Human prophylactic vaccine adjuvants and their determinant role in new vaccine formulations

Adjuvants have been considered for a long time to be an accessory and empirical component of vaccine formulations. However, accumulating evidence of their crucial role in initiating and directing the immune response has increased our awareness of the importance of adjuvant research in the past decade. Nevertheless, the importance of adjuvants still is not fully realized by many researchers working in the vaccine field, who are involved mostly in the search for better target antigens. The choice of a proper adjuvant can be determinant for obtaining the best results for a given vaccine candidate, but it is restricted due to intellectual property and know-how issues. Consequently, in most cases the selected adjuvant continues to be the aluminum salt, which has a record of safety, but predominantly constitutes a delivery system (DS). Ideally, new strategies should combine immune potentiators (IP) and DS by mixing both compounds or by obtaining structures that contain both IP and DS. In addition, the term immune polarizer has been introduced as an essential concept in the vaccine design strategies. Here, we review the theme, with emphasis on the discussion of the few licensed new adjuvants, the need for safe mucosal adjuvants and the adjuvant/immunopotentiating activity of conjugation. A summary of toxicology and regulatory issues will also be discussed, and the Finlay Adjuvant Platform is briefly summarized

A Pilot Study on Developing Mucosal Vaccine against Alveolar Echinococcosis (AE) Using Recombinant Tetraspanin 3: Vaccine Efficacy and Immunology

Humans and rodents become infected with E. multilocularis by oral ingesting of the eggs, which then develop into cysts in the liver and progress an endless proliferation. Untreated AE has a fatality rate of >90% in humans. Tetraspanins have been identified in Schistosoma and showed potential as the prospective vaccine candidates. In our recent study, we first identified seven tetraspanins in E. multilocularis and evaluated their protective efficacies as vaccines against AE when subcutaneously administered to BALB/c mice. Mucosal immunization of protective proteins is able to induce strong local and systemic immune responses, which might play a crucial role in protecting humans against E. multilocularis infection via the intestine, blood and liver. We focused on Em-TSP3, which achieved significant vaccine efficacy via both s.c. and i.n. routes. The adjuvanticity of nontoxic CpG OND as i.n. vaccine adjuvant was evaluated. The widespread expression of Em-TSP3 in all the developmental stages of E. multilocularis, and the strong local and systemic immune responses evoked by i.n. administration of rEm-TSP3 with CpG OND adjuvant suggest that this study might open the way for developing efficient, nontoxic human mucosal vaccines against AE

Systematic Review of Potential Health Risks Posed by Pharmaceutical, Occupational and Consumer Exposures to Metallic and Nanoscale Aluminum, Aluminum Oxides, Aluminum Hydroxide and Its Soluble Salts

Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by Krewski et al. (2007). Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of “total Al”assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold. The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al+ 3 to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)+ 2 and Al(H2O)6 + 3] that after complexation with O2•−, generate Al superoxides [Al(O2•)](H2O5)]+ 2. Semireduced AlO2• radicals deplete mitochondrial Fe and promote generation of H2O2, O2 • − and OH•. Thus, it is the Al+ 3-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates. Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimer\u27s disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants. The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances

Progress in understanding adjuvant immunotoxicity mechanisms.

Over the last twenty years research has provided an important insight into the mechanisms responsible for the immunotoxicity of both local and systemic adverse reactions following the use of immunostimulating drugs and adjuvants. In this article we provide an update of the present knowledge relating to the various parameters and reactants of the immune system at the cellular as well as molecular level that are believed to play a key role in reactogenicity. We discuss evidence obtained from observations in vitro, in vivo in animal models and from clinical applications, including adjuvants used in large scale vaccination today. The data discussed are mainly taken from animal models following hyperstimulation of the immune system; either by the use of very powerful adjuvants, like Freund's that are too toxic for use in practical vaccination, by deliberate high dose application of adjuvants or by the in vivo application of cytokines. Although such hyperstimulating regimens are unlikely to find their way into practical vaccination of humans, this information is of great value as it may facilitate the understanding of the toxicity mechanisms, aid the design of standardised models for the assessment of adjuvant safety and the possible application of new adjuvants in vaccines for humans

Sporothrix schenckii complex biology: environment and fungal pathogenicity

Sporothrix schenckii is a complex of various species of fungus found in soils, plants, decaying vegetables and other outdoor environments. It is the aetiological agent of sporotrichosis in humans and several animals. Humans and animals can acquire the disease through traumatic inoculation of the fungus into subcutaneous tissue. Despite the importance of sporotrichosis, it being currently regarded as an emergent disease in several countries, the factors driving its increasing medical importance are still largely unknown. There have only been a few studies addressing the influence of the environment on the virulence of these pathogens. However, recent studies have demonstrated that adverse conditions in its natural habitats can trigger the expression of different virulence factors that confer survival advantages both in animal hosts and in the environment. in this review, we provide updates on the important advances in the understanding of the biology of Spor. schenckii and the modification of its virulence linked to demonstrated or putative environmental factors.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Bioscience and Biotechnology Applied to Pharmacy Pos-graduate Program from Pharmaceutical Sciences Faculty, UNESP, Araraquara, SP, BrazilOriente Univ, Fac Chem Engn, Santiago de Cuba, CubaUniv Estadual Paulista, Fac Pharmaceut Sci, UNESP, BR-14801902 Araraquara, SP, BrazilMed Sci Univ, Toxicol & Biomed Ctr TOXIMED, Immunotoxicol Lab, Santiago de Cuba 90400, CubaUniversidade Federal de São Paulo, São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilCAPES: 07610130Web of Scienc

Human prophylactic vaccine adjuvants and their determinant role in new vaccine formulations

Adjuvants have been considered for a long time to be an accessory and empirical component of vaccine formulations. However, accumulating evidence of their crucial role in initiating and directing the immune response has increased our awareness of the importance of adjuvant research in the past decade. Nevertheless, the importance of adjuvants still is not fully realized by many researchers working in the vaccine field, who are involved mostly in the search for better target antigens. The choice of a proper adjuvant can be determinant for obtaining the best results for a given vaccine candidate, but it is restricted due to intellectual property and know-how issues. Consequently, in most cases the selected adjuvant continues to be the aluminum salt, which has a record of safety, but predominantly constitutes a delivery system (DS). Ideally, new strategies should combine immune potentiators (IP) and DS by mixing both compounds or by obtaining structures that contain both IP and DS. In addition, the term immune polarizer has been introduced as an essential concept in the vaccine design strategies. Here, we review the theme, with emphasis on the discussion of the few licensed new adjuvants, the need for safe mucosal adjuvants and the adjuvant/immunopotentiating activity of conjugation. A summary of toxicology and regulatory issues will also be discussed, and the Finlay Adjuvant Platform is briefly summarized