Aluminum-based vaccine adjuvants: much ado about nothing

The short version: Despite the concerns about aluminum-based adjuvants, there is an extensive history of their use (approaching 1 century) without any significant safety problems, and they represent a gold standard in vaccine adjuvants because of their safety. Aluminum-based adjuvants have remarkably low toxicity in people, and the idea that the adjuvants can cause neurological diseases in humans is poorly founded. It is also unrealistic for them to provoke autoimmune diseases, as well as allergy. Ultimately, aluminum-based adjuvants are critical supporters of the immune response, and the fact that we can use them to protect against infectious diseases is a phenomenal triumph of pharmacology.

In the global crisis with vaccine confidence a major point of persistent concern has to do with the non-antigenic components of vaccines, and, in particular, aluminum-based adjuvants seem to be worrisome for the vaccine hesitant. This is especially important now during the current pandemic, as COVID-19 is occupying the lion’s share of the healthcare system’s resources and we cannot afford to have resurgences in vaccine-preventable diseases. Let’s see what the data actually say.

What are aluminum-based adjuvants and why are aluminum-based adjuvants in vaccines?

Aluminum-based adjuvants are salts of the aluminum ion which serve to enhance immune responses. I’ve seen it stated several times by several individuals that they would be far more comfortable with vaccines if the vaccines contained just the antigens, without those “heavy metals” like aluminum. There are several substantial errors in understanding with these comments. Aluminum-based adjuvants are necessary in ensuring the efficacy of vaccines and furthermore do help to ensure their safety. Additionally, aluminum is itself among the lightest metals in existence, though the term “heavy metal” is largely meaningless from a chemistry standpoint and should probably be abandoned. Furthermore, the adjuvants in question are salts, not metals, and their properties are fundamentally different from the free metal species. Aluminum as a metal is so reactive that it is virtually always present as an ion, which is comparatively inert. For a more commonplace example: table salt, which you doubtlessly consume every day either through your food or as a condiment, is composed of a 1:1 ratio of sodium and chloride ions. Sodium metal however, is so reactive that if it comes into contact with water, it will explode and leave a pool of corrosive alkaline in its wake (which makes for some fascinating demonstrations). Chlorine gas was used as a chemical weapon in WW1 and forms bleach and hydrochloric acid upon reacting with water in our tissues. Yet, both sodium and chloride ions are critical for normal function of our cells.

Vaccine adjuvants work by helping to provide the necessary signals to the immune system for a productive immune response to be possible. They are used in those vaccines which lack the structural features necessary to be able to do this on their own e.g. toxoid and subunit vaccines. Live and killed vaccines, generally speaking, do not require vaccine adjuvants as they contain all the structural features necessary to mount an immune response (the principal exception to this is adjuvanted influenza vaccines, which while inactivated, are used in elderly patients in whom immunosenescent changes render it difficult to generate protection without a boost). Specifically, aluminum-based adjuvants are salts of aluminum, typically alum (potassium-aluminum hydroxide/sulfate/phosphate- the term is nonspecific)or aluminum oxyhydroxide which act through multiple concurrent mechanisms (elaborated upon below) to ensure a productive immune response. In particular, aluminum-based adjuvants do an excellent job of helping to produce antibodies, which is especially important for toxin-mediated diseases e.g. diphtheria and tetanus. Aluminum-based adjuvants are currently used in vaccines against tetanus, diphtheria, pertussis, pneumococcal, hepatitis B virus (HBV), hepatitis A virus (HAV), human papillomavirus (HPV), meningococcal, Haemophilus infuenzae type B (Hib), Japanese encephalitis (JE), and anthrax vaccines.

How do aluminum adjuvants work?

The immune system’s function can be explained largely in terms of two frameworks. The first is the older self vs. non-self concept which states that the immune system is capable of distinguishing between self and non-self antigens and will not respond to self-antigen. However, this is an older model which has encountered some issues as our understanding of immunology has evolved. In fact, it is essential that the immune system exhibit some levels of autoreactivity (the ability to respond to self-antigen) to be able to deal with infection (and in fact, during the development of lymphocytes it is a condition of their egress from primary lymphoid organs that they be able to recognize self-antigen, which is known as positive selection). Furthermore, we contain millions of non-self antigens in the form of our microbiota, which we, broadly speaking, tolerate. An alternate model is known as the danger model, which has been advanced largely by Matzinger and Janeway, and it explains quite a bit more than the comparatively simplistic self vs. non-self framework. It posits that it is not simply non-self antigens which induce immune responses but rather, the immune system actively senses danger signals (alarmins, also referred to as damage-associated molecular patterns (DAMPs)) and their presence is a prerequisite for the initiation of an immune response. For example, in gouty arthritis, there is a buildup of uric acid causing painful inflammation. Uric acid is a potent alarmin. Per the danger model, alarmins activate the pattern recognition receptors (PRRs) of innate immunity which go on to induce inflammation and eventually activate the adaptive immune system to clear the offending agent. This explains largely why it is not sufficient to just supply the immune system with the antigens you want for it to respond to with the hope of reliably inducing a response: these antigens alone do not contain alarmins and thus will not be able to produce the innate immune activation necessary for the activation of the adaptive immune system to produce specific effectors (antibodies and T cells). Ultimately, a productive immune response requires the activation of helper T cells. Helper T cells, also called CD4 T cells, are very diverse cells which will differentiate into any of several modules in response to the signals they receive to regulate the actions of other cells in fighting off infection. I have previously written about some of the functional divisions of helper T cells here.

We can elaborate upon this further with what is known as the 3-signal model:

Antigen-presenting cells (APCs; particularly dendritic cells) are specialized cells of the immune system who actively take up antigen and process it for presentation to T cells. They can go on to activate helper T cells, the brains of the immune system, which will orchestrate a complex cascade of events to generate a productive immune response. The 3-signal model explains that antigen presenting cells accomplish this in several steps and all 3 are necessary for the activation of the T cell. Signal 1 refers to the presentation of the antigen itself on an MHC protein. This however, is not sufficient for activation of a T cell. MHC proteins are expressed on every cell except red blood cells, and constantly presenting self-antigen. Hence if this were all it took, we would have rampant autoimmune diseases. Engagement of pattern recognition receptors in the antigen presenting cell will result in its expression of co-stimulatory molecules (usually CD80 or CD86), which are required for survival and proliferation of the T cell (signal 2). Finally, cytokines give the third signal which instruct the T cell in how to differentiate to most appropriately counter the microbial threat. However, before this, there is a requirement for signal 0: the engagement by an alarmin of a PRR. This is often the role of vaccine adjuvants.

The actions of aluminum adjuvants are quite complex to examine because multiple mechanisms are acting concurrently. There are several excellent reviews on the subject here, here, and here. To put it as briefly as possible, we have been using aluminum-based adjuvants to enhance vaccine responses for nearly a century, and while we did have strong evidence that they did indeed enhance those responses (especially production of antibodies), the cellular and molecular mechanisms underlying those effects were not well characterized for some time. To date, not everything has been worked out but our understanding is substantial.

One proposed mechanism for how aluminum-based adjuvants work is known as the depot effect, which suggests that aluminum-based adjuvants enhance antigen presentation by forming a stable deposit of those antigens where they can readily be accessed by APCs. The antigens are adsorbed onto the aluminum and indeed, this does seem to protect them from degradation before they can be taken up by APCs. However, this does not hold up very well in light of the finding that we still observe excellent vaccine responses even if the antigen-adjuvant depot is excised from the site of vaccination. Furthermore, DNA vaccines (there are none currently in routine use but research has been ongoing for decades), which encode antigens in DNA for one’s own cells to synthesize, also show enhanced responses with aluminum adjuvants- which is not explainable by a depot effect.

A better explanation is that aluminum adjuvants are potent inducers of inflammation at the injection site which serve to activate various components of the innate immune system. Multiple chemokines (small proteins that direct the localization of cells to a particular region of the body) are produced at the site of immunization that recruit macrophages, monocytes, immature dendritic cells, and polymorphonuclear granulocytes- all important actors in the innate immune system. Evidence supports that aluminum-based adjuvants enhance expression of costimulatory molecules on APCs, and result in the production of pro-inflammatory cytokines. The pro-inflammatory cytokines serve to enhance expression of MHC class II molecules required for antigen presentation. These can all be regarded as manifestations of supplying the immune system with signal 0.

As an aside for a moment, I would be remiss not to explain that while inflammation is commonly used in popular parlance to refer to a dangerous or pathological process, it is a crucial mechanism of protection by the body against infection. Excessive inflammation is certainly problematic, but failure to induce physiological levels in response to appropriate stimuli is no less serious.

A partial mechanistic answer for how aluminum-based adjuvants work comes from their ability to induce the NLRP3 inflammasome (also called the NALP3 inflammasome). The adjuvants seem to induce release of alarmins from the body, including uric acid, ATP, and heat shock protein 70 (HSP70), which activate of the NLRP3 inflammasome. There is also some evidence that aluminum adjuvants can give rise to reactive oxygen species that induce NLRP3 inflammasome formation. The NLRP3 inflammasome is a supramolecular complex of proteins that can form in response to various stimuli (e.g. uric acid, ATP) to activate procaspase 1. The inflammasome proteins contain a CARD (caspase-associated recruitment domain) which serve to recruit procaspase 1. Procaspase 1 undergoes autocleavage (it cuts itself into 2 pieces, which activates it as procaspase 1 is a zymogen- the inactive form of a protein) to produce active caspase 1. Caspases are mediators of cell death, and in this case lead to a form of cell death known as pyroptosis. Pyroptosis is unique because it is extremely pro-inflammatory and leads to release of the cytokines IL-1β and IL-18. IL-1β is a potent inducer of T cell division and strongly promotes antibody production. IL-18 induces production of interferon-γ which activates macrophages and is among the most potent inducers of inflammation in the body. The ATP released may also activate potassium loss from the cell via the P2X7 receptor which seems to also induce NLRP3 inflammasome activation.

The major mechanisms are described previously (and I hope sufficient for any readers) but for the sake of comprehensiveness, I will describe a few more ancillary mechanisms that have more recently come to light (though the discussion here gets a bit more technical, so I should emphasize that it is not necessary if you have read the previous part).

Oleszycka et al report that aluminum-based adjuvants also enhance production of the anti-inflammatory cytokine IL-10 by macrophages and dendritic cells, which suppresses Th1 responses. The induction of IL-10 may also explain, in part, the utility of these adjuvants in allergy immunotherapy. Additionally, aluminum-based adjuvants selectively inhibit IL-12, a cytokine required for the generation of Th1 cells (together with interferon-γ) via induction of the mTOR pathway. IL-10 is activated subsequently by the mTOR pathway. In a more direct mechanism, Flach et al, report that alum in the vaccine localizes to the lipid rafts of membranes of dendritic cell and induces the actions of the protein Syk, as antigens gradually dissociate from the adjuvant and enter the cell via macropinocytosis (cell drinking). Syk activates the enzyme PI3 kinase which enhances delivery of antigens through phagocytosis (cell eating) to obtain antigens that are still associated to the alum.

Khameneh et al. also shed some light on the responses caused by aluminum-based adjuvants. They report that there is a substantial increase in the production of IL-2, a pro-inflammatory cytokine particularly important for T cells because it promotes their proliferation and differentiation, following immunization with aluminum-based adjuvants. Per their study, the source of this IL-2 is the dendritic cells themselves in a pathway known as the Syk-NFAT-IL-2 axis (which further builds on the evidence previously discussed by Flach et al. who noted the importance of Syk), which is seemingly triggered by the phagocytosis of the adjuvants.

The precise role for DNA in the adjuvant effects of aluminum are unclear. In general, host DNA is a poor immunopotentiator, and rather it is CpG DNA (DNA with adjacent C and G bases in which the C is unmethylated) which promotes inflammation through TLR9. However, CpG islands are quite rare in the human genome- but not in bacteria. Still, some groups do report that DNA-evoked responses from aluminum-based adjuvants are important for their function. Marichal et al. describe that alum can induce local cytotoxicity that leads to the release of such DNA, which enhances Th2 responses. They argue that non-TLR9 DNA sensors induce inflammasome activation to liberate IL-1β and induce production of interferon-β1.

Taken together, aluminum-based adjuvants use multiple concurrent mechanisms to support a productive immune response.

Does the cumulative aluminum content from the childhood vaccination schedule amount to a level where toxicity concerns are justified?

A common ploy by anti-vaccine profiteers is to insinuate that the components of vaccines are toxic and thus vaccines are dangerous. This points to an incredible failure to understand even basic toxicology: “the dose makes the poison” is the first law of toxicology. We consume trace amounts of uranium through our diet, and yet uranium poisoning is extremely rare (and does not occur through dietary exposure). Aspirin is an essential medicine and yet, in excessive quantities can cause salicylism, a life-threatening toxicity. So, what does the data say for aluminum? Firstly, some things to establish: aluminum is everywhere. It is ubiquitous and unavoidable, being the third-most common element in the earth’s crust. We encounter it in the food we eat, in the air we breathe, even in breastmilk. The toxic species of concern when it comes to aluminum adjuvants is the aluminum ion. While considerably less reactive than the pure metal, aluminum ions are still fairly reactive because they are a group III metal, which means they are constantly attempting to balance achieving an octet and minimizing the absolute value of their formal charge (as an octet will produce a formal charge of -1). In chemistry parlance we would refer to aluminum as being a hard Lewis acid (as per HSAB theory) and tending to form poorly soluble complexes. As far as toxicity manifestations, there are a few. Among the largest sources of aluminum are antacids, and excess consumption is associated with osteomalacia (softening of the bones) because the aluminum substitutes for calcium. Occupational exposure to aluminum has been associated with lung fibrosis, but this is believed to be more related to the dust in environments where such exposure would occur rather than the aluminum itself. In animals, excess aluminum can cause the formation of neurofibrillary tangles and neurologic disease manifested by encephalopathy and seizures- but this is not observed in all animals, and non-human primates require over 1 year of aluminum infusion before these effects can become apparent. In those with substantial kidney impairment, a condition known as “dialysis dementia” or “dialysis encephalopathy” may develop from excess aluminum consumption (this was caused by aluminum in their diasylate fluid).

In considering the toxicity potential of any substance, one has to consider the pharmacokinetics, which broadly speaking are split into 4 considerations: absorption, distribution, metabolism, and excretion- ADME. Absorption is most properly defined as the ability of a drug, once administered, to move into the central compartment: the circulatory system. In virtually all cases, the pertinent consideration in evaluating absorption is bioavailability. The bioavailability of a drug is the proportion of it that can be taken in by a given route of administration. For instance, anything taken by the IV (intravenous) route will have 100% bioavailability, essentially by definition- all of it will end up directly into the circulation and from there it can make its way to the target tissue. In contrast, some things taken in by the PO route (per os, which is Latin for “by mouth”) can have very low bioavailability, like the antibiotic vancomycin, which has an oral bioavailability less than 10 %. Most people seem to think that the only way to take a drug is either by mouth or have it injected into you. Here is a non-comprehensive list of actual possible routes of administration:

  1. PO (Latin for per os meaning “by mouth”)
  2. sublingual
  3. intranasal
  4. intrathecal
  5. intracerebroventricular
  6. epidural
  7. per rectum
  8. intravenous
  9. intra-arterial
  10. intradermal
  11. intramuscular
  12. subcutaneous
  13. intraperitoneal
  14. transmucosal
  15. intracardiac
  16. intravesicular
  17. intravitreal
  18. intraocular
  19. extra-amniotic

All of these routes of administration have different kinetics and bioavailabilities which are specific to the substance in question. For aluminum, the PO route has a bioavailability of about 0.3%. For intramuscular injections, as would be done for adjuvanted vaccines (in general, this is preferred over subcutaneous administration for adjuvanted vaccines), the bioavailability is approximately 0.6%/day, with all of it eventually being absorbed into the circulation.

As for distribution, the aluminum salts in adjuvants attain their minimal solubility at physiological pH, forming highly local concentrated deposits of aluminum which slowly enter the circulation. Aluminum can complex with citrate ions in the plasma, and animal studies show it localizes to the kidneys, liver, and bone. Controversy exists regarding how aluminum can enter the central nervous system. For a while it was believed that the effect is mediated by transferrin which grabs the aluminum and goes to the CNS like is done for iron. However, some findings have emerged which call that into question. The binding affinity of transferrin for iron (which is much more abundant than aluminum in the body) is substantially greater (estimates range from 10² to 10²² times), and furthermore, Tf(Al2) (transferrin with aluminum bound to it) cannot bind the transferrin receptor. Therefore, this is probably not the mechanism. However, there are no known ion channels by which aluminum can enter either and given the stereoelectronics involved, it’s highly improbable that aluminum is making use of a common cation channel like those for sodium and potassium (aluminum has a +3 charge while those ions are all +1 and in the body is much larger than either of those ions, so it can’t fit through the channels). My pal Abe (the BBB scientist) and I discussed it and we think that the aluminum is piggybacking off the citrate transporter. Citrate is the major chelator for aluminum in the body. Of course, we couldn’t find any literature to support this so it’s all speculative. Suffice it to say that in the absence of severe renal dysfunction and/or inhumanly large quantities of aluminum and/or severe BBB dysfunction, there is no tenable risk for neuropathology from the aluminum in vaccines.

Metabolic considerations are not pertinent because aluminum ions are not metabolized, in a formal sense. In pharmacokinetics, metabolism almost always refers to first-pass metabolism effects wherein the proportion of an active drug is substantially reduced by its conversion in the liver to an inactive metabolite, which affects dosing considerations. Metabolic transformations often serve to enhance the ability of the drug to be cleared from the body e.g. adding functional groups that improve its solubility in blood so that it can be removed via the kidneys.

Elimination is accomplished by the kidneys primarily (> 95%). Indeed, aluminum toxicity is an incredibly rare phenomenon because it is basically restricted to those who have substantial impairments to their kidney function. Bishop et al. studied the parenteral feeding of preterm infants (who do have such renal impairments) to establish the safe limits of aluminum.

Per FDA guidelines, no vaccine can contain more than 850 μg of aluminum adjuvants (for context, a single grain of rice has a mass of about 25,000 μg). The FDA’s safety limits based on Bishop’s study establish a threshold of 4–5 μg/kg/day of aluminum. From the WHO growth chart, a 2-month-old child at the 50th percentile of weight has a mass of 5 kg, meaning that aluminum intake should not exceed 25 μg/day. Using the IM bioavailability of aluminum adjuvants (0.6%/day), we find that the most any vaccine can contribute is approximately 5.1 μg/day which is well below the minimal level required for toxicity. If we take an entire appointment, at 2 months a child should receive Hib, pneumococcal conjugate (PCV), DTaP, IPV, and hepatitis B vaccines per the CDC schedule. DTaP-IPV-Hib can be given as a single vaccine containing < 850 μg of aluminum adjuvants. Based on the data from CHOP, Hepatitis B and Hib vaccines contribute another 450 μg of aluminum which brings the total to 1300 μg or 1.3 mg (there will be some variation with the specific vaccines (combined vs. single-antigen) regarding aluminum adjuvant content). This means a total of 7.8 μg of aluminum adjuvants per day, still considerably less than the minimal risk level for toxicity. These calculations are consistent with the data on the matter which you can see here and here.

Furthermore, if aluminum-based adjuvants are, in the grand scheme of things, a significant contributor to the total aluminum burden over the life of a child, then we would expect to see significant differences in the overall aluminum content based on vaccination history. Karwoski et al examined just that and find no correlation between aluminum content in blood and hair and vaccination history. This would serve to indicate that despite appearances, aluminum is so ubiquitous in the environment that vaccines are likely not a significant contributor overall, further reducing the likelihood of toxicity.

Lastly, I’ll just include this small remark: given the importance of kidneys in the elimination of aluminum, one might assume that those who have significant kidney impairment may need alternative vaccination options- something with less aluminum. However, chronic renal disease is often associated with significant immunological impairments that must also be taken into consideration, and in particular, these patients are at higher risk for hepatitis B and pneumococcal vaccines. Guidelines for the vaccination of those with severe chronic renal disease do not require adjustments to account for the aluminum content of these adjuvants. This is because the aluminum content from these vaccines is still substantially lower than levels required to produce dialysis dementia (as the guidelines were written based on those who already had renal impairments).

Do aluminum adjuvants cause allergies?

In short, the idea that this is possible is poorly founded and belies a poor understanding of allergy and immunology as a whole. As far as I can tell, this stems from the observation that aluminum adjuvants bias towards Th2 immunity which is associated with allergy, and also the observation that the adjuvants can induce class switching of antibodies to IgE. IgE antibodies ARE pathogenic in allergy (type 1 hypersensitivity). However, there are subtleties to this that are often missed. Everyone (barring those with certain immunological defects) makes IgE- yet not everyone has allergy. Clearly then, IgE is not sufficient for allergic disease to develop. As it turns out, it is not merely IgE but rather high-affinity IgE that is required for allergic disease and anaphylaxis. In fact, low-affinity IgE can actually be protective against allergy by preventing high-affinity IgE from binding its Fcε receptors to trigger degranulation of mast cells (which leads to release of histamine- the major pathologic mechanism behind anaphylaxis and allergy). Additionally, regarding the tendency to promote Th2 responses, as I have written previously, the Th1-Th2 dichotomy is outdated. Berker et al elaborate in this review on specific deficiencies with this perspective given the interplay between other cell types involved in allergy. There is also the fact that aluminum adjuvants are not merely used in vaccines, but also in allergy immunotherapy, which tolerizes individuals against allergens (i.e. desensitizes them). Hence, this claim is unfounded. See here for a similar discussion.

Do aluminum adjuvants cause autoimmune disease?

There is no good evidence to support that aluminum adjuvants can cause autoimmune disease. In fact, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) formed a scientific committee and convened a 2-day workshop, consisting of technical experts from around the world representing academia, government regulatory agencies, and industry, to investigate and openly discuss the issues around adjuvant safety in vaccines. They state in their report:

Following extensive literature reviews by the HESI committee, and presentations by experts at the workshop, several key points were identified, including the value of animal models used to study autoimmunity and AID [(autoimmune disease)] toward studying novel vaccine adjuvants; whether there is scientific evidence indicating an intrinsic risk of autoimmunity and AID with adjuvants, or a higher risk resulting from the mechanism of action; and if there is compelling clinical data linking adjuvants and AID.The tripartite group of experts concluded that there is no compelling evidence supporting the association of vaccine adjuvants with autoimmunity signals.

The origins of this idea appear to be from the work of Yehuda Shoenfeld, who proposes a condition called autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA). There is a great deal to dissect in that sentence. Firstly, on the matter of Shoenfeld’s work: there is considerable evidence of fraud on his part, including falsifying figures in his publications and likely not contributing to some of them at all given that he has nearly 2000 of them as of the time of writing this in his approximately 50-year career (a pace that is entirely unrealistic for any researcher). Virtually every single publication on ASIA is authored by him. The scientific community at large has not received his ideas well. Regardless, the issues with this hypothesis are less to do with the questionable integrity of the one who promulgated it and more to do with its substantial inconsistencies. For one thing, the condition is defined so broadly that it is essentially meaningless, as it seemingly can be made to include any adverse reaction to a vaccine regardless of whether it is autoimmune in nature or not. Though of course, this is coming from the man who argued everything is autoimmune until proven otherwise.

I mean just look at the diagnostic criteria- evolvement of an autoimmune disease is a minor criterion. In other words, the autoimmune syndrome induced by adjuvants need not actually have proof of being autoimmune. Some of his major criteria are entirely normal responses to vaccination e.g. myalgia, pyrexia (fever). Per Shoenfeld, the autoimmune disease in question can arise decades after the initial vaccination, which is fairly absurd because it gives license to blame any autoimmune condition occurring at any time on any vaccine. There’s also considerable dishonesty in much of the data that Shoenfeld uses to support his condition. For instance, a great deal of it relies on animal models, but these animal models often receive the adjuvant in the incorrect formulation or use the wrong adjuvant altogether. Complete Freund’s adjuvant (CFA) is an oil-in-water emulsion of mycobacterial components that has some veterinary use that is known to be able to induce autoimmune disease in genetically susceptible mice- and yet Shoenfeld uses this as a defense that ASIA can occur in humans even though CFA is not and has never been used in human vaccination. In another study a mouse strain with a genetic predisposition to systemic lupus erythematosis (SLE) is given huge doses of aluminum to argue for the plausibility of ASIA. Setting this aside, empirical data on the matter firmly lay the canard to rest: this study of several hundred thousand individuals in Denmark receiving subcutaneous immunotherapy for allergy (which does contain aluminum adjuvants) finds that they had a lower incidence of autoimmune disease compared with those who received conventional treatment. From this it can be concluded that ASIA is so rare that its effects are not apparent in the study because even that sample size is too small to capture it and in fact would imply that adjuvants may have a protective effect against the development of autoimmune disease (not that anyone is claiming that), or, far more likely, ASIA is not a real condition. To expand the question more broadly as to whether or not vaccines as a whole can cause autoimmune disease, the answer is: exceedingly rarely. This review provides probably the most thorough examination of that particular question. The 1976 influenza vaccine did appear to rarely cause Guillain-Barre syndrome, an ascending paralysis condition that seemingly results from molecular mimicry (an inability of the immune system to distinguish self-antigens from non-self-antigens due to structural similarity). In particular, I find this remark salient:

Thus, the actual prevalence of autoimmune reactions to vaccination is remarkably low (much less than 1:10,000 of the hundreds of millions vaccine doses yearly administered in the world [16, 17]), probably as a consequence of the many redundant regulatory mechanisms active in the immune system [3].

In a previous section, I explained that there are a great deal of barriers to overcome to initiate ANY immune response (the 3 signal model). It is considerably more difficult to initiate an immune response against self-antigen. To begin with, strong reactions to self-antigen are selected against in the development of lymphocytes (negative selection). Secondly, without an infectious agent to supply constant stimulation of the innate immune system with danger signals, the immunopathology invoked from these reactions should be suppressed through peripheral tolerance mechanisms. I am considering a future post on the mechanisms of tolerance that prevent autoimmune disease to elaborate upon how this would work in detail, but translating these concepts simply is proving to be a challenge.

The development of an autoimmune disease is a complex phenomenon wherein many things have to go wrong at the same time for it to occur:

The idea that you can cause an autoimmune disease to occur simply by introducing a vaccine adjuvant has been likened by my pal, Professor Jen Totonchy PhD, to trying to collapse a building by throwing a rock at it.


Aluminum-based adjuvants potentiate the immune response through multiple concurrent mechanisms and are excellent inducers of antibodies. Despite questions arising about their safety, there is no good evidence to suggest that aluminum adjuvants are inherently unsafe. Links to allergy and autoimmune disease are likely unfounded, as are toxicity concerns.


  1. Murphy K, Weaver C. Janeway’s Immunobiology. 9th ed.; 2017.
  2. Klaassen C, Casarett L, Doull J. Casarett & Doull’s Toxicology. 9th ed. Blacklick: McGraw-Hill Publishing; 2019 p. 1139–1140.
  3. Guy B. The perfect mix: recent progress in adjuvant research. Nature Reviews Microbiology. 2007;5(7):396–397.
  4. Aimanianda, V., Haensler, J., Lacroix-Desmazes, S., Kaveri, S. V., & Bayry, J. (2009). Novel cellular and molecular mechanisms of induction of immune responses by aluminum adjuvants. Trends in Pharmacological Sciences, 30(6), 287–295. doi:10.1016/
  5. Tom, J. K., Albin, T. J., Manna, S., Moser, B. A., Steinhardt, R. C., & Esser-Kahn, A. P. (2018). Applications of Immunomodulatory Immune Synergies to Adjuvant Discovery and Vaccine Development. Trends in Biotechnology. doi:10.1016/j.tibtech.2018.10.004
  6. Hem, S. L., & HogenEsch, H. (2007). Relationship between physical and chemical properties of aluminum-containing adjuvants and immunopotentiation. Expert Review of Vaccines, 6(5), 685–698. doi:10.1586/14760584.6.5.685
  7. BREWER, J. (2006). (How) do aluminium adjuvants work? Immunology Letters, 102(1), 10–15. doi:10.1016/j.imlet.2005.08.002
  8. He, Y., Hara, H., & Núñez, G. (2016). Mechanism and Regulation of NLRP3 Inflammasome Activation. Trends in Biochemical Sciences, 41(12), 1012–1021. doi:10.1016/j.tibs.2016.09.002
  9. Li, H., Nookala, S., & Re, F. (2007). Aluminum Hydroxide Adjuvants Activate Caspase-1 and Induce IL-1 and IL-18 Release. The Journal of Immunology, 178(8), 5271–5276. doi:10.4049/jimmunol.178.8.5271
  10. Shi, J., Gao, W., & Shao, F. (2017). Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death. Trends in Biochemical Sciences, 42(4), 245–254. doi:10.1016/j.tibs.2016.10.004
  11. Mitkus, R. J., King, D. B., Hess, M. A., Forshee, R. A., & Walderhaug, M. O. (2011). Updated aluminum pharmacokinetics following infant exposures through diet and vaccination. Vaccine, 29(51), 9538–9
  12. Willhite, C. C., Karyakina, N. A., Yokel, R. A., Yenugadhati, N., Wisniewski, T. M., Arnold, I. M. F., … Krewski, D. (2014). Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts. Critical Reviews in Toxicology, 44(sup4), 1–80. doi:10.3109/10408444.2014.934439
  13. Berker, M., Frank, L. J., Geßner, A. L., Grassl, N., Holtermann, A. V., Höppner, S., … Woopen, C. M. P. (2017). Allergies — A T cells perspective in the era beyond the TH1/TH2 paradigm. Clinical Immunology, 174, 73–83. doi:10.1016/j.clim.2016.11.001
  14. Salemi, S., & D’Amelio, R. (2010). Could Autoimmunity Be Induced by Vaccination? International Reviews of Immunology, 29(3), 247–269. doi:10.3109/08830181003746304
  15. Weetman, A. P. (2012). The Immunopathogenesis of Chronic Autoimmune Thyroiditis One Century after Hashimoto. European Thyroid Journal. doi:10.1159/000343834
  16. Hawkes, D., Benhamu, J., Sidwell, T., Miles, R., & Dunlop, R. A. (2015). Revisiting adverse reactions to vaccines: A critical appraisal of Autoimmune Syndrome Induced by Adjuvants (ASIA). Journal of Autoimmunity, 59, 77–84. doi:10.1016/j.jaut.2015.02.005
  17. Pradeu, T., & Cooper, E. L. (2012). The danger theory: 20 years later. Frontiers in Immunology, 3. doi:10.3389/fimmu.2012.00287
  18. Fierens, K., & Kool, M. (2012). The Mechanism of Adjuvanticity of Aluminium-Containing Formulas. Current Pharmaceutical Design, 18(16), 2305–2313. doi:10.2174/138161212800166004
  19. Swanson K, Deng M, Ting J. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nature Reviews Immunology. 2019;19(8):477–489.
  20. HogenEsch, H., O’Hagan, D. T., & Fox, C. B. (2018). Optimizing the utilization of aluminum adjuvants in vaccines: you might just get what you want. Npj Vaccines, 3(1). doi:10.1038/s41541–018–0089-x
  21. He, P., Zou, Y., & Hu, Z. (2015). Advances in aluminum hydroxide-based adjuvant research and its mechanism. Human Vaccines & Immunotherapeutics, 11(2), 477–488. doi:10.1080/21645515.2014.1004026
  22. Vaccine Ingredients — Aluminum | Children’s Hospital of Philadelphia. 2020 [accessed 2020 May 8].
  23. Ameratunga, R., Gillis, D., Gold, M., Linneberg, A., & Elwood, J. M. (2017). Evidence Refuting the Existence of Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants (ASIA). The Journal of Allergy and Clinical Immunology: In Practice, 5(6), 1551–1555.e1. doi:10.1016/j.jaip.2017.06.033
  24. Goullé J, Grangeot-Keros L. Aluminum and vaccines: Current state of knowledge. Médecine et Maladies Infectieuses. 2020;50(1):16–21.
  25. Gowthaman U, Chen J, Zhang B, Flynn W, Lu Y, Song W, Joseph J, Gertie J, Xu L, Collet M et al. Identification of a T follicular helper cell subset that drives anaphylactic IgE. Science. 2019;365(6456):eaaw6433.
  26. Grzegorzewska, A. E. (2015). Prophylactic vaccinations in chronic kidney disease: Current status. Human Vaccines & Immunotherapeutics, 11(11), 2599–2605. doi:10.1080/21645515.2015.1034915
  27. Zubeldia, J., Ferrer, M., Dávila, I., & Justicia, J. (2019). Adjuvants in allergen-specific immunotherapy: modulating and enhancing the immune response. Journal of Investigational Allergology and Clinical Immunology, 29(2). doi:10.18176/jiaci.0349
  28. 2020 [accessed 2020 May 8].
  29. Bishop, N. J., Morley, R., Day, J. P., & Lucas, A. (1997). Aluminum Neurotoxicity in Preterm Infants Receiving Intravenous-Feeding Solutions. New England Journal of Medicine, 336(22), 1557–1562. doi:10.1056/nejm199705293362203
  30. Van der Laan, J. W., Gould, S., & Tanir, J. Y. (2015). Safety of vaccine adjuvants: Focus on autoimmunity. Vaccine, 33(13), 1507–1514. doi:10.1016/j.vaccine.2015.01.073
  31. 2020 [accessed 2020 May 8].
  32. Aluminum in Perspective. Thoughtscapism. 2020 [accessed 2020 May 8].
  33. Klein, L., Kyewski, B., Allen, P. M., & Hogquist, K. A. (2014). Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nature Reviews Immunology, 14(6), 377–391. doi:10.1038/nri3667
  34. So, A. K., & Martinon, F. (2017). Inflammation in gout: mechanisms and therapeutic targets. Nature Reviews Rheumatology, 13(11), 639–647. doi:10.1038/nrrheum.2017.155
  35. BELL, J. A. (1948). PERTUSSIS IMMUNIZATION. Journal of the American Medical Association, 137(15), 1276. doi:10.1001/jama.1948.02890490004002
  36. BELL J. DIPHTHERIA IMMUNIZATION. Journal of the American Medical Association. 1948;137(12):1009.
  37. Karwowski, M. P., Stamoulis, C., Wenren, L. M., Faboyede, G. M., Quinn, N., Gura, K. M., … Woolf, A. D. (2018). Blood and Hair Aluminum Levels, Vaccine History, and Early Infant Development: A Cross-Sectional Study. Academic Pediatrics, 18(2), 161–165. doi:10.1016/j.acap.2017.09.003
  38. Kool, M., Fierens, K., & Lambrecht, B. N. (2011). Alum adjuvant: some of the tricks of the oldest adjuvant. Journal of Medical Microbiology, 61(Pt_7), 927–934. doi:10.1099/jmm.0.038943–0
  39. Brunton L, Hilal-Dandan R, Knollmann B, Goodman L, Gilman A. The Pharmacologial Basis of Therapeutics. 13th ed. New York, etc.: McGraw-Hill; 2018.
  40. Mouchess, M. L., & Anderson, M. (2013). Central Tolerance Induction. Current Topics in Microbiology and Immunology, 69–86. doi:10.1007/82_2013_321
  41. Oleszycka, E., McCluskey, S., Sharp, F. A., Muñoz-Wolf, N., Hams, E., Gorman, A. L., … Lavelle, E. C. (2018). The vaccine adjuvant alum promotes IL-10 production that suppresses Th1 responses. European Journal of Immunology, 48(4), 705–715. doi:10.1002/eji.201747150
  42. Mori, A., Oleszycka, E., Sharp, F. A., Coleman, M., Ozasa, Y., Singh, M., O’Hagan, D. et al., The vaccine adjuvant alum inhibits IL-12 by promoting PI3 kinase signaling while chitosan does not inhibit IL-12 and enhances Th1 and Th17 responses. Eur. J. Immunol. 2012. 42: 2709–2719.
  43. Rose II, W. A., Okragly, A. J., Patel, C. N., & Benschop, R. J. (2015). IL-33 released by alum is responsible for early cytokine production and has adjuvant properties. Scientific Reports, 5(1). doi:10.1038/srep13146
  44. Wang, Y., Rahman, D., & Lehner, T. (2012). A Comparative Study of Stress-mediated Immunological Functions with the Adjuvanticity of Alum. Journal of Biological Chemistry, 287(21), 17152–17160. doi:10.1074/jbc.m112.347179
  45. Rose II, W. A., Okragly, A. J., Patel, C. N., & Benschop, R. J. (2015). IL-33 released by alum is responsible for early cytokine production and has adjuvant properties. Scientific Reports, 5(1). doi:10.1038/srep13146
  46. Marichal, T., Ohata, K., Bedoret, D., Mesnil, C., Sabatel, C., Kobiyama, K., … Desmet, C. J. (2011). DNA released from dying host cells mediates aluminum adjuvant activity. Nature Medicine, 17(8), 996–1002. doi:10.1038/nm.2403
  47. Flach, T. L., Ng, G., Hari, A., Desrosiers, M. D., Zhang, P., Ward, S. M., … Shi, Y. (2011). Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nature Medicine, 17(4), 479–487. doi:10.1038/nm.2306
  48. Plotkin S, Orenstein W, Offit P, Edwards K. Plotkin’s Vaccines . 7th ed. Saint Louis: Elsevier; 2017.
  49. Khameneh, H. J., Ho, A. W. S., Spreafico, R., Derks, H., Quek, H. Q. Y., & Mortellaro, A. (2016). The Syk–NFAT–IL-2 Pathway in Dendritic Cells Is Required for Optimal Sterile Immunity Elicited by Alum Adjuvants. The Journal of Immunology, 198(1), 196–204. doi:10.4049/jimmunol.1600420
  50. Wu, J., & Chen, Z. J. (2014). Innate Immune Sensing and Signaling of Cytosolic Nucleic Acids. Annual Review of Immunology, 32(1), 461–488. doi:10.1146/annurev-immunol-032713–120156

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