Under the Skin: The Evolving Story of Mpox

Summary

Mpox — formerly known as monkeypox — has been with us for decades. For most of that time, it circulated quietly in parts of Central and West Africa, occasionally spilling into human populations but rarely attracting sustained global attention. That changed in 2022, when thousands of cases appeared across Europe, North America, and beyond, driven by a lineage capable of sustained human-to-human transmission.

In this episode, we take a deeper look at what scientists have learned since that global outbreak — and why mpox is still very much a story in progress.

We explore how the virus moves through the body, why mpox lesions are painful rather than itchy, and what distinguishes it clinically from other rash illnesses. We examine the surprising role of human immune defenses in shaping viral evolution, including the APOBEC3 mutation signatures that left a genetic fingerprint on the lineage responsible for the 2022 outbreak.

We also look at the emergence of a new lineage — clade Ib — now driving sustained transmission in parts of Central Africa, and why researchers are paying close attention to reports of recombinant viruses formed when different lineages mix.

Beyond the virology, this episode examines the broader forces shaping the future of mpox: wildlife reservoirs that remain incompletely understood, the erosion of cross-protective immunity after smallpox eradication, the uneven global distribution of vaccines and surveillance resources, and the social dynamics that influence whether people seek testing and care.

Most mpox infections resolve on their own. But the story of this virus — like many zoonotic diseases — sits at the intersection of ecology, evolution, and global health equity.

And as the headlines fade, the science continues.

Listen here or scroll down to read full episode.

Full Episode

It starts with a fever. Not dramatic at first. Just that vague, heavy feeling behind the eyes. And muscles sore in a way that doesn’t quite match yesterday’s workout. A headache that sits low and stubborn at the base of the skull. You tell yourself it’s nothing. A virus. A rough week. Stress. Then the lymph nodes begin to swell — small, tender knots under the jaw, in the groin, in the armpits. That’s when something feels… off. And then the rash appears. At first it’s a single lesion. Maybe two. Small. Round. Easy to ignore if you want to. But they don’t behave like a typical rash. They deepen. They fill. They become painful — not itchy, not irritating — painful. Each lesion feels like a live wire under the skin.

More appear. They don’t all come at once. They emerge over days. On the hands. On the face. Sometimes in places that make sitting, walking, or even using the bathroom agonizing.

You Google. You scroll. You see headlines. You see photos. You see words like “outbreak” and “emergency” and “spreading.” And suddenly you’re not just sick. You’re isolated. Friends don’t know what to say. Employers aren’t sure what to do. Public messaging is confusing. Social media is worse. You worry about who you might have exposed. You replay the last two weeks in your head like security footage.

You count lesions. You count days. You wait for crusting. For healing. For the moment your body begins to win. And for most people — it does. But recovery is slow. And lonely. And often misunderstood. This isn’t a story about blame. It’s damn sure not a story about morality. It’s a story about a virus that has been with us for decades — mostly ignored, occasionally feared, and now evolving in ways that demand we pay attention. Because what we thought we knew about mpox is shifting. And what science is uncovering now may shape how we respond next.

This is Under the Skin: The Evolving Story of Mpox.

SETTING THE SCENE

Let’s zoom out. Mpox — formerly called monkeypox — is caused by an orthopoxvirus. That places it in the same viral family as smallpox. These are large, double-stranded DNA viruses. In fact, they're among the largest and most complex viruses known to infect humans. Unlike RNA viruses that mutate rapidly through copying errors, orthopoxviruses are genetically more stable — but they are not static and we'll get into that in a bit.

So, Mpox is a zoonotic disease, meaning it originates in animals and spills into humans, like bird flu, Nipah, and hantaviruses that we've talked about before. For decades, mpox was considered a relatively rare infection, mostly occurring in parts of Central and West Africa where the virus circulates in wildlife. And then came 2022.

The 2022–2023 outbreak changed global awareness almost overnight. Thousands of cases appeared across Europe, North America, and beyond — largely through close, sustained person-to-person contact. Public health systems scrambled. Vaccines were mobilized. Ring vaccination strategies were deployed. Case counts eventually fell.

Many people assumed the story was over. It wasn’t.

We are now in what many researchers describe as a second epidemic phase — spanning roughly 2023 through now — with different geographic patterns, different evolutionary signals, and deeper ecological questions coming into focus. And right now, global health authorities are watching :

• Sustained transmission in parts of Africa.

• The emergence of a historically more virulent clade — clade Ib.

• And, recently, confirmation of inter-clade recombinant viruses — genetic mixing events that suggest evolution is actively occurring.

That doesn’t mean panic. But it does mean attention. Because mpox isn’t just a headline from 2022. It’s a virus interacting with human behavior, ecological systems, surveillance fatigue, and global inequity — all at the same time.

And the central question becomes: What do we think we know about mpox…versus what the science is teaching us now?

HISTORY RECAP

OK, so mpox was first recognized in humans in 1970 in what is now the Democratic Republic of Congo. Smallpox eradication campaigns were underway at the time, and clinicians noticed patients with smallpox-like illness — but testing revealed a different orthopoxvirus. For decades, cases appeared in relatively small numbers, mostly in Central and West Africa. Two major genetic groupings emerged over time:

• Clade I — historically associated with Central Africa and higher mortality.

• Clade II — associated with West Africa and generally milder disease.

That two-clade picture held for decades. But as genomic sequencing improved and scientists looked more closely, both clades turned out to be more complex than they first appeared. Clade I has been subdivided into clade Ia and clade Ib. Clade II has been subdivided into clade IIa and clade IIb. You won't hear much about IIa in this episode — it's the less clinically prominent lineage and hasn't driven major outbreaks. But IIb? That's the one that changed everything in 2022. And clade Ib? That's the one demanding attention right now. Those two lineages are the central characters in the story we're telling today — and we'll come back to both of them in a moment.

Occasional exportation events happened in the meantime. In 2003, the United States saw an outbreak linked to imported African rodents that infected prairie dogs sold as pets. That episode underscored mpox's zoonotic roots — wildlife trade can move viruses across continents. But person-to-person transmission outside endemic regions was usually limited and self-contained.

Until 2022.

The global outbreak in 2022 was driven largely by that sub-lineage clade IIb. What made it different wasn't just geography — it was transmission dynamics. For the first time, sustained human-to-human spread occurred at scale across multiple continents, particularly through close physical and intimate contact networks. The virus wasn't behaving like a purely zoonotic spillover anymore. It had adapted — socially and biologically — to circulate between people. And importantly, public health response mattered.

Vaccination campaigns, behavioral risk communication, and community engagement helped bring cases down in many high-income countries. By late 2023, global headlines had faded. But in parts of Central Africa, transmission continued. And then something else began to emerge.

Remember clade Ib — the lineage we flagged a moment ago? This is where it becomes important. Clade Ib is distinct from clade Ia in ways that have caught researchers’ attention. While clade Ia has been the historically recognized Central African lineage — associated mostly with zoonotic spillover and household transmission — clade Ib has shown evidence of more efficient human-to-human spread, including through sexual contact.

It isn’t simply a more severe version of what came before. Clade I viruses have historically been associated with higher mortality than clade II viruses, and clade Ib sits within that broader family tree — but its exact clinical risk profile is still being defined as more data come in.

What researchers are seeing so far is a lineage spreading through some of the same intimate contact dynamics that characterized the 2022 clade IIb outbreak, but within a genetic background historically linked to more severe disease. That combination is what has public health authorities watching closely.

Reports of sustained clade Ib transmission emerged in the eastern DRC and began spreading to neighboring countries — not as isolated spillover events from animals, but as ongoing human-to-human chains. This was not the contained outbreak pattern of previous decades. It was something that looked, epidemiologically, more like what 2022 had shown was possible. And then another layer appeared.

The World Health Organization confirmed cases of a recombinant virus — containing genetic material from both clade Ib and clade IIb — detected in separate geographic locations. Recombination in DNA viruses happens when two related viral strains infect the same cell and exchange genetic segments. Think of it less like mutation and more like shuffling two decks of cards together. It doesn't automatically mean a more dangerous virus. But it does mean evolution is happening in real time — and that these lineages are co-circulating closely enough to meet inside the same host.

So when we talk about this being a "second time" — we're not simply repeating 2022.

We're looking at a post-2022 landscape shaped by:

• Prior human-to-human adaptation

• Ongoing transmission in endemic regions

• Emerging evolutionary events

• And uneven global response capacity

And that combination? That's where the story gets more complex.

THE VIRUS: TRANSMISSION & PATHOGENESIS

Remember the person from the cold open? The fever that didn't quite make sense. The lymph nodes swelling under the jaw. The rash that didn't itch — it hurt. Each of those symptoms has a biological explanation. And understanding that explanation changes how you think about this virus.

So let's follow mpox into the body.

How It Gets In. Mpox doesn't slip through intact skin the way some pathogens can. It needs an opening. Mucous membranes — the mouth, eyes, nose, genitals — are efficient entry points. So is broken or abraded skin. The virus can also enter through the respiratory tract via exposure to infectious respiratory droplets or particles during prolonged, close face-to-face contact.

That last route is worth pausing on. Because mpox is not airborne the way measles is. It doesn't linger in the air of a room after someone has left. Transmission by the respiratory route generally requires sustained proximity — not a brief shared elevator, not a crowded subway car. That distinction matters enormously for risk communication, and it's part of why ring vaccination strategies can actually work against mpox in ways they couldn't against something like measles.

What the 2022 outbreak clarified — and this was genuinely important new epidemiological information — is that close skin-to-skin contact and mucosal contact during intimacy are highly efficient transmission routes. The virus is present in lesion fluid, in skin crusts, saliva, and also in seminal fluid, but the most reliable driver of spread is still direct skin and mucosal contact, especially contact with lesions.

That's not a moral statement. That's virology.

Primary Viremia: The Quiet Phase. Once the virus enters the body, something happens that your immune system notices before you do. Mpox begins replicating locally at the site of entry. Then it moves — into the lymphatic system. This is why lymph node swelling is one of the earliest signs. The virus is traveling. It's being carried through lymphatic channels and begins seeding the bloodstream in what's called primary viremia. The lymph nodes are doing exactly what they're supposed to do — mounting a response, trying to contain the spread. They swell because they're working.

This is also the phase that produces those early nonspecific symptoms. The fever. The headache that sits low at the base of the skull. The muscle aches that don't quite match anything you did yesterday. Your immune system has recognized an invader and activated. Cytokines are flooding your system. You feel it as malaise — that heavy, wrong-feeling exhaustion — because your body has redirected enormous resources toward fighting.

You feel terrible. But your immune system is doing exactly what it should.

Secondary Viremia: The Rash Arrives. Then comes the second wave. After primary viremia, the virus spills back out of the lymph nodes and into the bloodstream in larger quantities — secondary viremia. And now it seeds the skin. This is when the rash appears. And here's something that distinguishes mpox clinically from other viral rashes — something that clinicians use diagnostically. The lesions tend to emerge and progress synchronously. They appear, they evolve — from flat macules to raised papules to fluid-filled vesicles to deep pustules — largely in step with one another. Compare that to chickenpox, where lesions appear in successive waves, leaving you with spots at completely different stages all at once. That synchrony is a fingerprint. It tells you something about the biology — one wave of viral seeding into the skin, rather than repeated pulses.

And why do mpox lesions hurt so much, rather than itch? Because this virus replicates deep. It goes into the dermis — the deeper layer of skin — rather than staying superficial. Nerve endings are more abundant and more engaged at that depth. The lesions aren't irritating the surface. They're inflaming tissue underneath it. That's the live wire sensation the person in our cold open described. That's not an exaggeration. That's dermis-level inflammation pressing on nerve fibers. In areas like the mouth, genitals, or rectum, that depth of involvement can make basic functions — eating, walking, using the bathroom — genuinely agonizing.

Why Smallpox Immunity Matters Here. There's one more piece of pathogenesis worth understanding — one that connects history to the present moment. Mpox and smallpox are both orthopoxviruses. Their surface proteins are similar enough that immune memory trained against one offers meaningful protection against the other. That's why smallpox vaccines work against mpox. Cross-reactive immunity.

For decades, that cross-reactive immunity provided a kind of background protection in human populations. Smallpox vaccination campaigns ran globally until 1980, when smallpox was declared eradicated. After that, routine vaccination stopped. Entirely.

That was the right call for smallpox. But it had an unintended consequence for mpox. Anyone born after roughly 1980 — depending on the country — grew up without smallpox vaccination. No cross-reactive immunity. A larger global population of fully susceptible hosts. And as that unvaccinated generation has grown, so has the proportion of people with no orthopoxvirus immunity at all.

It's one of the underappreciated reasons why mpox has more room to spread now than it did fifty years ago. The herd immunity buffer that smallpox vaccination inadvertently provided — it's been quietly eroding for four decades.

And as this virus replicates inside human hosts — navigating immune pressure, crossing into new tissues — it's also being shaped by that experience in ways we're only beginning to understand. More on that in a moment.

EVOLUTION & SURVEILLANCE

First, let’s talk about recombination. Because that word can sound terrifying if you don’t unpack it. Mpox is a DNA virus. Compared to RNA viruses — like influenza or SARS-CoV-2 — DNA viruses mutate more slowly. Their replication machinery proofreads. They don’t accumulate random typos at the same pace. But that doesn’t mean they’re evolution-proof.

And here's where it gets genuinely strange. One of the most significant sources of mutation in the 2022 mpox lineage didn't come from the virus making copying errors. It came from us.

Human cells carry an antiviral defense system — a family of enzymes called A-P-O-B-E-C three — scientists often shorten it to APOBEC so that's what I'll do here. OK, When a virus invades, APOBEC3 fights back by attacking viral DNA directly, introducing changes into the viral genetic code in an attempt to disrupt replication. Think of it as your cells trying to scramble the virus's instruction manual mid-read. It's a legitimate immune strategy. And against many viruses, it works.

But here's the twist. Genomic analysis of the clade IIb lineage — the one that drove the 2022 global outbreak — revealed that a striking proportion of the mutations accumulating in that viral lineage bore the specific fingerprint of APOBEC activity. The pattern was unmistakable. These weren't random copying errors. They were the signature of a host immune response leaving marks on a viral genome. And the virus kept spreading anyway.

What that tells us is subtle but important. The host immune system was actively trying to destabilize the virus — and in doing so, was inadvertently generating genetic diversity. Most of those mutations were probably harmless to the virus, or even damaging. But evolution is a numbers game. When you introduce variation at scale across millions of replication events, you are — however unintentionally — giving the virus raw material to work with. The host, in attempting to fight the virus, was also helping it explore genetic space.

That's not a reason for despair. APOBEC is still doing its job. Immune pressure is still a meaningful force. But it reframes the story of mpox's evolution in the 2022 outbreak. This wasn't purely a virus making mistakes. It was a virus and a host in a molecular negotiation — and the outcome of that negotiation is written into the genomes we've been sequencing ever since.

So when we say DNA viruses are more stable than RNA viruses — that's still true in a meaningful sense. But stability is relative. And mpox is proving that even a slow-moving evolutionary process, given enough hosts, enough transmission, and enough immune pressure, can generate change worth watching.

It's worth noting that the APOBEC signature is most clearly and extensively documented in the clade IIb lineage that drove the 2022 global outbreak. Whether the same mutational pattern dominates in clade Ib — the lineage currently driving concern in Central Africa — is still an active area of research. Early sequencing data suggest APOBEC-driven mutations are present there too, but the picture is still coming into focus. As genomic surveillance expands in endemic regions, that clarity will improve. And it matters — because if APOBEC-driven mutation is contributing to evolutionary pressure across multiple lineages simultaneously, the implications for how we think about mpox's long-term trajectory become more significant. This is exactly why sustained sequencing infrastructure isn't optional. It's how we find out.

There are two main ways viruses change. The first is mutation — and we’ve just seen an unexpected example of how that can happen, with APOBEC3 leaving its fingerprint on the viral genome. But there’s a second mechanism, and it works very differently. Remember that “two decks of cards” shuffling idea we mentioned earlier? That recombination idea? Well that happens when two related viral strains infect the same cell at the same time, and their genetic material mixes — producing new combinations of existing genes.

And here’s the key point: for poxviruses, that kind of genetic shuffling isn’t new. Recombination is a well-documented feature of this viral family. Scientists have observed it in laboratory settings and in nature across multiple orthopoxviruses. The molecular machinery that allows it to happen has been understood for decades. So when we say recombination has been detected in mpox, we’re not describing a virus that has suddenly developed a new capability. We’re describing a known evolutionary mechanism doing what it has always been capable of doing. That context actually sharpens the concern rather than softening it.

The question was never really can mpox recombine. The question is which lineages are recombining — and what that tells us about what's happening on the ground. Detecting inter-clade recombination between clade Ib and clade IIb isn't alarming because recombination itself is unprecedented. It's significant because it tells us something specific: that these two distinct lineages — one historically associated with Central Africa and higher severity, one with demonstrated capacity for sustained global spread — are circulating closely enough, in the same populations, in the same hosts, for this to happen at all. The mechanism isn't the surprise. The meeting is.

And the confirmed cases make that meeting harder to dismiss. They were separated by geography and time — suggesting this isn't a single laboratory artifact or one isolated event. Something is happening out there, in real populations, in real hosts.

Now pause. This is not evidence of a supervirus. This is not cause for panic. But it is a signal worth taking seriously. And here's why: most recombination events will be evolutionary dead ends. They won't spread. They won't confer advantage. But viral traits — like transmissibility, immune evasion, or disease severity — can be influenced by genetic changes. Evolution is a numbers game. The more the virus circulates, the more opportunities it has to explore genetic space. That means sustained transmission is the raw material of evolution.

And here's the second issue: surveillance fatigue. In 2022 and 2023, many high-income countries invested heavily in testing, sequencing, and case tracking. Once cases declined, resources shifted. Attention moved elsewhere. Labs went back to baseline capacity. Meanwhile, in parts of Central Africa where mpox is endemic, genomic sequencing infrastructure remains limited. That’s not due to lack of scientific expertise. It’s due to funding, equipment access, and long-term investment gaps. So when we detect a recombinant strain now, we have to ask: Is this new? Or is this simply the first time we’ve looked closely enough to notice?

Sustained genomic surveillance isn’t glamorous. It doesn’t make headlines. It’s quiet, repetitive, and expensive. But without it, viral evolution can slip under the radar. And mpox is reminding us of a broader lesson: Emerging infections don’t disappear just because the news cycle moves on.

ZOONOSES & ECOLOGY: THE ANIMAL LINK

Now let’s go back even further — before 2022, before 1970. Before humans were in the picture at all. Mpox is a zoonosis. That means its long-term home isn’t us. For years, researchers suspected rodents were the natural reservoir, but the specific species were unclear. Monkeys were never thought to be the true reservoir — despite the name "monkeypox." They were more likely incidental hosts, like humans. The name was simply an artifact of where the virus was first isolated — in a laboratory monkey in 1958 — not a reflection of where it actually lives long-term.

So where does it live? The honest answer is: we're still working that out. And that uncertainty is itself scientifically important.

What we can say is that rodents are the leading candidates. The fire-footed rope squirrel — a small forest rodent in Central Africa — has emerged as a species of particular interest. Studies have detected mpox viral DNA and antibodies in these squirrels at rates consistent with reservoir behavior, meaning they appear capable of carrying the virus without necessarily becoming severely ill, which is exactly the kind of relationship that allows a virus to persist quietly in a wildlife population over time. That's a meaningful signal.

But it's probably not the whole picture. The current evidence suggests we may be looking at a community of reservoir species rather than a single culprit — multiple rodent species potentially maintaining the virus across different ecological niches and geographic ranges. Identifying all of them is painstaking field work, and it's ongoing. What the strongest current evidence points to is rodents broadly, with the fire-footed rope squirrel as a leading candidate — not a confirmed, singular answer.

Why does that distinction matter? Because it shapes how we think about spillover risk. If the virus has multiple wildlife hosts across a range of habitats, the opportunities for it to cross into human populations are more varied and harder to predict than if it were concentrated in one species in one ecosystem.

And here's where the "monkey eating squirrel" story comes in. Field investigations have documented primates becoming infected after predating on infected rope squirrels. That's not clickbait. That's ecology. Predator eats prey. Virus crosses species. Occasionally, humans enter that chain — through hunting, bushmeat handling, wildlife trade, or habitat overlap. This is what spillover looks like. It's not mysterious. It's ecological proximity.

Why does identifying a true reservoir matter? Because control strategies differ depending on where the virus lives long-term. If mpox were purely human-adapted now, vaccination and behavior change might be sufficient to interrupt transmission globally. But if wildlife reservoirs continue to seed new spillover events, eradication becomes much more complicated. Surveillance needs to include animals. Risk messaging must account for ecological exposure. Conservation, land use, and food systems become part of the public health conversation.

And this is the uncomfortable truth about zoonotic diseases: They are often downstream consequences of how humans interact with ecosystems. Like deforestation. Wildlife trade. Habitat encroachment. Economic pressures that make bushmeat a necessity. Mpox is not just a virus story. It’s an ecosystem story. And once again, we’re reminded that zoonotic spillover is a One Health problem — where human health, animal health, and ecosystems are inseparable.

STIGMA & SOCIAL DYNAMICS

Now we need to talk about something equally important. Not the virus. Not the squirrel. Not the genome. The narrative. During the 2022 outbreak, cases clustered heavily within networks of men who have sex with men. That pattern was epidemiologically real. It reflected close-contact transmission dynamics within specific social and sexual networks. But here’s where nuance often gets lost. A virus exploiting a social network is not the same thing as a virus belonging to that community. Viruses don’t have identities. They have opportunities. And when messaging becomes careless — when headlines flatten complexity — stigma follows. Some people delayed seeking care because they feared judgment. Some avoided testing because they worried about disclosure. Some felt blamed simply for existing within a social network. And stigma doesn’t just hurt feelings. It slows response. Public health depends on trust. And trust depends on people believing that coming forward will not cost them dignity.

But there’s another layer here. Historically, mpox circulated in African countries for decades with limited global attention. When cases appeared in Europe and North America in 2022, the urgency shifted dramatically. That contrast did not go unnoticed. Communities that had lived with mpox for years saw a sudden surge of funding and vaccine mobilization — but largely once higher-income countries were affected.

Disease narratives matter. If a virus is framed as “someone else’s problem,” investment lags. If it’s framed as a moral issue, people hide. If it’s framed as rare or niche, surveillance wanes. And then evolution continues quietly. This is why careful language matters. Mpox is not a “gay disease.”It is not an “African disease.”It is not a “new disease.” It is a zoonotic orthopoxvirus interacting with human networks and global inequity. How we talk about it shapes how effectively we respond. And if we want vaccination campaigns to work…If we want people to seek care early…If we want surveillance data to be accurate…We have to separate biology from blame.

RING VACCINATION & LESSONS LEARNED

When mpox began spreading globally in 2022, public health officials didn’t start from scratch. They reached into a tool kit that had worked before. Ring vaccination. Ring vaccination is exactly what it sounds like. Instead of vaccinating an entire population, you create a “ring” around confirmed cases. You vaccinate close contacts. Then you vaccinate contacts of contacts when needed. You contain the outbreak like firefighters cutting a perimeter around a blaze.

This strategy was famously used during smallpox eradication. And because mpox is an orthopoxvirus — related to smallpox — existing smallpox vaccines offer protection.

In 2022, the vaccine most widely deployed was JYNNEOS — a non-replicating vaccine designed to protect against both smallpox and mpox. Let's talk about what JYNNEOS actually is. Because the specifics matter — both for understanding why it became the tool of choice, and for being honest about what we know and don't know.

JYNNEOS is a third-generation smallpox vaccine. The original vaccines used in eradication campaigns were live, replicating viruses — spectacularly effective, but carrying real risks for people with weakened immune systems or skin conditions like eczema. In some, the replicating vaccine virus could cause serious complications including myocarditis, encephalitis, and widespread skin involvement. JYNNEOS was developed specifically to solve that problem.

It's built from a modified vaccinia virus — MVA-BN — that is non-replicating and incapable of reproducing in human cells. It enters your cells, triggers an immune response, and stops. It cannot shed. It cannot spread. The severe adverse reactions associated with older replicating vaccines — myocarditis, encephalitis, eczema vaccinatum — were not observed during JYNNEOS's clinical development program. That safety profile is what makes it usable in immunocompromised individuals, people with HIV, and people with eczema — populations the older vaccines couldn't safely reach.

How do we know it works? Here's where intellectual honesty matters. FDA approval for smallpox rests on 22 clinical trials enrolling nearly 8,000 people, with JYNNEOS showing non-inferior immunogenicity compared to the older licensed vaccine. The mpox indication specifically is based on non-human primate survival data — vaccinated animals survived lethal mpox challenge at rates of 80% to 100%, compared to 0% to 40% in controls. That's animal data, not a human clinical trial — because you can't ethically challenge humans with mpox. The FDA's Animal Rule allows approval on that basis when human efficacy trials aren't feasible, combined with human safety and immunogenicity data. It's a legitimate pathway. But it means the precise efficacy figure in humans carries more uncertainty than a traditional Phase 3 trial would provide. Observational data from 2022 suggested around 86% effectiveness — but that comes from outbreak surveillance, not controlled conditions.

What we can say confidently: it's safe, it generates a robust immune response, and the evidence points consistently in one direction. It's a genuine tool — with an efficacy profile still being characterized across real-world populations and emerging clades.

One final practical note: Originally, JYNNEOS was given as a standard subcutaneous injection — half a milliliter under the skin, two doses a month apart. During the 2022 outbreak, regulators authorized an intradermal approach using one-fifth the dose to stretch limited vaccine supplies. That approach uses 80% less antigen, effectively multiplying available doses fivefold — with comparable immunogenicity. It was a meaningful innovation under pressure.

And in many high-income countries, ring vaccination worked — especially when combined with community engagement and behavior change. Cases declined. But here’s the nuance. Ring vaccination works best under certain conditions:

• When case detection is rapid

• When contact tracing is robust

• When transmission chains are relatively contained

• When people trust public health systems enough to participate

It struggles when:

• Surveillance is delayed

• Contacts are difficult to identify

• Transmission is sustained in broader community settings

• Or vaccines are scarce

And this is where the global picture diverges. In parts of Africa where mpox is endemic, ring vaccination has been much harder to operationalize at scale. Limited diagnostic infrastructure means cases aren’t always confirmed quickly. Rural geography complicates contact tracing. Vaccine access has historically been limited. So when we say “the outbreak was controlled,” we need to be precise about where.

The lesson here isn’t that ring vaccination failed. It’s that vaccination alone is not a strategy. It’s one tool. Effective outbreak control requires:

• Rapid diagnostics

• Transparent communication

• Community partnership

• Accessible clinical care

• And sustained investment — not just emergency funding

Mpox taught us that high-income countries can mobilize quickly when motivated. The question is whether that mobilization becomes sustained global capacity — or fades once domestic case counts fall.

GLOBAL INEQUITY

So let’s talk more about the uncomfortable part. Mpox circulated in Central and West Africa for decades before it became a global headline. Decades. Outbreaks occurred. Communities were affected. Scientists studied it. Clinicians treated it. But vaccine stockpiles remained concentrated elsewhere. Genomic sequencing capacity remained uneven. Global urgency remained low.

Then 2022 happened.

Within months, vaccines were deployed in Europe and North America. Public health messaging campaigns launched. Sequencing ramped up. Research funding accelerated. That rapid mobilization was impressive. But it also revealed something stark: We know how to respond when we decide to.

In many endemic regions, clinicians have long dealt with mpox in resource-constrained settings — limited diagnostics, limited vaccine access, limited sequencing infrastructure. Sustained transmission in these contexts creates two problems: First, human cost. Higher morbidity. Occasional higher mortality. Repeated outbreaks. Second, evolutionary opportunity. Viruses don’t evolve because of malice. They evolve because of replication. If transmission continues unchecked in areas without widespread vaccination or robust surveillance, the virus has more chances to adapt.

And here’s the global paradox: Underinvesting in endemic regions does not contain risk locally. It amplifies it globally. Genomic sequencing isn’t just a scientific luxury. It’s an early warning system. Vaccines aren’t just domestic protection. They reduce global evolutionary pressure. Equity in infectious disease response isn’t charity. It’s strategy.

If mpox continues circulating intensely in regions with limited access to countermeasures, the rest of the world remains connected to that evolutionary process — whether we acknowledge it or not. Pathogens do not care about GDP. Nowhere is this clearer than in how the treatment story unfolded.

For much of the 2022 outbreak and beyond, tecovirimat — an antiviral developed originally for smallpox — became the primary therapeutic option deployed in high-income countries. In the United States it was made available through an expanded access program. In the EU, UK, and Canada it was formally authorized. It was, for a time, held up as evidence that we had tools.

At the same time, two large randomized controlled trials were underway to actually test whether it worked. One — PALM007 — was conducted in the DRC. One — STOMP — was conducted largely in the United States and other higher-income countries. And it's worth pausing on why a trial like PALM007 happens in the DRC in the first place. Because the answer is scientifically straightforward: that's where the disease is. You cannot run a clade I mpox trial in a country with no clade I cases. The DRC is where the relevant viral strain circulates, where patient numbers are sufficient to generate meaningful data, and where the populations most affected by severe disease actually live. Conducting the trial there wasn't extraction. It was necessity. And participants received supportive care throughout — hydration, nutrition, treatment for secondary infections — resources that represented real investment in those communities.

But here's what that framing doesn't resolve. While the DRC trial was enrolling patients — including children, including higher-severity cases — wealthy nations were already deploying tecovirimat at scale based on animal data and cautious optimism. The uncertainty period, in other words, was not shared equally. High-income countries operated under the assumption that the drug worked. Endemic regions were still in the placebo-controlled phase.

And then both trials reported in late 2024 that tecovirimat did not meaningfully reduce the time it takes for mpox lesions to resolve compared to placebo. The drug appears safe. But the primary clinical benefit that justified its widespread use? The data didn't support it — at least not for the general population. Its role in the highest-risk patients, those with severe immunocompromise or advanced HIV, remains an open question that trials are still working to answer.

So the global health community is now recalibrating. But consider what that recalibration required: the communities bearing the heaviest burden of this disease generated the evidence that reframed treatment for everyone. And here's the question that history forces us to ask — not as accusation, but as honest reckoning: if those trials had shown dramatic efficacy, how long would it have taken for that treatment to reach the DRC at scale? The precedent from HIV antiretrovirals, from COVID vaccines, from countless interventions before them, suggests the answer is: not quickly. And not without years of advocacy, negotiation, and donor pressure.

That's where the inequity lives. Not in the decision to conduct rigorous science where disease exists — that part was appropriate. But in a system where the evidence burden consistently falls on endemic populations while the benefit assumption flows toward wealthier ones. Where the uncertainty is shared unevenly. And where a positive result would not have automatically meant access.

The communities that have lived with mpox the longest deserved better odds than that.

WHAT WE’RE WATCHING NOW

So where are we now? Not in panic. Not in complacency. In vigilance. Here’s what scientists and public health authorities are actively watching:

1. First up are recombinant viruses. Are these isolated evolutionary experiments — or do they begin to spread? Sequencing data will tell us whether recombinants gain any selective advantage or remain rare.

2. Clade Ib transmission dynamics. Historically associated with more severe disease, sustained transmission patterns need careful monitoring — especially in areas where healthcare access is limited.

3. Wildlife reservoir mapping. Field studies are expanding to better define which species maintain the virus long-term. If fire-footed rope squirrels are confirmed as primary reservoirs, ecological interventions and risk messaging can become more targeted.

4. Surveillance sustainability. Will countries maintain sequencing and diagnostic capacity now that headlines have faded? Or will we repeat the boom-and-bust cycle of outbreak attention? And here’s a real-time example of why sustained surveillance matters. Recently, Colorado’s wastewater surveillance program reported detection of mpox genetic material in one utility district — potentially the first detection since they began monitoring for it. Now — what does that mean?

Wastewater surveillance detects viral genetic fragments shed into sewage systems. People can shed virus before symptoms appear — and sometimes without noticeable symptoms at all. So a wastewater signal doesn’t automatically mean a surge in severe cases. It doesn’t mean widespread transmission. It doesn’t mean crisis. What it does mean is that somewhere in that catchment area, viral material is present.

It’s an early warning system. Now, having said that, CO does have 3 cases as of March 3, according to their dashboard. And shoutout to a new follower — you can find them on Twitter at CCSDMaskUp — who flagged this Colorado wastewater data.

During COVID, wastewater became a powerful complementary tool — sometimes detecting viral trends before clinical case counts rose. Now we’re seeing that same infrastructure applied to other pathogens, including mpox. And this is important. Because if mpox transmission begins increasing quietly in a community, wastewater may notice before headlines do. That’s what sustainable surveillance looks like: Not panic. Not speculation. Just quiet detection capacity running in the background.

5. Vaccine access strategies in Africa. Are doses reaching endemic regions in meaningful numbers? Are vaccination strategies tailored to local transmission realities?

And here’s the broader lens. Mpox is a test case. It’s not as transmissible as measles. It’s not as lethal as Ebola. It’s not as globally disruptive as COVID-19. But it sits in a category that may define the next several decades of infectious disease response: Zoonotic pathogens with moderate transmissibility, capable of human adaptation, interacting with global travel and ecological disruption, and evolving slowly — but steadily.

Mpox is not the worst-case scenario. It’s the warning shot. It’s what it looks like when a zoonotic virus experiments with sustained human transmission — and the world responds unevenly. The science is doing its job. Genomes are being sequenced. Reservoirs are being mapped. Vaccines exist. Tools exist. The question isn’t whether we have the capability. It’s whether we sustain the will.

PRACTICAL GUIDANCE: WHAT TO LOOK FOR & HOW TO REDUCE RISK

Before we close, let’s make this practical. Because awareness without guidance isn’t helpful. What does mpox actually look like?

The early symptoms can feel nonspecific:

• Fever

• Headache

• Muscle aches

• Fatigue

• Swollen lymph nodes

That swollen lymph node piece is important. It helps distinguish mpox from some other rash illnesses. Then comes the rash. And here’s what makes mpox different:

The lesions often start as flat spots, then become raised, then fluid-filled, then pustular — deep, firm, sometimes umbilicated in the center. They can be painful. Sometimes intensely painful. Especially in sensitive areas. Lesions can appear on:

• The face

• Hands and feet

• Genitals

• Around or inside the mouth

• Or elsewhere on the body

Not everyone gets hundreds of lesions. Some people get only a few. Some have primarily localized rash. Illness severity varies. Most people recover in 2–4 weeks. Certain groups face higher risk of serious illness and warrant close clinical monitoring. Immunocompromised individuals — including people living with untreated HIV or those on immunosuppressive therapies — can develop more extensive disease, with larger numbers of lesions, slower healing, and in some cases severe complications. Young children, particularly infants, are also at higher risk for severe outcomes. And during pregnancy, mpox can carry serious risks including pregnancy loss and complications for the newborn.

This isn't meant to be alarming. The majority of cases remain self-limiting. But if you fall into one of these groups — or you're caring for someone who does — early diagnosis and medical evaluation matter more, not less. Treatment options exist and are prioritized for higher-risk patients in some health systems, though the evidence base is still evolving.

During that 2–4 week recovery window, the virus can spread through:

• Close skin-to-skin contact

• Intimate contact

• Contact with contaminated bedding, clothing, or surfaces

• Prolonged face-to-face exposure

So what reduces risk?

First — awareness. If you have a new unexplained rash, especially with fever or swollen lymph nodes, get evaluated. Testing is available in many places. Early diagnosis helps prevent spread.

Second — vaccination. In countries where the JYNNEOS vaccine is available, it’s recommended for people at higher risk of exposure. That includes certain healthcare workers and people within networks where transmission is occurring. Vaccination doesn’t just protect individuals — it reduces the overall number of susceptible hosts.

Third — temporary behavior modification during outbreaks. This is not about policing identity. It’s about reducing opportunities for transmission when case counts are rising. Public health guidance may include temporarily limiting high-risk close contact settings during active outbreaks.

Fourth — isolation if infected. If diagnosed, avoid close physical contact until lesions have crusted, scabbed, and new skin has formed. That’s when infectiousness drops.

And finally — reduce stigma. If someone tells you they’ve been diagnosed, respond with support. The virus spreads through proximity, not morality.

Prevention is not about fear. It’s about informed choices.

CIRCLING BACK

Let’s return to the person in the cold open. The fever. The swollen lymph nodes. The lesions that hurt. The isolation. The waiting. That person is not a headline. They’re not a statistic. They’re not a symbol of a community. They’re not a morality tale. They’re someone whose immune system is fighting a virus that crossed from wildlife into human networks — and is now navigating a world still learning how to respond.

Mpox sits at the intersection of ecology, evolution, inequity, and narrative. It reminds us that zoonotic diseases don’t begin when they reach wealthy countries. That surveillance matters even when case counts fall. That evolution doesn’t stop because attention does. That stigma can spread faster than a virus. And that equity isn’t optional if we want stability.

Most people who get mpox recover. But the broader story — the evolutionary one — is still unfolding. And that story includes recombinant strains. Reservoir mapping. Vaccine distribution. And sustained transmission in places that have lived with this virus far longer than the headlines suggest.

Mpox isn’t the worst-case pathogen. It’s something more subtle. It’s a reminder. A reminder that the world is biologically connected. That ecology and human behavior are inseparable. That vigilance requires endurance. And that how we tell disease stories shapes what happens next.

The 2022 outbreak eventually slowed. Cases declined. The headlines moved on. But viruses don’t follow news cycles. Whether the world learns from that outbreak — whether surveillance continues, whether investment holds, whether equity becomes policy rather than promise — that part is still being written.

As always, science doesn't happen in a vacuum. Funding decisions, access policies, and global health equity are shaped by political will. Know where your representatives stand.

Citations

1. World Health Organization. Mpox: fact sheet. 26 August 2024.

2. http://www.who.int/news-room/fact-sheets/detail/monkeypox

3. World Health Organization. Global mpox trends. https://worldhealthorg.shinyapps.io/mpx_global/

4. World Health Organization. Multi-country outbreak of mpox: external situation report no. 62. 23 January 2026. Multi-country outbreak of mpox, External situation report #62

5. World Health Organization. Mpox: recombinant virus with genomic elements of clades Ib and IIb - Global https://www.who.int/emergencies/disease-outbreak-news/item/2026-DON595

6. FDA JYNNEOS page: https://www.fda.gov/vaccines-blood-biologics/jynneos

7. Thornhill, et al. (2022). Monkeypox virus infection in humans across 16 countries. New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa2207323

8. McCollum, A. M., & Damon, I. K. (2014). Human monkeypox. Clinical Infectious Diseases. https://academic.oup.com/cid/article/58/2/260/335791

9. Bunge, et al. (2022). The changing epidemiology of human monkeypox—A systematic review. PLoS Neglected Tropical Diseases. https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0010141

10. Molteni, et al. (2023). Selective events at individual sites underlie the evolution of monkeypox virus clades. Virus Evolution. https://academic.oup.com/ve/article/9/1/vead031/7175024

11. Otieno, et al. (2025). Global genomic surveillance of monkeypox virus. Nature Medicine. https://www.nature.com/articles/s41591-024-03370-3

12. Srivastava, et al. (2024). Clade Ib: a new emerging threat in the mpox outbreak. Frontiers in Pharmacology. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1504154/full

13. Riutord-Fe, et al. (2026). Transmission of MPXV from fire-footed rope squirrels to sooty mangabeys. Nature. https://www.nature.com/articles/s41586-025-10086-y

14. Rizk, et al. (2025). Update on mpox management: epidemiology, vaccines and therapeutics. Drugs. https://link.springer.com/article/10.1007/s40265-024-02117-1

15. Alakunle, et al. (2020). Monkeypox virus in Nigeria: infection biology, epidemiology, and evolution. Viruses. https://pmc.ncbi.nlm.nih.gov/articles/PMC7694534/

16. Rimoin, et al. (2010). Major increase in human monkeypox incidence 30 years after smallpox vaccination campaigns cease in the Democratic Republic of Congo. PNAS. https://www.pnas.org/doi/10.1073/pnas.1005769107

17. The PALM007 Writing Group (2024). Tecovirimat for Clade I Mpox in the Democratic Republic of Congo. New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa2412439

18. Zucker, et al. for the STOMP/A5418 Investigators (2026). Tecovirimat for the Treatment of Mpox. New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa2506495

19. Wolff Sagy, et al. (2023). Real-world effectiveness of a single dose of mpox vaccine in males. Nature Medicine. https://www.nature.com/articles/s41591-023-02229-3

20. Branda, F., Ciccozzi, M., & Scarpa, F. (2025). Mpox: genomic insights and public health implications. Infectious Diseases. https://www.tandfonline.com/doi/full/10.1080/23744235.2025.2494053?af=R