How effective is the monkeypox vaccine? Scientists scramble for clues as trials ramp up | Science

When monkeypox suddenly started spreading globally in May, the world was lucky 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 already dispensed thousands of doses to people in high-risk groups.

There is no doubt that the vaccine can help, but that is about all that is certain. It is unclear 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 recommended two doses, as some countries do to stretch the supply, or what protection a vaccine given after exposure may offer.

But the ethical and logistical complexities of the monkeypox crisis, which massively affects men who have sex with men (MSM), make these questions difficult to answer. Placebo-controlled clinical trials are cumbersome because MVA is already licensed and people are clamoring to get it. And vaccination clinics are often set up at short notice as doses become available, making it more difficult to organize a trial and recruit subjects. Researchers respond with a plethora of inventive trial designs.

The first evidence that smallpox vaccines also protect against monkeypox comes from a study in the 1980s in the Democratic Republic of Congo (then called Zaire), where the virus sometimes jumps from animals to humans, who then infect other people in their household. A study among patient contacts, smallpox vaccination was also 86% effective in preventing monkeypox. But the study involved a small number of cases, the virus was genetically quite different from the one currently spreading, and the smallpox vaccine was older with more side effects; MVA was developed as a safer alternative.

MVA has been approved 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, resulting in “very significant mucosal exposure, which is not the same as just brushing against someone.” ‘one”, explains Anne Rimoin, epidemiologist at the Institute. University of California, Los Angeles.

So far, there are few data on the effectiveness of the vaccine in the current epidemic. Among 276 people who were injected in a Paris hospital for 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 2 after more than 20 days. (That some people develop monkeypox within days of being infected is not surprising, says Jade Ghosn from 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, not least because no additional high-risk contacts could be established.) However, the study did not have a control group, making it impossible to say how many people would have developed monkeypox if no one had been vaccinated. And people wanting to get vaccinated may have lied about having had a high-risk contact. “This makes the results of these PEP studies very difficult to assess,” says immunologist Leif Erik Sander of the Charité clinic in Berlin, which is 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 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 place,” says biostatistician Natalie Dean of the University of Florida.

Giving a control group a placebo instead of a presumed effective vaccine is ethically risky, many researchers say. But Oxford University epidemiologist Richard Peto sees another way. Because the demand for the vaccine is so much higher than the supply, “Why not randomize the order in which people in the highest risk group are called?” Peto asks. So far, however, no one seems to have taken up this idea.

Sander considered a random design, but decided against it. “There was a lot of pushback,” he says. Instead, he has launched a so-called cohort study in which he hopes to recruit 5,000 vaccinated and 10,000 unvaccinated people at risk for monkeypox and follow them for 12 months. (Over time, some of the unvaccinated people will receive the vaccine so the groups can become more similar in size.) So far, about 800 people have been registered.

Groups may differ in ways other than their vaccination status — people with a lot of sexual contact may try harder to get vaccinated, for example — but there’s always an element of randomization, Sander says: Many doctors use lottery-like procedures to decide who gets the vaccine first.

A cohort study in France takes another approach. There, MSM already enrolled in a sexually transmitted disease study – and deemed at high risk for monkeypox – will receive MVA within the next 2 months. Ghosn, who is leading the study, hopes all participants will be 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 examine people seeking to be tested for monkeypox and compare the percentages of people vaccinated among those who test positive and negative. It’s “probably the strongest non-randomized approach to measuring vaccine effectiveness,” 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 configuration requires a good link between vaccination and test data. “If we can solve this problem, we can use such a design in our study,” says Marks. The Canadian province of Ontario is moving forward with a similar design, 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 people. vaccinated and unvaccinated; which requires further studies.

The US National Institute of Allergy and Infectious Diseases (NIAID) is planning a randomized trial, aiming to see if the vaccine supply can be stretched by giving people much lower doses. Participants will receive either two full doses or two one-fifth doses 4 weeks apart; a third arm can be added to test a tenth of the normal dose, says NIAID’s John Beigel, who is involved in the design of the study. The lower doses will be injected into the skin, which is known to elicit a stronger immune response than the standard subcutaneous injection. But the study, which is due to start in September, will only test whether split doses trigger a similar immune reaction to the full dose; it will not directly measure the effectiveness of the vaccine.

A strategy not tested in the trial, even if used, is to administer a single full dose. Available data suggests the regimen is less than two full doses, says Beigel: “We don’t believe it’s scientifically proven.”

With so many unanswered questions, it’s difficult to provide good information about vaccines to those at risk, says Will Nutland, a British community organizer who runs an organization for MSM sexual health. That shouldn’t deter people from getting vaccinated, he says: “I think most people understand…that it’s better to have some level of protection than no protection at all.”

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