Why use a placebo in some potential COVID-19 vaccine trials?

Medical Sciences Asked by pymekrolimus on August 29, 2021

With potential COVID-19 vaccine trials beginning around the globe, one vaccine approach is to induce the creation of antibodies in the participants.

The first phase of the trial will check whether the vaccine candidate induces the creation of antibodies to kill the coronavirus that causes COVID-19, and whether it provokes any serious adverse side effects.

Either the potential vaccine or a placebo will be given to participants.

Two doses of COVAX-19, or a placebo, will be injected into 40 healthy people between the ages of 18 and 65

As the aim of the trial is to check for the creation of antibodies, what is the purpose of having a placebo group? Would it be a reasonable assumption to conclude that it’s biologically impossible for the antibody to be created in the participant on placebo?

A standard example of the placebo effect would be in pain management – wherein participants will be given a painkiller or a sugar pill. There do exist known mechanisms for these effects, however in the case of creating an antibody – how can that be possible?

4 Answers

People could develop antibodies from natural exposure to the virus. The vaccine is trying to cause antibodies to exist in more people (and/or more strongly) than would express them naturally, therefore a good comparison group is a sample taken randomly in the same way as those getting the vaccine: a placebo group.

At the same time, these trials tend to assess safety outcomes; again, to assess safety you want to know that effects are no worse than those in some comparison population. Comparing to placebo is typically a gold standard for this comparison.

You're right that a placebo wouldn't be as necessary if we could prevent random exposure, but in the middle of a pandemic that isn't feasible.

Correct answer by Bryan Krause on August 29, 2021

Antibodies only reflect one part of the immune response: the humoral immunity.

There is another part of the immunity that can't be detected by dosing the antibodies: the cell-mediated immunity. It produces no antibodies. It only creates effector T-cells that can detect the presence of viruses (or some intra-cellular bacteria) inside body cells and destroy these cells or trigger apoptosis.

This is one reason why checking the clinical outcomes of a vaccine is interesting. The results will be compared to antibody titers for interpretation.

Answered by JeanV on August 29, 2021

People in the control group will behave differently if they know they're in the control group.

For example, it's not unreasonable to expect people will do less social distancing once they're vaccinated. This will increase their chances of being exposed to the virus.

Answered by BlueRaja - Danny Pflughoeft on August 29, 2021

Good question. A phase I trial normally has small numbers, is purely sized to test safety, and it would have no placebo arm. With side effects and antibodies are end points, and a placebo group, this would more often be called a combined phase I/II trial.

The purpose of the placebo should be to compare the proportion of side effects and antibodies in the vaccine arm and those in the placebo arm. However with only 20 people in each arm, this seems a bit, ehm, optimistic.

Imagine if 4 of the vaccinated people report a sore arm, 2 a headache and sore throat, and 2 a fever, that might be unacceptable. But headache and sore throat are common, and as well as fever during winter-time, when colds and influenza are running around. So I expect the reason for the placebo group is to be able to partially compensate for influenza-like illnesses in the community, so they could suggest that some of the reported vaccine side effects aren't from the vaccine. (Note, you can't just subtract one from the other -- with that few people in each group, random variation will be high, so it may be that more of the "placebo" folks got unlucky... but the vaccine still causes fevers in 10% of the vaccinated folks).

As far as antibodies, you're right -- assuming that in Adelaide, Australia the rates of COVID-19 are very low, then only the vaccinated volunteers could develop antibodies. But what if one of the vaccinated people gets a mild infection naturally? Then you'd better hope that 1-2 of the placebo volunteers do as well, so that you can know the antibody response isn't necessarily from the vaccine.

Or what if the antibody test is not quite accurate? What if it has some false positives? Then some of the placebo volunteers might test positive as well, and be a flag to take the positive results with a grain of salt.

Answered by wisdom_seeker on August 29, 2021

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