When monkeypox suddenly began to spread 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 African countries that have long been affected by monkeypox. But in Europe and North America, clinics have now given thousands of doses to people in high-risk groups.
There is no doubt that the vaccine can help, but that is all that is certain. It is not known exactly how well MVA protects against monkeypox, nor for how long. Nor is it clear how much protection is lost by administering one dose instead of the two recommended doses, as some countries are doing to increase supply, or how much protection a vaccine given after exposure can offer.
But the ethical and logistical complexities of the monkeypox crisis, which overwhelmingly affects men who have sex with men (MSM), make it difficult to answer these questions. Placebo-controlled clinical trials are challenging because MVA is already licensed and people are clamoring to get it.
And vaccine clinics are often set up on short notice when doses become available, making it more difficult to organize an experiment and enroll subjects. Researchers are responding with a plethora of test projects.
The earliest evidence that smallpox vaccines also protect against monkeypox came from a study conducted in the 1980s in the Democratic Republic of Congo (then called Zaire), in which the virus occasionally passed from animals to people, who then infected animals. others in their family. One study among patient contacts suggested that smallpox vaccination was 86% effective in preventing monkeypox as well.
But the study looked at a small number of cases, the virus was genetically very different from what is spreading now and the smallpox vaccine was older with more side effects; MVA was developed as a safer alternative.
MVA was cleared for monkeypox based on data from animal experiments and the immune response it triggers in humans. But its effectiveness has barely been tested on people, and not at all to prevent sexual transmission, which results in “A very significant exposure of the mucous membranes, which is not the same as just touching someone”says Anne Rimoin, an epidemiologist at the University of California, Los Angeles.
So far, there is scant data on how well the vaccine is working in the current outbreak. Among the 276 people who received an injection 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 report. preprint, 10 of them within 5 days of vaccination and two after more than 20 days.
The fact that some people develop monkeypox within days of being infected it is not surprisingsays Jade Ghosn of Bichat Hospital, who led the study. “The vaccine is not a miracle, it needs time to be effective”.
22 and 25 days after the vaccinations are a surprise, especially since further high-risk contacts could not be established. The study did not have a control group, however, 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 a high-risk contact. “This makes the results of these PEP studies really difficult to evaluate”says immunologist Leif Erik Sander of the Charité clinic in Berlin, which is starting a vaccine study in Germany.
Monkeypox: the ethical challenges of the vaccine
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 end up in this limbo of rehearsals and discover that if you had just done the study, you would surely have found yourself in a better situation”says University of Florida biostatistician Natalie Dean.
Giving a control group a placebo instead of a supposedly effective vaccine is ethically risky, many researchers say. But Oxford University epidemiologist Richard Peto sees another way. Since the demand for the vaccine is much higher than the supply, “Why not randomize the order in which people in the highest risk group are called?” asks Peto. So far, however, no one seems to have considered this idea.
Sander considered a randomized project but decided not to. “There have been many rejections”, He says. Instead, he has started a so-called cohort study in which he hopes to enroll 5,000 vaccinated and 10,000 unvaccinated at risk of monkeypox and follow them for 12 months. Over time, some of the unvaccinated people will receive the vaccination so that the groups can become more similar in size. About 800 people have been enrolled so far.
Groups may differ in different ways from their vaccination status, people with many sexual contacts may try harder to get vaccinated, for example, but there is still an element of randomization, says Sander: Many doctors use procedures very similar to the lottery. to decide who gets vaccinated first.
A cohort study in France is taking another approach. There, MSMs already enrolled in a sexually transmitted disease study, and believed to be at high risk for monkeypox, will receive MVA in the next 2 months. Ghosn, who runs the study, hopes to vaccinate all participants by the end of September and plans to compare infection rates. before and after vaccination.
Another option is a design “Negative test”, in which researchers look at people seeking the test for monkeypox and compare the percentages of people vaccinated between those who test positive and negative. This is “Probably the most effective non-randomized approach to measure vaccine efficacy”says Michael Marks, an epidemiologist at the London School of Hygiene & Tropical Medicine who is planning a trial of the vaccine with colleagues in Spain soon.
The negative test setting requires a good link between vaccination and test data. “If we can solve this problem, we could use such a design in our studio”says Marks. The Canadian province of Ontario is moving forward with a similar project, says Jeff Kwong of the University of Toronto.
The downside is that the data on tests and vaccinations alone they can’t answer many other questions, how immunity develops over time or whether disease severity differs between vaccinated and unvaccinated; which requires further study.
The U.S. National Institute of Allergy and Infectious Diseases (NIAID) is planning a randomized trial, aimed at finding out whether the vaccine supply can be expanded by giving people much smaller doses.
Participants will receive two full doses or two one-fifth doses 4 weeks apart; a third arm can be added to test one-tenth the normal dose, says John Beigel of NIAID, who is involved in the design of the study.
Lower doses will be injected into the skin, which is known to cause a more vigorous immune response than the standard subcutaneous shot. But the study, which is expected to begin in September, will only test whether fractional doses trigger an immune reaction similar to the full dose; it will not directly measure the effectiveness of the vaccine.
A strategy not tested in the study, even if used, consists of administering only a full dose. Available data suggests the regimen is less than two full doses, Beigel says: “We don’t think it’s scientifically supported.”
With so many unanswered questions it’s difficult to provide good vaccine information to those at risk, says Will Nutland, a UK community organizer who runs an MSM sexual health organization. That shouldn’t deter people from looking for shots, he says: “I think most people understand … it is better to have some level of protection than no protection at all.”
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