Article Summary
- The AstraZeneca Vaccine was not tested against an inert placebo, rather it was tested against a mixed group of placebo and the meningococcal vaccine. (Source from UK government).
- The meningococcal vaccine was also never tested against a placebo when licensed. (Statements from the manufacturer shown below.)
- The vaccines used in the USA were obligated by petition to use an inert saline placebo during phase two and three trials. (Petition and FDA statement below.)
Because of the perceived ethical controversies of using an inert placebo in vaccine trials most vaccines are not tested against an inert placebo.
This leads to the question of whether or not the Covid-19 vaccines granted emergency use authorization were tested against a saline placebo. The answer is a little more complicated than you might expect.
Different Placebo Choices for Countries’ Vaccine Trials
Not every country has the same approval processes or trial processes in approving or creating a vaccine. Therefore since the vaccines widely distributed come from two different countries the answers will be a bit different for each.
Although it is common world-wide to always test a vaccine against another vaccine and not against an inert placebo, there has been much scrutiny placed on the COVID-19 vaccines and their development. This scrutiny inspired a different approach in the US than in the UK.
In the United Kingdom, where the AstraZeneca vaccine was produced, the government information for healthcare providers states that participants in the trials received either two doses of the AstraZeneca Vaccine or “control.” But, what was that control?
If you read further under section 5.1 Pharmacodynamic properties, subtitled “Clinical efficacy” the information packet further states, “participants ≥18 years of age and seronegative at baseline received two doses of COVID-19 Vaccine AstraZeneca (N=5,807) or control (meningococcal vaccine or saline) (N=5829).”
So, there was more than one “placebo” used. As stated above those in the control group received either the meningococcal vaccine (a vaccine for meningitis) or a saline shot. There is no clarification or distinction of the groups, so we do not know how many received an inert placebo and how many got a control vaccine as a placebo. Nor do we know the specific outcomes for each of those groups compared against those who received the AstraZeneca Shot.
This design could skew the entire outcome of the trial in several ways. Especially when it comes to safety data; as it is impossible to distinguish whether the reactions recorded are due to the active control, or the placebo effect. When you compare two vaccines against each other rather than an inert placebo it is impossible to assess the true reactogenicity of each. These control groups should at least have been separated so that reactogenicity could have been established.
The most interesting part of the choice of using the meningococcal vaccine as the placebo is that, like most vaccines, the meningococcal vaccine has not been tested against an inert placebo either.
Placebos used to Assess the Meningococcal Vaccine
The information and screenshots I am about to present come from the informational packet directly from the manufacturer of the meningococcal vaccine, Glaxo-Smith Kline. These are called package inserts and are written for healthcare professionals. They must include trials used to determine that the product is safe and effective.
The BEXSERO meningococcal vaccine is a perfect example of all the types of placebos used in trials against vaccines.
The first trial listed on the insert shows that similarly to the AstraZeneca trials participants in the BEXSERO, (this is just a brand name of the vaccine), meningococcal vaccine trials were given either one dose of BEXSEROs or were in a group of placebo and control vaccine. However, it does not specify if the “placebo” was actually inert or not, however, just like the AstraZeneca trials the control group is never separated into inert placebo or control vaccine.
Here is the second trial used to show the safety and efficacy of BEXSERO:
Again this study does not include a true inert placebo, although a saline placebo was used, it was immediately followed by the MENVEO Meningococcal vaccine. This is as good as only giving the control vaccine. There are no participants who received only an inert placebo.
This is very similar to what the WHO calls an “add-on” in this trial design. According to the WHO it is perfectly fine that–
“Subjects are given either the trial vaccine mixed with an existing vaccine or the trial vaccine mixed with something considered to be inert, such as a placebo.”
Source: EXPERT CONSULTATION OF THE USE OF PLACEBOS IN VACCINE TRIALS. WORLD HEALTH ORGANIZATION, 2013.Geneva, Switzerland. Pg. 13
With this methodology, both groups would receive the trial vaccine. It is often used to justify giving several vaccines at one time or making vaccine combinations of vaccines like Pediarix, a combination of diphtheria, tetanus, pertussis, Hep B, and poliovirus vaccines.
The only difference we see with BEXSERO is that the control group is receiving a different kind of meningococcal vaccine rather than both groups receiving BEXSERO.
In the third trial of BESXERO listed on the package insert, we see yet another type of placebo that is not inert.
In this case, the placebo is specified to contain aluminum hydroxide. Aluminum hydroxide is a special kind of aluminum that is specifically used in vaccines to agitate the immune system, create more antibodies, and make the vaccine immunity longer lasting. It is not specified whether the placebo is saline mixed with aluminum or other substances that contain aluminum. However, what is clear is that yet again the placebo is not inert.
We see this type of placebo used in the last study listed as well.
So as surprising as it may be, AstraZeneca was tested against another vaccine that was tested against another vaccine, and neither has been solely tested against an inert placebo.
If you are wondering if I only chose BEXSERO as the example of meningococcal vaccines because it has studies like this, please look at all the other package inserts of meningococcal vaccines, none of them were ever tested against an inert placebo either. I chose BEXSERO because its studies are better than most other meningococcal vaccines, not worse.
But what about the other COVID-19 Vaccines? Were they tested against an Inert Placebo?
The other vaccines currently in use were all produced in the United States and this is where the scrutiny of COVID-19 vaccines comes in.
After trials had started in the US there was a Petition for Administrative Action filed by the Informed Consent Action Network on June 2, 2020. This petition required the FDA to certify that all phase two and phase three trials for COVID-19 vaccines produced in the US would use an inert saline placebo. This document also required several other things, including the placebo group being as large as the vaccinated group and that trials last at least 36 months.
This petition was accepted by the FDA and as seen in the trial data, saline placebos were used in the Moderna, Pfizer, and J&J vaccines phase two and phase three trials. But what about phase one you may ask?
These companies have not been very transparent about the status of their placebos in phase one. Moderna is the only company that admits that it did not use a saline placebo in its phase one trial. It used no placebo as it performed a purely observational study (Please see the second to last page of the document). Pfizer and J&J simply say that their trials were placebo-controlled, and although differentiate with their second and third phase trials that this is a saline placebo, they use only the word “placebo” to describe phase one.
So, the answer is, we don’t really know about phase one of these trials before the petition was filed. After the petition, it appears that each of these used a saline placebo in their trials.
However, the control group of these vaccines will not last long now that these manufacturers have a EUA. It appears that these companies plan to now offer the vaccine to each of those in their placebo group. Without a placebo group, it will be near impossible to know whether or not these vaccines cause long-term side effects.
Why This Matters
Why is this important? I will let the FDA itself answer this question.
“There are three principal difficulties in interpreting active-control trials. [Trials that do not use an inert placebo] … One problem is that there are numerous ways of conducting a study that can obscure differences between treatments, such as poor diagnostic criteria, poor methods of measurement, poor compliance, medication errors, or poor training of observers. As a general statement, carelessness of all kinds will tend to obscure differences between treatments. Where the objective of a study is to show a difference, investigators have powerful stimuli toward assuring study excellence. Active-control studies, however, which are intended to show no significant difference between treatments, do not provide the same incentives toward study excellence, and it is difficult to detect or assess the kinds of poor study quality that can arise. The other problem is that a finding of no difference between a test article and an effective treatment may not be meaningful.”
What is the FDA saying here? In essence, the FDA is stating that using an active-control, (aka another vaccine or vaccine ingredient) rather than a truly inert placebo makes it easy for the study to be compromised and for data to be hidden. It puts the study in the category of “low quality,” and finding no difference between the control group and the vaccine group doesn’t actually mean anything. It does not necessarily indicate safety or efficacy.
We should each keep this in mind as we make informed decisions about what we decide to put into our bodies and what may be mandatory to put into the bodies of entire nations.
For more on the Covid vaccine checkout our guide, Everything You Need to Know About the Covid Vaccine.
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