Transcutaneous Subunit Vaccine Delivery

This comprehensive volume compiles the concepts essential for the understanding of the pharmaceutical science and technology associated with the delivery of subunit vaccines. Twenty-one chapters are divided into four main parts: (I) Background; (2) Delivery Systems for Subunit Vaccines; (3) Delivery Routes, Devices and Dosage Forms; and (4) Pharmaceutical Analysis and Quality Control of Vaccines. Part one provide a basic background with respect to immunology and general vaccine classification. In part two, it presents representative types of vaccine delivery systems individually with focus on the physicochemical properties of the systems and their significance for the immune response they stimulate. These delivery systems include aluminum adjuvants, emulsions, liposomes, bilosomes, cubosomes/hexosomes, ISCOMs, virus-like particles, polymeric nano- and microparticles, gels, implants and cell-based delivery systems. Following these chapters, part three addresses the challenges associated with vaccine delivery via specific routes of administration—in particular subcutaneous, intramuscular, oral, nasal, pulmonary, transdermal and vaginal administration. Furthermore, the specific administration routes are discussed in combination with device technologies relevant for the respective routes as well as dosage forms appropriate for the device technology. Finally, the fourth part concerns pharmaceutical analysis and quality control of subunit vaccines.

Immunization is a powerful approach for the prevention and control of infectious disease, however despite the successes of modem vaccine development, there remain several notable obstacles for the advancement of vaccine-mediated improvements in global healthcare. Many of the current limitations in vaccine availability and administration are the result of obligate needle-based delivery, which in addition to contributing to reduced speed, ease, and compliance in administration, has been shown to contribute to reduced overall safety due to needle re-use and needle-based injuries. Needle-based vaccine delivery to immunologically passive tissues such as muscle may limit efficacy, thus motivating the targeting of more inherently potent immune-competent sites. These inherent limitations of needle-based vaccination on global health have led to a strong impetus to develop needle-free vaccination strategies which have the potential to improve vaccine efficacy and availability, enhance the ease, speed, and safety of vaccine administration, and reduce vaccination associated costs world-wide. Here we present the design and preclinical testing of several parallel materials strategies for the noninvasive delivery of subunit vaccines to the skin. We have utilized laser ablative micro-molding of poly(dimethylsiloxane) to generate bio resorbable poly(lactide-co-glycolide) micro-structured skin patches bearing -100 micron-scale needles arrayed across their surface. Upon topical application, these 'microneedle arrays' are able to safely, and painlessly insert into the immune-competent epidermal skin layers to generate microscopic conduits through which otherwise impermeant vaccines and therapeutics are able to passage into the body. We have leveraged this approach in combination with layer-by-layer (LbL) directed assembly to generate vaccine-loaded conformal coatings on the surface of these microneedle arrays, which are then delivered into the skin through topical patch application. The construction of coatings containing antigen-expressing plasmid DNA (pDNA), together with immune-stimulatory RNA, and degradable cationic polymers provided tunable control over vaccine dosage, rapid and effective vaccine delivery in murine and primate skin models, and potent immunogenicity against a model HIV antigen in mice. In this case, DNA vaccine delivery was able to elicit strong functional CD8' T cell and humoral responses matching or exceeding the potency of in vivo electroporation, currently the most promising approach for clinical DNA delivery in humans. Further efforts have explored the use of LbL for encapsulation and delivery of soluble and particulate protein subunit vaccines, giving enhanced generation of diverse and potent humoral responses in mice. In other work, we have developed an approach enabling rapid delivery of micron-scale degradable polymer matrices or hydrogel depots using dissolvable composite microneedle structures for the delivery of vaccines with programmable kinetics. These efforts have demonstrated the potential of persistent vaccine release on tuning immune potency following non-invasive microneedle delivery, including induction of potent effector and memory CD8* T cell responses and more powerful and diverse antigen-specific humoral responses. Finally, we have developed an approach for simple loading and delivery of clinically advanced recombinant adenoviral vaccine vectors from sugar-glass coatings on bioresorbable microneedles. Formulation in microneedle coatings improved vaccine stability at room temperature and preclinical testing of these vaccine patches in mice and nonhuman primates demonstrated equivalent immunogenicity compared to parenteral injection, eliciting strong systemic and disseminated mucosal CD8' and CD4* T cell responses to a model HIV antigen. These cellular responses were correlated with a similarly potent systemic and mucosal humoral response, together suggesting the utility of this approach for non-invasive adenoviral immunization in a model close to humans. Together these results strongly demonstrate the potential of materials engineering strategies for the effective formulation, delivery, and release of recombinant vaccines by microneedle patches targeting the skin. In addition to the significant practical advantages enabled by microneedle delivery including improved safety, convenience, and storage, we have shown that advanced formulation strategies paired with controlled release are able to initiate humoral and cellular adaptive immunity more potently than possible through parenteral injection. Comprehensive tests in both mice and primates have suggested that these principles may be broadly applied to enhance various recombinant vaccination strategies potentially targeting numerous disease targets. Finally, initial tests performed in nonhuman primates have indicated the promise of engineered microneedle approaches for successful translation to humans. Overall, these findings provide a strong basis for the continued development of similar vaccination strategies for the comprehensive transformation of conventional vaccination enabling significant vaccine-mediated improvements in global health.

The authoritative reference on recent developments in vaccinology New technologies, including recombinant protein and DNA, have sparked phenomenal progress in vaccine development and delivery systems. This unique resource brings scientists up to date on recent advances and provides the information they need to select candidate adjuvants. With chapters written by leading experts in their fields, Vaccine Adjuvants and Delivery Systems: * Provides a comprehensive overview of the rapidly evolving field and developing formulation methods * Covers cutting-edge technologies and gives the current status of adjuvants in clinical trials and those still in the pre-clinical stage * Includes detailed information on specific vaccine adjuvants, including MF59, TLR4 agonists, new iscoms, cytokines, polyphosphazenes, and more * Provides a historical perspective on the development of vaccine adjuvants and discusses the mechanisms of adjuvant actions * Covers some novel adjuvants and delivery systems and the safety evaluation of adjuvants A great reference for researchers, scientists, and students in vaccinology, biotechnology, immunology, and molecular biology, this resource is also valuable for researchers and scientists in veterinary medicine who work to prevent diseases in animals.

Provides comprehensive coverage of microneedles for delivering and monitoring patient drugs and vaccines Microneedles are an incredibly active research area and have the potential to revolutionize the way many medicines and vaccines are delivered. This comprehensive research book covers the major aspects relating to the use of microneedle arrays in enhancing both transdermal and intradermal drug delivery and provides a sound background to the use of microneedle arrays in enhanced delivery applications. Beginning with a history of the field and the various methods employed to produce microneedles from different materials, Microneedles for Drug and Vaccine Delivery and Patient Monitoring discusses the penetration of the stratum corneum by microneedles and the importance of application method and force and microneedle geometry (height, shape, inter-needle spacing). Transdermal and intradermal delivery research using microneedles is comprehensively and critically reviewed, focusing on the outcomes of in vivo animal and human studies. The book describes the important topics of safety and patient acceptability studies carried out to date. It also covers in detail the growing area for microneedle use in the monitoring of interstitial fluid contents. Finally, it reviews translational and regulatory developments in the microneedles field and describes the work ongoing in industry. The only book currently available on microneedles Filled with tables, graphs, and black and white images (photographs, micrographs) Authored by four experts in pharmaceutics Microneedles for Drug and Vaccine Delivery and Patient Monitoring is an ideal source for researchers in industry and academia working on drug delivery and transdermal delivery in particular, as well as for advanced students in pharmacy and pharmaceutical sciences.

This comprehensive, authoritative treatise covers all aspects of mucosal vaccines including their development, mechanisms of action, molecular/cellular aspects, and practical applications. The contributing authors and editors of this one-of-a-kind book are very well known in their respective fields. Mucosal Vaccines is organized in a unique format in which basic, clinical, and practical aspects of the mucosal immune system for vaccine development are described and discussed. This project is endorsed by the Society for Mucosal Immunology. Provides the latest views on mucosal vaccines Applies basic principles to the development of new vaccines Links basic, clinical, and practical aspects of mucosal vaccines to different infectious diseases Unique and user-friendly organization

The skin is an ideal organ for the safe and convenient delivery of vaccines, small molecules, and other biologics. Members of the Irvine and Hammond groups have developed a polyelectrolyte multilayer thin film-coated microneedle platform that can achieve simultaneous DNA and nanoparticle delivery. This delivery platform has the advantage of direct delivery of DNA or polymer nanoparticles to immune-active cells at the interface between the dermis and epidermis, enhancing uptake of the delivered cargo by resident immune cells. Ideal for the delivery of DNA vaccines, this platform aims to bridge the gap in the lack of efficient delivery platforms hampering the effectiveness of DNA vaccines. The ability to co-deliver polymer nanoparticles can serve as a conduit for delivering immune stimulating adjuvants or other drugs for therapeutic applications. An overview of current vaccine and delivery system research is presented. Market factors for the commercialization of the polyelectrolyte multilayer thin film-coated microneedle delivery platform are considered along with the risk factors in bringing this invention to market. An assessment of the intellectual property surrounding the platform is performed and a preliminary market entry strategy is developed for minimizing the risks commercialization.