What does the future look like for monkeypox?

On 29 April, a person in Nigeria developed an unusual rash and then travelled to the United Kingdom —carrying monkeypox with them. Since then, the virus has reached more than 70,000 people in over 100 countries. That has surprised health-care specialists around the world, because the sustained spread doesn’t resemble the sporadic pattern of previous monkeypox outbreaks in people, caused by a virus that lives in animals in Africa.

Almost six months after the virus started to spread, however, vaccination efforts and behavioural changes seem to be containing the current strain — at least in the United States and Europe (see ‘Monkeypox cases’). But the situation could still play out in several ways, say researchers. At best, the outbreak might fizzle out over the next few months or years. At worst, the virus could become endemic outside Africa by reaching new animal reservoirs, making it nearly impossible to eradicate. “There are so many factors at play that are working in opposing directions,” says Jessica Justman, an infectious-disease physician at Columbia University in New York City.

Specialists don’t expect that this year’s outbreak will cause the kind of worldwide disruption seen with COVID-19. The monkeypox virus doesn’t seem to be airborne like COVID-19, highly transmissible like smallpox or long-lasting in the body like HIV. It spreads mostly through sexual contact, and has been diagnosed mainly in men who have sex with men, particularly those with multiple sexual partners or who have anonymous sex. And although it causes severe, painful rashes, it is rarely fatal; the outbreak is a strain descended from the milder ‘clade 2’ monkeypox virus in West Africa. (A more deadly ‘clade 1’ virus is found in Central Africa.) It is not clear that the strain causing the current outbreak is any more intrinsically transmissible than its clade 2 ancestors; rather, a form of the virus could have reached a population whose behaviours led it to spread more rapidly, says Elliot Lefkowitz, a bioinformatician at the University of Alabama at Birmingham.

“I think we are in a good position to control this epidemic, but it will mostly rely on the behaviour of the population,” says Gerardo Chowell-Puente, an epidemiologist at Georgia State University in Atlanta.

With so much unknown about the latest monkeypox strain and so much contingent on how people respond, it is difficult to predict future trends. Still, researchers have developed scenarios to help plan for the different ways the outbreak might progress. Here are some of the big questions about monkeypox’s future.

What are the current trends?

In the United States and Europe, confirmed monkeypox infections have been declining since mid-August.

Public-health experts credit behavioural change: a study¹ by the US Centers for Disease Control and Prevention (CDC) that surveyed men who have sex with men found that around half had been curbing risky sexual activity because of concerns about the virus. Also probably helpful were public-health campaigns that told people what symptoms to look for and encouraged them to report cases, as well as vaccines that were offered to people at high risk (although the vaccines’ efficacy at reducing infection or spread is unclear).

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Still, the monkeypox case numbers have serious caveats, Justman says. Many people — and their physicians — probably do not recognize the symptoms or might be afraid to report an infection because of the stigma. “I have no confidence that all the people who need to be tested are being tested,” she says.

And some countries in South America and Africa are seeing the opposite trend. “It’s too early to say we have defeated it,” says infectious-disease physician Dimie Ogoina at Niger Delta University in Wilberforce Island, Nigeria. In that country, where the current outbreak is likely to have started, cases continue to rise, with a weekly record of 56 reported in September. The Nigeria Centre for Disease Control in Abuja says the country has seen more than 400 cases. That is a small number compared with the United States’ 26,000 cases, but is almost certainly a vast undercount; it is likely that many more are being missed in Nigeria than in the United States, Ogoina says. Nigeria does not have a strong disease-surveillance programme, and Ogoina expects that many people who catch the virus might not recognize the symptoms or go to physicians. Reported case numbers will always be undercounts, especially in areas that don’t have good surveillance programmes, agrees Rosamund Lewis, technical lead for monkeypox at the World Health Organization (WHO) in Geneva, Switzerland.

The WHO hopes to acquire 60,000 test kits to ship to Africa, but it is a logistical challenge to get people tested and diagnosed. It is also unclear whether the apparent rise in African cases reflects a true outbreak there or is the result of more thorough testing, Lewis says. She suspects that both factors contribute.

What do models project?

Because so little is known about how monkeypox spreads and how different factors could affect that, modelling more than a few weeks in advance is unlikely to produce an accurate result. The WHO does not release long-term monkeypox forecasts. And although the CDC releases a monthly technical report on the outbreak with a set of potential scenarios, the agency says it has only moderate confidence in its predictions. Its latest report, on 29 September, said that US cases are most likely to plateau or fall over the next month, but it is also possible they could increase exponentially (see go.nature.com/3sxrbmv).

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Chowell-Puente releases a weekly monkeypox forecast online, and follows trends in the United States and several countries in Europe. He uses several scenarios to produce an overall three-week forecast that has reflected real trends fairly accurately so far. As of 3 October, his forecast predicts that cases will either plateau or decline in the countries he models. Chowell-Puente says that although these trends could change if there is a new public-health policy, an alteration in the public’s behaviour or a mutation in the virus, they are unlikely to do so quickly. He hasn’t modelled cases in Africa, but says he might in the future.

Other models are more detailed, although not necessarily more accurate. One system, from researchers at RTI International (a non-profit global research institute headquartered in Research Triangle Park, North Carolina), used information from previous outbreaks of the monkeypox virus — specifically the clade 2 outbreaks — to project what could happen with the current strain. Previous notable clade 2 outbreaks include a short-lived one in the United States in 2003, which infected more than 70 people, and an outbreak in Nigeria that was spotted in 2017 and led to 146 suspected cases. From analyses of viral genomes, this seems to be the strain that led to the current situation.

Using information from those outbreaks — and assuming that the virus has not significantly mutated — Donal Bisanzio, an RTI epidemiologist who is based in Nottingham, UK, estimated viral transmissibility. He and his team modelled how the virus would spread over the course of weeks in a virtual high-income country of 50 million people. In as-yet-unpublished work, the model predicts that if the virtual country did nothing to combat the virus, it could expect around 6,000 cases (that is, infecting 0.01% of the population) before the outbreak fizzled out. This is largely because the virus is not very transmissible and because the model assumes (as is the case in countries such as the United States) that most older people have been vaccinated against smallpox, a related virus.

But the researchers found that the number of infections would drop significantly if infected people isolated themselves for three weeks (to wait out monkeypox’s possible incubation period), and if men who have sex with men curbed their sexual activity until the end of the outbreak. Vaccinating an infected person’s contacts could reduce infections slightly further.

Wouldn’t vaccination quash the outbreak?

Hundreds of thousands of doses have been distributed in Europe and the United States to help vaccinate people at high risk, such as men who have sex with men and people who have been in contact with someone exposed to the virus. Vaccinating everyone isn’t an option: the United States anticipates that fewer than two million doses of the most widely used vaccine — a repurposed smallpox jab — will be available this year.

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But it is unclear how much this has contributed to the slowdown in case numbers. One preprint², for instance, has suggested that, in people who have never had a smallpox inoculation, the vaccine does not seem to greatly boost levels of antibodies that can neutralize the monkeypox virus, and which are one component of an immune response. By contrast, the CDC has released crude case-rate data from US jurisdictions suggesting that monkeypox incidence — among those people recommended to receive the vaccine — has been more than ten times higher among unvaccinated than vaccinated individuals (see go.nature.com/3yifurf). (These data, however, were not controlled for age, underlying conditions, behaviour or other differences between the two groups). Several clinical trials testing vaccine effectiveness are under way.

It is also unclear how long vaccine effects will last. In an unpublished paper, Ogoina reports finding one unvaccinated person who was reinfected just nine months after recovering from his initial infection, suggesting that immunity might wane more quickly than scientists had anticipated.

But specialists don’t expect that the vaccine will become useless. The smallpox vaccine was invented some 180 years before the disease was eradicated, but in that time, the variola virus that causes smallpox — a relative of the monkeypox virus — never evolved to resist the jab, Lefkowitz says. And although there are no currently approved treatments for monkeypox, a few antiviral drugs used for smallpox are currently being tested for their efficacy against monkeypox.

What could cause cases to increase?

The US and European trends are encouraging, but if people sense that the danger has passed, Justman says, an increase in risky behaviour might cause a resurgence of the virus. She is particularly concerned about the virus’s potential to spread on university campuses, where students live in close quarters and might play sports that involve extended physical contact. “I don’t think things will stand still,” she says. “They will evolve, and our guidance will evolve.”

In Nigeria, meanwhile, Ogoina is concerned that the virus could spread quickly among people who are HIV-positive — nearly two million people in Nigeria alone. Although evidence is scarce, records from the 2017 outbreak there suggest that monkeypox is much more deadly in many of these individuals, who often have weakened immune systems.

What if the virus mutates?

Unlike RNA viruses such as SARS-CoV-2 or HIV, the monkeypox virus’s genome is composed of DNA, which tends to accrue mutations more slowly than RNA because it is more stable. A June paper in Nature Medicine³ surprised researchers when it reported that the virus that was spreading through Europe had picked up single-letter mutations much faster than previous poxviruses had. But these mutations seem to have had little effect; they are probably markers of where human antiviral enzymes have snipped at the virus in attempts to deactivate it, the researchers said. Scientists have also found areas of deletions or rearrangements in some monkeypox genomes; these are common in poxviruses and haven’t yet been linked to a change in function.

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It is difficult to estimate the chances of the virus becoming more transmissible in the future, Lefkowitz and others say, although that can’t be ruled out. One analysis (not yet peer reviewed) of the mutations in monkeypox DNA caused by human enzyme activity has inferred that the current strain might have first reached humans in 2016, before the outbreak was identified in Nigeria in 2017 (see go.nature.com/3stezeu). But researchers don’t know whether the virus has been continuously transmitting between humans undetected since then, or whether it hopped back into animals for a few years before crossing back into humans more recently, perhaps aided by a particular mutation. “There’s no one particular mutation in the current virus that is a smoking gun,” Lefkowitz says, in terms of making people more ill or more likely to spread the infection.

“We don’t understand transmission any better than we understand the pathogen,” he adds. Still, he says, the chance of a worrisome mutation arising increases the longer the outbreak goes on.

What if the virus finds a new reservoir?

Researchers still don’t know what animal in Africa serves as the most important monkeypox reservoir, carrying the virus and spreading it to humans. Rodents are a likely candidate: the 2003 US outbreak happened when rodents imported from Ghana infected pet prairie dogs. But the virus has also been found in numerous other mammals, including monkeys and anteaters.

In August, researchers found a dog in France that had contracted the virus from its owners, although it is unclear whether the animal could transmit it back to humans. The US CDC updated its guidance to discourage people with monkeypox from interacting with animals. But Chowell-Puente thinks it’s unlikely that monkeypox will find a permanent home among animals outside Africa, because the virus requires time to adapt to a new species and transmit. The current strain seems to prefer humans.

What would it take to eliminate monkeypox altogether?

In areas where animal-to-human transmission occurs, it will be impossible to eliminate the virus completely without a vaccine for people and (eventually) animals. Yet despite the risk that the virus might spread out of Africa again, Ogoina says that African countries have not yet received any vaccines. That’s because wealthy nations have not yet donated any doses to countries that cannot afford them.

Even if vaccines do arrive, behavioural changes will be needed to curb monkeypox, especially given the unanswered questions about vaccine effectiveness, says Adesola Yinka-Ogunleye, a London-based epidemiologist at the Nigeria Centre for Disease Control. “If we do not control monkeypox in endemic areas, then no matter the efforts put into non-endemic countries, we know we’re not going to achieve control,” she says.