What should the control arm be in a vaccine trial? Is it a placebo if it contains aluminum?

Why some trials need TWO control arms

Recently, former White House COVID Czar Ashish Jha stated that, contrary to what you may have heard, there are placebo controlled trials of vaccines. He cited one. The problem with his statement is that the placebo used in this trial was not ‘salt water’ but rather, contained aluminum. What does that mean?

Here is the paper

The concern about vaccine trials is that if the control arm is something other than inert- salt water— the trial might hide a harm. For instance, if aluminum is harmful, both the vaccine arm and the aluminum arm experience the harms, so you can’t know which harms are due to the vaccine.

Now, imagine if the HPV trial used a true salt water control arm. These were the rates of injection site pain and systemic events at time of aluminum placebo, but with salt water, these might be far lower.

If the side effects are much lower, than some girls getting the placebo might know they got the placebo and girls getting the vaccine might know they got the vaccine. It is possible that this will actually change sexual behavior. The group with arm pain might feel more protected and engage in more sex for instance, or the behavioral change might even more complicated and counterintuitive.

What if we make a vaccine that makes you feel bad so you spend 3 days in bed, and this time the control is true salt water. The control arm goes back to work immediately. If the endpoint is a flu in 2 weeks, the vaccine might protect you— but not because it works— but because it keeps you out of socializing!

In other words, there is a tension. The best control arm for safety (totally inert) might be different the best control arm for efficacy (something that fools you into thinking you got it). How do we reconcile these tensions?

The answer is sometimes you need more than one control arm. For a flu vaccine trial, you might need 3 arms— a trial of flu vaccine vs. placebo with equal arm pain vs. inert placebo. A comparison of the first and the third will tell you about side effects, and a comparison of the first and the second will tell you about the vaccine controlling for behavioral change.

Thankfully, some vaccine experts understand this.