How will the monkeypox outbreak develop? Long article "Nature"

Originally written by Sara Reardon

As the number of cases begins to decline in the United States and Europe, Nature analyzes the likely future trajectory of the outbreak
.

On 29 April, a person in Nigeria developed an abnormal rash and TA, who was carrying monkeypox virus, later arrived in the UK
.
Since then, the monkeypox virus has infected more than 70,000 people in more than 100 countries, surprising medical professionals around the world because the persistent transmission is very different from the previous spread of monkeypox virus in humans, which was caused
by a virus that hosts in African animals.

A public health notice
about monkeypox posted in Toronto, Canada.
Source: Steve Russell/Toronto Star/Getty

However, nearly 6 months after the monkeypox virus began to spread, vaccination and behavioural change seemed to have contained the development of the outbreak – at least in the United States and Europe (see "Monkeypox cases"
).
But researchers believe there are multiple possibilities
for future outbreaks.
In the best-case scenario, the outbreak subsides
in the coming months or years.
In the worst-case scenario, the virus enters a new animal reservoir and becomes endemic outside Africa, leaving clearance hopeless
.
Jessica Justman, an infectious disease doctor at Columbia University in New York, said: "There are a lot of counterproductive factors
here.
”

Source: WHO

Professionals believe that this year's monkeypox outbreak should not cause global paralysis like COVID-19
.
The monkeypox virus does not seem to be airborne like COVID-19, is not as contagious as smallpox, and does not survive
long in the body like HIV.
Monkeypox virus is mainly transmitted through sexual contact, and currently diagnosed mainly in men who have sex with men, especially those
who have multiple sexual partners or who have sex anonymously.
Although it causes severe, painful rashes but is rarely fatal, the circulating strain of monkeypox virus is a descendant
of the milder "clade 2" in West Africa.
(The more lethal "clade 1" virus was found
in Central Africa.
) It is unclear whether the strain of the current outbreak is more transmissible than its "clade 2" ancestor; It's also possible that some form of the virus entered a population that could make it spread faster, says
Elliot Lefkowitz, a bioinformatician at the University of Alabama at Birmingham.

Gerardo Chowell-Puente, an epidemiologist at Georgia State University, said: "We are now in a good position to bring the epidemic under control, but it depends mainly on the behavior of
the population.
”

The vast amount of unknown about the latest monkeypox strains, combined with an over-reliance on population responses, makes it difficult for scientists to predict subsequent developments
.
However, researchers have helped to anticipate the likely course
of the outbreak by constructing a variety of scenarios.
Here are some of the top questions
about the future trend of the monkeypox epidemic.

What is the current situation of the pandemic?

Since mid-August, confirmed monkeypox cases have declined
in the United States and Europe.

Public health experts attribute this to behavior change: a study by the Centers for Disease Control and Prevention (CDC)[1] that surveyed men who have sex with men found that about half avoided risky sexual activity
for fear of contracting the virus.
Equally useful are public health campaigns to guide people on which symptoms to look out for, encouraging people to report cases, and providing vaccination to high-risk populations (the efficacy of vaccines to prevent infection or transmission is unknown).

But Justman also said the monkeypox case numbers here need to be interpreted
with caution.
Many people and their doctors may not be able to detect symptoms or are reluctant to report
them because of shame.
"I don't think we did what we should have done
," she said.
”

Some countries in South America and Africa have seen opposite trends
.
In Nigeria, where the outbreak is likely to originate, the number of cases is growing, with a record-breaking 56 infections
reported in one week in September.
Dimie Ogoina, an infectious disease doctor at the local Niger Delta University, said: "It is too early
to say that we have defeated monkeypox.
The Nigerian CDC said there have been more than 400 cumulative infections
in the country.
While that number is far from the 26,000 cases in the United States, it is almost certainly smaller than the actual number of infections, and Nigeria is likely to have much more underreported cases than the United States, Ogoina said
.
Nigeria lacks a well-developed disease surveillance network, and Ogoina expects that many people infected with monkeypox may not notice symptoms or go to the doctor
.
Rosamund Lewis, the WHO's head of monkeypox technology, said the number of reported cases is always "a beat slower", especially in areas where surveillance is not in
place.

WHO hopes to get 60,000 test kits to send to Africa, but there are logistical difficulties
in testing and diagnosing people.
It's unclear whether the apparent increase in the number of cases in Africa reflects the real situation on the ground or whether it is due to wider official testing, Lewis said
.
She believes that both factors are combined
.

What are the results predicted by the model?

Because we know very little about how monkeypox spreads and how different factors affect it, future trends modeled weeks in advance may not be accurate
.
WHO has not issued long-term projections
for monkeypox outbreaks.
Although the CDC publishes monthly technical reports on the outbreak that suggest several possible scenarios, the agency says the predictions are not very reliable
.
The September 29 report indicates that the number of cases in the United States is likely to flatten or decline in the coming months, but it is also likely to increase exponentially (see go.
nature.
com/3sxrbmv).

Chowell-Puente publishes monkeypox forecasts online once a week and has been following the trajectory
of the outbreak in several countries in the United States and Europe.
He used multiple scenarios to forecast the next three weeks, and the predictions so far have been accurate
.
As of Oct.
3, his projections suggest that the number of cases could stabilize or begin to decline
in several of the countries he modeled.
Chowell-Puente said that while these trends may change with new public health policies, changes in public behavior or mutations of the virus, the pace of change will not be too fast
.
He has not yet modeled infections in Africa, but said such predictions
could be made in the future.

Other models are more detailed, although not necessarily more accurate
.
A system by RTI International, a nonprofit global research organization based in North Carolina's Research Triangle Park, used information from previous rounds of monkeypox outbreaks — particularly those caused by branch 2 — to predict the future development of
current strains.
Previous more severe branch 2 outbreaks included a brief outbreak in the United States in 2003, when more than 70 people were infected; There was also an outbreak in Nigeria in 2017 with a total of 146 suspected cases
.
Based on the analysis of the viral genome, branch 2 appears to be the strain
responsible for the current outbreak.

Using information from these outbreaks, and assuming that the virus has not yet mutated significantly, Donal Bisanzio, an epidemiologist at RTI in the UK, estimated the transmissibility
of the virus.
He and his team simulated the spread of the virus in a virtual high-income country of 50 million people over a period of weeks
.
In the yet-to-be-published study, models suggest that if the virtual country does not intervene, the number of cases before the outbreak subsides could be around 6,000 (or 0.
01% of the population will be infected).

This is largely because the virus is not very transmissible, and the model assumes (as is the case in countries such as the United States) that most older people have been vaccinated
against a related virus: smallpox.

But the researchers found that if infected people self-isolated for three weeks (waiting until the possible incubation period for monkeypox virus has passed) and men who have sex with men can refrain from sexual activity before the outbreak ends, the number of infected people drops
significantly.
Vaccinating close contacts of infected people can also further reduce the number of infections
.

Can't vaccines make the outbreak go away?

Hundreds of thousands of doses have been distributed in Europe and the United States to vaccinate high-risk groups, such as men who have sex with men and those
exposed to monkeypox.
Getting everyone vaccinated is unrealistic: The United States expects to supply fewer than 2 million doses of one of the most widely used vaccines available this year — a repurposed smallpox vaccine
.

However, it is unclear to what extent this has slowed the increase in the number of cases
.
A preprint paper [2] states that in people who have never received the smallpox vaccine, the vaccine does not appear to be able to significantly increase levels of antibodies that neutralize monkeypox virus, which is part of
the immune response.
In contrast, the CDC released rough incidence data for each jurisdiction, showing that among those recommended for the vaccine, the incidence rate in unvaccinated people was more than 10 times that of vaccinated people (see go.
nature.
com/3yifurf).

(But these data did not match age, underlying medical conditions, behavioural or other differences between the two groups.
)
Several clinical trials are currently being conducted to test the effectiveness
of vaccines.

We also don't know how long
the vaccine's effects last.
In an as-yet-unpublished paper, Ogoina said finding an unvaccinated person reinfected 9 months after the initial infection suggests that immunity may be declining faster
than expected.

But experts don't think vaccines will be useless
.
The smallpox vaccine was introduced 180 years before smallpox was eradicated, but during that time, the smallpox virus — a close relative of monkeypox virus — never evolved a vaccine-resistant variant
, Lefkowitz said.
Although there is currently no approved monkeypox treatment, several antiviral drugs against smallpox are being tested for their efficacy
against monkeypox.

What factors contribute to the increase in the number of cases?

The situation in the U.
S.
and Europe is encouraging, but if people think the danger is over, Justman said high-risk behaviors will increase again, which will lead to a resurgence
of the virus.
She is particularly concerned about the possible spread of monkeypox in universities, where students live close and many sports require a lot of physical contact
.
"I don't think things are set in stone," she said, "things are changing, and our guidance is changing
with them.
" ”

Dimie Ogoina is a doctor in Nigeria where monkeypox cases are on the rise
.
Source: KC Nwakalor/The New York Times/Redux/eyevine

Meanwhile, Ogoina is concerned that the virus in Nigeria will spread rapidly among HIV-positive people — there are nearly 2 million
HIV-positive people in Nigeria.
Although the evidence is insufficient, local records of the 2017 outbreak show that monkeypox is more deadly for these people, who often have weaker
immune systems.

What should I do if the virus mutates?

Unlike RNA viruses such as the new coronavirus or HIV, the genome of monkeypox virus is composed of DNA, and because it is more stable, it mutates much more slowly than RNA
.
A June paper in Nature Medicine [3] surprised researchers by reporting that monkeypox viruses circulating in Europe were mutating at a faster rate than previous pox viruses
.
But the impact of these variants appears to be minimal; They may be marks left by human antiviral enzymes that cut the virus in an attempt to inactivate it
.
Scientists have also identified some missing or rearranged regions in monkeypox's genome; This is common in pox viruses, and it has not been found to be associated with
altered functions.

At this stage, it is difficult to estimate the probability of the virus becoming more transmissible in the future, Lefkowitz et al.
said, but this possibility cannot be ruled out
.
An analysis of DNA variants in monkeypox caused by human enzyme activity (not yet peer-reviewed) concluded that the current strain may have entered the human body in 2016, before the 2017 outbreak in Nigeria (see go.
nature.
com/3stezeu).

But researchers don't know if the virus has been circulating in humans since then, or if it returned to the animal host and only recently re-spilled into humans several years later, possibly aided by a particular mutation
.
Lefkowitz says that "there is no mutation in the virus today that is definitive evidence," such as whether it is more pathogenic or contagious to humans
.

"We don't know much
more about how contagious it is than we do about this pathogen," he said.
But he believes that the probability of dangerous mutations increases as the outbreak
continues.

What should I do if the virus finds a new host?

Researchers still don't know which animals in Europe are the main reservoirs for monkeypox, carrying the virus and passing it on to humans
.
Rodents are a possible reservoir: the 2003 outbreak in the United States occurred when rodents imported from Ghana infected pet prairie dogs
.
However, the virus has also been found in a large number of other mammals, including monkeys and anteaters
.

In August, researchers discovered that a dog in France had contracted monkeypox virus from its owner, but it is unclear whether the dog could retransmit the virus to humans
.
The latest guidelines issued by the US Centers for Disease Control and Prevention recommend that people infected with monkeypox virus do not come into contact
with animals.
But Chowell-Puente believes animals outside Africa are unlikely to be permanent hosts for monkeypox virus because it takes time
for the virus to adapt to new species and spread.
Current strains appear to prefer humans
.

What to do to completely eliminate monkeypox?

In areas where animal-to-human transmission occurs, complete eradication of monkeypox is not possible
without vaccines for humans and (eventually) animals.
Despite the risk of another spread of monkeypox virus from Africa, Ogoina said African countries have not received any vaccines
.
That's because rich countries haven't donated any vaccines
to countries they can't afford to buy.

Even when vaccines are in place, behavioural changes are needed to contain the spread of monkeypox virus, especially when vaccine effectiveness is unknown, said Adesola Yinka-Ogunleye, an epidemiologist at the Nigerian CDC in London.

”

References:

1.
Delaney, K.
P.
 et al.
 MMWR Morb.
Mortal.
Wkly Rep.
 71, 1126–1130 (2022).

2.
Zaeck, L.
M.
 et al.
 Preprint at medRxiv https://doi.
org/10.
1101/2022.
08.
31.
22279414 (2022).

3.
Isidro, J.
 et al.
 Nature Med.
 28, 1569–1572 (2022).

The original article was published in the news feature section of Nature on October 2, 2022

© nature

doi: 10.
1038/d41586-022-03204-7

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