Monkeypox: What is known and unknown

As recently as early July, monkeypox case counts in the United States hovered under 100. Last week, the number of confirmed cases topped 14,000, with more than 41,000 affected worldwide.

“It’s not the same explosive spread like we saw with COVID,” says Stuart Isaacs, an associate professor of medicine at the Perelman School of Medicine. “But it’s concerning, and with more testing going on, I think we’re going to continue to find cases. There are probably many cases and transmissions going undetected.”

On Aug. 4, President Biden declared the outbreak a Public Health Emergency, following on the heels of an emergency declaration by the World Health Organization on July 23. Select cities, like San Francisco and New York, have declared their own emergencies.

Yet the public health response has failed to contain the disease, and a vaccine, while effective and approved, is in short supply. As the spread continues, so does misinformation and concern. While fatalities from this outbreak have been minimal, with none recorded in the U.S. and about a dozen noted around the world, the disease can cause painful and lasting lesions and sometimes intense fever and malaise. Vulnerable groups, such as children, the elderly, and the immunocompromised, may be particularly at risk of serious outcomes.

Isaacs, an expert on the poxvirus family, which includes monkeypox as well as smallpox, and vaccinia virus, the virus used to make the available vaccines, spoke with Penn Today about the outbreak. He shares key insights about what is known about the disease, including its presentation, prevention, and treatment, as well as thoughts about what to look for as the outbreak evolves.

Unlike earlier outbreaks, human-to-human transmission is driving the recent monkeypox spread

Monkeypox is a disease endemic to Africa and is considered a zoonotic disease, one that is transmitted from animals to people. Historically, Isaacs says, many people who became sick acquired the infection directly from an animal, such as being exposed while hunting. If human-to-human transmission occurred, he notes, it was typically confined to household contacts and rarely had a long chain of human-to-human spread.

Outbreaks outside Africa have occurred before, with animals playing a direct role in the spread. In 2003, for example, 72 people in the U.S. got monkeypox from exposures to pet prairie dogs that became infected when they were co-housed with infected rodents imported from Ghana. That outbreak lasted about two months, seemingly without human-to-human transmissions.

The situation today is a far cry from these earlier scenarios. Tens of thousands of people have been affected in 94 countries, and there is clear “extended community spread,” Isaacs says.

A standout characteristic of this outbreak is that it’s predominantly—though not exclusively—affecting men who have sex with men (MSM), and in many cases is being spread through sexual activity. Monkeypox was not traditionally thought of as a sexually transmitted infection (STI), but Isaacs says it’s clearly a sexually transmissible disease, because it can be passed through sexual activity and other types of intimate contact.

“Whether or not to call it an STI is a bit of a semantics argument,” Isaacs says. “It’s yet to be understood whether people without any lesions can transmit the disease through semen, or vaginal or rectal contact. What is clear is that transmission can occur with close, intimate contact.” Isaacs also stressed that while the outbreak is occurring most commonly in MSM social networks and that there is a focus to educate and vaccinate this group, everyone is susceptible to monkeypox virus infection in the right setting.

The presentation of the disease is also different from earlier known cases

Not only does the spread of the disease look different in this outbreak, the symptoms of disease also are slightly altered from what had previously been considered the norm.

“A person infected with the more classical monkeypox disease would have the prodrome, the suite of symptoms at the onset of disease, like fevers, myalgia, headache,” Isaacs says. “Then they’d begin to break out with a rash that could be diffuse and used to often be mistaken for smallpox. The lesions would all appear at the same time, in the same state of progression around the body.”

People who have been affected in the current outbreak, in contrast, “may present without any prodrome,” Isaacs says. “Someone may first notice lesions on the genital, perianal, or oral region and only later develop fever and achiness. Sometimes more lesions develop later, elsewhere on the body.”

Right now, scientists are unsure whether these differences in presentation could be partly due to genetic changes in the virus. Genetic sequencing has identified the circulating virus as a member of Clade II, formerly known as the West African clade, a group with shared genetic features. This clade is divided into two subtypes, with the new virus noted as Clade IIb.

Generally, people with monkeypox are considered most infectious when a rash is visible. But Isaacs says that, as was seen with COVID-19, it’s possible that asymptomatic or pre-symptomatic individuals may be capable of infecting others. Scientists will learn if that is the case during this current outbreak, he notes.

A vaccine is available, but there are hurdles to access

More than 600,000 doses of vaccine have been distributed to states to allocate to close contacts of those with confirmed monkeypox infections and to individuals considered at high risk of infection. Last week the Biden administration announced plans to make an additional 1.8 million vaccine doses available.

The vaccine being given is the Jynneos vaccine, which contains a live vaccinia virus that is incapable of reproducing inside the body. Based on data from the historical smallpox vaccines in Africa, the two-dose regimen is believed to be 85% effective at preventing infection.

A second vaccine exists that could prevent monkeypox, the ACAM2000 vaccine. Approved to prevent smallpox, ACAM2000 contains a live vaccinia virus that replicates after vaccination. Roughly 100 million doses of it are stored in the U.S. Strategic National Stockpile. The reason this vaccine is not being distributed, however, is its side effects.

“That vaccine is known to have a lot of minor and some significant adverse events, even potentially death if given to the wrong person,” Isaacs says. People with immune deficiencies or skin conditions, such as psoriasis or atopic dermatitis, should not receive the vaccine. And those who do receive it can shed live vaccinia virus, potentially endangering immunocompromised people around them.

Using such a vaccine could make sense if the outbreak was smallpox, which has a high mortality rate and is highly transmissible, says Isaacs. But with this clade of monkeypox, which is far less lethal than smallpox and also far less contagious, the risk-benefit calculation is different.

Unfortunately, far less of the Jynneos vaccine was immediately available, closer to 1 million doses, and thus the rollout to at-risk populations has been slow, with many people unable to get the vaccine at all and others unsure of when they’ll get the second of the two-shot series.

Recently, the FDA issued an emergency use authorization (EUA) enabling the Jynneos vaccine to be delivered through an intradermal shot, which can be as effective as a subcutaneous delivery while using only one-fifth of the vaccine material. Though this could stretch the vaccine supply, “there’s more of a local reaction to the intradermal approach, creating some inflammation, plus you have to inject it pretty perfectly to deliver the right dose,” Isaacs says. “That’s creating a lot of hesitancy about moving forward. You don’t want to make the vaccine less desirable. So scientifically, you have a way to extend the doses, but from the human side of things, we need to think about the implications of pursuing that approach.”

Even if vaccine distribution ramps up, Isaacs notes that the vaccine alone won’t ensure a return to normal life for those people at greatest risk of monkeypox.

“All the public health responses have to work together,” he says. “We need to target the population at risk and educate them about the disease, including how to recognize it and isolate to prevent further spread. The vaccine alone will not eliminate the outbreak.”

Laborious paperwork presents an obstacle to widespread use of an available therapeutic

Tecovirimat, or TPOXX, is an antiviral therapy that is FDA-approved to treat smallpox—not monkeypox. Its use for monkeypox is still considered experimental, permitted under what’s known as an expanded access protocol. This means doctors who want to prescribe it for their patients face pages and pages of paperwork. While the U.S. Centers for Disease Control and Prevention has rapidly decreased the amount of paperwork, it still cannot be used with a simple drug prescription.

“This creates a barrier, both from the provider side and the patient side, because as a doctor you have to be able to get a written consent from the person you want to treat with the drug,” says Isaacs. “We’re all hoping at some point there will be an emergency use authorization so the provider just has to tell the patient the side effects, hand out an information sheet, and then that’s it. But an EUA will require data showing its efficacy against the current outbreak of monkeypox.”

The fall season could present further challenges for the outbreak

As the outbreak continues, Isaacs is hopeful that some questions about the infection will be answered, such as: How long are people infectious? What modes of transmission are most common? How effective are the vaccine and the antiviral, and do they cut down on transmission or simply protect the individual to whom they’re given? Could simply covering up a healing lesion with a bandage or clothing minimize the risk of transmission, enabling a person to return to work or school?

But he foresees challenges ahead. With the back-to-school season comes a return to college campuses where students will exist in close quarters and engage in social networks and activities that could amplify spread. Younger students could also be at risk, particularly those at daycares or preschools who come into close contact with care providers. “I think that’s going to create some angst and problems,” Isaacs says.