Cases of monkeypox are popping up across the globe. But where did it come from? How does it work? And how can we treat it? It took looking all the way back to the beginning — 1500 BCE to be exact — to answer these pressing questions. 

WITH THE COVID - 19 pandemic slowing down, the world took a collective breath. But before anyone had a chance to exhale, reports of monkeypox cases across the world began to pop up. Questions about this new-to-us virus abound.

Many of the answers lie in not only the history and evolution of the virus, but also in some of the virus’ better studied relatives, including the infamous smallpox. 

Smallpox and monkeypox are members of the poxvirus family, which does not include chickenpox, despite the shared surname and uncomfortable, itchy lesions (1). Monkeypox and smallpox are both part of the genus Orthopoxvirus in the family Poxviridae. Both viruses cause similar symptoms (2). An infected individual first experiences fever and headaches, followed by swollen lymph nodes, and finally, painful, pustules all over the body. The hallmark pustules can persist for three weeks before they scab and heal, although they often leave behind long-lasting scars.

Distinguishing monkeypox from smallpox can be tricky, but monkeypox is generally milder, and swollen lymph nodes are less common in smallpox (3). Luckily, smallpox was eradicated in 1980 thanks to the smallpox vaccine, so if these symptoms arise, they are almost surely caused by the monkeypox virus.

Members of the Poxviridae family of viruses are brick-shaped with a structure akin to mitochondria (4). They have a thick outer shell composed of an inner membrane and outer membrane decorated with projections that protect their genomic DNA from the unfriendly immune cells floating around the body.

The projections — shaped like pawn pieces in a chess set — interact with receptors on the surface of cells and release their genetic material and viral enzymes into the cell, initiating viral replication (5). Eventually, viral-induced cell lysis occurs and spreads the virus to neighboring cells. 

Scientists reported the first case of monkeypox in humans in 1970. Like countless other viruses, monkeypox is a zoonotic virus, meaning that it originated in animals before jumping to humans. In the past, people caught monkeypox from animals such as prairie dogs. Many recent cases occurred in men who have sex with men, but that doesn’t mean that the virus is sexually transmitted. Monkeypox spreads from close contact, including via clothes and linens (6). Viral particles are found in the throat, which can lead to airborne transmission via respiratory droplets. 

Health officials are considering giving close contacts of people diagnosed with monkeypox a smallpox vaccine as a preventative measure since the vaccine dampens the virus’ side effects and shortens its course. Diagnosing, treating, and vaccinating against Poxviridae has a long history, dating all the way back to 1500 BCE.

Poxviruses, such as monkeypox and smallpox, have similar structures and cell invasion mechanisms. After using their extracellular receptors to attach to cells, they release their genetic material into the cell. 

Poxviruses, such as monkeypox and smallpox, have similar structures and cell invasion mechanisms. After using their extracellular receptors to attach to cells, they release their genetic material into the cell. 

genus

Description

viruses

Orthopoxviruses

The most well-known genus, thanks to smallpox, this large set of viruses infects a variety of animals. Don’t be fooled by their names. Like monkeyvirus, many of these can also infect humans.

Camelpox, Cowpox, Ectromelia, Horsepox, Monkeypox, Raccoonpox, Skunkpox, Taterapox virus, Uasin Gishu, Vaccinia virus (smallpox vaccine), Variola (smallpox virus), Volepox

Parapoxviruses

These viruses most often infect livestock and occasionally those who work directly with livestock.

Bovine papular stomatitis, Orf (sore mouth infection), Pseudocowpox, Parapoxvirus of red deer, Squirrel parapoxvirus

Molluscipoxvirus

This genus contains one virus that commonly infects kids and immunocompromised individuals.

Molluscum contagiosum virus

Yatapoxviruses

Scientists don’t know the natural host for these viruses, but they infect humans and primates across Africa.

Tanapox (Yaba-like disease virus), Yaba monkey tumor virus

Capripoxviruses

Like Parapoxviruses, viruses in this genus infect livestock including cattle, sheep, and goats. These viruses are often lethal and affect farmers’ profits. The World Health Organization for Animal Health lists these viruses as important for animal diseases

Sheeppox, Goatpox, Lumpy skin disease

Suipoxviruses

There is only one member of this genus, and it only infects swine.

Swinepox

Leporipoxviruses

These viruses are transmitted by mosquitoes to rabbits, hares, and squirrels. In the 1950s in Australia, one genus member, Myxoma virus, was intentionally released into the wild to remove European rabbits

Myxoma, Shope fibroma (Rabbit fibroma), Squirrel fibroma virus, Hare fibroma virus

Avipoxviruses

These viruses infect more than 200 species of birds. Birds often catch the virus from insect bites or inhalation.

Canarypox, Fowlpox, Juncopox, Mynahpox, Pigeonpox, Psittacinepox, Quailpox, Sparrowpox, Starlingpox, Turkeypox

There are eight genuses of poxviruses. Although all cause similar symptoms, including lesions, each infect different animals and are transmitted in different ways. 

Pox Viruses Through Time

Pox viruses have plagued humans since ancient times. Travel through time to follow the spread of smallpox, the invention of the world’s first ever vaccine to combat it, and the rise of monkeypox just as the world said goodbye to smallpox.

1580-1100 BCE

ANCIENT EGYPTIAN MUMMIES

Three ancient Egyptian mummies, including the Pharaoh Ramses V, have what appear to be remnants of smallpox lesions on their skin (7-8), suggesting that smallpox was present more than 3,000 years ago.

340 CE 
THE FIRST DETAILED DESCRIPTION OF SMALLPOX

The ancient Chinese physician, Ko Hung wrote the first definitive description of smallpox in his 340 CE text, Handbook of Medicines for Emergencies (8). He wrote, “Recently, some people have suffered from seasonal epidemic sores which attack the head, face, and trunk. In a short time, they spread all over the body. They look like red boils, all containing some white matter.”

622-750
EARLY MUSLIM CONQUESTS
1095-1291
THE CRUSADES
1500s
SMALLPOX EPIDEMICS IN CENTRAL AND SOUTH AMERICA
1600s
FIRST SMALLPOX EPIDEMICS IN NORTH AMERICA
600s-1700s 

EXPANSION AND EXPLORATION

With an expansion of trade routes, smallpox began to spread throughout the world. Researchers hypothesized that the Crusades led to smallpox becoming endemic in Europe by the 1500s. The slave trade and the colonization of the Americas spread smallpox to native populations that had never encountered the disease before, leading to many deaths (9).

1500s-1800s 

VARIOLATION

People in China noticed that those who survived smallpox did not become infected with the disease again, inspiring them to develop an early form of vaccination called variolation. Variolation (a word derived from the name of the smallpox virus, variola virus) involved inhaling dried smallpox scabs via the nose or rubbing a small amount of pus from a smallpox lesion into a scratch on the skin (8). In a small percentage of cases, variolation led to a lethal smallpox infection, but in most cases, people simply developed a mild infection and subsequent protection against the disease (10).

1796

THE SMALLPOX VACCINE

For years, physician Edward Jenner had heard the local legend that milkmaids did not catch smallpox because in their work with cows, they often caught and recovered from cowpox (10). To see whether this tale was true, he inoculated an 8-year-old boy with fluid from lesions from a dairymaid with an active cowpox infection. The boy developed a fever and lost his appetite, but after a couple of days, he felt well again. Jenner then inoculated him with pus from a fresh smallpox lesion, but the boy never developed the disease. Jenner named his new procedure “vaccination” because of its derivation from cows, called vacca in Latin.

1958

DISCOVERY OF MONKEYPOX

In April 1958, scientists at Statens Serum Institut received a shipment of cynomolgus monkeys from Singapore for polio vaccine research (11). By July, they noticed that some of the monkeys had developed pox-like lesions on their skin. A second shipment of monkeys also experienced an outbreak. They discovered that this new virus was related to other pox viruses, so they named it monkeypox.

1967 

THE SMALLPOX ERADICATION EFFORT

The World Health Organization (WHO) began the Intensified Eradication Program to rid the world of smallpox. The effort included mass vaccination campaigns and increased surveillance to help contain outbreaks (12).

1970

THE FIRST HUMAN MONKEYPOX CASE

When a 9-month-old boy arrived at a local hospital in the Basankusu region of Zaire (now the Democratic Republic of the Congo; DRC), doctors initially suspected that he was sick with smallpox. But after hearing back from the WHO Smallpox Reference Centre where they had sent the boy’s samples, they found that he was actually infected with the monkeypox virus and recorded the first known human infection of monkeypox (13).

1970-1979

MONKEYPOX SURVEILLANCE IN THE DRC

1980

THE GLOBAL ERADICATION OF SMALLPOX

1981-1986 

INTENSIFIED MONKEYPOX SURVEILLANCE

2003

THE FIRST MONKEYPOX OUTBREAK IN THE UNITED STATES

Eleven people in Wisconsin came down with pox-like symptoms after being bitten or scratched by pet prairie dogs that had been exposed to rodents imported from Ghana. Laboratory tests confirmed that both the prairie dogs and the people had been infected with the monkeypox virus. Overall, 72 people had confirmed or suspected cases of monkeypox during this outbreak (14).

2018-2021

MONKEYPOX OUTBREAKS IN NON-ENDEMIC COUNTRIES

The WHO reported isolated cases of monkeypox in Israel, the United Kingdom (UK), Singapore, and the United States from people traveling from Nigeria where monkeypox is currently endemic (15).

2022

THE ONGOING MULTI-COUNTRY MONKEYPOX OUTBREAK

In May 2022, the WHO reported that a resident of the UK who traveled to Nigeria fell ill with a later confirmed case of monkeypox (10). Since then, multiple countries throughout Europe, the Americas, Africa, and Asia have reported monkeypox cases (16).

Treating and Preventing Monkeypox 

People who contract monkeypox usually recover over the course of two to four weeks without any medical intervention. If people come into close contact with someone with monkeypox, or if they are at risk for severe symptoms, vaccines and antiviral medications are available to help. 

VACCINE

ACAM2000 - The Smallpox Vaccine 

While scientists originally developed the ACAM2000 vaccine for smallpox, it is about 85% effective against monkeypox because of the similarity among orthopoxviruses (17). Similar to the smallpox vaccine used in the mass vaccination effort to rid the world of smallpox, ACAM2000 uses a bifurcated needle to scratch a person’s skin and deliver a dose of live vaccinia virus. Vaccinia virus is related to smallpox, but it causes a much milder disease. After vaccination, a localized infection occurs at the vaccination site, and within 3-4 days, an itchy spot forms there (18). This sore blisters and eventually leaves a small scar. People vaccinated with ACAM2000 only need one dose, and they have full protection 28 days after vaccination (19). 

Because ACAM2000 is a live virus vaccine, it can spread to other sites of the body or to another person. This is dangerous because if that person is pregnant, immunocompromised, or has a skin condition like atopic dermatitis, the virus can cause serious and sometimes life-threatening health problems (18). In some cases, people vaccinated with ACAM2000 experienced severe side effects including pericarditis and myocarditis. Multiple countries around the world keep a stockpile of this vaccine (20); the United States has more than 100 million doses in its Strategic National Stockpile. 

JYNNEOS - A Monkeypox and Smallpox Vaccine 

Scientists at Bavarian Nordic developed the JYNNEOS vaccine for both monkeypox and smallpox as an alternative to ACAM2000 (21). Unlike the bifurcated needle administration used for the ACAM2000 vaccine, the JYNNEOS vaccine is a standard injection. It contains a live, replication-deficient modified vaccinia Ankara virus (19). Because this virus cannot replicate within the human body, it cannot spread to other parts of the body or to other people. It causes fewer side effects than ACAM2000 and can be safely administered to those who cannot receive the ACAM2000 vaccine. JYNNEOS requires two doses to be effective, and people are protected against infection two weeks after their last dose (19). Clinicians can also use both ACAM2000 and JYNNEOS to prevent monkeypox or lessen its symptoms by vaccinating people soon after they are exposed (19). Receiving a vaccine within four days of exposure can often prevent monkeypox altogether, and if a person gets the vaccine within 14 days, it can lessen the severity of monkeypox symptoms.

ANITVIRALS

Tecovirimat 

Tecovirimat is an antiviral made by SIGA Technologies that targets the orthopoxvirus protein p37 (23). Smallpox, monkeypox, and other orthopoxviruses need p37 to form enveloped virions, which help the virus to release from an infected cell and infect new ones (24). Tecovirimat is FDA-approved for smallpox treatment in adults and children, but the CDC has a non-research expanded access Investigational New Drug (EA-IND) protocol for it (25), which allows its use to treat monkeypox infections in adults and children weighing over 6.6 pounds. Animal studies and a human case report indicate that tecovirimat can shorten the duration of the monkeypox infection (26). Tecovirimat is available in both an oral and intravenous form. 

vaccine vials

Cross protection 

People who previously received the smallpox vaccine were well-protected against monkeypox infection during the 1981-1986 surveillance period in the DRC (17). Data from a 2005 monkeypox outbreak in the DRC, however, demonstrated that many people who had been vaccinated against smallpox contracted monkeypox (22), suggesting that smallpox vaccine-induced immunity wanes over time. Scientists at the CDC hypothesized that prior smallpox vaccination may have some protection against monkeypox but that it won’t be completely protective now. 

Brincidofovir 

Like tecovirimat, brincidofovir is an oral antiviral that is FDA approved to treat smallpox in adults and children. Made by Chimerix, brincidofovir is a lipid-conjugated form of the antiviral cidofovir. When a virus takes up brincidofovir, the lipid gets cleaved and releases cidofovir to inhibit viral DNA polymerase function, halting viral replication (27). Brincidofovir is effective against monkeypox and other orthopoxviruses in animal models, but its efficacy against monkeypox in humans has not been tested yet (28). 

Vaccinia Immune Globulin Intravenous 

Vaccinia immune globulin intravenous (VIGIV) consists of antibodies against the vaccinia virus used in the ACAM2000 vaccine (28). Clinicians currently use it to treat people with severe adverse reactions to the ACAM2000 vaccine. While its effectiveness at treating monkeypox is unknown, the CDC has an expanded access protocol for its use in the case of a monkeypox outbreak. VIGIV can also be given prophylactically to immunocompromised people who were exposed to monkeypox. 

On the Horizon 

In May of 2022, Moderna, which produced one of the now FDA-approved COVID-19 vaccines at lightning speed, announced that they are testing monkeypox vaccines at the preclinical level. Researchers from the United Kingdom analyzed the symptoms of 54 people with monkeypox and saw differences in the location and appearance of lesions from cases in previous pandemics (29). New treatments and vaccines may be needed as our understanding of the disease evolves. 

REFERENCES 

  • 1. Center for Disease Control and Prevention. Poxvirus Diseases. at <https://www.cdc.gov/ poxvirus/diseases.html> 
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  • 5. Moss, B. Poxvirus Cell Entry: How Many Proteins Does it Take? Viruses 4, 688-707 (2012).
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