The US could inoculate against monkeypox with smallpox vaccines — but it’s not that simple

Monkeypox, a viral disease transmitted through close skin contact that causes flu-like illness and painful rashes, has already infected nearly 19,000 people worldwide, most of them gay and bisexual men. Last week, it was declared a global public health emergency.

As anxiety about the virus mounts, Americans are increasingly frustrated that they don’t yet have widespread access to a vaccine called Jynneos that’s been approved by the Food and Drug Administration for preventing monkeypox transmission and disease. And some are asking why public health authorities aren’t also offering them a different vaccine it has in greater supply, one created to prevent smallpox but that also has a protective effect against monkeypox: ACAM2000.

It’s not that simple, though. Public health leaders are weighing significant trade-offs: While using the US’s stockpiles of smallpox vaccines might seem like an easy fix to this scary situation, the decision is much thornier than it appears. ACAM2000’s potentially concerning side effects, the complex way it has to be administered, and limits on who can safely receive the vaccine seriously complicate the risk-benefit calculation around using it.

Health officials aren’t likely to make ACAM2000 widely available unless something big about the monkeypox outbreak changes. Here’s why.

ACAM2000’s pro and cons

ACAM2000’s best feature right now is its availability: 100 million-odd doses of the vaccine are currently sitting on the shelves at the US Strategic National Stockpile, largely untouched.

But it comes with a long list of contingencies, among them its unwieldy administration. Although vaccinators give most routine immunizations using a simple in-and-out injection technique, ACAM2000 is inoculated into the skin with a two-pronged needle through a series of tiny jabs at the skin — enough to draw a droplet of blood. “You have to train people how to do it,” said Carlos del Rio, an infectious disease specialist at Emory University in Atlanta. “It is not a simple procedure.”

Also, immunizers can’t just assume ACAM2000 has worked in a person who’s received it: They need to check for proof — and that proof comes in the form of a single, kind of gnarly pustule that shows up at the inoculation site about a week after getting immunized. In a small percentage of people, the vaccine doesn’t “take” on the first try, and they require another shot.

There are also major limitations on who can safely receive ACAM2000. The vaccine contains live, weakened vaccinia virus — a relative of smallpox and monkeypox that’s not harmful to healthy people but can cause serious illness in people who are severely immunocompromised (including people with advanced or untreated HIV), pregnant people, people with eczema, and infants. That means people in these categories should not receive ACAM2000.

Furthermore, because people who get ACAM2000 shed live vaccinia virus from their inoculation-site pustule until it crusts over (usually about two weeks after vaccination), they have to keep the site carefully covered to avoid infecting someone in one of these risk groups. That means vaccinators should ask recipients about their high-risk close contacts, including pregnant people and those living with eczema or in immunocompromised states, said Amesh Adalja, a health security and emerging infectious diseases expert at Johns Hopkins Bloomberg School of Public Health.

Delivering ACAM2000 vaccines is not impossible, Adalja added: “The military does it all the time,” he said. “It’s just cumbersome, and it requires medical attention. It can’t just be done in an assembly-line manner.”

Critically, although ACAM2000 offered safety upgrades over its predecessor (Dryvax, which was instrumental in eliminating smallpox), it has important side effects. In a study involving about 3,000 people who were given the ACAM2000 vaccine, about 1 in every 175 people developed myocarditis, a condition in which the heart muscle becomes inflamed. The condition was so mild that it didn’t cause symptoms in most of the people who had it, and researchers only noticed it because they were monitoring patients so carefully for vaccine side effects. However, the finding raised concerns that if ACAM2000 were used in larger groups of people, it might lead to symptomatic or perhaps more severe cases of myocarditis.

All of this creates extraordinary challenges for giving lots of people ACAM2000 vaccines quickly: Before offering this vaccine, the person administering it needs to screen each patient for immunocompromised states and other disqualifiers, informing each one about the vaccine’s risks. “A doctor can do that with a patient — but it’s very hard for a public health agency to make that judgment,” said Adalja.

So while Jynneos can be given in public venues, like festivals and even bathhouses, ACAM2000 would be much better administered in a health care provider’s office. But for now, most vaccines are being given at public health clinics and are not being distributed through many doctor’s offices, said Adalja.

ACAM2000’s shortcomings would matter less if we were dealing with a smallpox outbreak — but we’re not

Despite ACAM2000’s shortcomings, its pros would still clearly outweigh its cons if it were being deployed to protect a large group of people from a credible threat of far-more-deadly smallpox infections, said Adalja. “If this was a smallpox biological weapons attack,” he said, “the risk-benefit ratio would be so different, and nobody would be having this discussion. People would be lining up to get it,” he said.

And whatever the operational challenges of vaccinating people with ACAM2000 at a large scale, they could be overcome, said Nirav Shah, Maine’s public health chief and president of the Association of State and Territorial Health Officers. “If we had a smallpox situation,” he said, “overnight, I would make [my team] experts in ACAM2000 administration. So it’s not insurmountable.”

But the balance of risk and benefit is not as clear when the goal is to prevent monkeypox infections, which are much less likely to be lethal, said Adalja. “Monkeypox is not likely to kill anybody in the United States. It’s hospitalized some percentage; it’s painful; you want to avoid getting it — but it’s not the same societal threat or individual threat that smallpox is,” he said. In the past, 30 percent of smallpox infections led to death.

As of July 20, according to the World Health Organization, five deaths had been reported as part of the current monkeypox outbreak, none of them in the US or Europe, where most of the population has some access to reliable medical care. On July 29, Brazil reported a sixth death due to monkeypox in a man with lymphoma and a weakened immune system.

The Food and Drug Administration, which considers this kind of risk-benefit balance when approving drugs and vaccines for use in the US, has approved ACAM2000 to prevent smallpox but not to prevent monkeypox. And while CDC has made the vaccine available for monkeypox prevention under an investigational protocol, few states have expressed interest in using it during the current outbreak, said Shah.

Jynneos and other STI prevention tools are what this monkeypox outbreak really needs

If no other vaccine options were available, ACAM2000 might look like a decent way to respond to this monkeypox outbreak. Even Dryvax, ACAM2000’s less safe predecessor, was an option when a cluster of monkeypox infections erupted in the American Midwest in 2003. As part of the response, health authorities vaccinated 30 people with the older vaccine to help stop the outbreak from spreading, with no serious adverse events reported.

The argument to offer ACAM2000 more widely right now would also be stronger if monkeypox threatened to spread rapidly to the entire US population. That’s not a likely scenario: For monkeypox to spread quickly in a group of people, infected people need to have a lot of close skin-to-skin contact with others who also have lots of skin-to-skin contact with others.

That characteristic — what in public health parlance is called “concurrency” — does describe the sexual networks of some people, including some men who have sex with other men. It also describes the network of nonsexual contacts that people in certain professions have, like day care workers or health care providers. But it doesn’t describe the general population, which means that, for most people, the risk of catching monkeypox is generally pretty low.

While the risk to the general population could increase if viral mutations turn out to confer different traits on newer versions of the virus, there is no evidence to prove that’s happened yet.

Meanwhile, many people are rightfully frustrated at Jynneos’s very limited supply. The fact that delays in finishing and shipping Jynneos vaccines occurred, in part, as a result of poor planning by the Food and Drug Administration — and that they’re happening in the wake of so many other institutional failures during the Covid-19 pandemic — only amplifies the collective frustration. It’s also a reminder of the many ways the US government failed members of the LGBTQ community, and gay men in particular, in the early years of the HIV/AIDS epidemic.

Shah said that to seriously consider broader use of ACAM2000 to prevent monkeypox, he’d need to see something unexpected or unusual in either the pathogen or the vaccine. “Evidence that monkeypox was becoming virulent in ways that have yet to be described” would be one reason, he said, or a major problem with Jynneos’s quality or supply might motivate more public health jurisdictions to offer ACAM2000 to selected people as an alternative to waiting for Jynneos.

The Department of Health and Human Services announced plans on Wednesday to send another 786,000 doses of Jynneos to states “as soon as possible,” and has said millions more will be delivered by mid-2023 — but that’s a long time away.

For now, public health authorities seem to have determined that this outbreak doesn’t justify the use of ACAM2000, said Adalja. “That might be an okay choice, but I think it just needs to be something that’s discussed.”

As the public waits for Jynneos availability to be scaled up, one of the things people seem to need most is clear, transparent information about monkeypox infection and the public health response to it. Out of a desire to avoid stigmatizing gay sex — as so much messaging during the HIV/AIDS outbreak did — some health communicators have been overly inclusive about describing who’s at risk. That’s led to confusion about how to best protect the people most likely to need protection — and least likely to know how to access it.

“What we need is information that’s accessible where people are,” said Sebastian Köhn, a Brooklyn resident who recently recovered from a monkeypox infection that resulted in six days of a 103 degrees Fahrenheit fever and two weeks of agonizing pain.

“We don’t need to be hysterical about it. But we do need to get accurate information out there about what this experience can be like,” he said, “because I really think that will help people make decisions that are right for them.”

Update, July 29, 1:50 pm: This story has been updated to reflect an additional death reported from monkeypox.