as we noted above, documented cases are on the decline in New York and San Francisco, as public health officials point to the impact of vaccination campaigns and behavioral changes among those most at risk, including reducing the number of sex partners people have.

Even if individual cities, or countries, can eliminate monkeypox, they won’t be able to move on entirely. They’ll have to continue surveillance to ensure the virus didn’t get established in animals locally — a source for potential future outbreaks. And with the virus still spreading elsewhere — the WHO has noted that infections are still increasing in Africa and Latin America — they’ll have to be on the lookout for reintroductions, particularly as people relax some of the behavioral changes they’ve made.

But if outbreaks are really brought under control in places in North America and Europe, the pressure on those countries to address the global problem of monkeypox will only increase. As the outbreak has shown, viruses that are defined as endemic to certain parts of the world don’t just stay there. Wealthy countries have also been criticized for not doing more to help the African nations that have animal reservoirs of the virus fight the pathogen, even as there were signs of more human-to-human transmission in recent years. Even now, as countries in Europe and North America have scooped up global vaccine supplies, those African countries don’t have access to vaccines. In the world of infectious diseases, memory is often short, and the public can quickly move on when something is no longer deemed a threat to them. We’ll see if this time is different.