Crucial role of Placebo Choice in Vaccine Trials: Misconceptions Explained

From the Vault. Originally posted 21 February 2018 and updated in 2021 during COVID-19

The notion that some of the most rigorous vaccine trials ever conducted are questionable on account of their well thought out comparisons and controls is ill conceived at best. For example, after over 300 million people vaccinated against HPV, and huge epidemiological studies from all over the world comparing outcomes in vaccinated and unvaccinated (discussed ad nausea in my previous blogs). Guess what! Vaccinated have better outcomes than unvaccinated. Anyway, for the sake of anyone who is wondering about what all the ruckus is about I have attempted to explain below.

A clinical placebo is a treatment that has no intended therapeutic effect. In a clinical trial a placebo could be a saline formulation which is typically relatively inactive when injected.  Or, it could be the formulated mix of salts and left over impurities that are present with the vaccine under investigation minus the active ingredient. Just to be clear, nothing, not even the noble gases, are completely inert under all conditions. “Inert’ is relative.

Vaccines often have an extra added ingredient, called the adjuvant, which works as an immune enhancer.  The adjuvant is sometimes included in the placebo formulation. [Click Here to read my series on aluminium adjuvants]

In using a placebo the investigators want to eliminate any thoughts, views, emotions and expectations as much as possible. Study participants will not know (they will be blind) to what treatment they receive, and often, so will most of the investigators (double blind).

I recommend this excellent history of the use of placebos published in The Conversation

It has been well argued  (and here) that if there is an existing vaccine for a disease that it cannot be withheld from trial participants in order to test the new one against a placebo. That means if a new generation vaccine is developed for a disease, its effectiveness will need to be compared to its predecessor, and a placebo will not be needed. An example is the newer Gardasil®9 vaccine. This new formulation contained nine instead of four different types of virus like particles. The pivotal trials compared the old and new vaccines head-to-head.

If you do not already have a vaccine against a disease then there is a case for using a placebo. An example of this was the first generation HPV vaccines. The formulated vaccine was put head to head with two different placebos

There are two major considerations when choosing the placebo.

The placebo effect and the new ingredient (the antigen)

The key objective of a placebo is to allow the participant to believe they have received the medicine being tested. In the case of an injectable vaccine the most common reaction is injection site pain, sometimes with minor redness and swelling. Often, the added adjuvant (immune enhancer) can be the main cause of the reaction and it is just doing its job. From a vaccinology perspective a mild to moderate injection site reaction is generally a good thing.

When you inject pure saline a very small proportion of recipients get sore arms where the injection was given.  A bigger proportion have a sore injection site when they get the placebo made from the formulation mix (missing the active vaccine). To make every injection as similar as possible in a vaccine study a good choice of placebo is the one that elicits an injection site reaction because the person is more likely to think they got the real deal.

If participants guess which group they are in (active versus placebo) then the study runs the risk of un-blinding. This can damage the integrity of the trial. Also, the investigators may guess which product is which just by looking at them. Simple differences like changes in smell, colour or viscosity could give it away.  It’s important that they appear identical to the investigator.

Another factor in placebo selection is the importance of understanding the role of the active ingredient (antigen or antibody generator). What difference to the reactogenicity and safety profile does the addition of the active ingredient play?

Many vaccine developers prefer to balance the safety profile (identified in the trial) by ensuring the products in the vaccine carrier are present in both the active and placebo products. This means both the active and placebo study arm should both have the same local reaction to the impurities and other ingredients such as buffers and adjuvants. Any additional reaction rates will be related to the active ingredient.

Some vaccine developers would prefer not to know if the active ingredient is the cause of the local reaction, and by not knowing can simply assert that they believe it is caused by the other ingredients and not by their antigen. Personally I prefer to know the relative contributions.

For a detailed list on vaccine ingredients and their function check out this from Oxford. 

The formulation without the active ingredient includes buffers, stabilisers and adjuvant. In the case of Gardasil there is sodium chloride (for tonicity), sodium borate (buffer), L-histidine (Stabiliser), polysorbate-80 (surfactant), and water for injection. When the active ingredient is added it is adsorbed to the adjuvant. One important question the investigators will want to answer is: What is the difference between a formulation that has just adjuvant and a formulation that has adjuvant adsorbed to active ingredient? Adsorbed means to adhere to via atoms, ion or molecules. In the case of vaccine adjuvant and antigen this is via the positive and negative charges on each (a positively charged antigen will require a negatively charged adjuvant).

Anyway, the choice of vaccine formulation minus the active ingredient as a placebo provides important data about the role of the active ingredient, which is the new kid on the block. Its behaviour when administered alone (without adjuvant in earlier phase studies) and in the full formulation is important.

Using the vaccine formulation mix minus the active ingredient is a normal practice in vaccine trials for the reasons outline above. For example, of three trials from different manufacturers for the same type of vaccine I am aware of, one used an adjuvant in the active formulation, and the adjuvant was not included in the placebo. Two of the three used the vaccine formulation mix in the placebo; the other trial used just saline as the placebo.

There were two different placebos used. The one used in most of the controls included the vaccine formulation mix minus the active ingredient. A smaller group received saline with some impurities (L-histidine, polysorbate-80 and sodium borate). Therefore most of the participants who received a placebo would have had injection site reactions similar to the vaccine recipients, fulfilling the requirement of the comparison. Basically these controls are stepwise progressions from the injection solution, injection solution with added adjuvant then the full formulation that included the active ingredient. For a fuller discussion on the Gardasil placebos see my archived Blog here. I have posted the table from that blog below.

Event	Gardasil (n=1165)	Saline placebo (n=594)
Any systemic event	541 (46.4%)	260 (44.5%)
Headache	221 (19.0%)	110 (18.8%)
Fever	100 (8.6%)	45 (7.7%)
Sore throat	52 (4.5%)	24 (4.1%)
Diarrhoea	43 (3.7%)	21 (3.6%)
Nausea	38 (3.3%)	22 (3.8%)
Abdominal pain	38 (3.3%)	17 (2.9%)
Nasopharyngitis (a cold)	34 (2.9%)	22 (3.8%)
Myalgia (muscle pain)	30 (2.6%)	10 (1.7%)
Vomiting	26 (2.2%)	18 (3.1%)
Dizziness	25 (2.1%)	9 (1.5%)
Arthralgia (joint pain)	21 (1.8%)	9 (1.5%)
Pain in extremity	19 (1.6%)	14 (2.4%)

Food and  Drug Administration, Clinical Review of Biologics License Application for Human Papillomavirus 6, 11, 16, 18 L1 Virus Like Particle Vaccine (S. cerevisiae) (STN 125126 GARDASIL), manufactured by Merck, Inc, Vaccines Clinical Trial Branch, Office of Vaccines Research and Review, Centre for Biologics Evaluation and Research, Editor. 2006, Food and Drug Administration.

*The ‘saline’ solution consists of water, 9.56mg sodium chloride, 0.78mg L-histidine and 50micrograms polysorbate-80

Here are the comparisons between the three different injections

Local Reaction	GARDASIL® (n=11778) (%)	Aluminium-containing placebo (n=9686) (%)	Carrier placebo (saline) (%)
Pain – Mild/Mod	83.9	75.4	48.6
Pain – Severe	2.8	1.3	0.6
Swelling – Mild/Mod	25.4	15.8	7.3
Swelling – Severe	2.0	0.6	0
Erythema – Mild/Mod	24.7	18.4	12.1
Erythema – Severe	0.9	0.4	N/A

Did vaccine recipients develop new medical conditions?

No. The subjects were followed up for new medical conditions. This means they were contacted in the twelfth month of the study and assessed for new conditions that may have developed since they were vaccinated. A slightly lower proportion of vaccine recipients reported a new medical condition compared with the saline recipients. 29% of vaccine recipients and 31% of control recipients reported new medical conditions (such as allergy, infection, neurological, musculoskeletal etc.)

Some people argue that the Gardasil clinical trials are meaningless because:

1. Most of the placebo recipients received the vaccine formulation minus the active ingredient and,
2. The saline wasn’t really saline because it included L-histidine (an amino acid).

These arguments are factually and logically fallacious.

• Fact: The placebos were true placebos by definition.
• Arguing that the placebos contained adjuvant, therefore nullifying the study results, is logically flawed for the above reasons, among others.

Just because a person imagines this is true does not make it true no matter how convinced they are. I know we live in a post truth world, but I live in hope some people are still interested in objective evidence!

The burden of proof that there is a problem such as harm from using a non-saline placebo rests with those who claim it is harmful in the face of the wide body of evidence on vaccine safety. In other words it is a logical error to make a claim and assert people prove your negative (“prove these placebos are safe”) because you cannot prove a negative