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About this book

This book provides a compilation of the current developments in mucosal nanovaccines, which are an attractive approach to fight against infectious and non-communicable diseases. Since nanomaterials possess unique properties; many of them have a positive effect on vaccine efficacy when used as antigen carriers and have been applied in vaccinology with significant advances over the past years. This book addresses the methodologies for mucosal nanovaccines synthesis; based on the following nanomaterials: gold, PLGA, silica, and chitosan nanoparticles; as well as nanogels, carbon nanotubes, liposomes, and Virus-like particles. A description of the immunogenic properties of the mucosal nanovaccines is presented, highlighting the improvements achieved with this approach when compared to conventional formulations. Mucosal vaccines constitute the most practical immunization approach since they are easy to administer (promoting patient´s comfort and increasing compliance), allow triggering relevant immune responses at both the site of administration and distant compartments, and thus may protect the main entry portal for pathogens (oral, nasal, and genital mucosae). In this context, the potential of nanovaccines to result in new mucosal formulations in the benefit of global health is analyzed.

Covers the synthesis and functionalization of nanomaterials for the development of nanovaccines;Discusses the underlying mechanisms involved in the induction of immune responses through mucosal compartments and the advantages of nanomaterials in the formulation of nanovaccines;Transmits the state of the art for the development of mucosal nanovaccines;Provides routes for the design and evaluation of mucosal nanovaccines;Presents key perspectives for the field of mucosal vaccine development.

Table of Contents

Frontmatter

Chapter 1. Nanovaccines and the History of Vaccinology

Abstract
Vaccines have been historically linked to prominent benefits for global health. The concept of vaccination was first recorded in Asia and subsequently consolidated by the better documented studies by Jenner and Pasteur during the eighteenth and nineteenth centuries. Later, mainly in the twentieth century, the design and production of vaccines were expanded to massively apply vaccines in the benefit of human and animal health, being prominently based on whole killed or attenuated bacteria or viruses. Next generation (subunit) vaccines based on few antigens and possibly some adjuvants have been proposed as the ideal vaccination approach since the risks (strain reversion to pathogenic forms, high reactogenicity, and expensive manufacture, among others) associated with the use of whole pathogens are avoided. The development of toxoids and the use of polysaccharide conjugates added an important piece to the vaccinology portfolio, leading to the first subunit vaccines; however, the application of these approaches in the clinic is only beginning and myriad efforts are ongoing to expand their use. Nanosized vaccines are a promise in this field since nanomaterials offer singular properties that may enhance the efficacy of subunit vaccines, thus resulting in innovative vaccines. Genetic engineering has made possible to introduce nanosized vaccines (based on virus-like particles) in the market, which target the hepatitis B virus and human papillomavirus and are produced in well-established platforms, namely recombinant yeasts and insect cells. Innovative recombinant platforms offering low cost and other advantages are under development; these include plant cells and algae, among others. Besides protein-based nanoparticles, the nanotechnology field offers a wide range of nanomaterials to be applied for vaccine nanotechnology that include metallic and polymeric nanoparticles, nanogels, carbon nanomaterials, and liposomes. A substantial progress in the vaccinology field is envisioned as a consequence of the application of such nanomaterials in the vaccinology field, especially on the development of mucosal vaccines.
Sergio Rosales-Mendoza, Omar González-Ortega

Chapter 2. The Mucosal Immune System: An Outlook for Nanovaccines Development

Abstract
In mammals, the mucosal immune system is a complex network of cells, tissues, and soluble molecules that orchestrate the defense against pathogens or malignant cells; this immune system substantially differs from the one acting at the central level. Nanovaccines have emerged as a promising approach for the development of innovative vaccines, having enhanced immunogenicity and avoiding the use of attenuated/inactivated pathogens. This chapter transmits the essential knowledge on the mucosal immune system required to understand the design and evaluation of nanovaccines, with special emphasis in the function of the nose-associated lymphoid tissue (NALT) and the gut-associated lymphoid tissue (GALT) since the nasal and oral routes are the most explored in nanovaccine development. Antigens administered by mucosal routes are essentially sampled by M-cells, epithelial cells, and dendritic cells; once the antigen reaches the submucosa antigen presenting cells (APCs) it establishes an immune synapse with lymphocytes, which triggers their differentiation and expansion in the lymph nodes. Among the lymphocytes subsets involved in the adaptive immunity, T helper cells are key since they support the response of T and B lymphocytes by producing Th1 and Th2 cytokine profiles, respectively, acquire a Th17 phenotype that contributes to IgA responses, or can rather have suppressive roles by acquiring the regulatory T-cell phenotype (Treg) that is of relevance in therapies against autoimmune or inflammatory conditions. In contrast, T cytotoxic lymphocytes are specialized in killing virus-infected or malignant cells, whereas B mucosal lymphocytes are specialized in antibody production (mainly secretory IgA), which is a key effector mechanism to protect against infectious agents in the mucosa. The use of adjuvants is critical to trigger the desired immune response when mucosal routes are used. Although GALT and NALT share most of the cell types, they differ in the organization and induced immune responses in different mucosal compartments. For instance, intranasal immunization efficiently induces humoral responses in the airways and genital organs, whereas oral immunization induces mainly systemic and intestinal humoral responses, which is explained by the traffic of lymphocytes controlled by homing molecules. The knowledge regarding function and structure of NALT is still limited with respect to GALT. The current knowledge on the mucosal immune system has aided in the development of several nanovaccine candidates and opportunities for designing optimal nanovaccines will be expanded as long as the knowledge on this complex immune system increases in the following years.
Sergio Rosales-Mendoza, Omar González-Ortega

Chapter 3. Gold-Based Mucosal Nanovaccines

Abstract
The development of new, efficacious subunit vaccines depends on the availability of adjuvants and delivery vehicles that favor proper antigen delivery and immunostimulation, able to provoke robust adaptive immune responses. Moreover, vaccines administered by non-parenteral routes are highly desirable due to costs reduction and high patient compliance. Gold nanoparticles (AuNPs) are biocompatible materials that can be conjugated with antigens, rendering attractive vaccine candidates. In this chapter, the state of the art on the development of AuNPs-based vaccines is transmitted along with a description of the synthesis and bioconjugation approaches applied in this technology. Promising AuNPs-based vaccine candidates developed thus far comprise vaccines against influenza, glanders, and tetanus; these vaccine candidates have been characterized at the preclinical level with promising findings in terms of protection against the target disease in animal models. Key perspectives for this field are also identified.
Sergio Rosales-Mendoza, Omar González-Ortega

Chapter 4. PLGA-Based Mucosal Nanovaccines

Abstract
Poly(D,L-lactic-co-glycolic acid) (PLGA or PLG) is a linear copolymer composed of lactic and glycolic acids with biodegradability and biocompatibility properties recognized by the FDA. PLGA nanoparticles have been applied in vaccinology as antigen delivery vehicles capable of protecting antigens from degradation and being efficiently captured by antigen presenting cells. The current status on the development of PLGA-based nanovaccines is presented in this chapter and the key perspectives for this topic identified. Bacterial, viral, and allergic diseases have been targeted by using PLGA-based formulations. For most of the candidates enhanced humoral responses providing immunoprotection against experimental pathogen challenges has been achieved. Enhancement of cytotoxic lymphocyte responses has also been proven, generating relevant perspectives in the field of cancer immunotherapy. The promising findings from the evaluations of PLGA-based nanovaccines justifies the completion of preclinical evaluations for many candidates and, given the experience on the use of PLGA in the biomedical field, the beginning of clinical trials is anticipated in the short term. Therefore, among the currently available nanomaterials, PLGA nanoparticles are one of the most promising for the development of nanovaccines.
Sergio Rosales-Mendoza, Omar González-Ortega

Chapter 5. Silica-Based Mucosal Nanovaccines

Abstract
The use of nanocarriers to enhance the immunogenicity of subunit vaccines is acquiring relevance in the vaccinology field. Silica-based nanomaterials have attractive characteristics for this application since they are biodegradable and biocompatible, can be easily conjugated with antigens and adjuvants, and exert immunostimulatory effects. The latter effects derive from the facts that silica nanoparticles are efficiently taken up by antigen presenting cells and induce inflammatory responses, able to traffic to lymph nodes, and proper delivery vehicles of some adjuvants such as CpG oligonucleotides. Herein, the synthesis and functionalization approaches for silica nanoparticles are presented and current developments on new vaccines based on them are analyzed. The preclinical analysis of silica-based nanovaccines reveals promising findings in vaccination models against infectious diseases (bacterial and viral) affecting humans and animals. Perspectives for the field are identified, which essentially contemplate the need of performing clinical trials, completing toxicity assessment, expanding the application to non-communicable diseases, and starting the development of multiepitope vaccines.
Sergio Rosales-Mendoza, Omar González-Ortega

Chapter 6. Nanogels-Based Mucosal Vaccines

Abstract
Innovative vaccines are required to fight human and animal diseases. Improved immunogenicity, safety, easy administration, and low cost are among the innovations that are pursued in this field. Nanogels are materials with attractive features to meet these requirements; they consist of solid, jelly like materials produced by crosslinking of synthetic or natural polymers (or a combination of both) with a high water-holding capacity. Herein, the state of the art of nanogels-based vaccines is provided. Synthesis and functionalization methods for nanogels are described. Thus far, several groups have evaluated nanogels as vaccine delivery vehicles leading to promising data for nanovaccines against cancer, obesity, and infectious diseases. The most advanced candidates are nanovaccines against cancer, based on cholesteryl pullulan nanogels, that have been evaluated in clinical trials revealing proper immunogenicity and safety. The key perspectives for this topic include expanding the assessment of mucosal vaccines and implementing green syntheses approaches, which could lead to lower production cost and enhanced safety.
Sergio Rosales-Mendoza, Omar González-Ortega

Chapter 7. Carbon Nanotubes-Based Mucosal Vaccines

Abstract
The use of nanomaterials is acquiring great potential in vaccinology since they can render effective vaccines due to their singular properties; nanomaterials can serve as carriers that efficiently deliver the antigen to antigen presenting cells and favor the critical steps on the elicitation of adaptive immune responses. In this chapter, the implications of carbon nanotubes (CNTs) in the vaccinology field are analyzed. Thus far, nanotubes-based mucosal vaccines have been designed mainly to fight diseases in fish looking to reduce production losses in aquaculture. Surprisingly, the use of nanotubes to develop mucosal vaccines for mammalians remains essentially unexplored, with only some studies dealing with their use as immunostimulants in the lungs to enhance immunity against cancer and influenza. One concern on this topic is the toxicity reported for CNTs in several studies, although still under debate. Thus, an important gap exists in this regard since there is a lack of detailed toxicity studies under exposure schemes resembling vaccination dosage. Overall, the functionalized forms of CNTs have shown reduced toxicity and exerted effects in immune cells. The critical avenues to expand the development of CNTs-based vaccines are discussed and although this application is at a very early stage of investigation; CNTs are considered an important piece in the portfolio of nanomaterials for vaccine development.
Sergio Rosales-Mendoza, Omar González-Ortega

Chapter 8. Chitosan-Based Mucosal Nanovaccines

Abstract
The race for vaccine development has as priority the formulation of subunit vaccines capable of developing robust and safe immune responses, which will overcome the disadvantages of the vaccines formulated with whole pathogens, namely high reactogenicity and in some cases the risk to develop the disease to which the vaccine is supposed to protect against. Moreover, the development of efficacious vaccines against non-communicable diseases imposes the challenge of efficiently breaking the immune tolerance against self-antigens. Chitosan is an attractive polymer that has been employed to develop nanovaccines with promising findings in preclinical evaluations. In the present chapter, an overview of the nanovaccines based on chitosan nanoparticles targeting human and animal diseases is presented. Chitosan-based nanovaccines have shown promising efficacy in animal models of several diseases with many of them being highly immunogenic when administered by mucosal routes, which are the most attractive approach for massive and painless immunization. Clinical evaluation of some chitosan-based adjuvants adds potential to this field.
Sergio Rosales-Mendoza, Omar González-Ortega

Chapter 9. Liposome-Based Nanovaccines

Abstract
Liposomes are nanosized lipid particles that have become attractive vaccine delivery vehicles given their properties that include versatility for functionalization, controlled charge, high encapsulation capacity, high surface, and efficient cellular uptake. This chapter contains a description of the liposomes preparation techniques and their application to develop mucosal nanovaccines. The analysis of the current literature reveals that there are many attractive vaccine candidates based on this technology, although the majority have been evaluated in parenteral schemes. The mucosal formulations tested thus far are against parasitic, bacterial, and viral diseases. A cancer vaccine was also developed. The formulations have been assessed in test animals and administered intranasally, orally, sublingually, and by the airways. Immunogenicity assessment in preclinical studies supports the use of liposomes to enhance cellular and humoral responses. Therefore, liposomes are effective nanoparticles and the outstanding findings from the preclinical evaluation of many mucosal vaccine candidates indicate that there is a good prospect for the initiation of clinical trials in the coming years. The challenges for this field comprise expanding the assessment of mucosal formulations, achieving high stability in the formulation, and scale-up production.
Sergio Rosales-Mendoza, Omar González-Ortega

Chapter 10. Virus-Like Particles-Based Mucosal Nanovaccines

Abstract
Virus-like particles (VLPs) are protein complexes that resemble a virus and constitute highly immunogenic entities as they mimic the pathogen at an important degree. Among nanovaccines, those based on VLPs are the most successful thus far with some formulations already commercialized (e.g., those against hepatitis B and E viruses and human papillomavirus). This chapter highlights the advantages of VLPs-based vaccines, describing approaches for their design and transmittance of the state of the art for mucosal VLPs-based vaccines development. Several candidates have been produced in insect cells, plants, and E. coli and mammalian cells; they have been mainly evaluated in i.n. and oral immunization schemes. i.n. vaccines against the influenza virus and the Norwalk virus are the most advanced applications. For the latter, i.n. formulations are under clinical evaluation. Perspectives for the field comprise the expansion of the use of low-cost platforms such as plants and bacteria, the development of multiepitopic/multivalent vaccines, and computationally designed VLPs. Mucosal VLPs-based vaccines stand as a major promising approach in vaccinology and the initiation of more clinical trials is envisaged in a short time.
Sergio Rosales-Mendoza, Omar González-Ortega

Chapter 11. Perspectives for the Field of Nanovaccines

Abstract
Nanomaterials can be used as antigen delivery vehicles with immunostimulatory activity, leading to an improved immune response, which is of relevance in the development of new vaccines termed nanovaccines. These are a promise of modern vaccinology to address some of the challenges in the field that include safety and efficacy enhancement and costs reduction. The previous chapters of this book were focused on individual nanomaterials applied to mucosal vaccine development (namely gold, PLGA, silica, and chitosan nanoparticles; nanotubes, nanogels, liposomes, and virus-like particles). In this chapter, the remaining challenges and possible breakthroughs for this field are identified and discussed. Thus far, the most advanced nanovaccines are those based on VLPs, nanogels, liposomes, and PLGA nanoparticles, being the former approach the one resulting in human and animal vaccines available in the market. Some clinical trials have supported the safety and efficacy of other nanovaccines, such as those based on nanogels and liposomes. Overall, it is required to expand clinical trials and the development of mucosal formulations, as well as to assess novel vaccine designs, such as those comprising biosynthesized nanomaterials or targeting specific cells, and optimize nanomaterials properties to avoid the use of accessory adjuvants. Controversies on toxicity, regulatory issues, and the difficulties to progress into clinical trials and commercialization are discussed. Indeed, we might have effective, safe, convenient, and cheap vaccines through nanotechnology in the near future.
Sergio Rosales-Mendoza, Omar González-Ortega

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