The world was fortunate that a vaccine was available when mo nkeypox began to spread. Monkeypox is a vaccine that was licensed for in Canada and the US. Regulators have followed suit. Some countries in Africa have been affected by monkeypox but no vaccine has been given to them. Clinics in Europe and North America now deliver thousands of doses to people in high risk groups.

The vaccine can help, but it's not certain. For how long, is not known. It's not clear how much protection is lost by giving just a single dose rather than the recommended two, as some countries are doing to stretch supply, or how much protection a vaccine given after exposure can give.

The ethical and logistical issues of the monkeypox crisis are making it difficult to answer. It's difficult to conduct a placebo-controlled clinical trial because people want to get it. It's harder to organize a trial when vaccine clinics are set up at short notice. There are a lot of trial designs.

The first evidence that the vaccine protects against monkeypox came from a study that took place in the Democratic Republic of the Congo in the 1980s. The study showed that the vaccine was effective at preventing monkeypox. The study looked at a small number of cases, the virus was different, and the vaccine was older and had more side effects.

Data from animal experiments and the immune response it causes in humans are what led to the license ofMVA. Anne Rimoin, an epidemiologist at the University of California, Los Angeles, says that it hasn't been tested for prevention of sexual transmission in people.

There isn't much data on how well the vaccine is working. French scientists reported in a recent preprint that 12 individuals who received a shot at a Paris hospital as post-exposure prophylaxis after reporting a high-risk contact developed a monkeypox infection, 10 of them within 5 days and two after 20 days. The leader of the study says that it's not surprising that some people would develop monkeypox a few days after being exposed. It takes time to be effective with the vaccine. The two cases occurring 22 and 25 days after the vaccine are a surprise. It's not possible to tell how many people would have developed monkeypox if there was no vaccine. It's possible that people lied about having high-risk contacts to get the vaccine. The Charité clinic in Berlin is setting up a vaccine study that will be difficult to evaluate because of that.

In a randomized trial, one group gets the vaccine and the other doesn't Natalie Dean, a biostatistician at the University of Florida, says that without a randomized study, you can end up in evidence limbo.

It is ethically dicey to give a placebo to a group of people. Richard Peto believes in a different way. Randomizing the order in which people in the highest risk group are called in is something that could be done. "Peto, what do you think?" No one seems to have thought of that idea.

A randomized design was considered by the man. He said there was a lot of resistance. He is starting a study in which he hopes to enroll 5000 people who are at risk of monkeypox and follow them for a year. Some of the unvaccinated people will get the shot so the groups will become more similar. About 800 people have signed up.

The groups may differ in ways other than their vaccine status, but there is still an element of randomness.

Another approach is being taken by a study in France. MSM who enroll in a study of sexually transmitted diseases will getMVA in the next 2 months. The leader of the study hopes to have everyone in the study vaccine by the end of the month.

In a test-negative design, researchers look at people who seek testing for monkeypox and compare the percentage of people who werevaccinated against those who did not. Michael Marks is an epidemiologist at the London School of Hygiene & Tropical Medicine who is planning a vaccine trial with colleagues in Spain.

Good linkage between vaccine and testing data is required for the test negative setup. Marks says that they may use a design like that if they can solve the problem. Jeff Kwong of the University of Toronto says that the Canadian province of Ontario is following in the footsteps of other countries. Testing and vaccine data alone can't answer many questions, such as how immunity develops over time or whether disease severity is different among the vaccine and unvaccinated.

A randomized trial is planned by the U.S. National Institute of Allergy and Infectious Diseases in order to find out if the vaccine supply can be stretched. A third arm may be added to the study to test one-tenth of the normal dose, says John Beigel, who is involved in designing the study. The immune response will be more vigorous when the lower doses are injected into the skin. The study won't measure vaccine efficacy directly, but will only test if fractional doses cause the same immune reaction as the full dose.

Even though it is being used, only one full dose is being given. Data shows that the regimen is not as good as two full doses.

Will Nutland is a U.K. community organizer who runs an organization for MSM sexual health. He says that most people understand that it's better to get some level of protection than no protection at all.