When mokeypox suddenly began to spread around the world in May, the world was fortunate in one respect: a vaccine was available. MVA, originally developed by Bavarian Nordic as a smallpox vaccine, has already been licensed against monkeypox in Canada and the United States. Since then, EU regulators have 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 already given thousands of doses to high-risk people.
There is no doubt that the vaccine can help, but that is about all that can be said for sure. It is not known exactly how well MVA protects against monkeypox and for how long. It’s also unclear how much protection is lost by giving just one dose, rather than the two recommended doses, as some countries are doing to increase supplies, or how much protection a vaccine given after exposure might offer.
But the ethical and logistical complexities of the monkeypox crisis, which predominantly affects men who have sex with men (MSM), make these questions difficult to answer. Placebo-controlled clinical trials are difficult because MVA is already licensed and people are clamoring to get it. Vaccination clinics often open at short notice when doses are available, making it difficult to organize trials and enroll subjects. Researchers are responding with a variety of inventive trial designs.
The first evidence that smallpox vaccines also protect against monkeypox came from research in the 1980s in the Democratic Republic of the Congo (then called Zaire), where the virus occasionally jumps from animals to humans, which then infect others in to his family A study of contacts of patients showed that smallpox vaccination was also 86% effective in preventing monkeypox. But the study looked at a small number of cases, the virus was genetically very different from the one currently circulating, and the smallpox vaccine was older 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 elicits in humans. But its effectiveness has hardly been tested in humans, and not at all for preventing sexual transmission, which results in “very significant damage to the mucosa, which is not the same as just combing someone’s hair,” says Ann Rimouane, an epidemiologist at the University of California, San Francisco. Los Angeles.
So far, there is little data on how well the vaccine is working in the current outbreak. French scientists reported in the latest preprint that among 276 people who were vaccinated in a Paris hospital as post-exposure prophylaxis (PSP) after a reported high-risk contact, 12 developed monkeypox infection., of which 10 within 5 days after vaccination and two after more than 20 days. (That some people develop monkeypox a few days after infection is not surprising, he says Jade Ghosn from Bichat Hospital, who led the study. “A vaccine is not a miracle, it takes time to become effective.” But the two cases that occurred 22 and 25 days after vaccination are surprising, especially since an additional high-risk contact could not be established.) However, the study did not have a control group, so it is impossible to determine how many people would have contracted monkeypox if no one had been vaccinated. And people willing to get vaccinated may have lied about having a high-risk contact. “This makes it difficult to evaluate the results of these PKP trials,” says immunologist Leif Eric Zander of the Charité Clinic in Berlin, who is organizing the vaccine trial in Germany.
A randomized trial in which one group receives the vaccine and the other does not would avoid such problems. Without a randomized trial, “you can find yourself in this limbo of evidence 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.
According to many researchers, giving a control group a placebo instead of a supposedly effective vaccine is ethically risky. But University of Oxford epidemiologist Richard Peto sees a different way. Since the demand for the vaccine is much higher than the supply, “why not randomize the order of calling people from the highest risk group?” Peto asks. So far, however, no one seems to have picked up on the idea.
Sander considered a randomized design but decided against it. “There was a lot of backtracking,” he says. Instead, he has started a so-called cohort study, in which he hopes to recruit 5,000 vaccinated and 10,000 unvaccinated people at risk of monkeypox and follow them for 12 months. (Over time, some of the unvaccinated people will get vaccinated, 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 vaccine status—for example, people with a lot of sex might make more of an effort to get vaccinated—but there’s still an element of randomization, Sander says: Many doctors use lottery procedures to make decisions. who gets the vaccine first.
A cohort study in France takes a different approach. There, MSM who have already participated in a sexually transmitted disease trial and are considered to be at high risk of contracting monkeypox will receive MVA within the next 2 months. Ghosn, who is leading 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 willing to be tested for monkeypox and compare the percentage of people who were vaccinated with those who tested positive and negative. It’s probably the most powerful non-randomized approach to measuring vaccine effectiveness,” says Michael Marks, an epidemiologist at the London School of Hygiene and Tropical Medicine, who is planning a vaccine trial soon with colleagues in Spain.
Setting up a negative test requires good correlation between vaccination and testing data. “If we can solve this problem, we can use this design in our research,” Marks says. The Canadian province of Ontario is planning a similar project, says Jeff Kwong of the University of Toronto. The downside is that testing and vaccination data alone cannot answer many other questions, such as how immunity develops over time or whether disease severity differs between vaccinated and unvaccinated; which requires additional research.
The US National Institute of Allergy and Infectious Diseases (NIAID) is indeed planning a randomized trial to see if vaccine stocks can be increased by giving people much smaller doses. Participants will receive either two full doses or two one-fifth doses 4 weeks apart; A third arm could be added to test for one-tenth the normal dose, says John Beigel of the NIAID, who is involved in the study’s design. Smaller doses will be injected into the skin, which is known to cause a more active immune response than a standard subcutaneous injection. But the study, which is expected to begin in September, will only test whether fractional doses produce the same immune response as a full dose; it will not measure vaccine effectiveness directly.
One strategy that has not been tested in research is to give only one full dose, although it is used. Available evidence suggests that the regimen is inferior to two full doses, says Beigel: “We don’t think that’s scientifically proven.”
With so many unanswered questions, it’s difficult to provide reliable information about vaccines to those at risk, says Will Nutland, a British community organizer who runs the sexual health organization MSM. That shouldn’t deter people from looking for shots, he says: “I think most people understand … that it’s better to have some level of protection than no protection at all.”