Rates of Release of Subcutaneously Injected Antigens in the Rat: Comparison of an Aqueous Preparation with Two Alum‐Precipitated Preparations

Leeling, Jerry L.; Muni, Indu A.; Helms, R J; Johnson, Ned

doi:10.1111/j.1398-9995.1979.tb04376.x

Cited by 8 publications

(4 citation statements)

References 7 publications

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“…The particulate nature of adsorbed antigens facilitates uptake by antigen-presenting cells via phagocytosis (Mannhalter et al, 1985; Morefield et al, 2005). Adsorbed antigens are more slowly released from the injection site (Leeling et al, 1979; Weissburg et al, 1995; Noe et al, 2010), but the kinetics are highly dependent on the strength of the adsorption. Electrostatically adsorbed antigens are rapidly released and diffuse away from the injection site at a higher rate than antigens adsorbed via ligand exchange (Noe et al, 2010).…”

Section: Role Of Adsorption In the Immunostimulating Effect Of Aluminmentioning

confidence: 99%

Mechanism of Immunopotentiation and Safety of Aluminum Adjuvants

HogenEsch¹

2013

Front. Immun.

309

281

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Aluminum-containing adjuvants are widely used in preventive vaccines against infectious diseases and in preparations for allergy immunotherapy. The mechanism by which they enhance the immune response remains poorly understood. Aluminum adjuvants selectively stimulate a Th2 immune response upon injection of mice and a mixed response in human beings. They support activation of CD8 T cells, but these cells do not undergo terminal differentiation to cytotoxic T cells. Adsorption of antigens to aluminum adjuvants enhances the immune response by facilitating phagocytosis and slowing the diffusion of antigens from the injection site which allows time for inflammatory cells to accumulate. The adsorptive strength is important as high affinity interactions interfere with the immune response. Adsorption can also affect the physical and chemical stability of antigens. Aluminum adjuvants activate dendritic cells via direct and indirect mechanisms. Phagocytosis of aluminum adjuvants followed by disruption of the phagolysosome activates NLRP3-inflammasomes resulting in the release of active IL-1β and IL-18. Aluminum adjuvants also activate dendritic cells by binding to membrane lipid rafts. Injection of aluminum-adjuvanted vaccines causes the release of uric acid, DNA, and ATP from damaged cells which in turn activate dendritic cells. The use of aluminum adjuvant is limited by weak stimulation of cell-mediated immunity. This can be enhanced by addition of other immunomodulatory molecules. Adsorption of these molecules is determined by the same mechanisms that control adsorption of antigens and can affect the efficacy of such combination adjuvants. The widespread use of aluminum adjuvants can be attributed in part to the excellent safety record based on a 70-year history of use. They cause local inflammation at the injection site, but also reduce the severity of systemic and local reactions by binding biologically active molecules in vaccines.

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Section: Role Of Adsorption In the Immunostimulating Effect Of Aluminmentioning

confidence: 99%

Mechanism of Immunopotentiation and Safety of Aluminum Adjuvants

HogenEsch¹

2013

Front. Immun.

309

281

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“…[15][16][17][18][19] The release rate of adsorbed antigen from injection site may depend on the strength of binding between antigen and aluminum. [20][21][22] Indeed, a decrease in the strength of antigen adsorption to aluminum (e.g., by phosphate pretreatment) was found to be inversely proportional to the internalization by dendritic cells in vitro 23,24 and to immunopotentiation in vivo. 15,25,26 These results are suggestive of a more efficient antigen uptake and/or processing when the antigen is poorly bound to the aluminum-containing adjuvant.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Antigen Adsorption Onto an Aluminum-Hydroxide Adjuvant Evaluated by High-Throughput Screening

Jully

Mathot

Moniotte

et al. 2016

Journal of Pharmaceutical Sciences

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The adsorption mechanism of antigen on aluminum adjuvant can affect antigen elution at the injection site and hence the immune response. Our aim was to evaluate adsorption onto aluminum hydroxide (AH) by ligand exchange and electrostatic interactions of model proteins and antigens, bovine serum albumin (BSA), β-casein, ovalbumin (OVA), hepatitis B surface antigen, and tetanus toxin (TT). A high-throughput screening platform was developed to measure adsorption isotherms in the presence of electrolytes and ligand exchange by a fluorescence-spectroscopy method that detects the catalysis of 6,8-difluoro-4-methylumbelliferyl phosphate by free hydroxyl groups on AH. BSA adsorption depended on predominant electrostatic interactions. Ligand exchange contributes to the adsorption of β-casein, OVA, hepatitis B surface antigen, and TT onto AH. Based on relative surface phosphophilicity and adsorption isotherms in the presence of phosphate and fluoride, the capacities of the proteins to interact with AH by ligand exchange followed the trend: OVA < β-casein < BSA < TT. This could be explained by both the content of ligands available in the protein structure for ligand exchange and the antigen's molecular weight. The high-throughput screening platform can be used to better understand the contributions of ligand exchange and electrostatic attractions governing the interactions between an antigen adsorbed onto aluminum-containing adjuvant.

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“…When a compound having cytotoxicity, like an aluminum-adjuvanted vaccine, persistently exists in the injured tissue, chronic immune activation can occurr and this can lead to an increased risk of autoimmune disease development (Ishihara and Hirano, 2002;Murakami and Hirano, 2012). The Al acts to keep the antigen at the site of inoculation, which may prolong the immune response at the injection site (Leeling et al, 1979;Noe et al, 2010;Hansen et al, 2009;Manhalter et al, 1985). Kashiwagi et al (2014) reported that Al containing vaccines induce inflammatory nodules at the injection site, and that the inflammatory nodules remain 6 months later.…”

Section: Discussionmentioning

confidence: 99%

“…Aluminum salt adjuvants (Als) as typified by aluminum hydroxide and aluminum phosphate have been widely used as vaccine adjuvant to elicit immunogenicity (Lindblad, 2004), such as formalin-inactivated diphtheria-pertussistetanus and conventional Salk inactivated polio vaccine (DPT-cIPV), H5N1 pandemic influenza vaccine, recombinant hepatitis B virus HBV vaccines, hepatitis A vaccine, 7-valent pneumococcal vaccine, and human papillomavirus vaccine (HPVV) in Japan. The Als have been proposed to work as adjuvant by activating innate immunity through the release of damage-associated molecular patterns (DAMPs) from injected tissues by form-ing weak cytotoxicity (Marichal et al, 2011;Kono and Rock, 2008), and Als can keep the antigen at the injection site (Leeling et al, 1979;Noe et al, 2010;Hansen et al, 2009) to promote its uptake by antigen-presenting cells, such as macrophages and dendritic cells (Morefield et al, 2005;Mannhalter et al, 1985). However, Al-containing vaccines induce some side effects as typified by local swelling, inflammation, and pain, and most of them are mild (Mark et al, 1999;Pittman et al, 2002;Gherardi et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

An investigation and assessment of the muscle damage and inflammation at injection site of aluminum-adjuvanted vaccines in guinea pigs

2022

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Aluminum salt adjuvants (Als) have been the most widely used adjuvants in vaccines and known to be effective in intramuscular inoculation. However, in rare cases, some Al containing vaccines caused serious adverse events such as chronic pain at the site of the injection. The Als cause mild tissue damage at the inoculation site, allowing the antigen to be locally retained at the inoculation site and thus potentiate innate immunity. This is required to elicit effectiveness of vaccination. However, there is concern that chronic muscle damage might potentially lead to serious adverse events, such as autoimmune disease and movement disorders. In this study, muscle damage caused by several Al containing vaccines were examined in guinea pigs. Mild and moderate inflammation were observed following Al containing split influenza virus vaccine, formalin-inactivated diphtheria-pertussis-tetanus and Salk polio vaccine. While massive inflammation and muscle damage were observed in Al-containing human papillomavirus vaccine-inoculated animals. However, the severities of damage were not associated with their Al contents. Masson's trichrome staining and immunostaining revealed that injured muscle at the inoculated site recovered within one month of vaccination, whereas inflammatory nodules remained. Flow cytometric analyses of the infiltrating cells revealed that the number of CD45 + lymphocytes and potential granulocytes were increased following vaccination. The number of infiltrated cells seemed to be associated with severity of muscle damages. These observations revealed that Al containing vaccine-induced muscle damage is reparable, and severity of transient muscle damages seemed to be determined by type of antigen or types of Al salts rather than Al content.

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Rates of Release of Subcutaneously Injected Antigens in the Rat: Comparison of an Aqueous Preparation with Two Alum‐Precipitated Preparations

Cited by 8 publications

References 7 publications

Mechanism of Immunopotentiation and Safety of Aluminum Adjuvants

Mechanism of Immunopotentiation and Safety of Aluminum Adjuvants

Mechanisms of Antigen Adsorption Onto an Aluminum-Hydroxide Adjuvant Evaluated by High-Throughput Screening

An investigation and assessment of the muscle damage and inflammation at injection site of aluminum-adjuvanted vaccines in guinea pigs

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