Relationship between Hemolytic Activity and Adsorption Capacity of Aluminum Hydroxide and Calcium Phosphate as Immunological Adjuvants for Biologicals

Katô, Hiroshi; Shibano, Michiko; Saito, Takuya; Yamaguchi, Junji; Yoshihara, Shinobu; Goto, Nobuichi

doi:10.1111/j.1348-0421.1994.tb01820.x

Cited by 20 publications

(10 citation statements)

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“…There is now ample literature [27][28][29][30][31][32][33][34][35][36][37][38][39] to support the conclusion that many of the surfactants, administered parenterally to humans in vaccines, such as aluminum, mercury, and polysorbate 80 (in the acidic pH range), raise blood surface tension, leading to an increase in surface tension of intracellular, extracellular, and interstitial water, resulting in a pathology that we will refer to henceforth as "water stress". Throughout this paper, we will refer to water stress as a property of interfacial water-interfacial tension-which destabilizes enzymes, protein structure, and cell membranes [20,21,[40][41][42][43][44][45][46][47][48][49].…”

Section: Introductionmentioning

confidence: 99%

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The Initial Common Pathway of Inflammation, Disease, and Sudden Death

Davidson¹,

Seneff²

2012

Entropy

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Abstract:In reviewing the literature pertaining to interfacial water, colloidal stability, and cell membrane function, we are led to propose that a cascade of events that begins with acute exogenous surfactant-induced interfacial water stress can explain the etiology of sudden death syndrome (SDS), as well as many other diseases associated with modern times. A systemic lowering of serum zeta potential mediated by exogenous cationic surfactant administration is the common underlying pathophysiology. The cascade leads to subsequent inflammation, serum sickness, thrombohemorrhagic phenomena, colloidal instability, and ultimately even death. We propose that a sufficient precondition for sudden death is lowered bioavailability of certain endogenous sterol sulfates, sulfated glycolipids, and sulfated glycosaminoglycans, which are essential in maintaining biological equipose, energy metabolism, membrane function, and thermodynamic stability in living organisms. Our literature review provides the basis for the presentation of a novel hypothesis as to the origin of endogenous bio-sulfates which involves energy transduction from sunlight. Our hypothesis is amply supported by a growing body of data showing that parenteral administration of substances that lower serum zeta potential results in kosmotropic cationic and/or chaotropic anionic interfacial water stress, and the resulting cascade.Keywords: inflammation; serum sickness; colloidal instability; interfacial water stress; bio-sulfates; Shwartzman phenomena; sudden death syndrome Glossary of TermsAnaphylaxis a severe, rapidly progressing, life-threatening, generalized allergic reaction. Biological equipoise a stable, non-equilibrium, dissipative system synonymous with life. Cholesterol sulfate (Ch-S)quantitatively the most important known sterol sulfate in human plasma where it regulates the activity of the serine proteases, in cell membranes where it has a stabilizing role, and in platelet membranes where it supports platelet adhesion. Coherence domain (CD)a water CD is a collection of liquid water molecules which oscillate in unison in tune with a self-trapped electromagnetic field at a well-defined frequency. The coherent oscillations produce an ensemble of quasi-free electrons, able to collect noise energy from the environment and transform it into high-grade coherent energy in the form of electron vortices. This high-grade energy may then activate biomolecules resonating with the water CD. Colloidal instabilitya property attributed to a colloidal suspension that develops when stabilizing repulsive steric and electrostatic forces between colliding particles are insufficient to prevent their natural tendency to aggregate into masses large enough to precipitate.Colloidal suspension a colloid that has a continuous liquid phase in which a solid is suspended in a liquid, e.g., our flowing blood. Exclusion zone (EZ)a glass-like, gel phase consisting of water CDs resonating in-phase, adjacent to hydrophilic surfaces, several hundred micrometers wide which excludes colloi...

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Section: Introductionmentioning

confidence: 99%

“…Aluminum hydroxide gels have been used as vaccine adjuvants for many years. There is a well-known relationship between hemolytic activity and adsorption capacity of aluminum hydroxide adjuvants [28]. Intraperitoneal exposure to aluminum sulfate in rats increases blood viscosity and red blood cell aggregation [86].…”

Section: Introductionmentioning

confidence: 99%

The Initial Common Pathway of Inflammation, Disease, and Sudden Death

Davidson¹,

Seneff²

2012

Entropy

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“…Calcium phosphate has also been used for allergen desensitization (6, 16). Early studies indicated that calcium phosphate particles produce strong adjuvant effects, induced less immunoglobulin E (IgE) than aluminum adjuvants, and elicited only minimal local irritation in animal experiments and human clinical trials (6,8,11,17).Here, we describe a unique formulation of calcium phosphate nanoparticles (CAP) which is distinct from the formulations of calcium phosphate described by European scientists (16) and demonstrate its use as an effective mucosal adjuvant. Our results indicate that following viral challenge, mice immunized with CAP-based formulations of herpes simplex virus type 2 (HSV-2) glycoprotein exhibited significantly increased survival rates and less severe clinical infection than controls.…”

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confidence: 99%

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Calcium Phosphate Nanoparticles Induce Mucosal Immunity and Protection against Herpes Simplex Virus Type 2

He¹,

Mitchell²,

Morçöl³

et al. 2002

Clin Vaccine Immunol

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Previously we reported that calcium phosphate nanoparticles (CAP) represented a superior alternative to alum adjuvants in mice immunized with viral protein. Additionally, we showed that CAP was safe and elicited no detectable immunoglobulin E (IgE) response. In this study, we demonstrated that following mucosal delivery of herpes simplex virus type 2 (HSV-2) antigen with CAP, CAP adjuvant enhanced protective systemic and mucosal immunity versus live virus. Mice were immunized intravaginally and intranasally with HSV-2 protein plus CAP adjuvant (HSV-2؉CAP), CAP alone, phosphate-buffered saline, or HSV-2 alone. HSV-2؉CAP induced HSV-specific mucosal IgA and IgG and concurrently enhanced systemic IgG responses. Our results demonstrate the potency of CAP as a mucosal adjuvant. Furthermore, we show that systemic immunity could be induced via the mucosal route following inoculation with CAP-based vaccine. Moreover, neutralizing antibodies were found in the sera of mice immunized intranasally or intravaginally with HSV-2؉CAP. Also, the results of our in vivo experiments indicated that mice vaccinated with HSV-2؉CAP were protected against live HSV-2 infection. In conclusion, these preclinical data support the hypothesis that CAP may be an effective mucosal adjuvant that protects against viral infection.Since mucosal surfaces act as the primary point of entry for most pathogens and the first line of defense against them, vaccines inducing effective mucosal immunity may reduce rates of infection and decrease the morbidity and mortality of infectious diseases. Currently, no safe and effective mucosal vaccine adjuvants are approved for human use.Mucosal vaccine delivery is a promising strategy. Mucosal vaccines administered in one part of the body can elicit an antibody response in mucosal tissues remote from the site of initial antigen exposure. This effect occurs because of the common mucosal immune system (13). A major obstacle to developing a mucosal vaccine in humans is finding a safe and effective adjuvant. Experimental mucosal adjuvants include cholera toxin, heat-labile enterotoxin, mutant toxins (LTK63 and LTR72), CpG oligodeoxynucleotide, polymerized liposomes, microparticles, and interleukins or immune modulators. None of these adjuvants is approved for use in humans (3,12,18).Biodegradable calcium phosphate particles have been investigated as an alternative to aluminum adjuvants for parenteral vaccines. Clinical studies conducted in France described the use of a calcium phosphate adjuvant for secondary or booster immunizations against diphtheria and tetanus (8). Calcium phosphate has also been used for allergen desensitization (6, 16). Early studies indicated that calcium phosphate particles produce strong adjuvant effects, induced less immunoglobulin E (IgE) than aluminum adjuvants, and elicited only minimal local irritation in animal experiments and human clinical trials (6,8,11,17).Here, we describe a unique formulation of calcium phosphate nanoparticles (CAP) which is distinct from the formulations of calciu...

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“…Although they effectively enhance immune responses, there are several disadvantages associated with their use (3,5,14). The disadvantages of alum-based adjuvants include the severity of local tissue irritation, the longer duration of the inflammatory reaction at the injection site, strong Th2 responses, minimal induction of cell-mediated immunity, and a propensity to elicit undesirable immunoglobulin E (IgE) responses (11,12,17,27). Alum compounds have also been shown to increase the levels of potential undesirable homocytotropic antibodies in animal species (9, 21).…”

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Calcium Phosphate Nanoparticle Adjuvant

He¹,

Mitchell²,

Johnson³

et al. 2000

Clin Diagn Lab Immunol

198

139

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Vaccination to protect against human infectious diseases may be enhanced by using adjuvants that can selectively stimulate immunoregulatory responses. In a murine model, a novel nanoparticulate adjuvant composed of calcium phosphate (CAP) was compared with the commonly used aluminum (alum) adjuvants for its ability to induce immunity to herpes simplex virus type 2 (HSV-2) and Epstein-Barr virus (EBV) infections. Results indicated that CAP was more potent as an adjuvant than alum, elicited little or no inflammation at the site of administration, induced high titers of immunoglobulin G2a (IgG2a) antibody and neutralizing antibody, and facilitated a high percentage of protection against HSV-2 infection. Additional benefits of CAP include (i) an insignificant IgE response, which is an important advantage over injection of alum compounds, and (ii) the fact that CAP is a natural constituent of the human body. Thus, CAP is very well tolerated and absorbed. These studies were performed with animal models. By virtue of the potency of this CAP adjuvant and the relative absence of side effects, we believe that this new CAP formulation has great potential for use as an adjuvant in humans.Historically, adjuvants have been necessary to improve vaccine efficacy in order to afford protection against infections. A key reason for this is that both attenuated virus preparations and, particularly, recombinant proteins are often poorly antigenic. In the past decade, several adjuvants have been evaluated in clinical trials. Calcium phosphate (CAP), MF59, aluminum (alum) compounds, and virosomes have been approved for human use in several European countries (23). In the United States, alum compounds are the most extensively used adjuvants in licensed vaccines for humans. Although they effectively enhance immune responses, there are several disadvantages associated with their use (3,5,14). The disadvantages of alum-based adjuvants include the severity of local tissue irritation, the longer duration of the inflammatory reaction at the injection site, strong Th2 responses, minimal induction of cell-mediated immunity, and a propensity to elicit undesirable immunoglobulin E (IgE) responses (11,12,17,27). Alum compounds have also been shown to increase the levels of potential undesirable homocytotropic antibodies in animal species (9, 21). Furthermore, alum-based vaccines are frequently ineffective for the induction of antiviral immunity (4). For these reasons, new adjuvants are being developed to enhance the immunity against weak antigens. New-generation adjuvants are designed to induce minimal side effects, enhance the duration of the immune response, and concurrently stimulate humoral, cellular, and mucosal immune responses. Furthermore, an ideal adjuvant would be biodegradable, economical, and simple to manufacture. In addition, it would have the potential to selectively trigger a defined class of immune response such as the T-helper 1 (Th1) CD4 ϩ T-cell response and cell-mediated immunity and have equal applicability for any new-genera...

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Relationship between Hemolytic Activity and Adsorption Capacity of Aluminum Hydroxide and Calcium Phosphate as Immunological Adjuvants for Biologicals

Cited by 20 publications

References 11 publications

The Initial Common Pathway of Inflammation, Disease, and Sudden Death

The Initial Common Pathway of Inflammation, Disease, and Sudden Death

Calcium Phosphate Nanoparticles Induce Mucosal Immunity and Protection against Herpes Simplex Virus Type 2

Calcium Phosphate Nanoparticle Adjuvant

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