Influenza virosomes as an efficient system for adjuvanted vaccine delivery

Immunopotentiating reconstituted influenza virosomes possess several characteristics defining them as vaccine adjuvants. Virosomes have been shown to provide vaccine components with protection from extracellular degradation; a regular, repetitive antigen structure aiding presentation to B lymphocytes and fully functional, fusion-active, influenza haemagglutinin envelope proteins that enables receptor-mediated uptake and intracellular processing of the antigen. In addition, virosomes, as vaccine delivery systems, have been shown to be safe and not to engender any antibodies against the phospholipid components. Through the use of virosomes as a delivery vehicle, a number of vaccines have been developed. In humans, virosome-based vaccines containing inactivated hepatitis A and influenza antigens have been found to be efficacious and well-tolerated and have been on the market for several years. Hepatitis B, nucleic acids, cytotoxic drugs, and tetanus and diphtheria toxoids have also been incorporated into virosomes. Further investigations are ongoing in order to define the full potential of virosomes in both prophylactic and immunotherapeutic applications.     

Influenza virosomes as an efficient system for adjuvanted vaccine delivery

Immunopotentiating reconstituted influenza virosomes possess several characteristics defining them as vaccine adjuvants. Virosomes have been shown to provide vaccine components with protection from extracellular degradation; a regular, repetitive antigen structure aiding presentation to B lymphocytes and fully functional, fusion-active, influenza haemagglutinin envelope proteins that enables receptor-mediated uptake and intracellular processing of the antigen. In addition, virosomes, as vaccine delivery systems, have been shown to be safe and not to engender any antibodies against the phospholipid components. Through the use of virosomes as a delivery vehicle, a number of vaccines have been developed. In humans, virosome-based vaccines containing inactivated hepatitis A and influenza antigens have been found to be efficacious and well-tolerated and have been on the market for several years. Hepatitis B, nucleic acids, cytotoxic drugs, and tetanus and diphtheria toxoids have also been incorporated into virosomes. Further investigations are ongoing in order to define the full potential of virosomes in both prophylactic and immunotherapeutic applications.     

Anthrax prevention and treatment: utility of therapy combining antibiotic plus vaccine

The intentional release of anthrax spores in 2001 confirmed this pathogen's ability to cause widespread panic, morbidity and mortality. While individuals exposed to anthrax can be successfully treated with antibiotics, pre-exposure vaccination can reduce susceptibility to infection-induced illness. Concern over the safety and immunogenicity of the licensed US vaccine (Anthrax Vaccine Adsorbed (AVA)) has fueled research into alternatives. Second-generation anthrax vaccines based on purified recombinant protective antigen (rPA) have entered clinical trials. These rPA vaccines induce neutralizing antibodies that prevent illness, but the magnitude and duration of the resultant protective response is modest. Efforts are underway to bolster the immunogenicity of rPA by combining it with adjuvants and other immunostimulatory agents. Third generation vaccines are under development that utilize a wide variety of immunization platforms, antigens, adjuvants, delivery methods and routes of delivery to optimize the induction of a protective immunity. For the foreseeable future, vaccination will rely on first and second generation vaccines co-administered with immune adjuvants. Optimal post-exposure treatment of immunologically naive individuals should include a combination of vaccine plus antibiotic therapy.     

Recent advances in mucosal vaccine development.

Proper stimulation of the mucosal immune system is critical for the effective protection of mucosal surfaces against colonization and invasion of infectious agents. This requires administration of vaccine antigens directly to various mucosal sites. Due to the low absorption efficiency of mucosally delivered vaccines, however, almost all of the currently marketed vaccines are administered parentally. In addition, sub-optimal immune responses are frequently induced by mucosal immunization and the use of mucosal adjuvants is commonly required. As a result, development of successful mucosal vaccines depends largely on the improvement of mucosal antigen delivery and on the discovery of new and effective mucosal adjuvants. In this review, recent advances in both areas are briefly discussed.     

Poly-D,L-lactide-co-poly(ethylene glycol) microspheres as potential vaccine delivery systems.

Adjuvants aimed at increasing the immunogenicity of recombinant antigens remain a focus in vaccine development. Worldwide, there is currently considerable care for the development of biodegradable microspheres as controlled release of vaccines, since the major disadvantage of several currently available vaccines is the need for repeated administration. Microspheres prepared from the biodegradable and biocompatible polymers, the polylactide (PLA) or polylactide-co-glycolide (PLGA), have been shown to be effective adjuvants for a number of antigens. This review mainly focuses on polylactide-co-poly(ethylene glycol) (PELA) microspheres adjuvant as vaccine delivery systems by summarizing our and other research groups' investigation on properties of the microspheres formulation encapsulating several kinds of antigens. The results indicate that compared with the commonly used PLA and PLGA, PELA showed several potentials in vaccine delivery systems, which may be due to the block copolymer have its capability to provide a biomaterial having a broad range of amphiphilic structure. PELA microspheres can control the rate of release of entrapped antigens and therefore, offer potential for the development of single-dose vaccines. The PELA microspheres have shown great potential as a next generation adjuvant to replace or complement existing aluminum salts for vaccine potential. The review mainly aims to promote the investigation of PELA microspheres adjuvant for antigens for worldwide researcher.     

Enhancement of vaccine potency through improved delivery

The need for more potent, safe and well-characterised vaccines has necessitated the discovery and development of new vaccine technologies. These include adjuvants to target the innate immune system to provide a stimulus that potentiates the development of an antigen-specific immune response, and delivery systems to ensure that the antigen and adjuvant are localised to the appropriate immune compartments. Several such technologies are being tested in human clinical trials and a few have been licensed for limited use in human vaccines. This review will highlight some of the promising technologies that may have an impact on how vaccines are administered.     

Developing effective delivery systems for Chlamydia vaccines

Members of the genus Chlamydia cause a plethora of ocular, genital and respiratory diseases, with severe complications, such as blinding trachoma, pelvic inflammatory disease, ectopic pregnancy and tubal factor infertility, interstitial pneumonia, and chronic diseases that may include atherosclerosis, multiple sclerosis, adult-onset asthma and Alzheimer's disease. The current medical opinion is that an effective prophylactic vaccine would constitute the best approach to protect the human population from the most severe consequences of these infections. There are three essential and mutually inclusive areas of challenge confronting researchers developing Chlamydia vaccines. These are to define the elements of protective immunity and the basis of vaccine evaluation, the judicious selection of an immunogenic and safe antigen(s) to form the basis of a subunit vaccine, and to develop effective delivery systems that boost the immune response to achieve long-lasting protective immunity. The development of delivery vehicles and adjuvants to boost protective long-term immunity against chlamydiae currently poses the greatest challenge in vaccine research. However, enormous progress is being made in the construction of novel delivery systems, such as DNA and plasmid expression systems, viral vectors, and living and non-living bacterial delivery systems, and the use of chemical adjuvants. In addition, there is increasing effort being made in designing delivery strategies involving specific immunomodulatory procedures that modify the cytokine and chemokine environment, upregulate co-stimulatory molecules and target vaccines to specific mucosal sites. These efforts will likely culminate in an efficacious chlamydial vaccine in the near future.     

Mannose receptor-targeted vaccines

Targeting antigens to endocytic receptors on professional antigen-presenting cells (APCs) represents an attractive strategy to enhance the efficacy of vaccines. Such APC-targeted vaccines have an exceptional ability to guide exogenous protein antigens into vesicles that efficiently process the antigen for major histocompatibility complex class I and class II presentation. Efficient targeting not only requires high specificity for the receptor that is abundantly expressed on the surface of APCs, but also the ability to be rapidly internalised and loaded into compartments that contain elements of the antigen-processing machinery. The mannose receptor (MR) and related C-type lectin receptors are particularly designed to sample antigens (self and non-self), much like pattern recognition receptors, to integrate the innate with adaptive immune responses. In fact, a variety of approaches involving delivery of antigens to the MR have demonstrated effective induction of potent cellular and humoral immune responses. Yet, although several lines of evidence in diverse experimental systems attest to the efficacy of targeted vaccine strategies, it is becoming increasingly clear that additional signals, such as those afforded by adjuvants, may be critical to elicit sustained immunity. Therefore, MR-targeted vaccines are likely to be most efficacious in vivo when combined with agents that elicit complementary activation signals. Certainly, a better understanding of the mechanism associated with the induction of immune responses as a result of targeting antigens to the MR, will be important in exploiting MR-targeted vaccines not only for mounting immune defenses against cancer and infectious disease, but also for specific induction of tolerance in the treatment of autoimmune disease.     

Mannose receptor-targeted vaccines

Targeting antigens to endocytic receptors on professional antigen-presenting cells (APCs) represents an attractive strategy to enhance the efficacy of vaccines. Such APC-targeted vaccines have an exceptional ability to guide exogenous protein antigens into vesicles that efficiently process the antigen for major histocompatibility complex class I and class II presentation. Efficient targeting not only requires high specificity for the receptor that is abundantly expressed on the surface of APCs, but also the ability to be rapidly internalised and loaded into compartments that contain elements of the antigen-processing machinery. The mannose receptor (MR) and related C-type lectin receptors are particularly designed to sample antigens (self and non-self), much like pattern recognition receptors, to integrate the innate with adaptive immune responses. In fact, a variety of approaches involving delivery of antigens to the MR have demonstrated effective induction of potent cellular and humoral immune responses. Yet, although several lines of evidence in diverse experimental systems attest to the efficacy of targeted vaccine strategies, it is becoming increasingly clear that additional signals, such as those afforded by adjuvants, may be critical to elicit sustained immunity. Therefore, MR-targeted vaccines are likely to be most efficacious in vivo when combined with agents that elicit complementary activation signals. Certainly, a better understanding of the mechanism associated with the induction of immune responses as a result of targeting antigens to the MR, will be important in exploiting MR-targeted vaccines not only for mounting immune defenses against cancer and infectious disease, but also for specific induction of tolerance in the treatment of autoimmune disease.     

Blinatumomab: enlisting serial killer T-cells in the war against hematologic malignancies

The skin is an attractive route for delivery of vaccines because it is accessible and contains immunocompetent cells. This opens up the possibility that, in the future, vaccines could be administered in a simple, safe and practical way without requiring the use of needles and syringes. This review focuses on the methods developed to deliver vaccines via the intact skin. Candidate vaccine antigens can be delivered topically using particulate delivery systems and patch formulations containing the antigen with an ADP-ribosylating exotoxin as an adjuvant. The duration and type of elicited immune responses depend on the antigen, the adjuvant and the method of delivery. Already, the first clinical trial of transcutaneous delivery of vaccines has demonstrated the proof of the principle. However, despite these successes, there are several challenges ahead to be addressed before vaccines administered with a patch will be available over the counter.     

Antigens onto bare skin: a 'painless' paradigm shift in vaccine delivery

The skin is an attractive route for delivery of vaccines because it is accessible and contains immunocompetent cells. This opens up the possibility that, in the future, vaccines could be administered in a simple, safe and practical way without requiring the use of needles and syringes. This review focuses on the methods developed to deliver vaccines via the intact skin. Candidate vaccine antigens can be delivered topically using particulate delivery systems and patch formulations containing the antigen with an ADP-ribosylating exotoxin as an adjuvant. The duration and type of elicited immune responses depend on the antigen, the adjuvant and the method of delivery. Already, the first clinical trial of transcutaneous delivery of vaccines has demonstrated the proof of the principle. However, despite these successes, there are several challenges ahead to be addressed before vaccines administered with a patch will be available over the counter.     

Coadsorption of HIV-1 p24 and gp120 proteins to surfactant-free anionic PLA nanoparticles preserves antigenicity and immunogenicity.

Biodegradable micro- or nanoparticles with surface adsorbed antigens represent a promising method for in vivo delivery of vaccines. Most vaccines, licensed or under development, are based on combined delivery of multiple antigens. Thus, we investigated the feasibility of combining two vaccine antigens, HIV-1 p24 and gp120 proteins, on the surface of surfactant-free anionic PLA nanoparticles obtained by an improved solvent diffusion method. The analysis of adsorption isotherms has shown that both proteins had similar and high affinities for the nanoparticles. Coadsorption of p24 and gp120 onto the same PLA particle was evidenced by sandwich ELISA, using antibodies directed against one protein for particle capture and the other one for detection. To assess structural integrity, the antigenicity of free and PLA-adsorbed antigens was compared by competition ELISA, using a set of 6 anti-p24 and 7 anti-gp120 antibodies, as well as soluble CD4. The antigenicity of proteins on the nanoparticle surface was well preserved, adsorbed either individually or in combination. Furthermore, both antigens maintained their immunogenicity, since high antibody titres (10(6) for p24 and 10(5) for gp120) were elicited in mice with monovalent and divalent PLA formulations. Taken together our results show that development of multivalent vaccines based on anionic PLA nanoparticles is possible. Moreover, coadsorption of a ligand for cell-specific targeting or of an immunostimulatory molecule will further extend the field of application of delivery systems based on charged micro- and nanoparticles.     

Vaccines of the future: from rational design to clinical development. 17-19 October 2001, Paris,France

The Institut Pasteur (France) sponsors and organises a series of Euroconferences on important topics in biology, medicine and environmental sciences which facilitate a large exchange of ideas between basic and applied scientists from the Institut Pasteur, other academic institutions, and pharmaceutical companies. This Euroconference focused on the most recent advances currently affecting the way vaccine development is approached. The identification of new target antigens for vaccination purposes is presently facilitated by the availability of genome sequences from a growing number of important pathogens and tumours. The identification of T-cell epitopes and the subsequent optimisation of these target sequences allows the design of vaccines which are significantly improved with respect to their capacity to stimulate cellular immunity. In parallel, various antigen formulations, adjuvants and delivery systems are being developed and tested with the aim of eliciting broad immune responses in humans. These new orientations capitalise on recent major advances in the understanding of the use of therapeutic vaccines and expands on their use from being solely profilactic. Specific issues related to the development of therapeutic vaccines directed against diseases such as cancer or chronic infectious disease were presented.     

Vaccines of the Future: From Rational Design to Clinical Development

The Institut Pasteur (France) sponsors and organises a series of Euroconferences on important topics in biology, medicine and environmental sciences which facilitate a large exchange of ideas between basic and applied scientists from the Institut Pasteur, other academic institutions, and pharmaceutical companies. This Euroconference focused on the most recent advances currently affecting the way vaccine development is approached. The identification of new target antigens for vaccination purposes is presently facilitated by the availability of genome sequences from a growing number of important pathogens and tumours. The identification of T-cell epitopes and the subsequent optimisation of these target sequences allows the design of vaccines which are significantly improved with respect to their capacity to stimulate cellular immunity. In parallel, various antigen formulations, adjuvants and delivery systems are being developed and tested with the aim of eliciting broad immune responses in humans. These new orientations capitalise on recent major advances in the understanding of the use of therapeutic vaccines and expands on their use from being solely profilactic. Specific issues related to the development of therapeutic vaccines directed against diseases such as cancer or chronic infectious disease were presented.     

Viral vectors for gene transfer into antigen presenting cells

Crucial insights for vaccine development have come from examining how the immune system responds to antimicrobial vaccines, as well as to viral vectors employed for gene therapy. The effectiveness of a vaccine depends upon both the method of antigen delivery and the presentation of antigen to lymphocytes. Much focus has turned to delivering antigens to dendritic cells, to promote clinically beneficial T- and B-cell responses. Recombinant viral vectors represent a powerful vehicle to deliver genes encoding microbial- or tumor-derived antigens to generate clinically beneficial immunity. Dendritic cell-based and viral vector-based vaccines are currently being evaluated in clinical trials as a means of inducing antitumor immunity.     

DNA vaccines for non-infectious diseases: new treatments for tumour and allergy

The last decade of DNA vaccine research was characterised by a pioneer spirit and enormous enthusiasm, with a large number of publications demonstrating the usefulness of this approach. Unfortunately, DNA vaccines have not necessarily met the high clinical expectations and a number of complications need to be overcome. In the case of cancer and allergy, the requirements for achieving the objectives are very different. Vaccines against allergies need to suppress or alter an unwanted immune response, while a cancer DNA vaccine has to overcome tolerance and/or immune suppression and initiate a powerful immune response. This review addresses currently used general optimisation strategies for DNA vaccines such as modification of immunisation regimens, improving the delivery systems and using molecular adjuvants. In addition, cancer-specific approaches, such as the stimulation of innate and adaptive immunity with replicase-based DNA vaccines, and targeting non-tumour-associated antigens (TAAs) are discussed. Specifically for the optimisation of DNA vaccination against allergies, procedures such as allergen gene recoding, T helper (Th)1 modulation, and the creation of safe DNA vaccines by gene fragmentation, ubiquitination or using artificial hypoallergens are being analysed. These strategies, individually or in combination, hold the potential of making DNA vaccines useful for application in the clinic.     

DNA vaccines for non-infectious diseases: new treatments for tumour and allergy

The last decade of DNA vaccine research was characterised by a pioneer spirit and enormous enthusiasm, with a large number of publications demonstrating the usefulness of this approach. Unfortunately, DNA vaccines have not necessarily met the high clinical expectations and a number of complications need to be overcome. In the case of cancer and allergy, the requirements for achieving the objectives are very different. Vaccines against allergies need to suppress or alter an unwanted immune response, while a cancer DNA vaccine has to overcome tolerance and/or immune suppression and initiate a powerful immune response. This review addresses currently used general optimisation strategies for DNA vaccines such as modification of immunisation regimens, improving the delivery systems and using molecular adjuvants. In addition, cancer-specific approaches, such as the stimulation of innate and adaptive immunity with replicase-based DNA vaccines, and targeting non-tumour-associated antigens (TAAs) are discussed. Specifically for the optimisation of DNA vaccination against allergies, procedures such as allergen gene recoding, T helper (Th)1 modulation, and the creation of safe DNA vaccines by gene fragmentation, ubiquitination or using artificial hypoallergens are being analysed. These strategies, individually or in combination, hold the potential of making DNA vaccines useful for application in the clinic.     

Immunomodulatory properties of vitamins, flavonoids and plant oils and their potential as vaccine adjuvants and delivery systems

INTRODUCTION: During the past century, vaccinologists have attempted to mimic pathogens in their immune-enhancing capacity. This led to the development of life-saving vaccines based on live attenuated viruses, bacteria and toxoids. Hence, intense research in vaccine adjuvant discovery has focused on toll like receptors, mutant toxins and viral and bacterial vectors. Nutritive components such as vitamins and select polyphenols also possess immunomodulating properties without the potential toxic and adverse side effects of agents that mimic danger signals. AREAS COVERED: This review pertains to immunomodulatory properties of nutritive components, that is vitamins A, C, D, E, flavonoids and plant oils, as potential vaccine adjuvants and delivery systems, covering Pubmed publication searches from 1980 through 2011. EXPERT OPINION: This relatively unexplored field of the potential of nutritive components as vaccine adjuvants holds great promise to promote the development of effective and above all safe vaccines. Hence the future focus should be placed on enhancing their efficacy, mainly through novel approaches in designing structural derivatives, formulations, delivery systems and routes of administration. As safety has been the major issue in development of novel vaccines, this new approach will probably result in new discoveries in designing safe and effective vaccines.     

The potential of topical DNA vaccines adjuvanted by cytokines

To improve the efficacy of DNA immunization epidermal Langerhans cells are attractive targets to deliver antigen-encoding plasmid DNA. Topical vaccination with naked plasmid DNA has been shown to induce immune responses, and their potency might be improved by chemical and physical methods aimed to enhance the efficiency of plasmid DNA delivery into the skin. Cytokines have also been evaluated as adjuvants for DNA vaccines because they influence the host immune response. This review focuses on the action of several cytokines tested as molecular adjuvants for DNA vaccines and the combination of them with the DermaVir Patch vaccine. DermaVir vaccine, topically administered under a patch, consists of a plasmid DNA that is chemically formulated into a nanoparticle to support vaccine delivery into epidermal Langerhans cells and to induce antigen-specific memory T cells.     

The potential of topical DNA vaccines adjuvanted by cytokines

To improve the efficacy of DNA immunization epidermal Langerhans cells are attractive targets to deliver antigen-encoding plasmid DNA. Topical vaccination with naked plasmid DNA has been shown to induce immune responses, and their potency might be improved by chemical and physical methods aimed to enhance the efficiency of plasmid DNA delivery into the skin. Cytokines have also been evaluated as adjuvants for DNA vaccines because they influence the host immune response. This review focuses on the action of several cytokines tested as molecular adjuvants for DNA vaccines and the combination of them with the DermaVir Patch vaccine. DermaVir vaccine, topically administered under a patch, consists of a plasmid DNA that is chemically formulated into a nanoparticle to support vaccine delivery into epidermal Langerhans cells and to induce antigen-specific memory T cells.