Vaccination part 14
Adjuvants
Adjuvants (Latin adjuvant- ‘helping towards’) are agents added to vaccines to enhance the innate immune response necessary to develop an adaptive immune response to the primary vaccine ingredient. These permit the use of smaller doses of the immunizing agent, the use of vaccine components of lesser immunogenicity in “subunit” vaccines, the vaccination of infants whose immune systems reside in a non-inflammatory posture, and a more effective vaccine response in the elderly.
Gaston Ramon, a veterinarian working at the Pasteur Institute in 1920, noted that higher specific antibody titers to the diphtheria vaccine were detected in horses that developed abscesses at the injection site, and that the effect of vaccination was enhanced by inciting an inflammatory response at the site of administration, prompting the inclusion of pro-inflammatory ingredients in vaccines. Around the same time, Glenny et.al. discovered the adjuvant effect of aluminum salts.
Adjuvants are not required, & are not used, in live attenuated viral vaccines, such as measles, mumps, rubella, varicella, rotavirus, the oral (Sabine) polio vaccine, or the live attenuated nasal influenza vaccine, in which pathogen associated molecular patterns (PAMPs) of the attenuated pathogen suffice to ensure an innate immune response to the vaccine.
The most common adjuvants in use are proprietary preparations of the aluminum salts aluminum hydroxide and aluminum phosphate, often appearing under their trade names Alhydrogel®, Rehydragel®, and Adju-Phos® and colloquially but imprecisely referred to as alum.
In addition to aluminum salts,
saponins derived from the bark of tree Quillaja saponaria or from the leaves of Quillaja brasiliensis,
proprietary squalene (derived from shark liver) oil-in-water emulsions, such as MF59 and ASO3,
CpG 1018 (a short (22-mer) oligonucleotide sequence containing CpG motifs),
and AS01B (3-O-desacyl-4 ́-monophosphoryl lipid A, an attenuated form of the endotoxin lipopolysaccharide, isolated from the outer cell wall of Salmonella enterica, along with QS-21, a triterpene glucoside extracted from the bark of Quillaja saponaria)
are used as adjuvants in some vaccines. The highly immunogenic formaldehyde-inactivated diphtheria toxoid component of the DTaP, DT, and dT vaccines serves alongside aluminum salts as an adjuvant for the tetanus and pertussis components and is included as an essential ingredient in these vaccines even in regions where diphtheria is no longer a concern.
The mechanisms of action of vaccine adjuvants appear to be complex and are not fully understood. One action is to incite an innate immune response with inflammation at the site of injection, with innate immune cell activation and cytokine and chemokine production impacting cellular recruitment and activation at the site of vaccine administration, to ensure uptake of the vaccine antigen(s) by dendritic cells, which serve as professional antigen presenting cells to cells of the adaptive immune response. Adjuvants may also impact the longevity of antigen in the body, assisting antigen in forming a depot and enhancing antigen presentation through an extended period of immune cell stimulation. Existing vaccine adjuvants appear to primarily direct an antibody response, rather than a CD8+ cytotoxic T-cell response, to the vaccine antigen(s). Current vaccine research is directed to the development of adjuvants to encourage T-cell responses to vaccination.
The unqualified suggestion is often encountered that aluminum salt adjuvants “have an excellent safety profile,” based on their longstanding use in vaccines.
The safety of aluminum salts is often defended with claims such as
“Aluminum is the third most abundant element after oxygen and silicon, and it is the most abundant metal, making up almost 9 percent of the earth's crust. Aluminum is found in plants, soil, water and air. Most plants have low quantities of aluminum, but a few are known to be aluminum accumulators, including some types of tea plants, grasses and orchids.
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Aluminum can be found in food-related products including pots and pans; storage containers, such as beverage cans; and foil. Aluminum is found in numerous foods and beverages including fruits and vegetables, beer and wine, seasonings, flour, cereals, nuts, dairy products, baby formulas, and honey. Typically, adults ingest 7 to 9 milligrams of aluminum per day. Aluminum is used for manufacturing of airplanes, siding, roofing materials, paints, pigments, fuels and cigarette filters.
(Somehow the mention of aluminum’s presence in cigarette filters is less than reassuring of its safety).
Aluminum is found in health products including antacids, buffered aspirin, antiperspirants and some vaccines.”
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The aluminum contained in vaccines is similar to that found in a liter (about 1 quart or 32 fluid ounces) of infant formula. While infants receive about 4.4 milligrams of aluminum in the first six months of life from vaccines, they receive more than that in their diet. Breast-fed infants ingest about 7 milligrams, formula-fed infants ingest about 38 milligrams, and infants who are fed soy formula ingest almost 117 milligrams of aluminum during the first six months of life.
This is a false equivalency; note that the gastrointestinal bioavailability of aluminum is approximately 0.1% from food and drinks, translating that 7-117mg ingested during the first six months of life to 0.007 - 0.117mg absorbed (compared to 4 milligrams of intramuscular aluminum from vaccines over the same period); the 7-9 mg ingested daily by adults translates to a daily absorbed dose of 0.007-0.009mg. Dermal bioavailability of aluminum (e.g. from aluminum chlorohydrate antiperspirants) is still lower, at 0.012%.
The Al(3+) (aq) cation, is highly biologically reactive, proinflammatory (hence its use as a vaccine adjuvant), and a potent neurotoxin. The major route of aluminum clearance from the circulation is via the kidneys and is facilitated by chelation to citrate, but most (80–90%) of the aluminum in the circulation is bound to serum protein (mainly transferrin and albumin) and is therefore unfilterable by the renal glomeruli. Aluminum is taken up from the circulation by a number of tissues, including bone, brain, liver, heart, spleen, and muscle. 40% of parentally-administered aluminum is retained in adults and 75% in neonates. The elimination half-life of aluminum from the adult brain is ~7 years; that of the infant is unknown. Detailed toxicokinetics are difficult to obtain, as there are no available radioactive aluminum isotopes with appropriate half-lives to permit study in living subjects.
Apart from the potential toxicity per se of aluminum salt adjuvants, we need to consider the consequences of inviting an inflammatory response in infants in general. The immune system in infancy assumes a non-inflammatory posture for good reason, with the brilliant and intricate work-around of relying on maternally-conferred passive immunity for defense against infectious disease, and we don’t fully understand the consequences of violating this.
In contrast to the CDC’s assertion that aluminum salt adjuvants “have an excellent safety profile,” I’d suggest that we need to accept that the safety profile of these agents, particularly in infancy, is poorly understood, and suspicious at best.
In the pre-licensure clinical trials of the Gardasil® human papillomavirus (HPV) vaccine, Merck's proprietary highly reactogenic amorphous aluminium hydroxyphosphate sulfate adjuvant was used as “placebo” in the control arm, removing potential adverse effects related to this adjuvant in the vaccine arm from attention. No parallel study has been performed to compare the adjuvant-containing “placebo” with a true inactive placebo nor to establish its safety in short- or long-term use.
Important information. Thank you, Will.