So I'm told that there's some confusion going on about what placebos for vaccine trials should be.

Let's chat about this one.

It's really common to hear from anti-vaccine people that a lot of vaccines are not tested against "true placebo," which is saline apparently.

This is a fallacy with many components to it.

Fundamentally the point of a placebo is to give you information about whether or not a treatment works.

There are a lot of different kinds of placebos; in vaccine trials it's a sham treatment- something that looks like the vaccine but isn't.

The point of this is for blinding. As we all know at this point, you can't tell a vaccine works until people actually start to get sick (or, if you have very detailed knowledge of the pathogenesis you can look at a correlate of protection and measure that).

But there are ethical issues with the use of placebo, specifically the need to provide all individuals with a standard of care.

What this means is that if an effective vaccine for a disease already exists, and you want to make a next-generation vaccine...

the people in your clinical trial who get placebo get the last approved vaccine for that disease.

For example: let's say right now I want to make a conjugate vaccine that covers additional strains of pneumococcus (there are ~92).

That means the placebo group will get PCV13 (a pneumococcal conjugate vaccine that covers 13 strains). That's because we know that this already works and it is not ethically acceptable to leave these people unprotected against 13 strains of pneumococci that we can prevent.

Historically for example, HPV-9 was compared against HPV-4, which was compared against HPV-2. You can't leave people totally unprotected against the diseases.

There's also no reason to get a vaccine to market that doesn't work at least as well as the one before it.

So, what about first-generation vaccines?

Well, if there's no standard of care, it is generally considered acceptable to use saline.

HOWEVER, you may run into some issues there from a methodology standpoint.

A saline injection does not feel like most vaccine injections. You don't really get the same kind of profile of injection site reactions, and that's a problem because blinding in your vaccine trial is REALLY important.

If your placebo group is all super careful suddenly about not getting the disease because a significant amount of them think they got placebo whereas your vaccine group has those reactogenicity effects and is relatively careless about their risk...

you can conceivably end up with data that really underestimate the efficacy of the vaccine.

So sometimes you can use a vaccine against a different disease. Vaccines as a group generally produce similar symptoms after you get them.

This way you preserve your blinding, everyone goes about their business with confounders evenly distributed as per randomization, and you get an accurate measure of efficacy in your trial.

That's why some COVID-19 vaccine candidates compared to non-COVID vaccines in trials.

The "placebo" vaccines have been licensed with a known safety profile; they are a suitable basis for comparison. And again, you really need a placebo group more for efficacy than considerations of safety.

There Is meticulous public health data for a bunch of different conditions.

If an experimental vaccine were causing any of them, you could compare it to background rates to see if the difference was statistically significant and then do more detailed probes for a causal link.

That is going to be true essentially regardless of what placebo you use- provided that the placebo in question preserves blinding effectively.

You can read more here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844122/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157320/