Aluminum hydroxide; Aluminum phosphate
Status: approved; marketed
Organizations involved (major manufacturers):
Reheis Inc. – Manuf.
Superfos – Manuf.
Sanofi Aventis S.A. – Manuf.
Description: Aluminum hydroxide and aluminum phosphate-based vaccine adjuvants are used as matrices or carriers for vaccine antigens, and act to increase immune response to co-formulated vaccine antigens. These highly purified amorphous colloidal gels have a positive charge and readily adsorb most negatively charged substances, such as proteins, at neutral pH. The protein adsorbing capacity of an adjuvant is a major determinant of the amount of aluminum per dose. Aluminum adjuvants with higher protein-binding capacity allow use of lower amounts of aluminum per dose. Adsorption of protein is dependent on the pI (isoelectric pH) of the protein and the pH of the medium. A protein with a lower pI adsorbs to the positively charged aluminum ions more strongly than a protein with a higher pI. Adsorptive capacity is also affected by the types and concentrations of electrolytes present. Aluminum adjuvants generally appear as white, translucent or gels (similar to some aluminum-based antiperspirants).
Adjuvants are presumed to augment the immunogenicity of vaccine antigens by mechanisms including: 1) the prolongation of antigen exposure to antigen-presenting cells by the creation of a depot at the site of injection, 2) the activation of antigen-presenting cells, such as monocytes or macrophages, to release cytokines that can promote T-cell helper, B-cell, and cytotoxic T lymphocyte (CTL) responses, 3) the introduction of antigen into the MHC Class I processing pathway. As a result, adjuvanted vaccines may induce a more favorable and earlier antibody response with higher titers, longer persistence over time, and increased memory responses and CD8+ MHC Class I-restricted CTL responses, compared to comparable non-adjuvanted vaccines.
Aluminum salts are generally weaker adjuvants than emulsion adjuvants (e.g., oil-in-water emulsions). However, the aluminum salts have a solid record for mild inflammatory reactions, safety, and efficacy for generating immunological memory. Aluminum salts are the most common type of adjuvant, and are the only approved adjuvants in the U.S. Aluminum salt adjuvants, e.g., hydroxides and phosphates, are used with protein antigens as alum-adsorbed and alum-precipitated vaccines.
Aluminum hydroxide and aluminum phosphate gels available from commercial sources include Alhydrogel (aluminum hydroxide, 3% suspension in water) and Adju-fos (aluminum phosphate, 2% suspension in saline) supplied by Superfos (Ved-baek, Denmark). Reheis (Berkeley Heights, NJ), another major manufacturer of aluminum adjuvants, is the source for the Rehydragel (aluminum hydroxide gels) and Rehydraphos (aluminum phosphate gel) product lines.
As examples, the following vaccines contained the following reported total aluminum salts content. Aluminum hydroxide adjuvant per dose: Infanrix (DTaP), 0.625 mg; Havrix (pediatric hepatitis A vaccine), 0.25 mg; Vaqta (pediatric hepatitis A vaccine), 0.225 mg; Engerix B (hepatitis B vaccine), 0.25 mg; PedVax Hib, 0.225 mg; Twinrix (Hepatitis A-hepatitis B; also contains aluminum phosphate), 0.45 mg; and Pediarix (DTaP-IPV-hepatitis B; also contains aluminum phosphate), 0.85 mg. Aluminum phosphate as adjuvant: Prevnar (pneumococcal conjugate), 0.125 mg; Td (adult; from Massachusetts Dept. of Public Health), 0.45 mg; and Daptacel (DTaP), 0.33 mg. Aluminum sulfate as adjuvant: Tripedia (DTaP), 0.17 mg; Td (adult from Sanofi Pasteur), 0.28 mg; Comvax (Hib-hepatitis B), .225 mg and Recombivax HB (hepatitis B), 0.5 mg. [from the Pediatrics Online Web site, Oct. 2003].
Some vaccines have been reformulated to reduce their total aluminum content or have been discontinued. Previously, U.S. vaccines providing the highest doses of aluminum (for a complete course of vaccination) included Tetanus Toxoid Adsorbed from Wyeth Labs. and Swiss Serum and Vaccine Inst., both with 5.1 mg; DTP-Hib (Tetramune) from Lederle Labs. with 3.4 mg; DTaP (Infanrix) from GlaxoSmithKline with 3.1 mg; Tetanus Toxoid Adsorbed from Lederle with 2.9 mg; DTaP (Certiva) from Baxter with 2.5 mg.; and DTP from BioPort Corp. with 2.0 mg.
Superfos (Denmark), represented in the U.S. by Accurate Chemical and Scientific Co. (Westbury, NY), manufactures Alhydrogel. This appears to be the most commonly used, most established aluminum hydroxide adjuvant product line. Alhy-drogel is composed of 2.0% aluminum oxide (Al2O3); has a protein binding capacity of 0.9 mg bovine serum albumin/mg Al2O3 (also reported as 50-200 mg protein/g Al2O3); pH of 6.5; and viscosity of about 1,200 cps. Average particle size is 0.912 micron (µ) with 47% less than 1 µ and 0.0% less than 0.2 µ.
Reheis (U.S), a major source for Aluminum Hydroxide Gel adjuvants, offers:
a) Rehydragel LV (Low Viscosity Gel -Sterile) is a highly active protein adsorbent formulated for use as a fluid adjuvant with a low viscosity. Rehydragel LV is composed of 1.8-2.2% aluminum oxide (Al2O3); has a minimum protein binding capacity of 1.5 mg bovine serum albumin/mg Al2O3; is a fluid with a typical viscosity of 600 cps and maximum viscosity of 3,000 cps; pH of 5.8-6.8; and is sterile. Average particle size is 0.92 microns (µ) with 45% less than 1 µ and 1.4% less than 0.2 µ. Rehy-dragel LV has essentially the same Al2O3 content (2%) and average particle size as Alhydrogel but with a lower viscosity and higher protein binding capacity.
b) Rehydragel HPA (High Protein Adsorbancy - Sterile) provides a higher (> 67%) protein adsorbing capacity than other (e.g., LV) formulations without any increase in aluminum oxide solids content, attributed to its lower particle size distribution. Rehydragel HPA is composed of 1.8-2.2% aluminum oxide (Al2O3); has a minimum protein binding capacity of 2.5 mg bovine serum albumin/mg Al2O3; is a thixotropic fluid; pH of 5.8-6.8; and is sterile. Average particle size is 0.34 microns (µ) with 92% less than 1 µ and 14.4% less than 0.2 µ. It meets or exceeds all U.S.P. specifications for aluminum hydroxide gel, except for acid neutralization capacity. It is a thixotropic colloidal alumina gel composed of extremely fine submicron particles, resulting in a very stable physical suspension. Its thixotropic nature is not reduced by dilution, providing a stable physical suspension that can be maintained with dilution (e.g., 1-2% Al2O3). This allows used of lower levels of adjuvant while retaining adsorptive capability, higher antigen dosage levels, longer antigen release periods, improved immune response, greater suspension stability, reduced tissue response, and easier handling.
c) Rehydragel CG (Compressed Gel), a non-sterile product containing a higher level (9.5%) aluminum hydroxide content, is often used in veterinary and, perhaps, in human vaccines requiring high adjuvant levels, or is diluted (e.g., to 0.2-0.5%) and used to increase vaccine viscosity or stabilize vaccine suspension. Rehydragel CG is composed of 8.5-10.5% aluminum oxide (Al2O3); has a minimum protein binding capacity of 1.0 mg bovine serum albumin/mg Al2O3; gel consistency; and pH of 7.0-8.0.
d) Rehydragel LG is an intermediate oxide, thixotropic, aluminum hydroxide gel with intermediate protein adsorbancy. Its thixotropic flowable nature allows improved handling.
Reheis also manufactures Aluminum Phosphate Gel (Rehy--draphos), an amorphous aluminum hydroxy-phosphate with an acidic isoelectric point of 4.6. This property, combined with its high surface area, provides a high protein adsorbtive capacity for positively charged antigens. Reheis reports that Rehy-dra-phos is particularly suited for use in diphtheria, pertussis, and tetanus vaccines (and combinations of these), especially where aluminum hydroxide adjuvants do not provide sufficient antigen binding. Rehydraphos contains aluminum phosphate (AlPO4) 1.9-2.1% and aluminum oxide (Al2O3) 0.85-0.95%; has a minimum protein binding capacity ranging up to 0.5 mg lysozyme/mg Al2O3; and pH of 6.0-7.0. It is a low viscosity fluid suspension available in sterile and non-sterile formulations.
Few vaccines marketed in the U.S. disclose their adjuvant composition, i.e., the specific product(s) used.
Nomenclature: Aluminum-based Adjuvants [BIO]; Alhy-dro-gel [TR reg. to Superfos]; Rehydragel [TR reg. to Reheis]; Re-hy-dra-phos [TR reg. to Reheis]; Adju-fos [TR reg. to Super-fos]; alu-minum hydroxide [SY]; aluminum phosphate [SY]; alum [SY]; potassium aluminum sulfate [SY]; aluminum oxy-hy-droxide [SY]; amorphous aluminum hydroxyphosphate [SY]; amorphous aluminum hydroxyphosphate sulfate [SY for alum]
Aluminum phosphate refers to a precipitate of insoluble aluminum phosphate (amorphous, semi-crystalline or crystalline), generally prepared by mixing soluble aluminum salts and phosphoric acid salts. Aluminum hydroxide refers to a precipitate of insoluble (amorphous, semi-crystalline or crystalline) aluminum hydroxide, generally prepared by neutralizing a solution of aluminum salts. The commonly-used term “alum” refers to aluminum hydroxide, e.g., Alhydrogel or Rehy-dragel.
Medical: Aluminum-based adjuvants have been used for nearly 70 years. They are generally considered safe with few adverse reactions, other than frequent soreness and swelling at the injection site. Aluminum in vaccines has been reported (Aug. 1998 Lancet) to be associated with macrophagic myofascitis (MMF), a new inflammatory muscle disease of unknown origin linked to accumulation of aluminum in macrophages, but there is no consensus yet regarding this.
Companies involvement:
Full monograph
937 Aluminum Vaccine Adjuvants
Nomenclature:
Aluminum-based Adjuvants [BIO]
Alhydrogel [TR assigned to Superfos]
Rehydragel [TR assigned to Reheis]
Rehydraphos [TR assigned to Reheis]
Adju-fos [TR assigned to Superfos]
alum [SY]
aluminum hydroxide [SY]
aluminum oxyhydroxide [SY]
aluminum phosphate [SY]
amorphous aluminum hydroxyphosphate [SY]
amorphous aluminum hydroxyphosphate sulfate [SY for alum]
potassium aluminum sulfate [SY]
FDA Class: Bologic BLA
Year of approval (FDA) = 1937
Date of 1st FDA approval = 19370000
(in format YYYYMMDD)
Index Terms:
adjuvants
influenza virus
non-Hodgkin's lymphoma (NHL)
suspension cell culture
aluminum hydroxide
aluminum phosphate
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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