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► To date, mucosal vaccines are poorly efficient. ► Select antigens, adjuvant and design new mucosal routes of administration. ► Induce protective immunity at mucosal surfaces. ► Mucosal vaccine would make immunization procedures easier for mass administration. Mucosal surfaces are the major entrance for infectious pathogens and therefore mucosal immune responses serve as a first line of defence. Most current immunization procedures are obtained by parenteral injection and only few vaccines are administered by mucosal route, because of its low efficiency. However, targeting of mucosal compartments to induce protective immunity at both mucosal sites and systemic level represents a great challenge. Major efforts are made to develop new mucosal candidate vaccines by selecting appropriate antigens with high immunogenicity, designing new mucosal routes of administration and selecting immune-stimulatory adjuvant molecules. The aim of mucosal vaccines is to induce broad potent protective immunity by specific neutralizing antibodies at mucosal surfaces and by induction of cellular immunity. Moreover, an efficient mucosal vaccine would make immunization procedures easier and be better suited for mass administration. This review focuses on contemporary developments of mucosal vaccination approaches using different routes of administration.

Mucosal vaccines are designed to elicit both a strong systemic and mucosal immune response gaining importance as the next generation of vaccines to combat the respiratory coronavirus disease 2019 (COVID-19). The ability of these vaccines to induce mucosal immune responses in the upper respiratory tract may allow efficient prevention of infection and transmission, which could potentially reduce virus circulation in the population. In addition, they have the advantage that they can be administered by non-medical personnel and without needles. Several preclinical studies in small animal models and non-human primates, but also early phase clinical studies confirmed the capability of mucosal COVID-19 candidate vaccines to induce long-lasting immunity and to provide protection against an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to five vaccines which are already approved/licensed, at least 28 mucosal COVID-19 vaccines, based on different vaccine platforms, are currently being tested in clinical trials. However, clinical data for most of the conducted and completed clinical trials are not publicly available yet. In addition, several initiated trials have been terminated or were withdrawn. In this review, we aim to discuss the advantages and disadvantages of mucosal COVID-19 vaccines and to summarize the current status of mucosal COVID-19 vaccines in clinical development, with an emphasis on the most advanced candidates and the key findings observed in preclinical animal models and clinical studies.

•Metabolism and safety profile of chitosan and its derivatives on mucosal application.•Mechanisms of chitosan as potent mucosal adjuvant.•Different types and forms of chitosan in pre-clinical applications.•Clinical perspectives. Mucosal vaccination, which is shown to elicit systemic and mucosal immune responses, serves as a non-invasive and convenient alternative to parenteral administration, with stronger capability in combatting diseases at the site of entry. The exploration of potent mucosal adjuvants is emerging as a significant area, based on the continued necessity to amplify the immune responses to a wide array of antigens that are poorly immunogenic at the mucosal sites. As one of the inspirations from the ocean, chitosan-based mucosal adjuvants have been developed with unique advantages, such as, ability of mucosal adhesion, distinct trait of opening the junctions to allow the paracellular transport of antigen, good tolerability and biocompatibility, which guaranteed the great potential in capitalizing on their application in human clinical trials. In this review, the state of art of chitosan and its derivatives as mucosal adjuvants, including thermo-sensitive chitosan system as mucosal adjuvant that were newly developed by author's group, was described, as well as the clinical application perspective. After a brief introduction of mucosal adjuvants, chitosan and its derivatives as robust immune potentiator were discussed in detail and depth, in regard to the metabolism, safety profile, mode of actions and preclinical and clinical applications, which may shed light on the massive clinical application of chitosan as mucosal adjuvant.

Avian influenza virus (AIV) poses a persistent threat to global poultry production and public health. Long-term immunization programs have established a foundational immune barrier, significantly mitigating the risk of highly pathogenic avian influenza outbreaks. However, the high mutability of AIV, complex biosafety requirements, and the accelerating scale of poultry production underscore the need for enhanced mucosal protection. Mucosal immunity represents a critical defense against respiratory virus invasion in poultry, rapidly mobilizing local antibodies, cellular immune responses, and innate defense mechanisms. Recent advances in mucosal vaccine platforms—including viral vectors, nucleic acid vaccines, nanoparticle-based delivery systems, and water- or spray-administered formulations—have demonstrated potential in poultry models to enhance local immune responses, reduce viral shedding, and improve herd-level immune uniformity. This review provides a systematic overview of the unique structural and immunological features of avian mucosal tissues, summarizes the latest developments in mucosal vaccine technologies, and discusses their potential applications and challenges within integrated avian influenza control strategies.

Vaccine adjuvants induce innate immune responses and the addition of adjuvants to the vaccine helps to induce protective immunity in the host. Vaccines utilizing live attenuated or killed whole pathogens usually contain endogenous adjuvants, such as bacterial cell wall products and their genomic nucleic acids, which act as pathogen-associated molecular patterns and are sufficient to induce adaptive immune responses. However, purified protein- or antigen-based vaccines, including component or recombinant vaccines, usually lose these endogenous innate immune stimulators, so the addition of an exogenous adjuvant is essential for the success of these vaccine types. Although this adjuvant requirement is mostly the same for parental and mucosal vaccines, the development of mucosal vaccine adjuvants requires the specialized consideration of adapting the adjuvants to characteristic mucosal conditions. This review provides a brief overview of mucosa-associated immune response induction processes, such as antigen uptake and dendritic cell subset-dependent antigen presentation. It also highlights several mucosal vaccine adjuvants from recent reports, particularly focusing on their modes of action.

Mucosal surfaces are continuously exposed to the external environment and therefore represent the largest lymphoid organ of the body. In the mucosal immune system, gut-associated lymphoid tissues (GALTs), including Peyer's patches and isolated lymphoid follicles, play an important role in the induction of antigen-specific immune responses in the gut. GALTs have unique organogenesis characteristics and interact with the network of dendritic cells and T cells for the simultaneous induction and regulation of IgA responses and oral tolerance. In these lymphoid tissues, antigens are up taken by M cells in the epithelial layer, and antigen-specific immune responses are subsequently initiated by GALT cells. Nasopharynx- and tear-duct-associated lymphoid tissues (NALTs and TALTs) are key organized lymphoid structures in the respiratory tract and ocular cavities, respectively, and have been shown to interact with each other. Mucosal surfaces are also characterized by host-microbe interactions that affect the genesis and maturation of mucosa-associated lymphoid tissues and the induction and regulation of innate and acquired mucosal immune responses. Because most harmful pathogens enter the body through mucosal surfaces by ingestion, inhalation, or sexual contact, the mucosa is a candidate site for vaccination. Mucosal vaccination has some physiological and practical advantages, such as decreased costs and reduced risk of needle-stick injuries and transmission of bloodborne diseases, and it is painless. Recently, the application of modern bioengineering and biochemical engineering technologies, including gene transformation and manipulation systems, resulted in the development of systems to express vaccine antigens in transgenic plants and nanogels, which will usher in a new era of delivery systems for mucosal vaccine antigens. In this review, based on some of our research group's thirty seven years of progress and effort, we highlight the unique features of mucosal immune systems and the application of mucosal immunity to the development of a new generation of vaccines.

The recent SARS-CoV-2 pandemic has demonstrated the importance of vaccines in controlling outbreaks and in preparing for emerging viruses. Platform technologies are highly relevant as they reduce the time taken for vaccine development, market authorisation and production. Here, we present a novel platform based on modified, membrane-permeable hepatitis B virus (HBV) capsids that can flexibly carry various antigens via an adapter. The SARS-CoV2 spike-derived receptor binding domain serves as the antigen. This study aims to identify the most robust system for producing stable carrier/cargo complexes by comparing various platforms. The thereby identified system was used for detailed characterization of the immune response including its capacity for enabling needle free immunization by oral/nasal application. A comparison of various adapter systems (StrepTag, AviTag, SpyTag and DogTag) for coupling the cargo antigen to the cell-permeable capsid as the carrier revealed that the DogCatcher/DogTag system outperforms the others with regard to the yield, assembly and stability of the particles, as well as antigen loading onto the carrier surface. Immunization of mice showed that antigens coupled to the carrier induce a much stronger immune response than free, uncoupled antigens. Loading the capsid interior with CpG as an adjuvant further increased the immune response. Notably, the antigen carrier's cell permeability enables oral/nasal immunization, resulting in significant titres of neutralizing IgG and IgA antibodies. Taken together, this novel platform can be used as a flexible base for quickly adapting vaccines against emerging viruses. Most interestingly, the platform's cell permeability allows for needle-free immunization via the oral/nasal route. •The rational design and robust recombinant production of various HBV capsid-based vaccine platforms.•The flexible loading of cargo antigens via an adapter-based approach.•A comparative analysis of different platform and antigen-loaded platforms with respect to yield, structure, stability, and antigen load.•Coupling the free antigen to the vaccine carrier strongly enhances immunogenicity.•The interior of the carrier platform can be loaded with a small amount of CpG as an adjuvant, which further enhances the immune response.•The carrier platform's cell permeability enables needle-free immunisation via the oral/nasal route.•Oral/nasal immunization leads to significant induction of mucosal and humoral immunity.

•We used IgG1 and dimeric IgA2 versions of the V3-loop specific mAb HGN194.•HGN194 IgG1 given iv at a low dose to monkeys: 0% protection from SHIV infection.•Same iv HGN194 IgG1 dose plus mucosally administered dimeric IgA2: 100% protection.•HGN194 dimeric IgA2 given mucosally as single agent: only 17% protection.•Systemic plus mucosal passive immunization: proof-of-concept for defense-in-depth. Although IgA is the most abundantly produced immunoglobulin in humans, its role in preventing HIV-1 acquisition, which occurs mostly via mucosal routes, remains unclear. In our passive mucosal immunizations of rhesus macaques (RMs), the anti-HIV-1 neutralizing monoclonal antibody (nmAb) HGN194, given either as dimeric IgA1 (dIgA1) or dIgA2 intrarectally (i.r.), protected 83% or 17% of the RMs against i.r. simian-human immunodeficiency virus (SHIV) challenge, respectively. Data from the RV144 trial implied that vaccine-induced plasma IgA counteracted the protective effector mechanisms of IgG1 with the same epitope specificity. We thus hypothesized that mucosal dIgA2 might diminish the protection provided by IgG1 mAbs targeting the same epitope. To test our hypothesis, we administered HGN194 IgG1 intravenously (i.v.) either alone or combined with i.r. HGN194 dIgA2. We enrolled SHIV-exposed, persistently aviremic RMs protected by previously administered nmAbs; RM anti-human IgG responses were undetectable. However, low-level SIV Gag-specific proliferative T-cell responses were found. These animals resemble HIV-exposed, uninfected humans, in which local and systemic cellular immune responses have been observed. HGN194 IgG1 and dIgA2 used alone and the combination of the two neutralized the challenge virus equally well in vitro. All RMs given only i.v. HGN194 IgG1 became infected. In contrast, all RMs given HGN194 IgG1+dIgA2 were completely protected against high-dose i.r. SHIV-1157ipEL-p challenge. These data imply that combining suboptimal defenses at the mucosal and systemic levels can completely prevent virus acquisition. Consequently, active vaccination should focus on defense-in-depth, a strategy that seeks to build up defensive fall-back positions well behind the fortified frontline.

COVID-19-specific vaccines are efficient prophylactic weapons against SARS-CoV-2 virus. However, boosting innate responses may represent an innovative way to immediately fight future emerging viral infections or boost vaccines. MV130 is a mucosal immunotherapy, based on a mixture of whole heat-inactivated bacteria, that has shown clinical efficacy against recurrent viral respiratory infections. Herein, we show that the prophylactic intranasal administration of this immunotherapy confers heterologous protection against SARS-CoV-2 infection in susceptible K18-hACE2 mice. Furthermore, in C57BL/6 mice, prophylactic administration of MV130 improves the immunogenicity of two different COVID-19 vaccine formulations targeting the SARS-CoV-2 spike (S) protein, inoculated either intramuscularly or intranasally. Independently of the vaccine candidate and vaccination route used, intranasal prophylaxis with MV130 boosted S-specific responses, including CD8 + -T cell activation and the production of S-specific mucosal IgA antibodies. Therefore, the bacterial mucosal immunotherapy MV130 protects against SARS-CoV-2 infection and improves COVID-19 vaccines immunogenicity.

Over the past two decades, lactic acid bacteria (LAB) have been intensively studied as potential bacterial carriers for therapeutic materials, such as vaccine antigens, to the mucosal tissues. LAB have several attractive advantages as carriers of mucosal vaccines, and the effectiveness of LAB vaccines has been demonstrated in numerous studies. Research on LAB vaccines to date has focused on whether antigen-specific immunity, particularly antibody responses, can be induced. However, with recent developments in immunology, microbiology, and vaccinology, more detailed analyses of the underlying mechanisms, especially, of the induction of cell-mediated immunity and memory cells, have been required for vaccine development and licensure. In this mini-review, we will discuss the issues, including (i) immune responses other than antibody production, (ii) persistence of LAB vaccine immunity, (iii) comparative evaluation of LAB vaccines with any existing or reference vaccines, (iv) strategies for increasing the effectiveness of LAB vaccines, and (iv) effects of microbiota on the efficacy of LAB vaccines. Although these issues have been rarely studied or discussed to date in relation to LAB vaccine research, further understanding of them is critical for the practical application of LAB vaccine systems.