I know that the studies done by Pfizer, et al, used standard methods with a placebo control group. If you read about blinded experiments here, it mentions:

A common cause for unblinding is the presence of side effects (or effects) in the treatment group. In pharmacological trials, premature unblinding can be reduced with the use of an active placebo, which conceals treatment allocation by ensuring the presence of side effects in both groups.

As we know, the covid vaccines have some side effects. Anecdotally, I know many people who reported feeling a bit sick for a day after getting one. So my question is, did this "unblind" the participants in the covid vaccine trials? Or did they use a placebo that caused some level of irritation, in order to better hide this?

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    There's no ethical way to add side effects to a placebo. The risk of giving someone something that will cause myalgias/fatigue/headache/a sore arm/allergic reaction/whatever outweighs the benefit to the individual (there is no benefit to the participant with a study-based placebo.) While it may only cause temporary discomfort, it will always do worse in some. "First do no harm" is an important guiding principle. I had no side effects whatsoever to my first, second, or third doses of the (real) vaccine. (I was disappointed; my immune system isn't what it used to be.). Jan 15, 2022 at 15:31
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    @anongoodnurse Maybe you should reread the sentence you quoted, and not leave off the first part. It starts with "In some cases...". So, actually you're wrong, the answer isn't right there. Plus, if they never add side effects, then that what are they talking about with an "active placebo" that is "ensuring the presence of side effects" ?
    – Curt
    Jan 16, 2022 at 7:23
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    @Curt - You're right. I skimmed that and only saw the part that agreed with my opinion. I sincerely apologize; I was rash and added insult to injury. I never encountered a study with active placebo and didn't even know that was a thing, so I read up on it. (Thanks for that. I like learning something new, and I always prefer to learn when I am wrong.) It turns out that 99% of trials are carried out with passive placebo, so I can understand my not running into it. Not an excuse. Again, I'm sorry for insulting you. Thanks for pointing me in the right direction. Jan 16, 2022 at 15:12
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    @anongoodnurse Thanks. We all make mistakes. Admitting it in public is rare these days, at least in certain areas, so it's nice to see. +1 to you for that. :)
    – Curt
    Jan 16, 2022 at 19:47
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    @anongoodnurse kudos on taking the opportunity to learn! Incidentally, the AstraZeneca trial is one of those rare examples with an active control (see my answer below).
    – De Novo
    Jan 22, 2022 at 6:28

2 Answers 2


Of the three vaccine products that have been approved or had emergency use authorization in the United States, all used saline placebo in the clinical trial.

From the Pfizer Polack et al paper:

With the use of an interactive Web-based system, participants in the trial were randomly assigned in a 1:1 ratio to receive 30 μg of BNT162b2 (0.3 ml volume per dose) or saline placebo.

From the Moderna Baden et al paper:

Injections were given 28 days apart, in the same arm, in a volume of 0.5 ml containing 100 μg of mRNA-1273 or saline placebo.

From the Johnson & Johnson Sadoff et al paper:

Participants were randomly assigned in a 1:1 ratio, with the use of randomly permuted blocks, to receive either Ad26.COV2.S or saline placebo.

Thus, we should expect that a mild salt water solution would not elicit much of an immune response. This is a potential weakness of the trial design. Nonetheless, the results were sufficient to result in full approval of the Pfizer product.


The AstraZeneca COVID-19 vaccine approved by EU and UK regulatory authorities used a meningitis vaccine as the control in phase 2/3 trials.

From the methods section of their paper:

Participants were randomly assigned to receive either the ChAdOx1 nCoV-19 vaccine or the quadrivalent MenACWY protein-polysaccharide conjugate vaccine. MenACWY was used as a comparator vaccine rather than a saline placebo to maintain masking of participants who had local or systemic reactions.

Confidence intervals for side effects overlapped between the treatment and control groups (see the appendix in the above linked paper), though the study wasn't powered to detect moderate differences. It seems these investigators may have met their goal of avoiding unmasking due to side effects.

This doesn't guarantee that unmasking didn't occur for some other reason. I'd note that no masking assessment was reported, though it rarely is. It is possible to assess masking by, e.g., asking participants whether they think they received the treatment or control. Unmasking can occur for a variety of reasons, side effects are just one of them. For example, trials of interventions that are a bit more complex than a pill (e.g., injection, IV) often don't blind staff who administer the intervention and control, but keep the participants, investigators, and the people who collect the data blind. This comes with a risk of unmasking, but is balanced against the challenge (and likely failure) of making the intervention and treatment look exactly alike, push exactly alike, etc.

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    When I wrote my answer, I had sworn some trial has used a pneumococcal vaccine as a control. I tried googling / PubMeding all sorts of variations of “COVID trial pneumococcus control” and all I could find were trials of administering them together. It was meningococcus. Oops. Nice find!
    – Ian Campbell
    Jan 22, 2022 at 14:38
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    Wow, that's stunning! Interesting that the control group stats for adverse reactions isn't included in the paper, but need to be downloaded separately. There were not many, but there were significant (well, depends on how that's defined)/serious side effects in the control group. I'd have liked to be in the room with the ethics committee for that discussion. Wow, and thanks for the heads up! Very, very interesting. :) And wow, was I wrong, wrong, wrong!!! Thank you! Jan 22, 2022 at 19:38
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    @anongoodnurse This thread makes me wonder what you think of sham procedures as controls in surgical/interventional trials. ORBITA would be a well-known modern example.
    – Carey Gregory
    Jan 22, 2022 at 23:49
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    @CareyGregory - I have mixed feelings about it. In essence, to truly blind (double mask) a surgical trial, one must willfully withhold a needed treatment. I firmly believe in First do no harm. In most studies, the controls, the people, usually don't do it for altruistic reasons (though in the covid trials, many could have done so.) They do it with hope of being in the treatment group, or monetary compensation, or some other ethical imbalance (being offered a surgery they cannot afford vs. the risk of being a control.) Altruism is fine; taking advantage of someone's weakness is not. Jan 23, 2022 at 14:18
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    @CareyGregory - So with some sham surgical procedures, I'm more in the "OK" range (like with knee surgeries), but others, not. I guess overall, I'm glad they're advancing knowledge of the efficacy of surgical interventions, but I really wish monetary compensation didn't drive so many surgical procedures in the first place. (Can you tell I really struggle with the ethics of this?) Jan 23, 2022 at 14:32

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