Against what does a vaccine need to be tested in the context of a clinical trial? The answer that pops immediately to mind is “a placebo.” In the medical sciences, things get compared to placebos to see if they have inherent potency or if it’s all about the theatre and natural circumstances surrounding them. And because placebos are frequently thought of as sugar pills and saline injections, it’s understandable that some people look at vaccine trials and are puzzled as to why, in specific cases, the experimental vaccine was not compared to an injection of a saline solution. “Where’s the saline placebo?” they’ll protest on Facebook. It turns out that, like with most things in life, digging for answers reveals a complexity that wasn’t apparent from the get-go. There are good reasons not to use a true placebo, and then there are more questionable justifications.
If, at the recommendation of a friend, you decided to “do your own research” on the topic, I understand the resulting confusion. The World Health Organization had to convene an expert panel on the issue of placebos in vaccine trials after acknowledging that guidance documents from different international bodies were conflicting. This is because vaccines don’t exist in a vacuum: their circumstances help dictate the kind of control they should be pitted against. A vaccine can be the first of its kind against a disease or it may be a challenger to the throne. It may immunize against more strains than a preexisting vaccine or it may be identical to a vaccine on the market except for the addition of a special molecule meant to boost the immune reaction. A saline injection may be an ethically valid control in some of these instances but not in others.
The simplest situation is the one we are facing right now with COVID-19: a new disease for which no vaccine currently exists. I reached out to Dr. Brian Ward, a McGill professor involved in vaccine research, who told me that, in a case like this, “regulators typically insist that the initial phase III studies [where, after safety testing in humans, the vaccine is tested for its capacity to protect human volunteers against the disease] be conducted with a placebo (saline) arm to establish absolute vaccine efficacy.” This insistence, however, is not ironclad. The scientists behind the trial will propose what they want to use as a control and the regulators, I was told, can accept, refuse, recommend, or insist.
This being said, there is a persistent argument online that contaminates minds like a bad virus: that no vaccine has ever been compared to a saline solution. This is simply untrue. The website Virology Down Under lists specific trials of important vaccines that were placebo-controlled and this article from the Vaccines Work Blog specifically lists a number of saline placebo vaccine studies.
But it’s important to realize that, in some cases, testing a new vaccine against a saline injection is considered unethical. Imagine that a safe and effective vaccine is currently available in our country and that a company is testing a new one that is supposed to be even more effective. Depriving half of the trial participants of the preexisting vaccine and giving them a placebo instead would not be fair: it would actually be unethical.
So now we arrive at a particularly tricky example: a trial where, by all indications, a saline placebo should be used but is not. A team in the United Kingdom is conducting a trial of a new COVID-19 vaccine (charmingly called ChAdOx1 nCOV-19) and they are comparing it not to a saline injection but to a vaccine against meningitis. It has been reported as the only frontrunner for a COVID-19 vaccine that is not using a true placebo as a control. The World Health Organization’s expert panel on placebos used in vaccine trials does underscore the validity of using a different vaccine as a control (one whose safety is well characterized), but notes that it “may also be less acceptable to regulators or public health authorities and potentially delay approval or adoption of a new vaccine.” I reached out to the team conducting the UK trial and was told the reason they changed their mind from using a saline injection to using the meningitis vaccine was that saline injections don’t cause a sore arm, which might unwittingly reveal to the volunteers what group they are in. No soreness after the injection? You may have received a placebo, which could alter your behaviour and thus add a nasty variable to explain away the results of the trial.
This official explanation, however, is questionable. Injecting a saline solution into a muscle can be associated with side effects, as many vaccine trials have demonstrated. Also, comparing an experimental COVID-19 vaccine that has so far been shown to cause a fair amount of physical reactions (pain, fever) to a meningitis vaccine that can also cause these temporary side effects will certainly paint a kinder picture of the COVID vaccine. But there is a more generous argument to be made for administering the control group with a vaccine against meningitis: to give them something of value.
I wish the road to vaccine approval had clearer rules. What we are left with is a human system that has served us quite well in the past (with regards to vaccine safety and efficacy) but which is susceptible to excessive pressure. The bottom line is that, as far as COVID-19 vaccines are concerned, clinical trial data will be presented to regulatory authorities... but also to fellow scientists. And it will be scrutinized by good-faith researchers and by anti-vaccine activists alike. Only by interpreting the data in light of solid scientific judgment and not ideological denialism will we be able to make a sound decision.
