When monkeypox suddenly started spreading globally in May, the world was fortunate in one respect: a vaccine was available. MVA, originally developed by Bavarian Nordic as a smallpox vaccine, was already licensed for monkeypox in Canada and the United States. EU regulators have since followed suit. Vaccine supplies are limited, and no doses have been shared with countries in Africa that have long been affected by monkeypox. But in Europe and North America, clinics have by now delivered thousands of doses to people in high-risk groups.
There’s little doubt the vaccine can help, but that’s about all that’s certain. Exactly how well MVA protects against monkeypox and for how long is not known. Nor is it clear how much protection is lost by giving just a single dose rather than the recommended two doses, as some countries are doing to stretch supply, or how much protection a vaccine given after exposure can offer.
But the ethical and logistical complexities of the monkeypox crisis, which is overwhelmingly affecting men who have sex with men (MSM), are making these questions hard to answer. Placebo-controlled clinical trials are fraught because MVA is already licensed and people are clamoring to get it. And vaccine clinics are often set up at short notice as doses become available, making it harder to organize a trial and enroll subjects. Researchers are responding with a plethora of inventive trial designs.
The first evidence that smallpox vaccines also protect against monkeypox came from a study in the 1980s in the Democratic Republic of the Congo (then called Zaire), where the virus occasionally jumps from animals to people, who then infect others in their household. A study among patients’ contacts suggested smallpox vaccination was 86% effective at preventing monkeypox as well. But the study looked at a small number of cases, the virus was genetically quite different than the one now spreading, and the smallpox vaccine was an older one with more side effects; MVA was developed as a safer alternative.
MVA was licensed for monkeypox based on data from animal experiments and the immune response it triggers in humans. But its efficacy has barely been tested in people, and not at all for preventing sexual transmission, which results in “very significant mucosal exposure, which is not the same thing as just brushing up against somebody,” says Anne Rimoin, an epidemiologist at the University of California, Los Angeles.
So far, there’s scant data on how well the vaccine is working in the current outbreak. Among 276 individuals who received a shot at a Paris hospital as post-exposure prophylaxis (PEP) after reporting a high-risk contact, 12 developed a monkeypox infection, French scientists reported in a recent preprint, 10 of them within 5 days of vaccination and two after more than 20 days. (That some people would develop monkeypox a few days after being infected is not surprising, says Jade Ghosn of Bichat Hospital, who led the study. “The vaccine is not a miracle, it needs time to be effective.” But the two cases occurring 22 and 25 days after vaccination are a surprise, especially because no additional high-risk contact could be established.) The study had no control group, however, making it impossible to tell how many people would have developed monkeypox if no one had been vaccinated. And people eager to be vaccinated may have lied about having had a high-risk contact. “That makes results from these studies on PEP really hard to evaluate,” says immunologist Leif Erik Sander of the Charité clinic in Berlin, who’s setting up a vaccine study in Germany.
A randomized trial—in which one group receives the vaccine and the other does not—would avoid such problems. Without a randomized study, “you can end up in this evidence limbo and find that if you had just done the trial, you would have been in a much better situation,” says biostatistician Natalie Dean of the University of Florida.
Giving a control group a placebo instead of a presumably effective vaccine is ethically dicey, many researchers say. But University of Oxford epidemiologist Richard Peto sees another way. Because demand for the vaccine is so much higher than supply, “Why not randomize the order in which people in the highest risk group are called in?” Peto asks. So far, however, no one seems to have taken up that idea.
Sander considered a randomized design but decided against it. “There was a lot of pushback,” he says. Instead, he has started a so-called cohort study in which he hopes to enroll 5000 vaccinated and 10,000 unvaccinated people at risk of monkeypox and follow them for 12 months. (Over time, some of the unvaccinated people will receive the shot so the groups may become more similar in size.) So far, about 800 people have been enrolled.
The groups may differ in ways other than their vaccine status—people with lots of sexual contacts may try harder to get vaccinated, for example—but there is still an element of randomization, Sander says: Many doctors are using lottery-type procedures to decide who gets the vaccine first.
A cohort study in France is taking another approach. There, MSM already enrolled in a study of sexually transmitted diseases—and deemed at high risk of monkeypox—will get MVA in the next 2 months. Ghosn, who runs the study, hopes to have all participants vaccinated by the end of September and plans to compare infection rates before and after vaccination.
Another option is a “test-negative” design, in which researchers look at people who seek testing for monkeypox and compare the percentages of people who were vaccinated among those who test positive and negative. This is “probably the strongest nonrandomized approach to measuring vaccine efficacy,” says Michael Marks, an epidemiologist at the London School of Hygiene & Tropical Medicine who is planning a vaccine trial soon with colleagues in Spain.
The test-negative setup requires good linkage between vaccination and testing data. “If we can solve that issue we may use such a design in our study,” Marks says. The Canadian province of Ontario is going ahead with a similar design, says Jeff Kwong of the University of Toronto. The drawback is that testing and vaccination data alone can’t answer many other questions, such as how immunity develops over time or whether disease severity is different among the vaccinated and the unvaccinated; that requires additional studies.
The U.S. National Institute of Allergy and Infectious Diseases (NIAID) does plan a randomized trial, aimed at finding out if the vaccine supply can be stretched by giving people much smaller doses. Participants will either get two full doses or two one-fifth doses 4 weeks apart; a third arm may be added to test one-tenth of the normal dose, says NIAID’s John Beigel, who is involved in designing the study. The lower doses will be injected into the skin, which is known to cause a more vigorous immune response than the standard subcuteanous shot. But the study, expected to start in September, will only test whether fractional doses trigger a similar immune reaction as the full dose; it won’t measure vaccine efficacy directly.
One strategy not tested in the trial, even though it is being used, is giving just one full dose. Available data suggest that regimen is inferior to two full doses, Beigel says: “We don’t think it’s scientifically supported.”
With so many unanswered questions it’s hard to provide good vaccine information to those at risk, says Will Nutland, a U.K community organizer who runs an organization for MSM sexual health. That should not deter people from seeking the shots, he says: “I think most people understand … that it is better to receive some level of protection than no protection at all."