By Helen Petousis Harris 20/02/2017 20


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.

  1. Once injected the vaccine antigen and the aluminium adjuvant tend to dissociate in the fluid around the cells in the muscle.
  2. Other proteins in the fluid gather around the aluminium adjuvant.
  3. The aluminium forms an aggregate which traps the vaccine antigen
  4. The aluminium adjuvants attract and activate important immune cells that are required for an effective immune response.
  5. These cells take up a combination of the antigen and the antigen along with the adjuvant.
  6. The cells take their ‘cargo’ to the local lymph node where the adaptive immune response that will result in protection against disease occurs
  7. 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 *)

(%)

n=9686
Pain

Mild/Mod

Severe

83.9

81.1

2.8

75.4

74.1

1.3

48.6

48.0

0.6

Swelling*

Mild/Mod

Severe

25.4

23.3

2.0

15.8

15.2

0.6

7.3

7.3

0

Erythema*

Mild/Mod

Severe

24.7

23.7

0.9

18.4

18.0

0.4

12.1

12.1

0

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.)

Key points

  • 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.


20 Responses to “Was the Gardasil vaccine ever compared with a placebo?”

    • Fiona these are cases I have considered in the previous post. My reasons, and those of the rest of the scientific community for excluding them as any kind of proof of causality are listed. The claims are far fetched, scratching at the door of fantasy. If Little and colleagues truly wanted to do the community a favour they would undertake work that first defines the condition and provides a time frame following vaccination in which the event must occur in order to be caused by it. Then they could conduct an epidemiological study like real scientists do in order to investigate their hypothesis. A well considered opinion on this can be found here by David Hawkes and Jim Buttery can be found in the Current Opinion in Obstetrics and Gynecology.

      • The TGA has admitted that the placebos used in Protocol 018, tables 11 and 12, do not represent the contents stated in the trial data and will amend this. This was stated in 2015.The saline placebo, was not saline. Both the ‘saline placebo’ and the ‘non alum’ placebo contents will be corrected, to state what was used. You can verify this with the TGA.

        • Fiona you are correct. The non-aluminium placebo was indeed the isotonic carrier and while primarily a saline solution, not saline by the definition of sodium chloride and water. I will amend my blog to reflect this. Of course this does not change any of my arguments.

          I would also point out that of the components in the carrier 9.56mg is Sodium Chloride, the three other components make up less than 0.87mg of the formulation.

          • The TGA will disclose ensure the full disclsoure of all the contents, in the placebo, which was not a saline placebo and the non alum solution.

  • Fiona: “The TGA will disclose ensure the full disclsoure of all the contents, in the placebo, which was not a saline placebo and the non alum solution.” What is your problem? As far as I understand Helen’s post; standard, well tested and understood protocols were used in the trials. So the results are valid and comforting to those of us with daughters! The risks of remaining unvaccinated are orders of magnitude larger than the risks of accepting the vaccine. Helen has already answered your question clearly and patently. I don’t understand your problem.

    • That’s pretty much what I though when I read her comments. She’s nit picking at something that doesn’t effect the overall safety profile of Gardasil.

      And, Gardasil is recommended for boys too now, so even those with sons should be comforted 🙂

  • You have stated the incorrect amount of Sodium borate. It is not 0.35 micrograms, it is 35micrograms or .035milligrams

  • On the placebo issue, if you were aiming to mask possible side-effects caused by the adjuvant, is this not how you would design an experiment to do so?

    On adjuvants…
    “The biggest remaining challenge in the adjuvant field is to decipher the potential relationship between adjuvants and rare vaccine adverse reactions, such as narcolepsy, macrophagic myofasciitis or Alzheimer’s disease. While existing adjuvants based on aluminium salts have a strong safety record, there are ongoing needs for new adjuvants and more intensive research into adjuvants and their effects.”

    “Despite a lack of good-quality evidence we do not recommend that any further research on this topic is undertaken.”

    I would like to be convinced but those links just raise more questions. Could you please give your professional opinion on this article? https://healthcareinamerica.us/did-chinese-scientists-find-autisms-missing-puzzle-piece-2d50be5b9122#.rtjb06fsg

    • Paul I think Maurice has summed it up.

      The evidence for vaccines of any kind not causing autism is beyond extensive. From what I see on your link there are a range of studies, some are certainly interesting in their own right. The problem is that a study showing maternal immune activation in the lab and potential neurological outcomes is not a study that shows vaccines cause cause autism. The cherry picked studies on this site are coupled with flights of fancy, the drawing of very long bows. I come back to the point I labour constantly. Vaccinated children are more healthy/have less adverse outcomes that unvaccinated children. That is not an alternative fact, it is a real fact. If vaccines caused autism wouldn’t you expect more autism in vaccinated children???

      If you are interested in the role of infection and fever, like influenza, during pregnancy and neurological outcomes in the baby then there is an area that is exciting. There is evidence to show infection in pregnancy can have quite far reaching affects on the baby. I can also tell you that flu vaccination in pregnancy is associated with better infant outcomes. I think this would be a good topic for a blog. Will try to get to it.

  • How to assess a website:

    First question:
    What does the URL tell us? In this case it is unusual: not a university, UN, govt site or any authoritative site. A quick Google search on Healthcare-us yields nothing useful. Not a strong start.

    Second question: What about the author?
    Another quick search on J.B. Handley brings up nothing useful. That is strange; anyone with any credibility generally comes up straight away. What about Generation Rescue? An answer. That is clearly an anti-vax source; The author is likely strongly biased against vaccines.

    Third question: Content.
    The Wikipedia piece on Generation Rescue concludes with this comment, “Much of Generation Rescue’s case is based on publications that do not go through a proper peer review process”. (https://en.wikipedia.org/wiki/Generation_Rescue). Certainly some of the papers presented have reputable scientific publishers, but I am inclined to agree with the Wikipedia author(s). The piece looks like a cherry picked Gish gallop to me. Which is typical for anti-vax material.

    Fourth question: What are other authors saying (Triangulation)? That is Helen’s area but the scientific and medical community have looked for problems with adjutants and found nothing. I suggest you follow Helen’s chain of evidence as a starting point.

    In conclusion: It looks like baloney to me. (https://www.brainpickings.org/2014/01/03/baloney-detection-kit-carl-sagan/)

  • Just reading the link you provided regarding safety, the “Comparative Safety of Vaccine Adjuvants: A Summary of Current Evidence and Future Needs” and felt it didn’t really provide any reassurance of aluminium adjuvant safety.
    On the contrary it said that it wasn’t fully understood how aluminium adjuvants work and also in a roundabout way, that there was a need to develop new, safer, non-inflammatory adjuvants.
    Some of the more serious adverse events/associations listed in the paper were:
    -a propensity to induce Th2 immune bias which increases risk of allergy and anaphylaxis
    -Alzheimer’s
    -Macrophagic Myofasciitis described as a “combination of musculoskeletal pain, chronic fatigue, and cognitive disturbance (which) generates chronic disability with possible social exclusion.”

    Petrovsky said assessing the whether these conditions were caused by vaccination was difficult as there was a lack of data, and also there could be a long time between receiving a shot and when symptoms arose.
    Personally, I find that if someone says they don’t fully understand a subject and there’s lack of data, I don’t associate that with a long record of safety, it just shows we have kept doing the same thing for years without really knowing why.

    • Toni, I think you make good points but have also been selective in what you have taken from the article (And this article is the opinion of a single individual). First, the bottom line on aluminium salts as adjuvants is that they have a strong safety record. I think you have also pulled out the discussion on extreme cases such as the RSV vaccine that failed miserably in early clinical studies. With respect to serious events, these are not events that are associated with the vaccines that we use. For example there is no increased risk for allergic disease in vaccinated children. The Th2 bias is toward the antigen in question, this does not mean the whole immune system gets twisted. I think the authors have explored the potential hypothesis that have been raised over the years. It is important to visit these regularly. The overwhelming evidence supports the on going safety of aluminium adjuvants. Also, remember that we know the safety of adjuvants primarily through the safety profiles of the vaccines and a vast number of studies comparing safety outcomes in vaccinated and unvaccinated. Pointing out what is not known about something does not negate what is known. Petrovsky is highlighting out areas for research. The long (80 year) record of safety is indeed a long record of safety which is why we continue to use aluminium salts as adjuvants which in turn get studied and reviewed by many experts in many countries including the WHO.

      • Hi Helen, thanks for the response. Just so I understand, you’re saying the safety record of aluminium adjuvants is not assessed separately? So we rely on the safety record of each vaccine as a measure of the safety of the adjuvant?
        Given that the body of research over the last 30 years has established aluminium as a mammalian neurotoxin; shouldn’t we demand that the safety of this substance – previously taken for granted – now be evaluated in a scientific manner? Surely if it is as safe as claimed, then there would be no problem with such an assessment.

        • Toni, no, that is not what I am saying. What I am saying is that there is vast amount contributing to the totality of evidence, including the safety profiles of the vaccines themselves. The safety data on aluminium adjuvants ranges from laboratory in vitro and in vivo experiments, clinical studies in humans receiving only the adjuvant as well as studies on full vaccine formulation safety. The totality of evidence is considerable. Re being a neurotoxin, aluminium does not cause Alzheimer’s as some people claim, it is a neurotoxin in situations of high doses combined with renal failure. Vaccines do not even figure in terms of the dosage and renal failure is not relevant. Everything is poison however, it is the dose that makes the poison. Aluminium adjuvants have been scientifically assessed using many angles of investigation which is why regulators (who are very fussy about these things) have so much confidence in them and allow them for wide spread use in humans.

  • PS * Just wanted to point out that the description of the symptoms of Macrophagic Myofasciitis were mine, not Petrovsky’s.

  • Would you be able to suggest a suitable review or meta analysis on aluminium adjuvant safety that I could read? (Preferably one that is not behind a paywall!!) Thanks.

    • Firstly perhaps you could explain why you think a clinical trail study looking purely at aluminium would be more useful than a trial of an adjuvanted vaccine with a saline comparator? Is it vaccine safety you are concerned about? I am not sure what a clinical trail of aluminium adjuvant would contribute to the argument about vaccine safety and it is not a trail that would happen for pragmatic and ethical reasons.

      • Re- a clinical trial, how can any adverse events due to aluminium adjuvants be separated from that caused by the active ingredients if the two are not tested separately?

        Yes, vaccine safety is a major concern. The research on aluminium toxicity extends beyond that related to renal failure; aluminium has been shown experimentally in vitro and in vivo, variously using rats/rat cells and human cells, to induce motor neuron death, inflammation, learning and memory deficits and is thought to cause oxidative stress and mitochondrial impairment.

        In humans it is suspected to be linked with various neurodegenerative diseases, but because the precise way in which aluminium causes these conditions is unknown, the issue is controversial. Still, it is widely accepted by researchers that aluminium is a neurotoxin and has an adverse effect on the CNS. (see Kawahara’s 2011 review – Link between Aluminum and the Pathogenesis of Alzheimer’s Disease: The Integration of the Aluminum and Amyloid Cascade Hypotheses)

        It seems that excipients like aluminium, which are already in use, are currently not subject to regulatory status independent of the product in which they are included.
        For proposed new excipients, the FDA recommends a safety database including safety profiles and risk-benefit assessments so they can establish permissible and safe limits of the product. If new excipients have to be evaluated for safety, why would older substances, like aluminium, not be subject to the same process and resulting safety standards, especially as it is a substance well established as a mammalian neurotoxin?

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