Current Pharmaceutical Biotechnology - Volume 14, Issue 10, 2013

Production of long-lived, high affinity humoral immunity is an essential characteristic of successful vaccination and requires cognate interactions between T and B cells in germinal centers. Within germinal centers, specialized T follicular helper cells assist B cells and regulate the antibody response by mediating the differentiation of B cells into memory or plasma cells after exposure to T cell-dependent antigens. It is now appreciated that local immune responses are also essential for protection against infectious diseases that gain entry to the host by the mucosal route; therefore, targeting the mucosal compartments is the optimum strategy to induce protective immunity. However, because the gastrointestinal mucosae are exposed to large amounts of environmental and dietary antigens on a daily basis, immune regulatory mechanisms exist to favor tolerance and discourage autoimmunity at these sites. Thus, mucosal vaccination strategies must ensure that the immunogen is efficiently taken up by the antigen presenting cells, and that the vaccine is capable of activating humoral and cellular immunity, while avoiding the induction of tolerance. Despite significant progress in mucosal vaccination, this potent platform for immunotherapy and disease prevention must be further explored and refined. Here we discuss recent progress in the understanding of the role of different phenotypes of B cells in the development of an efficacious mucosal vaccine against infectious disease.

The risk of plague as a bioweapon has prompted increasing research efforts to develop plague vaccines due to its extreme virulence and the ease of its transmission. Subunit vaccines that contain F1 and LcrV antigens of Y. pestis have been tested for safety and immunogenicity, but doubts have been raised about whether subunit vaccines that engender antibody responses will protect against pneumonic plague, which requires both humeral and cellular immune responses for protection. The live, attenuated vaccine EV76, a pgm locus deficient Y. pestis strain, has been used for a long time in the Former Soviet Union and some Asian countries, but is not commercially available in the US and Europe due to safety concerns. However, the live attenuated Y. pestis vaccines are still considered to be the most effective way to prevent plague. In this review, we present our opinions about rationally creating live, safe and immunogenic Y. pestis vaccines with potential use for human based on established researches.

Brucella spp. are facultative intracellular bacteria that cause brucellosis, which is a globally occurring zoonotic disease that is characterized by abortion in domestic animals and undulant fever, arthritis, endocarditis, and meningitis in humans. There are currently no licensed vaccines against brucellosis for human use, and only a few licensed live Brucella vaccines are available for use in animals. However, the available animal vaccines may cause abortion and are associated with lower protection rates in animals and higher virulence in humans. Much research has been performed recently to develop novel Brucella vaccines for the prevention and control of animal brucellosis. This article discusses the approaches and strategies for novel live attenuated vaccine development.

Acinetobacter baumannii has become an important cause of human infections, most notably in the hospital setting. In addition, the global dissemination of multidrug resistant strains has complicated effective antibiotic therapy of infections produced by this pathogen, necessitating the development of novel treatment and prevention strategies. Active and passive immunization approaches have begun to be explored in experimental animal models as potential alternative therapies for A. baumannii. In the present review, we discuss the advantages and disadvantages of each therapeutic strategy with respect to A. baumannii infections, and summarize the recent studies that have explored these approaches. The single antigen candidates that have been tested include, the outer membrane protein OmpA, the membrane transporter Ata, the biofilm-associated protein Bap, the K1 capsular polysaccharide and the membrane associated polysaccharide poly-N-acetyl-β -(1-6)-glucosamine. Strategies employing multicomponent antigens include inactivated whole cells, outer membrane complexes and outer membrane vesicles. The strengths and limitations of each approach are discussed and the challenges that remain to be addressed for successful A. baumannii vaccine development are highlighted.

Shigella was first discovered in 1897 and is a major causative agent of dysenteric diarrhea. The number of affected patients has decreased globally because of improved sanitary conditions; however, Shigella still causes serious problems in many subjects, including young children and the elderly, especially in developing countries. Although antibiotics may be effective, a vaccine would be the most powerful solution to combat shigellosis because of the emergence of drug-resistant strains. However, the development of a vaccine is hampered by several problems. First, there is no suitable animal model that can replace human-based studies for the investigation of the in vivo mechanisms of Shigella vaccines. Mouse, guinea pig, rat, rabbit, and nonhuman primates could be used as models for shigellosis, but they do not represent human shigellosis and each has its own weaknesses. However, a recent murine model based on peritoneal infection with virulent S. flexneri 2a is promising. Moreover, although the inflammatory responses and mechanisms such as pathogenassociated molecular patterns and danger-associated molecular patterns have been studied, the pathology and immunology of Shigella are still not clearly defined. Despite these obstacles, many vaccine candidates have been developed, including live attenuated, killed whole cells, conjugated, and subunit vaccines. The development of Shigella vaccines also demands considerations of the cost, routes of administration, ease of storage (stability), cross-reactivity, safety, and immunogenicity. The main aim of this review is to provide a detailed introduction to the many promising vaccine candidates and animal models currently available, including the newly developed mouse model.

Clostridium perfringens alpha-toxin is thought to be an important agent in gas gangrene, which is a lifethreatening infection with fever, pain, edema, myonecrosis, and gas production. The toxin (370 residues) is composed of an N-terminal domain (1-250 residues, N-domain) in which the catalytic site is found and a C-terminal domain (251-370 residues, C-domain) responsible for binding to membranes. During the past decade, recombinant DNA technology has been employed to develop second-generation vaccines, including site-directed mutants and the C-domain of the toxin, to prevent gas gangrene. These immunities have led to protection against the lethal effects of wild-type C. perfringens in mice. C-domain vaccines are capable of protecting against heterologous clostridia causing clostridial myonecrosis. This article summarizes the current knowledge on vaccines against alpha-toxin.

Nucleic acid drugs are promising new therapeutics for the treatment of various diseases including genetic diseases, viral diseases, and cancer. However, their poor intracellular bioavailability and rapid degradation hinder their development as drugs. Therefore, the main challenge is to develop an efficient delivery system. Calcium phosphate has been widely used to transfect cultured cells for 40 years, due to its safety, simply of production and noticeable efficacy of transfection. Unfortunately, calcium phosphate particles show poor colloidal stability because of uncontrolled growth, which impedes their practical use. Recently, investigators have designed a variety of biodegradable calcium phosphate nanocarriers and achieved efficient gene delivery both in vitro and in vivo with low toxicity. In this review, we focus on the current research activity in the development of calcium phosphate nanoparticlss for gene delivery. Calcium phosphate nanoparticles are mainly classified into lipid coated and polymer coated ones for discussion. In addition, cellular uptake and intracellular trafficking of calcium phosphate nanoparticles are also mentioned.

Advanced drug delivery formulations are presently recognized as promising tools for overcoming the adverse physicochemical properties of conventional drug molecules, such as poor water solubility, which often leads to poor drug bioavailability. Oral drug delivery is considered as the easiest and most convenient route of drug administration. However, via the current trends utilizing combinatorial chemistry and high throughput screening in drug development, new drug molecules are moving towards lipophilic and poorly water-soluble large molecules, and the oral delivery route is becoming increasingly challenging. In this context, formulation of poorly soluble and/or permeable drugs using mesoporous materials and nanocrystals technology have proven to be highly successful due to the greater surface/volume ratio of these systems, resulting in improvements in dissolution and bioavailability, as well as enhanced drug permeability. This review addresses the issues of poorly water-soluble drugs with a major focus on recent developments in the application of the mesoporous materials (e.g., porous silicon and silica) and nanocrystals in drug delivery applications. In addition, we present several recent examples of the significant potential of these materials for the pharmaceutical field.