Aluminium assay and evaluation of the local reaction at several time points after intramuscular administration of aluminium containing vaccines in the Cynomolgus monkey

Verdier, F.; Burnett, Roger M.; Michelet, Claire; Moretto, Philippe; Fievet-Groyne, Françoise; Sauzeat, Elisabeth

doi:10.1016/j.vaccine.2004.09.012

Cited by 120 publications

(78 citation statements)

References 21 publications

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“…This is in accord with the decade-long good safety record of aluminum and magnesium oxides and salts as vaccine adjuvants, antacids and laxatives (Verdier et al, 2005).…”

Section: Discussionsupporting

confidence: 68%

Toxicity and Biomedical Imaging of Layered Nanohybrids in the Mouse

Flesken‐Nikitin¹,

Toshkov²,

Naskar

et al. 2007

Toxicol Pathol

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Layered nanohybrids (LNH) are a promising nonviral system allowing controlled drug and DNA delivery. In order to test the toxicity of LNH consisting of a magnesium/aluminum core, mice were subjected to subcutaneous, intraperitoneal, and intravenous injections of these nanoparticles at three doses. Intravenous injections resulted in 8% (1 out of 12) lethality at doses 100 µl and 200 µl of 6.96 × 10 −4 M solution, while all mice survived after LNH administration by any other routes. Histopathological alterations were limited to mild localized inflammatory lesions in the lungs and the dermis after intravenous and subcutaneous administration, respectively. LNH labeled with Lucifer Yellow were readily detectable in both locations by fluorescent microscopy. To test their potential for intravital imaging, LNH-Lucifer Yellow were injected into the ovarian bursa and successfully visualized by multiphoton microscopy within the ovarian surface epithelial cells. In similar experiments, the ovary and the ovarian bursa were readily detectable by magnetic resonance imaging after administration of modified LNH, where aluminum was substituted for gadolinium. Taken together, these results demonstrate minimal in vivo toxicity of LNH and illuminate their potential as multifunctional nanoscale particles suitable for combination of intravital biomedical imaging with controlled drug release.

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“…This is in accord with the decade-long good safety record of aluminum and magnesium oxides and salts as vaccine adjuvants, antacids and laxatives (Verdier et al, 2005).…”

Section: Discussionsupporting

confidence: 68%

Toxicity and Biomedical Imaging of Layered Nanohybrids in the Mouse

Flesken‐Nikitin¹,

Toshkov²,

Naskar

et al. 2007

Toxicol Pathol

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“…Alhydrogel® biopersistence was confirmed in a variety of laboratory animal models up to 6-12 months post-injection, in both the injected muscle (Verdier et al, 2005;Authier et al, 2006;Khan et al, 2013;Eidi et al, 2015) and distant lymphoid organs . Particles traffic from an injected tissue to the dLNs is size-dependent, smaller particles (20-200 nm) being able to drain in a free form whereas medium-sized particles (0.5-2 µm) are exclusively subjected to cell transportation (Manolova et al, 2008).…”

Section: Discussionmentioning

confidence: 82%

Non-linear dose-response of aluminium hydroxide adjuvant particles: Selective low dose neurotoxicity

et al. 2017

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Nonlinear dose-response of aluminium hydroxide adjuvant particles: selective low dose neurotoxicity.Toxicology http://dx.doi.org/10.1016/j.tox. 2016.11.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. An unusual neuro-toxicological pattern limited to a low dose of Alhydrogel ® was observed.Neurobehavioural changes, including decreased activity levels and altered anxiety-like behaviour, were observed compared to controls in animals exposed to 200 µg Al/kg but not at 400 and 800 µg Al/kg. Consistently, microglial number appeared increased in the ventral forebrain of the 200 µg Al/kg group. Cerebral Al levels were selectively increased in animals exposed to the lowest dose, while muscle granulomas had almost completely disappeared at 6 months in these animals.We conclude that Alhydrogel® injected at low dose in mouse muscle may selectively induce long-term Al cerebral accumulation and neurotoxic effects. To explain this unexpected result, an avenue that could be explored in the future relates to the adjuvant size since the injected suspensions corresponding to the lowest dose, but not to the highest doses, exclusively contained small agglomerates in the bacteria-size range known to favour capture and, presumably, transportation by monocyte-lineage cells. In any event, the view that Alhydrogel® neurotoxicity obeys "the dose makes the poison" rule of classical chemical toxicity appears overly simplistic.

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“…Aluminum hydroxide, like IFA, is not readily biodegradable. Previous studies have shown that aluminum hydroxide persisted for at least 6 months after intramuscular administration [40]. The documented side effects following subcutaneous administration of aluminum hydroxide include pruritic subcutaneous nodules [41,42], delayed hypersensitivity [41] and severe granulomatous inflammation [5].…”

Section: Discussionmentioning

confidence: 99%

Chitosan solution enhances both humoral and cell-mediated immune responses to subcutaneous vaccination

Zaharoff

Rogers

Hance

et al. 2007

Vaccine

302

193

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The development of safe, novel adjuvants is necessary to maximize the efficacy of new and/or available vaccines. Chitosan is a non-toxic, biocompatible, biodegradable, natural polysaccharide derived from the exoskeletons of crustaceans and insects. Chitosan's biodegradability, immunological activity and high viscosity make it an excellent candidate as a depot/adjuvant for parenteral vaccination. To this end, we explored chitosan solution as an adjuvant for subcutaneous vaccination of mice with a model protein antigen. We found that chitosan enhanced antigen-specific antibody titers over 5-fold and antigen-specific splenic CD4 + proliferation over 6-fold. Strong increases in antibody titers together with robust delayed-type hypersensitivity (DTH) responses revealed that chitosan induced both humoral and cell-mediated immune responses. When compared with traditional vaccine adjuvants, chitosan was equipotent to incomplete Freund's adjuvant (IFA) and superior to aluminum hydroxide. Mechanistic studies revealed that chitosan exhibited at least two characteristics that may allow it to function as an immune adjuvant. First, the viscous chitosan solution created an antigen depot. More specifically, less than 9% of a protein antigen, when delivered in saline, remained at the injection site after 8 hours. However, more than 60% of a protein antigen delivered in chitosan remained at the injection site for 7 days. Second, chitosan induced a transient 67% cellular expansion in draining lymph nodes. The expansion peaked between 14 and 21 days after chitosan injection and diminished as the polysaccharide was degraded. These mechanistic studies, taken together with the enhancement of a vaccine response, demonstrate that chitosan is a promising and safe platform for parenteral vaccine delivery.

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Aluminium assay and evaluation of the local reaction at several time points after intramuscular administration of aluminium containing vaccines in the Cynomolgus monkey

Cited by 120 publications

References 21 publications

Toxicity and Biomedical Imaging of Layered Nanohybrids in the Mouse

Toxicity and Biomedical Imaging of Layered Nanohybrids in the Mouse

Non-linear dose-response of aluminium hydroxide adjuvant particles: Selective low dose neurotoxicity

Chitosan solution enhances both humoral and cell-mediated immune responses to subcutaneous vaccination

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