This is important because
Vaccines are unique medicinal products in that even single doses.....could lead to a prolonged pharmacodynamic effect (i.e. life-long immunity) through the generation of immune memory
No other medicinal product has such a prolonged pharmacodynamic effect. 1
The single biggest concern about the safety of adjuvants used to enhance the immune response for vaccines, is the risk of excessive immunostimulation resulting in autoimmune disease in susceptible individuals. How would that happen? Before we go into more detailed mechanisms, let me first outline a few key concepts about our immune system, that are critical to understanding the effects of adjuvants.
The immune system is a network, not a hierarchy.
The immune system is:
- complex - involves a large number of cells, organs, and molecules
- networked - every part is connected to every other part through the circulation of cells and molecules through the tissues and organs, via the ciruclatory and lymphatic systems, and through transmission of signals between cells (which we will talk a great deal about)
- decentralized - unlike the nervous system (which has the brain) or the circulatory system (with the heart), there is no 'master organ' that controls or overrides the rest of the immune system.
These 3 features in combination means that
Local events can have distant/systemic effects
Here are some examples:
- A flu vaccine given into a muscle induces an immune response which activates certain cells, some of which retain 'immunological memory' of the antigen. These cells circulate through the body, so that next time when the flu virus enters say via the lungs, these 'memory cells' can start a strong, specific immune response at the respiratory tract membrane where the virus is.
- A upper respiratory infection results in fever and headache not (necessarily) because the virus is in the blood or in your brain, but because in fighting the virus at the respiratory membrane, the cells of the immune system give off certain chemicals that act not just locally, but also move into the circulation and induce such 'systemic' effects.
- Cells that are activated (for reasons that I'll get to later) to react towards self-antigens at a particular site, can migrate to other parts of the body where such self-antigens are also present, and trigger an autoimmune response. A dramatic example of that can be found in the case of eye injury, in a condition called sympathetic ophthalmia. Some antigens in the eyes are not normally exposed to the immune system. When an injury occurs that causes these antigens to be released into the blood, an immune response starts which attacks not only the injured eye, but also the healthy one.
Squalene-induced arthritis in mice
In a series of experiments 2-5, scientists at the prestigious Karolinska Institute at Stockholm (where they decide who gets the Nobel Prize for medicine each year), injected squalene (among other oils, see chart below) into the tail of mice, inducing arthritis.
They found that squalene was mostly located in the injection site and the nearest lymph nodes (LNs) but not in the joints. This of course (partly) echoes what GSK says, the only difference being the mice are definitely not ok - they were all suffering from the equivalent of rheumatoid arthritis in humans!
btw There were also significant amounts of squalene in the spleen and liver - important for later discussions..
Next, the researchers took cells from the LNs of this first group of mice, and injected them into other mice that were not exposed to squalene, and discovered that they could transfer the arthritis to the second group of mice.
Interestingly, while arthritis occurred in 100% of mice given cells from the LNs closest to the injection site (draining LNs), even cells from non-draining LNs were able to transfer arthritis to 50% of the mice.
What do these experiments tell us? They show that adjuvants can have non-specific (ie unrelated to any antigen, since none were given here) effects that are not restricted to the injection site. They also show that the adjuvant caused changes in the cells of the immune system (in the LNs) which were similarly able to induce disease in other mice.
You can stop reading right here, if you want ;-D, because the above is already plenty enough IMO to debunk the misinformation from GSK. But now that I got started (since I've done all that legwork, you know... lol) let's carry on, for our own education, GSK or no GSK...
The immune system is a product of evolution - and a work in progress.
You may have learned somewhere the concept of 'self' and 'non-self', that our immune system has evolved to defend against invaders while at the same time 'tolerating' our own 'self' tissues, ie not mount an immune response against them. While the concept is important (more later), in reality, such differentiation is not hard-wired by default, but instead requires a large and varied set of processes running properly, to keep things from going awry.
It's a bit like buying a PC - whereas Windows may come pre-installed and there are some functions that appear to run without you having to do anything, these functions are in reality a result of a variety of patches that those geeks at Microsoft came up with over the years - no doubt partly in response to irate customers! In the same way, our immune system is not perfectly designed fresh out of the factory, but is a result of hundreds of millions of years of evolution, of adapting to challenges that our primordial ancestors encountered, and challenges that we still encounter today.
Just as the latest bestest version of Windows still has bugs in it because no one has come up with the magic patch that fixes everything - indeed patches often create new problems while solving old ones - our immune system is similarly 'buggy', which is why problems like allergy, autoimmune diseases, cancer etc, are so common! The sum total effect of a particular immune response depends on a delicate balance between many processes each of which may pull or push towards one endpoint rather than another. When the balance is tipped or skewed towards an undesirable effect, disease happens.
As you will see later, the definition of 'undesirable' depends on the circumstances...
There is only one immune system
Compared to other areas of the medical sciences, immunology is a relatively young and evolving discipline. Our understanding of immunology is/was dependent on the technology available. When viewed at the level of the organism (ie human) as a whole, the self vs non-self hypothesis offers a simple functional account of how things work. But as immunology advanced to a point where we can now hone in to mechanisms at the subcellular and even molecular level, we discover that the hypothesis breaks down. One of the most important concepts that emerged in recent years, is that at the most fundamental level, the immune system offers the same process for different types of triggers, whether they are exogenous substances, infectious agents, vaccination, self-antigens, or tumor antigens.
In other words, how our immune system responds to an antigen is not primarily dependent on whether it is self or non-self - eg our body regularly 'tolerates' such non-self agents as commensal bacteria in the gut, environmental pollutants, and the growing fetus in pregnancy. Note that the first one is beneficial, the second one is toxic, and the third, well, desirable!
Mounting an immune response to otherwise 'innocuous' substances such as pollen or cow's milk protein is the basis of allergy. Mounting an immune response to self tissues can result in autoimmunity. But there are times when we want our immune system to respond to self-antigens, eg to stop the growth of cancer cells. The following table 6 illustrates whether an immune response is beneficial depends on circumstances.
But what determines the outcome, then, if it isn't self vs non-self?
According to Silverstein 7:
All potential immunogens are recognized by the system using the same set of 'rules', without discrimination between 'self' and 'nonself' or between the 'toxic' and the 'benign'. In every response, whether positive or negative, the factors mobilized and the balance between protection and damage depend upon the quality, quantity, location, and timing of immunogen presentation, as well as upon properties of the host.
That last statement, is central to our understanding of immunology, and the utility and potential hazards of vaccine adjuvants.
Genetics play a big role
In the context of adjuvants and autoimmunity, the most important 'property of the host' is the presence or absence of genetic susceptibility to autoimmune diseases. This is very important and I can't emphasize it enough. Even in animal experiments like the ones described above, the results are dramatically different depending on the strain of mice used. That said, I don't think we need to go further into details of genetics, for now, except to remember that it is important.
With all these concepts in place, we are now ready, in the next diary, to explore (in a hugely simplified way) the actual immune response itself. We will see how the characteristics of the microenvironment in which the immune response takes place affect the outcome. Which is exactly why adjuvants are effective in enhancing immunogenicity against the vaccine antigen, but also why they can cause problems against self-antigens.
As a teaser, let me end with this quote 8:
Collectively, the secondary signaling necessary for induction of an autoimmune disease has been referred to as the adjuvant effect.
References:
- Brennan FR, Dougan G. Non-clinical safety evaluation of novel vaccines and adjuvants: new products, new strategies. Vaccine. 2005 May 2;23(24):3210-22. PudMed
- Carlson BC, Jansson AM, Larsson A, Bucht A, Lorentzen JC. The endogenous adjuvant squalene can induce a chronic T-cell-mediated arthritis in rats. Am J Pathol. 2000 Jun;156(6):2057-65. PubMed
- Holm BC, Lorentzen JC, Bucht A. Adjuvant oil induces waves of arthritogenic lymph node cells prior to arthritis onset. Clin Exp Immunol. 2004 Jul;137(1):59-64. PubMed
- Holm BC, Svelander L, Bucht A, Lorentzen JC. The arthritogenic adjuvant squalene does not accumulate in joints, but gives rise to pathogenic cells in both draining and non-draining lymph nodes. Clin Exp Immunol. 2002 Mar;127(3):430-5. PubMed
- Lorentzen JC. Identification of arthritogenic adjuvants of self and foreign origin. Scand J Immunol. 1999 Jan;49(1):45-50. PubMed
- Kenneth M. Murphy, Paul Travers, Mark Walport. Janeway's Immunobiology, Seventh Edition, 2008
- Silverstein AM, Rose NR. There is only one immune system! The view from immunopathology. Semin Immunol. 2000 Jun;12(3):173-8; PubMed
- Rose NR. The adjuvant effect in infection and autoimmunity. Clin Rev Allergy Immunol. 2008 Jun;34(3):279-82.PubMed
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