There’s a shortage of monkeypox vaccine. Could one dose instead of two suffice?

As the monkeypox outbreak grows, the preferred vaccine to combat it is in short supply—a problem that’s only getting worse now that countries are expanding access to the vaccine. But there is a strategy that could double overnight the number of people who can be vaccinated: use a single shot instead of the recommended two.

Compelling data from monkey and human studies suggest a single dose of the vaccine—produced by Bavarian Nordic and sold under three different brand names—solidly protects against monkeypox, and that the second dose mainly serves to extend the durability of protection.

The United Kingdom, Germany, and Canada are offering the vaccine to anyone deemed at high risk of infection—for now that’s primarily men who have sex with men (MSM) who have multiple partners. The United States at first limited the vaccine to contacts of confirmed cases, including health care workers, but on 28 June also began to offer it to people at high risk of infection who had presumed exposures, which includes MSM who have had multiple partners “in an area where monkeypox is spreading.”

There’s no way to put a hard number on it, but millions of people worldwide are now eligible for the vaccine. Yet there are nowhere near enough doses of vaccine, which contains a virus called modified vaccinia Ankara (MVA), to quickly get all of them the recommended two doses, which are normally spaced 4 weeks apart.

The United Kingdom is already giving people just one shot for now, advising them that they might want the second dose if they have an ongoing risk. And some public health officials and scientists say time is of the essence for a broader vaccination campaign among high-risk people if countries hope to prevent the epidemic from getting out of hand and the virus establishing itself outside areas where it is already endemic. 

Bavarian Nordic CEO Paul Chaplin, an immunologist, also embraces the single dose plan. Studies have shown that immune responses triggered by a single shot of the MVA vaccine declines after 2 years, which is why the approved vaccine schedule calls for a second shot. But Chaplin says immune memory is so robust after a single dose that a booster given 2 years later leads to the same immune response as the standard schedule. If countries decide to use single shots now, they have a long time to add the booster and still achieve the durability benefit, he believes. “There are a lot of data to support the single shot,” Chaplin says. 

Bernard Moss, a virologist at the U.S. National Institute of Allergy and Infectious Diseases who studied the efficacy of a single-dose MVA vaccine in monkeys, says he’s reluctant to make public health recommendations—but also volunteers: “I think a single dose in an emergency setting is reasonable.” The Centers for Disease Control and Prevention (CDC), however, says the United States will stick with the two-dose regimen because that’s what is approved by the Food and Drug Administration (FDA).

Growing outbreak

More than 5700 people in 66 countries have contracted monkeypox since early May, and the number is steadily increasing. According to the World Health Organization (WHO), the majority of confirmed cases are in MSM. But the virus has affected other groups as well, including a few children.

Bavarian Nordic’s product is one of two FDA-approved vaccines for monkeypox. Both were developed to target its cousin, smallpox, but animal studies suggest both protect against monkeypox as well.

One, named ACAM2000, is a modern version of the age-old smallpox vaccine, made from unmodified vaccinia virus, that helped eradicate that disease from humans, a feat WHO celebrated as complete in 1980. FDA approved ACAM2000 in 2007, and the United States has enough of it in its Strategic National Stockpile (SNS) to vaccinate the country’s entire population if there is a bioterror attack with smallpox. Some of the vaccine has been used “off label” for monkeypox in the current outbreak. But vaccinia copies itself after vaccination, which can lead to serious disease, especially in people who have compromised immune systems from HIV—which has a high prevalence among MSM—or other factors.

MVA, the virus in Bavarian Nordic’s vaccine, does not replicate in the body and is much safer, which makes it the preferred vaccine for the monkeypox outbreak. Known as Jynneos in the United States, Imvanex in Europe, and Imvamune in Canada, MVA is the only vaccine FDA has explicitly approved for monkeypox. Because monkeypox is so rare, the company had no human efficacy data when it applied for approval from FDA; the agency granted its license in 2019 in part based on studies showing the vaccine protected animals from monkeypox.

In the United States, SNS will make 56,000 Jynneos doses available to states immediately, officials said during a 28 June White House press conference. Because that’s not nearly enough to meet potential demand, the government has devised a four-tiered allocation system that prioritizes locales with the highest monkeypox rates and the largest population at high risk. Officials said they expect to receive an additional 296,000 doses from Bavarian Nordic “in the coming days.”

The European Commission’s Health Emergency Preparedness and Response Authority has purchased 109,090 doses of the vaccine—only some of which are immediately available—and is also prioritizing locations with high case numbers. (The first 5300 doses were shipped to Spain; Portugal, Germany, and Belgium are next.)

Individual countries in Europe have purchased supplies of the vaccine as well, but numbers are hard to confirm. All told, the world has about 1 million doses of the vaccine in hand, Chaplin says. Supply will steadily increase later this year. Bavarian Nordic already has an additional 1 million doses available for the United States, which still require FDA’s blessing because they were produced at a new plant in Denmark, Chaplin says, and the U.S. government today announced the purchase of another 2.5 million doses to be delivered by early 2023.

But the supply of vaccine to prevent monkeypox today “remains very constrained,” said a 15 June WHO monkeypox guidance, which encourages countries that have doses to share them with those that have limited or no supply.

The constraints are intensifying given the expanded eligibility for the vaccine. Initially, many countries followed WHO guidance and offered vaccination to only two groups. One was people who were at high risk of infection because of their occupation: health care workers, outbreak response teams, and lab workers who might handle viral samples. The other was people who had been in close contact with a known case; the vaccine can work post-exposure, ideally if given within 4 days but up to 2 weeks after contact occurs. Now, several countries are effectively offering the vaccine both as pre- and postexposure prophylaxis to anyone at high risk.

At a press conference this week announcing U.S. plans to expand vaccination, CDC Director Rochelle Walensky stated that two MVA doses are needed as “it takes about 2 weeks after your second dose for maximum protection.”

Faster protection

In a study published in The New England Journal of Medicine in 2019, Chaplin and colleagues compared immune responses in people given either MVA or ACAM2000. With smallpox virus, levels of neutralizing antibodies are seen as a key indicator of protection, so the same idea extends to monkeypox virus. The researchers found that 14 days after a single dose, the levels of antibodies that neutralize the monkeypox peaked with MVA, at a level nearly identical to that triggered by ACAM2000. Given that the vaccines are presumed to work postexposure if given within 2 weeks of contact, this suggests that a single dose of MVA could prevent many cases of disease and slow spread.

In a 2008 monkey study led by Moss, published in the Proceedings of the National Academy of Sciences, researchers compared preexposure vaccination against monkeypox from a single dose of MVA and one dose of a cruder version of ACAM2000 called Dryvax. Because MVA does not make copies of itself, the team gave it at a higher dose—similar to what’s used in the Bavarian Nordic shot today—than the Dryvax vaccine.

Both vaccines worked well, but MVA appeared to work faster. Levels of neutralizing antibodies and CD8 cells—critical immune actors that destroy infected cells—both rose more rapidly with MVA, which Moss and coworkers concluded was because it took time for Dryvax to replicate to levels that matched the initial shot of MVA. What’s more, when they injected the animals with the monkeypox virus just 4 days after vaccination, it grew less well in monkeys vaccinated with MVA.

In a statement to Science, CDC stressed that a single dose of the vaccine hasn’t been studied in any outbreak and cautioned that it is “challenging” to extrapolate from immune responses in earlier studies and protection in animal studies.

At this week’s press conference, there was no discussion of temporarily giving only one dose in U.S. vaccination campaign. But when asked about the option by Science, Peter Marks, the head of FDA’s vaccine division, said “we’re looking into this.”

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