Why are Covid-19 vaccine trials taking so long?

The whole world is waiting for a Covid-19 vaccine. More than 100 different vaccines are being investigated, and 42 of them are already being tested in humans, which is breakneck progress in the world of vaccine development.

There are already 11 vaccines in phase 3 trials, using thousands of volunteer subjects to test whether a vaccine really works. If any one of these 11 trials is successful, as many scientists hope, then the world could finally begin the opening process all over again.

However, by all accounts, we are still a few months away from having an approved vaccine. Why does this take so long? Today I will try to answer this question. It’s a bit of math, but we don’t need much to get the basic idea across.

In a phase 3 trial, we give the vaccine to large numbers of people to see if it works. Some of the current 11 trials use up to 40,000 volunteers, so let’s use that number for discussion. In the trial, we could give the real vaccine to half the volunteers (20,000 people) and a placebo to the other 20,000. A placebo is a harmless injection, usually just saline, that will have no effect. The volunteers do not know if they are receiving something real; This is called “blinding”.

Then we wait. Here’s the catch: We don’t intentionally infect anyone, so we have to wait for naturally occurring infections to show up, and it could take a long time to see them. Subjects simply go on with their lives, and if they do get sick, the study records that fact.

So the question is, how many people in each group of 20,000 will be infected in the first week? The first month? Two months? The answer is that we just don’t know. To speed things up, the scientists conducting the trials try to select volunteers who are more likely than most people to get infected, but we can’t really control the number of people who get sick.

Suppose that after just one week of testing, 3 people in the placebo group get Covid-19, and no one in the vaccine group gets sick. So far so good, right? But it is not possible to conclude that a vaccine will work based on just 3 cases. Statistics tell us that those 3 cases could have happened by chance. (More precisely, if 3 cases occur in the 40,000 subjects, and if the vaccine does not work at all, then there is still a 12.5% ​​chance that all 3 cases will occur in the placebo group.)

Suppose 2 months go by and now we have 100 people in the placebo group who got sick and only 10 infections in the vaccine arm. This is much, much better: without getting into the math, a 100 versus 10 difference would be very significant, suggesting that the vaccine reduced cases by 90%.

But what if 2 months go by and the placebo group only has 10 cases? Even if the vaccine group has zero cases, such a small number will not be enough to give us confidence that we have an effective vaccine. We want to see as many cases as possible, but we cannot force the issue. We have to wait.

In the US, the FDA has announced that a vaccine must protect at least 50% of people to be declared effective. This means that we need to see enough cases to be sure that a vaccine confers that degree of protection. 50% is a fairly low bar, but so far none of the trials have announced preliminary results showing they have met that standard.

(Aside: “blinding” is really important in these trials. If subjects know they are receiving a placebo, they might be very careful to avoid exposure to the virus. This would artificially depress the number of cases in the placebo group. Conversely, if they know they are getting the vaccine, they might be more reckless, increasing exposures and cases in that group. For the results to be valid, we need all subjects to behave in the same way).

A faster option? There is a way to speed up this process: a “challenge” test, where subjects are intentionally infected with the virus. The UK is preparing to start such a trial in January, first administering vaccines to healthy volunteers and then exposing them to the SARS-CoV-2 virus about a month later. This is a much faster way to determine if a vaccine is working, but it creates serious ethical dilemmas, because we do not have a cure for the virus. If the world has an effective vaccine in January, I hope the challenge test will be canceled. That would not be a bad result.