Gardasil was assessed in Double Blind Randomised Placebo Controlled Trials that used the fully formulated vaccine and compared it with two different placebos, the aluminium adjuvant and a saline solution.
What is a placebo?
A placebo is a substance as similar as possible to the active drug except it has no therapeutic effect. It does not need to be ‘inert’. The best placebo is one that mimics the active therapy as much as possible. This is because the ‘placebo effect’ is a powerful phenomenon and to truly measure the effect of an active product it important that all recipients are equally as likely to think they received the “real deal’.
What is an adjuvant?
“Adjuvant” is derived from the Latin “adjuvare” which means to help.
Adjuvants are added to vaccines in order to help the immune response, specifically:
- Improve the immune response so that a greater amount of antibody is produced or guide a more desirable selection of immune effectors
- Reduce the amount of active ingredient required as that can be challenging and expensive to produce
- Reduce the number of doses required
The most commonly used adjuvants in vaccines are aluminium salts which have been licenced and used in humans for well over 70 years. They cause inflammation at the injection site which is an important process in generating an immune response to the vaccine. In vaccine formulations the active ingredient (antigen) is adsorbed (adhered) to at least some degree to the aluminium adjuvant. This makes a tasty combination for the immune system to respond to.
Adjuvants are an important and very active area of research.
What is an aluminium adjuvant?
Aluminium is the most common metallic element on earth and is in the food we eat and water we drink. Babies are born with aluminium in their body and receive more through breast milks and formula.
Aluminium adjuvants are a range of aluminium-based salts that vary in their affinity (attraction) to the active ingredients. The choice of adjuvant will depend on the chemical properties of the antigen (e.g. positively or negatively charged). Many vaccines contain a tiny bit of aluminium to enhance the immune response. The quantity is miniscule compared to the regular exposure we have over our life time.
Aluminium adjuvants have been used in vaccines for over 70 years and their safety in this context is well established.
What adverse events are associated with aluminium adjuvants?
There are a range of adverse events known to be associated with aluminium adjuvants. These include:
- (Very rare) Sterile abscesses, subcutaneous nodules, granulomatous inflammation, contact hypersensitivity
- (Relatively common) Erythema (redness)
While there are gaps in the literature, no associations have been found with serious or long-lasting events.
Aluminium adjuvants cause injection site reactions (mild to moderate injection site reactions are a good thing). Systemic events are rare and consist of post-immunisation headache, arthralgia and myalgia (joint and muscle aches).
What happens to aluminium adjuvants in the body?
Below is a general stepwise process.
- Once injected the vaccine antigen and the aluminium adjuvant tend to dissociate in the fluid around the cells in the muscle.
- Other proteins in the fluid gather around the aluminium adjuvant.
- The aluminium forms an aggregate which traps the vaccine antigen
- The aluminium adjuvants attract and activate important immune cells that are required for an effective immune response.
- These cells take up a combination of the antigen and the antigen along with the adjuvant.
- The cells take their ‘cargo’ to the local lymph node where the adaptive immune response that will result in protection against disease occurs
- Most aluminium is then excreted in the urine and faeces over a period of several days
Some adjuvant can remain at the injection site for a long period of time and occasionally cause a lesion (see above for adverse events).
Ultimately, the tiny amount of aluminium in vaccines is absorbed into the blood then eliminated in urine.
Observations using humans show 50% is eliminated in 24 hours, 85% after 13 days, and 96% after 1178 days. Bone is the primary long term reservoir for aluminium that we acquire through our life time. [Here and here.]
So if aluminium causes an inflammatory response why was it used as a placebo?
There are several reasons why aluminium is used as a placebo in vaccine trials.
- It is desirable to mimic the formulated product as closely as possible without a therapeutic effect.
- It is important that people think they may have got the real drug. Some placebos are more effective than others. The more noticeable the placebo it the more effective it is.
- Aluminium salts have an established safety record therefore they provide a good comparator
- The question being asked in the studies was around the effectiveness and safety of the new product – in other words Gardasil, if you take the vaccine antigen (the HPV virus like particles) away then you are left with an empty formulation. It makes a perfect placebo.
What placebos’ were used in the Gardasil trials?
Most people who received a placebo in the Gardasil trials got aluminium adjuvant. However there was one protocol (Protocol 18) conducted in 9-15 year old girls and boys where the placebo used was a saline solution. In this study 1184 were randomised to receive the vaccine and 596 randomised to receive the saline solution placebo. The proportion of participants completing the study was similar in each group. The proportion of systemic events was comparable in each group. Keep in mind that we expect some people to have a transient generalised response such as fever after a vaccine. These were generally mild to moderate in intensity. As would be expected, there were more injection-site reactions in the Gardasil group compared with the placebo group.
|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
|Local Reaction||GARDASIL® n=11778 (%)||Aluminium-containing placebo (%)||Carrier placebo (saline *)
Did vaccine recipients develop new medical conditions?
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 placebo recipients. 29% of vaccine recipients and 31% of placebo recipients reported a new medical conditions (such as allergy, infection, neurological, musculoskeletal etc.)
- A placebo is a substance that is non-therapeutic and ideally mimics the drug being tested as closely as possible. The placebo effect is very powerful and must be carefully controlled for in studies
- An adjuvant is a substance that enhances the immune response. Aluminium salts are the most widely used
- Aluminium adjuvants cause reactions at the injection site but systemic reactions are uncommon
- Most aluminium is absorbed into the blood then excreted from the body
- The Gardasil trials used two placebos, one was the aluminium adjuvant, the other a saline solution placebo.
- There was no difference in overall systemic events or the development of new medical conditions between those receiving the vaccine and those receiving the saline solution placebo.
Updated 21/2/17 to reflect that the saline had two other components (L-histadine and polysorbate-80). To the best of my knowledge the 0.35 micrograms of sodium borate present in the full vaccine formulation is a residual from the adjuvant related manufacturing process and therefore have excluded, keen to hear if someone can verify.
Links added to the BLA 8/7/19